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Thrombectomy shows efficacy for basilar artery strokes
MONTREAL – A randomized trial designed to definitively test the efficacy of mechanical thrombectomy for treating acute ischemic strokes caused by basilar artery occlusion fell victim to slow recruitment and crossovers that muddied the intention-to-treat results, but the per-protocol and as-treated analyses both showed that thrombectomy was superior to best medical therapy in a multicenter, randomized study with 131 Chinese patients.
“Our findings should be considered in the context of the best evidence currently available, and progressive loss of equipoise for endovascular therapy for severe, large-vessel occlusion strokes,” Raul G. Nogueira, MD, said at the World Stroke Congress. “This was not a perfect trial, but it’s the best data we have, by far, at least for now” on the value of mechanical thrombectomy for treating acute ischemic stroke caused by a basilar artery occlusion, added Dr. Nogueira, professor of neurology and director of the neuroendovascular service at Emory University, Atlanta.
In the study’s per-protocol analysis, which considered patients who received their randomized treatment, the study’s primary endpoint of a modified Rankin Scale (mRS) score of 0-3 at 90 days after treatment was 44% in 63 patients who underwent thrombectomy and 26% in 51 patients randomized to best medical therapy who remained on that regimen, a statistically significant difference, Dr. Nogueira reported. In the as-treated analysis, which considered all enrolled patients based on the treatment they actually received regardless of randomization group, 77 patients treated with thrombectomy had a 47% rate of achieving the primary outcome, compared with 24% of 54 controls, also a statistically significant difference.
In contrast, the prespecified primary analysis for the study, the intention-to-treat analysis that considered patients based on their randomization assignment regardless of the treatment they actually received, showed that after 90 days the rate of patients with a mRS score of 0-3 was 42% in 66 thrombectomy patients and 32% among 65 controls, a difference that was not significant; this is a finding that, from a purist’s standpoint, makes the trial’s result neutral. The per-protocol and as-treated analyses were also prespecified steps in the study’s design, but not primary endpoints.
Despite the shortcoming for the primary analysis, Dr. Nogueira said that he found the per-protocol and as-treated findings very persuasive. “I personally could not randomize these patients” in the future to not receive mechanical thrombectomy, he confessed from the podium.
The BEST trial randomized 131 patients at any of 28 Chinese sites between April 2015 and September 2017. Patients had to enter within 8 hours of stroke onset. The original trial design called for enrolling 344 patients, but the steering committee decided in 2017 to prematurely stop the study because of a progressive drop in enrollment of patients, and “excessive” crossovers from the control arm to thrombectomy, a total of 14 patients. During the final month of the trial, 6 of 10 patients assigned by randomization to receive best medical care instead underwent thrombectomy. “At that point, we pretty much had to stop,” Dr. Nogueira said. Enrolled patients averaged about 65 years old, about 90% had a basilar artery occlusion and about 10% a vertebral artery occlusion, about 30% received intravenous alteplase, and the median National Institutes of Health Stroke Scale score at entry was about 30.
The major adverse effect from thrombectomy seen in the study was symptomatic intracranial hemorrhage, which occurred in 5 of the 77 patients (6%) actually treated with thrombectomy, compared with none of the 54 patients not treated with thrombectomy. This modest rate of intracranial hemorrhages was “not unexpected,” Dr. Nogueira noted.
Acute ischemic strokes caused by a basilar artery occlusion are relatively uncommon, accounting for about 1% of all acute ischemic strokes and 5%-10% of acute ischemic strokes caused by occlusion of a proximal intracranial artery. But when these strokes occur, they are a “neurological catastrophe,” Dr. Nogueira said, causing severe disability or mortality in about 70% of patients.
BEST had no commercial funding. Dr. Nogueira reported no disclosures.
SOURCE: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.
MONTREAL – A randomized trial designed to definitively test the efficacy of mechanical thrombectomy for treating acute ischemic strokes caused by basilar artery occlusion fell victim to slow recruitment and crossovers that muddied the intention-to-treat results, but the per-protocol and as-treated analyses both showed that thrombectomy was superior to best medical therapy in a multicenter, randomized study with 131 Chinese patients.
“Our findings should be considered in the context of the best evidence currently available, and progressive loss of equipoise for endovascular therapy for severe, large-vessel occlusion strokes,” Raul G. Nogueira, MD, said at the World Stroke Congress. “This was not a perfect trial, but it’s the best data we have, by far, at least for now” on the value of mechanical thrombectomy for treating acute ischemic stroke caused by a basilar artery occlusion, added Dr. Nogueira, professor of neurology and director of the neuroendovascular service at Emory University, Atlanta.
In the study’s per-protocol analysis, which considered patients who received their randomized treatment, the study’s primary endpoint of a modified Rankin Scale (mRS) score of 0-3 at 90 days after treatment was 44% in 63 patients who underwent thrombectomy and 26% in 51 patients randomized to best medical therapy who remained on that regimen, a statistically significant difference, Dr. Nogueira reported. In the as-treated analysis, which considered all enrolled patients based on the treatment they actually received regardless of randomization group, 77 patients treated with thrombectomy had a 47% rate of achieving the primary outcome, compared with 24% of 54 controls, also a statistically significant difference.
In contrast, the prespecified primary analysis for the study, the intention-to-treat analysis that considered patients based on their randomization assignment regardless of the treatment they actually received, showed that after 90 days the rate of patients with a mRS score of 0-3 was 42% in 66 thrombectomy patients and 32% among 65 controls, a difference that was not significant; this is a finding that, from a purist’s standpoint, makes the trial’s result neutral. The per-protocol and as-treated analyses were also prespecified steps in the study’s design, but not primary endpoints.
Despite the shortcoming for the primary analysis, Dr. Nogueira said that he found the per-protocol and as-treated findings very persuasive. “I personally could not randomize these patients” in the future to not receive mechanical thrombectomy, he confessed from the podium.
The BEST trial randomized 131 patients at any of 28 Chinese sites between April 2015 and September 2017. Patients had to enter within 8 hours of stroke onset. The original trial design called for enrolling 344 patients, but the steering committee decided in 2017 to prematurely stop the study because of a progressive drop in enrollment of patients, and “excessive” crossovers from the control arm to thrombectomy, a total of 14 patients. During the final month of the trial, 6 of 10 patients assigned by randomization to receive best medical care instead underwent thrombectomy. “At that point, we pretty much had to stop,” Dr. Nogueira said. Enrolled patients averaged about 65 years old, about 90% had a basilar artery occlusion and about 10% a vertebral artery occlusion, about 30% received intravenous alteplase, and the median National Institutes of Health Stroke Scale score at entry was about 30.
The major adverse effect from thrombectomy seen in the study was symptomatic intracranial hemorrhage, which occurred in 5 of the 77 patients (6%) actually treated with thrombectomy, compared with none of the 54 patients not treated with thrombectomy. This modest rate of intracranial hemorrhages was “not unexpected,” Dr. Nogueira noted.
Acute ischemic strokes caused by a basilar artery occlusion are relatively uncommon, accounting for about 1% of all acute ischemic strokes and 5%-10% of acute ischemic strokes caused by occlusion of a proximal intracranial artery. But when these strokes occur, they are a “neurological catastrophe,” Dr. Nogueira said, causing severe disability or mortality in about 70% of patients.
BEST had no commercial funding. Dr. Nogueira reported no disclosures.
SOURCE: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.
MONTREAL – A randomized trial designed to definitively test the efficacy of mechanical thrombectomy for treating acute ischemic strokes caused by basilar artery occlusion fell victim to slow recruitment and crossovers that muddied the intention-to-treat results, but the per-protocol and as-treated analyses both showed that thrombectomy was superior to best medical therapy in a multicenter, randomized study with 131 Chinese patients.
“Our findings should be considered in the context of the best evidence currently available, and progressive loss of equipoise for endovascular therapy for severe, large-vessel occlusion strokes,” Raul G. Nogueira, MD, said at the World Stroke Congress. “This was not a perfect trial, but it’s the best data we have, by far, at least for now” on the value of mechanical thrombectomy for treating acute ischemic stroke caused by a basilar artery occlusion, added Dr. Nogueira, professor of neurology and director of the neuroendovascular service at Emory University, Atlanta.
In the study’s per-protocol analysis, which considered patients who received their randomized treatment, the study’s primary endpoint of a modified Rankin Scale (mRS) score of 0-3 at 90 days after treatment was 44% in 63 patients who underwent thrombectomy and 26% in 51 patients randomized to best medical therapy who remained on that regimen, a statistically significant difference, Dr. Nogueira reported. In the as-treated analysis, which considered all enrolled patients based on the treatment they actually received regardless of randomization group, 77 patients treated with thrombectomy had a 47% rate of achieving the primary outcome, compared with 24% of 54 controls, also a statistically significant difference.
In contrast, the prespecified primary analysis for the study, the intention-to-treat analysis that considered patients based on their randomization assignment regardless of the treatment they actually received, showed that after 90 days the rate of patients with a mRS score of 0-3 was 42% in 66 thrombectomy patients and 32% among 65 controls, a difference that was not significant; this is a finding that, from a purist’s standpoint, makes the trial’s result neutral. The per-protocol and as-treated analyses were also prespecified steps in the study’s design, but not primary endpoints.
Despite the shortcoming for the primary analysis, Dr. Nogueira said that he found the per-protocol and as-treated findings very persuasive. “I personally could not randomize these patients” in the future to not receive mechanical thrombectomy, he confessed from the podium.
The BEST trial randomized 131 patients at any of 28 Chinese sites between April 2015 and September 2017. Patients had to enter within 8 hours of stroke onset. The original trial design called for enrolling 344 patients, but the steering committee decided in 2017 to prematurely stop the study because of a progressive drop in enrollment of patients, and “excessive” crossovers from the control arm to thrombectomy, a total of 14 patients. During the final month of the trial, 6 of 10 patients assigned by randomization to receive best medical care instead underwent thrombectomy. “At that point, we pretty much had to stop,” Dr. Nogueira said. Enrolled patients averaged about 65 years old, about 90% had a basilar artery occlusion and about 10% a vertebral artery occlusion, about 30% received intravenous alteplase, and the median National Institutes of Health Stroke Scale score at entry was about 30.
The major adverse effect from thrombectomy seen in the study was symptomatic intracranial hemorrhage, which occurred in 5 of the 77 patients (6%) actually treated with thrombectomy, compared with none of the 54 patients not treated with thrombectomy. This modest rate of intracranial hemorrhages was “not unexpected,” Dr. Nogueira noted.
Acute ischemic strokes caused by a basilar artery occlusion are relatively uncommon, accounting for about 1% of all acute ischemic strokes and 5%-10% of acute ischemic strokes caused by occlusion of a proximal intracranial artery. But when these strokes occur, they are a “neurological catastrophe,” Dr. Nogueira said, causing severe disability or mortality in about 70% of patients.
BEST had no commercial funding. Dr. Nogueira reported no disclosures.
SOURCE: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.
REPORTING FROM THE WORLD STROKE CONGRESS
Key clinical point:
Major finding: In the as-treated analysis, thrombectomy produced a 47% rate of modified Rankin Scale scores of 0-3 after 90 days, compared with 24% in controls.
Study details: BEST, a multicenter, randomized trial with 131 Chinese patients.
Disclosures: BEST had no commercial funding. Dr. Nogueira reported no disclosures.
Source: Nogueira RG et al. Int J Stroke. 2018;13(2_suppl):227, Abstract 978.
Acute stroke thrombolysis worked safely despite GI bleed or malignancy
CHICAGO – A recent history of GI bleeding or malignancy may not be a valid contraindication to thrombolytic therapy in patients with an acute ischemic stroke, based on a review of outcomes from more than 40,000 U.S. stroke patients.
The analysis showed that, among 40,396 U.S. patients who had an acute ischemic stroke during 2009-2015 and received timely treatment with alteplase, “we did not find statistically significant increased rates of in-hospital mortality or bleeding” in the small number of patients who received alteplase (Activase) despite a recent GI bleed or diagnosed GI malignancy, Taku Inohara, MD, said at the American Heart Association scientific sessions. The 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke deemed thrombolytic therapy with alteplase in these types of patients contraindicated, based on consensus expert opinion (Stroke. 2018 March;49[3]:e66-e110).
“Further study is needed to evaluate the safety of recombinant tissue–type plasminogen activator [alteplase] in this specific population,” suggested Dr. Inohara, a cardiologist and research fellow at Duke University, Durham, N.C.
His analysis used data collected by the Get With the Guidelines–Stroke program, a voluntary quality promotion and improvement program that during 2009-2015 included records for more than 633,000 U.S. stroke patients that could be linked with records kept by the Centers for Medicare & Medicaid Services. From this database, 40,396 patients (6%) treated with alteplase within 4.5 hours of stroke onset were identified. The alteplase-treated patients included 93 with a diagnosis code during the prior year for a GI malignancy and 43 with a diagnostic code within the prior 21 days for a GI bleed.
Dr. Inohara and his associates determined patients’ mortality during their stroke hospitalization, as well as several measures of functional recovery at hospital discharge and thrombolysis-related complications. For each of these endpoints, the rate among patients with a GI malignancy, a GI bleed, or the rate among a combined group of both patients showed no statistically significant differences, compared with the more than 40,000 other patients without a GI complication after adjustment for several demographic and clinical between-group differences. However, Dr. Inohara cautioned that residual or unmeasured confounding may exist that distorts these findings. The rate of in-hospital mortality, the prespecified primary endpoint for the analysis, was 10% among patients with either type of GI complication and 9% in those without. The rate of serious thrombolysis-related complications was 7% in the patients with GI disease and 9% in those without.
In a separate analysis of the complete database of more than 633,000 patients, Dr. Inohara and his associates found 148 patients who had either a GI bleed or malignancy and otherwise qualified for thrombolytic therapy but did not receive this treatment. This meant that overall, in this large U.S. experience, 136 of 284 (48%) acute ischemic stroke patients who qualified for thrombolysis but had a GI complication nonetheless received thrombolysis. Further analysis showed that the patients not treated with thrombolysis had at admission an average National Institutes of Health Stroke Scale score of 11, compared with an average score of 14 among patients who received thrombolysis.
This apparent selection for thrombolytic treatment of patients with more severe strokes “may have overestimated risk in the patients with GI disease,” Dr. Inohara said.
Dr. Inohara reported receiving research funding from Boston Scientific.
SOURCE: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract 12291.
CHICAGO – A recent history of GI bleeding or malignancy may not be a valid contraindication to thrombolytic therapy in patients with an acute ischemic stroke, based on a review of outcomes from more than 40,000 U.S. stroke patients.
The analysis showed that, among 40,396 U.S. patients who had an acute ischemic stroke during 2009-2015 and received timely treatment with alteplase, “we did not find statistically significant increased rates of in-hospital mortality or bleeding” in the small number of patients who received alteplase (Activase) despite a recent GI bleed or diagnosed GI malignancy, Taku Inohara, MD, said at the American Heart Association scientific sessions. The 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke deemed thrombolytic therapy with alteplase in these types of patients contraindicated, based on consensus expert opinion (Stroke. 2018 March;49[3]:e66-e110).
“Further study is needed to evaluate the safety of recombinant tissue–type plasminogen activator [alteplase] in this specific population,” suggested Dr. Inohara, a cardiologist and research fellow at Duke University, Durham, N.C.
His analysis used data collected by the Get With the Guidelines–Stroke program, a voluntary quality promotion and improvement program that during 2009-2015 included records for more than 633,000 U.S. stroke patients that could be linked with records kept by the Centers for Medicare & Medicaid Services. From this database, 40,396 patients (6%) treated with alteplase within 4.5 hours of stroke onset were identified. The alteplase-treated patients included 93 with a diagnosis code during the prior year for a GI malignancy and 43 with a diagnostic code within the prior 21 days for a GI bleed.
Dr. Inohara and his associates determined patients’ mortality during their stroke hospitalization, as well as several measures of functional recovery at hospital discharge and thrombolysis-related complications. For each of these endpoints, the rate among patients with a GI malignancy, a GI bleed, or the rate among a combined group of both patients showed no statistically significant differences, compared with the more than 40,000 other patients without a GI complication after adjustment for several demographic and clinical between-group differences. However, Dr. Inohara cautioned that residual or unmeasured confounding may exist that distorts these findings. The rate of in-hospital mortality, the prespecified primary endpoint for the analysis, was 10% among patients with either type of GI complication and 9% in those without. The rate of serious thrombolysis-related complications was 7% in the patients with GI disease and 9% in those without.
In a separate analysis of the complete database of more than 633,000 patients, Dr. Inohara and his associates found 148 patients who had either a GI bleed or malignancy and otherwise qualified for thrombolytic therapy but did not receive this treatment. This meant that overall, in this large U.S. experience, 136 of 284 (48%) acute ischemic stroke patients who qualified for thrombolysis but had a GI complication nonetheless received thrombolysis. Further analysis showed that the patients not treated with thrombolysis had at admission an average National Institutes of Health Stroke Scale score of 11, compared with an average score of 14 among patients who received thrombolysis.
This apparent selection for thrombolytic treatment of patients with more severe strokes “may have overestimated risk in the patients with GI disease,” Dr. Inohara said.
Dr. Inohara reported receiving research funding from Boston Scientific.
SOURCE: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract 12291.
CHICAGO – A recent history of GI bleeding or malignancy may not be a valid contraindication to thrombolytic therapy in patients with an acute ischemic stroke, based on a review of outcomes from more than 40,000 U.S. stroke patients.
The analysis showed that, among 40,396 U.S. patients who had an acute ischemic stroke during 2009-2015 and received timely treatment with alteplase, “we did not find statistically significant increased rates of in-hospital mortality or bleeding” in the small number of patients who received alteplase (Activase) despite a recent GI bleed or diagnosed GI malignancy, Taku Inohara, MD, said at the American Heart Association scientific sessions. The 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke deemed thrombolytic therapy with alteplase in these types of patients contraindicated, based on consensus expert opinion (Stroke. 2018 March;49[3]:e66-e110).
“Further study is needed to evaluate the safety of recombinant tissue–type plasminogen activator [alteplase] in this specific population,” suggested Dr. Inohara, a cardiologist and research fellow at Duke University, Durham, N.C.
His analysis used data collected by the Get With the Guidelines–Stroke program, a voluntary quality promotion and improvement program that during 2009-2015 included records for more than 633,000 U.S. stroke patients that could be linked with records kept by the Centers for Medicare & Medicaid Services. From this database, 40,396 patients (6%) treated with alteplase within 4.5 hours of stroke onset were identified. The alteplase-treated patients included 93 with a diagnosis code during the prior year for a GI malignancy and 43 with a diagnostic code within the prior 21 days for a GI bleed.
Dr. Inohara and his associates determined patients’ mortality during their stroke hospitalization, as well as several measures of functional recovery at hospital discharge and thrombolysis-related complications. For each of these endpoints, the rate among patients with a GI malignancy, a GI bleed, or the rate among a combined group of both patients showed no statistically significant differences, compared with the more than 40,000 other patients without a GI complication after adjustment for several demographic and clinical between-group differences. However, Dr. Inohara cautioned that residual or unmeasured confounding may exist that distorts these findings. The rate of in-hospital mortality, the prespecified primary endpoint for the analysis, was 10% among patients with either type of GI complication and 9% in those without. The rate of serious thrombolysis-related complications was 7% in the patients with GI disease and 9% in those without.
In a separate analysis of the complete database of more than 633,000 patients, Dr. Inohara and his associates found 148 patients who had either a GI bleed or malignancy and otherwise qualified for thrombolytic therapy but did not receive this treatment. This meant that overall, in this large U.S. experience, 136 of 284 (48%) acute ischemic stroke patients who qualified for thrombolysis but had a GI complication nonetheless received thrombolysis. Further analysis showed that the patients not treated with thrombolysis had at admission an average National Institutes of Health Stroke Scale score of 11, compared with an average score of 14 among patients who received thrombolysis.
This apparent selection for thrombolytic treatment of patients with more severe strokes “may have overestimated risk in the patients with GI disease,” Dr. Inohara said.
Dr. Inohara reported receiving research funding from Boston Scientific.
SOURCE: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract 12291.
REPORTING FROM THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: In-hospital mortality after thrombolysis was 10% in those with a GI bleed or malignancy and 9% in those without.
Study details: A review of Medicare records for 40,396 acute ischemic stroke patients treated with thrombolysis during 2009-2015.
Disclosures: Dr. Inohara reported receiving research funding from Boston Scientific.
Source: Inohara T et al. Circulation. 2018 Nov 6;138[suppl 1], Abstract A12291.
Latest intranasal insulin results for Alzheimer’s muddied by malfunctioning inhaler
BARCELONA –
Instead of doing poorly, patients using the faulty device actually experienced better outcomes than did those who entered the study later and used a more reliable inhaler, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
A secondary analysis of the ViaNase device subgroup “replicated findings in our original studies,” which used the same atomizer, said Dr. Craft, a professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C. “We remain optimistic, but clearly we are at the beginning of understanding optimal insulin doses and delivery techniques for this population.”
The 289-patient, placebo-controlled study was predicated by a prior successful study by Dr. Craft and her colleagues, published in 2012 in JAMA Neurology. That trial randomized 104 patients with amnestic mild cognitive impairment (MCI) or mild-moderate Alzheimer’s to placebo or intranasal insulin 20 or 40 IU. After 4 months, subjects in both insulin groups showed preserved cognition and functional abilities, as well as increased cerebral glucose metabolism.
The ViaNase device was manufactured by Kurve Technology. But the company redesigned it for the new trial, adding an electronic timing component, which Dr. Craft said, was supposed to increase ease of use.
“Unfortunately, there were frequent malfunctions of this mechanism for the first 49 patients – so much so that we had to discontinue using the device and switch to a newer one,” for the other 240 patients in the study. This intranasal drug-delivery system, called the Precisions Olfactory Delivery (POD) device, is made by Impel NeuroPharma. Dr. Craft’s trial is its first investigation in patients with Alzheimer’s disease.
The new study randomized 289 patients with MCI or mild Alzheimer’s to twice-daily sprays with a placebo device, or to intranasal insulin 40 IU for 12 months, followed by a 6-month, open-label period. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognition measure (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) a memory composite measure, activities of daily living, cerebrospinal fluid biomarkers, and MRI of the hippocampus and entorhinal cortex.
Because of the device problems, Dr. Craft conducted separate analyses for the user groups. The primary was an intent-to-treat (ITT), mixed-model, repeat-measures analysis of the 240 using the POD device. The model controlled for age, sex, genetic risk status, and investigation site. An exploratory ITT analysis looked only at the ADAS-Cog 12 in the 49 who used the ViaNase device. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. About 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.
At 12 months, there was no between-group difference on the ADAS-Cog 12 measure; both groups increased by about 4 points, indicating worsening. Nor were there any changes in any of the Alzheimer’s-related biomarkers: amyloid-beta 40 and 42, total tau, or phosphorylated tau. There was a small but statistically significant difference in the sizes of the hippocampus and entorhinal cortex.
The ViaNase group fared somewhat better in the secondary analysis of the ADAS-Cog12. The measure increased by about 5 points in the placebo group, and about 2.5 points in the insulin group. The significant separation was evident at 3 months and continued to widen over the course of the study.
Compliance was very good in the larger group – around 85%. It was lower in the ViaNase group, probably because of the device’s unreliability. Retention was good in both groups. There were no significant differences in adverse events and no obvious safety issues.
The 6-month, open-label period will close out before the end of the year. In the meantime, Dr. Craft is conducting additional subgroup analyses on the 12-month data.
Dr. Craft has served as a consultant for GlaxoSmithKline and Accera.
SOURCE: Craft S et al. J Prev Alz Dis 2018;5(S1):S9, Abstract OC2.
BARCELONA –
Instead of doing poorly, patients using the faulty device actually experienced better outcomes than did those who entered the study later and used a more reliable inhaler, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
A secondary analysis of the ViaNase device subgroup “replicated findings in our original studies,” which used the same atomizer, said Dr. Craft, a professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C. “We remain optimistic, but clearly we are at the beginning of understanding optimal insulin doses and delivery techniques for this population.”
The 289-patient, placebo-controlled study was predicated by a prior successful study by Dr. Craft and her colleagues, published in 2012 in JAMA Neurology. That trial randomized 104 patients with amnestic mild cognitive impairment (MCI) or mild-moderate Alzheimer’s to placebo or intranasal insulin 20 or 40 IU. After 4 months, subjects in both insulin groups showed preserved cognition and functional abilities, as well as increased cerebral glucose metabolism.
The ViaNase device was manufactured by Kurve Technology. But the company redesigned it for the new trial, adding an electronic timing component, which Dr. Craft said, was supposed to increase ease of use.
“Unfortunately, there were frequent malfunctions of this mechanism for the first 49 patients – so much so that we had to discontinue using the device and switch to a newer one,” for the other 240 patients in the study. This intranasal drug-delivery system, called the Precisions Olfactory Delivery (POD) device, is made by Impel NeuroPharma. Dr. Craft’s trial is its first investigation in patients with Alzheimer’s disease.
The new study randomized 289 patients with MCI or mild Alzheimer’s to twice-daily sprays with a placebo device, or to intranasal insulin 40 IU for 12 months, followed by a 6-month, open-label period. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognition measure (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) a memory composite measure, activities of daily living, cerebrospinal fluid biomarkers, and MRI of the hippocampus and entorhinal cortex.
Because of the device problems, Dr. Craft conducted separate analyses for the user groups. The primary was an intent-to-treat (ITT), mixed-model, repeat-measures analysis of the 240 using the POD device. The model controlled for age, sex, genetic risk status, and investigation site. An exploratory ITT analysis looked only at the ADAS-Cog 12 in the 49 who used the ViaNase device. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. About 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.
At 12 months, there was no between-group difference on the ADAS-Cog 12 measure; both groups increased by about 4 points, indicating worsening. Nor were there any changes in any of the Alzheimer’s-related biomarkers: amyloid-beta 40 and 42, total tau, or phosphorylated tau. There was a small but statistically significant difference in the sizes of the hippocampus and entorhinal cortex.
The ViaNase group fared somewhat better in the secondary analysis of the ADAS-Cog12. The measure increased by about 5 points in the placebo group, and about 2.5 points in the insulin group. The significant separation was evident at 3 months and continued to widen over the course of the study.
Compliance was very good in the larger group – around 85%. It was lower in the ViaNase group, probably because of the device’s unreliability. Retention was good in both groups. There were no significant differences in adverse events and no obvious safety issues.
The 6-month, open-label period will close out before the end of the year. In the meantime, Dr. Craft is conducting additional subgroup analyses on the 12-month data.
Dr. Craft has served as a consultant for GlaxoSmithKline and Accera.
SOURCE: Craft S et al. J Prev Alz Dis 2018;5(S1):S9, Abstract OC2.
BARCELONA –
Instead of doing poorly, patients using the faulty device actually experienced better outcomes than did those who entered the study later and used a more reliable inhaler, Suzanne Craft, PhD, said at the Clinical Trials on Alzheimer’s Disease conference.
A secondary analysis of the ViaNase device subgroup “replicated findings in our original studies,” which used the same atomizer, said Dr. Craft, a professor of gerontology and geriatric medicine at Wake Forest University, Winston-Salem, N.C. “We remain optimistic, but clearly we are at the beginning of understanding optimal insulin doses and delivery techniques for this population.”
The 289-patient, placebo-controlled study was predicated by a prior successful study by Dr. Craft and her colleagues, published in 2012 in JAMA Neurology. That trial randomized 104 patients with amnestic mild cognitive impairment (MCI) or mild-moderate Alzheimer’s to placebo or intranasal insulin 20 or 40 IU. After 4 months, subjects in both insulin groups showed preserved cognition and functional abilities, as well as increased cerebral glucose metabolism.
The ViaNase device was manufactured by Kurve Technology. But the company redesigned it for the new trial, adding an electronic timing component, which Dr. Craft said, was supposed to increase ease of use.
“Unfortunately, there were frequent malfunctions of this mechanism for the first 49 patients – so much so that we had to discontinue using the device and switch to a newer one,” for the other 240 patients in the study. This intranasal drug-delivery system, called the Precisions Olfactory Delivery (POD) device, is made by Impel NeuroPharma. Dr. Craft’s trial is its first investigation in patients with Alzheimer’s disease.
The new study randomized 289 patients with MCI or mild Alzheimer’s to twice-daily sprays with a placebo device, or to intranasal insulin 40 IU for 12 months, followed by a 6-month, open-label period. The primary outcome was the Alzheimer’s Disease Assessment Scale-Cognition measure (ADAS-Cog 12). Secondary outcomes were the Clinical Dementia Rating Scale sum of boxes (CDR-sb) a memory composite measure, activities of daily living, cerebrospinal fluid biomarkers, and MRI of the hippocampus and entorhinal cortex.
Because of the device problems, Dr. Craft conducted separate analyses for the user groups. The primary was an intent-to-treat (ITT), mixed-model, repeat-measures analysis of the 240 using the POD device. The model controlled for age, sex, genetic risk status, and investigation site. An exploratory ITT analysis looked only at the ADAS-Cog 12 in the 49 who used the ViaNase device. Patients were a mean of 71 years old, with a mean Mini Mental State Exam score of 25. About 42% were positive for the high-risk apolipoprotein E epsilon-4 allele.
At 12 months, there was no between-group difference on the ADAS-Cog 12 measure; both groups increased by about 4 points, indicating worsening. Nor were there any changes in any of the Alzheimer’s-related biomarkers: amyloid-beta 40 and 42, total tau, or phosphorylated tau. There was a small but statistically significant difference in the sizes of the hippocampus and entorhinal cortex.
The ViaNase group fared somewhat better in the secondary analysis of the ADAS-Cog12. The measure increased by about 5 points in the placebo group, and about 2.5 points in the insulin group. The significant separation was evident at 3 months and continued to widen over the course of the study.
Compliance was very good in the larger group – around 85%. It was lower in the ViaNase group, probably because of the device’s unreliability. Retention was good in both groups. There were no significant differences in adverse events and no obvious safety issues.
The 6-month, open-label period will close out before the end of the year. In the meantime, Dr. Craft is conducting additional subgroup analyses on the 12-month data.
Dr. Craft has served as a consultant for GlaxoSmithKline and Accera.
SOURCE: Craft S et al. J Prev Alz Dis 2018;5(S1):S9, Abstract OC2.
REPORTING FROM CTAD
Resection, neurostimulation combo found successful in eloquent cortical regions
NEW ORLEANS – Concurrent surgical resection and implanted strip electrodes eliminated refractory focal seizures in two patients with focal cortical dysplasia and reduced them by 62% in a third patient, according a report presented at the annual meeting of the American Epilepsy Society.
None of the patients had been considered surgical candidates because their seizure foci were in eloquent cortical regions; if fully resected, patients would have experienced marked neurologic deficits. But the combination procedure of flanking the incomplete resected foci with implanted electrodes allowed neurosurgeons to remove less tissue, preserving function while effectively treating previously untreatable seizures, Emily Mirro said at the meeting.
The two-in-one technique makes good surgical sense for these patients, she said in an interview. “If we simply performed the resection and closed without implanting the electrodes, just waiting to see if seizures develop or not, then going back to implant the electrodes, the surgery is riskier and more difficult,” said Ms. Mirro, director of field clinical engineering for NeuroPace, which makes the stimulator system.
At the meeting, she presented three case studies on behalf of primary authors Lawrence Shuer, MD, and Babak Razavi, MD, PhD, both of Stanford (Calif.) University.
The first patient was a 26-year-old with a focal cortical dysplasia in the right parietal region, causing about six seizures each month. At the time of surgery, surgeons flanked the resected region with four cortical strip leads over sensory cortex. The RNS System detected the first postsurgical seizure 1 month afterward. Five months later, the system was enabled at 0.5 milliamps. For the next year, the patient received about 100 stimulations per day, amounting to a total daily stimulation time of about 20 seconds. Electrographic seizures did return, at which point the system increased neurostimulation to about 2,000 per day (a total stimulation time of about 7 minutes per day). At 1.3 years, the patient remains seizure free.
Patient two was a 20-year-old with a left frontal transmantle cortical dysplasia that involved the inferior frontal sulcus. The baseline seizure frequency was about two per day. Surgeons removed the dysplastic area with a 2.0 cm x 0.5 cm resection; the deficit was flanked with two left-front cortical strip leads. In the following 9 days, the patient experienced eight seizures. At 14 days out, the system was enabled at 1 milliamp. This patient became seizure free and remains so at 1.3 years, with about 100 stimulations per day to suppress electrographic abnormalities.
The third patient, also 20 years old, had a left-parietal resection to the margin of the motor cortex. The baseline seizure frequency was up to 150 nocturnal events per month and several seizures during each day as well. The resection was flanked by one strip lead over the motor cortex; one depth lead implanted into it. Immediately after surgery, the patient experienced both electrographic and clinical seizures. The stimulator was enabled a week after surgery at 0.5 milliamps; this was titrated to 3 milliamps over 1.4 years. At last follow-up, the patient had about a 62% reduction in seizure frequency; all are now nocturnal.
None of the patients experienced any peri- or postoperative surgical complications.
Ms. Mirro is an employee of NeuroPace.
SOURCE: Razavi B et al. AES 2018, Abstract 2.315
NEW ORLEANS – Concurrent surgical resection and implanted strip electrodes eliminated refractory focal seizures in two patients with focal cortical dysplasia and reduced them by 62% in a third patient, according a report presented at the annual meeting of the American Epilepsy Society.
None of the patients had been considered surgical candidates because their seizure foci were in eloquent cortical regions; if fully resected, patients would have experienced marked neurologic deficits. But the combination procedure of flanking the incomplete resected foci with implanted electrodes allowed neurosurgeons to remove less tissue, preserving function while effectively treating previously untreatable seizures, Emily Mirro said at the meeting.
The two-in-one technique makes good surgical sense for these patients, she said in an interview. “If we simply performed the resection and closed without implanting the electrodes, just waiting to see if seizures develop or not, then going back to implant the electrodes, the surgery is riskier and more difficult,” said Ms. Mirro, director of field clinical engineering for NeuroPace, which makes the stimulator system.
At the meeting, she presented three case studies on behalf of primary authors Lawrence Shuer, MD, and Babak Razavi, MD, PhD, both of Stanford (Calif.) University.
The first patient was a 26-year-old with a focal cortical dysplasia in the right parietal region, causing about six seizures each month. At the time of surgery, surgeons flanked the resected region with four cortical strip leads over sensory cortex. The RNS System detected the first postsurgical seizure 1 month afterward. Five months later, the system was enabled at 0.5 milliamps. For the next year, the patient received about 100 stimulations per day, amounting to a total daily stimulation time of about 20 seconds. Electrographic seizures did return, at which point the system increased neurostimulation to about 2,000 per day (a total stimulation time of about 7 minutes per day). At 1.3 years, the patient remains seizure free.
Patient two was a 20-year-old with a left frontal transmantle cortical dysplasia that involved the inferior frontal sulcus. The baseline seizure frequency was about two per day. Surgeons removed the dysplastic area with a 2.0 cm x 0.5 cm resection; the deficit was flanked with two left-front cortical strip leads. In the following 9 days, the patient experienced eight seizures. At 14 days out, the system was enabled at 1 milliamp. This patient became seizure free and remains so at 1.3 years, with about 100 stimulations per day to suppress electrographic abnormalities.
The third patient, also 20 years old, had a left-parietal resection to the margin of the motor cortex. The baseline seizure frequency was up to 150 nocturnal events per month and several seizures during each day as well. The resection was flanked by one strip lead over the motor cortex; one depth lead implanted into it. Immediately after surgery, the patient experienced both electrographic and clinical seizures. The stimulator was enabled a week after surgery at 0.5 milliamps; this was titrated to 3 milliamps over 1.4 years. At last follow-up, the patient had about a 62% reduction in seizure frequency; all are now nocturnal.
None of the patients experienced any peri- or postoperative surgical complications.
Ms. Mirro is an employee of NeuroPace.
SOURCE: Razavi B et al. AES 2018, Abstract 2.315
NEW ORLEANS – Concurrent surgical resection and implanted strip electrodes eliminated refractory focal seizures in two patients with focal cortical dysplasia and reduced them by 62% in a third patient, according a report presented at the annual meeting of the American Epilepsy Society.
None of the patients had been considered surgical candidates because their seizure foci were in eloquent cortical regions; if fully resected, patients would have experienced marked neurologic deficits. But the combination procedure of flanking the incomplete resected foci with implanted electrodes allowed neurosurgeons to remove less tissue, preserving function while effectively treating previously untreatable seizures, Emily Mirro said at the meeting.
The two-in-one technique makes good surgical sense for these patients, she said in an interview. “If we simply performed the resection and closed without implanting the electrodes, just waiting to see if seizures develop or not, then going back to implant the electrodes, the surgery is riskier and more difficult,” said Ms. Mirro, director of field clinical engineering for NeuroPace, which makes the stimulator system.
At the meeting, she presented three case studies on behalf of primary authors Lawrence Shuer, MD, and Babak Razavi, MD, PhD, both of Stanford (Calif.) University.
The first patient was a 26-year-old with a focal cortical dysplasia in the right parietal region, causing about six seizures each month. At the time of surgery, surgeons flanked the resected region with four cortical strip leads over sensory cortex. The RNS System detected the first postsurgical seizure 1 month afterward. Five months later, the system was enabled at 0.5 milliamps. For the next year, the patient received about 100 stimulations per day, amounting to a total daily stimulation time of about 20 seconds. Electrographic seizures did return, at which point the system increased neurostimulation to about 2,000 per day (a total stimulation time of about 7 minutes per day). At 1.3 years, the patient remains seizure free.
Patient two was a 20-year-old with a left frontal transmantle cortical dysplasia that involved the inferior frontal sulcus. The baseline seizure frequency was about two per day. Surgeons removed the dysplastic area with a 2.0 cm x 0.5 cm resection; the deficit was flanked with two left-front cortical strip leads. In the following 9 days, the patient experienced eight seizures. At 14 days out, the system was enabled at 1 milliamp. This patient became seizure free and remains so at 1.3 years, with about 100 stimulations per day to suppress electrographic abnormalities.
