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Neurologic disease eventually affects half of women and one-third of men
Around one-half of women and one-third of men will develop dementia, stroke, or parkinsonism during their lifetime, based on results from the population-based Rotterdam study published in the Oct. 1 online edition of the Journal of Neurology, Neurosurgery & Psychiatry.
The study involved 12,102 individuals (57.7% women) who were aged 45 years or older and free from neurologic disease at baseline who were followed for 26 years.
Silvan Licher, MD, and colleagues from the University Medical Center Rotterdam (the Netherlands) found that a 45-year-old woman had a 48.2% overall remaining lifetime risk of developing dementia, stroke, or parkinsonism, while a 45-year-old man had a 36.3% lifetime risk.
“There are currently no disease-modifying drugs available for dementia and most causes of parkinsonism, and prevention of stroke is hampered by suboptimal adherence to effective preventive strategies or unmet guideline thresholds,” the authors wrote. “Yet, a delay in onset of these common neurologic diseases by merely a few years could reduce the population burden of these diseases substantially.”
Women aged 45 years had a significantly higher lifetime risk than men of developing dementia (31.4% vs. 18.6% respectively) and stroke (21.6% vs. 19.3%), but the risk of parkinsonism was similar between the sexes.
Women also had a significantly greater lifetime risk of developing more than one neurologic disease, compared with men (4% vs. 3.1%, P less than .001), largely because of the overlap between dementia and stroke.
At age 45 women had the greatest risk of dementia, but as men and women aged, their remaining lifetime risk of dementia increased relative to other neurologic diseases. After age 85 years, 66.6% of first diagnoses in women and 55.6% in men were dementia.
By comparison, first manifestation of stroke was the greatest threat to men aged 45. Men were also at a significantly higher risk for stroke at a younger age – before age 75 years – than were women (8.4% vs. 5.8%).
In the case of parkinsonism, the lifetime risk peaked earlier than it did for dementia and stroke, and was relatively low after the age of 85 years, with no significant differences in risk between men and women.
The authors also considered what effect a delay in disease onset and occurrence might have on remaining lifetime risk for neurologic disease. They found that a 1, 2, or 3-year delay in the onset of all neurologic disease was associated with a 20% reduction in lifetime risk in individuals aged 45 years or older, and a greater than 50% reduction in risk in the very oldest.
A 3-year delay in the onset of dementia reduced the lifetime risk by 15% for both men and women aged 45 years and granted a 30% reduction in risk to those aged 45 years or older.
The Rotterdam study is supported by Erasmus MC and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research, The Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission and the Municipality of Rotterdam, the Netherlands Consortium for Healthy Ageing, and the Dutch Heart Foundation. No conflicts of interest were declared.
SOURCE: Licher S et al. JNNP. 2018 Oct 1. doi: 10.1136/jnnp-2018-318650.
Around one-half of women and one-third of men will develop dementia, stroke, or parkinsonism during their lifetime, based on results from the population-based Rotterdam study published in the Oct. 1 online edition of the Journal of Neurology, Neurosurgery & Psychiatry.
The study involved 12,102 individuals (57.7% women) who were aged 45 years or older and free from neurologic disease at baseline who were followed for 26 years.
Silvan Licher, MD, and colleagues from the University Medical Center Rotterdam (the Netherlands) found that a 45-year-old woman had a 48.2% overall remaining lifetime risk of developing dementia, stroke, or parkinsonism, while a 45-year-old man had a 36.3% lifetime risk.
“There are currently no disease-modifying drugs available for dementia and most causes of parkinsonism, and prevention of stroke is hampered by suboptimal adherence to effective preventive strategies or unmet guideline thresholds,” the authors wrote. “Yet, a delay in onset of these common neurologic diseases by merely a few years could reduce the population burden of these diseases substantially.”
Women aged 45 years had a significantly higher lifetime risk than men of developing dementia (31.4% vs. 18.6% respectively) and stroke (21.6% vs. 19.3%), but the risk of parkinsonism was similar between the sexes.
Women also had a significantly greater lifetime risk of developing more than one neurologic disease, compared with men (4% vs. 3.1%, P less than .001), largely because of the overlap between dementia and stroke.
