"We need to be responsible individuals with how we shepherd in this new technology." From the Endometriosis Foundation of America's 4th Annual Medical Symposium: The American Perspective, March 11, 2013

Related article: The robot is gaining ground in gynecologic surgery. Should you be using it?
A roundtable discussion with:
Arnold P. Advincula, MD
Cheryl B. Iglesia, MD
Rosanne M. Kho, MD
Jamal Mourad, DO
Marie Fidela R. Paraiso, MD
Jason D. Wright, MD

"We need to be responsible individuals with how we shepherd in this new technology." From the Endometriosis Foundation of America's 4th Annual Medical Symposium: The American Perspective, March 11, 2013

Related article: The robot is gaining ground in gynecologic surgery. Should you be using it?
A roundtable discussion with:
Arnold P. Advincula, MD
Cheryl B. Iglesia, MD
Rosanne M. Kho, MD
Jamal Mourad, DO
Marie Fidela R. Paraiso, MD
Jason D. Wright, MD

"We need to be responsible individuals with how we shepherd in this new technology." From the Endometriosis Foundation of America's 4th Annual Medical Symposium: The American Perspective, March 11, 2013

Related article: The robot is gaining ground in gynecologic surgery. Should you be using it?
A roundtable discussion with:
Arnold P. Advincula, MD
Cheryl B. Iglesia, MD
Rosanne M. Kho, MD
Jamal Mourad, DO
Marie Fidela R. Paraiso, MD
Jason D. Wright, MD

Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.

In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.

The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).

Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.

Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.

Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."

Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.

Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.

Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.

Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.

Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.

Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.

Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.

Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.

In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.

The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).

Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.

Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.

Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."

Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.

Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.

Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.

Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.

Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.

Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.

Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.

Greater dietary fiber intake is significantly associated with a lower risk of first stroke, according to a study published online ahead of print March 28 in Stroke. Investigators searched several electronic databases for healthy participant studies published between January 1990 and May 2012 that reported fiber intake and incidence of first hemorrhagic or ischemic stroke. The group identified eight cohort studies from the United States, Europe, Australia, and Japan that met their inclusion criteria. Total dietary fiber intake was inversely associated with risk of hemorrhagic plus ischemic stroke. The researchers found evidence of heterogeneity between the studies. Soluble fiber intake of 4 g/day was not associated with stroke risk reduction, and the investigators found evidence of low heterogeneity on this point between the studies.

In women who have episodic migraine, the ratio of high molecular weight to low molecular weight ictal adiponectin (ADP) may be associated with migraine severity and predict acute treatment response, according to a study published in the March Headache. Investigators collected peripheral blood specimens from women with episodic migraine before and after acute abortive treatment with sumatriptan and naproxen sodium or placebo. In all participants, increases in the ratio of high molecular weight to low molecular weight ADP were associated with increases in pain severity. For every 0.25-μg/mL increase in low molecular weight ADP, pain severity decreased by 0.20. In treatment responders, total ADP levels were reduced at 30, 60, and 120 minutes after treatment, compared with onset.

The FDA has approved Tecfidera (dimethyl fumarate) capsules to treat adults with relapsing forms of multiple sclerosis (MS). In two clinical trials, patients with MS who took dimethyl fumarate had fewer relapses compared with people who received placebo. In one of the trials, patients who took dimethyl fumarate experienced a worsening of disability less often than patients who took a placebo. Dimethyl fumarate may decrease a person's white blood cell count, but the drug was not associated with a significant increase in infections in clinical trials. Before starting treatment, and annually thereafter, the FDA recommends that a patient's white blood cell count be assessed by a health care provider. Flushing and stomach problems were the most common adverse reactions reported. Tecfidera is manufactured by Biogen Idec (Weston, Massachusetts).

Mild cognitive impairment (MCI) at the time of Parkinson's disease diagnosis may predict a highly increased risk for early dementia, according to a study published online ahead of print March 25 in JAMA Neurology. Researchers examined data for a population-based cohort of 182 patients with incident Parkinson's disease who were monitored for three years. Significantly more patients with MCI than without MCI at baseline (27.0% versus 0.7%) progressed to dementia during follow-up. Mild cognitive impairment at the one-year visit was associated with a similar progression rate to dementia (ie, 27.8%) and reversion rate to normal cognition (ie, 19.4%). Among the 22 patients with persistent MCI at baseline and the one-year visit, 10 developed dementia and two reverted to normal cognition by the end of the study.

Higher consumption of green tea and coffee may reduce the risk of cardiovascular disease and stroke, according to a study published online ahead of print March 14 in Stroke. Investigators studied 82,369 Japanese persons between ages 45 and 74 without cardiovascular disease or cancer. Green tea and coffee consumption was assessed by a self-administered questionnaire at baseline. Compared with seldom drinking green tea, the multivariable-adjusted hazard ratios of all strokes were 0.86 and 0.80 in individuals who drank two to three and four or more cups of green tea per day, respectively. Compared with seldom drinking coffee, the multivariable-adjusted hazard ratios of all strokes were 0.89, 0.80, and 0.81 for individuals who drank coffee three to six times per week, once daily, and twice or more daily, respectively.

Updated Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries recommend against the use of steroids, including methylprednisolone, in acute spinal cord injury in the first 24 to 48 hours after injury. The use of steroids previously was recommended for this indication with consideration of the risk–reward profile, as evaluated by the physician. In the first new treatment guidelines in a decade, which were issued by the Joint Section on Disorders of the Spine and Peripheral Nerves of the Congress of Neurological Surgeons and the American Association of Neurological Surgeons, the standard has been revised based on the lack of medical evidence supporting the benefits of these drugs in the clinical setting. The report cites strong evidence that "high-dose steroids are associated with harmful side effects, including death."

Abnormalities in cortical surface area may indicate an individual's predisposition to developing migraine, and abnormalities in cortical thickness may result from migraine-related processes, according to research published online ahead of print March 26 in Radiology. Investigators took T2-weighted and three-dimensional T1-weighted MRIs of the brain for 63 migraineurs and 18 controls. They estimated cortical thickness and cortical surface area. Compared with control subjects, patients with migraine had reduced cortical thickness and surface area in pain-processing regions. These reductions were greater in regions involved in executive functions and visual-motion processing. Cortical thickness and cortical surface area abnormalities had minimal areas of overlap. Cortical thickness and surface area abnormalities were related to aura and white matter hyperintensities, but not to disease duration and attack frequency.

Primary stroke centers are more likely to administer t-PA than noncertified hospitals, according to research published online ahead of print March 26 in the Journal of the American Heart Association. Investigators analyzed data obtained from the Nationwide Inpatient Sample between 2004 and 2009 for patients age 18 or older with a primary diagnosis of acute ischemic stroke. IV t-PA was administered to 3.1% of patients overall. The drug was given to 2.2% of patients at noncertified hospitals and to 6.7% of patients at primary stroke centers. Between 2004 and 2009, t-PA administration increased from 1.4% to 3.3% of patients at noncertified hospitals and from 6.0% to 7.6% of patients at primary stroke centers. In a multivariable model, evaluation at a primary stroke center was significantly associated with t-PA use.

Control and prevention of risk factors such as hypertension earlier in life may limit or delay neuropathologic brain changes such as Alzheimer's disease with aging, researchers reported in a study published online ahead of print March 18 in JAMA Neurology. The investigators studied 118 cognitively normal adults ages 47 to 89. Participants were classified as having hypertension if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic on seven occasions. Participants underwent Ab PET imaging with radiotracer fluorine 18–labeled florbetapir, were genotyped for apolipoprotein E, and were classified as ε4+ or ε4−. Subjects with hypertension and at least one ε4 allele had significantly more amyloid burden than those with one or no risk factors.

Physicians can discontinue chronic antipsychotic medication for many elderly adults with Alzheimer's dementia and neuropsychiatric symptoms without causing detrimental effects on their behavior, according to a review published online March 28 in the Cochrane Database of Systematic Reviews. Investigators examined data from nine randomized controlled trials that compared antipsychotic withdrawal strategies with continuation of antipsychotics in patients with dementia. Although neurologists have concerns about the potential adverse events of antipsychotics, it is not clear whether withdrawal is beneficial for patients' cognition or psychomotor status. In two studies of patients whose agitation or psychosis had previously responded well to antipsychotic treatment, discontinuation was associated with an increased risk of relapse or shorter time to relapse. Two studies suggested that patients with severe neuropsychiatric symptoms at baseline could benefit from continuing their antipsychotic medication.

Greater exposure to pathogens associated with stroke risk and atherosclerosis may correlate with poorer cognitive performance, according to research published in the March 26 Neurology. Investigators tested for various pathogens (eg, Chlamydia pneumonia and Helicobacter pylori) in 1,625 participants in the Northern Manhattan Study. The researchers assessed patients' cognitive performance at baseline and at annual follow-up visits. Higher infectious burden index was associated with worse cognition. Each standard deviation in infectious burden correlated with a 0.77-point decline in Mini-Mental State Examination (MMSE) score. Adjustment for risk factors weakened the effect, however. Infectious burden was associated with an MMSE score of 24 or lower. Infectious burden was not associated with cognitive decline over time. Past infections may contribute to cognitive impairment, said the researchers.