The third patient, also 20 years old, had a left-parietal resection to the margin of the motor cortex. The baseline seizure frequency was up to 150 nocturnal events per month and several seizures during each day as well. The resection was flanked by one strip lead over the motor cortex; one depth lead implanted into it. Immediately after surgery, the patient experienced both electrographic and clinical seizures. The stimulator was enabled a week after surgery at 0.5 milliamps; this was titrated to 3 milliamps over 1.4 years. At last follow-up, the patient had about a 62% reduction in seizure frequency; all are now nocturnal.
None of the patients experienced any peri- or postoperative surgical complications.
Ms. Mirro is an employee of NeuroPace.
SOURCE: Razavi B et al. AES 2018, Abstract 2.315
REPORTING FROM AES 2018
Key clinical point:
Major finding: Two patients became seizure free and one had a 62% reduction in seizures.
Study details: A three-patient case series.
Disclosures: NeuroPace makes the neurostimulator used in the study. The presenter is an employee of NeuroPace.
Source: Razavi B et al. AES 2018, Abstract 2.315.
Infertility appears to be increased among women with epilepsy
NEW ORLEANS – based on a retrospective study presented at the annual meeting of the American Epilepsy Society.
Data recorded in the 2010-2014 Epilepsy Birth Control Registry indicates a 9.2% infertility rate and a 22.5% impaired fecundity rate among American women with epilepsy. Both rates are higher than the general population infertility rate of 6.0% and the 12.1% rate of impaired fecundity cited by the Centers for Disease Control and Prevention.
However, differences between the study of women with epilepsy and the study of the general population may limit the validity of this comparison, said Devon B. MacEachern, clinical and research coordinator at Neuroendocrine Associates in Wellesley Hills, Mass.
It is likewise uncertain whether use of antiepileptic drugs (AEDs) affects women’s fertility or fecundity.
The Epilepsy Birth Control Registry collected data from an Internet-based survey of 1,144 community-dwelling women with epilepsy aged 18-47 years. Participants provided information about demographics, epilepsy, AEDs, reproduction, and contraception.
The researchers focused on rates of infertility, impaired fecundity, and live birth or unaborted pregnancy among 978 American women, and additionally examined whether these outcomes were related to AED use.
Infertility was defined as the percentage of participants who had unprotected sex but did not become pregnant by 1 year. Impaired fecundity was the percentage of participants who were infertile or did not carry a pregnancy to live birth. The study excluded from the impaired fecundity analysis the 41 respondents whose only outcomes were induced abortions. The 18% of pregnancies that terminated as induced abortions were excluded from the live birth rate analysis.
In all, 373 registry participants had 724 pregnancies and 422 births between 1981 and 2013. The women had an average of 2.15 pregnancies at a mean age of 24.9 years (range, 13-44 years). In addition, 38 women (9.2%) tried to conceive, but were infertile. Of 306 women with a first pregnancy, 222 (72.5%) had a live birth. Among 292 women with two pregnancies, 260 (89.0%) had at least one live birth, and 180 (61.6%) had two live births.
Of the 373 women, 84 (22.5%) with pregnancies had impaired fecundity. The risk of impaired fecundity tended to be higher among women on AED polytherapy than among women on no AED (risk ratio, 1.74).
The ratio of live births to pregnancy (71.0%) was similar among women on no AEDs (71.3%), those on AED monotherapy (71.8%), and those on polytherapy (69.7%). The live birth rate was 67.5% for women taking enzyme-inducing AEDs, 89.1% for women taking glucuronidated AEDs, 72.8% for women taking nonenzyme-inducing AEDs, 63.3% for women taking enzyme-inhibiting AEDs, and 69.7% for women on polytherapy. Lamotrigine use was associated with the highest ratio of live births to pregnancies at 89.1%; valproate use was associated with the lowest ratio of live births to pregnancies at 63.3%.
The investigation was funded by the Epilepsy Foundation and Lundbeck.
SOURCE: MacEachern DB et al. AES 2018, Abstract 1.426.
NEW ORLEANS – based on a retrospective study presented at the annual meeting of the American Epilepsy Society.
Data recorded in the 2010-2014 Epilepsy Birth Control Registry indicates a 9.2% infertility rate and a 22.5% impaired fecundity rate among American women with epilepsy. Both rates are higher than the general population infertility rate of 6.0% and the 12.1% rate of impaired fecundity cited by the Centers for Disease Control and Prevention.
However, differences between the study of women with epilepsy and the study of the general population may limit the validity of this comparison, said Devon B. MacEachern, clinical and research coordinator at Neuroendocrine Associates in Wellesley Hills, Mass.
It is likewise uncertain whether use of antiepileptic drugs (AEDs) affects women’s fertility or fecundity.
The Epilepsy Birth Control Registry collected data from an Internet-based survey of 1,144 community-dwelling women with epilepsy aged 18-47 years. Participants provided information about demographics, epilepsy, AEDs, reproduction, and contraception.
The researchers focused on rates of infertility, impaired fecundity, and live birth or unaborted pregnancy among 978 American women, and additionally examined whether these outcomes were related to AED use.
Infertility was defined as the percentage of participants who had unprotected sex but did not become pregnant by 1 year. Impaired fecundity was the percentage of participants who were infertile or did not carry a pregnancy to live birth. The study excluded from the impaired fecundity analysis the 41 respondents whose only outcomes were induced abortions. The 18% of pregnancies that terminated as induced abortions were excluded from the live birth rate analysis.
In all, 373 registry participants had 724 pregnancies and 422 births between 1981 and 2013. The women had an average of 2.15 pregnancies at a mean age of 24.9 years (range, 13-44 years). In addition, 38 women (9.2%) tried to conceive, but were infertile. Of 306 women with a first pregnancy, 222 (72.5%) had a live birth. Among 292 women with two pregnancies, 260 (89.0%) had at least one live birth, and 180 (61.6%) had two live births.
Of the 373 women, 84 (22.5%) with pregnancies had impaired fecundity. The risk of impaired fecundity tended to be higher among women on AED polytherapy than among women on no AED (risk ratio, 1.74).
The ratio of live births to pregnancy (71.0%) was similar among women on no AEDs (71.3%), those on AED monotherapy (71.8%), and those on polytherapy (69.7%). The live birth rate was 67.5% for women taking enzyme-inducing AEDs, 89.1% for women taking glucuronidated AEDs, 72.8% for women taking nonenzyme-inducing AEDs, 63.3% for women taking enzyme-inhibiting AEDs, and 69.7% for women on polytherapy. Lamotrigine use was associated with the highest ratio of live births to pregnancies at 89.1%; valproate use was associated with the lowest ratio of live births to pregnancies at 63.3%.
The investigation was funded by the Epilepsy Foundation and Lundbeck.
SOURCE: MacEachern DB et al. AES 2018, Abstract 1.426.
NEW ORLEANS – based on a retrospective study presented at the annual meeting of the American Epilepsy Society.
Data recorded in the 2010-2014 Epilepsy Birth Control Registry indicates a 9.2% infertility rate and a 22.5% impaired fecundity rate among American women with epilepsy. Both rates are higher than the general population infertility rate of 6.0% and the 12.1% rate of impaired fecundity cited by the Centers for Disease Control and Prevention.
However, differences between the study of women with epilepsy and the study of the general population may limit the validity of this comparison, said Devon B. MacEachern, clinical and research coordinator at Neuroendocrine Associates in Wellesley Hills, Mass.
It is likewise uncertain whether use of antiepileptic drugs (AEDs) affects women’s fertility or fecundity.
The Epilepsy Birth Control Registry collected data from an Internet-based survey of 1,144 community-dwelling women with epilepsy aged 18-47 years. Participants provided information about demographics, epilepsy, AEDs, reproduction, and contraception.
The researchers focused on rates of infertility, impaired fecundity, and live birth or unaborted pregnancy among 978 American women, and additionally examined whether these outcomes were related to AED use.
Infertility was defined as the percentage of participants who had unprotected sex but did not become pregnant by 1 year. Impaired fecundity was the percentage of participants who were infertile or did not carry a pregnancy to live birth. The study excluded from the impaired fecundity analysis the 41 respondents whose only outcomes were induced abortions. The 18% of pregnancies that terminated as induced abortions were excluded from the live birth rate analysis.
In all, 373 registry participants had 724 pregnancies and 422 births between 1981 and 2013. The women had an average of 2.15 pregnancies at a mean age of 24.9 years (range, 13-44 years). In addition, 38 women (9.2%) tried to conceive, but were infertile. Of 306 women with a first pregnancy, 222 (72.5%) had a live birth. Among 292 women with two pregnancies, 260 (89.0%) had at least one live birth, and 180 (61.6%) had two live births.
Of the 373 women, 84 (22.5%) with pregnancies had impaired fecundity. The risk of impaired fecundity tended to be higher among women on AED polytherapy than among women on no AED (risk ratio, 1.74).
The ratio of live births to pregnancy (71.0%) was similar among women on no AEDs (71.3%), those on AED monotherapy (71.8%), and those on polytherapy (69.7%). The live birth rate was 67.5% for women taking enzyme-inducing AEDs, 89.1% for women taking glucuronidated AEDs, 72.8% for women taking nonenzyme-inducing AEDs, 63.3% for women taking enzyme-inhibiting AEDs, and 69.7% for women on polytherapy. Lamotrigine use was associated with the highest ratio of live births to pregnancies at 89.1%; valproate use was associated with the lowest ratio of live births to pregnancies at 63.3%.
The investigation was funded by the Epilepsy Foundation and Lundbeck.
SOURCE: MacEachern DB et al. AES 2018, Abstract 1.426.
REPORTING FROM AES 2018
Key clinical point: Women with epilepsy may have more difficulty conceiving or carrying a pregnancy to term than women without epilepsy.
Major finding: The rate of infertility is 9.2% and the rate of impaired fecundity is 22.5% among women with epilepsy.
Study details: A retrospective analysis of 373 participants in the Epilepsy Birth Control Registry.
Disclosures: The investigation was funded by the Epilepsy Foundation and Lundbeck.
Source: MacEachern DB et al. AES 2018, Abstract 1.426.
Frontal lobe epilepsy elevates seizure risk during pregnancy
based on a study reported by Paula E. Voinescu, MD, PhD, at the annual meeting of the American Epilepsy Society.
The single center study included data on 76 pregnancies in women with focal epilepsy –17 of them in patients with frontal lobe epilepsy – and 38 pregnancies in women with generalized epilepsy. Seizures were more frequent during pregnancy, compared with baseline, in 5.5% of women with generalized epilepsy, 22.6% of women with focal epilepsies, and 53.0% of women with frontal lobe epilepsy, said Dr. Voinescu, lead author of the study and a neurologist at Brigham and Women’s Hospital in Boston.
“Frontal lobe epilepsy is known to be difficult to manage in general and often resistant to therapy, but it isn’t clear why the seizures got worse among pregnant women because the levels of medication in their blood was considered adequate. Until more research provides treatment guidance, doctors should carefully monitor their pregnant patients who have focal epilepsy to see if their seizures increase despite adequate blood levels and then adjust their medication if necessary,” she advised. “As we know from other research, seizures during pregnancy can increase the risk of distress and neurodevelopmental delays for the baby, as well as the risk of miscarriage.”
For the study, Dr. Voinescu and her colleagues analyzed prospectively collected clinical data from 99 pregnant women followed at Brigham and Women’s Hospital between 2013 and 2018.
The researchers excluded patients with abortions, seizure onset during pregnancy, poorly defined preconception seizure frequency, nonepileptic seizures, antiepileptic drug (AED) noncompliance, and pregnancies that were enrolled in other studies. The investigators documented patients’ seizure types and AED regimens and recorded seizure frequency during the 9 months before conception, during pregnancy, and 9 months postpartum. The researchers summed all seizures for each individual for each interval. They defined seizure frequency worsening as any increase above the preconception baseline, and evaluated differences between focal and generalized epilepsy and between frontal lobe and other focal epilepsies.
Increased seizure activity tended to occur in women on more than one AED, according to Dr. Voinescu. In women with frontal lobe epilepsy, seizure worsening during pregnancy was most likely to begin in the second trimester.
The gap in seizure frequency between the groups narrowed in the 9-month postpartum period. Seizures were more frequent during the postpartum period, compared with baseline, in 12.12% of women with generalized epilepsy, 20.14% of women with focal epilepsies, and 20.00% of women with frontal lobe epilepsy.
Future analyses will evaluate the influence of AED type and concentration and specific timing on seizure control during pregnancy and the postpartum period, Dr. Voinescu said. Future studies should also include measures of sleep, which may be a contributory mechanism to the differences found between these epilepsy types.
Dr. Voinescu reported receiving funding from the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation through the Susan Spencer Clinical Research Fellowship.
SOURCE: Voinescu PE et al. AES 2018, Abstract 3.236.
based on a study reported by Paula E. Voinescu, MD, PhD, at the annual meeting of the American Epilepsy Society.
The single center study included data on 76 pregnancies in women with focal epilepsy –17 of them in patients with frontal lobe epilepsy – and 38 pregnancies in women with generalized epilepsy. Seizures were more frequent during pregnancy, compared with baseline, in 5.5% of women with generalized epilepsy, 22.6% of women with focal epilepsies, and 53.0% of women with frontal lobe epilepsy, said Dr. Voinescu, lead author of the study and a neurologist at Brigham and Women’s Hospital in Boston.
“Frontal lobe epilepsy is known to be difficult to manage in general and often resistant to therapy, but it isn’t clear why the seizures got worse among pregnant women because the levels of medication in their blood was considered adequate. Until more research provides treatment guidance, doctors should carefully monitor their pregnant patients who have focal epilepsy to see if their seizures increase despite adequate blood levels and then adjust their medication if necessary,” she advised. “As we know from other research, seizures during pregnancy can increase the risk of distress and neurodevelopmental delays for the baby, as well as the risk of miscarriage.”
For the study, Dr. Voinescu and her colleagues analyzed prospectively collected clinical data from 99 pregnant women followed at Brigham and Women’s Hospital between 2013 and 2018.
The researchers excluded patients with abortions, seizure onset during pregnancy, poorly defined preconception seizure frequency, nonepileptic seizures, antiepileptic drug (AED) noncompliance, and pregnancies that were enrolled in other studies. The investigators documented patients’ seizure types and AED regimens and recorded seizure frequency during the 9 months before conception, during pregnancy, and 9 months postpartum. The researchers summed all seizures for each individual for each interval. They defined seizure frequency worsening as any increase above the preconception baseline, and evaluated differences between focal and generalized epilepsy and between frontal lobe and other focal epilepsies.
Increased seizure activity tended to occur in women on more than one AED, according to Dr. Voinescu. In women with frontal lobe epilepsy, seizure worsening during pregnancy was most likely to begin in the second trimester.
The gap in seizure frequency between the groups narrowed in the 9-month postpartum period. Seizures were more frequent during the postpartum period, compared with baseline, in 12.12% of women with generalized epilepsy, 20.14% of women with focal epilepsies, and 20.00% of women with frontal lobe epilepsy.
Future analyses will evaluate the influence of AED type and concentration and specific timing on seizure control during pregnancy and the postpartum period, Dr. Voinescu said. Future studies should also include measures of sleep, which may be a contributory mechanism to the differences found between these epilepsy types.
Dr. Voinescu reported receiving funding from the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation through the Susan Spencer Clinical Research Fellowship.
SOURCE: Voinescu PE et al. AES 2018, Abstract 3.236.
based on a study reported by Paula E. Voinescu, MD, PhD, at the annual meeting of the American Epilepsy Society.
The single center study included data on 76 pregnancies in women with focal epilepsy –17 of them in patients with frontal lobe epilepsy – and 38 pregnancies in women with generalized epilepsy. Seizures were more frequent during pregnancy, compared with baseline, in 5.5% of women with generalized epilepsy, 22.6% of women with focal epilepsies, and 53.0% of women with frontal lobe epilepsy, said Dr. Voinescu, lead author of the study and a neurologist at Brigham and Women’s Hospital in Boston.
“Frontal lobe epilepsy is known to be difficult to manage in general and often resistant to therapy, but it isn’t clear why the seizures got worse among pregnant women because the levels of medication in their blood was considered adequate. Until more research provides treatment guidance, doctors should carefully monitor their pregnant patients who have focal epilepsy to see if their seizures increase despite adequate blood levels and then adjust their medication if necessary,” she advised. “As we know from other research, seizures during pregnancy can increase the risk of distress and neurodevelopmental delays for the baby, as well as the risk of miscarriage.”
For the study, Dr. Voinescu and her colleagues analyzed prospectively collected clinical data from 99 pregnant women followed at Brigham and Women’s Hospital between 2013 and 2018.
The researchers excluded patients with abortions, seizure onset during pregnancy, poorly defined preconception seizure frequency, nonepileptic seizures, antiepileptic drug (AED) noncompliance, and pregnancies that were enrolled in other studies. The investigators documented patients’ seizure types and AED regimens and recorded seizure frequency during the 9 months before conception, during pregnancy, and 9 months postpartum. The researchers summed all seizures for each individual for each interval. They defined seizure frequency worsening as any increase above the preconception baseline, and evaluated differences between focal and generalized epilepsy and between frontal lobe and other focal epilepsies.
Increased seizure activity tended to occur in women on more than one AED, according to Dr. Voinescu. In women with frontal lobe epilepsy, seizure worsening during pregnancy was most likely to begin in the second trimester.
The gap in seizure frequency between the groups narrowed in the 9-month postpartum period. Seizures were more frequent during the postpartum period, compared with baseline, in 12.12% of women with generalized epilepsy, 20.14% of women with focal epilepsies, and 20.00% of women with frontal lobe epilepsy.
Future analyses will evaluate the influence of AED type and concentration and specific timing on seizure control during pregnancy and the postpartum period, Dr. Voinescu said. Future studies should also include measures of sleep, which may be a contributory mechanism to the differences found between these epilepsy types.
Dr. Voinescu reported receiving funding from the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation through the Susan Spencer Clinical Research Fellowship.
SOURCE: Voinescu PE et al. AES 2018, Abstract 3.236.
REPORTING FROM AES 2018
Key clinical point: Women with focal epilepsy, especially frontal lobe epilepsy, may need closer monitoring during pregnancy.
Major finding: Compared with baseline, seizures were more frequent during pregnancy in 53% of women with frontal lobe epilepsy.
Study details: An analysis of prospectively collected data from 114 pregnancies.
Disclosures: Dr. Voinescu reported receiving funding from the American Brain Foundation, the American Epilepsy Society, and the Epilepsy Foundation through the Susan Spencer Clinical Research Fellowship.
Source: Voinescu PE et al. AES 2018, Abstract 3.236.
Cannabis for peripheral neuropathy: The good, the bad, and the unknown
Marijuana, which is still illegal under federal law but legal in 30 states for medical purposes as of this writing, has shown promising results for treating peripheral neuropathy. Studies suggest that cannabis may be an option for patients whose pain responds poorly to standard treatments; however, its use may be restricted by cognitive and psychiatric adverse effects, particularly at high doses.1
In this article, we discuss the basic pharmacology of cannabis and how it may affect neuropathic pain. We review clinical trials on its use for peripheral neuropathy and provide guidance for its use.
PERIPHERAL NEUROPATHY IS COMMON AND COMPLEX
An estimated 20 million people in the United States suffer from neuropathic pain. The prevalence is higher in certain populations, with 26% of people over age 65 and 30% of patients with diabetes mellitus affected.2–4
Peripheral neuropathy is a complex, chronic state that occurs when nerve fibers are damaged, dysfunctional, or injured, sending incorrect signals to pain centers in the central nervous system.5 It is characterized by weakness, pain, and paresthesias that typically begin in the hands or feet and progress proximally.4 Symptoms depend on the number and types of nerves affected.
In many cases, peripheral neuropathy is idiopathic, but common causes include diabetes, alcoholism, human immunodeficiency virus (HIV) infection, and autoimmune disease. Others include toxicity from chemotherapy and heavy metals.
Peripheral neuropathy significantly worsens quality of life and function. Many patients experience emotional, cognitive, and functional problems, resulting in high rates of medical and psychiatric comorbidities and occupational impairment.4,6,7 Yet despite its clinical and epidemiologic significance, it is often undertreated.8
STANDARD TREATMENTS INADEQUATE
Peripheral neuropathy occurs in patients with a wide range of comorbidities and is especially difficult to treat. Mainstays of therapy include anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors.9 A more invasive option is spinal cord stimulation.
These treatments can have considerable adverse effects, and response rates remain suboptimal, with pain relief insufficient to improve quality of life for many patients.9,10 Better treatments are needed to improve clinical outcomes and patient experience.11
CANNABIS: A MIX OF COMPOUNDS
Cannabis sativa has been used as an analgesic for centuries. The plant contains more than 400 chemical compounds and is often used for its euphoric properties. Long-term use may lead to addiction and cognitive impairment.12,13
Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main components and the 2 best-studied cannabinoids with analgesic effects.
THC is the primary psychoactive component of cannabis. Its effects include relaxation, altered perception, heightened sensations, increased libido, and perceptual distortions of time and space. Temporary effects may include decreased short-term memory, dry mouth, impaired motor function, conjunctival injection, paranoia, and anxiety.
CBD is nonpsychoactive and has anti-inflammatory and antioxidant properties. It has been shown to reduce pain and inflammation without the effects of THC.14
Other compounds in the cannabis plant include phytocannabinoids, flavonoids, and tapenoids, which may produce individual, interactive, or synergistic effects.15 Different strains of cannabis have varying amounts of the individual components, making comparisons among clinical studies difficult.
THE ENDOCANNABINOID SYSTEM
The endogenous mammalian cannabinoid system plays a regulatory role in the development, homeostasis, and neuroplasticity of the central nervous system. It is also involved in modulating pain transmission in the nociceptive pathway.
Two of the most abundant cannabinoid endogenous ligands are anandamide and 2-arachidonylglycerol.9 These endocannabinoids are produced on demand in the central nervous system to reduce pain by acting as a circuit breaker.16–18 They target the G protein-coupled cannabinoid receptors CB1 and CB2, located throughout the central and peripheral nervous system and in organs and tissues.12
CB1 receptors are found primarily in the central nervous system, specifically in areas involved in movement, such as the basal ganglia and cerebellum, as well as in areas involved in memory, such as the hippocampus.12 They are also abundant in brain regions implicated in conducting and modulating pain signals, including the periaqueductal gray and the dorsal horn of the spinal cord.16–20
CB2 receptors are mostly found in peripheral tissues and organs, mainly those involved in the immune system, including splenic, tonsillar, and hematopoietic cells.12 They help regulate inflammation, allodynia, and hyperalgesia.17
Modifying response to injury
Following a nerve injury, neurons along the nociceptive pathway may become more reactive and responsive in a process known as sensitization.21 The process involves a cascade of cellular events that result in sprouting of pain-sensitive nerve endings.21,22
Cannabinoids are thought to reduce pain by modifying these cellular events. They also inhibit nociceptive conduction in the dorsal horn of the spinal cord and in the ascending spinothalamic tract.20 CB1 receptors found in nociceptive terminals along the peripheral nervous system impede pain conduction, while activation of CB2 receptors in immune cells decreases the release of nociceptive agents.
STUDIES OF CANNABIS FOR NEUROPATHIC PAIN
A number of studies have evaluated cannabis for treating neuropathic pain. Overall, available data support the efficacy of smoked or inhaled cannabis in its flower form when used as monotherapy or adjunctive therapy for relief of neuropathic pain of various etiologies. Many studies also report secondary benefits, including better sleep and functional improvement.23,24
However, adverse effects are common, especially at high doses, and include difficulty concentrating, lightheadedness, fatigue, and tachycardia. More serious reported adverse effects include anxiety, paranoia, and psychosis.
Wilsey et al, 2008: Neuropathic pain reduced
Wilsey et al25 conducted a double-blind, placebo-controlled crossover study that assessed the effects of smoking cannabis in 38 patients with central or peripheral neuropathic pain. Participants were assigned to smoke either high- or low-dose cannabis (7% or 3.5% delta-9-THC) or placebo cigarettes. Cigarettes were smoked during treatment sessions using the following regimen: 2 puffs at 60 minutes from baseline, 3 puffs at 120 minutes, and 4 puffs at 180 minutes. Patients were assessed after each set of puffs and for 2 hours afterwards. The primary outcome was spontaneous relief of pain as measured by a visual analog scale.
Pain intensity was comparable and significantly reduced in both treatment groups compared with placebo. At the high dose, some participants experienced neurocognitive impairment in attention, learning, memory, and psychomotor speed; only learning and memory declined at the low dose.
Ellis et al, 2009: Pain reduction in HIV neuropathy
Ellis et al23 conducted a double-blind, placebo-controlled crossover trial in patients with HIV neuropathy that was unresponsive to at least 2 analgesics with different modes of action. During each treatment week, participants were randomly assigned to smoke either active cannabis or placebo, while continuing their standard therapy. Titration started at 4% THC and was adjusted based on tolerability and efficacy. Twenty-eight of the 34 enrolled patients completed both cannabis and placebo treatments. The principal outcome was change in pain intensity from baseline at the end of each week, using the Descriptor Differential Scale of Pain Intensity.
Of the 28 patients, 46% achieved an average pain reduction of 3.3 points (30%). One patient experienced cannabis-induced psychosis, and another developed an intractable cough, which resolved with smoking cessation.
Ware et al, 2010: Reduced posttraumatic or postsurgical neuropathic pain
Ware et al24 performed a randomized crossover trial in 21 patients with posttraumatic or postsurgical neuropathic pain. Participants inhaled 4 different formulations of cannabis (containing 0%, 2.5%, 6.0%, and 9.4% THC) during 4 14-day periods. They inhaled a 25-mg dose through a pipe 3 times a day for the first 5 days of each cycle, followed by a 9-day washout period. Daily average pain intensity was measured using a numeric rating scale. The investigators also assessed mood, sleep, quality of life, and adverse effects.
Patients in the 9.4% THC group reported significantly less pain and better sleep, with average pain scores decreasing from 6.1 to 5.4 on an 11-point scale. Although the benefit was modest, the authors noted that the pain had been refractory to standard treatments.
The number of reported adverse events increased with greater potency and were most commonly throat irritation, burning sensation, headache, dizziness, and fatigue. This study suggests that THC potency affects tolerability, with higher doses eliciting clinically important adverse effects, some of which may reduce the ability to perform activities of daily living, such as driving.
Wilsey et al, 2013: Use in resistant neuropathic pain
Wilsey et al26 conducted another double-blind, placebo-controlled crossover study assessing the effect of vaporized cannabis on central and peripheral neuropathic pain resistant to first-line pharmacotherapies. Dose-effect relationships were explored using medium-dose (3.5%), low-dose (1.3%), and placebo cannabis. The primary outcome measure was a 30% reduction in pain intensity based on a visual analog scale.
In the placebo group, 26% of patients achieved this vs 57% of the low-dose cannabis group and 61% of those receiving the medium dose. No significant difference was found between the 2 active doses in reducing neuropathic pain, and both were more effective than placebo. The number needed to treat to achieve a 30% reduction in pain was about 3 for both cannabis groups compared with placebo. Psychoactive effects were minimal, of short duration, and reversible.
Wallace et al, 2015: Use in diabetic peripheral neuropathy
Wallace et al27 conducted a randomized, double-blind, placebo-controlled crossover study evaluating cannabis for diabetic peripheral neuropathy in 16 patients. Each had experienced at least 6 months of neuropathic pain in their feet. The participants inhaled a single dose of 1%, 4%, or 7% THC cannabis or placebo. Spontaneous pain was reported with a visual analog scale and also tested with a foam brush and von Frey filament at intervals until 4 hours after treatment.
Pain scores were lower with treatment compared with placebo, with high-dose cannabis having the greatest analgesic effect. Pain reduction lasted for the full duration of the test. Cannabis recipients had declines in attention and working memory, with the high-dose group experiencing the greatest impact 15 minutes after treatment. High-dose recipients also had poorer scores on testing of quick task-switching, with the greatest effect at 2 hours.27
Research and market cannabis are not equal
Results of US studies must be qualified. Most have used cannabis provided by the National Institute of Drug Abuse (NIDA),23–26 which differs in potency from commercially available preparations. This limits the clinical usefulness of the analysis of benefits and risks.
Vergara et al28 found that NIDA varieties contained much lower THC levels and as much as 23 times the cannabinol content as cannabis in state-legalized markets.
Studies based on NIDA varieties likely underestimate the risks of consumer-purchased cannabis, as THC is believed to be most responsible for the risk of psychosis and impaired driving and cognition.24,28
CBD MAY PROTECT AGAINST ADVERSE EFFECTS
Studies of CBD alone are limited to preclinical data.29 Evidence suggests that CBD alone or combined with THC can suppress chronic neuropathic pain, and that CBD may have a protective effect after nerve injury.30
Nabiximols, an oromucosal spray preparation with equal amounts of THC and CBD, has been approved in Canada as well as in European countries including the United Kingdom. Although its use has not been associated with many of the adverse effects of inhaled cannabis,30–32 evidence of efficacy from clinical trials has been mixed.
Lynch et al,31 in a 2014 randomized, double-blind, placebo-controlled crossover pilot study31 evaluated nabiximols in 16 patients with neuropathic pain related to chemotherapy. No statistically significant difference was found between treatment and placebo. However, the trial was underpowered.
Serpell et al,32 in a 2014 European randomized, placebo-controlled parallel-group study, evaluated 246 patients with peripheral neuropathy with allodynia, with 128 receiving active treatment (THC-CBD oromucosal spray) and 118 receiving placebo. Over the 15-week study, participants continued their current analgesic treatments.
Pain was reduced in the treatment group, but the difference from placebo was not statistically significant. However, the treatment group reported significantly better sleep quality and Patient Global Impression of Change measures (reflecting a patient’s belief of treatment efficacy).
META-ANALYSES CONFIRM EFFECT
Three meta-analyses of available studies of the effects of cannabis on neuropathic pain have been completed.
Andreae et al, 2015: 5 trials, 178 patients
Andreae et al1 evaluated 5 randomized controlled trials in 178 patients in North America. All had had neuropathy for at least 3 months, with a pain level of at least about 3 on a scale of 10. Two studies had patients with HIV-related neuropathy; the other 3 involved patients with neuropathy related to trauma, diabetes, complex regional pain syndrome, or spinal cord injury. All trials used whole cannabis plant provided by NIDA, and the main outcomes were patient-reported pain scales. No study evaluated pain beyond 2 weeks after trial termination.
They found that 1 of every 5 to 6 patients treated with cannabis had at least a 30% pain reduction.
Nugent et al, 2017: 13 trials, 246 patients
Nugent et al33 reviewed 13 trials in 246 patients that evaluated the effects of different cannabis-based preparations on either central or peripheral neuropathic pain from various conditions. Actively treated patients were more likely to report a 30% improvement in neuropathic pain. Again, studies tended to be small and brief.
Cochrane review, 2018: 16 trials, 1,750 patients
A Cochrane review34 analyzed 16 trials (in 1,750 patients) lasting 2 to 26 weeks. Treatments included an oromucosal spray with a plant-derived combination of THC and CBD, nabilone, inhaled herbal cannabis, and plant-derived THC.
With cannabis-based treatments, significantly more people achieved 50% or greater pain relief than with placebo (21% vs 17%, number needed to treat 20); 30% pain reduction was achieved in 39% of treated patients vs 33% of patients taking placebo (number needed to treat 11).
On the other hand, significantly more participants withdrew from studies because of adverse events with cannabis-based treatments than placebo (10% vs 5%), with psychiatric disorders occurring in 17% of patients receiving active treatment vs 5% of those receiving placebo (number needed to harm 10).
The primary studies suffered from methodologic limitations including small size, short duration, and inconsistency of formulations and study designs. Further evaluation of long-term efficacy, tolerability, and addiction potential is critical to determine the risk-benefit ratio.
RISKS OF CANNABIS USE
Like any drug therapy, cannabis has effects that may limit its use. Cannabis can affect a person’s psyche, physiology, and lifestyle.
Impaired attention, task speed
Neurocognitive changes associated with cannabis use—especially dizziness, fatigue, and slowed task-switching—could affect driving and other complex tasks. Evidence indicates that such activities should be avoided in the hours after treatment.26,27,32,33
Concern over brain development
Most worrisome is the effect of long-term cannabis use on brain development in young adults. Regular use of cannabis at an early age is associated with lower IQ, decline in school performance, and lower rates of high school graduation.35
Avoid in psychiatric patients
It is unlikely that cannabis can be safely used in patients with psychiatric illnesses. Anxiety, depression, and psychotic disorders can be exacerbated by the regular use of cannabis, and the risk of developing these conditions is increased while using cannabis.36,37
High concentrations of THC (the highest concentration used in the above studies was 9.5%) can cause anxiety, paranoia, and psychosis.
Respiratory effects
Long-term cannabis smoking may cause wheezing, cough, dyspnea, and exacerbations of chronic bronchitis. There is some evidence that symptoms improve after stopping smoking.33,38
SHOULD WE RECOMMEND CANNABIS?
Where cannabis can be legally used, doctors should be familiar with the literature and its limitations so that they can counsel patients on the best use and potential risks and benefits of cannabis treatment.
A recent conceptualization of pain suggests that a pain score reflects a composite of sensory factors (eg, tissue damage), cognitive factors (eg, beliefs about pain), and affective factors (eg, anxiety, depression).39 Physicians should keep this in mind when evaluating patients to better assess the risks and benefits of cannabis. While pharmacotherapy may address sensory factors, cognitive behavioral therapy may help alter beliefs about the pain as well as anxiety and depressive symptoms that might influence subjective reports.
Ideally, patients being considered for cannabis treatment would have a type of neuropathic pain proven to respond to cannabis in randomized, controlled studies, as well as evidence of failed first-line treatments.
Relative contraindications include depression, anxiety, substance use, psychotic disorders, and respiratory conditions, and these should also be considered.
Although current research shows an analgesic benefit of cannabis on neuropathic pain comparable to that of gabapentin,40 further investigation is needed to better evaluate long-term safety, efficacy, and interactions with standard therapies. Until we have a more complete picture, we should use the current literature, along with a thorough knowledge of each patient, to determine if the benefits of cannabis therapy outweigh the risks.
Acknowledgments: We thank Camillo Ferrari, BS, and Christina McMahon, BA, for their helpful comments.
- Andreae MH, Carter GM, Shaparin N, et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. J Pain 2015; 16(12):1221–1232. doi:10.1016/j.jpain.2015.07.009
- National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet. www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet. Accessed November 14, 2018.
- Mold JW, Vesely SK, Keyl BA, Schenk JB, Roberts M. The prevalence, predictors, and consequences of peripheral sensory neuropathy in older adults. J Am Board Fam Med 2004; 17(5):308–318. doi:10.3122/jabfm.17.5.309
- Bansal D, Gudala K, Muthyala H, Esam HP, Nayakallu R, Bhansali A. Prevalence and risk factors of developing peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig 2014; 5(6):714–721. doi:10.1111/jdi.12223
- Finnerup NB, Haroutounian S, Kamerman P, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain 2016; 157(8):1599–1606. doi:10.1097/j.pain.0000000000000492
- Maldonado R, Banos JE, Cabanero D. The endocannabinoid system and neuropathic pain. Pain 2016; 157(suppl 1):S23–S32. doi:10.1097/j.pain.0000000000000428
- Zeng L, Alongkronrusmee D, van Rijn RM. An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US. J Pain Res 2017; 10:219–228. doi:10.2147/JPR.S125987
- Callaghan BC, Price RS, Feldman EL. Distal symmetric polyneuropathy: a review. JAMA 2015; 314(20):2172–2181. doi:10.1001/jama.2015.13611
- Adams AS, Callaghan B, Grant RW. Overcoming barriers to diabetic polyneuropathy management in primary care. Healthc (Amst) 2017; 5(4):171–173. doi:10.1016/j.hjdsi.2016.10.003
- Gwak YS, Kim HY, Lee BH, Yang CH. Combined approaches for the relief of spinal cord injury-induced neuropathic pain. Complement Ther Med 2016; 25:27–33. doi:10.1016/j.ctim.2015.12.021
- Majithia N, Loprinzi CL, Smith TJ. New practical approaches to chemotherapy-induced neuropathic pain: prevention, assessment, and treatment. Oncology 2016; 30(11):1020–1029. pmid:27854104
- Grotenhermen F. Cannabinoids and the endocannabinoid system. Cannabinoids 2006; 1(1):10–14.
- Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA 2015; 313(24):2474–2483. doi:10.1001/jama.2015.6199
- Campos AC, Fogaça MV, Scarante FF, et al. Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front Pharmacol 2017; 8:269. doi:10.3389/fphar.2017.00269
- Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163(7):1344–1364. doi:10.1111/j.1476-5381.2011.01238.x
- Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA. Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr Neurosci 2017; Jul 7: 1–20. doi:10.1080/1028415X.2017.1347373
- Hillard CJ. Circulating endocannabinoids: from whence do they come and where are they going? Neuropsychopharmacology 2018; 43(1):155–172. doi:10.1038/npp.2017.130
- Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 1991; 11(2):563–583. pmid:1992016
- Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience1998; 83(2):393–411. pmid:9460749
- Russo EB, Hohmann AG. Role of cannabinoids in pain management. In: Deer TR, Leong MS, ed. Comprehensve Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. New York, NY: Springer; 2013:181–193.