At age 45 women had the greatest risk of dementia, but as men and women aged, their remaining lifetime risk of dementia increased relative to other neurologic diseases. After age 85 years, 66.6% of first diagnoses in women and 55.6% in men were dementia.
By comparison, first manifestation of stroke was the greatest threat to men aged 45. Men were also at a significantly higher risk for stroke at a younger age – before age 75 years – than were women (8.4% vs. 5.8%).
In the case of parkinsonism, the lifetime risk peaked earlier than it did for dementia and stroke, and was relatively low after the age of 85 years, with no significant differences in risk between men and women.
The authors also considered what effect a delay in disease onset and occurrence might have on remaining lifetime risk for neurologic disease. They found that a 1, 2, or 3-year delay in the onset of all neurologic disease was associated with a 20% reduction in lifetime risk in individuals aged 45 years or older, and a greater than 50% reduction in risk in the very oldest.
A 3-year delay in the onset of dementia reduced the lifetime risk by 15% for both men and women aged 45 years and granted a 30% reduction in risk to those aged 45 years or older.
The Rotterdam study is supported by Erasmus MC and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research, The Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission and the Municipality of Rotterdam, the Netherlands Consortium for Healthy Ageing, and the Dutch Heart Foundation. No conflicts of interest were declared.
SOURCE: Licher S et al. JNNP. 2018 Oct 1. doi: 10.1136/jnnp-2018-318650.
Around one-half of women and one-third of men will develop dementia, stroke, or parkinsonism during their lifetime, based on results from the population-based Rotterdam study published in the Oct. 1 online edition of the Journal of Neurology, Neurosurgery & Psychiatry.
The study involved 12,102 individuals (57.7% women) who were aged 45 years or older and free from neurologic disease at baseline who were followed for 26 years.
Silvan Licher, MD, and colleagues from the University Medical Center Rotterdam (the Netherlands) found that a 45-year-old woman had a 48.2% overall remaining lifetime risk of developing dementia, stroke, or parkinsonism, while a 45-year-old man had a 36.3% lifetime risk.
“There are currently no disease-modifying drugs available for dementia and most causes of parkinsonism, and prevention of stroke is hampered by suboptimal adherence to effective preventive strategies or unmet guideline thresholds,” the authors wrote. “Yet, a delay in onset of these common neurologic diseases by merely a few years could reduce the population burden of these diseases substantially.”
Women aged 45 years had a significantly higher lifetime risk than men of developing dementia (31.4% vs. 18.6% respectively) and stroke (21.6% vs. 19.3%), but the risk of parkinsonism was similar between the sexes.
Women also had a significantly greater lifetime risk of developing more than one neurologic disease, compared with men (4% vs. 3.1%, P less than .001), largely because of the overlap between dementia and stroke.
At age 45 women had the greatest risk of dementia, but as men and women aged, their remaining lifetime risk of dementia increased relative to other neurologic diseases. After age 85 years, 66.6% of first diagnoses in women and 55.6% in men were dementia.
By comparison, first manifestation of stroke was the greatest threat to men aged 45. Men were also at a significantly higher risk for stroke at a younger age – before age 75 years – than were women (8.4% vs. 5.8%).
In the case of parkinsonism, the lifetime risk peaked earlier than it did for dementia and stroke, and was relatively low after the age of 85 years, with no significant differences in risk between men and women.
The authors also considered what effect a delay in disease onset and occurrence might have on remaining lifetime risk for neurologic disease. They found that a 1, 2, or 3-year delay in the onset of all neurologic disease was associated with a 20% reduction in lifetime risk in individuals aged 45 years or older, and a greater than 50% reduction in risk in the very oldest.
A 3-year delay in the onset of dementia reduced the lifetime risk by 15% for both men and women aged 45 years and granted a 30% reduction in risk to those aged 45 years or older.
The Rotterdam study is supported by Erasmus MC and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research, The Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission and the Municipality of Rotterdam, the Netherlands Consortium for Healthy Ageing, and the Dutch Heart Foundation. No conflicts of interest were declared.