Smoking cessation was associated with a decreased risk of cardiovascular disease events, and subsequent weight gain did not modify this association, researchers reported in the March 13 JAMA. Investigators analyzed data collected from 1984 through 2011 in the Framingham Offspring Study. Participants' self-reported smoking status was recorded during four-year examinations. Median four-year weight gain was 2.7 kg for recent smoking quitters without diabetes, 3.6 kg for recent quitters with diabetes, and 0.9 kg for long-term quitters. After adjustment for cardiovascular risk factors, compared with smokers, recent smoking quitters had a hazard ratio for cardiovascular disease of 0.47, and long-term quitters had a hazard ratio of 0.46. The results changed minimally after further adjustment for weight change. Similar point estimates for participants with diabetes did not reach statistical significance.

Women who enter menopause prematurely after bilateral ovariectomy may have a significantly increased risk for cognitive decline and dementia, according to a study published online ahead of print March 9 in Brain. The investigators studied rats 10 weeks after they had undergone bilateral ovariectomy and found that long-term estrogen deprivation dramatically increased the hippocampal CA3 region's sensitivity to ischemic stress, which correlated with a worse cognitive outcome. Long-term ovariectomized rats had robust hyperinduction of Alzheimer's disease-related proteins in the CA3 region. Following ischemic stress, amyloid-precursor protein processing switched from nonamyloidogenic to amyloidogenic. Replacement of 17β-estradiol at the end of the estrogen-deprivation period could not prevent CA3 hypersensitivity and amyloidogenesis, but if 17β-estradiol was initiated at ovariectomy and maintained throughout the estrogen deprivation period, it completely prevented these events.

A 57-year-old man presented to the emergency department (ED) with a two-day history of worsening shortness of breath, light-headedness, and back pain. The patient, who had a history of ankylosing spondylitis, had been receiving weekly therapy from a chiropractor for about 10 years. One week before presenting to the ED, he had begun to undergo daily manipulations under anesthesia (MUA)—an aggressive chiropractic procedure that is administered while the patient is under monitored, procedural sedation. After the second day of treatment, the patient began to experience worsening back pain and progressive light-headedness and shortness of breath.

At a follow-up visit with his chiropractor, he was found to have decreased O2 saturation and was directed to go to the hospital for evaluation. On arrival at the ED, the patient was awake and alert. He had intact motor strength in all extremities, no sensory abnormalities, intact symmetric reflexes, and no bladder or bowel dysfunction, with a negative Babinski sign. His O2 saturation was 92% on 5 L of oxygen. An absence of breath sounds was noted on the left side.

Chest x-ray (see Figure 1) was performed, which demonstrated complete opacification of the left hemithorax, consistent with a large pleural effusion or hemothorax. CT scan of the thoracic spine showed diffuse ankylosis. A complex oblique coronal and transversely oriented fracture with 7 mm of displacement was identified, beginning at the right anterior inferior lateral margin of the T8 vertebral body and extending centrally and inferiorly to the left and right into the T9 vertebral body. The fracture continued through the right T9-10 neural foramen and what was probably the right fused T9-10 facet joint. The fracture exited through the left superior and lateral margin of the T10 vertebral body and the left T10-11 neural foramen (see Figures 2, 3, and 4).

A chest tube was inserted in the ED, and 1,600 mL of old blood was immediately drained. The patient was admitted to the ICU on the trauma service. He was taken to surgery for open reduction and internal fixation of his unstable thoracic spine fracture on day 3 of hospitalization, after his pulmonary condition stabilized. Pedicle screws were placed from T7 through T12 during the spinal fusion. Good reduction of the fracture was observed following the spine surgery (see Figures 5 and 6). At the conclusion of surgery, an epidural catheter was placed in the thoracic spine to administer pain control.

After the spine portion of the procedure, the patient was repositioned and underwent video-assisted thoracoscopic surgery of the left hemithorax for evacuation of retained hemothorax. The patient tolerated the procedure well and was taken to the ICU for recovery.

On postoperative day 2, the patient complained of chest pain and experienced hypoxemia with activity. CT angiography of the chest demonstrated bilateral segmental and subsegmental pulmonary emboli. The epidural catheter was discontinued. Six hours later, a heparin drip was started, and the patient was transitioned to therapeutic enoxaparin and warfarin. When methicillin-sensitive Staphylococcus aureus (MSSA) was detected in his hemothorax fluid, he was treated with a course of nafcillin.

The patient was discharged to home on postoperative day 12. He has remained neurologically intact and has returned to his former work activities. He is not taking narcotic pain medications.

Discussion
Chiropractic care is a popular alternative health care modality in the United States. Researchers for the 2007 National Health Interview Study¹ reported an annual use of chiropractic manipulation of 8.6%, while the Medical Expenditure Panel Survey² data yielded an estimate of 12.6 million adults using chiropractic manipulation in 2006—translating to a prevalence of 5.6%. Despite the popularity of chiropractic medicine, few well-designed studies have been conducted to support its use.^3,4 Because of its designation as an alternative therapy, however, chiropractic manipulation has not been subjected to rigorous efficacy and safety evaluations.⁵

Given the inconsistency of the evidence to support chiropractic manipulation, the practice's safety profile is a concern. The risks associated with spinal manipulation are generally described in case reports and small series. Most serious adverse events described in the literature are cerebrovascular in nature and tend to occur after cervical manipulation.^6,7 Fractures after spine manipulation are exceedingly rare, and published literature on this topic consists of a few isolated case reports, with all fractures occurring in the cervical spine in patients with an underlying pathologic condition.^8-10

In 2009, Gouveia et al⁵ reviewed the published literature regarding all adverse events resulting from chiropractic manipulation. The authors found one randomized controlled trial, two case-control studies, six prospective studies, 12 surveys, three retrospective studies, and 100 case reports. The spectrum of complications identified ranged from benign and transient, such as local discomfort, to far more serious: stroke, myelopathy, radiculopathy, subdural hematoma, spinal fluid leakage, cauda equina syndrome, herniated disc, diaphragmatic palsy, and vertebral fractures. The authors were unable to perform a true meta-analysis because of the heterogeneity of the data, but they concluded that complications associated with chiropractic procedures are "frequent."⁵

Manipulations Under Anesthesia
MUA is a procedure that combines chiropractic adjustments and manipulations with general anesthesia or procedural sedation.¹¹ The theory behind this strategy is that the anesthesia or sedation reduces pain and muscle spasm that may hinder the manipulation, allowing the practitioner to more effectively break up joint adhesions and reduce segmental dysfunction than if the patient had not undergone anesthesia.¹¹

MUA is generally indicated in patients who have not responded to a 4- to 8-week trial of traditional manipulation therapy.¹² It is also considered in patients who have "painful and restricting muscular guarding [that] interferes with the performance of spinal adjustments, mobilizations, and soft tissue release techniques."¹³

In the chiropractic literature, between 3% and 10% of patients are estimated to be candidates for MUA.^12,14 It is not completely clear, however, what diagnoses are most likely to be treated successfully with this technique. Contraindications to MUA are generally the same as those for manipulation in conscious patients. A published list of contraindications from the Committee for Manipulation under Anesthesia (2003)¹⁵ included malignancy with bony metastasis, tuberculosis of the bone, recent fracture, acute arthritis, acute gout, diabetic neuropathy, syphilitic articular lesions, excessive spinal osteoporosis, disk fragmentation, direct nerve root impingement, and evidence of cord or caudal compression by tumor, ankylosis, or other space-occupying lesions.

MUA generally begins with deep procedural sedation, managed by an anesthesiologist. Once an adequate level of sedation is achieved, the manipulations are performed. Both high- and low-velocity thrusts are used, but it is recommended that the force exerted should be much less, and the manipulations performed with more caution, than in patients who are not anesthetized.¹²

For the thoracic spine, the patient is manipulated in the supine position with the arms crossed over the chest. The practitioner places one hand in a fist under the spine with the other hand on the patient's crossed arms, then delivers an anterior-to-posterior thrust. This is repeated until all affected segments have been treated.^11,12

Literature to support the use of MUA for various indications is largely anecdotal. The largest published series¹³ is of 177 patients with chronic spinal pain who each underwent three MUA sessions followed by four to six weeks of traditional manipulations. The authors found that pain, as measured by visual analog scale, was reduced by 62% in patients with cervical spine pain, and by 60% in patients with lumbar pain. No adverse events were reported in the study.

Kohlbeck and Haldeman¹² reviewed the reported complications of MUA across all published literature. They found that in 17 published papers, the overall complication rate was 0.7%, mainly represented by transitory increased pain. No spinal fractures were reported.