- Vranken JH. Elucidation of pathophysiology and treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem 2012; 12(4):304–314. pmid:23033930
- Yamanaka H, Noguchi K. Pathophysiology of neuropathic pain: molecular mechanisms underlying central sensitization in the dorsal horn in neuropathic pain. Brain Nerve 2012; 64(11):1255–1265. Japanese. pmid:23131736
- Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34(3):672–680. doi:10.1038/npp.2008.120
- Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010; 182(14):E694–E701. doi:10.1503/cmaj.091414
- Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008; 9(6):506–521. doi:10.1016/j.jpain.2007.12.010
- Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013; 14(2):136–148. doi:10.1016/j.jpain.2012.10.009
- Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 2015; 16(7):616–627. doi:10.1016/j.jpain.2015.03.008
- Vergara D, Bidwell LC, Gaudino R, et al. Compromised external validity: federally produced cannabis does not reflect legal markets. Scientific Reports. 2017; 7(1):1-8. doi:10.1038/srep46528
- Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterized by allodynia: a randomized, double-blind, placebo-controlled clinical trial. Pain 2007; 133(1–3):210–220. doi:10.1016/j.pain.2007.08.028
- Philpott HT, O’Brien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain 2017; 158(12):2442–2451. doi:10.1097/j.pain.0000000000001052
- Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 2014; 47(1):166–173. doi:10.1016/j.jpainsymman.2013.02.018
- Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain 2014; 18(7):999–1012. doi:10.1002/j.1532-2149.2013.00445.x
- Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review. Ann Intern Med 2017; 167(5):319–331. doi:10.7326/M17-0155
- Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018; 3:CD012182. doi:10.1002/14651858.CD012182.pub2
- Castellanos-Ryan N, Pingault JB, Parent S, Vitaro F, Tremblay RE, Seguin JR. Adolescent cannabis use, change in neurocognitive function, and high-school graduation: a longitudinal study from early adolescence to young adulthood. Dev Psychopathol 2017; 29(4):1253–1266. doi:10.1017/S0954579416001280
- Karila L, Roux P, Benyamina A, et al. Acute and long-term effects of cannabis use: a review. Curr Pharm Des 2014; 20(25):4112–4118. pmid:24001294
- Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001; 178:116–122. pmid:11157424
- National Academies of Science, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC: The National Academy Press; 2017. doi:10.17226/24625
- Modesto-Lowe V, Griard L, Chaplin M. Cancer pain in the opioid-addicted patient: can we treat it right? J Opioid Manag 2012; 8(3):167–175. doi:10.5055/jom.2012.0113
- Grant I. Medicinal cannabis and painful sensory neuropathy. Virtual Mentor 2013; 15(5):466–469. doi:10.1001/virtualmentor.2013.15.5.oped1-1305
Marijuana, which is still illegal under federal law but legal in 30 states for medical purposes as of this writing, has shown promising results for treating peripheral neuropathy. Studies suggest that cannabis may be an option for patients whose pain responds poorly to standard treatments; however, its use may be restricted by cognitive and psychiatric adverse effects, particularly at high doses.1
In this article, we discuss the basic pharmacology of cannabis and how it may affect neuropathic pain. We review clinical trials on its use for peripheral neuropathy and provide guidance for its use.
PERIPHERAL NEUROPATHY IS COMMON AND COMPLEX
An estimated 20 million people in the United States suffer from neuropathic pain. The prevalence is higher in certain populations, with 26% of people over age 65 and 30% of patients with diabetes mellitus affected.2–4
Peripheral neuropathy is a complex, chronic state that occurs when nerve fibers are damaged, dysfunctional, or injured, sending incorrect signals to pain centers in the central nervous system.5 It is characterized by weakness, pain, and paresthesias that typically begin in the hands or feet and progress proximally.4 Symptoms depend on the number and types of nerves affected.
In many cases, peripheral neuropathy is idiopathic, but common causes include diabetes, alcoholism, human immunodeficiency virus (HIV) infection, and autoimmune disease. Others include toxicity from chemotherapy and heavy metals.
Peripheral neuropathy significantly worsens quality of life and function. Many patients experience emotional, cognitive, and functional problems, resulting in high rates of medical and psychiatric comorbidities and occupational impairment.4,6,7 Yet despite its clinical and epidemiologic significance, it is often undertreated.8
STANDARD TREATMENTS INADEQUATE
Peripheral neuropathy occurs in patients with a wide range of comorbidities and is especially difficult to treat. Mainstays of therapy include anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors.9 A more invasive option is spinal cord stimulation.
These treatments can have considerable adverse effects, and response rates remain suboptimal, with pain relief insufficient to improve quality of life for many patients.9,10 Better treatments are needed to improve clinical outcomes and patient experience.11
CANNABIS: A MIX OF COMPOUNDS
Cannabis sativa has been used as an analgesic for centuries. The plant contains more than 400 chemical compounds and is often used for its euphoric properties. Long-term use may lead to addiction and cognitive impairment.12,13
Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main components and the 2 best-studied cannabinoids with analgesic effects.
THC is the primary psychoactive component of cannabis. Its effects include relaxation, altered perception, heightened sensations, increased libido, and perceptual distortions of time and space. Temporary effects may include decreased short-term memory, dry mouth, impaired motor function, conjunctival injection, paranoia, and anxiety.
CBD is nonpsychoactive and has anti-inflammatory and antioxidant properties. It has been shown to reduce pain and inflammation without the effects of THC.14
Other compounds in the cannabis plant include phytocannabinoids, flavonoids, and tapenoids, which may produce individual, interactive, or synergistic effects.15 Different strains of cannabis have varying amounts of the individual components, making comparisons among clinical studies difficult.
THE ENDOCANNABINOID SYSTEM
The endogenous mammalian cannabinoid system plays a regulatory role in the development, homeostasis, and neuroplasticity of the central nervous system. It is also involved in modulating pain transmission in the nociceptive pathway.
Two of the most abundant cannabinoid endogenous ligands are anandamide and 2-arachidonylglycerol.9 These endocannabinoids are produced on demand in the central nervous system to reduce pain by acting as a circuit breaker.16–18 They target the G protein-coupled cannabinoid receptors CB1 and CB2, located throughout the central and peripheral nervous system and in organs and tissues.12
CB1 receptors are found primarily in the central nervous system, specifically in areas involved in movement, such as the basal ganglia and cerebellum, as well as in areas involved in memory, such as the hippocampus.12 They are also abundant in brain regions implicated in conducting and modulating pain signals, including the periaqueductal gray and the dorsal horn of the spinal cord.16–20
CB2 receptors are mostly found in peripheral tissues and organs, mainly those involved in the immune system, including splenic, tonsillar, and hematopoietic cells.12 They help regulate inflammation, allodynia, and hyperalgesia.17
Modifying response to injury
Following a nerve injury, neurons along the nociceptive pathway may become more reactive and responsive in a process known as sensitization.21 The process involves a cascade of cellular events that result in sprouting of pain-sensitive nerve endings.21,22
Cannabinoids are thought to reduce pain by modifying these cellular events. They also inhibit nociceptive conduction in the dorsal horn of the spinal cord and in the ascending spinothalamic tract.20 CB1 receptors found in nociceptive terminals along the peripheral nervous system impede pain conduction, while activation of CB2 receptors in immune cells decreases the release of nociceptive agents.
STUDIES OF CANNABIS FOR NEUROPATHIC PAIN
A number of studies have evaluated cannabis for treating neuropathic pain. Overall, available data support the efficacy of smoked or inhaled cannabis in its flower form when used as monotherapy or adjunctive therapy for relief of neuropathic pain of various etiologies. Many studies also report secondary benefits, including better sleep and functional improvement.23,24
However, adverse effects are common, especially at high doses, and include difficulty concentrating, lightheadedness, fatigue, and tachycardia. More serious reported adverse effects include anxiety, paranoia, and psychosis.
Wilsey et al, 2008: Neuropathic pain reduced
Wilsey et al25 conducted a double-blind, placebo-controlled crossover study that assessed the effects of smoking cannabis in 38 patients with central or peripheral neuropathic pain. Participants were assigned to smoke either high- or low-dose cannabis (7% or 3.5% delta-9-THC) or placebo cigarettes. Cigarettes were smoked during treatment sessions using the following regimen: 2 puffs at 60 minutes from baseline, 3 puffs at 120 minutes, and 4 puffs at 180 minutes. Patients were assessed after each set of puffs and for 2 hours afterwards. The primary outcome was spontaneous relief of pain as measured by a visual analog scale.
Pain intensity was comparable and significantly reduced in both treatment groups compared with placebo. At the high dose, some participants experienced neurocognitive impairment in attention, learning, memory, and psychomotor speed; only learning and memory declined at the low dose.
Ellis et al, 2009: Pain reduction in HIV neuropathy
Ellis et al23 conducted a double-blind, placebo-controlled crossover trial in patients with HIV neuropathy that was unresponsive to at least 2 analgesics with different modes of action. During each treatment week, participants were randomly assigned to smoke either active cannabis or placebo, while continuing their standard therapy. Titration started at 4% THC and was adjusted based on tolerability and efficacy. Twenty-eight of the 34 enrolled patients completed both cannabis and placebo treatments. The principal outcome was change in pain intensity from baseline at the end of each week, using the Descriptor Differential Scale of Pain Intensity.
Of the 28 patients, 46% achieved an average pain reduction of 3.3 points (30%). One patient experienced cannabis-induced psychosis, and another developed an intractable cough, which resolved with smoking cessation.
Ware et al, 2010: Reduced posttraumatic or postsurgical neuropathic pain
Ware et al24 performed a randomized crossover trial in 21 patients with posttraumatic or postsurgical neuropathic pain. Participants inhaled 4 different formulations of cannabis (containing 0%, 2.5%, 6.0%, and 9.4% THC) during 4 14-day periods. They inhaled a 25-mg dose through a pipe 3 times a day for the first 5 days of each cycle, followed by a 9-day washout period. Daily average pain intensity was measured using a numeric rating scale. The investigators also assessed mood, sleep, quality of life, and adverse effects.
Patients in the 9.4% THC group reported significantly less pain and better sleep, with average pain scores decreasing from 6.1 to 5.4 on an 11-point scale. Although the benefit was modest, the authors noted that the pain had been refractory to standard treatments.
The number of reported adverse events increased with greater potency and were most commonly throat irritation, burning sensation, headache, dizziness, and fatigue. This study suggests that THC potency affects tolerability, with higher doses eliciting clinically important adverse effects, some of which may reduce the ability to perform activities of daily living, such as driving.
Wilsey et al, 2013: Use in resistant neuropathic pain
Wilsey et al26 conducted another double-blind, placebo-controlled crossover study assessing the effect of vaporized cannabis on central and peripheral neuropathic pain resistant to first-line pharmacotherapies. Dose-effect relationships were explored using medium-dose (3.5%), low-dose (1.3%), and placebo cannabis. The primary outcome measure was a 30% reduction in pain intensity based on a visual analog scale.
In the placebo group, 26% of patients achieved this vs 57% of the low-dose cannabis group and 61% of those receiving the medium dose. No significant difference was found between the 2 active doses in reducing neuropathic pain, and both were more effective than placebo. The number needed to treat to achieve a 30% reduction in pain was about 3 for both cannabis groups compared with placebo. Psychoactive effects were minimal, of short duration, and reversible.
Wallace et al, 2015: Use in diabetic peripheral neuropathy
Wallace et al27 conducted a randomized, double-blind, placebo-controlled crossover study evaluating cannabis for diabetic peripheral neuropathy in 16 patients. Each had experienced at least 6 months of neuropathic pain in their feet. The participants inhaled a single dose of 1%, 4%, or 7% THC cannabis or placebo. Spontaneous pain was reported with a visual analog scale and also tested with a foam brush and von Frey filament at intervals until 4 hours after treatment.
Pain scores were lower with treatment compared with placebo, with high-dose cannabis having the greatest analgesic effect. Pain reduction lasted for the full duration of the test. Cannabis recipients had declines in attention and working memory, with the high-dose group experiencing the greatest impact 15 minutes after treatment. High-dose recipients also had poorer scores on testing of quick task-switching, with the greatest effect at 2 hours.27
Research and market cannabis are not equal
Results of US studies must be qualified. Most have used cannabis provided by the National Institute of Drug Abuse (NIDA),23–26 which differs in potency from commercially available preparations. This limits the clinical usefulness of the analysis of benefits and risks.
Vergara et al28 found that NIDA varieties contained much lower THC levels and as much as 23 times the cannabinol content as cannabis in state-legalized markets.
Studies based on NIDA varieties likely underestimate the risks of consumer-purchased cannabis, as THC is believed to be most responsible for the risk of psychosis and impaired driving and cognition.24,28
CBD MAY PROTECT AGAINST ADVERSE EFFECTS
Studies of CBD alone are limited to preclinical data.29 Evidence suggests that CBD alone or combined with THC can suppress chronic neuropathic pain, and that CBD may have a protective effect after nerve injury.30
Nabiximols, an oromucosal spray preparation with equal amounts of THC and CBD, has been approved in Canada as well as in European countries including the United Kingdom. Although its use has not been associated with many of the adverse effects of inhaled cannabis,30–32 evidence of efficacy from clinical trials has been mixed.
Lynch et al,31 in a 2014 randomized, double-blind, placebo-controlled crossover pilot study31 evaluated nabiximols in 16 patients with neuropathic pain related to chemotherapy. No statistically significant difference was found between treatment and placebo. However, the trial was underpowered.
Serpell et al,32 in a 2014 European randomized, placebo-controlled parallel-group study, evaluated 246 patients with peripheral neuropathy with allodynia, with 128 receiving active treatment (THC-CBD oromucosal spray) and 118 receiving placebo. Over the 15-week study, participants continued their current analgesic treatments.
Pain was reduced in the treatment group, but the difference from placebo was not statistically significant. However, the treatment group reported significantly better sleep quality and Patient Global Impression of Change measures (reflecting a patient’s belief of treatment efficacy).
META-ANALYSES CONFIRM EFFECT
Three meta-analyses of available studies of the effects of cannabis on neuropathic pain have been completed.
Andreae et al, 2015: 5 trials, 178 patients
Andreae et al1 evaluated 5 randomized controlled trials in 178 patients in North America. All had had neuropathy for at least 3 months, with a pain level of at least about 3 on a scale of 10. Two studies had patients with HIV-related neuropathy; the other 3 involved patients with neuropathy related to trauma, diabetes, complex regional pain syndrome, or spinal cord injury. All trials used whole cannabis plant provided by NIDA, and the main outcomes were patient-reported pain scales. No study evaluated pain beyond 2 weeks after trial termination.
They found that 1 of every 5 to 6 patients treated with cannabis had at least a 30% pain reduction.
Nugent et al, 2017: 13 trials, 246 patients
Nugent et al33 reviewed 13 trials in 246 patients that evaluated the effects of different cannabis-based preparations on either central or peripheral neuropathic pain from various conditions. Actively treated patients were more likely to report a 30% improvement in neuropathic pain. Again, studies tended to be small and brief.
Cochrane review, 2018: 16 trials, 1,750 patients
A Cochrane review34 analyzed 16 trials (in 1,750 patients) lasting 2 to 26 weeks. Treatments included an oromucosal spray with a plant-derived combination of THC and CBD, nabilone, inhaled herbal cannabis, and plant-derived THC.
With cannabis-based treatments, significantly more people achieved 50% or greater pain relief than with placebo (21% vs 17%, number needed to treat 20); 30% pain reduction was achieved in 39% of treated patients vs 33% of patients taking placebo (number needed to treat 11).
On the other hand, significantly more participants withdrew from studies because of adverse events with cannabis-based treatments than placebo (10% vs 5%), with psychiatric disorders occurring in 17% of patients receiving active treatment vs 5% of those receiving placebo (number needed to harm 10).
The primary studies suffered from methodologic limitations including small size, short duration, and inconsistency of formulations and study designs. Further evaluation of long-term efficacy, tolerability, and addiction potential is critical to determine the risk-benefit ratio.
RISKS OF CANNABIS USE
Like any drug therapy, cannabis has effects that may limit its use. Cannabis can affect a person’s psyche, physiology, and lifestyle.
Impaired attention, task speed
Neurocognitive changes associated with cannabis use—especially dizziness, fatigue, and slowed task-switching—could affect driving and other complex tasks. Evidence indicates that such activities should be avoided in the hours after treatment.26,27,32,33
Concern over brain development
Most worrisome is the effect of long-term cannabis use on brain development in young adults. Regular use of cannabis at an early age is associated with lower IQ, decline in school performance, and lower rates of high school graduation.35
Avoid in psychiatric patients
It is unlikely that cannabis can be safely used in patients with psychiatric illnesses. Anxiety, depression, and psychotic disorders can be exacerbated by the regular use of cannabis, and the risk of developing these conditions is increased while using cannabis.36,37
High concentrations of THC (the highest concentration used in the above studies was 9.5%) can cause anxiety, paranoia, and psychosis.
Respiratory effects
Long-term cannabis smoking may cause wheezing, cough, dyspnea, and exacerbations of chronic bronchitis. There is some evidence that symptoms improve after stopping smoking.33,38
SHOULD WE RECOMMEND CANNABIS?
Where cannabis can be legally used, doctors should be familiar with the literature and its limitations so that they can counsel patients on the best use and potential risks and benefits of cannabis treatment.
A recent conceptualization of pain suggests that a pain score reflects a composite of sensory factors (eg, tissue damage), cognitive factors (eg, beliefs about pain), and affective factors (eg, anxiety, depression).39 Physicians should keep this in mind when evaluating patients to better assess the risks and benefits of cannabis. While pharmacotherapy may address sensory factors, cognitive behavioral therapy may help alter beliefs about the pain as well as anxiety and depressive symptoms that might influence subjective reports.
Ideally, patients being considered for cannabis treatment would have a type of neuropathic pain proven to respond to cannabis in randomized, controlled studies, as well as evidence of failed first-line treatments.
Relative contraindications include depression, anxiety, substance use, psychotic disorders, and respiratory conditions, and these should also be considered.
Although current research shows an analgesic benefit of cannabis on neuropathic pain comparable to that of gabapentin,40 further investigation is needed to better evaluate long-term safety, efficacy, and interactions with standard therapies. Until we have a more complete picture, we should use the current literature, along with a thorough knowledge of each patient, to determine if the benefits of cannabis therapy outweigh the risks.
Acknowledgments: We thank Camillo Ferrari, BS, and Christina McMahon, BA, for their helpful comments.
Marijuana, which is still illegal under federal law but legal in 30 states for medical purposes as of this writing, has shown promising results for treating peripheral neuropathy. Studies suggest that cannabis may be an option for patients whose pain responds poorly to standard treatments; however, its use may be restricted by cognitive and psychiatric adverse effects, particularly at high doses.1
In this article, we discuss the basic pharmacology of cannabis and how it may affect neuropathic pain. We review clinical trials on its use for peripheral neuropathy and provide guidance for its use.
PERIPHERAL NEUROPATHY IS COMMON AND COMPLEX
An estimated 20 million people in the United States suffer from neuropathic pain. The prevalence is higher in certain populations, with 26% of people over age 65 and 30% of patients with diabetes mellitus affected.2–4
Peripheral neuropathy is a complex, chronic state that occurs when nerve fibers are damaged, dysfunctional, or injured, sending incorrect signals to pain centers in the central nervous system.5 It is characterized by weakness, pain, and paresthesias that typically begin in the hands or feet and progress proximally.4 Symptoms depend on the number and types of nerves affected.
In many cases, peripheral neuropathy is idiopathic, but common causes include diabetes, alcoholism, human immunodeficiency virus (HIV) infection, and autoimmune disease. Others include toxicity from chemotherapy and heavy metals.
Peripheral neuropathy significantly worsens quality of life and function. Many patients experience emotional, cognitive, and functional problems, resulting in high rates of medical and psychiatric comorbidities and occupational impairment.4,6,7 Yet despite its clinical and epidemiologic significance, it is often undertreated.8
STANDARD TREATMENTS INADEQUATE
Peripheral neuropathy occurs in patients with a wide range of comorbidities and is especially difficult to treat. Mainstays of therapy include anticonvulsants, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors.9 A more invasive option is spinal cord stimulation.
These treatments can have considerable adverse effects, and response rates remain suboptimal, with pain relief insufficient to improve quality of life for many patients.9,10 Better treatments are needed to improve clinical outcomes and patient experience.11
CANNABIS: A MIX OF COMPOUNDS
Cannabis sativa has been used as an analgesic for centuries. The plant contains more than 400 chemical compounds and is often used for its euphoric properties. Long-term use may lead to addiction and cognitive impairment.12,13
Tetrahydrocannabinol (THC) and cannabidiol (CBD) are the main components and the 2 best-studied cannabinoids with analgesic effects.
THC is the primary psychoactive component of cannabis. Its effects include relaxation, altered perception, heightened sensations, increased libido, and perceptual distortions of time and space. Temporary effects may include decreased short-term memory, dry mouth, impaired motor function, conjunctival injection, paranoia, and anxiety.
CBD is nonpsychoactive and has anti-inflammatory and antioxidant properties. It has been shown to reduce pain and inflammation without the effects of THC.14
Other compounds in the cannabis plant include phytocannabinoids, flavonoids, and tapenoids, which may produce individual, interactive, or synergistic effects.15 Different strains of cannabis have varying amounts of the individual components, making comparisons among clinical studies difficult.
THE ENDOCANNABINOID SYSTEM
The endogenous mammalian cannabinoid system plays a regulatory role in the development, homeostasis, and neuroplasticity of the central nervous system. It is also involved in modulating pain transmission in the nociceptive pathway.
Two of the most abundant cannabinoid endogenous ligands are anandamide and 2-arachidonylglycerol.9 These endocannabinoids are produced on demand in the central nervous system to reduce pain by acting as a circuit breaker.16–18 They target the G protein-coupled cannabinoid receptors CB1 and CB2, located throughout the central and peripheral nervous system and in organs and tissues.12
CB1 receptors are found primarily in the central nervous system, specifically in areas involved in movement, such as the basal ganglia and cerebellum, as well as in areas involved in memory, such as the hippocampus.12 They are also abundant in brain regions implicated in conducting and modulating pain signals, including the periaqueductal gray and the dorsal horn of the spinal cord.16–20
CB2 receptors are mostly found in peripheral tissues and organs, mainly those involved in the immune system, including splenic, tonsillar, and hematopoietic cells.12 They help regulate inflammation, allodynia, and hyperalgesia.17
Modifying response to injury
Following a nerve injury, neurons along the nociceptive pathway may become more reactive and responsive in a process known as sensitization.21 The process involves a cascade of cellular events that result in sprouting of pain-sensitive nerve endings.21,22
Cannabinoids are thought to reduce pain by modifying these cellular events. They also inhibit nociceptive conduction in the dorsal horn of the spinal cord and in the ascending spinothalamic tract.20 CB1 receptors found in nociceptive terminals along the peripheral nervous system impede pain conduction, while activation of CB2 receptors in immune cells decreases the release of nociceptive agents.
STUDIES OF CANNABIS FOR NEUROPATHIC PAIN
A number of studies have evaluated cannabis for treating neuropathic pain. Overall, available data support the efficacy of smoked or inhaled cannabis in its flower form when used as monotherapy or adjunctive therapy for relief of neuropathic pain of various etiologies. Many studies also report secondary benefits, including better sleep and functional improvement.23,24
However, adverse effects are common, especially at high doses, and include difficulty concentrating, lightheadedness, fatigue, and tachycardia. More serious reported adverse effects include anxiety, paranoia, and psychosis.
Wilsey et al, 2008: Neuropathic pain reduced
Wilsey et al25 conducted a double-blind, placebo-controlled crossover study that assessed the effects of smoking cannabis in 38 patients with central or peripheral neuropathic pain. Participants were assigned to smoke either high- or low-dose cannabis (7% or 3.5% delta-9-THC) or placebo cigarettes. Cigarettes were smoked during treatment sessions using the following regimen: 2 puffs at 60 minutes from baseline, 3 puffs at 120 minutes, and 4 puffs at 180 minutes. Patients were assessed after each set of puffs and for 2 hours afterwards. The primary outcome was spontaneous relief of pain as measured by a visual analog scale.
Pain intensity was comparable and significantly reduced in both treatment groups compared with placebo. At the high dose, some participants experienced neurocognitive impairment in attention, learning, memory, and psychomotor speed; only learning and memory declined at the low dose.
Ellis et al, 2009: Pain reduction in HIV neuropathy
Ellis et al23 conducted a double-blind, placebo-controlled crossover trial in patients with HIV neuropathy that was unresponsive to at least 2 analgesics with different modes of action. During each treatment week, participants were randomly assigned to smoke either active cannabis or placebo, while continuing their standard therapy. Titration started at 4% THC and was adjusted based on tolerability and efficacy. Twenty-eight of the 34 enrolled patients completed both cannabis and placebo treatments. The principal outcome was change in pain intensity from baseline at the end of each week, using the Descriptor Differential Scale of Pain Intensity.
Of the 28 patients, 46% achieved an average pain reduction of 3.3 points (30%). One patient experienced cannabis-induced psychosis, and another developed an intractable cough, which resolved with smoking cessation.
Ware et al, 2010: Reduced posttraumatic or postsurgical neuropathic pain
Ware et al24 performed a randomized crossover trial in 21 patients with posttraumatic or postsurgical neuropathic pain. Participants inhaled 4 different formulations of cannabis (containing 0%, 2.5%, 6.0%, and 9.4% THC) during 4 14-day periods. They inhaled a 25-mg dose through a pipe 3 times a day for the first 5 days of each cycle, followed by a 9-day washout period. Daily average pain intensity was measured using a numeric rating scale. The investigators also assessed mood, sleep, quality of life, and adverse effects.
Patients in the 9.4% THC group reported significantly less pain and better sleep, with average pain scores decreasing from 6.1 to 5.4 on an 11-point scale. Although the benefit was modest, the authors noted that the pain had been refractory to standard treatments.
The number of reported adverse events increased with greater potency and were most commonly throat irritation, burning sensation, headache, dizziness, and fatigue. This study suggests that THC potency affects tolerability, with higher doses eliciting clinically important adverse effects, some of which may reduce the ability to perform activities of daily living, such as driving.
Wilsey et al, 2013: Use in resistant neuropathic pain
Wilsey et al26 conducted another double-blind, placebo-controlled crossover study assessing the effect of vaporized cannabis on central and peripheral neuropathic pain resistant to first-line pharmacotherapies. Dose-effect relationships were explored using medium-dose (3.5%), low-dose (1.3%), and placebo cannabis. The primary outcome measure was a 30% reduction in pain intensity based on a visual analog scale.
In the placebo group, 26% of patients achieved this vs 57% of the low-dose cannabis group and 61% of those receiving the medium dose. No significant difference was found between the 2 active doses in reducing neuropathic pain, and both were more effective than placebo. The number needed to treat to achieve a 30% reduction in pain was about 3 for both cannabis groups compared with placebo. Psychoactive effects were minimal, of short duration, and reversible.
Wallace et al, 2015: Use in diabetic peripheral neuropathy
Wallace et al27 conducted a randomized, double-blind, placebo-controlled crossover study evaluating cannabis for diabetic peripheral neuropathy in 16 patients. Each had experienced at least 6 months of neuropathic pain in their feet. The participants inhaled a single dose of 1%, 4%, or 7% THC cannabis or placebo. Spontaneous pain was reported with a visual analog scale and also tested with a foam brush and von Frey filament at intervals until 4 hours after treatment.
Pain scores were lower with treatment compared with placebo, with high-dose cannabis having the greatest analgesic effect. Pain reduction lasted for the full duration of the test. Cannabis recipients had declines in attention and working memory, with the high-dose group experiencing the greatest impact 15 minutes after treatment. High-dose recipients also had poorer scores on testing of quick task-switching, with the greatest effect at 2 hours.27
Research and market cannabis are not equal
Results of US studies must be qualified. Most have used cannabis provided by the National Institute of Drug Abuse (NIDA),23–26 which differs in potency from commercially available preparations. This limits the clinical usefulness of the analysis of benefits and risks.
Vergara et al28 found that NIDA varieties contained much lower THC levels and as much as 23 times the cannabinol content as cannabis in state-legalized markets.
Studies based on NIDA varieties likely underestimate the risks of consumer-purchased cannabis, as THC is believed to be most responsible for the risk of psychosis and impaired driving and cognition.24,28
CBD MAY PROTECT AGAINST ADVERSE EFFECTS
Studies of CBD alone are limited to preclinical data.29 Evidence suggests that CBD alone or combined with THC can suppress chronic neuropathic pain, and that CBD may have a protective effect after nerve injury.30
Nabiximols, an oromucosal spray preparation with equal amounts of THC and CBD, has been approved in Canada as well as in European countries including the United Kingdom. Although its use has not been associated with many of the adverse effects of inhaled cannabis,30–32 evidence of efficacy from clinical trials has been mixed.
Lynch et al,31 in a 2014 randomized, double-blind, placebo-controlled crossover pilot study31 evaluated nabiximols in 16 patients with neuropathic pain related to chemotherapy. No statistically significant difference was found between treatment and placebo. However, the trial was underpowered.
Serpell et al,32 in a 2014 European randomized, placebo-controlled parallel-group study, evaluated 246 patients with peripheral neuropathy with allodynia, with 128 receiving active treatment (THC-CBD oromucosal spray) and 118 receiving placebo. Over the 15-week study, participants continued their current analgesic treatments.
Pain was reduced in the treatment group, but the difference from placebo was not statistically significant. However, the treatment group reported significantly better sleep quality and Patient Global Impression of Change measures (reflecting a patient’s belief of treatment efficacy).
META-ANALYSES CONFIRM EFFECT
Three meta-analyses of available studies of the effects of cannabis on neuropathic pain have been completed.
Andreae et al, 2015: 5 trials, 178 patients
Andreae et al1 evaluated 5 randomized controlled trials in 178 patients in North America. All had had neuropathy for at least 3 months, with a pain level of at least about 3 on a scale of 10. Two studies had patients with HIV-related neuropathy; the other 3 involved patients with neuropathy related to trauma, diabetes, complex regional pain syndrome, or spinal cord injury. All trials used whole cannabis plant provided by NIDA, and the main outcomes were patient-reported pain scales. No study evaluated pain beyond 2 weeks after trial termination.
They found that 1 of every 5 to 6 patients treated with cannabis had at least a 30% pain reduction.
Nugent et al, 2017: 13 trials, 246 patients
Nugent et al33 reviewed 13 trials in 246 patients that evaluated the effects of different cannabis-based preparations on either central or peripheral neuropathic pain from various conditions. Actively treated patients were more likely to report a 30% improvement in neuropathic pain. Again, studies tended to be small and brief.
Cochrane review, 2018: 16 trials, 1,750 patients
A Cochrane review34 analyzed 16 trials (in 1,750 patients) lasting 2 to 26 weeks. Treatments included an oromucosal spray with a plant-derived combination of THC and CBD, nabilone, inhaled herbal cannabis, and plant-derived THC.
With cannabis-based treatments, significantly more people achieved 50% or greater pain relief than with placebo (21% vs 17%, number needed to treat 20); 30% pain reduction was achieved in 39% of treated patients vs 33% of patients taking placebo (number needed to treat 11).
On the other hand, significantly more participants withdrew from studies because of adverse events with cannabis-based treatments than placebo (10% vs 5%), with psychiatric disorders occurring in 17% of patients receiving active treatment vs 5% of those receiving placebo (number needed to harm 10).
The primary studies suffered from methodologic limitations including small size, short duration, and inconsistency of formulations and study designs. Further evaluation of long-term efficacy, tolerability, and addiction potential is critical to determine the risk-benefit ratio.
RISKS OF CANNABIS USE
Like any drug therapy, cannabis has effects that may limit its use. Cannabis can affect a person’s psyche, physiology, and lifestyle.
Impaired attention, task speed
Neurocognitive changes associated with cannabis use—especially dizziness, fatigue, and slowed task-switching—could affect driving and other complex tasks. Evidence indicates that such activities should be avoided in the hours after treatment.26,27,32,33
Concern over brain development
Most worrisome is the effect of long-term cannabis use on brain development in young adults. Regular use of cannabis at an early age is associated with lower IQ, decline in school performance, and lower rates of high school graduation.35
Avoid in psychiatric patients
It is unlikely that cannabis can be safely used in patients with psychiatric illnesses. Anxiety, depression, and psychotic disorders can be exacerbated by the regular use of cannabis, and the risk of developing these conditions is increased while using cannabis.36,37
High concentrations of THC (the highest concentration used in the above studies was 9.5%) can cause anxiety, paranoia, and psychosis.
Respiratory effects
Long-term cannabis smoking may cause wheezing, cough, dyspnea, and exacerbations of chronic bronchitis. There is some evidence that symptoms improve after stopping smoking.33,38
SHOULD WE RECOMMEND CANNABIS?
Where cannabis can be legally used, doctors should be familiar with the literature and its limitations so that they can counsel patients on the best use and potential risks and benefits of cannabis treatment.
A recent conceptualization of pain suggests that a pain score reflects a composite of sensory factors (eg, tissue damage), cognitive factors (eg, beliefs about pain), and affective factors (eg, anxiety, depression).39 Physicians should keep this in mind when evaluating patients to better assess the risks and benefits of cannabis. While pharmacotherapy may address sensory factors, cognitive behavioral therapy may help alter beliefs about the pain as well as anxiety and depressive symptoms that might influence subjective reports.
Ideally, patients being considered for cannabis treatment would have a type of neuropathic pain proven to respond to cannabis in randomized, controlled studies, as well as evidence of failed first-line treatments.
Relative contraindications include depression, anxiety, substance use, psychotic disorders, and respiratory conditions, and these should also be considered.
Although current research shows an analgesic benefit of cannabis on neuropathic pain comparable to that of gabapentin,40 further investigation is needed to better evaluate long-term safety, efficacy, and interactions with standard therapies. Until we have a more complete picture, we should use the current literature, along with a thorough knowledge of each patient, to determine if the benefits of cannabis therapy outweigh the risks.
Acknowledgments: We thank Camillo Ferrari, BS, and Christina McMahon, BA, for their helpful comments.
- Andreae MH, Carter GM, Shaparin N, et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. J Pain 2015; 16(12):1221–1232. doi:10.1016/j.jpain.2015.07.009
- National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet. www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet. Accessed November 14, 2018.
- Mold JW, Vesely SK, Keyl BA, Schenk JB, Roberts M. The prevalence, predictors, and consequences of peripheral sensory neuropathy in older adults. J Am Board Fam Med 2004; 17(5):308–318. doi:10.3122/jabfm.17.5.309
- Bansal D, Gudala K, Muthyala H, Esam HP, Nayakallu R, Bhansali A. Prevalence and risk factors of developing peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig 2014; 5(6):714–721. doi:10.1111/jdi.12223
- Finnerup NB, Haroutounian S, Kamerman P, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain 2016; 157(8):1599–1606. doi:10.1097/j.pain.0000000000000492
- Maldonado R, Banos JE, Cabanero D. The endocannabinoid system and neuropathic pain. Pain 2016; 157(suppl 1):S23–S32. doi:10.1097/j.pain.0000000000000428
- Zeng L, Alongkronrusmee D, van Rijn RM. An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US. J Pain Res 2017; 10:219–228. doi:10.2147/JPR.S125987
- Callaghan BC, Price RS, Feldman EL. Distal symmetric polyneuropathy: a review. JAMA 2015; 314(20):2172–2181. doi:10.1001/jama.2015.13611
- Adams AS, Callaghan B, Grant RW. Overcoming barriers to diabetic polyneuropathy management in primary care. Healthc (Amst) 2017; 5(4):171–173. doi:10.1016/j.hjdsi.2016.10.003
- Gwak YS, Kim HY, Lee BH, Yang CH. Combined approaches for the relief of spinal cord injury-induced neuropathic pain. Complement Ther Med 2016; 25:27–33. doi:10.1016/j.ctim.2015.12.021
- Majithia N, Loprinzi CL, Smith TJ. New practical approaches to chemotherapy-induced neuropathic pain: prevention, assessment, and treatment. Oncology 2016; 30(11):1020–1029. pmid:27854104
- Grotenhermen F. Cannabinoids and the endocannabinoid system. Cannabinoids 2006; 1(1):10–14.
- Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA 2015; 313(24):2474–2483. doi:10.1001/jama.2015.6199
- Campos AC, Fogaça MV, Scarante FF, et al. Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front Pharmacol 2017; 8:269. doi:10.3389/fphar.2017.00269
- Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163(7):1344–1364. doi:10.1111/j.1476-5381.2011.01238.x
- Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA. Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr Neurosci 2017; Jul 7: 1–20. doi:10.1080/1028415X.2017.1347373
- Hillard CJ. Circulating endocannabinoids: from whence do they come and where are they going? Neuropsychopharmacology 2018; 43(1):155–172. doi:10.1038/npp.2017.130
- Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 1991; 11(2):563–583. pmid:1992016
- Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience1998; 83(2):393–411. pmid:9460749
- Russo EB, Hohmann AG. Role of cannabinoids in pain management. In: Deer TR, Leong MS, ed. Comprehensve Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. New York, NY: Springer; 2013:181–193.