SOURCE: Licher S et al. JNNP. 2018 Oct 1. doi: 10.1136/jnnp-2018-318650.
FROM JOURNAL OF NEUROLOGY, NEUROSURGERY & PSYCHIATRY
Major finding: A 45-year-old woman has a 48.2% lifetime risk of stroke, dementia, or parkinsonism, while a man has a 36.3% lifetime risk.
Study details: Population-based cohort study in 12,102 individuals.
Disclosures: The Rotterdam study is supported by Erasmus MC and Erasmus University Rotterdam, The Netherlands Organization for Scientific Research, The Netherlands Organization for Health Research and Development, the Research Institute for Diseases in the Elderly, The Netherlands Genomics Initiative, the Ministry of Education, Culture and Science, the Ministry of Health, Welfare and Sports, the European Commission and the Municipality of Rotterdam, the Netherlands Consortium for Healthy Ageing, and the Dutch Heart Foundation. No financial conflicts of interest were declared.
Source: Licher S et al. JNNP. 2018 Oct 1. doi: 10.1136/jnnp-2018-318650.
Concurrent ‘never event’ prescribing may worsen dementia in Parkinson’s
Nearly half of Medicare beneficiaries with Parkinson’s disease were concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor, with higher rates of potential prescribing errors seen among women and Hispanic patients, according to a cross-sectional analysis of Centers for Medicare & Medicaid Services data published in JAMA Neurology.
“Coadministration of a drug with high anticholinergic activity and an [acetylcholinesterase inhibitor] represents a frank prescribing error because these drugs have opposing pharmacologic effects,” wrote Sneha Mantri, MD, of the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center, and her colleagues. “In patients with Parkinson disease, who bear additional risks of cognitive impairment and vulnerability to anticholinergic activity, coprescribing of an [acetylcholinesterase inhibitor] and a high-potency anticholinergic medication can be considered a never event because it is a medication error likely to contribute to disability.”
Dr. Mantri and her colleagues analyzed the inpatient, outpatient, and prescription data of 268,407 Medicare beneficiaries with Parkinson’s, of whom 73,093 patients (27.2%) were prescribed a minimum of one antidementia medication fill. Patients were mean 78.9 years old, and the demographics of the Medicare beneficiaries were 50.1% male, 86.7% white, 5.5% black, 2.7% Hispanic, 2.7% Asian, and 0.7% Native American. The most common antidementia prescriptions were donepezil hydrochloride (63.0%), memantine hydrochloride (41.8%), and rivastigmine tartrate (26.4%). The researchers measured medications in cases of coprescription with potential anticholinergic (ACH) activity using the Anticholinergic Cognitive Burden Scale.
They found antidementia medication use was associated with patients who were black (adjusted odds ratio, 1.33; 95% confidence interval, 1.28-1.38) and Hispanic (aOR, 1.28; 95% CI, 1.22-1.35). Meanwhile, a negative association was found between Native American patients and antidementia medication use (aOR, 0.62; 95% CI, 0.51-0.74) compared with white patients and women (aOR, 0.85; 95% CI, 0.84-0.87) compared with men. The researchers noted that 28,495 patients (44.5%) were prescribed concurrently one high-potency anticholinergic and acetylcholinesterase inhibitors, with higher rates of prescribing seen for Hispanic (aOR, 1.11; 95% CI, 1.00-1.23) and women (aOR, 1.30; 95% CI, 1.25-1.35). High prevalence clusters of this type of prescribing were statistically high in the Southern and Midwestern states, they added.
Limitations included the study of a single year of data and the absence of conclusive data of dementia prevalence among Parkinson’s patients based on antidementia medication use alone and potential off-label use of antidementia medication analyzed in the study, the researchers said.
“In determining whether anticholinergic drug exposure has a causal role in clinical dementia in Parkinson disease, future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” Dr. Mantri and her colleagues wrote. “Such an approach will allow the calculation of anticholinergic drug safety in terms that are easily understood, such as number needed to harm.”
This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors report no relevant conflicts of interest.