This case demonstrates a rare but serious complication of chiropractic MUA. It is unclear exactly what mechanism of injury led to an unstable thoracic spine fracture with massive hemothorax, and the precise cause will probably never be known. The clinicians who treated the case patient find it curious that the reported rate of adverse events following this procedure is so low, but they suspect an element of reporting bias in the chiropractic literature.

Conclusion
Iatrogenic injury after chiropractic manipulation is uncommon, but it can be devastating. Few serious complications of chiropractic MUA have been reported, but the literature is lacking in well-designed research studies. Despite the dearth of clinical trials to support its safety and efficacy, use of MUA has continued in the chiropractic community. This case demonstrates that serious adverse outcomes can occur, and more rigorous studies are needed to delineate the true benefits and risks of this set of chiropractic procedures.

References
1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;12:1-9.

2. Davis MA, Sirovich BE, Weeks WB. Utilization and expenditures on chiropractic care in the United States from 1997 to 2006. Health Serv Res. 2009;45:748-761.

3. Canadian Chiropractic Association; Canadian Federation of Chiropractic Regulatory Boards; Clinical Practice Guidelines Development Initiative; Guidelines Development Committee. Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash. J Can Chiropr Assoc. 2005;49:417-421.

4.

Hurwitz EL, Aker PD, Adams AH, et al. Manipulation and mobilization of the cervical spine: a systematic review of the literature. Spine (Phila Pa 1976). 1996;21:1746-1760.

5.Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions: a systematic review. Spine (Phila Pa 1976). 2009;34:E405-E413. 

6. Di Fabio RP. Manipulation of the cervical spine: risks and benefits. Phys Ther. 1999;79:50-65.

7. Nadareishvili Z, Norris JW. Stroke from traumatic arterial dissection. Lancet. 1999;354:159-160.

8. Austin RT. Pathological vertebral fractures after spinal manipulation. Br Med J (Clin Res Ed). 1985;291:1114-1115.

9. Ea HK, Weber AJ, Yon F, Lioté F. Osteoporotic fracture of the dens revealed by cervical manipulation. Joint Bone Spine. 2004;71:246-250.

10. Schmitz A, Lutterbey G, von Engelhardt L, et al. Pathological cervical fracture after spinal manipulation in a pregnant patient. J Manipulative Physiol Ther. 2005;28:633-636.

11. Cremata E, Collins S, Clauson W, et al. Manipulation under anesthesia: a report of four cases. J Manipulative Physiol Ther. 2005;28:526-533.

12. Kohlbeck FJ, Haldeman S. Medication-assisted spinal manipulation. Spine J. 2002;2:288-302.

13. West DT, Mathews RS, Miller MR, Kent GM. Effective management of spinal pain in one hundred seventy-seven patients evaluated for manipulation under anesthesia. J Manipulative Physiol Ther. 1999;22:299-308.

14. Morey LW Jr. Osteopathic manipulation under general anesthesia. J Am Osteopath Assoc. 1973;73:116-127.

15. Tain L, Gunderson C, Cremata E, et al; Committee for Manipulation Under Anesthesia. Recommendations to the Industrial Medical Council Work Group of California for manipulation under anesthesia use for injured workers. Sacramento, CA: Industrial Medical Council; 2003.

A 57-year-old man presented to the emergency department (ED) with a two-day history of worsening shortness of breath, light-headedness, and back pain. The patient, who had a history of ankylosing spondylitis, had been receiving weekly therapy from a chiropractor for about 10 years. One week before presenting to the ED, he had begun to undergo daily manipulations under anesthesia (MUA)—an aggressive chiropractic procedure that is administered while the patient is under monitored, procedural sedation. After the second day of treatment, the patient began to experience worsening back pain and progressive light-headedness and shortness of breath.

At a follow-up visit with his chiropractor, he was found to have decreased O2 saturation and was directed to go to the hospital for evaluation. On arrival at the ED, the patient was awake and alert. He had intact motor strength in all extremities, no sensory abnormalities, intact symmetric reflexes, and no bladder or bowel dysfunction, with a negative Babinski sign. His O2 saturation was 92% on 5 L of oxygen. An absence of breath sounds was noted on the left side.

Chest x-ray (see Figure 1) was performed, which demonstrated complete opacification of the left hemithorax, consistent with a large pleural effusion or hemothorax. CT scan of the thoracic spine showed diffuse ankylosis. A complex oblique coronal and transversely oriented fracture with 7 mm of displacement was identified, beginning at the right anterior inferior lateral margin of the T8 vertebral body and extending centrally and inferiorly to the left and right into the T9 vertebral body. The fracture continued through the right T9-10 neural foramen and what was probably the right fused T9-10 facet joint. The fracture exited through the left superior and lateral margin of the T10 vertebral body and the left T10-11 neural foramen (see Figures 2, 3, and 4).

A chest tube was inserted in the ED, and 1,600 mL of old blood was immediately drained. The patient was admitted to the ICU on the trauma service. He was taken to surgery for open reduction and internal fixation of his unstable thoracic spine fracture on day 3 of hospitalization, after his pulmonary condition stabilized. Pedicle screws were placed from T7 through T12 during the spinal fusion. Good reduction of the fracture was observed following the spine surgery (see Figures 5 and 6). At the conclusion of surgery, an epidural catheter was placed in the thoracic spine to administer pain control.

After the spine portion of the procedure, the patient was repositioned and underwent video-assisted thoracoscopic surgery of the left hemithorax for evacuation of retained hemothorax. The patient tolerated the procedure well and was taken to the ICU for recovery.

On postoperative day 2, the patient complained of chest pain and experienced hypoxemia with activity. CT angiography of the chest demonstrated bilateral segmental and subsegmental pulmonary emboli. The epidural catheter was discontinued. Six hours later, a heparin drip was started, and the patient was transitioned to therapeutic enoxaparin and warfarin. When methicillin-sensitive Staphylococcus aureus (MSSA) was detected in his hemothorax fluid, he was treated with a course of nafcillin.

The patient was discharged to home on postoperative day 12. He has remained neurologically intact and has returned to his former work activities. He is not taking narcotic pain medications.

Discussion
Chiropractic care is a popular alternative health care modality in the United States. Researchers for the 2007 National Health Interview Study¹ reported an annual use of chiropractic manipulation of 8.6%, while the Medical Expenditure Panel Survey² data yielded an estimate of 12.6 million adults using chiropractic manipulation in 2006—translating to a prevalence of 5.6%. Despite the popularity of chiropractic medicine, few well-designed studies have been conducted to support its use.^3,4 Because of its designation as an alternative therapy, however, chiropractic manipulation has not been subjected to rigorous efficacy and safety evaluations.⁵

Given the inconsistency of the evidence to support chiropractic manipulation, the practice's safety profile is a concern. The risks associated with spinal manipulation are generally described in case reports and small series. Most serious adverse events described in the literature are cerebrovascular in nature and tend to occur after cervical manipulation.^6,7 Fractures after spine manipulation are exceedingly rare, and published literature on this topic consists of a few isolated case reports, with all fractures occurring in the cervical spine in patients with an underlying pathologic condition.^8-10

In 2009, Gouveia et al⁵ reviewed the published literature regarding all adverse events resulting from chiropractic manipulation. The authors found one randomized controlled trial, two case-control studies, six prospective studies, 12 surveys, three retrospective studies, and 100 case reports. The spectrum of complications identified ranged from benign and transient, such as local discomfort, to far more serious: stroke, myelopathy, radiculopathy, subdural hematoma, spinal fluid leakage, cauda equina syndrome, herniated disc, diaphragmatic palsy, and vertebral fractures. The authors were unable to perform a true meta-analysis because of the heterogeneity of the data, but they concluded that complications associated with chiropractic procedures are "frequent."⁵

Manipulations Under Anesthesia
MUA is a procedure that combines chiropractic adjustments and manipulations with general anesthesia or procedural sedation.¹¹ The theory behind this strategy is that the anesthesia or sedation reduces pain and muscle spasm that may hinder the manipulation, allowing the practitioner to more effectively break up joint adhesions and reduce segmental dysfunction than if the patient had not undergone anesthesia.¹¹

MUA is generally indicated in patients who have not responded to a 4- to 8-week trial of traditional manipulation therapy.¹² It is also considered in patients who have "painful and restricting muscular guarding [that] interferes with the performance of spinal adjustments, mobilizations, and soft tissue release techniques."¹³

In the chiropractic literature, between 3% and 10% of patients are estimated to be candidates for MUA.^12,14 It is not completely clear, however, what diagnoses are most likely to be treated successfully with this technique. Contraindications to MUA are generally the same as those for manipulation in conscious patients. A published list of contraindications from the Committee for Manipulation under Anesthesia (2003)¹⁵ included malignancy with bony metastasis, tuberculosis of the bone, recent fracture, acute arthritis, acute gout, diabetic neuropathy, syphilitic articular lesions, excessive spinal osteoporosis, disk fragmentation, direct nerve root impingement, and evidence of cord or caudal compression by tumor, ankylosis, or other space-occupying lesions.