- Vranken JH. Elucidation of pathophysiology and treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem 2012; 12(4):304–314. pmid:23033930
- Yamanaka H, Noguchi K. Pathophysiology of neuropathic pain: molecular mechanisms underlying central sensitization in the dorsal horn in neuropathic pain. Brain Nerve 2012; 64(11):1255–1265. Japanese. pmid:23131736
- Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34(3):672–680. doi:10.1038/npp.2008.120
- Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010; 182(14):E694–E701. doi:10.1503/cmaj.091414
- Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008; 9(6):506–521. doi:10.1016/j.jpain.2007.12.010
- Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013; 14(2):136–148. doi:10.1016/j.jpain.2012.10.009
- Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 2015; 16(7):616–627. doi:10.1016/j.jpain.2015.03.008
- Vergara D, Bidwell LC, Gaudino R, et al. Compromised external validity: federally produced cannabis does not reflect legal markets. Scientific Reports. 2017; 7(1):1-8. doi:10.1038/srep46528
- Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterized by allodynia: a randomized, double-blind, placebo-controlled clinical trial. Pain 2007; 133(1–3):210–220. doi:10.1016/j.pain.2007.08.028
- Philpott HT, O’Brien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain 2017; 158(12):2442–2451. doi:10.1097/j.pain.0000000000001052
- Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 2014; 47(1):166–173. doi:10.1016/j.jpainsymman.2013.02.018
- Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain 2014; 18(7):999–1012. doi:10.1002/j.1532-2149.2013.00445.x
- Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review. Ann Intern Med 2017; 167(5):319–331. doi:10.7326/M17-0155
- Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018; 3:CD012182. doi:10.1002/14651858.CD012182.pub2
- Castellanos-Ryan N, Pingault JB, Parent S, Vitaro F, Tremblay RE, Seguin JR. Adolescent cannabis use, change in neurocognitive function, and high-school graduation: a longitudinal study from early adolescence to young adulthood. Dev Psychopathol 2017; 29(4):1253–1266. doi:10.1017/S0954579416001280
- Karila L, Roux P, Benyamina A, et al. Acute and long-term effects of cannabis use: a review. Curr Pharm Des 2014; 20(25):4112–4118. pmid:24001294
- Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001; 178:116–122. pmid:11157424
- National Academies of Science, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC: The National Academy Press; 2017. doi:10.17226/24625
- Modesto-Lowe V, Griard L, Chaplin M. Cancer pain in the opioid-addicted patient: can we treat it right? J Opioid Manag 2012; 8(3):167–175. doi:10.5055/jom.2012.0113
- Grant I. Medicinal cannabis and painful sensory neuropathy. Virtual Mentor 2013; 15(5):466–469. doi:10.1001/virtualmentor.2013.15.5.oped1-1305
- Andreae MH, Carter GM, Shaparin N, et al. Inhaled cannabis for chronic neuropathic pain: a meta-analysis of individual patient data. J Pain 2015; 16(12):1221–1232. doi:10.1016/j.jpain.2015.07.009
- National Institute of Neurological Disorders and Stroke. Peripheral Neuropathy Fact Sheet. www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Peripheral-Neuropathy-Fact-Sheet. Accessed November 14, 2018.
- Mold JW, Vesely SK, Keyl BA, Schenk JB, Roberts M. The prevalence, predictors, and consequences of peripheral sensory neuropathy in older adults. J Am Board Fam Med 2004; 17(5):308–318. doi:10.3122/jabfm.17.5.309
- Bansal D, Gudala K, Muthyala H, Esam HP, Nayakallu R, Bhansali A. Prevalence and risk factors of developing peripheral diabetic neuropathy in type 2 diabetes mellitus in a tertiary care setting. J Diabetes Investig 2014; 5(6):714–721. doi:10.1111/jdi.12223
- Finnerup NB, Haroutounian S, Kamerman P, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain 2016; 157(8):1599–1606. doi:10.1097/j.pain.0000000000000492
- Maldonado R, Banos JE, Cabanero D. The endocannabinoid system and neuropathic pain. Pain 2016; 157(suppl 1):S23–S32. doi:10.1097/j.pain.0000000000000428
- Zeng L, Alongkronrusmee D, van Rijn RM. An integrated perspective on diabetic, alcoholic, and drug-induced neuropathy, etiology, and treatment in the US. J Pain Res 2017; 10:219–228. doi:10.2147/JPR.S125987
- Callaghan BC, Price RS, Feldman EL. Distal symmetric polyneuropathy: a review. JAMA 2015; 314(20):2172–2181. doi:10.1001/jama.2015.13611
- Adams AS, Callaghan B, Grant RW. Overcoming barriers to diabetic polyneuropathy management in primary care. Healthc (Amst) 2017; 5(4):171–173. doi:10.1016/j.hjdsi.2016.10.003
- Gwak YS, Kim HY, Lee BH, Yang CH. Combined approaches for the relief of spinal cord injury-induced neuropathic pain. Complement Ther Med 2016; 25:27–33. doi:10.1016/j.ctim.2015.12.021
- Majithia N, Loprinzi CL, Smith TJ. New practical approaches to chemotherapy-induced neuropathic pain: prevention, assessment, and treatment. Oncology 2016; 30(11):1020–1029. pmid:27854104
- Grotenhermen F. Cannabinoids and the endocannabinoid system. Cannabinoids 2006; 1(1):10–14.
- Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA 2015; 313(24):2474–2483. doi:10.1001/jama.2015.6199
- Campos AC, Fogaça MV, Scarante FF, et al. Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front Pharmacol 2017; 8:269. doi:10.3389/fphar.2017.00269
- Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011; 163(7):1344–1364. doi:10.1111/j.1476-5381.2011.01238.x
- Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA. Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr Neurosci 2017; Jul 7: 1–20. doi:10.1080/1028415X.2017.1347373
- Hillard CJ. Circulating endocannabinoids: from whence do they come and where are they going? Neuropsychopharmacology 2018; 43(1):155–172. doi:10.1038/npp.2017.130
- Herkenham M, Lynn AB, Johnson MR, Melvin LS, de Costa BR, Rice KC. Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study. J Neurosci 1991; 11(2):563–583. pmid:1992016
- Tsou K, Brown S, Sañudo-Peña MC, Mackie K, Walker JM. Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system. Neuroscience1998; 83(2):393–411. pmid:9460749
- Russo EB, Hohmann AG. Role of cannabinoids in pain management. In: Deer TR, Leong MS, ed. Comprehensve Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches. New York, NY: Springer; 2013:181–193.
- Vranken JH. Elucidation of pathophysiology and treatment of neuropathic pain. Cent Nerv Syst Agents Med Chem 2012; 12(4):304–314. pmid:23033930
- Yamanaka H, Noguchi K. Pathophysiology of neuropathic pain: molecular mechanisms underlying central sensitization in the dorsal horn in neuropathic pain. Brain Nerve 2012; 64(11):1255–1265. Japanese. pmid:23131736
- Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34(3):672–680. doi:10.1038/npp.2008.120
- Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ 2010; 182(14):E694–E701. doi:10.1503/cmaj.091414
- Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008; 9(6):506–521. doi:10.1016/j.jpain.2007.12.010
- Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013; 14(2):136–148. doi:10.1016/j.jpain.2012.10.009
- Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 2015; 16(7):616–627. doi:10.1016/j.jpain.2015.03.008
- Vergara D, Bidwell LC, Gaudino R, et al. Compromised external validity: federally produced cannabis does not reflect legal markets. Scientific Reports. 2017; 7(1):1-8. doi:10.1038/srep46528
- Nurmikko TJ, Serpell MG, Hoggart B, Toomey PJ, Morlion BJ, Haines D. Sativex successfully treats neuropathic pain characterized by allodynia: a randomized, double-blind, placebo-controlled clinical trial. Pain 2007; 133(1–3):210–220. doi:10.1016/j.pain.2007.08.028
- Philpott HT, O’Brien M, McDougall JJ. Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis. Pain 2017; 158(12):2442–2451. doi:10.1097/j.pain.0000000000001052
- Lynch ME, Cesar-Rittenberg P, Hohmann AG. A double-blind, placebo-controlled, crossover pilot trial with extension using an oral mucosal cannabinoid extract for treatment of chemotherapy-induced neuropathic pain. J Pain Symptom Manage 2014; 47(1):166–173. doi:10.1016/j.jpainsymman.2013.02.018
- Serpell M, Ratcliffe S, Hovorka J, et al. A double-blind, randomized, placebo-controlled, parallel group study of THC/CBD spray in peripheral neuropathic pain treatment. Eur J Pain 2014; 18(7):999–1012. doi:10.1002/j.1532-2149.2013.00445.x
- Nugent SM, Morasco BJ, O’Neil ME, et al. The effects of cannabis among adults with chronic pain and an overview of general harms: a systematic review. Ann Intern Med 2017; 167(5):319–331. doi:10.7326/M17-0155
- Mücke M, Phillips T, Radbruch L, Petzke F, Häuser W. Cannabis-based medicines for chronic neuropathic pain in adults. Cochrane Database Syst Rev 2018; 3:CD012182. doi:10.1002/14651858.CD012182.pub2
- Castellanos-Ryan N, Pingault JB, Parent S, Vitaro F, Tremblay RE, Seguin JR. Adolescent cannabis use, change in neurocognitive function, and high-school graduation: a longitudinal study from early adolescence to young adulthood. Dev Psychopathol 2017; 29(4):1253–1266. doi:10.1017/S0954579416001280
- Karila L, Roux P, Benyamina A, et al. Acute and long-term effects of cannabis use: a review. Curr Pharm Des 2014; 20(25):4112–4118. pmid:24001294
- Johns A. Psychiatric effects of cannabis. Br J Psychiatry 2001; 178:116–122. pmid:11157424
- National Academies of Science, Engineering, and Medicine. The health effects of cannabis and cannabinoids: the current state of evidence and recommendations for research. Washington, DC: The National Academy Press; 2017. doi:10.17226/24625
- Modesto-Lowe V, Griard L, Chaplin M. Cancer pain in the opioid-addicted patient: can we treat it right? J Opioid Manag 2012; 8(3):167–175. doi:10.5055/jom.2012.0113
- Grant I. Medicinal cannabis and painful sensory neuropathy. Virtual Mentor 2013; 15(5):466–469. doi:10.1001/virtualmentor.2013.15.5.oped1-1305
KEY POINTS
- Small clinical studies have found that cannabis provides benefits for peripheral neuropathy, including pain reduction, better sleep, and improved function, even in patients with symptoms refractory to standard therapies.
- Adverse effects such as throat irritation, headache, and dizziness are common, and serious neuropsychiatric effects can occur at high doses.
- Safety may not be adequately assessed in US trials because cannabis supplied by the National Institute of Drug Abuse is less potent than commercially available products.
Geriatrics update 2018: Challenges in mental health, mobility, and postdischarge care
Unfortunately, recent research has not unveiled a breakthrough for preventing or treating cognitive impairment or Alzheimer disease. But several studies from the last 2 years are helping to drive the field of geriatrics forward, providing evidence of what does and does not help a variety of issues specific to the elderly.
Based on a search of the 2017 and 2018 literature, this article presents new evidence on preventing and treating cognitive impairment, managing dementia-associated behavioral disturbances and delirium, preventing falls, and improving inpatient mobility and posthospital care transitions.
COGNITIVE IMPAIRMENT, DEMENTIA: STILL NO SILVER BULLET
With the exception of oral anticoagulation treatment for atrial fibrillation, there is little evidence that pharmacologic or nonpharmacologic interventions slow the onset or progression of Alzheimer disease.
Nonpharmacologic interventions
Home occupational therapy. A 2-year home-based occupational therapy intervention1 showed no evidence of slowing functional decline in patients with Alzheimer disease. The randomized controlled trial involving 180 participants consisted of monthly sessions of an intensive, well-established collaborative-care management model that included fall prevention and other safety strategies, personalized training in activities of daily living, exercise, and education. Outcome measures for activities of daily living did not differ significantly between the treatment and control groups.1
Physical activity. Whether physical activity interventions slow cognitive decline and prevent dementia in cognitively intact adults was examined in a systematic review of 32 trials.2 Most of the trials followed patients for 6 months; a few stretched for 1 or 2 years.
Evidence was insufficient to prove cognitive benefit for short-term, single-component or multicomponent physical activity interventions. However, a multidomain physical activity intervention that also included dietary modifications and cognitive training did show a delay in cognitive decline, but only “low-strength” evidence.2
Nutritional supplements. The antioxidants vitamin E and selenium were studied for their possible cognitive benefit in the double-blind randomized Prevention of Alzheimer Disease by Vitamin E and Selenium trial3 in 3,786 asymptomatic men ages 60 and older. Neither supplement was found to prevent dementia over a 7-year follow-up period.
A review of 38 trials4 evaluated the effects on cognition of omega-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C, beta-carotene, and multi-ingredient supplements. It found insufficient evidence to recommend any over-the-counter supplement for cognitive protection in adults with normal cognition or mild cognitive impairment.
Pharmacologic treatments
Testosterone supplementation. The Testosterone Trials tested the effects of testosterone gel vs placebo for 1 year on 493 men over age 65 with low testosterone (< 275 ng/mL) and with subjective memory complaints and objective memory performance deficits. Treatment was not associated with improved memory or other cognitive functions compared with placebo.5
Antiamyloid drugs. A randomized, double-blind, placebo-controlled trial in nearly 2,000 patients evaluated verubecestat, an oral beta-site amyloid precursor protein-cleaving enzyme-1 inhibitor that reduces the amyloid-beta level in cerebrospinal fluid.6
Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer disease, while adverse events including rashes, falls, injuries, sleep disturbances, suicidal ideation, weight loss, and hair color change were more common in the treatment groups. The trial was terminated early because of futility at 50 months.
And in a placebo-controlled trial of solanezumab, a monoclonal antibody directed against the amyloid beta peptide, no benefit was demonstrated at 80 weeks in more than 2,000 patients with Alzheimer disease.7
Multiple common agents. A well-conducted systematic review8 of 51 trials of at least a 6-month duration did not support the use of antihypertensive agents, diabetes medications, nonsteroidal anti-inflammatory drugs, aspirin, hormones, or lipid-lowering drugs for cognitive protection for people with normal cognition or mild cognitive impairment.
However, some studies found reassuring evidence that standard therapies for other conditions do not worsen cognitive decline and are protective for atrial fibrillation.8
Proton-pump inhibitors. Concern exists for a potential link between dementia risk and proton-pump inhibitors, which are widely used to treat acid-related gastrointestinal disorders.9
A prospective population-based cohort study10 of nearly 3,500 people ages 65 and older without baseline dementia screened participants for dementia every 2 years over a mean period of 7.5 years and provided further evaluation for those who screened positive. Use of proton-pump inhibitors was not found to be associated with dementia risk, even with high cumulative exposure.
Results from this study do not support avoiding proton-pump inhibitors out of concern for dementia risk, although long-term use is associated with other safety concerns.
Oral anticoagulation. The increased risk of dementia with atrial fibrillation is well documented.11
A retrospective study12 based on a Swedish health registry and using more than 444,000 patients covering more than 1.5 million years at risk found that oral anticoagulant treatment at baseline conferred a 29% lower risk of dementia in an intention-to-treat analysis and a 48% lower risk in on-treatment analysis compared with no oral anticoagulation therapy. No difference was found between new oral anticoagulants and warfarin.
Transcatheter aortic valve implantation is not associated with cognitive decline
For patients with severe aortic stenosis who are not surgical candidates, transcatheter aortic valve implantation is superior to standard medical therapy,13 but there are concerns of neurologic and cognitive changes after the procedure.14 A meta-analysis of 18 studies assessing cognitive performance in more than 1,000 patients (average age ≥ 80) after undergoing the procedure for severe aortic stenosis found no significant cognitive performance changes from baseline perioperatively or 3 or 6 months later.15
TREATING DEMENTIA-ASSOCIATED BEHAVIORAL DISTURBANCES
Behavioral and psychiatric symptoms often accompany dementia, but no drugs have yet been approved by the US Food and Drug Administration (FDA) to address them in this population. Nonpharmacologic interventions are recommended as first-line therapy.
Antipsychotics are not recommended
Antipsychotics are often prescribed,16 although they are associated with metabolic syndrome17 and increased risks of stroke and death.18 The FDA has issued black box warnings against using antipsychotics for behavioral management in patients with dementia. Further, the American Geriatrics Society and the American Psychiatric Association do not endorse using them as initial therapy for behavioral and psychological symptoms of dementia.16,19
The Centers for Medicare and Medicaid Services partnered with nursing homes to improve the quality of care for patients with dementia, with results measured as the rate of prescribing antipsychotic medications. Although the use of psychotropic medications declined after initiating the partnership, the use of mood stabilizers increased, possibly as a substitute for antipsychotics.20
Dextromethorphan-quinidine use is up, despite modest evidence of benefit
A consumer news report in 2017 stated that the use of dextromethorphan-quinidine in long-term care facilities increased by nearly 400% between 2012 and 2016.21
Evidence for its benefits comes from a 10-week, phase 2, randomized controlled trial conducted at 42 US study sites with 194 patients with probable Alzheimer disease. Compared with the placebo group, the active treatment group had mildly reduced agitation but an increased risk of falls, dizziness, and diarrhea. However, rates of adverse effects were low, and the authors concluded that treatment was generally well tolerated.22
Pimavanserin: No long-term benefit for psychosis
In a phase 2, randomized, double-blind, placebo-controlled trial in 181 patients with possible or probable Alzheimer disease and psychotic symptoms, pimavanserin was associated with improved symptoms as measured by the Neuropsychiatric Inventory–Nursing Home Version psychosis score at 6 weeks, but no difference was found compared with placebo at 12 weeks. The treatment group had more adverse events, including agitation, aggression, peripheral edema, anxiety, and symptoms of dementia, although the differences were not statistically significant.23
DELIRIUM: AVOID ANTIPSYCHOTICS
Delirium is common in hospitalized older adults, especially those who have baseline cognitive or functional impairment and are exposed to precipitating factors such as treatment with anticholinergic or narcotic medications, infection, surgery, or admission to an intensive care unit.24
Delirium at discharge predicts poor outcomes
In a prospective study of 152 hospitalized patients with delirium, those who either did not recover from delirium or had only partially recovered at discharge were more likely to visit the emergency department, be rehospitalized, or die during the subsequent 3 months than those who had fully recovered from delirium at discharge.25
Multicomponent, patient-centered approach can help
A randomized trial in 377 patients in Taiwan evaluated the use of a modified Hospital Elder Life Program, consisting of 3 protocols focused on orienting communication, oral and nutritional assistance, and early mobilization. Patients were at least 65 years old and undergoing elective abdominal surgery with expected length of hospital stay longer than 6 days. The program, administered daily during hospitalization, significantly lowered postoperative delirium by 56% and hospital stay by 2 days compared with usual care.26
Prophylactic haloperidol does not improve outcomes
In a multicenter randomized, double-blind, placebo-controlled trial, van den Boogaard et al studied prophylactic intravenous haloperidol in nearly 1,800 critically ill patients at high risk of delirium.27 Haloperidol did not improve survival at 28 days compared with placebo. For secondary outcomes, including delirium incidence, delirium-free and coma-free days, duration of mechanical ventilation, and hospital and intensive care department length of stay, treatment was not found to differ statistically from placebo.
Antipsychotics may worsen delirium
A double-blind, parallel-arm, dose-titrated randomized trial, conducted at 11 Australian hospices or hospitals with palliative care services, administered oral risperidone, haloperidol, or placebo to 247 patients with life-limiting illness and delirium. Both treatment groups had higher delirium symptom scores than the placebo group.28
In addition, a systematic review and meta-analysis of 19 studies found no benefit of antipsychotic medications for preventing or treating delirium in hospitalized adults.29
Antipsychotics are often continued indefinitely
A retrospective chart review at a US academic health system found30 that among 487 patients with a new antipsychotic medication prescribed during hospitalization, 147 (30.2%) were discharged on an antipsychotic. Of these, 121 (82.3%) had a diagnosis of delirium. Only 15 (12.4%) had discharge summaries that included instructions for discontinuing the drug.
Another US health system retrospectively reviewed antipsychotic use and found31 that out of 260 patients who were newly exposed to an antipsychotic drug during hospitalization, 146 (56.2%) were discharged on an antipsychotic drug, and 65% of these patients were still on the drug at the time of the next hospital admission.
EXERCISE, EXERCISE, EXERCISE
Exercise recommended, but not vitamin D, to prevent falls
In 2018, the US Preventive Services Task Force updated its recommendations for preventing falls in community-dwelling older adults.32 Based on the findings of several trials, the task force recommends exercise interventions for adults age 65 and older who are at increased risk for falls. Gait, balance, and functional training were studied in 17 trials, resistance training in 13, flexibility in 8, endurance training in 5, and tai chi in 3, with 5 studies including general physical activity. Exercise interventions most commonly took place for 3 sessions per week for 12 months (range 2–42 months).
The task force also recommends against vitamin D supplementation for fall prevention in community-dwelling adults age 65 or older who are not known to have osteoporosis or vitamin D deficiency.
Early mobilization helps inpatients
Hospitalized older adults usually spend most of their time in bed. Forty-five previously ambulatory patients (age ≥ 65 without dementia or delirium) in a Veterans Affairs hospital were monitored with wireless accelerometers and were found to spend, on average, 83% of the measured hospital stay in bed. Standing or walking time ranged from 0.2% to 21%, with a median of only 3% (43 minutes a day).33
Since falls with injury became a Centers for Medicare and Medicaid Services nonreimbursable hospital-acquired condition, tension has arisen between promoting mobility and preventing falls.34 Two studies evaluating the adoption of mobility-restricting approaches such as bed-alarms, “fall-alert” signs, supervision of patients in the bathroom, and ensuring patients’ walking aids are within reach, did not find a significant reduction in falls or fall-related injuries.35,36
A clinically significant loss of community mobility is common after hospitalization in older adults.37 Older adults who developed mobility impairment during hospitalization had a higher risk of death in a large, retrospective study.38 A large Canadian multisite intervention trial39 that promoted early mobilization in older patients who were admitted to general medical wards resulted in increased mobilization and significantly shorter hospital stays.
POSTHOSPITAL CARE NEEDS IMPROVEMENT
After hospitalization, older adults who have difficulty with activities of daily living or complex medical needs often require continued care.
About 20% of hospitalized Medicare beneficiaries in the United States are discharged to skilled nursing facilities.40 This is often a stressful transition, and most people have little guidance on selecting a facility and simply choose one based on its proximity to home.41
A program of frequent visits by hospital-employed physicians and advanced practice professionals at skilled nursing facilities resulted in a significantly lower 30-day readmission rate compared with nonparticipating skilled nursing facilities in the same geographic area.42
Home healthcare is recommended after hospital discharge at a rapidly increasing rate. Overall referral rates increased from 8.6% to 14.1% between 2001 and 2012, and from 14.3% to 24.0% for patients with heart failure.43 A qualitative study of home healthcare nurses found a need for improved care coordination between home healthcare agencies and discharging hospitals, including defining accountability for orders and enhancing communication.44
- Callahan CM, Boustani MA, Schmid AA, et al. Targeting functional decline in Alzheimer disease: a randomized trial. Ann Intern Med 2017; 166(3):164–171. doi:10.7326/M16-0830
- Brasure M, Desai P, Davila H, et al. Physical activity interventions in preventing cognitive decline and Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):30–38. doi:10.7326/M17-1528
- Kryscio RJ, Abner EL, Caban-Holt A, et al. Association of antioxidant supplement use and dementia in the Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial (PREADViSE). JAMA Neurol 2017; 74(5):567–573. doi:10.1001/jamaneurol.2016.5778
- Butler M, Nelson VA, Davila H, et al. Over-the-counter supplement interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):52–62. doi:10.7326/M17-1530
- Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA 2017; 317(7):717–727. doi:10.1001/jama.2016.21044
- Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 2018; 378(18):1691–1703. doi:10.1056/NEJMoa1706441
- Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018; 378(4):321–330. doi:10.1056/NEJMoa1705971
- Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):39–51. doi:10.7326/M17-1529
- Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol 2016; 73(4):410–416. doi:10.1001/jamaneurol.2015.4791
- Gray SL, Walker RL, Dublin S, et al. Proton pump inhibitor use and dementia risk: prospective population-based study. J Am Geriatr Soc 2018; 66(2):247–253. doi:10.1111/jgs.15073
- de Bruijn RF, Heeringa J, Wolters FJ, et al. Association between atrial fibrillation and dementia in the general population. JAMA Neurol 2015; 72(11):1288–1294. doi:10.1001/jamaneurol.2015.2161
- Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J 2018; 39(6):453–460. doi:10.1093/eurheartj/ehx579
- Leon MB, Smith CR, Mack M, et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010; 363(17):1597–1607. doi:10.1056/NEJMoa1008232
- Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA 2016; 316(6):592–601. doi:10.1001/jama.2016.10302
- Khan MM, Herrmann N, Gallagher D, et al. Cognitive outcomes after transcatheter aortic valve implantation: a metaanalysis. J Am Geriatr Soc 2018; 66(2):254–262. doi:10.1111/jgs.15123
- Choosing Wisely; ABIM Foundation. American Geriatrics Society: ten things physicians and patients should question. www.choosingwisely.org/societies/american-geriatrics-society. Accessed November 6, 2018.
- Lieberman JA 3rd. Metabolic changes associated with antipsychotic use. Prim Care Companion J Clin Psychiatry 2004; 6(suppl 2):8–13. pmid:16001095
- Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294(15):1934–1943. doi:10.1001/jama.294.15.1934
- Choosing Wisely; ABIM Foundation. American Psychiatric Association: five things physicians and patients should question. www.choosingwisely.org/societies/american-psychiatric-association. Accessed November 6, 2018.
- Maust DT, Kim HM, Chiang C, Kales HC. Association of the Centers for Medicare & Medicaid Services’ National Partnership to improve dementia care with the use of antipsychotics and other psychotropics in long-term care in the United States from 2009 to 2014. JAMA Intern Med 2018; 178(5):640–647. doi:10.1001/jamainternmed.2018.0379
- CNN. The little red pill being pushed on the elderly. www.cnn.com/2017/10/12/health/nuedexta-nursing-homes-invs/index.html. Accessed November 6, 2018.
- Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA 2015; 314(12):1242–1254. doi:10.1001/jama.2015.10214
- Ballard C, Banister C, Khan Z, et al; ADP Investigators. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol 2018; 17(3):213–222. doi:10.1016/S1474-4422(18)30039-5
- Inouye SK. Delirium in older persons. N Engl J Med 2006; 354(11):1157–1165. doi:10.1056/NEJMra052321
- Cole MG, McCusker J, Bailey R, et al. Partial and no recovery from delirium after hospital discharge predict increased adverse events. Age Ageing 2017; 46(1):90–95. doi:10.1093/ageing/afw153
- Chen CC, Li HC, Liang JT, et al. Effect of a modified hospital elder life program on delirium and length of hospital stay in patients undergoing abdominal surgery: a cluster randomized clinical trial. JAMA Surg 2017; 152(9):827–834. doi:10.1001/jamasurg.2017.1083
- van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: the REDUCE randomized clinical trial. JAMA 2018; 319(7):680–690. doi:10.1001/jama.2018.0160
- Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med 2017; 177(1):34–42. doi:10.1001/jamainternmed.2016.7491
- Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. J Am Geriatr Soc 2016; 64(4):705–714. doi:10.1111/jgs.14076
- Johnson KG, Fashoyin A, Madden-Fuentes R, Muzyk AJ, Gagliardi JP, Yanamadala M. Discharge plans for geriatric inpatients with delirium: a plan to stop antipsychotics? J Am Geriatr Soc 2017; 65(10):2278–2281. doi:10.1111/jgs.15026
- Loh KP, Ramdass S, Garb JL, et al. Long-term outcomes of elders discharged on antipsychotics. J Hosp Med 2016; 11(8):550–555. doi:10.1002/jhm.2585
- US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Interventions to prevent falls in community-dwelling older adults: US Preventive Services Task Force Recommendation statement. JAMA 2018; 319(16):1696–1704. doi:10.1001/jama.2018.3097
- Brown CJ, Redden DT, Flood KL, Allman RM. The underrecognized epidemic of low mobility during hospitalization of older adults. J Am Geriatr Soc 2009; 57(9):1660–1665. doi:10.1111/j.1532-5415.2009.02393.x
- Growdon ME, Shorr RI, Inouye SK. The tension between promoting mobility and preventing falls in the hospital. JAMA Intern Med 2017; 177(6):759–760. doi:10.1001/jamainternmed.2017.0840
- Barker AL, Morello RT, Wolfe R, et al. 6-PACK programme to decrease fall injuries in acute hospitals: cluster randomised controlled trial. BMJ 2016; 352:h6781. doi:10.1136/bmj.h6781
- Shorr RI, Chandler AM, Mion LC, et al. Effects of an intervention to increase bed alarm use to prevent falls in hospitalized patients: a cluster randomized trial. Ann Intern Med 2012; 157(10):692–699. doi:10.7326/0003-4819-157-10-201211200-00005
- Loyd C, Beasley TM, Miltner RS, Clark D, King B, Brown CJ. Trajectories of community mobility recovery after hospitalization in older adults. J Am Geriatr Soc 2018; 66(7):1399–1403. doi:10.1111/jgs.15397
- Valiani V, Chen Z, Lipori G, Pahor M, Sabbá C, Manini TM. Prognostic value of Braden Activity subscale for mobility status in hospitalized older adults. J Hosp Med 2017; 12(6):396–401. doi:10.12788/jhm.2748
- Liu B, Moore JE, Almaawiy U, et al; MOVE ON Collaboration. Outcomes of mobilisation of vulnerable elders in Ontario (MOVE ON): a multisite interrupted time series evaluation of an implementation intervention to increase patient mobilisation. Age Ageing 2018; 47(1):112–119. doi:10.1093/ageing/afx128
- Report to Congress: Medicare Payment Policy. Medicare Payment Advisory Commission 2016. www.medpac.gov/docs/default-source/reports/march-2016-report-to-the-congress-medicare-payment-policy.pdf?sfvrsn=0. Accessed November 6, 2018.
- Gadbois EA, Tyler DA, Mor V. Selecting a skilled nursing facility for postacute care: individual and family perspectives. J Am Geriatr Soc 2017; 65(11):2459–2465. doi:10.1111/jgs.14988
- Kim LD, Kou L, Hu B, Gorodeski EZ, Rothberg MB. Impact of a connected care model on 30-day readmission rates from skilled nursing facilities. J Hosp Med 2017; 12(4):238–244. doi:10.12788/jhm.2710
- Jones CD, Ginde AA, Burke RE, Wald HL, Masoudi FA, Boxer RS. Increasing home healthcare referrals upon discharge from U.S. hospitals: 2001-2012. J Am Geriatr Soc 2015; 63(6):1265–1266. doi:10.1111/jgs.13467
- Jones CD, Jones J, Richard A, et al. “Connecting the dots”: a qualitative study of home health nurse perspectives on coordinating care for recently discharged patients. J Gen Intern Med 2017; 32(10):1114–1121. doi:10.1007/s11606-017-4104-0
Unfortunately, recent research has not unveiled a breakthrough for preventing or treating cognitive impairment or Alzheimer disease. But several studies from the last 2 years are helping to drive the field of geriatrics forward, providing evidence of what does and does not help a variety of issues specific to the elderly.
Based on a search of the 2017 and 2018 literature, this article presents new evidence on preventing and treating cognitive impairment, managing dementia-associated behavioral disturbances and delirium, preventing falls, and improving inpatient mobility and posthospital care transitions.
COGNITIVE IMPAIRMENT, DEMENTIA: STILL NO SILVER BULLET
With the exception of oral anticoagulation treatment for atrial fibrillation, there is little evidence that pharmacologic or nonpharmacologic interventions slow the onset or progression of Alzheimer disease.
Nonpharmacologic interventions
Home occupational therapy. A 2-year home-based occupational therapy intervention1 showed no evidence of slowing functional decline in patients with Alzheimer disease. The randomized controlled trial involving 180 participants consisted of monthly sessions of an intensive, well-established collaborative-care management model that included fall prevention and other safety strategies, personalized training in activities of daily living, exercise, and education. Outcome measures for activities of daily living did not differ significantly between the treatment and control groups.1
Physical activity. Whether physical activity interventions slow cognitive decline and prevent dementia in cognitively intact adults was examined in a systematic review of 32 trials.2 Most of the trials followed patients for 6 months; a few stretched for 1 or 2 years.
Evidence was insufficient to prove cognitive benefit for short-term, single-component or multicomponent physical activity interventions. However, a multidomain physical activity intervention that also included dietary modifications and cognitive training did show a delay in cognitive decline, but only “low-strength” evidence.2
Nutritional supplements. The antioxidants vitamin E and selenium were studied for their possible cognitive benefit in the double-blind randomized Prevention of Alzheimer Disease by Vitamin E and Selenium trial3 in 3,786 asymptomatic men ages 60 and older. Neither supplement was found to prevent dementia over a 7-year follow-up period.
A review of 38 trials4 evaluated the effects on cognition of omega-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C, beta-carotene, and multi-ingredient supplements. It found insufficient evidence to recommend any over-the-counter supplement for cognitive protection in adults with normal cognition or mild cognitive impairment.
Pharmacologic treatments
Testosterone supplementation. The Testosterone Trials tested the effects of testosterone gel vs placebo for 1 year on 493 men over age 65 with low testosterone (< 275 ng/mL) and with subjective memory complaints and objective memory performance deficits. Treatment was not associated with improved memory or other cognitive functions compared with placebo.5
Antiamyloid drugs. A randomized, double-blind, placebo-controlled trial in nearly 2,000 patients evaluated verubecestat, an oral beta-site amyloid precursor protein-cleaving enzyme-1 inhibitor that reduces the amyloid-beta level in cerebrospinal fluid.6
Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer disease, while adverse events including rashes, falls, injuries, sleep disturbances, suicidal ideation, weight loss, and hair color change were more common in the treatment groups. The trial was terminated early because of futility at 50 months.
And in a placebo-controlled trial of solanezumab, a monoclonal antibody directed against the amyloid beta peptide, no benefit was demonstrated at 80 weeks in more than 2,000 patients with Alzheimer disease.7
Multiple common agents. A well-conducted systematic review8 of 51 trials of at least a 6-month duration did not support the use of antihypertensive agents, diabetes medications, nonsteroidal anti-inflammatory drugs, aspirin, hormones, or lipid-lowering drugs for cognitive protection for people with normal cognition or mild cognitive impairment.
However, some studies found reassuring evidence that standard therapies for other conditions do not worsen cognitive decline and are protective for atrial fibrillation.8
Proton-pump inhibitors. Concern exists for a potential link between dementia risk and proton-pump inhibitors, which are widely used to treat acid-related gastrointestinal disorders.9
A prospective population-based cohort study10 of nearly 3,500 people ages 65 and older without baseline dementia screened participants for dementia every 2 years over a mean period of 7.5 years and provided further evaluation for those who screened positive. Use of proton-pump inhibitors was not found to be associated with dementia risk, even with high cumulative exposure.
Results from this study do not support avoiding proton-pump inhibitors out of concern for dementia risk, although long-term use is associated with other safety concerns.
Oral anticoagulation. The increased risk of dementia with atrial fibrillation is well documented.11
A retrospective study12 based on a Swedish health registry and using more than 444,000 patients covering more than 1.5 million years at risk found that oral anticoagulant treatment at baseline conferred a 29% lower risk of dementia in an intention-to-treat analysis and a 48% lower risk in on-treatment analysis compared with no oral anticoagulation therapy. No difference was found between new oral anticoagulants and warfarin.
Transcatheter aortic valve implantation is not associated with cognitive decline
For patients with severe aortic stenosis who are not surgical candidates, transcatheter aortic valve implantation is superior to standard medical therapy,13 but there are concerns of neurologic and cognitive changes after the procedure.14 A meta-analysis of 18 studies assessing cognitive performance in more than 1,000 patients (average age ≥ 80) after undergoing the procedure for severe aortic stenosis found no significant cognitive performance changes from baseline perioperatively or 3 or 6 months later.15
TREATING DEMENTIA-ASSOCIATED BEHAVIORAL DISTURBANCES
Behavioral and psychiatric symptoms often accompany dementia, but no drugs have yet been approved by the US Food and Drug Administration (FDA) to address them in this population. Nonpharmacologic interventions are recommended as first-line therapy.
Antipsychotics are not recommended
Antipsychotics are often prescribed,16 although they are associated with metabolic syndrome17 and increased risks of stroke and death.18 The FDA has issued black box warnings against using antipsychotics for behavioral management in patients with dementia. Further, the American Geriatrics Society and the American Psychiatric Association do not endorse using them as initial therapy for behavioral and psychological symptoms of dementia.16,19
The Centers for Medicare and Medicaid Services partnered with nursing homes to improve the quality of care for patients with dementia, with results measured as the rate of prescribing antipsychotic medications. Although the use of psychotropic medications declined after initiating the partnership, the use of mood stabilizers increased, possibly as a substitute for antipsychotics.20
Dextromethorphan-quinidine use is up, despite modest evidence of benefit
A consumer news report in 2017 stated that the use of dextromethorphan-quinidine in long-term care facilities increased by nearly 400% between 2012 and 2016.21
Evidence for its benefits comes from a 10-week, phase 2, randomized controlled trial conducted at 42 US study sites with 194 patients with probable Alzheimer disease. Compared with the placebo group, the active treatment group had mildly reduced agitation but an increased risk of falls, dizziness, and diarrhea. However, rates of adverse effects were low, and the authors concluded that treatment was generally well tolerated.22
Pimavanserin: No long-term benefit for psychosis
In a phase 2, randomized, double-blind, placebo-controlled trial in 181 patients with possible or probable Alzheimer disease and psychotic symptoms, pimavanserin was associated with improved symptoms as measured by the Neuropsychiatric Inventory–Nursing Home Version psychosis score at 6 weeks, but no difference was found compared with placebo at 12 weeks. The treatment group had more adverse events, including agitation, aggression, peripheral edema, anxiety, and symptoms of dementia, although the differences were not statistically significant.23
DELIRIUM: AVOID ANTIPSYCHOTICS
Delirium is common in hospitalized older adults, especially those who have baseline cognitive or functional impairment and are exposed to precipitating factors such as treatment with anticholinergic or narcotic medications, infection, surgery, or admission to an intensive care unit.24
Delirium at discharge predicts poor outcomes
In a prospective study of 152 hospitalized patients with delirium, those who either did not recover from delirium or had only partially recovered at discharge were more likely to visit the emergency department, be rehospitalized, or die during the subsequent 3 months than those who had fully recovered from delirium at discharge.25
Multicomponent, patient-centered approach can help
A randomized trial in 377 patients in Taiwan evaluated the use of a modified Hospital Elder Life Program, consisting of 3 protocols focused on orienting communication, oral and nutritional assistance, and early mobilization. Patients were at least 65 years old and undergoing elective abdominal surgery with expected length of hospital stay longer than 6 days. The program, administered daily during hospitalization, significantly lowered postoperative delirium by 56% and hospital stay by 2 days compared with usual care.26
Prophylactic haloperidol does not improve outcomes
In a multicenter randomized, double-blind, placebo-controlled trial, van den Boogaard et al studied prophylactic intravenous haloperidol in nearly 1,800 critically ill patients at high risk of delirium.27 Haloperidol did not improve survival at 28 days compared with placebo. For secondary outcomes, including delirium incidence, delirium-free and coma-free days, duration of mechanical ventilation, and hospital and intensive care department length of stay, treatment was not found to differ statistically from placebo.