SOURCE: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
Describing the prescribing patterns of antidementia medication for patients with Parkinson’s disease is useful, particularly with regard to black and Hispanic patients, but the analysis by Sneha Mantri, MD, and her colleagues has methodological issues that limit its impact, wrote Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, wrote in an editorial.
While the researchers used the Anticholinergic Cognitive Burden (ACB) Scale and graded acetylcholinesterase inhibitor and high anticholinergic (ACH) activity medication combinations with the highest ACB score (3 on a scale of 0 to 3) and labeled them as a prescribing error, the ACB scale score alone should not be the sole determination of whether a prescription combination is deemed an error, the authors said.
“A problem, however, arises in defining the coadministration of an antidementia drug and a medication with high ACH activity as a prescribing error or a never event in all clinical circumstances,” the authors wrote. “Across the literature in this area, the most important principle repeatedly emphasized was that these resources are intended to identify potentially inappropriate medication (not inappropriate medications), and the recommendations and ratings provided cannot replace patient-specific clinical judgment.”
Further, medications such as clozapine and quetiapine fumarate are often prescribed for patients with Parkinson’s disease–related psychosis as a standard of care; those medications also have an ACB score of 3, which would label them as prescribing errors and never events under the study by Mantri et al., the authors continued.
“Variability in ACH activity scoring methods is an additional concern, as no criterion standard exists for ranking relative ACH activity and the scores for medications to treat Parkinson disease (such as quetiapine for Parkinson disease psychosis) can markedly differ between the scales commonly used (such as the ACB Scale),” they wrote.
Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, are affiliated with the Fixel Center for Neurological Diseases in the department of neurology at the University of Florida in Gainesville. These comments summarize their editorial (JAMA Neurol. 2018 Oct 1 doi: 10.1001/jamaneurol.2018.2826).They reported no relevant conflicts of interest.
Describing the prescribing patterns of antidementia medication for patients with Parkinson’s disease is useful, particularly with regard to black and Hispanic patients, but the analysis by Sneha Mantri, MD, and her colleagues has methodological issues that limit its impact, wrote Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, wrote in an editorial.
While the researchers used the Anticholinergic Cognitive Burden (ACB) Scale and graded acetylcholinesterase inhibitor and high anticholinergic (ACH) activity medication combinations with the highest ACB score (3 on a scale of 0 to 3) and labeled them as a prescribing error, the ACB scale score alone should not be the sole determination of whether a prescription combination is deemed an error, the authors said.
“A problem, however, arises in defining the coadministration of an antidementia drug and a medication with high ACH activity as a prescribing error or a never event in all clinical circumstances,” the authors wrote. “Across the literature in this area, the most important principle repeatedly emphasized was that these resources are intended to identify potentially inappropriate medication (not inappropriate medications), and the recommendations and ratings provided cannot replace patient-specific clinical judgment.”
Further, medications such as clozapine and quetiapine fumarate are often prescribed for patients with Parkinson’s disease–related psychosis as a standard of care; those medications also have an ACB score of 3, which would label them as prescribing errors and never events under the study by Mantri et al., the authors continued.
“Variability in ACH activity scoring methods is an additional concern, as no criterion standard exists for ranking relative ACH activity and the scores for medications to treat Parkinson disease (such as quetiapine for Parkinson disease psychosis) can markedly differ between the scales commonly used (such as the ACB Scale),” they wrote.
Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, are affiliated with the Fixel Center for Neurological Diseases in the department of neurology at the University of Florida in Gainesville. These comments summarize their editorial (JAMA Neurol. 2018 Oct 1 doi: 10.1001/jamaneurol.2018.2826).They reported no relevant conflicts of interest.
Describing the prescribing patterns of antidementia medication for patients with Parkinson’s disease is useful, particularly with regard to black and Hispanic patients, but the analysis by Sneha Mantri, MD, and her colleagues has methodological issues that limit its impact, wrote Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, wrote in an editorial.
While the researchers used the Anticholinergic Cognitive Burden (ACB) Scale and graded acetylcholinesterase inhibitor and high anticholinergic (ACH) activity medication combinations with the highest ACB score (3 on a scale of 0 to 3) and labeled them as a prescribing error, the ACB scale score alone should not be the sole determination of whether a prescription combination is deemed an error, the authors said.