MUA generally begins with deep procedural sedation, managed by an anesthesiologist. Once an adequate level of sedation is achieved, the manipulations are performed. Both high- and low-velocity thrusts are used, but it is recommended that the force exerted should be much less, and the manipulations performed with more caution, than in patients who are not anesthetized.¹²

For the thoracic spine, the patient is manipulated in the supine position with the arms crossed over the chest. The practitioner places one hand in a fist under the spine with the other hand on the patient's crossed arms, then delivers an anterior-to-posterior thrust. This is repeated until all affected segments have been treated.^11,12

Literature to support the use of MUA for various indications is largely anecdotal. The largest published series¹³ is of 177 patients with chronic spinal pain who each underwent three MUA sessions followed by four to six weeks of traditional manipulations. The authors found that pain, as measured by visual analog scale, was reduced by 62% in patients with cervical spine pain, and by 60% in patients with lumbar pain. No adverse events were reported in the study.

Kohlbeck and Haldeman¹² reviewed the reported complications of MUA across all published literature. They found that in 17 published papers, the overall complication rate was 0.7%, mainly represented by transitory increased pain. No spinal fractures were reported.

This case demonstrates a rare but serious complication of chiropractic MUA. It is unclear exactly what mechanism of injury led to an unstable thoracic spine fracture with massive hemothorax, and the precise cause will probably never be known. The clinicians who treated the case patient find it curious that the reported rate of adverse events following this procedure is so low, but they suspect an element of reporting bias in the chiropractic literature.

Conclusion
Iatrogenic injury after chiropractic manipulation is uncommon, but it can be devastating. Few serious complications of chiropractic MUA have been reported, but the literature is lacking in well-designed research studies. Despite the dearth of clinical trials to support its safety and efficacy, use of MUA has continued in the chiropractic community. This case demonstrates that serious adverse outcomes can occur, and more rigorous studies are needed to delineate the true benefits and risks of this set of chiropractic procedures.

References
1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;12:1-9.

2. Davis MA, Sirovich BE, Weeks WB. Utilization and expenditures on chiropractic care in the United States from 1997 to 2006. Health Serv Res. 2009;45:748-761.

3. Canadian Chiropractic Association; Canadian Federation of Chiropractic Regulatory Boards; Clinical Practice Guidelines Development Initiative; Guidelines Development Committee. Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash. J Can Chiropr Assoc. 2005;49:417-421.

4.

Hurwitz EL, Aker PD, Adams AH, et al. Manipulation and mobilization of the cervical spine: a systematic review of the literature. Spine (Phila Pa 1976). 1996;21:1746-1760.

5.Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions: a systematic review. Spine (Phila Pa 1976). 2009;34:E405-E413. 

6. Di Fabio RP. Manipulation of the cervical spine: risks and benefits. Phys Ther. 1999;79:50-65.

7. Nadareishvili Z, Norris JW. Stroke from traumatic arterial dissection. Lancet. 1999;354:159-160.

8. Austin RT. Pathological vertebral fractures after spinal manipulation. Br Med J (Clin Res Ed). 1985;291:1114-1115.

9. Ea HK, Weber AJ, Yon F, Lioté F. Osteoporotic fracture of the dens revealed by cervical manipulation. Joint Bone Spine. 2004;71:246-250.

10. Schmitz A, Lutterbey G, von Engelhardt L, et al. Pathological cervical fracture after spinal manipulation in a pregnant patient. J Manipulative Physiol Ther. 2005;28:633-636.

11. Cremata E, Collins S, Clauson W, et al. Manipulation under anesthesia: a report of four cases. J Manipulative Physiol Ther. 2005;28:526-533.

12. Kohlbeck FJ, Haldeman S. Medication-assisted spinal manipulation. Spine J. 2002;2:288-302.

13. West DT, Mathews RS, Miller MR, Kent GM. Effective management of spinal pain in one hundred seventy-seven patients evaluated for manipulation under anesthesia. J Manipulative Physiol Ther. 1999;22:299-308.

14. Morey LW Jr. Osteopathic manipulation under general anesthesia. J Am Osteopath Assoc. 1973;73:116-127.

15. Tain L, Gunderson C, Cremata E, et al; Committee for Manipulation Under Anesthesia. Recommendations to the Industrial Medical Council Work Group of California for manipulation under anesthesia use for injured workers. Sacramento, CA: Industrial Medical Council; 2003.

A 57-year-old man presented to the emergency department (ED) with a two-day history of worsening shortness of breath, light-headedness, and back pain. The patient, who had a history of ankylosing spondylitis, had been receiving weekly therapy from a chiropractor for about 10 years. One week before presenting to the ED, he had begun to undergo daily manipulations under anesthesia (MUA)—an aggressive chiropractic procedure that is administered while the patient is under monitored, procedural sedation. After the second day of treatment, the patient began to experience worsening back pain and progressive light-headedness and shortness of breath.

At a follow-up visit with his chiropractor, he was found to have decreased O2 saturation and was directed to go to the hospital for evaluation. On arrival at the ED, the patient was awake and alert. He had intact motor strength in all extremities, no sensory abnormalities, intact symmetric reflexes, and no bladder or bowel dysfunction, with a negative Babinski sign. His O2 saturation was 92% on 5 L of oxygen. An absence of breath sounds was noted on the left side.

Chest x-ray (see Figure 1) was performed, which demonstrated complete opacification of the left hemithorax, consistent with a large pleural effusion or hemothorax. CT scan of the thoracic spine showed diffuse ankylosis. A complex oblique coronal and transversely oriented fracture with 7 mm of displacement was identified, beginning at the right anterior inferior lateral margin of the T8 vertebral body and extending centrally and inferiorly to the left and right into the T9 vertebral body. The fracture continued through the right T9-10 neural foramen and what was probably the right fused T9-10 facet joint. The fracture exited through the left superior and lateral margin of the T10 vertebral body and the left T10-11 neural foramen (see Figures 2, 3, and 4).

A chest tube was inserted in the ED, and 1,600 mL of old blood was immediately drained. The patient was admitted to the ICU on the trauma service. He was taken to surgery for open reduction and internal fixation of his unstable thoracic spine fracture on day 3 of hospitalization, after his pulmonary condition stabilized. Pedicle screws were placed from T7 through T12 during the spinal fusion. Good reduction of the fracture was observed following the spine surgery (see Figures 5 and 6). At the conclusion of surgery, an epidural catheter was placed in the thoracic spine to administer pain control.

After the spine portion of the procedure, the patient was repositioned and underwent video-assisted thoracoscopic surgery of the left hemithorax for evacuation of retained hemothorax. The patient tolerated the procedure well and was taken to the ICU for recovery.

On postoperative day 2, the patient complained of chest pain and experienced hypoxemia with activity. CT angiography of the chest demonstrated bilateral segmental and subsegmental pulmonary emboli. The epidural catheter was discontinued. Six hours later, a heparin drip was started, and the patient was transitioned to therapeutic enoxaparin and warfarin. When methicillin-sensitive Staphylococcus aureus (MSSA) was detected in his hemothorax fluid, he was treated with a course of nafcillin.

The patient was discharged to home on postoperative day 12. He has remained neurologically intact and has returned to his former work activities. He is not taking narcotic pain medications.

Discussion
Chiropractic care is a popular alternative health care modality in the United States. Researchers for the 2007 National Health Interview Study¹ reported an annual use of chiropractic manipulation of 8.6%, while the Medical Expenditure Panel Survey² data yielded an estimate of 12.6 million adults using chiropractic manipulation in 2006—translating to a prevalence of 5.6%. Despite the popularity of chiropractic medicine, few well-designed studies have been conducted to support its use.^3,4 Because of its designation as an alternative therapy, however, chiropractic manipulation has not been subjected to rigorous efficacy and safety evaluations.⁵

Given the inconsistency of the evidence to support chiropractic manipulation, the practice's safety profile is a concern. The risks associated with spinal manipulation are generally described in case reports and small series. Most serious adverse events described in the literature are cerebrovascular in nature and tend to occur after cervical manipulation.^6,7 Fractures after spine manipulation are exceedingly rare, and published literature on this topic consists of a few isolated case reports, with all fractures occurring in the cervical spine in patients with an underlying pathologic condition.^8-10

In 2009, Gouveia et al⁵ reviewed the published literature regarding all adverse events resulting from chiropractic manipulation. The authors found one randomized controlled trial, two case-control studies, six prospective studies, 12 surveys, three retrospective studies, and 100 case reports. The spectrum of complications identified ranged from benign and transient, such as local discomfort, to far more serious: stroke, myelopathy, radiculopathy, subdural hematoma, spinal fluid leakage, cauda equina syndrome, herniated disc, diaphragmatic palsy, and vertebral fractures. The authors were unable to perform a true meta-analysis because of the heterogeneity of the data, but they concluded that complications associated with chiropractic procedures are "frequent."⁵

Manipulations Under Anesthesia
MUA is a procedure that combines chiropractic adjustments and manipulations with general anesthesia or procedural sedation.¹¹ The theory behind this strategy is that the anesthesia or sedation reduces pain and muscle spasm that may hinder the manipulation, allowing the practitioner to more effectively break up joint adhesions and reduce segmental dysfunction than if the patient had not undergone anesthesia.¹¹

MUA is generally indicated in patients who have not responded to a 4- to 8-week trial of traditional manipulation therapy.¹² It is also considered in patients who have "painful and restricting muscular guarding [that] interferes with the performance of spinal adjustments, mobilizations, and soft tissue release techniques."¹³

In the chiropractic literature, between 3% and 10% of patients are estimated to be candidates for MUA.^12,14 It is not completely clear, however, what diagnoses are most likely to be treated successfully with this technique. Contraindications to MUA are generally the same as those for manipulation in conscious patients. A published list of contraindications from the Committee for Manipulation under Anesthesia (2003)¹⁵ included malignancy with bony metastasis, tuberculosis of the bone, recent fracture, acute arthritis, acute gout, diabetic neuropathy, syphilitic articular lesions, excessive spinal osteoporosis, disk fragmentation, direct nerve root impingement, and evidence of cord or caudal compression by tumor, ankylosis, or other space-occupying lesions.