Antipsychotics may worsen delirium
A double-blind, parallel-arm, dose-titrated randomized trial, conducted at 11 Australian hospices or hospitals with palliative care services, administered oral risperidone, haloperidol, or placebo to 247 patients with life-limiting illness and delirium. Both treatment groups had higher delirium symptom scores than the placebo group.28
In addition, a systematic review and meta-analysis of 19 studies found no benefit of antipsychotic medications for preventing or treating delirium in hospitalized adults.29
Antipsychotics are often continued indefinitely
A retrospective chart review at a US academic health system found30 that among 487 patients with a new antipsychotic medication prescribed during hospitalization, 147 (30.2%) were discharged on an antipsychotic. Of these, 121 (82.3%) had a diagnosis of delirium. Only 15 (12.4%) had discharge summaries that included instructions for discontinuing the drug.
Another US health system retrospectively reviewed antipsychotic use and found31 that out of 260 patients who were newly exposed to an antipsychotic drug during hospitalization, 146 (56.2%) were discharged on an antipsychotic drug, and 65% of these patients were still on the drug at the time of the next hospital admission.
EXERCISE, EXERCISE, EXERCISE
Exercise recommended, but not vitamin D, to prevent falls
In 2018, the US Preventive Services Task Force updated its recommendations for preventing falls in community-dwelling older adults.32 Based on the findings of several trials, the task force recommends exercise interventions for adults age 65 and older who are at increased risk for falls. Gait, balance, and functional training were studied in 17 trials, resistance training in 13, flexibility in 8, endurance training in 5, and tai chi in 3, with 5 studies including general physical activity. Exercise interventions most commonly took place for 3 sessions per week for 12 months (range 2–42 months).
The task force also recommends against vitamin D supplementation for fall prevention in community-dwelling adults age 65 or older who are not known to have osteoporosis or vitamin D deficiency.
Early mobilization helps inpatients
Hospitalized older adults usually spend most of their time in bed. Forty-five previously ambulatory patients (age ≥ 65 without dementia or delirium) in a Veterans Affairs hospital were monitored with wireless accelerometers and were found to spend, on average, 83% of the measured hospital stay in bed. Standing or walking time ranged from 0.2% to 21%, with a median of only 3% (43 minutes a day).33
Since falls with injury became a Centers for Medicare and Medicaid Services nonreimbursable hospital-acquired condition, tension has arisen between promoting mobility and preventing falls.34 Two studies evaluating the adoption of mobility-restricting approaches such as bed-alarms, “fall-alert” signs, supervision of patients in the bathroom, and ensuring patients’ walking aids are within reach, did not find a significant reduction in falls or fall-related injuries.35,36
A clinically significant loss of community mobility is common after hospitalization in older adults.37 Older adults who developed mobility impairment during hospitalization had a higher risk of death in a large, retrospective study.38 A large Canadian multisite intervention trial39 that promoted early mobilization in older patients who were admitted to general medical wards resulted in increased mobilization and significantly shorter hospital stays.
POSTHOSPITAL CARE NEEDS IMPROVEMENT
After hospitalization, older adults who have difficulty with activities of daily living or complex medical needs often require continued care.
About 20% of hospitalized Medicare beneficiaries in the United States are discharged to skilled nursing facilities.40 This is often a stressful transition, and most people have little guidance on selecting a facility and simply choose one based on its proximity to home.41
A program of frequent visits by hospital-employed physicians and advanced practice professionals at skilled nursing facilities resulted in a significantly lower 30-day readmission rate compared with nonparticipating skilled nursing facilities in the same geographic area.42
Home healthcare is recommended after hospital discharge at a rapidly increasing rate. Overall referral rates increased from 8.6% to 14.1% between 2001 and 2012, and from 14.3% to 24.0% for patients with heart failure.43 A qualitative study of home healthcare nurses found a need for improved care coordination between home healthcare agencies and discharging hospitals, including defining accountability for orders and enhancing communication.44
Unfortunately, recent research has not unveiled a breakthrough for preventing or treating cognitive impairment or Alzheimer disease. But several studies from the last 2 years are helping to drive the field of geriatrics forward, providing evidence of what does and does not help a variety of issues specific to the elderly.
Based on a search of the 2017 and 2018 literature, this article presents new evidence on preventing and treating cognitive impairment, managing dementia-associated behavioral disturbances and delirium, preventing falls, and improving inpatient mobility and posthospital care transitions.
COGNITIVE IMPAIRMENT, DEMENTIA: STILL NO SILVER BULLET
With the exception of oral anticoagulation treatment for atrial fibrillation, there is little evidence that pharmacologic or nonpharmacologic interventions slow the onset or progression of Alzheimer disease.
Nonpharmacologic interventions
Home occupational therapy. A 2-year home-based occupational therapy intervention1 showed no evidence of slowing functional decline in patients with Alzheimer disease. The randomized controlled trial involving 180 participants consisted of monthly sessions of an intensive, well-established collaborative-care management model that included fall prevention and other safety strategies, personalized training in activities of daily living, exercise, and education. Outcome measures for activities of daily living did not differ significantly between the treatment and control groups.1
Physical activity. Whether physical activity interventions slow cognitive decline and prevent dementia in cognitively intact adults was examined in a systematic review of 32 trials.2 Most of the trials followed patients for 6 months; a few stretched for 1 or 2 years.
Evidence was insufficient to prove cognitive benefit for short-term, single-component or multicomponent physical activity interventions. However, a multidomain physical activity intervention that also included dietary modifications and cognitive training did show a delay in cognitive decline, but only “low-strength” evidence.2
Nutritional supplements. The antioxidants vitamin E and selenium were studied for their possible cognitive benefit in the double-blind randomized Prevention of Alzheimer Disease by Vitamin E and Selenium trial3 in 3,786 asymptomatic men ages 60 and older. Neither supplement was found to prevent dementia over a 7-year follow-up period.
A review of 38 trials4 evaluated the effects on cognition of omega-3 fatty acids, soy, ginkgo biloba, B vitamins, vitamin D plus calcium, vitamin C, beta-carotene, and multi-ingredient supplements. It found insufficient evidence to recommend any over-the-counter supplement for cognitive protection in adults with normal cognition or mild cognitive impairment.
Pharmacologic treatments
Testosterone supplementation. The Testosterone Trials tested the effects of testosterone gel vs placebo for 1 year on 493 men over age 65 with low testosterone (< 275 ng/mL) and with subjective memory complaints and objective memory performance deficits. Treatment was not associated with improved memory or other cognitive functions compared with placebo.5
Antiamyloid drugs. A randomized, double-blind, placebo-controlled trial in nearly 2,000 patients evaluated verubecestat, an oral beta-site amyloid precursor protein-cleaving enzyme-1 inhibitor that reduces the amyloid-beta level in cerebrospinal fluid.6
Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer disease, while adverse events including rashes, falls, injuries, sleep disturbances, suicidal ideation, weight loss, and hair color change were more common in the treatment groups. The trial was terminated early because of futility at 50 months.
And in a placebo-controlled trial of solanezumab, a monoclonal antibody directed against the amyloid beta peptide, no benefit was demonstrated at 80 weeks in more than 2,000 patients with Alzheimer disease.7
Multiple common agents. A well-conducted systematic review8 of 51 trials of at least a 6-month duration did not support the use of antihypertensive agents, diabetes medications, nonsteroidal anti-inflammatory drugs, aspirin, hormones, or lipid-lowering drugs for cognitive protection for people with normal cognition or mild cognitive impairment.
However, some studies found reassuring evidence that standard therapies for other conditions do not worsen cognitive decline and are protective for atrial fibrillation.8
Proton-pump inhibitors. Concern exists for a potential link between dementia risk and proton-pump inhibitors, which are widely used to treat acid-related gastrointestinal disorders.9
A prospective population-based cohort study10 of nearly 3,500 people ages 65 and older without baseline dementia screened participants for dementia every 2 years over a mean period of 7.5 years and provided further evaluation for those who screened positive. Use of proton-pump inhibitors was not found to be associated with dementia risk, even with high cumulative exposure.
Results from this study do not support avoiding proton-pump inhibitors out of concern for dementia risk, although long-term use is associated with other safety concerns.
Oral anticoagulation. The increased risk of dementia with atrial fibrillation is well documented.11
A retrospective study12 based on a Swedish health registry and using more than 444,000 patients covering more than 1.5 million years at risk found that oral anticoagulant treatment at baseline conferred a 29% lower risk of dementia in an intention-to-treat analysis and a 48% lower risk in on-treatment analysis compared with no oral anticoagulation therapy. No difference was found between new oral anticoagulants and warfarin.
Transcatheter aortic valve implantation is not associated with cognitive decline
For patients with severe aortic stenosis who are not surgical candidates, transcatheter aortic valve implantation is superior to standard medical therapy,13 but there are concerns of neurologic and cognitive changes after the procedure.14 A meta-analysis of 18 studies assessing cognitive performance in more than 1,000 patients (average age ≥ 80) after undergoing the procedure for severe aortic stenosis found no significant cognitive performance changes from baseline perioperatively or 3 or 6 months later.15
TREATING DEMENTIA-ASSOCIATED BEHAVIORAL DISTURBANCES
Behavioral and psychiatric symptoms often accompany dementia, but no drugs have yet been approved by the US Food and Drug Administration (FDA) to address them in this population. Nonpharmacologic interventions are recommended as first-line therapy.
Antipsychotics are not recommended
Antipsychotics are often prescribed,16 although they are associated with metabolic syndrome17 and increased risks of stroke and death.18 The FDA has issued black box warnings against using antipsychotics for behavioral management in patients with dementia. Further, the American Geriatrics Society and the American Psychiatric Association do not endorse using them as initial therapy for behavioral and psychological symptoms of dementia.16,19
The Centers for Medicare and Medicaid Services partnered with nursing homes to improve the quality of care for patients with dementia, with results measured as the rate of prescribing antipsychotic medications. Although the use of psychotropic medications declined after initiating the partnership, the use of mood stabilizers increased, possibly as a substitute for antipsychotics.20
Dextromethorphan-quinidine use is up, despite modest evidence of benefit
A consumer news report in 2017 stated that the use of dextromethorphan-quinidine in long-term care facilities increased by nearly 400% between 2012 and 2016.21
Evidence for its benefits comes from a 10-week, phase 2, randomized controlled trial conducted at 42 US study sites with 194 patients with probable Alzheimer disease. Compared with the placebo group, the active treatment group had mildly reduced agitation but an increased risk of falls, dizziness, and diarrhea. However, rates of adverse effects were low, and the authors concluded that treatment was generally well tolerated.22
Pimavanserin: No long-term benefit for psychosis
In a phase 2, randomized, double-blind, placebo-controlled trial in 181 patients with possible or probable Alzheimer disease and psychotic symptoms, pimavanserin was associated with improved symptoms as measured by the Neuropsychiatric Inventory–Nursing Home Version psychosis score at 6 weeks, but no difference was found compared with placebo at 12 weeks. The treatment group had more adverse events, including agitation, aggression, peripheral edema, anxiety, and symptoms of dementia, although the differences were not statistically significant.23
DELIRIUM: AVOID ANTIPSYCHOTICS
Delirium is common in hospitalized older adults, especially those who have baseline cognitive or functional impairment and are exposed to precipitating factors such as treatment with anticholinergic or narcotic medications, infection, surgery, or admission to an intensive care unit.24
Delirium at discharge predicts poor outcomes
In a prospective study of 152 hospitalized patients with delirium, those who either did not recover from delirium or had only partially recovered at discharge were more likely to visit the emergency department, be rehospitalized, or die during the subsequent 3 months than those who had fully recovered from delirium at discharge.25
Multicomponent, patient-centered approach can help
A randomized trial in 377 patients in Taiwan evaluated the use of a modified Hospital Elder Life Program, consisting of 3 protocols focused on orienting communication, oral and nutritional assistance, and early mobilization. Patients were at least 65 years old and undergoing elective abdominal surgery with expected length of hospital stay longer than 6 days. The program, administered daily during hospitalization, significantly lowered postoperative delirium by 56% and hospital stay by 2 days compared with usual care.26
Prophylactic haloperidol does not improve outcomes
In a multicenter randomized, double-blind, placebo-controlled trial, van den Boogaard et al studied prophylactic intravenous haloperidol in nearly 1,800 critically ill patients at high risk of delirium.27 Haloperidol did not improve survival at 28 days compared with placebo. For secondary outcomes, including delirium incidence, delirium-free and coma-free days, duration of mechanical ventilation, and hospital and intensive care department length of stay, treatment was not found to differ statistically from placebo.
Antipsychotics may worsen delirium
A double-blind, parallel-arm, dose-titrated randomized trial, conducted at 11 Australian hospices or hospitals with palliative care services, administered oral risperidone, haloperidol, or placebo to 247 patients with life-limiting illness and delirium. Both treatment groups had higher delirium symptom scores than the placebo group.28
In addition, a systematic review and meta-analysis of 19 studies found no benefit of antipsychotic medications for preventing or treating delirium in hospitalized adults.29
Antipsychotics are often continued indefinitely
A retrospective chart review at a US academic health system found30 that among 487 patients with a new antipsychotic medication prescribed during hospitalization, 147 (30.2%) were discharged on an antipsychotic. Of these, 121 (82.3%) had a diagnosis of delirium. Only 15 (12.4%) had discharge summaries that included instructions for discontinuing the drug.
Another US health system retrospectively reviewed antipsychotic use and found31 that out of 260 patients who were newly exposed to an antipsychotic drug during hospitalization, 146 (56.2%) were discharged on an antipsychotic drug, and 65% of these patients were still on the drug at the time of the next hospital admission.
EXERCISE, EXERCISE, EXERCISE
Exercise recommended, but not vitamin D, to prevent falls
In 2018, the US Preventive Services Task Force updated its recommendations for preventing falls in community-dwelling older adults.32 Based on the findings of several trials, the task force recommends exercise interventions for adults age 65 and older who are at increased risk for falls. Gait, balance, and functional training were studied in 17 trials, resistance training in 13, flexibility in 8, endurance training in 5, and tai chi in 3, with 5 studies including general physical activity. Exercise interventions most commonly took place for 3 sessions per week for 12 months (range 2–42 months).
The task force also recommends against vitamin D supplementation for fall prevention in community-dwelling adults age 65 or older who are not known to have osteoporosis or vitamin D deficiency.
Early mobilization helps inpatients
Hospitalized older adults usually spend most of their time in bed. Forty-five previously ambulatory patients (age ≥ 65 without dementia or delirium) in a Veterans Affairs hospital were monitored with wireless accelerometers and were found to spend, on average, 83% of the measured hospital stay in bed. Standing or walking time ranged from 0.2% to 21%, with a median of only 3% (43 minutes a day).33
Since falls with injury became a Centers for Medicare and Medicaid Services nonreimbursable hospital-acquired condition, tension has arisen between promoting mobility and preventing falls.34 Two studies evaluating the adoption of mobility-restricting approaches such as bed-alarms, “fall-alert” signs, supervision of patients in the bathroom, and ensuring patients’ walking aids are within reach, did not find a significant reduction in falls or fall-related injuries.35,36
A clinically significant loss of community mobility is common after hospitalization in older adults.37 Older adults who developed mobility impairment during hospitalization had a higher risk of death in a large, retrospective study.38 A large Canadian multisite intervention trial39 that promoted early mobilization in older patients who were admitted to general medical wards resulted in increased mobilization and significantly shorter hospital stays.
POSTHOSPITAL CARE NEEDS IMPROVEMENT
After hospitalization, older adults who have difficulty with activities of daily living or complex medical needs often require continued care.
About 20% of hospitalized Medicare beneficiaries in the United States are discharged to skilled nursing facilities.40 This is often a stressful transition, and most people have little guidance on selecting a facility and simply choose one based on its proximity to home.41
A program of frequent visits by hospital-employed physicians and advanced practice professionals at skilled nursing facilities resulted in a significantly lower 30-day readmission rate compared with nonparticipating skilled nursing facilities in the same geographic area.42
Home healthcare is recommended after hospital discharge at a rapidly increasing rate. Overall referral rates increased from 8.6% to 14.1% between 2001 and 2012, and from 14.3% to 24.0% for patients with heart failure.43 A qualitative study of home healthcare nurses found a need for improved care coordination between home healthcare agencies and discharging hospitals, including defining accountability for orders and enhancing communication.44
- Callahan CM, Boustani MA, Schmid AA, et al. Targeting functional decline in Alzheimer disease: a randomized trial. Ann Intern Med 2017; 166(3):164–171. doi:10.7326/M16-0830
- Brasure M, Desai P, Davila H, et al. Physical activity interventions in preventing cognitive decline and Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):30–38. doi:10.7326/M17-1528
- Kryscio RJ, Abner EL, Caban-Holt A, et al. Association of antioxidant supplement use and dementia in the Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial (PREADViSE). JAMA Neurol 2017; 74(5):567–573. doi:10.1001/jamaneurol.2016.5778
- Butler M, Nelson VA, Davila H, et al. Over-the-counter supplement interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):52–62. doi:10.7326/M17-1530
- Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA 2017; 317(7):717–727. doi:10.1001/jama.2016.21044
- Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 2018; 378(18):1691–1703. doi:10.1056/NEJMoa1706441
- Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018; 378(4):321–330. doi:10.1056/NEJMoa1705971
- Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):39–51. doi:10.7326/M17-1529
- Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol 2016; 73(4):410–416. doi:10.1001/jamaneurol.2015.4791
- Gray SL, Walker RL, Dublin S, et al. Proton pump inhibitor use and dementia risk: prospective population-based study. J Am Geriatr Soc 2018; 66(2):247–253. doi:10.1111/jgs.15073
- de Bruijn RF, Heeringa J, Wolters FJ, et al. Association between atrial fibrillation and dementia in the general population. JAMA Neurol 2015; 72(11):1288–1294. doi:10.1001/jamaneurol.2015.2161
- Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J 2018; 39(6):453–460. doi:10.1093/eurheartj/ehx579
- Leon MB, Smith CR, Mack M, et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010; 363(17):1597–1607. doi:10.1056/NEJMoa1008232
- Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA 2016; 316(6):592–601. doi:10.1001/jama.2016.10302
- Khan MM, Herrmann N, Gallagher D, et al. Cognitive outcomes after transcatheter aortic valve implantation: a metaanalysis. J Am Geriatr Soc 2018; 66(2):254–262. doi:10.1111/jgs.15123
- Choosing Wisely; ABIM Foundation. American Geriatrics Society: ten things physicians and patients should question. www.choosingwisely.org/societies/american-geriatrics-society. Accessed November 6, 2018.
- Lieberman JA 3rd. Metabolic changes associated with antipsychotic use. Prim Care Companion J Clin Psychiatry 2004; 6(suppl 2):8–13. pmid:16001095
- Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294(15):1934–1943. doi:10.1001/jama.294.15.1934
- Choosing Wisely; ABIM Foundation. American Psychiatric Association: five things physicians and patients should question. www.choosingwisely.org/societies/american-psychiatric-association. Accessed November 6, 2018.
- Maust DT, Kim HM, Chiang C, Kales HC. Association of the Centers for Medicare & Medicaid Services’ National Partnership to improve dementia care with the use of antipsychotics and other psychotropics in long-term care in the United States from 2009 to 2014. JAMA Intern Med 2018; 178(5):640–647. doi:10.1001/jamainternmed.2018.0379
- CNN. The little red pill being pushed on the elderly. www.cnn.com/2017/10/12/health/nuedexta-nursing-homes-invs/index.html. Accessed November 6, 2018.
- Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA 2015; 314(12):1242–1254. doi:10.1001/jama.2015.10214
- Ballard C, Banister C, Khan Z, et al; ADP Investigators. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol 2018; 17(3):213–222. doi:10.1016/S1474-4422(18)30039-5
- Inouye SK. Delirium in older persons. N Engl J Med 2006; 354(11):1157–1165. doi:10.1056/NEJMra052321
- Cole MG, McCusker J, Bailey R, et al. Partial and no recovery from delirium after hospital discharge predict increased adverse events. Age Ageing 2017; 46(1):90–95. doi:10.1093/ageing/afw153
- Chen CC, Li HC, Liang JT, et al. Effect of a modified hospital elder life program on delirium and length of hospital stay in patients undergoing abdominal surgery: a cluster randomized clinical trial. JAMA Surg 2017; 152(9):827–834. doi:10.1001/jamasurg.2017.1083
- van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: the REDUCE randomized clinical trial. JAMA 2018; 319(7):680–690. doi:10.1001/jama.2018.0160
- Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med 2017; 177(1):34–42. doi:10.1001/jamainternmed.2016.7491
- Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. J Am Geriatr Soc 2016; 64(4):705–714. doi:10.1111/jgs.14076
- Johnson KG, Fashoyin A, Madden-Fuentes R, Muzyk AJ, Gagliardi JP, Yanamadala M. Discharge plans for geriatric inpatients with delirium: a plan to stop antipsychotics? J Am Geriatr Soc 2017; 65(10):2278–2281. doi:10.1111/jgs.15026
- Loh KP, Ramdass S, Garb JL, et al. Long-term outcomes of elders discharged on antipsychotics. J Hosp Med 2016; 11(8):550–555. doi:10.1002/jhm.2585
- US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Interventions to prevent falls in community-dwelling older adults: US Preventive Services Task Force Recommendation statement. JAMA 2018; 319(16):1696–1704. doi:10.1001/jama.2018.3097
- Brown CJ, Redden DT, Flood KL, Allman RM. The underrecognized epidemic of low mobility during hospitalization of older adults. J Am Geriatr Soc 2009; 57(9):1660–1665. doi:10.1111/j.1532-5415.2009.02393.x
- Growdon ME, Shorr RI, Inouye SK. The tension between promoting mobility and preventing falls in the hospital. JAMA Intern Med 2017; 177(6):759–760. doi:10.1001/jamainternmed.2017.0840
- Barker AL, Morello RT, Wolfe R, et al. 6-PACK programme to decrease fall injuries in acute hospitals: cluster randomised controlled trial. BMJ 2016; 352:h6781. doi:10.1136/bmj.h6781
- Shorr RI, Chandler AM, Mion LC, et al. Effects of an intervention to increase bed alarm use to prevent falls in hospitalized patients: a cluster randomized trial. Ann Intern Med 2012; 157(10):692–699. doi:10.7326/0003-4819-157-10-201211200-00005
- Loyd C, Beasley TM, Miltner RS, Clark D, King B, Brown CJ. Trajectories of community mobility recovery after hospitalization in older adults. J Am Geriatr Soc 2018; 66(7):1399–1403. doi:10.1111/jgs.15397
- Valiani V, Chen Z, Lipori G, Pahor M, Sabbá C, Manini TM. Prognostic value of Braden Activity subscale for mobility status in hospitalized older adults. J Hosp Med 2017; 12(6):396–401. doi:10.12788/jhm.2748
- Liu B, Moore JE, Almaawiy U, et al; MOVE ON Collaboration. Outcomes of mobilisation of vulnerable elders in Ontario (MOVE ON): a multisite interrupted time series evaluation of an implementation intervention to increase patient mobilisation. Age Ageing 2018; 47(1):112–119. doi:10.1093/ageing/afx128
- Report to Congress: Medicare Payment Policy. Medicare Payment Advisory Commission 2016. www.medpac.gov/docs/default-source/reports/march-2016-report-to-the-congress-medicare-payment-policy.pdf?sfvrsn=0. Accessed November 6, 2018.
- Gadbois EA, Tyler DA, Mor V. Selecting a skilled nursing facility for postacute care: individual and family perspectives. J Am Geriatr Soc 2017; 65(11):2459–2465. doi:10.1111/jgs.14988
- Kim LD, Kou L, Hu B, Gorodeski EZ, Rothberg MB. Impact of a connected care model on 30-day readmission rates from skilled nursing facilities. J Hosp Med 2017; 12(4):238–244. doi:10.12788/jhm.2710
- Jones CD, Ginde AA, Burke RE, Wald HL, Masoudi FA, Boxer RS. Increasing home healthcare referrals upon discharge from U.S. hospitals: 2001-2012. J Am Geriatr Soc 2015; 63(6):1265–1266. doi:10.1111/jgs.13467
- Jones CD, Jones J, Richard A, et al. “Connecting the dots”: a qualitative study of home health nurse perspectives on coordinating care for recently discharged patients. J Gen Intern Med 2017; 32(10):1114–1121. doi:10.1007/s11606-017-4104-0
- Callahan CM, Boustani MA, Schmid AA, et al. Targeting functional decline in Alzheimer disease: a randomized trial. Ann Intern Med 2017; 166(3):164–171. doi:10.7326/M16-0830
- Brasure M, Desai P, Davila H, et al. Physical activity interventions in preventing cognitive decline and Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):30–38. doi:10.7326/M17-1528
- Kryscio RJ, Abner EL, Caban-Holt A, et al. Association of antioxidant supplement use and dementia in the Prevention of Alzheimer’s Disease by Vitamin E and Selenium Trial (PREADViSE). JAMA Neurol 2017; 74(5):567–573. doi:10.1001/jamaneurol.2016.5778
- Butler M, Nelson VA, Davila H, et al. Over-the-counter supplement interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):52–62. doi:10.7326/M17-1530
- Resnick SM, Matsumoto AM, Stephens-Shields AJ, et al. Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment. JAMA 2017; 317(7):717–727. doi:10.1001/jama.2016.21044
- Egan MF, Kost J, Tariot PN, et al. Randomized trial of verubecestat for mild-to-moderate Alzheimer’s disease. N Engl J Med 2018; 378(18):1691–1703. doi:10.1056/NEJMoa1706441
- Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018; 378(4):321–330. doi:10.1056/NEJMoa1705971
- Fink HA, Jutkowitz E, McCarten JR, et al. Pharmacologic interventions to prevent cognitive decline, mild cognitive impairment, and clinical Alzheimer-type dementia: a systematic review. Ann Intern Med 2018; 168(1):39–51. doi:10.7326/M17-1529
- Gomm W, von Holt K, Thomé F, et al. Association of proton pump inhibitors with risk of dementia: a pharmacoepidemiological claims data analysis. JAMA Neurol 2016; 73(4):410–416. doi:10.1001/jamaneurol.2015.4791
- Gray SL, Walker RL, Dublin S, et al. Proton pump inhibitor use and dementia risk: prospective population-based study. J Am Geriatr Soc 2018; 66(2):247–253. doi:10.1111/jgs.15073
- de Bruijn RF, Heeringa J, Wolters FJ, et al. Association between atrial fibrillation and dementia in the general population. JAMA Neurol 2015; 72(11):1288–1294. doi:10.1001/jamaneurol.2015.2161
- Friberg L, Rosenqvist M. Less dementia with oral anticoagulation in atrial fibrillation. Eur Heart J 2018; 39(6):453–460. doi:10.1093/eurheartj/ehx579
- Leon MB, Smith CR, Mack M, et al; PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 2010; 363(17):1597–1607. doi:10.1056/NEJMoa1008232
- Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA 2016; 316(6):592–601. doi:10.1001/jama.2016.10302
- Khan MM, Herrmann N, Gallagher D, et al. Cognitive outcomes after transcatheter aortic valve implantation: a metaanalysis. J Am Geriatr Soc 2018; 66(2):254–262. doi:10.1111/jgs.15123
- Choosing Wisely; ABIM Foundation. American Geriatrics Society: ten things physicians and patients should question. www.choosingwisely.org/societies/american-geriatrics-society. Accessed November 6, 2018.
- Lieberman JA 3rd. Metabolic changes associated with antipsychotic use. Prim Care Companion J Clin Psychiatry 2004; 6(suppl 2):8–13. pmid:16001095
- Schneider LS, Dagerman KS, Insel P. Risk of death with atypical antipsychotic drug treatment for dementia: meta-analysis of randomized placebo-controlled trials. JAMA 2005; 294(15):1934–1943. doi:10.1001/jama.294.15.1934
- Choosing Wisely; ABIM Foundation. American Psychiatric Association: five things physicians and patients should question. www.choosingwisely.org/societies/american-psychiatric-association. Accessed November 6, 2018.
- Maust DT, Kim HM, Chiang C, Kales HC. Association of the Centers for Medicare & Medicaid Services’ National Partnership to improve dementia care with the use of antipsychotics and other psychotropics in long-term care in the United States from 2009 to 2014. JAMA Intern Med 2018; 178(5):640–647. doi:10.1001/jamainternmed.2018.0379
- CNN. The little red pill being pushed on the elderly. www.cnn.com/2017/10/12/health/nuedexta-nursing-homes-invs/index.html. Accessed November 6, 2018.
- Cummings JL, Lyketsos CG, Peskind ER, et al. Effect of dextromethorphan-quinidine on agitation in patients with Alzheimer disease dementia: a randomized clinical trial. JAMA 2015; 314(12):1242–1254. doi:10.1001/jama.2015.10214
- Ballard C, Banister C, Khan Z, et al; ADP Investigators. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with Alzheimer’s disease psychosis: a phase 2, randomised, placebo-controlled, double-blind study. Lancet Neurol 2018; 17(3):213–222. doi:10.1016/S1474-4422(18)30039-5
- Inouye SK. Delirium in older persons. N Engl J Med 2006; 354(11):1157–1165. doi:10.1056/NEJMra052321
- Cole MG, McCusker J, Bailey R, et al. Partial and no recovery from delirium after hospital discharge predict increased adverse events. Age Ageing 2017; 46(1):90–95. doi:10.1093/ageing/afw153
- Chen CC, Li HC, Liang JT, et al. Effect of a modified hospital elder life program on delirium and length of hospital stay in patients undergoing abdominal surgery: a cluster randomized clinical trial. JAMA Surg 2017; 152(9):827–834. doi:10.1001/jamasurg.2017.1083
- van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of haloperidol on survival among critically ill adults with a high risk of delirium: the REDUCE randomized clinical trial. JAMA 2018; 319(7):680–690. doi:10.1001/jama.2018.0160
- Agar MR, Lawlor PG, Quinn S, et al. Efficacy of oral risperidone, haloperidol, or placebo for symptoms of delirium among patients in palliative care: a randomized clinical trial. JAMA Intern Med 2017; 177(1):34–42. doi:10.1001/jamainternmed.2016.7491
- Neufeld KJ, Yue J, Robinson TN, Inouye SK, Needham DM. Antipsychotic medication for prevention and treatment of delirium in hospitalized adults: a systematic review and meta-analysis. J Am Geriatr Soc 2016; 64(4):705–714. doi:10.1111/jgs.14076
- Johnson KG, Fashoyin A, Madden-Fuentes R, Muzyk AJ, Gagliardi JP, Yanamadala M. Discharge plans for geriatric inpatients with delirium: a plan to stop antipsychotics? J Am Geriatr Soc 2017; 65(10):2278–2281. doi:10.1111/jgs.15026
- Loh KP, Ramdass S, Garb JL, et al. Long-term outcomes of elders discharged on antipsychotics. J Hosp Med 2016; 11(8):550–555. doi:10.1002/jhm.2585
- US Preventive Services Task Force; Grossman DC, Curry SJ, Owens DK, et al. Interventions to prevent falls in community-dwelling older adults: US Preventive Services Task Force Recommendation statement. JAMA 2018; 319(16):1696–1704. doi:10.1001/jama.2018.3097
- Brown CJ, Redden DT, Flood KL, Allman RM. The underrecognized epidemic of low mobility during hospitalization of older adults. J Am Geriatr Soc 2009; 57(9):1660–1665. doi:10.1111/j.1532-5415.2009.02393.x
- Growdon ME, Shorr RI, Inouye SK. The tension between promoting mobility and preventing falls in the hospital. JAMA Intern Med 2017; 177(6):759–760. doi:10.1001/jamainternmed.2017.0840
- Barker AL, Morello RT, Wolfe R, et al. 6-PACK programme to decrease fall injuries in acute hospitals: cluster randomised controlled trial. BMJ 2016; 352:h6781. doi:10.1136/bmj.h6781
- Shorr RI, Chandler AM, Mion LC, et al. Effects of an intervention to increase bed alarm use to prevent falls in hospitalized patients: a cluster randomized trial. Ann Intern Med 2012; 157(10):692–699. doi:10.7326/0003-4819-157-10-201211200-00005
- Loyd C, Beasley TM, Miltner RS, Clark D, King B, Brown CJ. Trajectories of community mobility recovery after hospitalization in older adults. J Am Geriatr Soc 2018; 66(7):1399–1403. doi:10.1111/jgs.15397
- Valiani V, Chen Z, Lipori G, Pahor M, Sabbá C, Manini TM. Prognostic value of Braden Activity subscale for mobility status in hospitalized older adults. J Hosp Med 2017; 12(6):396–401. doi:10.12788/jhm.2748
- Liu B, Moore JE, Almaawiy U, et al; MOVE ON Collaboration. Outcomes of mobilisation of vulnerable elders in Ontario (MOVE ON): a multisite interrupted time series evaluation of an implementation intervention to increase patient mobilisation. Age Ageing 2018; 47(1):112–119. doi:10.1093/ageing/afx128
- Report to Congress: Medicare Payment Policy. Medicare Payment Advisory Commission 2016. www.medpac.gov/docs/default-source/reports/march-2016-report-to-the-congress-medicare-payment-policy.pdf?sfvrsn=0. Accessed November 6, 2018.
- Gadbois EA, Tyler DA, Mor V. Selecting a skilled nursing facility for postacute care: individual and family perspectives. J Am Geriatr Soc 2017; 65(11):2459–2465. doi:10.1111/jgs.14988
- Kim LD, Kou L, Hu B, Gorodeski EZ, Rothberg MB. Impact of a connected care model on 30-day readmission rates from skilled nursing facilities. J Hosp Med 2017; 12(4):238–244. doi:10.12788/jhm.2710
- Jones CD, Ginde AA, Burke RE, Wald HL, Masoudi FA, Boxer RS. Increasing home healthcare referrals upon discharge from U.S. hospitals: 2001-2012. J Am Geriatr Soc 2015; 63(6):1265–1266. doi:10.1111/jgs.13467
- Jones CD, Jones J, Richard A, et al. “Connecting the dots”: a qualitative study of home health nurse perspectives on coordinating care for recently discharged patients. J Gen Intern Med 2017; 32(10):1114–1121. doi:10.1007/s11606-017-4104-0
KEY POINTS
- Oral anticoagulant treatment for atrial fibrillation helps preserve cognitive function.
- Antipsychotics are not recommended as initial therapy for dementia-associated behavioral disturbances or for hospitalization-induced delirium.
- A multicomponent inpatient program can help prevent postoperative delirium in hospitalized patients.
- The US Preventive Services Task Force recommends exercise to prevent falls.
- Early mobility should be encouraged for hospitalized patients.
- Better continuity of care between hospitals and skilled nursing facilities can reduce hospital readmission rates.
Narcolepsy: Diagnosis and management
Narcolepsy was originally described in the late 1800s by the French physician Jean-Baptiste-Edouard Gélineau, who reported the case of a wine merchant suffering from somnolence. In this first description, he coined the term narcolepsie by joining the Greek words narke (numbness or stupor) and lepsis (attack).1
Since then, the disorder has been further characterized, and some insight into its biological underpinnings has been established. Importantly, treatments have improved and expanded, facilitating its management and thereby improving quality of life for those with the disorder.
This review focuses on clinically relevant features of the disorder and proposes management strategies.
CLINICAL FEATURES
Narcolepsy is characterized by instability of sleep-wake transitions.
Daytime sleepiness
Clinically, narcolepsy manifests with excessive daytime sleepiness that can be personally and socially disabling. Cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations can also be present,2,3 but they are not necessary for diagnosis. In fact, a minority of patients with narcolepsy have all these symptoms.4 Narcolepsy is divided into type 1 (with cataplexy) and type 2 (without cataplexy).2
Sleepiness tends to be worse with inactivity, and sleep can often be irresistible. Sleep attacks can come on suddenly and may be brief enough to manifest as a lapse in consciousness.
Short naps tend to be refreshing. Rapid eye movement (REM) latency—the interval between falling asleep and the onset of the REM sleep—is short in narcolepsy, and since the REM stage is when dreaming occurs, naps often include dreaming. Therefore, when taking a history, it is worthwhile to ask patients whether they dream during naps; a yes answer supports the diagnosis of narcolepsy.5
In children, sleepiness can manifest in reduced concentration and behavioral issues.6 Napping after age 5 or 6 is considered abnormal and may reflect pathologic sleepiness.7
Cataplexy
Cataplexy—transient muscle weakness triggered by emotion—is a specific feature of narcolepsy type 1. It often begins in the facial muscles and can manifest with slackening of the jaw or brief dropping of the head. However, episodes can be more dramatic and, if the trunk and limb muscles are affected, can result in collapsing to the ground.
Cataplexy usually has its onset at about the same time as the sleepiness associated with narcolepsy, but it can arise even years later.8 Episodes can last from a few seconds to 2 minutes. Consciousness is always preserved. A range of emotions can trigger cataplexy, but typically the emotion is a positive one such as laughter or excitement.9 Deep tendon reflexes disappear in cataplexy, so checking reflexes during a witnessed episode can be clinically valuable.2
Cataplexy can worsen with stress and insufficient sleep, occasionally with “status cataplecticus,” in which repeated, persistent episodes of cataplexy occur over several hours.8 Status cataplecticus can be spontaneous or an effect of withdrawal from anticataplectic medications.2
Cataplexy is thought to represent intrusion of REM sleep and its associated muscle atonia during wakefulness.