“A problem, however, arises in defining the coadministration of an antidementia drug and a medication with high ACH activity as a prescribing error or a never event in all clinical circumstances,” the authors wrote. “Across the literature in this area, the most important principle repeatedly emphasized was that these resources are intended to identify potentially inappropriate medication (not inappropriate medications), and the recommendations and ratings provided cannot replace patient-specific clinical judgment.”
Further, medications such as clozapine and quetiapine fumarate are often prescribed for patients with Parkinson’s disease–related psychosis as a standard of care; those medications also have an ACB score of 3, which would label them as prescribing errors and never events under the study by Mantri et al., the authors continued.
“Variability in ACH activity scoring methods is an additional concern, as no criterion standard exists for ranking relative ACH activity and the scores for medications to treat Parkinson disease (such as quetiapine for Parkinson disease psychosis) can markedly differ between the scales commonly used (such as the ACB Scale),” they wrote.
Christopher W. Hess, MD, Michael S. Okun, MD, and Adolfo Ramirez-Zamora, MD, are affiliated with the Fixel Center for Neurological Diseases in the department of neurology at the University of Florida in Gainesville. These comments summarize their editorial (JAMA Neurol. 2018 Oct 1 doi: 10.1001/jamaneurol.2018.2826).They reported no relevant conflicts of interest.
Nearly half of Medicare beneficiaries with Parkinson’s disease were concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor, with higher rates of potential prescribing errors seen among women and Hispanic patients, according to a cross-sectional analysis of Centers for Medicare & Medicaid Services data published in JAMA Neurology.
“Coadministration of a drug with high anticholinergic activity and an [acetylcholinesterase inhibitor] represents a frank prescribing error because these drugs have opposing pharmacologic effects,” wrote Sneha Mantri, MD, of the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center, and her colleagues. “In patients with Parkinson disease, who bear additional risks of cognitive impairment and vulnerability to anticholinergic activity, coprescribing of an [acetylcholinesterase inhibitor] and a high-potency anticholinergic medication can be considered a never event because it is a medication error likely to contribute to disability.”
Dr. Mantri and her colleagues analyzed the inpatient, outpatient, and prescription data of 268,407 Medicare beneficiaries with Parkinson’s, of whom 73,093 patients (27.2%) were prescribed a minimum of one antidementia medication fill. Patients were mean 78.9 years old, and the demographics of the Medicare beneficiaries were 50.1% male, 86.7% white, 5.5% black, 2.7% Hispanic, 2.7% Asian, and 0.7% Native American. The most common antidementia prescriptions were donepezil hydrochloride (63.0%), memantine hydrochloride (41.8%), and rivastigmine tartrate (26.4%). The researchers measured medications in cases of coprescription with potential anticholinergic (ACH) activity using the Anticholinergic Cognitive Burden Scale.
They found antidementia medication use was associated with patients who were black (adjusted odds ratio, 1.33; 95% confidence interval, 1.28-1.38) and Hispanic (aOR, 1.28; 95% CI, 1.22-1.35). Meanwhile, a negative association was found between Native American patients and antidementia medication use (aOR, 0.62; 95% CI, 0.51-0.74) compared with white patients and women (aOR, 0.85; 95% CI, 0.84-0.87) compared with men. The researchers noted that 28,495 patients (44.5%) were prescribed concurrently one high-potency anticholinergic and acetylcholinesterase inhibitors, with higher rates of prescribing seen for Hispanic (aOR, 1.11; 95% CI, 1.00-1.23) and women (aOR, 1.30; 95% CI, 1.25-1.35). High prevalence clusters of this type of prescribing were statistically high in the Southern and Midwestern states, they added.
Limitations included the study of a single year of data and the absence of conclusive data of dementia prevalence among Parkinson’s patients based on antidementia medication use alone and potential off-label use of antidementia medication analyzed in the study, the researchers said.
“In determining whether anticholinergic drug exposure has a causal role in clinical dementia in Parkinson disease, future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” Dr. Mantri and her colleagues wrote. “Such an approach will allow the calculation of anticholinergic drug safety in terms that are easily understood, such as number needed to harm.”