MUA generally begins with deep procedural sedation, managed by an anesthesiologist. Once an adequate level of sedation is achieved, the manipulations are performed. Both high- and low-velocity thrusts are used, but it is recommended that the force exerted should be much less, and the manipulations performed with more caution, than in patients who are not anesthetized.¹²

For the thoracic spine, the patient is manipulated in the supine position with the arms crossed over the chest. The practitioner places one hand in a fist under the spine with the other hand on the patient's crossed arms, then delivers an anterior-to-posterior thrust. This is repeated until all affected segments have been treated.^11,12

Literature to support the use of MUA for various indications is largely anecdotal. The largest published series¹³ is of 177 patients with chronic spinal pain who each underwent three MUA sessions followed by four to six weeks of traditional manipulations. The authors found that pain, as measured by visual analog scale, was reduced by 62% in patients with cervical spine pain, and by 60% in patients with lumbar pain. No adverse events were reported in the study.

Kohlbeck and Haldeman¹² reviewed the reported complications of MUA across all published literature. They found that in 17 published papers, the overall complication rate was 0.7%, mainly represented by transitory increased pain. No spinal fractures were reported.

This case demonstrates a rare but serious complication of chiropractic MUA. It is unclear exactly what mechanism of injury led to an unstable thoracic spine fracture with massive hemothorax, and the precise cause will probably never be known. The clinicians who treated the case patient find it curious that the reported rate of adverse events following this procedure is so low, but they suspect an element of reporting bias in the chiropractic literature.

Conclusion
Iatrogenic injury after chiropractic manipulation is uncommon, but it can be devastating. Few serious complications of chiropractic MUA have been reported, but the literature is lacking in well-designed research studies. Despite the dearth of clinical trials to support its safety and efficacy, use of MUA has continued in the chiropractic community. This case demonstrates that serious adverse outcomes can occur, and more rigorous studies are needed to delineate the true benefits and risks of this set of chiropractic procedures.

References
1. Barnes PM, Bloom B, Nahin RL. Complementary and alternative medicine use among adults and children: United States, 2007. Natl Health Stat Report. 2008;12:1-9.

2. Davis MA, Sirovich BE, Weeks WB. Utilization and expenditures on chiropractic care in the United States from 1997 to 2006. Health Serv Res. 2009;45:748-761.

3. Canadian Chiropractic Association; Canadian Federation of Chiropractic Regulatory Boards; Clinical Practice Guidelines Development Initiative; Guidelines Development Committee. Chiropractic clinical practice guideline: evidence-based treatment of adult neck pain not due to whiplash. J Can Chiropr Assoc. 2005;49:417-421.

4.

Hurwitz EL, Aker PD, Adams AH, et al. Manipulation and mobilization of the cervical spine: a systematic review of the literature. Spine (Phila Pa 1976). 1996;21:1746-1760.

5.Gouveia LO, Castanho P, Ferreira JJ. Safety of chiropractic interventions: a systematic review. Spine (Phila Pa 1976). 2009;34:E405-E413. 

6. Di Fabio RP. Manipulation of the cervical spine: risks and benefits. Phys Ther. 1999;79:50-65.

7. Nadareishvili Z, Norris JW. Stroke from traumatic arterial dissection. Lancet. 1999;354:159-160.

8. Austin RT. Pathological vertebral fractures after spinal manipulation. Br Med J (Clin Res Ed). 1985;291:1114-1115.

9. Ea HK, Weber AJ, Yon F, Lioté F. Osteoporotic fracture of the dens revealed by cervical manipulation. Joint Bone Spine. 2004;71:246-250.

10. Schmitz A, Lutterbey G, von Engelhardt L, et al. Pathological cervical fracture after spinal manipulation in a pregnant patient. J Manipulative Physiol Ther. 2005;28:633-636.

11. Cremata E, Collins S, Clauson W, et al. Manipulation under anesthesia: a report of four cases. J Manipulative Physiol Ther. 2005;28:526-533.

12. Kohlbeck FJ, Haldeman S. Medication-assisted spinal manipulation. Spine J. 2002;2:288-302.

13. West DT, Mathews RS, Miller MR, Kent GM. Effective management of spinal pain in one hundred seventy-seven patients evaluated for manipulation under anesthesia. J Manipulative Physiol Ther. 1999;22:299-308.

14. Morey LW Jr. Osteopathic manipulation under general anesthesia. J Am Osteopath Assoc. 1973;73:116-127.

15. Tain L, Gunderson C, Cremata E, et al; Committee for Manipulation Under Anesthesia. Recommendations to the Industrial Medical Council Work Group of California for manipulation under anesthesia use for injured workers. Sacramento, CA: Industrial Medical Council; 2003.

To read the full study, click here.

To read the full study, click here.

To read the full study, click here.

“Counseling is a must with this smoking cessation aid,” stated a PURL published in March 2012 (J Fam Pract. 2012;61:156, 176). “Varenicline [Chantix] is associated with a small but significant harmful effect on CV outcomes.” That statement, and the PURL itself, was based on a meta-analysis published in 2011 by Singh et al.1 The meta-analysis included 14 randomized controlled trials (RCTs) that compared varenicline with placebo for the occurrence of serious cardiovascular disease (CVD) events, including myocardial infarction, coronary artery disease, arrhythmias, stroke, sudden death, and any related coronary death. RCTs that reported no CVD events were excluded.

Using a Peto odds ratio [OR] for analysis, Singh et al reported that varenicline use increased the risk of CVD events compared with placebo (OR=1.72; 95% CI, 1.09-2.71). A more recent meta-analysis by Prochaska et al,² however, challenges the validity of the Singh meta-analysis. As members of the Family Physicians Inquiries Network, which produces the PURLs, we would like to address the questions this newer study raises about varenicline’s actual risk.

The Prochaska meta-analysis included all 14 RCTs analyzed by Singh, and used the same CVD event outcome measures. In addition, Prochaska included 8 trials in which no CVD events were reported, some of which were published after the Singh meta-analysis. And rather than use the Peto OR to estimate the risk, Prochaska calculated the absolute risk (AR). The result? The researchers found no difference in CVD events in the varenicline group compared with placebo (AR=0.27; 95% CI, -0.10 to 0.63; P=.15).

This is a good example of how inclusion criteria, subsequently published clinical trials, and the choice of statistical methods can lead to conflicting conclusions from meta-analyses on the same topic. Including studies that showed no adverse CVD events is more likely to capture the true risk than excluding them, and reporting AR is more meaningful than estimating relative risk based on the Peto OR.

Therefore, the Prochaska findings are more convincing. Given the effectiveness of varenicline and the known benefits of successful smoking cessation, it is important for clinicians to understand that the true risk of CVD adverse events attributable to varenicline is extremely low or even nonexistent.

Dionna Brown, MD
Bernard Ewigman, MD, MSPH
Chicago

“Counseling is a must with this smoking cessation aid,” stated a PURL published in March 2012 (J Fam Pract. 2012;61:156, 176). “Varenicline [Chantix] is associated with a small but significant harmful effect on CV outcomes.” That statement, and the PURL itself, was based on a meta-analysis published in 2011 by Singh et al.1 The meta-analysis included 14 randomized controlled trials (RCTs) that compared varenicline with placebo for the occurrence of serious cardiovascular disease (CVD) events, including myocardial infarction, coronary artery disease, arrhythmias, stroke, sudden death, and any related coronary death. RCTs that reported no CVD events were excluded.

Using a Peto odds ratio [OR] for analysis, Singh et al reported that varenicline use increased the risk of CVD events compared with placebo (OR=1.72; 95% CI, 1.09-2.71). A more recent meta-analysis by Prochaska et al,² however, challenges the validity of the Singh meta-analysis. As members of the Family Physicians Inquiries Network, which produces the PURLs, we would like to address the questions this newer study raises about varenicline’s actual risk.