Sleep paralysis, hallucinations
Sleep paralysis and hallucinations are other features of narcolepsy that reflect this REM dissociation from sleep.
Sleep paralysis occurs most commonly upon awakening, but sometimes just before sleep onset. In most cases, it is manifested by inability to move the limbs or speak, lasting several seconds or, in rare cases, minutes at a time. Sleep paralysis can be associated with a sensation of fear or suffocation, especially when initially experienced.8
Hypnopompic hallucinations, occurring upon awakening, are more common than hypnagogic hallucinations, which are experienced before falling asleep. The hallucinations are often vivid and usually visual, although other types of hallucinations are possible. Unlike those that occur in psychotic disorders, the hallucinations tend to be associated with preserved insight that they are not real.10
Notably, both sleep paralysis and hallucinations are nonspecific symptoms that are common in the general population.8,11,12
Fragmented sleep
Although they are very sleepy, people with narcolepsy generally cannot stay asleep for very long. Their sleep tends to be extremely fragmented, and they often wake up several times a night.2
This sleep pattern reflects the inherent instability of sleep-wake transitions in narcolepsy. In fact, over a 24-hour period, adults with narcolepsy have a normal amount of sleep.13 In children, however, when narcolepsy first arises, the 24-hour sleep time can increase abruptly and can sometimes be associated with persistent cataplexy that can manifest as a clumsy gait.14
Weight gain, obstructive sleep apnea
Weight gain is common, particularly after symptom onset, and especially in children. As a result, obesity is a frequent comorbidity.15 Because obstructive sleep apnea can consequently develop, all patients with narcolepsy require screening for sleep-disordered breathing.
Other sleep disorders often accompany narcolepsy and are more common than in the general population.16 In a study incorporating both clinical and polysomnographic data of 100 patients with narcolepsy, insomnia was the most common comorbid sleep disorder, with a prevalence of 28%; others were REM sleep behavior disorder (24%), restless legs syndrome (24%), obstructive sleep apnea (21%), and non-REM parasomnias.17
PSYCHOSOCIAL CONSEQUENCES
Narcolepsy has significant psychosocial consequences. As a result of their symptoms, people with narcolepsy may not be able to meet academic or work-related demands.
Additionally, their risk of a motor vehicle accident is 3 to 4 times higher than in the general population, and more than one-third of patients have been in an accident due to sleepiness.18 There is some evidence to show that treatment eliminates this risk.19
Few systematic studies have examined mood disorders in narcolepsy. However, studies tend to show a higher prevalence of psychiatric disorders than in the general population, with depression and anxiety the most com-mon.20,21
DIAGNOSIS IS OFTEN DELAYED
The prevalence of narcolepsy type 1 is between 25 and 100 per 100,000 people.22 In a Mayo Clinic study,23 the incidence of narcolepsy type 1 was estimated to be 0.74 per 100,000 person-years. Epidemiologic data on narcolepsy type 2 are sparse, but patients with narcolepsy without cataplexy are thought to represent only 36% of all narcolepsy patients.23
Diagnosis is often delayed, with the average time between the onset of symptoms and the diagnosis ranging from 8 to 22 years. With increasing awareness, the efficiency of the diagnostic process is improving, and this delay is expected to lessen accordingly.24
Symptoms most commonly arise in the second decade; but the age at onset ranges significantly, between the first and fifth decades. Narcolepsy has a bimodal distribution in incidence, with the biggest peak at approximately age 15 and second smaller peak in the mid-30s. Some studies have suggested a slight male predominance.23,25
DIAGNOSIS
History is key
The history should include specific questions about the hallmark features of narcolepsy, including cataplexy, sleep paralysis, and sleep-related hallucinations. For individual assessment of subjective sleepiness, the Epworth Sleepiness Scale or Pediatric Daytime Sleepiness Scale can be administered quickly in the office setting.26,27
The Epworth score is calculated from the self-rated likelihood of falling asleep in 8 different situations, with possible scores of 0 (would never doze) to 3 (high chance of dozing) on each question, for a total possible score of 0 to 24. Normal total scores are between 0 and 10, while scores greater than 10 reflect pathologic sleepiness. Scores on the Epworth Sleepiness Scale in those with narcolepsy tend to reflect moderate to severe sleepiness, or at least 13, as opposed to patients with obstructive sleep apnea, whose scores commonly reflect milder sleepiness.28
Testing with actigraphy and polysomnography
It is imperative to rule out insufficient sleep and other sleep disorders as a cause of daytime sleepiness. This can be done with a careful clinical history, actigraphy with sleep logs, and polysomnography.
In the 2 to 4 weeks before actigraphy and subsequent testing, all medications with alerting or sedating properties (including antidepressants) should be tapered off to prevent influence on the results of the study.
Delayed sleep-phase disorder presents at a similar age as narcolepsy and can be associated with similar degrees of sleepiness. However, individuals with delayed sleep phase disorder have an inappropriately timed sleep-wake cycle so that there is a shift in their desired sleep onset and awakening times. It is common—prevalence estimates vary but average about 1% in the general population.29
Insufficient sleep syndrome is even more common, especially in teenagers and young adults, with increasing family, social, and academic demands. Sleep needs vary across the life span. A teenager needs 8 to 10 hours of sleep per night, and a young adult needs 7 to 9 hours. A study of 1,285 high school students found that 10.4% were not getting enough sleep.30
If actigraphy data suggest a circadian rhythm disorder or insufficient sleep that could explain the symptoms of sleepiness, then further testing should be halted and these specific issues should be addressed. In these cases, working with the patient toward maintaining a regular sleep-wake schedule with 7 to 8 hours of nightly sleep will often resolve symptoms.
If actigraphy demonstrates the patient is maintaining a regular sleep schedule and allowing adequate time for nightly sleep, the next step is polysomnography.
Polysomnography is performed to detect other disorders that can disrupt sleep, such as sleep-disordered breathing or periodic limb movement disorder.2,5 In addition, polysomnography can provide assurance that adequate sleep was obtained prior to the next step in testing.
Multiple sleep latency test
If sufficient sleep is obtained on polysomnograpy (at least 6 hours for an adult) and no other sleep disorder is identified, a multiple sleep latency test is performed. A urine toxicology screen is typically performed on the day of the test to ensure that drugs are not affecting the results.
The multiple sleep latency test consists of 4 to 5 nap opportunities at 2-hour intervals in a quiet dark room conducive to sleep, during which both sleep and REM latency are recorded. The sleep latency of those with narcolepsy is significantly shortened, and the diagnosis of narcolepsy requires an average sleep latency of less than 8 minutes.
Given the propensity for REM sleep in narcolepsy, another essential feature for diagnosis is the sleep-onset REM period (SOREMP). A SOREMP is defined as a REM latency of less than 15 minutes. A diagnosis of narcolepsy re-quires a SOREMP in at least 2 of the naps in a multiple sleep latency test (or 1 nap if the shortened REM latency is seen during polysomnography).31
The multiple sleep latency test has an imperfect sensitivity, though, and should be repeated when there is a high suspicion of narcolepsy.32–34 It is not completely specific either, and false-positive results occur. In fact, SOREMPs can be seen in the general population, particularly in those with a circadian rhythm disorder, insufficient sleep, or sleep-disordered breathing. Two or more SOREMPs in an multiple sleep latency test can be seen in a small proportion of the general population.35 The results of a multiple sleep latency test should be interpreted in the clinical context.
Differential diagnosis
Narcolepsy type 1 is distinguished from type 2 by the presence of cataplexy. A cerebrospinal fluid hypocretin 1 level of 110 pg/mL or less, or less than one-third of the mean value obtained in normal individuals, can substitute for the multiple sleep latency test in diagnosing narcolepsy type 1.31 Currently, hypocretin testing is generally not performed in clinical practice, although it may become a routine part of the narcolepsy evaluation in the future.
Thus, according to the International Classification of Sleep Disorders, 3rd edition,31 the diagnosis of narcolepsy type 1 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder, and at least 1 of the following:
- Cataplexy and mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing (1 of which can be on the preceding night’s polysomography)
- Cerebrospinal fluid hypocretin 1 levels less than 110 pg/mL or one-third the baseline normal levels and mean sleep latency ≤ 8 minutes with ≥ 2 SOREMPs on multiple sleep latency testing.
Similarly, the diagnosis of narcolepsy type 2 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder, plus:
- Mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing.
Idiopathic hypersomnia, another disorder of central hypersomnolence, is also characterized by disabling sleepiness. It is diagnostically differentiated from narcolepsy, as there are fewer than 2 SOREMPs. As opposed to narcolepsy, in which naps tend to be refreshing, even prolonged naps in idiopathic hypersomnia are often not helpful in restoring wakefulness. In idiopathic hypersomnia, sleep is usually not fragmented, and there are few nocturnal arousals. Sleep times can often be prolonged as well, whereas in narcolepsy total sleep time through the day may not be increased but is not consolidated.
Kleine-Levin syndrome is a rarer disorder of hypersomnia. It is episodic compared with the relatively persistent sleepiness in narcolepsy and idiopathic hypersomnia. Periods of hypersomnia occur intermittently for days to weeks and are accompanied by cognitive and behavioral changes including hyperphagia and hypersexuality.4
LINKED TO HYPOCRETIN DEFICIENCY
Over the past 2 decades, the underlying pathophysiology of narcolepsy type 1 has been better characterized.
Narcolepsy type 1 has been linked to a deficiency in hypocretin in the central nervous system.36 Hypocretin (also known as orexin) is a hormone produced in the hypothalamus that acts on multiple brain regions and maintains alertness. For unclear reasons, hypothalamic neurons producing hypocretin are selectively reduced in narcolepsy type 1. Hypocretin also stabilizes wakefulness and inhibits REM sleep; therefore, hypocretin deficiency can lead to inappropriate intrusions of REM sleep onto wakefulness, leading to the hallmark features of narcolepsy—cataplexy, sleep-related hallucinations, and sleep paralysis.37 According to one theory, cataplexy is triggered by emotional stimuli because of a pathway between the medial prefrontal cortex and the amygdala to the pons.38
Cerebrospinal fluid levels of hypocretin in patients with narcolepsy type 2 tend to be normal, and the biologic underpinnings of narcolepsy type 2 remain mysterious. However, in the subgroup of those with narcolepsy type 2 in which hypocretin is low, many individuals go on to develop cataplexy, thereby evolving to narcolepsy type 1.36
POSSIBLE AUTOIMMUNE BASIS
Narcolepsy is typically a sporadic disorder, although familial cases have been described. The risk of a parent with narcolepsy having a child who is affected is approximately 1%.5
Narcolepsy type 1 is strongly associated with HLA-DQB1*0602, with up to 95% of those affected having at least one allele.39 Having 2 copies of the allele further increases the risk of developing narcolepsy.40 However, this allele is far from specific for narcolepsy with cataplexy, as it occurs in 12% to 38% of the general population.41 Therefore, HLA typing currently has limited clinical utility. The exact cause is as yet unknown, but substantial literature proposes an autoimmune basis of the disorder, given the strong association with the HLA subtype.42–44
After the 2009 H1N1 influenza pandemic, there was a significant increase in the incidence of narcolepsy with cataplexy, which again sparked interest in an autoimmune etiology underlying the disorder. Pandemrix, an H1N1 vaccine produced as a result of the 2009 pandemic, appeared to also be associated with an increase in the incidence of narcolepsy. An association with other upper respiratory infections has also been noted, further supporting a possible autoimmune basis.
A few studies have looked for serum autoantibodies involved in the pathogenesis of narcolepsy. Thus far, only one has been identified, an antibody to Tribbles homolog 2, found in 20% to 40% of those with new onset of nar-colepsy.42–44
TREATMENTS FOR DAYTIME SLEEPINESS
As with many chronic disorders, the treatment of narcolepsy consists of symptomatic rather than curative management, which can be done through both pharmacologic and nonpharmacologic means.
Nondrug measures
Scheduled naps lasting 15 to 20 minutes can help improve alertness.45 A consistent sleep schedule with good sleep hygiene, ensuring sufficient nightly sleep, is also important. In one study, the combination of scheduled naps and regular nocturnal sleep times reduced the level of daytime sleepiness and unintentional daytime sleep. Daytime naps were most helpful for those with the highest degree of daytime sleepiness.45
Strategic use of caffeine can be helpful and can reduce dependence on pharmacologic treatment.
Screening should be performed routinely for other sleep disorders, such as sleep-disordered breathing, which should be treated if identified.5,18 When being treated for other medical conditions, individuals with narcolepsy should avoid medications that can cause sedation, such as opiates or barbiturates; alcohol should be minimized or avoided.
Networking with other individuals with narcolepsy through support groups such as Narcolepsy Network can be valuable for learning coping skills and connecting with community resources. Psychological counseling for the patient, and sometimes the family, can also be useful. School-age children may need special accommodations such as schedule adjustments to allow for scheduled naps or frequent breaks to maintain alertness.
People with narcolepsy tend to function better in careers that do not require long periods of sitting, as sleepiness tends to be worse, but instead offer flexibility and require higher levels of activity that tend to combat sleepiness. They should not work as commercial drivers.18
Medications
While behavioral interventions in narcolepsy are vital, they are rarely sufficient, and drugs that promote daytime wakefulness are used as an adjunct (Table 2).46
Realistic expectations should be established when starting, as some degree of residual sleepiness usually remains even with optimal medical therapy. Medications should be strategically scheduled to maximize alertness during necessary times such as at work or school or during driving. Patients should specifically be counseled to avoid driving if sleepy.18,47
Modafinil is often used as a first-line therapy, given its favorable side-effect profile and low potential for abuse. Its pharmacologic action has been debated but it probably acts as a selective dopamine reuptake inhibitor. It is typically taken twice daily (upon waking and early afternoon) and is usually well tolerated.
Potential side effects include headache, nausea, dry mouth, anorexia, diarrhea, and, rarely, Stevens-Johnson syndrome. Cardiovascular side effects are minimal, making it a favorable choice in older patients.18,48
A trial in 283 patients showed significantly lower levels of sleepiness in patients taking modafinil 200 mg or 400 mg than in a control group. Other trials have supported these findings and showed improved driving performance on modafinil.18
Notably, modafinil can increase the metabolism of oral contraceptives, thereby reducing their efficacy. Women of childbearing age should be warned about this interaction and should be transitioned to nonhormonal forms of contraception.2,47
Armodafinil, a purified R-isomer of modafinil, has a longer half-life and requires only once-daily dosing.5
If modafinil or armodafinil fails to optimally manage daytime sleepiness, a traditional stimulant such as methylphenidate or an amphetamine is often used.
Methylphenidate and amphetamines primarily inhibit the reuptake and increase the release of the monoamines, mainly dopamine, and to a lesser degree serotonin and norepinephrine.
These drugs have more significant adverse effects that can involve the cardiovascular system, causing hypertension and arrhythmias. Anorexia, weight loss, and, particularly with high doses, psychosis can occur.49
These drugs should be avoided in patients with a history of significant cardiovascular disease. Before starting stimulant therapy, a thorough cardiovascular examination should be done, often including electrocardiography to ensure there is no baseline arrhythmia.
Patients on these medications should be followed closely to ensure that blood pressure, pulse, and weight are not negatively affected.18,50 Addiction and tolerance can develop with these drugs, and follow-up should include assessment for dependence. Some states may require prescription drug monitoring to ensure the drugs are not being abused or diverted.
Short- and long-acting formulations of both methylphenidate and amphetamines are available, and a long-acting form is often used in conjunction with a short-acting form as needed.18
Addiction and drug-seeking behavior can develop but are unusual in those taking stimulants to treat narcolepsy.49
Follow-up
Residual daytime sleepiness can be measured subjectively through the Epworth Sleepiness Scale on follow-up. If necessary, a maintenance-of-wakefulness test can provide an objective assessment of treatment efficacy.18
As narcolepsy is a chronic disorder, treatment should evolve with time. Most medications that treat narcolepsy are categorized by the US Food and Drug Administration as pregnancy category C, as we do not have adequate studies in human pregnancies to evaluate their effects. When a patient with narcolepsy becomes pregnant, she should be counseled about the risks and benefits of remaining on therapy. Treatment should balance the risks of sleepiness with the potential risks of remaining on medications.50 In the elderly, as cardiovascular comorbidities tend to increase, the risks and benefits of therapy should be routinely reevaluated.
For cataplexy
Sodium oxybate,51–53 the most potent anticataplectic drug, is the sodium salt of gamma hydroxybutyrate, a metabolite of gamma-aminobutyric acid. Sodium oxybate can be prescribed in the United States, Canada, and Europe. The American Academy of Sleep Medicine recommends sodium oxybate for cataplexy, daytime sleepiness, and disrupted sleep based on 3 level-1 studies and 2 level-4 studies.46
Sodium oxybate increases slow-wave sleep, improves sleep continuity, and often helps to mitigate daytime sleepiness. Due to its short half-life, its administration is unusual: the first dose is taken before bedtime and the second dose 2.5 to 4 hours later. Some patients set an alarm clock to take the second dose, while others awaken spontaneously to take the second dose. Most patients find that with adherence to dosing and safety instructions, sodium oxybate can serve as a highly effective form of treatment of both excessive sleepiness and cataplexy and may reduce the need for stimulant-based therapies.
The most common adverse effects are nausea, mood swings, and enuresis. Occasionally, psychosis can result and limit use of the drug. Obstructive sleep apnea can also develop or worsen.52 Because of its high salt content, sodium oxybate should be used with caution in those with heart failure, hypertension, or renal impairment. Its relative, gamma hydroxybutyrate, causes rapid sedation and has been notorious for illegal use as a date rape drug.
In the United States, sodium oxybate is distributed only through a central pharmacy to mitigate potential abuse. Due to this system, the rates of diversion are extremely low, estimated in a postmarketing analysis to be 1 instance per 5,200 patients treated. In the same study, abuse and dependence were both rare as well, about 1 case for every 2,600 and 6,500 patients treated.6,18,52,53
Antidepressants promote the action of norepinephrine and, to a lesser degree, serotonin, thereby suppressing REM sleep.
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is often used as a first-line treatment for cataplexy. Selective serotonin reuptake inhibitors such as fluoxetine are also used with success. Tricyclic antidepressants such as protriptyline or clomipramine are extremely effective for cataplexy, but are rarely used due to their adverse effects.2,47
FUTURE WORK
While our understanding of narcolepsy has advanced, there are still gaps in our knowledge of the disorder—namely, the specific trigger for the loss of hypocretin neurons in type 1 narcolepsy and the underlying pathophysiology of type 2.
A number of emerging therapies target the hypocretin system, including peptide replacement, neuronal transplant, and immunotherapy preventing hypocretin neuronal cell death.50,54,55 Additional drugs designed to improve alertness that do not involve the hypocretin system are also being developed, including a histamine inverse agonist.50,56 Sodium oxybate and modafinil, although currently approved for use in adults, are still off-label in pediatric practice. Studies of the safety and efficacy of these medications in children are needed.7,57
- Gélineau J. De la narcolepsie. Gazette des Hôpitaux Civils et Militaires 1880; part a, 53:626–628, part b, 54:635–637.
- Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007; 369(9560):499–511. doi:10.1016/S0140-6736(07)60237-2
- Scammell TE. Clinical features and diagnosis of narcolepsy in adults. In: Eichler AF, ed. UpToDate. Waltham, MA: UpToDate; 2018. www.uptodate.com. Accessed October 31, 2018.
- Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 2004; 5(1):37–41. pmid:14725825
- Scammell TE. Narcolepsy. N Engl J Med 2015; 373(27):2654–2662. doi:10.1056/NEJMra1500587
- Babiker MO, Prasad M. Narcolepsy in children: a diagnostic and management approach. Pediatr Neurol 2015; 52(6):557–565. doi:10.1016/j.pediatrneurol.2015.02.020
- Kotagal S. Narcolepsy in children. In: UpToDate, Eichler AF, ed. UpToDate, Waltham, MA. www.uptodate.com. Accessed October 31, 2018.
- Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003; 53(2):154–166. doi:10.1002/ana.10444
- Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Lammers GJ. The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med 2011; 12(1):12–18. doi:10.1016/j.sleep.2010.05.010
- Plazzi G, Fabbri C, Pizza F, Serretti A. Schizophrenia-like symptoms in narcolepsy type 1: shared and distinctive clinical characteristics. Neuropsychobiology 2015; 71(4):218–224. doi:10.1159/000432400
- Ohayon MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 2000; 97(2-3):153–164. pmid:11166087
- Sharpless BA, Barber JP. Lifetime prevalence rates of sleep paralysis: a systematic review. Sleep Med Rev 2011;5(5):311–315. doi:10.1016/j.smrv.2011.01.007
- Broughton R, Dunham W, Newman J, Lutley K, Duschesne P, Rivers M. Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched controls. Electroencephalogr Clin Neurophysiol 1988; 70(6):473–481. pmid:2461281
- Pizza F, Franceschini C, Peltola H, et al. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain 2013; 136(pt 12):3787–3795. doi:10.1093/brain/awt277
- Kotagal S, Krahn LE, Slocumb N. A putative link between childhood narcolepsy and obesity. Sleep Med 2004; 5(2):147–150. doi:10.1016/j.sleep.2003.10.006
- Pizza F, Tartarotti S, Poryazova R, Baumann CR, Bassetti CL. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur Neurol 2013; 70(1-2):22–26. doi:10.1159/000348719
- Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the Innsbruck narcolepsy cohort. J Clin Sleep Med 2013; 9(8):805–812. doi:10.5664/jcsm.2926
- Scammell TE. Treatment of narcolepsy in adults. In: Eichler AF, ed. UpToDate, Waltham, MA. www.uptodate.com. Accessed October 31, 2018.
- Pizza F, Jaussent I, Lopez R, et al. Car crashes and central disorders of hypersomnolence: a French study. PLoS One 2015; 10(6):e0129386. doi:10.1371/journal.pone.0129386
- Fortuyn HD, Lappenschaar MA, Furer JW, et al. Anxiety and mood disorders in narcolepsy: a case-control study. Gen Hosp Psychiatry 2010; 32(1):49–56. doi:10.1016/j.genhosppsych.2009.08.007
- Ruoff CM, Reaven NL, Funk SE, et al. High rates of psychiatric comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study of 9,312 patients in the United States. J Clin Psychiatry 2017; 78(2):171–176. doi:10.4088/JCP.15m10262
- Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007; 30(1):13–26. pmid:17310860
- Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 2002; 25(2):197–202. pmid:11902429
- Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med 2014; 15(5):502–507. doi:10.1016/j.sleep.2014.01.015
- Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001; 57(11):2029–2033. pmid:11739821
- Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14(6):540–545. pmid:1798888
- Drake C, Nickel C, Burduvali E, Roth T, Jefferson C, Badia P. The pediatric daytime sleepiness scale (PDSS): sleep habits and school outcomes in middle-school children. Sleep 2003; 26(4):455–458. pmid:12841372
- van der Heide A, van Schie MK, Lammers GJ, et al. Comparing treatment effect measurements in narcolepsy: the sustained attention to response task, Epworth sleepiness scale and maintenance of wakefulness test. Sleep 2015; 38(7):1051–1058. doi:10.5665/sleep.4810
- Nesbitt AD. Delayed sleep-wake phase disorder. J Thorac Dis 2018; 10(suppl 1):S103–S111. doi:10.21037/jtd.2018.01.11
- Pallesen S, Saxvig IW, Molde H, Sørensen E, Wilhelmsen-Langeland A, Bjorvatn B. Brief report: behaviorally induced insufficient sleep syndrome in older adolescents: prevalence and correlates. J Adolesc 2011; 34(2):391–395. doi:10.1016/j.adolescence.2010.02.005
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Disorders; 2014.
- Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013; 9(8):789–795. doi:10.5664/jcsm.2922
- Andlauer O, Moore H, Jouhier L, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol 2013; 70(7):891–902. doi:10.1001/jamaneurol.2013.1589
- Cairns A, Bogan R. Prevalence and clinical correlates of a short onset REM period (SOREMP) during routine PSG. Sleep 2015; 38(10):1575–1581. doi:10.5665/sleep.5050
- Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 2006; 129(6):1609–1623. doi:10.1093/brain/awl079
- Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355(9197):39–40. doi:10.1016/S0140-6736(99)05582-8
- Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6(9):991–997. doi:10.1038/79690
- Oishi Y, Williams RH, Agostinelli L, et al. Role of the medial prefrontal cortex in cataplexy. J Neurosci 2013; 33(23):9743–9751. doi:10.1523/JNEUROSCI.0499-13.2013
- Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.. Sleep 1997; 20(11):1012–1020. pmid:9456467
- Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E. HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens 1998; 51(1):96–100. pmid:9459509
- Akintomide GS, Rickards H. Narcolepsy: a review. Neuropsychiatr Dis Treat 2011; 7(1):507–518. doi:10.2147/NDT.S23624
- Mahlios J, De la Herrán-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol 2013; 23(5):767–773. doi:10.1016/j.conb.2013.04.013
- Degn M, Kornum BR. Type 1 narcolepsy: a CD8(+) T cell-mediated disease? Ann N Y Acad Sci 2015;1 351:80–88. doi:10.1111/nyas.12793
- Liblau RS, Vassalli A, Seifinejad A, Tafti M. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol 2015; 14(3):318–328. doi:10.1016/S1474-4422(14)70218-2
- Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001; 24(4):385–391. pmid:11403522
- Morgenthaler TI, Kapur VK, Brown TM, et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007; 30(12):1705–1711. pmid:18246980
- Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics 2012; 9(4):739–752. doi:10.1007/s13311-012-0150-9
- Roth T, Schwartz JR, Hirshkowitz M, Erman MK, Dayno JM, Arora S. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007; 3(6):595–602. pmid:17993041
- Auger RR, Goodman SH, Silber MH, Krahn LE, Pankratz VS, Slocumb NL. Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study. Sleep 2005; 28(6):667–672. pmid:16477952
- Abad VC, Guilleminault C. New developments in the management of narcolepsy. Nat Sci Sleep 2017; 9:39–57. doi:10.2147/NSS.S103467
- Drakatos P, Lykouras D, D’Ancona G, et al. Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice. Sleep Med 2017; 35:80–84. doi:10.1016/j.sleep.2017.03.028
- Mansukhani MP, Kotagal S. Sodium oxybate in the treatment of childhood narcolepsy–cataplexy: a retrospective study. Sleep Med 2012; 13(6):606–610. doi:10.1016/j.sleep.2011.10.032
- Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med 2009; 5(4):365–371. pmid:19968016
- Weinhold SL, Seeck-Hirschner M, Nowak A, Hallschmid M, Göder R, Baier PC. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res 2014; 262:8–13. doi:10.1016/j.bbr.2013.12.045
- Arias-Carrión O, Murillo-Rodriguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One 2014; 9(4):e95342. doi:10.1371/journal.pone.0095342
- Leu-Semenescu S, Nittur N, Golmard JL, Arnulf I. Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review. Sleep Med 2014; 15(6):681–687. doi:10.1016/j.sleep.2014.01.021
- Lecendreux M, Bruni O, Franco P, et al. Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J Sleep Res 2012; 21(4):481–483. doi:10.1111/j.1365-2869.2011.00991.x
Narcolepsy was originally described in the late 1800s by the French physician Jean-Baptiste-Edouard Gélineau, who reported the case of a wine merchant suffering from somnolence. In this first description, he coined the term narcolepsie by joining the Greek words narke (numbness or stupor) and lepsis (attack).1
Since then, the disorder has been further characterized, and some insight into its biological underpinnings has been established. Importantly, treatments have improved and expanded, facilitating its management and thereby improving quality of life for those with the disorder.
This review focuses on clinically relevant features of the disorder and proposes management strategies.
CLINICAL FEATURES
Narcolepsy is characterized by instability of sleep-wake transitions.
Daytime sleepiness
Clinically, narcolepsy manifests with excessive daytime sleepiness that can be personally and socially disabling. Cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations can also be present,2,3 but they are not necessary for diagnosis. In fact, a minority of patients with narcolepsy have all these symptoms.4 Narcolepsy is divided into type 1 (with cataplexy) and type 2 (without cataplexy).2
Sleepiness tends to be worse with inactivity, and sleep can often be irresistible. Sleep attacks can come on suddenly and may be brief enough to manifest as a lapse in consciousness.
Short naps tend to be refreshing. Rapid eye movement (REM) latency—the interval between falling asleep and the onset of the REM sleep—is short in narcolepsy, and since the REM stage is when dreaming occurs, naps often include dreaming. Therefore, when taking a history, it is worthwhile to ask patients whether they dream during naps; a yes answer supports the diagnosis of narcolepsy.5
In children, sleepiness can manifest in reduced concentration and behavioral issues.6 Napping after age 5 or 6 is considered abnormal and may reflect pathologic sleepiness.7
Cataplexy
Cataplexy—transient muscle weakness triggered by emotion—is a specific feature of narcolepsy type 1. It often begins in the facial muscles and can manifest with slackening of the jaw or brief dropping of the head. However, episodes can be more dramatic and, if the trunk and limb muscles are affected, can result in collapsing to the ground.
Cataplexy usually has its onset at about the same time as the sleepiness associated with narcolepsy, but it can arise even years later.8 Episodes can last from a few seconds to 2 minutes. Consciousness is always preserved. A range of emotions can trigger cataplexy, but typically the emotion is a positive one such as laughter or excitement.9 Deep tendon reflexes disappear in cataplexy, so checking reflexes during a witnessed episode can be clinically valuable.2
Cataplexy can worsen with stress and insufficient sleep, occasionally with “status cataplecticus,” in which repeated, persistent episodes of cataplexy occur over several hours.8 Status cataplecticus can be spontaneous or an effect of withdrawal from anticataplectic medications.2
Cataplexy is thought to represent intrusion of REM sleep and its associated muscle atonia during wakefulness.
Sleep paralysis, hallucinations
Sleep paralysis and hallucinations are other features of narcolepsy that reflect this REM dissociation from sleep.
Sleep paralysis occurs most commonly upon awakening, but sometimes just before sleep onset. In most cases, it is manifested by inability to move the limbs or speak, lasting several seconds or, in rare cases, minutes at a time. Sleep paralysis can be associated with a sensation of fear or suffocation, especially when initially experienced.8
Hypnopompic hallucinations, occurring upon awakening, are more common than hypnagogic hallucinations, which are experienced before falling asleep. The hallucinations are often vivid and usually visual, although other types of hallucinations are possible. Unlike those that occur in psychotic disorders, the hallucinations tend to be associated with preserved insight that they are not real.10
Notably, both sleep paralysis and hallucinations are nonspecific symptoms that are common in the general population.8,11,12
Fragmented sleep
Although they are very sleepy, people with narcolepsy generally cannot stay asleep for very long. Their sleep tends to be extremely fragmented, and they often wake up several times a night.2
This sleep pattern reflects the inherent instability of sleep-wake transitions in narcolepsy. In fact, over a 24-hour period, adults with narcolepsy have a normal amount of sleep.13 In children, however, when narcolepsy first arises, the 24-hour sleep time can increase abruptly and can sometimes be associated with persistent cataplexy that can manifest as a clumsy gait.14
Weight gain, obstructive sleep apnea
Weight gain is common, particularly after symptom onset, and especially in children. As a result, obesity is a frequent comorbidity.15 Because obstructive sleep apnea can consequently develop, all patients with narcolepsy require screening for sleep-disordered breathing.
Other sleep disorders often accompany narcolepsy and are more common than in the general population.16 In a study incorporating both clinical and polysomnographic data of 100 patients with narcolepsy, insomnia was the most common comorbid sleep disorder, with a prevalence of 28%; others were REM sleep behavior disorder (24%), restless legs syndrome (24%), obstructive sleep apnea (21%), and non-REM parasomnias.17
PSYCHOSOCIAL CONSEQUENCES
Narcolepsy has significant psychosocial consequences. As a result of their symptoms, people with narcolepsy may not be able to meet academic or work-related demands.
Additionally, their risk of a motor vehicle accident is 3 to 4 times higher than in the general population, and more than one-third of patients have been in an accident due to sleepiness.18 There is some evidence to show that treatment eliminates this risk.19
Few systematic studies have examined mood disorders in narcolepsy. However, studies tend to show a higher prevalence of psychiatric disorders than in the general population, with depression and anxiety the most com-mon.20,21
DIAGNOSIS IS OFTEN DELAYED
The prevalence of narcolepsy type 1 is between 25 and 100 per 100,000 people.22 In a Mayo Clinic study,23 the incidence of narcolepsy type 1 was estimated to be 0.74 per 100,000 person-years. Epidemiologic data on narcolepsy type 2 are sparse, but patients with narcolepsy without cataplexy are thought to represent only 36% of all narcolepsy patients.23
Diagnosis is often delayed, with the average time between the onset of symptoms and the diagnosis ranging from 8 to 22 years. With increasing awareness, the efficiency of the diagnostic process is improving, and this delay is expected to lessen accordingly.24
Symptoms most commonly arise in the second decade; but the age at onset ranges significantly, between the first and fifth decades. Narcolepsy has a bimodal distribution in incidence, with the biggest peak at approximately age 15 and second smaller peak in the mid-30s. Some studies have suggested a slight male predominance.23,25
DIAGNOSIS
History is key
The history should include specific questions about the hallmark features of narcolepsy, including cataplexy, sleep paralysis, and sleep-related hallucinations. For individual assessment of subjective sleepiness, the Epworth Sleepiness Scale or Pediatric Daytime Sleepiness Scale can be administered quickly in the office setting.26,27
The Epworth score is calculated from the self-rated likelihood of falling asleep in 8 different situations, with possible scores of 0 (would never doze) to 3 (high chance of dozing) on each question, for a total possible score of 0 to 24. Normal total scores are between 0 and 10, while scores greater than 10 reflect pathologic sleepiness. Scores on the Epworth Sleepiness Scale in those with narcolepsy tend to reflect moderate to severe sleepiness, or at least 13, as opposed to patients with obstructive sleep apnea, whose scores commonly reflect milder sleepiness.28
Testing with actigraphy and polysomnography
It is imperative to rule out insufficient sleep and other sleep disorders as a cause of daytime sleepiness. This can be done with a careful clinical history, actigraphy with sleep logs, and polysomnography.
In the 2 to 4 weeks before actigraphy and subsequent testing, all medications with alerting or sedating properties (including antidepressants) should be tapered off to prevent influence on the results of the study.
Delayed sleep-phase disorder presents at a similar age as narcolepsy and can be associated with similar degrees of sleepiness. However, individuals with delayed sleep phase disorder have an inappropriately timed sleep-wake cycle so that there is a shift in their desired sleep onset and awakening times. It is common—prevalence estimates vary but average about 1% in the general population.29
Insufficient sleep syndrome is even more common, especially in teenagers and young adults, with increasing family, social, and academic demands. Sleep needs vary across the life span. A teenager needs 8 to 10 hours of sleep per night, and a young adult needs 7 to 9 hours. A study of 1,285 high school students found that 10.4% were not getting enough sleep.30
If actigraphy data suggest a circadian rhythm disorder or insufficient sleep that could explain the symptoms of sleepiness, then further testing should be halted and these specific issues should be addressed. In these cases, working with the patient toward maintaining a regular sleep-wake schedule with 7 to 8 hours of nightly sleep will often resolve symptoms.
If actigraphy demonstrates the patient is maintaining a regular sleep schedule and allowing adequate time for nightly sleep, the next step is polysomnography.
Polysomnography is performed to detect other disorders that can disrupt sleep, such as sleep-disordered breathing or periodic limb movement disorder.2,5 In addition, polysomnography can provide assurance that adequate sleep was obtained prior to the next step in testing.
Multiple sleep latency test
If sufficient sleep is obtained on polysomnograpy (at least 6 hours for an adult) and no other sleep disorder is identified, a multiple sleep latency test is performed. A urine toxicology screen is typically performed on the day of the test to ensure that drugs are not affecting the results.
The multiple sleep latency test consists of 4 to 5 nap opportunities at 2-hour intervals in a quiet dark room conducive to sleep, during which both sleep and REM latency are recorded. The sleep latency of those with narcolepsy is significantly shortened, and the diagnosis of narcolepsy requires an average sleep latency of less than 8 minutes.
Given the propensity for REM sleep in narcolepsy, another essential feature for diagnosis is the sleep-onset REM period (SOREMP). A SOREMP is defined as a REM latency of less than 15 minutes. A diagnosis of narcolepsy re-quires a SOREMP in at least 2 of the naps in a multiple sleep latency test (or 1 nap if the shortened REM latency is seen during polysomnography).31
The multiple sleep latency test has an imperfect sensitivity, though, and should be repeated when there is a high suspicion of narcolepsy.32–34 It is not completely specific either, and false-positive results occur. In fact, SOREMPs can be seen in the general population, particularly in those with a circadian rhythm disorder, insufficient sleep, or sleep-disordered breathing. Two or more SOREMPs in an multiple sleep latency test can be seen in a small proportion of the general population.35 The results of a multiple sleep latency test should be interpreted in the clinical context.
Differential diagnosis
Narcolepsy type 1 is distinguished from type 2 by the presence of cataplexy. A cerebrospinal fluid hypocretin 1 level of 110 pg/mL or less, or less than one-third of the mean value obtained in normal individuals, can substitute for the multiple sleep latency test in diagnosing narcolepsy type 1.31 Currently, hypocretin testing is generally not performed in clinical practice, although it may become a routine part of the narcolepsy evaluation in the future.
Thus, according to the International Classification of Sleep Disorders, 3rd edition,31 the diagnosis of narcolepsy type 1 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder, and at least 1 of the following:
- Cataplexy and mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing (1 of which can be on the preceding night’s polysomography)
- Cerebrospinal fluid hypocretin 1 levels less than 110 pg/mL or one-third the baseline normal levels and mean sleep latency ≤ 8 minutes with ≥ 2 SOREMPs on multiple sleep latency testing.
Similarly, the diagnosis of narcolepsy type 2 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder, plus:
- Mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing.