This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors report no relevant conflicts of interest.
SOURCE: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
Nearly half of Medicare beneficiaries with Parkinson’s disease were concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor, with higher rates of potential prescribing errors seen among women and Hispanic patients, according to a cross-sectional analysis of Centers for Medicare & Medicaid Services data published in JAMA Neurology.
“Coadministration of a drug with high anticholinergic activity and an [acetylcholinesterase inhibitor] represents a frank prescribing error because these drugs have opposing pharmacologic effects,” wrote Sneha Mantri, MD, of the Parkinson’s Disease Research, Education, and Clinical Center at the Philadelphia VA Medical Center, and her colleagues. “In patients with Parkinson disease, who bear additional risks of cognitive impairment and vulnerability to anticholinergic activity, coprescribing of an [acetylcholinesterase inhibitor] and a high-potency anticholinergic medication can be considered a never event because it is a medication error likely to contribute to disability.”
Dr. Mantri and her colleagues analyzed the inpatient, outpatient, and prescription data of 268,407 Medicare beneficiaries with Parkinson’s, of whom 73,093 patients (27.2%) were prescribed a minimum of one antidementia medication fill. Patients were mean 78.9 years old, and the demographics of the Medicare beneficiaries were 50.1% male, 86.7% white, 5.5% black, 2.7% Hispanic, 2.7% Asian, and 0.7% Native American. The most common antidementia prescriptions were donepezil hydrochloride (63.0%), memantine hydrochloride (41.8%), and rivastigmine tartrate (26.4%). The researchers measured medications in cases of coprescription with potential anticholinergic (ACH) activity using the Anticholinergic Cognitive Burden Scale.
They found antidementia medication use was associated with patients who were black (adjusted odds ratio, 1.33; 95% confidence interval, 1.28-1.38) and Hispanic (aOR, 1.28; 95% CI, 1.22-1.35). Meanwhile, a negative association was found between Native American patients and antidementia medication use (aOR, 0.62; 95% CI, 0.51-0.74) compared with white patients and women (aOR, 0.85; 95% CI, 0.84-0.87) compared with men. The researchers noted that 28,495 patients (44.5%) were prescribed concurrently one high-potency anticholinergic and acetylcholinesterase inhibitors, with higher rates of prescribing seen for Hispanic (aOR, 1.11; 95% CI, 1.00-1.23) and women (aOR, 1.30; 95% CI, 1.25-1.35). High prevalence clusters of this type of prescribing were statistically high in the Southern and Midwestern states, they added.
Limitations included the study of a single year of data and the absence of conclusive data of dementia prevalence among Parkinson’s patients based on antidementia medication use alone and potential off-label use of antidementia medication analyzed in the study, the researchers said.
“In determining whether anticholinergic drug exposure has a causal role in clinical dementia in Parkinson disease, future studies may take a clinical trial approach, in which high-potency anticholinergic medications are replaced with lower-potency alternatives, and the change in cognitive testing and cognitive trajectory are measured,” Dr. Mantri and her colleagues wrote. “Such an approach will allow the calculation of anticholinergic drug safety in terms that are easily understood, such as number needed to harm.”
This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors report no relevant conflicts of interest.
SOURCE: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
FROM JAMA NEUROLOGY
Key clinical point: Medicare beneficiaries with Parkinson’s disease often are concurrently prescribed a high-potency anticholinergic medication and an acetylcholinesterase inhibitor.
Major finding: More than 44% of patients experienced at least one never event, with higher rates of potential prescribing errors seen in Hispanic patients (adjusted OR, 1.11) and women (adjusted OR, 1.30).
Study details: An analysis of inpatient, outpatient, and prescription data for 268,407 Medicare beneficiaries with Parkinson’s disease over 12 months.
Disclosures: This study was funded by a grant from the National Institute of Neurological Diseases and Stroke of the National Institutes of Health. The authors reported no relevant conflicts of interest.
Source: Mantri S et al. JAMA Neurol. 2018 Oct 1. doi: 10.1001/jamaneurol.2018.2820.
Low-dose ketamine controls pain from severe chest injury, while sparing opioid consumption
SAN DIEGO – while reducing opioid consumption.