The Prochaska meta-analysis included all 14 RCTs analyzed by Singh, and used the same CVD event outcome measures. In addition, Prochaska included 8 trials in which no CVD events were reported, some of which were published after the Singh meta-analysis. And rather than use the Peto OR to estimate the risk, Prochaska calculated the absolute risk (AR). The result? The researchers found no difference in CVD events in the varenicline group compared with placebo (AR=0.27; 95% CI, -0.10 to 0.63; P=.15).

This is a good example of how inclusion criteria, subsequently published clinical trials, and the choice of statistical methods can lead to conflicting conclusions from meta-analyses on the same topic. Including studies that showed no adverse CVD events is more likely to capture the true risk than excluding them, and reporting AR is more meaningful than estimating relative risk based on the Peto OR.

Therefore, the Prochaska findings are more convincing. Given the effectiveness of varenicline and the known benefits of successful smoking cessation, it is important for clinicians to understand that the true risk of CVD adverse events attributable to varenicline is extremely low or even nonexistent.

Dionna Brown, MD
Bernard Ewigman, MD, MSPH
Chicago

“Counseling is a must with this smoking cessation aid,” stated a PURL published in March 2012 (J Fam Pract. 2012;61:156, 176). “Varenicline [Chantix] is associated with a small but significant harmful effect on CV outcomes.” That statement, and the PURL itself, was based on a meta-analysis published in 2011 by Singh et al.1 The meta-analysis included 14 randomized controlled trials (RCTs) that compared varenicline with placebo for the occurrence of serious cardiovascular disease (CVD) events, including myocardial infarction, coronary artery disease, arrhythmias, stroke, sudden death, and any related coronary death. RCTs that reported no CVD events were excluded.

Using a Peto odds ratio [OR] for analysis, Singh et al reported that varenicline use increased the risk of CVD events compared with placebo (OR=1.72; 95% CI, 1.09-2.71). A more recent meta-analysis by Prochaska et al,² however, challenges the validity of the Singh meta-analysis. As members of the Family Physicians Inquiries Network, which produces the PURLs, we would like to address the questions this newer study raises about varenicline’s actual risk.

The Prochaska meta-analysis included all 14 RCTs analyzed by Singh, and used the same CVD event outcome measures. In addition, Prochaska included 8 trials in which no CVD events were reported, some of which were published after the Singh meta-analysis. And rather than use the Peto OR to estimate the risk, Prochaska calculated the absolute risk (AR). The result? The researchers found no difference in CVD events in the varenicline group compared with placebo (AR=0.27; 95% CI, -0.10 to 0.63; P=.15).

This is a good example of how inclusion criteria, subsequently published clinical trials, and the choice of statistical methods can lead to conflicting conclusions from meta-analyses on the same topic. Including studies that showed no adverse CVD events is more likely to capture the true risk than excluding them, and reporting AR is more meaningful than estimating relative risk based on the Peto OR.

Therefore, the Prochaska findings are more convincing. Given the effectiveness of varenicline and the known benefits of successful smoking cessation, it is important for clinicians to understand that the true risk of CVD adverse events attributable to varenicline is extremely low or even nonexistent.

Dionna Brown, MD
Bernard Ewigman, MD, MSPH
Chicago

CASE: Worsening insomnia

Mr. Q, age 44, presents for evaluation of altered mental status characterized by disorientation, impaired attention and concentration, paranoid delusions, and prominent auditory and visual hallucinations. His initial Folstein Mini-Mental State Examination (MMSE) score is 7 of 30, indicating severe impairment. He further describes a recent history of nausea, intermittent vomiting, and anorexia. He takes hydrocodone/acetaminophen, 5/500 mg, 4 times daily for lower back and joint pain. Additionally, he has a pacemaker, which was placed when Mr. Q was in his late 30s to treat sinus bradycardia.

Mr. Q’s fiancée describes his 6-month history of worsening sleep disturbance, noting insomnia, fractured sleep, dream enactment, and daytime fatigue. During this time, Mr. Q averaged 3 to 4 hours of sleep nightly without day-time naps. Ten days ago, he stopped sleeping completely and his cognitive function decompensated rapidly. He became increasingly paranoid, believing government agents had been dispatched to kill him. Several days before admission, Mr. Q developed auditory and visual hallucinations. He reports that he hears voices warning him of Armageddon and sees reincarnated spirits of deceased relatives. He describes his mood as “fine” and “okay” and lacks insight into his psychiatric symptoms other than his sleeplessness.

Mr. Q’s family says he has a history of transient mild depression after his older brother died from an unknown neurologic disease 3 years ago. Mr. Q did not receive pharmacotherapy or psychotherapy but his symptoms resolved. His family says that Mr. Q has been using marijuana daily for several years, but they are unaware of other substance use. They deny a family history of psychiatric illness.

On physical examination, Mr. Q appears thin, agitated, and in mild distress. He has a fever of 99.2°F. His blood pressure drops intermittently from a baseline of 120/70 mm Hg to 100/60 mm Hg, at which point he experiences transient normal sinus tachycardia. Neurologic examination reveals psychomotor agitation and diffuse myoclonic tremor.

The authors’ observations

Table 1

Differential diagnosis of insomnia

Medications that can cause or exacerbate insomnia

EVALUATION: Inconclusive results

Routine laboratory studies reveal mild normocytic anemia and mild hypokalemia. Liver panel, renal function, cardiac profile, brain natriuretic peptide level, folate and vitamin B12 levels, thyroid studies, and human immunodeficiency virus serology are negative or within normal limits. Urinalysis reveals the presence of ketones, indicative of Mr. Q’s recent anorexia. Chest radiography and CT imaging of the head, abdomen, and pelvis also are unremarkable. MRI is contraindicated because of Mr. Q’s implanted pacemaker. Pulse oximetry does not suggest apneic events. Mr. Q and his family refuse a lumbar puncture, which precludes cerebrospinal fluid (CSF) analysis. Electroencephalography (EEG) records normal patterns of wakefulness oscillating with transient periods of stage 1 sleep. A detailed family interview reveals that Mr. Q’s older brother had a history of epilepsy and died at age 49 following a prolonged hospitalization for recurrent seizures and similar insomnia symptoms. History from the patient’s paternal lineage is not available.

The authors’ observations

American Psychiatric Association practice guidelines³ do not support first-line use of benzodiazepines for non-alcohol withdrawal-related delirium. Benzodiazepines are ineffective for treating delirium and may exacerbate symptoms.⁴ Laboratory evidence confirmed Mr. Q has no history of alcohol or benzodiazepine use. Although treating the underlying cause of delirium is essential, prescribing a sedative-hypnotic medication such as zolpidem for Mr. Q’s insomnia may worsen his condition. These agents are known to impair cognition and may induce or intensify psychosis.⁵ Melatonin and melatonin receptor agonists, such as ramelteon, promote sleep by regulating the sleep-wake rhythm through their action on melatonin receptors in the hypothalamus.⁶ Recently, a randomized control trial (RCT)⁷ found melatonin protected against delirium in hospitalized patients age ≥65. However, no RCT has examined use of exogenous melatonin or melatonin receptor agonists to treat delirium. In Mr. Q’s case, we chose to administer haloperidol. First- and second-generation antipsychotics have shown efficacy in treating acute delirium. Although more clinical experience has accumulated using first-generation agents such as haloperidol, a 2007 Cochrane meta-analysis⁸ demonstrated equal benefit with second-generation antipsychotics, while noting a decreased incidence of adverse effects.

TREATMENT: Adverse effects

Mr. Q receives an IM injection of haloperidol, 5 mg, for severe agitation, followed 15 hours later by IM aripiprazole, 9.75 mg. Within hours of receiving aripiprazole, Mr. Q develops hyperkinetic perioral and tongue movements. He initially is diagnosed with acute reactionary dystonia, although closer examination reveals myoclonus consistent with his overall presentation. Additionally, his QTc interval increases by 120 ms. Subsequently, all antipsychotics are stopped. We prescribe lorazepam, 1 mg IM every 4 hours as needed, for agitation. Mr. Q receives 2 consecutive doses of lorazepam, although neither effectively reduces his agitation or promotes sleep. Mr. Q is not assessed with positron-emission tomography (PET) or polysomnography.