Idiopathic hypersomnia, another disorder of central hypersomnolence, is also characterized by disabling sleepiness. It is diagnostically differentiated from narcolepsy, as there are fewer than 2 SOREMPs. As opposed to narcolepsy, in which naps tend to be refreshing, even prolonged naps in idiopathic hypersomnia are often not helpful in restoring wakefulness. In idiopathic hypersomnia, sleep is usually not fragmented, and there are few nocturnal arousals. Sleep times can often be prolonged as well, whereas in narcolepsy total sleep time through the day may not be increased but is not consolidated.
Kleine-Levin syndrome is a rarer disorder of hypersomnia. It is episodic compared with the relatively persistent sleepiness in narcolepsy and idiopathic hypersomnia. Periods of hypersomnia occur intermittently for days to weeks and are accompanied by cognitive and behavioral changes including hyperphagia and hypersexuality.4
LINKED TO HYPOCRETIN DEFICIENCY
Over the past 2 decades, the underlying pathophysiology of narcolepsy type 1 has been better characterized.
Narcolepsy type 1 has been linked to a deficiency in hypocretin in the central nervous system.36 Hypocretin (also known as orexin) is a hormone produced in the hypothalamus that acts on multiple brain regions and maintains alertness. For unclear reasons, hypothalamic neurons producing hypocretin are selectively reduced in narcolepsy type 1. Hypocretin also stabilizes wakefulness and inhibits REM sleep; therefore, hypocretin deficiency can lead to inappropriate intrusions of REM sleep onto wakefulness, leading to the hallmark features of narcolepsy—cataplexy, sleep-related hallucinations, and sleep paralysis.37 According to one theory, cataplexy is triggered by emotional stimuli because of a pathway between the medial prefrontal cortex and the amygdala to the pons.38
Cerebrospinal fluid levels of hypocretin in patients with narcolepsy type 2 tend to be normal, and the biologic underpinnings of narcolepsy type 2 remain mysterious. However, in the subgroup of those with narcolepsy type 2 in which hypocretin is low, many individuals go on to develop cataplexy, thereby evolving to narcolepsy type 1.36
POSSIBLE AUTOIMMUNE BASIS
Narcolepsy is typically a sporadic disorder, although familial cases have been described. The risk of a parent with narcolepsy having a child who is affected is approximately 1%.5
Narcolepsy type 1 is strongly associated with HLA-DQB1*0602, with up to 95% of those affected having at least one allele.39 Having 2 copies of the allele further increases the risk of developing narcolepsy.40 However, this allele is far from specific for narcolepsy with cataplexy, as it occurs in 12% to 38% of the general population.41 Therefore, HLA typing currently has limited clinical utility. The exact cause is as yet unknown, but substantial literature proposes an autoimmune basis of the disorder, given the strong association with the HLA subtype.42–44
After the 2009 H1N1 influenza pandemic, there was a significant increase in the incidence of narcolepsy with cataplexy, which again sparked interest in an autoimmune etiology underlying the disorder. Pandemrix, an H1N1 vaccine produced as a result of the 2009 pandemic, appeared to also be associated with an increase in the incidence of narcolepsy. An association with other upper respiratory infections has also been noted, further supporting a possible autoimmune basis.
A few studies have looked for serum autoantibodies involved in the pathogenesis of narcolepsy. Thus far, only one has been identified, an antibody to Tribbles homolog 2, found in 20% to 40% of those with new onset of nar-colepsy.42–44
TREATMENTS FOR DAYTIME SLEEPINESS
As with many chronic disorders, the treatment of narcolepsy consists of symptomatic rather than curative management, which can be done through both pharmacologic and nonpharmacologic means.
Nondrug measures
Scheduled naps lasting 15 to 20 minutes can help improve alertness.45 A consistent sleep schedule with good sleep hygiene, ensuring sufficient nightly sleep, is also important. In one study, the combination of scheduled naps and regular nocturnal sleep times reduced the level of daytime sleepiness and unintentional daytime sleep. Daytime naps were most helpful for those with the highest degree of daytime sleepiness.45
Strategic use of caffeine can be helpful and can reduce dependence on pharmacologic treatment.
Screening should be performed routinely for other sleep disorders, such as sleep-disordered breathing, which should be treated if identified.5,18 When being treated for other medical conditions, individuals with narcolepsy should avoid medications that can cause sedation, such as opiates or barbiturates; alcohol should be minimized or avoided.
Networking with other individuals with narcolepsy through support groups such as Narcolepsy Network can be valuable for learning coping skills and connecting with community resources. Psychological counseling for the patient, and sometimes the family, can also be useful. School-age children may need special accommodations such as schedule adjustments to allow for scheduled naps or frequent breaks to maintain alertness.
People with narcolepsy tend to function better in careers that do not require long periods of sitting, as sleepiness tends to be worse, but instead offer flexibility and require higher levels of activity that tend to combat sleepiness. They should not work as commercial drivers.18
Medications
While behavioral interventions in narcolepsy are vital, they are rarely sufficient, and drugs that promote daytime wakefulness are used as an adjunct (Table 2).46
Realistic expectations should be established when starting, as some degree of residual sleepiness usually remains even with optimal medical therapy. Medications should be strategically scheduled to maximize alertness during necessary times such as at work or school or during driving. Patients should specifically be counseled to avoid driving if sleepy.18,47
Modafinil is often used as a first-line therapy, given its favorable side-effect profile and low potential for abuse. Its pharmacologic action has been debated but it probably acts as a selective dopamine reuptake inhibitor. It is typically taken twice daily (upon waking and early afternoon) and is usually well tolerated.
Potential side effects include headache, nausea, dry mouth, anorexia, diarrhea, and, rarely, Stevens-Johnson syndrome. Cardiovascular side effects are minimal, making it a favorable choice in older patients.18,48
A trial in 283 patients showed significantly lower levels of sleepiness in patients taking modafinil 200 mg or 400 mg than in a control group. Other trials have supported these findings and showed improved driving performance on modafinil.18
Notably, modafinil can increase the metabolism of oral contraceptives, thereby reducing their efficacy. Women of childbearing age should be warned about this interaction and should be transitioned to nonhormonal forms of contraception.2,47
Armodafinil, a purified R-isomer of modafinil, has a longer half-life and requires only once-daily dosing.5
If modafinil or armodafinil fails to optimally manage daytime sleepiness, a traditional stimulant such as methylphenidate or an amphetamine is often used.
Methylphenidate and amphetamines primarily inhibit the reuptake and increase the release of the monoamines, mainly dopamine, and to a lesser degree serotonin and norepinephrine.
These drugs have more significant adverse effects that can involve the cardiovascular system, causing hypertension and arrhythmias. Anorexia, weight loss, and, particularly with high doses, psychosis can occur.49
These drugs should be avoided in patients with a history of significant cardiovascular disease. Before starting stimulant therapy, a thorough cardiovascular examination should be done, often including electrocardiography to ensure there is no baseline arrhythmia.
Patients on these medications should be followed closely to ensure that blood pressure, pulse, and weight are not negatively affected.18,50 Addiction and tolerance can develop with these drugs, and follow-up should include assessment for dependence. Some states may require prescription drug monitoring to ensure the drugs are not being abused or diverted.
Short- and long-acting formulations of both methylphenidate and amphetamines are available, and a long-acting form is often used in conjunction with a short-acting form as needed.18
Addiction and drug-seeking behavior can develop but are unusual in those taking stimulants to treat narcolepsy.49
Follow-up
Residual daytime sleepiness can be measured subjectively through the Epworth Sleepiness Scale on follow-up. If necessary, a maintenance-of-wakefulness test can provide an objective assessment of treatment efficacy.18
As narcolepsy is a chronic disorder, treatment should evolve with time. Most medications that treat narcolepsy are categorized by the US Food and Drug Administration as pregnancy category C, as we do not have adequate studies in human pregnancies to evaluate their effects. When a patient with narcolepsy becomes pregnant, she should be counseled about the risks and benefits of remaining on therapy. Treatment should balance the risks of sleepiness with the potential risks of remaining on medications.50 In the elderly, as cardiovascular comorbidities tend to increase, the risks and benefits of therapy should be routinely reevaluated.
For cataplexy
Sodium oxybate,51–53 the most potent anticataplectic drug, is the sodium salt of gamma hydroxybutyrate, a metabolite of gamma-aminobutyric acid. Sodium oxybate can be prescribed in the United States, Canada, and Europe. The American Academy of Sleep Medicine recommends sodium oxybate for cataplexy, daytime sleepiness, and disrupted sleep based on 3 level-1 studies and 2 level-4 studies.46
Sodium oxybate increases slow-wave sleep, improves sleep continuity, and often helps to mitigate daytime sleepiness. Due to its short half-life, its administration is unusual: the first dose is taken before bedtime and the second dose 2.5 to 4 hours later. Some patients set an alarm clock to take the second dose, while others awaken spontaneously to take the second dose. Most patients find that with adherence to dosing and safety instructions, sodium oxybate can serve as a highly effective form of treatment of both excessive sleepiness and cataplexy and may reduce the need for stimulant-based therapies.
The most common adverse effects are nausea, mood swings, and enuresis. Occasionally, psychosis can result and limit use of the drug. Obstructive sleep apnea can also develop or worsen.52 Because of its high salt content, sodium oxybate should be used with caution in those with heart failure, hypertension, or renal impairment. Its relative, gamma hydroxybutyrate, causes rapid sedation and has been notorious for illegal use as a date rape drug.
In the United States, sodium oxybate is distributed only through a central pharmacy to mitigate potential abuse. Due to this system, the rates of diversion are extremely low, estimated in a postmarketing analysis to be 1 instance per 5,200 patients treated. In the same study, abuse and dependence were both rare as well, about 1 case for every 2,600 and 6,500 patients treated.6,18,52,53
Antidepressants promote the action of norepinephrine and, to a lesser degree, serotonin, thereby suppressing REM sleep.
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is often used as a first-line treatment for cataplexy. Selective serotonin reuptake inhibitors such as fluoxetine are also used with success. Tricyclic antidepressants such as protriptyline or clomipramine are extremely effective for cataplexy, but are rarely used due to their adverse effects.2,47
FUTURE WORK
While our understanding of narcolepsy has advanced, there are still gaps in our knowledge of the disorder—namely, the specific trigger for the loss of hypocretin neurons in type 1 narcolepsy and the underlying pathophysiology of type 2.
A number of emerging therapies target the hypocretin system, including peptide replacement, neuronal transplant, and immunotherapy preventing hypocretin neuronal cell death.50,54,55 Additional drugs designed to improve alertness that do not involve the hypocretin system are also being developed, including a histamine inverse agonist.50,56 Sodium oxybate and modafinil, although currently approved for use in adults, are still off-label in pediatric practice. Studies of the safety and efficacy of these medications in children are needed.7,57
Narcolepsy was originally described in the late 1800s by the French physician Jean-Baptiste-Edouard Gélineau, who reported the case of a wine merchant suffering from somnolence. In this first description, he coined the term narcolepsie by joining the Greek words narke (numbness or stupor) and lepsis (attack).1
Since then, the disorder has been further characterized, and some insight into its biological underpinnings has been established. Importantly, treatments have improved and expanded, facilitating its management and thereby improving quality of life for those with the disorder.
This review focuses on clinically relevant features of the disorder and proposes management strategies.
CLINICAL FEATURES
Narcolepsy is characterized by instability of sleep-wake transitions.
Daytime sleepiness
Clinically, narcolepsy manifests with excessive daytime sleepiness that can be personally and socially disabling. Cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations can also be present,2,3 but they are not necessary for diagnosis. In fact, a minority of patients with narcolepsy have all these symptoms.4 Narcolepsy is divided into type 1 (with cataplexy) and type 2 (without cataplexy).2
Sleepiness tends to be worse with inactivity, and sleep can often be irresistible. Sleep attacks can come on suddenly and may be brief enough to manifest as a lapse in consciousness.
Short naps tend to be refreshing. Rapid eye movement (REM) latency—the interval between falling asleep and the onset of the REM sleep—is short in narcolepsy, and since the REM stage is when dreaming occurs, naps often include dreaming. Therefore, when taking a history, it is worthwhile to ask patients whether they dream during naps; a yes answer supports the diagnosis of narcolepsy.5
In children, sleepiness can manifest in reduced concentration and behavioral issues.6 Napping after age 5 or 6 is considered abnormal and may reflect pathologic sleepiness.7
Cataplexy
Cataplexy—transient muscle weakness triggered by emotion—is a specific feature of narcolepsy type 1. It often begins in the facial muscles and can manifest with slackening of the jaw or brief dropping of the head. However, episodes can be more dramatic and, if the trunk and limb muscles are affected, can result in collapsing to the ground.
Cataplexy usually has its onset at about the same time as the sleepiness associated with narcolepsy, but it can arise even years later.8 Episodes can last from a few seconds to 2 minutes. Consciousness is always preserved. A range of emotions can trigger cataplexy, but typically the emotion is a positive one such as laughter or excitement.9 Deep tendon reflexes disappear in cataplexy, so checking reflexes during a witnessed episode can be clinically valuable.2
Cataplexy can worsen with stress and insufficient sleep, occasionally with “status cataplecticus,” in which repeated, persistent episodes of cataplexy occur over several hours.8 Status cataplecticus can be spontaneous or an effect of withdrawal from anticataplectic medications.2
Cataplexy is thought to represent intrusion of REM sleep and its associated muscle atonia during wakefulness.
Sleep paralysis, hallucinations
Sleep paralysis and hallucinations are other features of narcolepsy that reflect this REM dissociation from sleep.
Sleep paralysis occurs most commonly upon awakening, but sometimes just before sleep onset. In most cases, it is manifested by inability to move the limbs or speak, lasting several seconds or, in rare cases, minutes at a time. Sleep paralysis can be associated with a sensation of fear or suffocation, especially when initially experienced.8
Hypnopompic hallucinations, occurring upon awakening, are more common than hypnagogic hallucinations, which are experienced before falling asleep. The hallucinations are often vivid and usually visual, although other types of hallucinations are possible. Unlike those that occur in psychotic disorders, the hallucinations tend to be associated with preserved insight that they are not real.10
Notably, both sleep paralysis and hallucinations are nonspecific symptoms that are common in the general population.8,11,12
Fragmented sleep
Although they are very sleepy, people with narcolepsy generally cannot stay asleep for very long. Their sleep tends to be extremely fragmented, and they often wake up several times a night.2
This sleep pattern reflects the inherent instability of sleep-wake transitions in narcolepsy. In fact, over a 24-hour period, adults with narcolepsy have a normal amount of sleep.13 In children, however, when narcolepsy first arises, the 24-hour sleep time can increase abruptly and can sometimes be associated with persistent cataplexy that can manifest as a clumsy gait.14
Weight gain, obstructive sleep apnea
Weight gain is common, particularly after symptom onset, and especially in children. As a result, obesity is a frequent comorbidity.15 Because obstructive sleep apnea can consequently develop, all patients with narcolepsy require screening for sleep-disordered breathing.
Other sleep disorders often accompany narcolepsy and are more common than in the general population.16 In a study incorporating both clinical and polysomnographic data of 100 patients with narcolepsy, insomnia was the most common comorbid sleep disorder, with a prevalence of 28%; others were REM sleep behavior disorder (24%), restless legs syndrome (24%), obstructive sleep apnea (21%), and non-REM parasomnias.17
PSYCHOSOCIAL CONSEQUENCES
Narcolepsy has significant psychosocial consequences. As a result of their symptoms, people with narcolepsy may not be able to meet academic or work-related demands.
Additionally, their risk of a motor vehicle accident is 3 to 4 times higher than in the general population, and more than one-third of patients have been in an accident due to sleepiness.18 There is some evidence to show that treatment eliminates this risk.19
Few systematic studies have examined mood disorders in narcolepsy. However, studies tend to show a higher prevalence of psychiatric disorders than in the general population, with depression and anxiety the most com-mon.20,21
DIAGNOSIS IS OFTEN DELAYED
The prevalence of narcolepsy type 1 is between 25 and 100 per 100,000 people.22 In a Mayo Clinic study,23 the incidence of narcolepsy type 1 was estimated to be 0.74 per 100,000 person-years. Epidemiologic data on narcolepsy type 2 are sparse, but patients with narcolepsy without cataplexy are thought to represent only 36% of all narcolepsy patients.23
Diagnosis is often delayed, with the average time between the onset of symptoms and the diagnosis ranging from 8 to 22 years. With increasing awareness, the efficiency of the diagnostic process is improving, and this delay is expected to lessen accordingly.24
Symptoms most commonly arise in the second decade; but the age at onset ranges significantly, between the first and fifth decades. Narcolepsy has a bimodal distribution in incidence, with the biggest peak at approximately age 15 and second smaller peak in the mid-30s. Some studies have suggested a slight male predominance.23,25
DIAGNOSIS
History is key
The history should include specific questions about the hallmark features of narcolepsy, including cataplexy, sleep paralysis, and sleep-related hallucinations. For individual assessment of subjective sleepiness, the Epworth Sleepiness Scale or Pediatric Daytime Sleepiness Scale can be administered quickly in the office setting.26,27
The Epworth score is calculated from the self-rated likelihood of falling asleep in 8 different situations, with possible scores of 0 (would never doze) to 3 (high chance of dozing) on each question, for a total possible score of 0 to 24. Normal total scores are between 0 and 10, while scores greater than 10 reflect pathologic sleepiness. Scores on the Epworth Sleepiness Scale in those with narcolepsy tend to reflect moderate to severe sleepiness, or at least 13, as opposed to patients with obstructive sleep apnea, whose scores commonly reflect milder sleepiness.28
Testing with actigraphy and polysomnography
It is imperative to rule out insufficient sleep and other sleep disorders as a cause of daytime sleepiness. This can be done with a careful clinical history, actigraphy with sleep logs, and polysomnography.
In the 2 to 4 weeks before actigraphy and subsequent testing, all medications with alerting or sedating properties (including antidepressants) should be tapered off to prevent influence on the results of the study.
Delayed sleep-phase disorder presents at a similar age as narcolepsy and can be associated with similar degrees of sleepiness. However, individuals with delayed sleep phase disorder have an inappropriately timed sleep-wake cycle so that there is a shift in their desired sleep onset and awakening times. It is common—prevalence estimates vary but average about 1% in the general population.29
Insufficient sleep syndrome is even more common, especially in teenagers and young adults, with increasing family, social, and academic demands. Sleep needs vary across the life span. A teenager needs 8 to 10 hours of sleep per night, and a young adult needs 7 to 9 hours. A study of 1,285 high school students found that 10.4% were not getting enough sleep.30
If actigraphy data suggest a circadian rhythm disorder or insufficient sleep that could explain the symptoms of sleepiness, then further testing should be halted and these specific issues should be addressed. In these cases, working with the patient toward maintaining a regular sleep-wake schedule with 7 to 8 hours of nightly sleep will often resolve symptoms.
If actigraphy demonstrates the patient is maintaining a regular sleep schedule and allowing adequate time for nightly sleep, the next step is polysomnography.
Polysomnography is performed to detect other disorders that can disrupt sleep, such as sleep-disordered breathing or periodic limb movement disorder.2,5 In addition, polysomnography can provide assurance that adequate sleep was obtained prior to the next step in testing.
Multiple sleep latency test
If sufficient sleep is obtained on polysomnograpy (at least 6 hours for an adult) and no other sleep disorder is identified, a multiple sleep latency test is performed. A urine toxicology screen is typically performed on the day of the test to ensure that drugs are not affecting the results.
The multiple sleep latency test consists of 4 to 5 nap opportunities at 2-hour intervals in a quiet dark room conducive to sleep, during which both sleep and REM latency are recorded. The sleep latency of those with narcolepsy is significantly shortened, and the diagnosis of narcolepsy requires an average sleep latency of less than 8 minutes.
Given the propensity for REM sleep in narcolepsy, another essential feature for diagnosis is the sleep-onset REM period (SOREMP). A SOREMP is defined as a REM latency of less than 15 minutes. A diagnosis of narcolepsy re-quires a SOREMP in at least 2 of the naps in a multiple sleep latency test (or 1 nap if the shortened REM latency is seen during polysomnography).31
The multiple sleep latency test has an imperfect sensitivity, though, and should be repeated when there is a high suspicion of narcolepsy.32–34 It is not completely specific either, and false-positive results occur. In fact, SOREMPs can be seen in the general population, particularly in those with a circadian rhythm disorder, insufficient sleep, or sleep-disordered breathing. Two or more SOREMPs in an multiple sleep latency test can be seen in a small proportion of the general population.35 The results of a multiple sleep latency test should be interpreted in the clinical context.
Differential diagnosis
Narcolepsy type 1 is distinguished from type 2 by the presence of cataplexy. A cerebrospinal fluid hypocretin 1 level of 110 pg/mL or less, or less than one-third of the mean value obtained in normal individuals, can substitute for the multiple sleep latency test in diagnosing narcolepsy type 1.31 Currently, hypocretin testing is generally not performed in clinical practice, although it may become a routine part of the narcolepsy evaluation in the future.
Thus, according to the International Classification of Sleep Disorders, 3rd edition,31 the diagnosis of narcolepsy type 1 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurologic disorder, mental disorder, medication use, or substance use disorder, and at least 1 of the following:
- Cataplexy and mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing (1 of which can be on the preceding night’s polysomography)
- Cerebrospinal fluid hypocretin 1 levels less than 110 pg/mL or one-third the baseline normal levels and mean sleep latency ≤ 8 minutes with ≥ 2 SOREMPs on multiple sleep latency testing.
Similarly, the diagnosis of narcolepsy type 2 requires excessive daytime sleepiness for at least 3 months that cannot be explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder, plus:
- Mean sleep latency of 8 minutes or less with at least 2 SOREMPs on multiple sleep latency testing.
Idiopathic hypersomnia, another disorder of central hypersomnolence, is also characterized by disabling sleepiness. It is diagnostically differentiated from narcolepsy, as there are fewer than 2 SOREMPs. As opposed to narcolepsy, in which naps tend to be refreshing, even prolonged naps in idiopathic hypersomnia are often not helpful in restoring wakefulness. In idiopathic hypersomnia, sleep is usually not fragmented, and there are few nocturnal arousals. Sleep times can often be prolonged as well, whereas in narcolepsy total sleep time through the day may not be increased but is not consolidated.
Kleine-Levin syndrome is a rarer disorder of hypersomnia. It is episodic compared with the relatively persistent sleepiness in narcolepsy and idiopathic hypersomnia. Periods of hypersomnia occur intermittently for days to weeks and are accompanied by cognitive and behavioral changes including hyperphagia and hypersexuality.4
LINKED TO HYPOCRETIN DEFICIENCY
Over the past 2 decades, the underlying pathophysiology of narcolepsy type 1 has been better characterized.
Narcolepsy type 1 has been linked to a deficiency in hypocretin in the central nervous system.36 Hypocretin (also known as orexin) is a hormone produced in the hypothalamus that acts on multiple brain regions and maintains alertness. For unclear reasons, hypothalamic neurons producing hypocretin are selectively reduced in narcolepsy type 1. Hypocretin also stabilizes wakefulness and inhibits REM sleep; therefore, hypocretin deficiency can lead to inappropriate intrusions of REM sleep onto wakefulness, leading to the hallmark features of narcolepsy—cataplexy, sleep-related hallucinations, and sleep paralysis.37 According to one theory, cataplexy is triggered by emotional stimuli because of a pathway between the medial prefrontal cortex and the amygdala to the pons.38
Cerebrospinal fluid levels of hypocretin in patients with narcolepsy type 2 tend to be normal, and the biologic underpinnings of narcolepsy type 2 remain mysterious. However, in the subgroup of those with narcolepsy type 2 in which hypocretin is low, many individuals go on to develop cataplexy, thereby evolving to narcolepsy type 1.36
POSSIBLE AUTOIMMUNE BASIS
Narcolepsy is typically a sporadic disorder, although familial cases have been described. The risk of a parent with narcolepsy having a child who is affected is approximately 1%.5
Narcolepsy type 1 is strongly associated with HLA-DQB1*0602, with up to 95% of those affected having at least one allele.39 Having 2 copies of the allele further increases the risk of developing narcolepsy.40 However, this allele is far from specific for narcolepsy with cataplexy, as it occurs in 12% to 38% of the general population.41 Therefore, HLA typing currently has limited clinical utility. The exact cause is as yet unknown, but substantial literature proposes an autoimmune basis of the disorder, given the strong association with the HLA subtype.42–44
After the 2009 H1N1 influenza pandemic, there was a significant increase in the incidence of narcolepsy with cataplexy, which again sparked interest in an autoimmune etiology underlying the disorder. Pandemrix, an H1N1 vaccine produced as a result of the 2009 pandemic, appeared to also be associated with an increase in the incidence of narcolepsy. An association with other upper respiratory infections has also been noted, further supporting a possible autoimmune basis.
A few studies have looked for serum autoantibodies involved in the pathogenesis of narcolepsy. Thus far, only one has been identified, an antibody to Tribbles homolog 2, found in 20% to 40% of those with new onset of nar-colepsy.42–44
TREATMENTS FOR DAYTIME SLEEPINESS
As with many chronic disorders, the treatment of narcolepsy consists of symptomatic rather than curative management, which can be done through both pharmacologic and nonpharmacologic means.
Nondrug measures
Scheduled naps lasting 15 to 20 minutes can help improve alertness.45 A consistent sleep schedule with good sleep hygiene, ensuring sufficient nightly sleep, is also important. In one study, the combination of scheduled naps and regular nocturnal sleep times reduced the level of daytime sleepiness and unintentional daytime sleep. Daytime naps were most helpful for those with the highest degree of daytime sleepiness.45
Strategic use of caffeine can be helpful and can reduce dependence on pharmacologic treatment.
Screening should be performed routinely for other sleep disorders, such as sleep-disordered breathing, which should be treated if identified.5,18 When being treated for other medical conditions, individuals with narcolepsy should avoid medications that can cause sedation, such as opiates or barbiturates; alcohol should be minimized or avoided.
Networking with other individuals with narcolepsy through support groups such as Narcolepsy Network can be valuable for learning coping skills and connecting with community resources. Psychological counseling for the patient, and sometimes the family, can also be useful. School-age children may need special accommodations such as schedule adjustments to allow for scheduled naps or frequent breaks to maintain alertness.
People with narcolepsy tend to function better in careers that do not require long periods of sitting, as sleepiness tends to be worse, but instead offer flexibility and require higher levels of activity that tend to combat sleepiness. They should not work as commercial drivers.18
Medications
While behavioral interventions in narcolepsy are vital, they are rarely sufficient, and drugs that promote daytime wakefulness are used as an adjunct (Table 2).46
Realistic expectations should be established when starting, as some degree of residual sleepiness usually remains even with optimal medical therapy. Medications should be strategically scheduled to maximize alertness during necessary times such as at work or school or during driving. Patients should specifically be counseled to avoid driving if sleepy.18,47
Modafinil is often used as a first-line therapy, given its favorable side-effect profile and low potential for abuse. Its pharmacologic action has been debated but it probably acts as a selective dopamine reuptake inhibitor. It is typically taken twice daily (upon waking and early afternoon) and is usually well tolerated.
Potential side effects include headache, nausea, dry mouth, anorexia, diarrhea, and, rarely, Stevens-Johnson syndrome. Cardiovascular side effects are minimal, making it a favorable choice in older patients.18,48
A trial in 283 patients showed significantly lower levels of sleepiness in patients taking modafinil 200 mg or 400 mg than in a control group. Other trials have supported these findings and showed improved driving performance on modafinil.18
Notably, modafinil can increase the metabolism of oral contraceptives, thereby reducing their efficacy. Women of childbearing age should be warned about this interaction and should be transitioned to nonhormonal forms of contraception.2,47
Armodafinil, a purified R-isomer of modafinil, has a longer half-life and requires only once-daily dosing.5
If modafinil or armodafinil fails to optimally manage daytime sleepiness, a traditional stimulant such as methylphenidate or an amphetamine is often used.
Methylphenidate and amphetamines primarily inhibit the reuptake and increase the release of the monoamines, mainly dopamine, and to a lesser degree serotonin and norepinephrine.
These drugs have more significant adverse effects that can involve the cardiovascular system, causing hypertension and arrhythmias. Anorexia, weight loss, and, particularly with high doses, psychosis can occur.49
These drugs should be avoided in patients with a history of significant cardiovascular disease. Before starting stimulant therapy, a thorough cardiovascular examination should be done, often including electrocardiography to ensure there is no baseline arrhythmia.
Patients on these medications should be followed closely to ensure that blood pressure, pulse, and weight are not negatively affected.18,50 Addiction and tolerance can develop with these drugs, and follow-up should include assessment for dependence. Some states may require prescription drug monitoring to ensure the drugs are not being abused or diverted.
Short- and long-acting formulations of both methylphenidate and amphetamines are available, and a long-acting form is often used in conjunction with a short-acting form as needed.18
Addiction and drug-seeking behavior can develop but are unusual in those taking stimulants to treat narcolepsy.49
Follow-up
Residual daytime sleepiness can be measured subjectively through the Epworth Sleepiness Scale on follow-up. If necessary, a maintenance-of-wakefulness test can provide an objective assessment of treatment efficacy.18
As narcolepsy is a chronic disorder, treatment should evolve with time. Most medications that treat narcolepsy are categorized by the US Food and Drug Administration as pregnancy category C, as we do not have adequate studies in human pregnancies to evaluate their effects. When a patient with narcolepsy becomes pregnant, she should be counseled about the risks and benefits of remaining on therapy. Treatment should balance the risks of sleepiness with the potential risks of remaining on medications.50 In the elderly, as cardiovascular comorbidities tend to increase, the risks and benefits of therapy should be routinely reevaluated.
For cataplexy
Sodium oxybate,51–53 the most potent anticataplectic drug, is the sodium salt of gamma hydroxybutyrate, a metabolite of gamma-aminobutyric acid. Sodium oxybate can be prescribed in the United States, Canada, and Europe. The American Academy of Sleep Medicine recommends sodium oxybate for cataplexy, daytime sleepiness, and disrupted sleep based on 3 level-1 studies and 2 level-4 studies.46
Sodium oxybate increases slow-wave sleep, improves sleep continuity, and often helps to mitigate daytime sleepiness. Due to its short half-life, its administration is unusual: the first dose is taken before bedtime and the second dose 2.5 to 4 hours later. Some patients set an alarm clock to take the second dose, while others awaken spontaneously to take the second dose. Most patients find that with adherence to dosing and safety instructions, sodium oxybate can serve as a highly effective form of treatment of both excessive sleepiness and cataplexy and may reduce the need for stimulant-based therapies.
The most common adverse effects are nausea, mood swings, and enuresis. Occasionally, psychosis can result and limit use of the drug. Obstructive sleep apnea can also develop or worsen.52 Because of its high salt content, sodium oxybate should be used with caution in those with heart failure, hypertension, or renal impairment. Its relative, gamma hydroxybutyrate, causes rapid sedation and has been notorious for illegal use as a date rape drug.
In the United States, sodium oxybate is distributed only through a central pharmacy to mitigate potential abuse. Due to this system, the rates of diversion are extremely low, estimated in a postmarketing analysis to be 1 instance per 5,200 patients treated. In the same study, abuse and dependence were both rare as well, about 1 case for every 2,600 and 6,500 patients treated.6,18,52,53
Antidepressants promote the action of norepinephrine and, to a lesser degree, serotonin, thereby suppressing REM sleep.
Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is often used as a first-line treatment for cataplexy. Selective serotonin reuptake inhibitors such as fluoxetine are also used with success. Tricyclic antidepressants such as protriptyline or clomipramine are extremely effective for cataplexy, but are rarely used due to their adverse effects.2,47
FUTURE WORK
While our understanding of narcolepsy has advanced, there are still gaps in our knowledge of the disorder—namely, the specific trigger for the loss of hypocretin neurons in type 1 narcolepsy and the underlying pathophysiology of type 2.
A number of emerging therapies target the hypocretin system, including peptide replacement, neuronal transplant, and immunotherapy preventing hypocretin neuronal cell death.50,54,55 Additional drugs designed to improve alertness that do not involve the hypocretin system are also being developed, including a histamine inverse agonist.50,56 Sodium oxybate and modafinil, although currently approved for use in adults, are still off-label in pediatric practice. Studies of the safety and efficacy of these medications in children are needed.7,57
- Gélineau J. De la narcolepsie. Gazette des Hôpitaux Civils et Militaires 1880; part a, 53:626–628, part b, 54:635–637.
- Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007; 369(9560):499–511. doi:10.1016/S0140-6736(07)60237-2
- Scammell TE. Clinical features and diagnosis of narcolepsy in adults. In: Eichler AF, ed. UpToDate. Waltham, MA: UpToDate; 2018. www.uptodate.com. Accessed October 31, 2018.
- Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 2004; 5(1):37–41. pmid:14725825
- Scammell TE. Narcolepsy. N Engl J Med 2015; 373(27):2654–2662. doi:10.1056/NEJMra1500587
- Babiker MO, Prasad M. Narcolepsy in children: a diagnostic and management approach. Pediatr Neurol 2015; 52(6):557–565. doi:10.1016/j.pediatrneurol.2015.02.020
- Kotagal S. Narcolepsy in children. In: UpToDate, Eichler AF, ed. UpToDate, Waltham, MA. www.uptodate.com. Accessed October 31, 2018.
- Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003; 53(2):154–166. doi:10.1002/ana.10444
- Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Lammers GJ. The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med 2011; 12(1):12–18. doi:10.1016/j.sleep.2010.05.010
- Plazzi G, Fabbri C, Pizza F, Serretti A. Schizophrenia-like symptoms in narcolepsy type 1: shared and distinctive clinical characteristics. Neuropsychobiology 2015; 71(4):218–224. doi:10.1159/000432400
- Ohayon MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 2000; 97(2-3):153–164. pmid:11166087
- Sharpless BA, Barber JP. Lifetime prevalence rates of sleep paralysis: a systematic review. Sleep Med Rev 2011;5(5):311–315. doi:10.1016/j.smrv.2011.01.007
- Broughton R, Dunham W, Newman J, Lutley K, Duschesne P, Rivers M. Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched controls. Electroencephalogr Clin Neurophysiol 1988; 70(6):473–481. pmid:2461281
- Pizza F, Franceschini C, Peltola H, et al. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain 2013; 136(pt 12):3787–3795. doi:10.1093/brain/awt277
- Kotagal S, Krahn LE, Slocumb N. A putative link between childhood narcolepsy and obesity. Sleep Med 2004; 5(2):147–150. doi:10.1016/j.sleep.2003.10.006
- Pizza F, Tartarotti S, Poryazova R, Baumann CR, Bassetti CL. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur Neurol 2013; 70(1-2):22–26. doi:10.1159/000348719
- Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the Innsbruck narcolepsy cohort. J Clin Sleep Med 2013; 9(8):805–812. doi:10.5664/jcsm.2926
- Scammell TE. Treatment of narcolepsy in adults. In: Eichler AF, ed. UpToDate, Waltham, MA. www.uptodate.com. Accessed October 31, 2018.
- Pizza F, Jaussent I, Lopez R, et al. Car crashes and central disorders of hypersomnolence: a French study. PLoS One 2015; 10(6):e0129386. doi:10.1371/journal.pone.0129386
- Fortuyn HD, Lappenschaar MA, Furer JW, et al. Anxiety and mood disorders in narcolepsy: a case-control study. Gen Hosp Psychiatry 2010; 32(1):49–56. doi:10.1016/j.genhosppsych.2009.08.007
- Ruoff CM, Reaven NL, Funk SE, et al. High rates of psychiatric comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study of 9,312 patients in the United States. J Clin Psychiatry 2017; 78(2):171–176. doi:10.4088/JCP.15m10262
- Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007; 30(1):13–26. pmid:17310860
- Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 2002; 25(2):197–202. pmid:11902429
- Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med 2014; 15(5):502–507. doi:10.1016/j.sleep.2014.01.015
- Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001; 57(11):2029–2033. pmid:11739821
- Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14(6):540–545. pmid:1798888
- Drake C, Nickel C, Burduvali E, Roth T, Jefferson C, Badia P. The pediatric daytime sleepiness scale (PDSS): sleep habits and school outcomes in middle-school children. Sleep 2003; 26(4):455–458. pmid:12841372
- van der Heide A, van Schie MK, Lammers GJ, et al. Comparing treatment effect measurements in narcolepsy: the sustained attention to response task, Epworth sleepiness scale and maintenance of wakefulness test. Sleep 2015; 38(7):1051–1058. doi:10.5665/sleep.4810
- Nesbitt AD. Delayed sleep-wake phase disorder. J Thorac Dis 2018; 10(suppl 1):S103–S111. doi:10.21037/jtd.2018.01.11
- Pallesen S, Saxvig IW, Molde H, Sørensen E, Wilhelmsen-Langeland A, Bjorvatn B. Brief report: behaviorally induced insufficient sleep syndrome in older adolescents: prevalence and correlates. J Adolesc 2011; 34(2):391–395. doi:10.1016/j.adolescence.2010.02.005
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Disorders; 2014.
- Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013; 9(8):789–795. doi:10.5664/jcsm.2922
- Andlauer O, Moore H, Jouhier L, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol 2013; 70(7):891–902. doi:10.1001/jamaneurol.2013.1589
- Cairns A, Bogan R. Prevalence and clinical correlates of a short onset REM period (SOREMP) during routine PSG. Sleep 2015; 38(10):1575–1581. doi:10.5665/sleep.5050
- Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 2006; 129(6):1609–1623. doi:10.1093/brain/awl079
- Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355(9197):39–40. doi:10.1016/S0140-6736(99)05582-8
- Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6(9):991–997. doi:10.1038/79690
- Oishi Y, Williams RH, Agostinelli L, et al. Role of the medial prefrontal cortex in cataplexy. J Neurosci 2013; 33(23):9743–9751. doi:10.1523/JNEUROSCI.0499-13.2013
- Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.. Sleep 1997; 20(11):1012–1020. pmid:9456467
- Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E. HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens 1998; 51(1):96–100. pmid:9459509
- Akintomide GS, Rickards H. Narcolepsy: a review. Neuropsychiatr Dis Treat 2011; 7(1):507–518. doi:10.2147/NDT.S23624
- Mahlios J, De la Herrán-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol 2013; 23(5):767–773. doi:10.1016/j.conb.2013.04.013
- Degn M, Kornum BR. Type 1 narcolepsy: a CD8(+) T cell-mediated disease? Ann N Y Acad Sci 2015;1 351:80–88. doi:10.1111/nyas.12793
- Liblau RS, Vassalli A, Seifinejad A, Tafti M. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol 2015; 14(3):318–328. doi:10.1016/S1474-4422(14)70218-2
- Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001; 24(4):385–391. pmid:11403522
- Morgenthaler TI, Kapur VK, Brown TM, et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007; 30(12):1705–1711. pmid:18246980
- Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics 2012; 9(4):739–752. doi:10.1007/s13311-012-0150-9
- Roth T, Schwartz JR, Hirshkowitz M, Erman MK, Dayno JM, Arora S. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007; 3(6):595–602. pmid:17993041
- Auger RR, Goodman SH, Silber MH, Krahn LE, Pankratz VS, Slocumb NL. Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study. Sleep 2005; 28(6):667–672. pmid:16477952
- Abad VC, Guilleminault C. New developments in the management of narcolepsy. Nat Sci Sleep 2017; 9:39–57. doi:10.2147/NSS.S103467
- Drakatos P, Lykouras D, D’Ancona G, et al. Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice. Sleep Med 2017; 35:80–84. doi:10.1016/j.sleep.2017.03.028
- Mansukhani MP, Kotagal S. Sodium oxybate in the treatment of childhood narcolepsy–cataplexy: a retrospective study. Sleep Med 2012; 13(6):606–610. doi:10.1016/j.sleep.2011.10.032
- Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med 2009; 5(4):365–371. pmid:19968016
- Weinhold SL, Seeck-Hirschner M, Nowak A, Hallschmid M, Göder R, Baier PC. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res 2014; 262:8–13. doi:10.1016/j.bbr.2013.12.045
- Arias-Carrión O, Murillo-Rodriguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One 2014; 9(4):e95342. doi:10.1371/journal.pone.0095342
- Leu-Semenescu S, Nittur N, Golmard JL, Arnulf I. Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review. Sleep Med 2014; 15(6):681–687. doi:10.1016/j.sleep.2014.01.021
- Lecendreux M, Bruni O, Franco P, et al. Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J Sleep Res 2012; 21(4):481–483. doi:10.1111/j.1365-2869.2011.00991.x
- Gélineau J. De la narcolepsie. Gazette des Hôpitaux Civils et Militaires 1880; part a, 53:626–628, part b, 54:635–637.
- Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet 2007; 369(9560):499–511. doi:10.1016/S0140-6736(07)60237-2
- Scammell TE. Clinical features and diagnosis of narcolepsy in adults. In: Eichler AF, ed. UpToDate. Waltham, MA: UpToDate; 2018. www.uptodate.com. Accessed October 31, 2018.
- Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med 2004; 5(1):37–41. pmid:14725825
- Scammell TE. Narcolepsy. N Engl J Med 2015; 373(27):2654–2662. doi:10.1056/NEJMra1500587
- Babiker MO, Prasad M. Narcolepsy in children: a diagnostic and management approach. Pediatr Neurol 2015; 52(6):557–565. doi:10.1016/j.pediatrneurol.2015.02.020
- Kotagal S. Narcolepsy in children. In: UpToDate, Eichler AF, ed. UpToDate, Waltham, MA. www.uptodate.com. Accessed October 31, 2018.
- Scammell TE. The neurobiology, diagnosis, and treatment of narcolepsy. Ann Neurol 2003; 53(2):154–166. doi:10.1002/ana.10444
- Overeem S, van Nues SJ, van der Zande WL, Donjacour CE, van Mierlo P, Lammers GJ. The clinical features of cataplexy: a questionnaire study in narcolepsy patients with and without hypocretin-1 deficiency. Sleep Med 2011; 12(1):12–18. doi:10.1016/j.sleep.2010.05.010
- Plazzi G, Fabbri C, Pizza F, Serretti A. Schizophrenia-like symptoms in narcolepsy type 1: shared and distinctive clinical characteristics. Neuropsychobiology 2015; 71(4):218–224. doi:10.1159/000432400
- Ohayon MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res 2000; 97(2-3):153–164. pmid:11166087
- Sharpless BA, Barber JP. Lifetime prevalence rates of sleep paralysis: a systematic review. Sleep Med Rev 2011;5(5):311–315. doi:10.1016/j.smrv.2011.01.007
- Broughton R, Dunham W, Newman J, Lutley K, Duschesne P, Rivers M. Ambulatory 24 hour sleep-wake monitoring in narcolepsy-cataplexy compared to matched controls. Electroencephalogr Clin Neurophysiol 1988; 70(6):473–481. pmid:2461281
- Pizza F, Franceschini C, Peltola H, et al. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain 2013; 136(pt 12):3787–3795. doi:10.1093/brain/awt277
- Kotagal S, Krahn LE, Slocumb N. A putative link between childhood narcolepsy and obesity. Sleep Med 2004; 5(2):147–150. doi:10.1016/j.sleep.2003.10.006
- Pizza F, Tartarotti S, Poryazova R, Baumann CR, Bassetti CL. Sleep-disordered breathing and periodic limb movements in narcolepsy with cataplexy: a systematic analysis of 35 consecutive patients. Eur Neurol 2013; 70(1-2):22–26. doi:10.1159/000348719
- Frauscher B, Ehrmann L, Mitterling T, et al. Delayed diagnosis, range of severity, and multiple sleep comorbidities: a clinical and polysomnographic analysis of 100 patients of the Innsbruck narcolepsy cohort. J Clin Sleep Med 2013; 9(8):805–812. doi:10.5664/jcsm.2926
- Scammell TE. Treatment of narcolepsy in adults. In: Eichler AF, ed. UpToDate, Waltham, MA. www.uptodate.com. Accessed October 31, 2018.
- Pizza F, Jaussent I, Lopez R, et al. Car crashes and central disorders of hypersomnolence: a French study. PLoS One 2015; 10(6):e0129386. doi:10.1371/journal.pone.0129386
- Fortuyn HD, Lappenschaar MA, Furer JW, et al. Anxiety and mood disorders in narcolepsy: a case-control study. Gen Hosp Psychiatry 2010; 32(1):49–56. doi:10.1016/j.genhosppsych.2009.08.007
- Ruoff CM, Reaven NL, Funk SE, et al. High rates of psychiatric comorbidity in narcolepsy: findings from the Burden of Narcolepsy Disease (BOND) study of 9,312 patients in the United States. J Clin Psychiatry 2017; 78(2):171–176. doi:10.4088/JCP.15m10262
- Longstreth WT Jr, Koepsell TD, Ton TG, Hendrickson AF, van Belle G. The epidemiology of narcolepsy. Sleep. 2007; 30(1):13–26. pmid:17310860
- Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep 2002; 25(2):197–202. pmid:11902429
- Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med 2014; 15(5):502–507. doi:10.1016/j.sleep.2014.01.015
- Dauvilliers Y, Montplaisir J, Molinari N, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology 2001; 57(11):2029–2033. pmid:11739821
- Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14(6):540–545. pmid:1798888
- Drake C, Nickel C, Burduvali E, Roth T, Jefferson C, Badia P. The pediatric daytime sleepiness scale (PDSS): sleep habits and school outcomes in middle-school children. Sleep 2003; 26(4):455–458. pmid:12841372
- van der Heide A, van Schie MK, Lammers GJ, et al. Comparing treatment effect measurements in narcolepsy: the sustained attention to response task, Epworth sleepiness scale and maintenance of wakefulness test. Sleep 2015; 38(7):1051–1058. doi:10.5665/sleep.4810
- Nesbitt AD. Delayed sleep-wake phase disorder. J Thorac Dis 2018; 10(suppl 1):S103–S111. doi:10.21037/jtd.2018.01.11
- Pallesen S, Saxvig IW, Molde H, Sørensen E, Wilhelmsen-Langeland A, Bjorvatn B. Brief report: behaviorally induced insufficient sleep syndrome in older adolescents: prevalence and correlates. J Adolesc 2011; 34(2):391–395. doi:10.1016/j.adolescence.2010.02.005
- American Academy of Sleep Medicine. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Disorders; 2014.
- Trotti LM, Staab BA, Rye DB. Test-retest reliability of the multiple sleep latency test in narcolepsy without cataplexy and idiopathic hypersomnia. J Clin Sleep Med 2013; 9(8):789–795. doi:10.5664/jcsm.2922
- Andlauer O, Moore H, Jouhier L, et al. Nocturnal rapid eye movement sleep latency for identifying patients with narcolepsy/hypocretin deficiency. JAMA Neurol 2013; 70(7):891–902. doi:10.1001/jamaneurol.2013.1589
- Cairns A, Bogan R. Prevalence and clinical correlates of a short onset REM period (SOREMP) during routine PSG. Sleep 2015; 38(10):1575–1581. doi:10.5665/sleep.5050
- Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 2006; 129(6):1609–1623. doi:10.1093/brain/awl079
- Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000; 355(9197):39–40. doi:10.1016/S0140-6736(99)05582-8
- Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000; 6(9):991–997. doi:10.1038/79690
- Oishi Y, Williams RH, Agostinelli L, et al. Role of the medial prefrontal cortex in cataplexy. J Neurosci 2013; 33(23):9743–9751. doi:10.1523/JNEUROSCI.0499-13.2013
- Mignot E, Hayduk R, Black J, Grumet FC, Guilleminault C. HLA DQB1*0602 is associated with cataplexy in 509 narcoleptic patients.. Sleep 1997; 20(11):1012–1020. pmid:9456467
- Pelin Z, Guilleminault C, Risch N, Grumet FC, Mignot E. HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens 1998; 51(1):96–100. pmid:9459509
- Akintomide GS, Rickards H. Narcolepsy: a review. Neuropsychiatr Dis Treat 2011; 7(1):507–518. doi:10.2147/NDT.S23624
- Mahlios J, De la Herrán-Arita AK, Mignot E. The autoimmune basis of narcolepsy. Curr Opin Neurobiol 2013; 23(5):767–773. doi:10.1016/j.conb.2013.04.013
- Degn M, Kornum BR. Type 1 narcolepsy: a CD8(+) T cell-mediated disease? Ann N Y Acad Sci 2015;1 351:80–88. doi:10.1111/nyas.12793
- Liblau RS, Vassalli A, Seifinejad A, Tafti M. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol 2015; 14(3):318–328. doi:10.1016/S1474-4422(14)70218-2
- Rogers AE, Aldrich MS, Lin X. A comparison of three different sleep schedules for reducing daytime sleepiness in narcolepsy. Sleep 2001; 24(4):385–391. pmid:11403522
- Morgenthaler TI, Kapur VK, Brown TM, et al; Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007; 30(12):1705–1711. pmid:18246980
- Mignot EJ. A practical guide to the therapy of narcolepsy and hypersomnia syndromes. Neurotherapeutics 2012; 9(4):739–752. doi:10.1007/s13311-012-0150-9
- Roth T, Schwartz JR, Hirshkowitz M, Erman MK, Dayno JM, Arora S. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007; 3(6):595–602. pmid:17993041
- Auger RR, Goodman SH, Silber MH, Krahn LE, Pankratz VS, Slocumb NL. Risks of high-dose stimulants in the treatment of disorders of excessive somnolence: a case-control study. Sleep 2005; 28(6):667–672. pmid:16477952
- Abad VC, Guilleminault C. New developments in the management of narcolepsy. Nat Sci Sleep 2017; 9:39–57. doi:10.2147/NSS.S103467
- Drakatos P, Lykouras D, D’Ancona G, et al. Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice. Sleep Med 2017; 35:80–84. doi:10.1016/j.sleep.2017.03.028
- Mansukhani MP, Kotagal S. Sodium oxybate in the treatment of childhood narcolepsy–cataplexy: a retrospective study. Sleep Med 2012; 13(6):606–610. doi:10.1016/j.sleep.2011.10.032
- Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL. Safety overview of postmarketing and clinical experience of sodium oxybate (Xyrem): abuse, misuse, dependence, and diversion. J Clin Sleep Med 2009; 5(4):365–371. pmid:19968016
- Weinhold SL, Seeck-Hirschner M, Nowak A, Hallschmid M, Göder R, Baier PC. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res 2014; 262:8–13. doi:10.1016/j.bbr.2013.12.045
- Arias-Carrión O, Murillo-Rodriguez E. Effects of hypocretin/orexin cell transplantation on narcoleptic-like sleep behavior in rats. PLoS One 2014; 9(4):e95342. doi:10.1371/journal.pone.0095342
- Leu-Semenescu S, Nittur N, Golmard JL, Arnulf I. Effects of pitolisant, a histamine H3 inverse agonist, in drug-resistant idiopathic and symptomatic hypersomnia: a chart review. Sleep Med 2014; 15(6):681–687. doi:10.1016/j.sleep.2014.01.021
- Lecendreux M, Bruni O, Franco P, et al. Clinical experience suggests that modafinil is an effective and safe treatment for paediatric narcolepsy. J Sleep Res 2012; 21(4):481–483. doi:10.1111/j.1365-2869.2011.00991.x
KEY POINTS
- Features of narcolepsy include daytime sleepiness, sleep attacks, cataplexy (in narcolepsy type 1), sleep paralysis, and sleep-related hallucinations.
- People with narcolepsy feel sleepy and can fall asleep quickly, but they do not stay asleep for long. They go into rapid eye movement sleep soon after falling asleep. Total sleep time is normal, but sleep is fragmented.
- Scheduled naps lasting 15 to 20 minutes can improve alertness. A consistent sleep schedule with good sleep hygiene is also important.
- Modafinil, methylphenidate, and amphetamines are used to manage daytime sleepiness, and sodium oxybate and antidepressants are used for cataplexy.
What can I do when first-line measures are not enough for vasovagal syncope?
Vasovagal syncope is usually benign, and although it often recurs, increasing fluid and salt intake and performing counter-pressure maneuvers are usually sufficient.1 However, if patients continue to have syncopal episodes despite these first-line measures, other options include drug therapy with midodrine, fludrocortisone, beta-blockers, or selective serotonin reuptake inhibitors; orthostatic training; and, in some cases, pacemaker implantation. The 2017 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society (ACC/AHA/HRS) are helpful in the management of these patients.1
RATIONALE
Although vasovagal syncope is considered benign, it can result in injury and can significantly affect quality of life.
The diagnosis can often be established in the initial evaluation with a structured history, physical examination, and electrocardiography. If the diagnosis is still unclear, tilt-table testing can be useful and has an ACC/AHA/HRS class IIa (moderate) recommendation.1 Once the diagnosis of vasovagal syncope is made, first-line measures can be instituted.
FIRST-LINE MEASURES
An explanation of the diagnosis, education on avoiding triggers such as prolonged standing and warm environments, coping with potentially stressful visits to the doctor or dentist, and reassurance that the condition is benign are all strongly recommended (class I).1
Initial measures include performing physical counter-pressure maneuvers (class IIa), increasing salt and fluid intake (class IIb) in the absence of contraindications, and, in selected patients, reducing or withdrawing hypotensive medications when appropriate (class IIb).
Physical counter-pressure maneuvers are recommended for patients whose syncopal episodes have a sufficiently long prodromal period. Maneuvers include the following:
- Leg crossing: crossing the legs while tensing leg, abdominal, and buttock muscles
- Handgrip: maximally contracting a rubber ball or other object in the dominant hand
- Squatting
- Limb or abdominal contractions
- Arm tensing: contracting both arms by gripping one hand with the other and abducting both arms.2
The effectiveness of counter-pressure maneuvers was studied by van Dijk et al2 in a multicenter prospective randomized clinical trial that included 223 patients with recurrent vasovagal syncope associated with prodromal symptoms. They concluded that these maneuvers decreased the recurrence of syncopal episodes, with a relative risk reduction of 0.36 (95% confidence interval 0.11–0.53, P < .005) and were low-cost and risk-free.
Confirming the diagnosis of vasovagal syncope with tilt-table testing may reassure the patient. It can also help the patient learn to identify the symptoms associated with a vasovagal episode, which in turn may encourage timely use of physical counter-pressure maneuvers at the onset.
The evidence for increasing salt and fluid intake for patients with vasovagal syncope is limited. But in the absence of a contraindication such as hypertension, renal disease, or heart failure, it may be reasonable to encourage the ingestion of 2 L to 3 L of fluid per day and a total of 6 g to 9 g of salt per day (around 1 to 2 heaping teaspoons of salt).1
MEDICAL THERAPY
In patients who continue to have syncopal episodes despite adequate use of first-line measures, medical therapy can be considered. Unfortunately, evidence supporting drug therapy for recurrent syncope is limited.3 Options include midodrine (class IIa), fludrocortisone (class IIb), beta-blockers (class IIb), and selective serotonin reuptake inhibitors (class IIb).1
Midodrine has the strongest recommendation and is a reasonable option if there is no history of hypertension, heart failure, or urinary retention. It is a peripheral alpha-agonist that ameliorates the reduction in peripheral sympathetic neural outflow responsible for venous pooling and vasodepression in vasovagal syncope.4–6
Fludrocortisone results in increased blood volume due to mineralocorticoid activity. In the Prevention of Syncope Trial 2 of fludrocortisone vs placebo, patients on fludrocortisone had a “marginally nonsignificant” reduction in recurrence of syncope over 1 year (hazard ratio 0.69, P = .069).7
Overall, beta-blockers have failed to prevent syncope in randomized controlled trials. But in a meta-analysis that included patients from the Prevention of Syncope Trial,8 an age-dependent benefit of beta-blockers was noted in patients age 42 and older.9 Therefore, a beta-blocker may be a reasonable option in patients in this age group with recurrent vasovagal syncope.1
Serotonin has central effects on blood pressure and heart rate that can induce syncope. However, evidence for the effectiveness of selective serotonin reuptake inhibitors in the prevention of recurrent vasovagal syncope has been contradictory in small trials.10,11
When choosing a drug, contraindications should be considered, including possible effects during pregnancy in women of childbearing age.
OTHER MEASURES
Orthostatic training, with repetitive tilt-table testing until a test is negative, or with daily standing quietly against a wall for prolonged periods of time, has not been shown to have sustained benefit in reducing the recurrence of syncopal episodes (class IIb recommendation).1
Dual-chamber pacing can be considered in carefully selected patients age 40 or older with syncope and documented asystole of at least 3 seconds or spontaneous pauses of at least 6 seconds without syncope on implantable loop recorder monitoring (class IIb recommendation).1,12,13 Strict patient selection increases the likelihood that pacing will be effective.1 For example, patients with documented asystole during syncope and a tilt-table test that induces minimal or no vasodepressor response are more likely to respond than patients with a positive tilt-table test with a vasodepressor (hypotensive) response.13
Tilt-table testing may also be considered to identify patients with a hypotensive response who would be less likely to respond to permanent cardiac pacing.14
Compression garments carry a class IIa recommendation for orthostatic hypotension,1 but they have not been adequately studied in vasovagal syncope.
- Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2017; 136(5):e60–e122. doi:10.1161/CIR.0000000000000499
- van Dijk N, Quartieri F, Blanc JJ, Garcia-Civera R, Brignole M, Moya A, Wieling W; PC-Trial Investigators. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol 2006; 48(8):1652–1657. doi:10.1016/j.jacc.2006.06.059
- Romme JJ, Reitsma JB, Black CN, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev 2011; (10):CD004194. doi:10.1002/14651858.CD004194.pub3
- Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 2001; 12(8):935–938. pmid:11513446
- Romme JJ, van Dijk N, Go-Schön IK, Reitsma JB, Wieling W. Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial). Europace 2011; 13(11):1639–1647. doi:10.1093/europace/eur200
- Samniah N, Sakaguchi S, Lurie KG, Iskos D, Benditt DG. Efficacy and safety of midodrine hydrochloride in patients with refractory vasovagal syncope. Am J Cardiol 2001; 88(1):A7, 80–83. pmid:11423066
- Sheldon R, Raj SR, Rose MS, et al; POST 2 Investigators. Fludrocortisone for the prevention of vasovagal syncope: a randomized, placebo-controlled trial. J Am Coll Cardiol 2016; 68(1):1–9. doi:10.1016/j.jacc.2016.04.030
- Sheldon R, Connolly S, Rose S, et al; POST Investigators. Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 2006; 113(9):1164–1170. doi:10.1161/CIRCULATIONAHA.105.535161
- Sheldon RS, Morillo CA, Klingenheben T, Krahn AD, Sheldon A, Rose MS. Age-dependent effect of beta-blockers in preventing vasovagal syncope. Circ Arrhythm Electrophysiol 2012; 5(5):920–926. doi:10.1161/CIRCEP.112.974386
- Takata TS, Wasmund SL, Smith ML, et al. Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction associated with carotid sinus massage and/or lower body negative pressure in healthy volunteers. Circulation 2002; 106(12):1500–1504. pmid:12234955
- Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999; 33(5):1227–1230. pmid:10193720
- Brignole M, Menozzi C, Moya A, et al; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012; 125(21):2566–2571. doi:10.1161/CIRCULATIONAHA.111.082313
- Brignole M, Donateo P, Tomaino M, et al; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol 2014; 7(1):10–16. doi:10.1161/CIRCEP.113.001103
- Sheldon RS, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015; 12(6):e41–e63. doi:10.1016/j.hrthm.2015.03.029
Vasovagal syncope is usually benign, and although it often recurs, increasing fluid and salt intake and performing counter-pressure maneuvers are usually sufficient.1 However, if patients continue to have syncopal episodes despite these first-line measures, other options include drug therapy with midodrine, fludrocortisone, beta-blockers, or selective serotonin reuptake inhibitors; orthostatic training; and, in some cases, pacemaker implantation. The 2017 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society (ACC/AHA/HRS) are helpful in the management of these patients.1
RATIONALE
Although vasovagal syncope is considered benign, it can result in injury and can significantly affect quality of life.
The diagnosis can often be established in the initial evaluation with a structured history, physical examination, and electrocardiography. If the diagnosis is still unclear, tilt-table testing can be useful and has an ACC/AHA/HRS class IIa (moderate) recommendation.1 Once the diagnosis of vasovagal syncope is made, first-line measures can be instituted.
FIRST-LINE MEASURES
An explanation of the diagnosis, education on avoiding triggers such as prolonged standing and warm environments, coping with potentially stressful visits to the doctor or dentist, and reassurance that the condition is benign are all strongly recommended (class I).1
Initial measures include performing physical counter-pressure maneuvers (class IIa), increasing salt and fluid intake (class IIb) in the absence of contraindications, and, in selected patients, reducing or withdrawing hypotensive medications when appropriate (class IIb).
Physical counter-pressure maneuvers are recommended for patients whose syncopal episodes have a sufficiently long prodromal period. Maneuvers include the following:
- Leg crossing: crossing the legs while tensing leg, abdominal, and buttock muscles
- Handgrip: maximally contracting a rubber ball or other object in the dominant hand
- Squatting
- Limb or abdominal contractions
- Arm tensing: contracting both arms by gripping one hand with the other and abducting both arms.2
The effectiveness of counter-pressure maneuvers was studied by van Dijk et al2 in a multicenter prospective randomized clinical trial that included 223 patients with recurrent vasovagal syncope associated with prodromal symptoms. They concluded that these maneuvers decreased the recurrence of syncopal episodes, with a relative risk reduction of 0.36 (95% confidence interval 0.11–0.53, P < .005) and were low-cost and risk-free.
Confirming the diagnosis of vasovagal syncope with tilt-table testing may reassure the patient. It can also help the patient learn to identify the symptoms associated with a vasovagal episode, which in turn may encourage timely use of physical counter-pressure maneuvers at the onset.
The evidence for increasing salt and fluid intake for patients with vasovagal syncope is limited. But in the absence of a contraindication such as hypertension, renal disease, or heart failure, it may be reasonable to encourage the ingestion of 2 L to 3 L of fluid per day and a total of 6 g to 9 g of salt per day (around 1 to 2 heaping teaspoons of salt).1
MEDICAL THERAPY
In patients who continue to have syncopal episodes despite adequate use of first-line measures, medical therapy can be considered. Unfortunately, evidence supporting drug therapy for recurrent syncope is limited.3 Options include midodrine (class IIa), fludrocortisone (class IIb), beta-blockers (class IIb), and selective serotonin reuptake inhibitors (class IIb).1
Midodrine has the strongest recommendation and is a reasonable option if there is no history of hypertension, heart failure, or urinary retention. It is a peripheral alpha-agonist that ameliorates the reduction in peripheral sympathetic neural outflow responsible for venous pooling and vasodepression in vasovagal syncope.4–6
Fludrocortisone results in increased blood volume due to mineralocorticoid activity. In the Prevention of Syncope Trial 2 of fludrocortisone vs placebo, patients on fludrocortisone had a “marginally nonsignificant” reduction in recurrence of syncope over 1 year (hazard ratio 0.69, P = .069).7
Overall, beta-blockers have failed to prevent syncope in randomized controlled trials. But in a meta-analysis that included patients from the Prevention of Syncope Trial,8 an age-dependent benefit of beta-blockers was noted in patients age 42 and older.9 Therefore, a beta-blocker may be a reasonable option in patients in this age group with recurrent vasovagal syncope.1
Serotonin has central effects on blood pressure and heart rate that can induce syncope. However, evidence for the effectiveness of selective serotonin reuptake inhibitors in the prevention of recurrent vasovagal syncope has been contradictory in small trials.10,11
When choosing a drug, contraindications should be considered, including possible effects during pregnancy in women of childbearing age.
OTHER MEASURES
Orthostatic training, with repetitive tilt-table testing until a test is negative, or with daily standing quietly against a wall for prolonged periods of time, has not been shown to have sustained benefit in reducing the recurrence of syncopal episodes (class IIb recommendation).1
Dual-chamber pacing can be considered in carefully selected patients age 40 or older with syncope and documented asystole of at least 3 seconds or spontaneous pauses of at least 6 seconds without syncope on implantable loop recorder monitoring (class IIb recommendation).1,12,13 Strict patient selection increases the likelihood that pacing will be effective.1 For example, patients with documented asystole during syncope and a tilt-table test that induces minimal or no vasodepressor response are more likely to respond than patients with a positive tilt-table test with a vasodepressor (hypotensive) response.13
Tilt-table testing may also be considered to identify patients with a hypotensive response who would be less likely to respond to permanent cardiac pacing.14
Compression garments carry a class IIa recommendation for orthostatic hypotension,1 but they have not been adequately studied in vasovagal syncope.
Vasovagal syncope is usually benign, and although it often recurs, increasing fluid and salt intake and performing counter-pressure maneuvers are usually sufficient.1 However, if patients continue to have syncopal episodes despite these first-line measures, other options include drug therapy with midodrine, fludrocortisone, beta-blockers, or selective serotonin reuptake inhibitors; orthostatic training; and, in some cases, pacemaker implantation. The 2017 guidelines from the American College of Cardiology, American Heart Association, and Heart Rhythm Society (ACC/AHA/HRS) are helpful in the management of these patients.1
RATIONALE
Although vasovagal syncope is considered benign, it can result in injury and can significantly affect quality of life.
The diagnosis can often be established in the initial evaluation with a structured history, physical examination, and electrocardiography. If the diagnosis is still unclear, tilt-table testing can be useful and has an ACC/AHA/HRS class IIa (moderate) recommendation.1 Once the diagnosis of vasovagal syncope is made, first-line measures can be instituted.
FIRST-LINE MEASURES
An explanation of the diagnosis, education on avoiding triggers such as prolonged standing and warm environments, coping with potentially stressful visits to the doctor or dentist, and reassurance that the condition is benign are all strongly recommended (class I).1
Initial measures include performing physical counter-pressure maneuvers (class IIa), increasing salt and fluid intake (class IIb) in the absence of contraindications, and, in selected patients, reducing or withdrawing hypotensive medications when appropriate (class IIb).
Physical counter-pressure maneuvers are recommended for patients whose syncopal episodes have a sufficiently long prodromal period. Maneuvers include the following:
- Leg crossing: crossing the legs while tensing leg, abdominal, and buttock muscles
- Handgrip: maximally contracting a rubber ball or other object in the dominant hand
- Squatting
- Limb or abdominal contractions
- Arm tensing: contracting both arms by gripping one hand with the other and abducting both arms.2
The effectiveness of counter-pressure maneuvers was studied by van Dijk et al2 in a multicenter prospective randomized clinical trial that included 223 patients with recurrent vasovagal syncope associated with prodromal symptoms. They concluded that these maneuvers decreased the recurrence of syncopal episodes, with a relative risk reduction of 0.36 (95% confidence interval 0.11–0.53, P < .005) and were low-cost and risk-free.
Confirming the diagnosis of vasovagal syncope with tilt-table testing may reassure the patient. It can also help the patient learn to identify the symptoms associated with a vasovagal episode, which in turn may encourage timely use of physical counter-pressure maneuvers at the onset.
The evidence for increasing salt and fluid intake for patients with vasovagal syncope is limited. But in the absence of a contraindication such as hypertension, renal disease, or heart failure, it may be reasonable to encourage the ingestion of 2 L to 3 L of fluid per day and a total of 6 g to 9 g of salt per day (around 1 to 2 heaping teaspoons of salt).1
MEDICAL THERAPY
In patients who continue to have syncopal episodes despite adequate use of first-line measures, medical therapy can be considered. Unfortunately, evidence supporting drug therapy for recurrent syncope is limited.3 Options include midodrine (class IIa), fludrocortisone (class IIb), beta-blockers (class IIb), and selective serotonin reuptake inhibitors (class IIb).1
Midodrine has the strongest recommendation and is a reasonable option if there is no history of hypertension, heart failure, or urinary retention. It is a peripheral alpha-agonist that ameliorates the reduction in peripheral sympathetic neural outflow responsible for venous pooling and vasodepression in vasovagal syncope.4–6
Fludrocortisone results in increased blood volume due to mineralocorticoid activity. In the Prevention of Syncope Trial 2 of fludrocortisone vs placebo, patients on fludrocortisone had a “marginally nonsignificant” reduction in recurrence of syncope over 1 year (hazard ratio 0.69, P = .069).7
Overall, beta-blockers have failed to prevent syncope in randomized controlled trials. But in a meta-analysis that included patients from the Prevention of Syncope Trial,8 an age-dependent benefit of beta-blockers was noted in patients age 42 and older.9 Therefore, a beta-blocker may be a reasonable option in patients in this age group with recurrent vasovagal syncope.1
Serotonin has central effects on blood pressure and heart rate that can induce syncope. However, evidence for the effectiveness of selective serotonin reuptake inhibitors in the prevention of recurrent vasovagal syncope has been contradictory in small trials.10,11
When choosing a drug, contraindications should be considered, including possible effects during pregnancy in women of childbearing age.
OTHER MEASURES
Orthostatic training, with repetitive tilt-table testing until a test is negative, or with daily standing quietly against a wall for prolonged periods of time, has not been shown to have sustained benefit in reducing the recurrence of syncopal episodes (class IIb recommendation).1
Dual-chamber pacing can be considered in carefully selected patients age 40 or older with syncope and documented asystole of at least 3 seconds or spontaneous pauses of at least 6 seconds without syncope on implantable loop recorder monitoring (class IIb recommendation).1,12,13 Strict patient selection increases the likelihood that pacing will be effective.1 For example, patients with documented asystole during syncope and a tilt-table test that induces minimal or no vasodepressor response are more likely to respond than patients with a positive tilt-table test with a vasodepressor (hypotensive) response.13
Tilt-table testing may also be considered to identify patients with a hypotensive response who would be less likely to respond to permanent cardiac pacing.14
Compression garments carry a class IIa recommendation for orthostatic hypotension,1 but they have not been adequately studied in vasovagal syncope.
- Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2017; 136(5):e60–e122. doi:10.1161/CIR.0000000000000499
- van Dijk N, Quartieri F, Blanc JJ, Garcia-Civera R, Brignole M, Moya A, Wieling W; PC-Trial Investigators. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol 2006; 48(8):1652–1657. doi:10.1016/j.jacc.2006.06.059
- Romme JJ, Reitsma JB, Black CN, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev 2011; (10):CD004194. doi:10.1002/14651858.CD004194.pub3
- Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 2001; 12(8):935–938. pmid:11513446
- Romme JJ, van Dijk N, Go-Schön IK, Reitsma JB, Wieling W. Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial). Europace 2011; 13(11):1639–1647. doi:10.1093/europace/eur200
- Samniah N, Sakaguchi S, Lurie KG, Iskos D, Benditt DG. Efficacy and safety of midodrine hydrochloride in patients with refractory vasovagal syncope. Am J Cardiol 2001; 88(1):A7, 80–83. pmid:11423066
- Sheldon R, Raj SR, Rose MS, et al; POST 2 Investigators. Fludrocortisone for the prevention of vasovagal syncope: a randomized, placebo-controlled trial. J Am Coll Cardiol 2016; 68(1):1–9. doi:10.1016/j.jacc.2016.04.030
- Sheldon R, Connolly S, Rose S, et al; POST Investigators. Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 2006; 113(9):1164–1170. doi:10.1161/CIRCULATIONAHA.105.535161
- Sheldon RS, Morillo CA, Klingenheben T, Krahn AD, Sheldon A, Rose MS. Age-dependent effect of beta-blockers in preventing vasovagal syncope. Circ Arrhythm Electrophysiol 2012; 5(5):920–926. doi:10.1161/CIRCEP.112.974386
- Takata TS, Wasmund SL, Smith ML, et al. Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction associated with carotid sinus massage and/or lower body negative pressure in healthy volunteers. Circulation 2002; 106(12):1500–1504. pmid:12234955
- Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999; 33(5):1227–1230. pmid:10193720
- Brignole M, Menozzi C, Moya A, et al; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012; 125(21):2566–2571. doi:10.1161/CIRCULATIONAHA.111.082313
- Brignole M, Donateo P, Tomaino M, et al; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol 2014; 7(1):10–16. doi:10.1161/CIRCEP.113.001103
- Sheldon RS, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015; 12(6):e41–e63. doi:10.1016/j.hrthm.2015.03.029
- Shen WK, Sheldon RS, Benditt DG, et al. 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2017; 136(5):e60–e122. doi:10.1161/CIR.0000000000000499
- van Dijk N, Quartieri F, Blanc JJ, Garcia-Civera R, Brignole M, Moya A, Wieling W; PC-Trial Investigators. Effectiveness of physical counterpressure maneuvers in preventing vasovagal syncope: the Physical Counterpressure Manoeuvres Trial (PC-Trial). J Am Coll Cardiol 2006; 48(8):1652–1657. doi:10.1016/j.jacc.2006.06.059
- Romme JJ, Reitsma JB, Black CN, et al. Drugs and pacemakers for vasovagal, carotid sinus and situational syncope. Cochrane Database Syst Rev 2011; (10):CD004194. doi:10.1002/14651858.CD004194.pub3
- Perez-Lugones A, Schweikert R, Pavia S, et al. Usefulness of midodrine in patients with severely symptomatic neurocardiogenic syncope: a randomized control study. J Cardiovasc Electrophysiol 2001; 12(8):935–938. pmid:11513446
- Romme JJ, van Dijk N, Go-Schön IK, Reitsma JB, Wieling W. Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial). Europace 2011; 13(11):1639–1647. doi:10.1093/europace/eur200
- Samniah N, Sakaguchi S, Lurie KG, Iskos D, Benditt DG. Efficacy and safety of midodrine hydrochloride in patients with refractory vasovagal syncope. Am J Cardiol 2001; 88(1):A7, 80–83. pmid:11423066
- Sheldon R, Raj SR, Rose MS, et al; POST 2 Investigators. Fludrocortisone for the prevention of vasovagal syncope: a randomized, placebo-controlled trial. J Am Coll Cardiol 2016; 68(1):1–9. doi:10.1016/j.jacc.2016.04.030
- Sheldon R, Connolly S, Rose S, et al; POST Investigators. Prevention of Syncope Trial (POST): a randomized, placebo-controlled study of metoprolol in the prevention of vasovagal syncope. Circulation 2006; 113(9):1164–1170. doi:10.1161/CIRCULATIONAHA.105.535161
- Sheldon RS, Morillo CA, Klingenheben T, Krahn AD, Sheldon A, Rose MS. Age-dependent effect of beta-blockers in preventing vasovagal syncope. Circ Arrhythm Electrophysiol 2012; 5(5):920–926. doi:10.1161/CIRCEP.112.974386
- Takata TS, Wasmund SL, Smith ML, et al. Serotonin reuptake inhibitor (Paxil) does not prevent the vasovagal reaction associated with carotid sinus massage and/or lower body negative pressure in healthy volunteers. Circulation 2002; 106(12):1500–1504. pmid:12234955
- Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999; 33(5):1227–1230. pmid:10193720
- Brignole M, Menozzi C, Moya A, et al; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Pacemaker therapy in patients with neurally mediated syncope and documented asystole: third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation 2012; 125(21):2566–2571. doi:10.1161/CIRCULATIONAHA.111.082313
- Brignole M, Donateo P, Tomaino M, et al; International Study on Syncope of Uncertain Etiology 3 (ISSUE-3) Investigators. Benefit of pacemaker therapy in patients with presumed neurally mediated syncope and documented asystole is greater when tilt test is negative: an analysis from the third International Study on Syncope of Uncertain Etiology (ISSUE-3). Circ Arrhythm Electrophysiol 2014; 7(1):10–16. doi:10.1161/CIRCEP.113.001103
- Sheldon RS, Grubb BP, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015; 12(6):e41–e63. doi:10.1016/j.hrthm.2015.03.029