The authors’ observations

There was no evidence of neurologic disease on Mr. Q’s CT scan and EEG was within normal limits. Other imaging and laboratory studies did not reveal possible infection, malignancy, or cardiovascular disease. Despite its rarity, we considered the possibility of a prion disease, given Mr. Q’s unique presentation and family history. Familial fatal insomnia (FFI) is an autosomal dominant disease caused by a point mutation in the prion protein gene. Prion proteins are theorized to play a role in myelin stability. The aberrant isoform produced in FFI is structurally misfolded so that it resists degradation by proteolytic enzymes. The accumulation of irregular prion proteins in the medial thalamic nucleus results in progressive neurodegeneration. Patients with FFI present with increasingly severe insomnia, mild fever, dysautonomia, spontaneous myoclonus, cognitive dysfunction, and hallucinations.⁹ Generally, patients die from sudden cardiorespiratory failure or ensuing infections 9 to 24 months after symptom onset. In vivo, FFI diagnosis is suggested by a loss of sleep spindles on polysomnogram and by decreased thalamic metabolism on PET scan. Other imaging modalities and testing, including EEG and CSF analysis, lack sensitivity and/or specificity.¹⁰

OUTCOME: Improvement, discharge

On his fourth hospital day, Mr. Q’s symptoms begin to remit spontaneously. His gastrointestinal (GI) upset improves and the following night he sleeps for approximately 4 hours. As his sleep improves, his delusional thinking and hallucinations resolve. Orientation, memory, and concentration gradually improve. Before discharge, his MMSE score is 24 out of 30, indicating improved cognition. His heart rate, blood pressure, and body temperature normalize and his myoclonus improves. Mr. Q is discharged after 6 days in the hospital and returns home. He follows up with his primary care physician, denies any recurrence of sleep disturbance, and reports that his cognition and perception have returned to his baseline.

The authors’ observations

Table 3

DSM-IV-TR diagnostic criteria for opioid withdrawal

• Morin CM, Benca R. Chronic insomnia. Lancet. 2012; 379(9821):1129-1141.
  
• Pressman MR, Orr WC, eds. Understanding sleep: the evolution and treatment of sleep disorders. Washington, DC: American Psychological Association; 1997.
  
• NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements. 2005;22(2):1-30.
  

• Albuterol • Proventil, Ventolin
  
• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin, Zyban
  
• Dextroamphetamine • Dexadrine
  
• Haloperidol • Haldol
  
• Hydrocodone/Acetaminophen • Vicodin
  
• Lamotrigine • Lamictal
  
• Lorazepam • Ativan
  
• Methylphenidate • Methylin, Ritalin
  
• Phenylephrine • Neo-Synephrine
  
• Pseudoephedrine • Sudafed
  
• Ramelteon • Rozerem
  
• Theophylline • Elixophyllin, Slo-Phyllin
  
• Zolpidem • Ambien
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Worsening insomnia

Mr. Q, age 44, presents for evaluation of altered mental status characterized by disorientation, impaired attention and concentration, paranoid delusions, and prominent auditory and visual hallucinations. His initial Folstein Mini-Mental State Examination (MMSE) score is 7 of 30, indicating severe impairment. He further describes a recent history of nausea, intermittent vomiting, and anorexia. He takes hydrocodone/acetaminophen, 5/500 mg, 4 times daily for lower back and joint pain. Additionally, he has a pacemaker, which was placed when Mr. Q was in his late 30s to treat sinus bradycardia.

Mr. Q’s fiancée describes his 6-month history of worsening sleep disturbance, noting insomnia, fractured sleep, dream enactment, and daytime fatigue. During this time, Mr. Q averaged 3 to 4 hours of sleep nightly without day-time naps. Ten days ago, he stopped sleeping completely and his cognitive function decompensated rapidly. He became increasingly paranoid, believing government agents had been dispatched to kill him. Several days before admission, Mr. Q developed auditory and visual hallucinations. He reports that he hears voices warning him of Armageddon and sees reincarnated spirits of deceased relatives. He describes his mood as “fine” and “okay” and lacks insight into his psychiatric symptoms other than his sleeplessness.

Mr. Q’s family says he has a history of transient mild depression after his older brother died from an unknown neurologic disease 3 years ago. Mr. Q did not receive pharmacotherapy or psychotherapy but his symptoms resolved. His family says that Mr. Q has been using marijuana daily for several years, but they are unaware of other substance use. They deny a family history of psychiatric illness.

On physical examination, Mr. Q appears thin, agitated, and in mild distress. He has a fever of 99.2°F. His blood pressure drops intermittently from a baseline of 120/70 mm Hg to 100/60 mm Hg, at which point he experiences transient normal sinus tachycardia. Neurologic examination reveals psychomotor agitation and diffuse myoclonic tremor.

The authors’ observations

Table 1

Differential diagnosis of insomnia

Medications that can cause or exacerbate insomnia

EVALUATION: Inconclusive results

Routine laboratory studies reveal mild normocytic anemia and mild hypokalemia. Liver panel, renal function, cardiac profile, brain natriuretic peptide level, folate and vitamin B12 levels, thyroid studies, and human immunodeficiency virus serology are negative or within normal limits. Urinalysis reveals the presence of ketones, indicative of Mr. Q’s recent anorexia. Chest radiography and CT imaging of the head, abdomen, and pelvis also are unremarkable. MRI is contraindicated because of Mr. Q’s implanted pacemaker. Pulse oximetry does not suggest apneic events. Mr. Q and his family refuse a lumbar puncture, which precludes cerebrospinal fluid (CSF) analysis. Electroencephalography (EEG) records normal patterns of wakefulness oscillating with transient periods of stage 1 sleep. A detailed family interview reveals that Mr. Q’s older brother had a history of epilepsy and died at age 49 following a prolonged hospitalization for recurrent seizures and similar insomnia symptoms. History from the patient’s paternal lineage is not available.

The authors’ observations

American Psychiatric Association practice guidelines³ do not support first-line use of benzodiazepines for non-alcohol withdrawal-related delirium. Benzodiazepines are ineffective for treating delirium and may exacerbate symptoms.⁴ Laboratory evidence confirmed Mr. Q has no history of alcohol or benzodiazepine use. Although treating the underlying cause of delirium is essential, prescribing a sedative-hypnotic medication such as zolpidem for Mr. Q’s insomnia may worsen his condition. These agents are known to impair cognition and may induce or intensify psychosis.⁵ Melatonin and melatonin receptor agonists, such as ramelteon, promote sleep by regulating the sleep-wake rhythm through their action on melatonin receptors in the hypothalamus.⁶ Recently, a randomized control trial (RCT)⁷ found melatonin protected against delirium in hospitalized patients age ≥65. However, no RCT has examined use of exogenous melatonin or melatonin receptor agonists to treat delirium. In Mr. Q’s case, we chose to administer haloperidol. First- and second-generation antipsychotics have shown efficacy in treating acute delirium. Although more clinical experience has accumulated using first-generation agents such as haloperidol, a 2007 Cochrane meta-analysis⁸ demonstrated equal benefit with second-generation antipsychotics, while noting a decreased incidence of adverse effects.

TREATMENT: Adverse effects

Mr. Q receives an IM injection of haloperidol, 5 mg, for severe agitation, followed 15 hours later by IM aripiprazole, 9.75 mg. Within hours of receiving aripiprazole, Mr. Q develops hyperkinetic perioral and tongue movements. He initially is diagnosed with acute reactionary dystonia, although closer examination reveals myoclonus consistent with his overall presentation. Additionally, his QTc interval increases by 120 ms. Subsequently, all antipsychotics are stopped. We prescribe lorazepam, 1 mg IM every 4 hours as needed, for agitation. Mr. Q receives 2 consecutive doses of lorazepam, although neither effectively reduces his agitation or promotes sleep. Mr. Q is not assessed with positron-emission tomography (PET) or polysomnography.

The authors’ observations

There was no evidence of neurologic disease on Mr. Q’s CT scan and EEG was within normal limits. Other imaging and laboratory studies did not reveal possible infection, malignancy, or cardiovascular disease. Despite its rarity, we considered the possibility of a prion disease, given Mr. Q’s unique presentation and family history. Familial fatal insomnia (FFI) is an autosomal dominant disease caused by a point mutation in the prion protein gene. Prion proteins are theorized to play a role in myelin stability. The aberrant isoform produced in FFI is structurally misfolded so that it resists degradation by proteolytic enzymes. The accumulation of irregular prion proteins in the medial thalamic nucleus results in progressive neurodegeneration. Patients with FFI present with increasingly severe insomnia, mild fever, dysautonomia, spontaneous myoclonus, cognitive dysfunction, and hallucinations.⁹ Generally, patients die from sudden cardiorespiratory failure or ensuing infections 9 to 24 months after symptom onset. In vivo, FFI diagnosis is suggested by a loss of sleep spindles on polysomnogram and by decreased thalamic metabolism on PET scan. Other imaging modalities and testing, including EEG and CSF analysis, lack sensitivity and/or specificity.¹⁰

OUTCOME: Improvement, discharge

On his fourth hospital day, Mr. Q’s symptoms begin to remit spontaneously. His gastrointestinal (GI) upset improves and the following night he sleeps for approximately 4 hours. As his sleep improves, his delusional thinking and hallucinations resolve. Orientation, memory, and concentration gradually improve. Before discharge, his MMSE score is 24 out of 30, indicating improved cognition. His heart rate, blood pressure, and body temperature normalize and his myoclonus improves. Mr. Q is discharged after 6 days in the hospital and returns home. He follows up with his primary care physician, denies any recurrence of sleep disturbance, and reports that his cognition and perception have returned to his baseline.

The authors’ observations

Table 3

DSM-IV-TR diagnostic criteria for opioid withdrawal

• Morin CM, Benca R. Chronic insomnia. Lancet. 2012; 379(9821):1129-1141.
  
• Pressman MR, Orr WC, eds. Understanding sleep: the evolution and treatment of sleep disorders. Washington, DC: American Psychological Association; 1997.
  
• NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements. 2005;22(2):1-30.
  

• Albuterol • Proventil, Ventolin
  
• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin, Zyban
  
• Dextroamphetamine • Dexadrine
  
• Haloperidol • Haldol
  
• Hydrocodone/Acetaminophen • Vicodin
  
• Lamotrigine • Lamictal
  
• Lorazepam • Ativan
  
• Methylphenidate • Methylin, Ritalin
  
• Phenylephrine • Neo-Synephrine
  
• Pseudoephedrine • Sudafed
  
• Ramelteon • Rozerem
  
• Theophylline • Elixophyllin, Slo-Phyllin
  
• Zolpidem • Ambien
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Worsening insomnia

Mr. Q, age 44, presents for evaluation of altered mental status characterized by disorientation, impaired attention and concentration, paranoid delusions, and prominent auditory and visual hallucinations. His initial Folstein Mini-Mental State Examination (MMSE) score is 7 of 30, indicating severe impairment. He further describes a recent history of nausea, intermittent vomiting, and anorexia. He takes hydrocodone/acetaminophen, 5/500 mg, 4 times daily for lower back and joint pain. Additionally, he has a pacemaker, which was placed when Mr. Q was in his late 30s to treat sinus bradycardia.

Mr. Q’s fiancée describes his 6-month history of worsening sleep disturbance, noting insomnia, fractured sleep, dream enactment, and daytime fatigue. During this time, Mr. Q averaged 3 to 4 hours of sleep nightly without day-time naps. Ten days ago, he stopped sleeping completely and his cognitive function decompensated rapidly. He became increasingly paranoid, believing government agents had been dispatched to kill him. Several days before admission, Mr. Q developed auditory and visual hallucinations. He reports that he hears voices warning him of Armageddon and sees reincarnated spirits of deceased relatives. He describes his mood as “fine” and “okay” and lacks insight into his psychiatric symptoms other than his sleeplessness.

Mr. Q’s family says he has a history of transient mild depression after his older brother died from an unknown neurologic disease 3 years ago. Mr. Q did not receive pharmacotherapy or psychotherapy but his symptoms resolved. His family says that Mr. Q has been using marijuana daily for several years, but they are unaware of other substance use. They deny a family history of psychiatric illness.

On physical examination, Mr. Q appears thin, agitated, and in mild distress. He has a fever of 99.2°F. His blood pressure drops intermittently from a baseline of 120/70 mm Hg to 100/60 mm Hg, at which point he experiences transient normal sinus tachycardia. Neurologic examination reveals psychomotor agitation and diffuse myoclonic tremor.

The authors’ observations

Table 1

Differential diagnosis of insomnia

Medications that can cause or exacerbate insomnia

EVALUATION: Inconclusive results

Routine laboratory studies reveal mild normocytic anemia and mild hypokalemia. Liver panel, renal function, cardiac profile, brain natriuretic peptide level, folate and vitamin B12 levels, thyroid studies, and human immunodeficiency virus serology are negative or within normal limits. Urinalysis reveals the presence of ketones, indicative of Mr. Q’s recent anorexia. Chest radiography and CT imaging of the head, abdomen, and pelvis also are unremarkable. MRI is contraindicated because of Mr. Q’s implanted pacemaker. Pulse oximetry does not suggest apneic events. Mr. Q and his family refuse a lumbar puncture, which precludes cerebrospinal fluid (CSF) analysis. Electroencephalography (EEG) records normal patterns of wakefulness oscillating with transient periods of stage 1 sleep. A detailed family interview reveals that Mr. Q’s older brother had a history of epilepsy and died at age 49 following a prolonged hospitalization for recurrent seizures and similar insomnia symptoms. History from the patient’s paternal lineage is not available.

The authors’ observations

American Psychiatric Association practice guidelines³ do not support first-line use of benzodiazepines for non-alcohol withdrawal-related delirium. Benzodiazepines are ineffective for treating delirium and may exacerbate symptoms.⁴ Laboratory evidence confirmed Mr. Q has no history of alcohol or benzodiazepine use. Although treating the underlying cause of delirium is essential, prescribing a sedative-hypnotic medication such as zolpidem for Mr. Q’s insomnia may worsen his condition. These agents are known to impair cognition and may induce or intensify psychosis.⁵ Melatonin and melatonin receptor agonists, such as ramelteon, promote sleep by regulating the sleep-wake rhythm through their action on melatonin receptors in the hypothalamus.⁶ Recently, a randomized control trial (RCT)⁷ found melatonin protected against delirium in hospitalized patients age ≥65. However, no RCT has examined use of exogenous melatonin or melatonin receptor agonists to treat delirium. In Mr. Q’s case, we chose to administer haloperidol. First- and second-generation antipsychotics have shown efficacy in treating acute delirium. Although more clinical experience has accumulated using first-generation agents such as haloperidol, a 2007 Cochrane meta-analysis⁸ demonstrated equal benefit with second-generation antipsychotics, while noting a decreased incidence of adverse effects.

TREATMENT: Adverse effects

Mr. Q receives an IM injection of haloperidol, 5 mg, for severe agitation, followed 15 hours later by IM aripiprazole, 9.75 mg. Within hours of receiving aripiprazole, Mr. Q develops hyperkinetic perioral and tongue movements. He initially is diagnosed with acute reactionary dystonia, although closer examination reveals myoclonus consistent with his overall presentation. Additionally, his QTc interval increases by 120 ms. Subsequently, all antipsychotics are stopped. We prescribe lorazepam, 1 mg IM every 4 hours as needed, for agitation. Mr. Q receives 2 consecutive doses of lorazepam, although neither effectively reduces his agitation or promotes sleep. Mr. Q is not assessed with positron-emission tomography (PET) or polysomnography.

The authors’ observations

There was no evidence of neurologic disease on Mr. Q’s CT scan and EEG was within normal limits. Other imaging and laboratory studies did not reveal possible infection, malignancy, or cardiovascular disease. Despite its rarity, we considered the possibility of a prion disease, given Mr. Q’s unique presentation and family history. Familial fatal insomnia (FFI) is an autosomal dominant disease caused by a point mutation in the prion protein gene. Prion proteins are theorized to play a role in myelin stability. The aberrant isoform produced in FFI is structurally misfolded so that it resists degradation by proteolytic enzymes. The accumulation of irregular prion proteins in the medial thalamic nucleus results in progressive neurodegeneration. Patients with FFI present with increasingly severe insomnia, mild fever, dysautonomia, spontaneous myoclonus, cognitive dysfunction, and hallucinations.⁹ Generally, patients die from sudden cardiorespiratory failure or ensuing infections 9 to 24 months after symptom onset. In vivo, FFI diagnosis is suggested by a loss of sleep spindles on polysomnogram and by decreased thalamic metabolism on PET scan. Other imaging modalities and testing, including EEG and CSF analysis, lack sensitivity and/or specificity.¹⁰

OUTCOME: Improvement, discharge

On his fourth hospital day, Mr. Q’s symptoms begin to remit spontaneously. His gastrointestinal (GI) upset improves and the following night he sleeps for approximately 4 hours. As his sleep improves, his delusional thinking and hallucinations resolve. Orientation, memory, and concentration gradually improve. Before discharge, his MMSE score is 24 out of 30, indicating improved cognition. His heart rate, blood pressure, and body temperature normalize and his myoclonus improves. Mr. Q is discharged after 6 days in the hospital and returns home. He follows up with his primary care physician, denies any recurrence of sleep disturbance, and reports that his cognition and perception have returned to his baseline.

The authors’ observations

Table 3

DSM-IV-TR diagnostic criteria for opioid withdrawal

• Morin CM, Benca R. Chronic insomnia. Lancet. 2012; 379(9821):1129-1141.
  
• Pressman MR, Orr WC, eds. Understanding sleep: the evolution and treatment of sleep disorders. Washington, DC: American Psychological Association; 1997.
  
• NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements. 2005;22(2):1-30.
  

• Albuterol • Proventil, Ventolin
  
• Aripiprazole • Abilify
  
• Bupropion • Wellbutrin, Zyban
  
• Dextroamphetamine • Dexadrine
  
• Haloperidol • Haldol
  
• Hydrocodone/Acetaminophen • Vicodin
  
• Lamotrigine • Lamictal
  
• Lorazepam • Ativan
  
• Methylphenidate • Methylin, Ritalin
  
• Phenylephrine • Neo-Synephrine
  
• Pseudoephedrine • Sudafed
  
• Ramelteon • Rozerem
  
• Theophylline • Elixophyllin, Slo-Phyllin
  
• Zolpidem • Ambien
  

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.