The anesthetic didn’t make much difference in pain control or opioid use overall in a randomized study of 93 patients with thoracic injury Nathan Kugler, MD, said at the annual meeting of the American Association for the Surgery of Trauma. But among severely injured patients, it cut the opioid mean equivalency dose by about 164 mg over the 48-hour infusion and by 328 mg over a mean hospital stay while maintaining pain control, said Dr. Kugler, a surgical resident at the Medical College of Wisconsin, Milwaukee.
“With increasing focus on multimodal pain strategies, opioid-based regimens continue to be the backbone of pain control,” he said. “We have used ketamine effectively for failure of maximum therapy and demonstrated an opioid-sparing effect.” This new research shows that the drug can be an effective adjunct for acute pain control for severely injured patients in the emergency setting.
The study recruited 93 patients with thoracic injury; they had a mean of six broken ribs, mostly caused by motor vehicle accidents. Most of the patients were male (75%), and their mean age was 46 years. The mean Injury Severity Score was about 15; about 30% had flail chest.
All patients received a standardized acute pain medication regime comprising acetaminophen, nonsteroidal anti-inflammatories, methocarbamol (Robaxin), and intravenous opioids. Regional therapies included rib block with an epidural catheter. In addition, they were randomized to placebo infusions or to 48 hours of IV ketamine at 2.5 mcg/kg per minute. “To put this in perspective, for a 70-kg patient, that is a mean of 10.5 mg/hour,” Dr. Kugler said.
The primary endpoint was a reduction of at least 2 points on an 11-point pain scale. Secondary endpoints included opioid use in oral morphine equivalents (OME); respiratory complications; and psychoactive events. The primary outcome was assessed with an area under the curve model.
In the overall group, there was no significant between-group difference in pain score. Nor were there differences in the total OME at 12-24 hours (184 mg ketamine vs. 230 mg placebo), or at 48 hours (86 vs. 113 mg).
Dr. Kugler also looked at these outcomes in patients who had only rib fractures independent of other chest injury. He saw no significant differences in pain scores or OME at 24 or 48 hours.
However, significant differences did emerge in the group of severely injured patients with an Injury Severity Score of more than 15. There were no differences in pain scores at either time point. However, ketamine allowed patients to achieve the same level of pain control with significantly less opioid medication. The OME at 12-24 hours was 50.5 mg vs 94 mg. At 24-48 hours, it was 87 mg vs. 64 mg.
This worked out to a mean OME savings of 148 mg over a patient’s entire hospitalization.
“We saw a very nice separation of opioid consumption that began early and continued to separate over the 48-hour infusion and even after it was discontinued,” Dr. Kugler said.
This benefit was achieved without any additional adverse events, he added. There were no significant differences in confusion; epidural placement; length of stay; respiratory event, sedation, hallucinations, delusions or disturbing dreams; or unplanned transfers to the ICU.
Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, also of the Medical College of Wisconsin, Milwaukee, are both paid consultants for InnoVital Systems.
SAN DIEGO – while reducing opioid consumption.
The anesthetic didn’t make much difference in pain control or opioid use overall in a randomized study of 93 patients with thoracic injury Nathan Kugler, MD, said at the annual meeting of the American Association for the Surgery of Trauma. But among severely injured patients, it cut the opioid mean equivalency dose by about 164 mg over the 48-hour infusion and by 328 mg over a mean hospital stay while maintaining pain control, said Dr. Kugler, a surgical resident at the Medical College of Wisconsin, Milwaukee.
“With increasing focus on multimodal pain strategies, opioid-based regimens continue to be the backbone of pain control,” he said. “We have used ketamine effectively for failure of maximum therapy and demonstrated an opioid-sparing effect.” This new research shows that the drug can be an effective adjunct for acute pain control for severely injured patients in the emergency setting.
The study recruited 93 patients with thoracic injury; they had a mean of six broken ribs, mostly caused by motor vehicle accidents. Most of the patients were male (75%), and their mean age was 46 years. The mean Injury Severity Score was about 15; about 30% had flail chest.
All patients received a standardized acute pain medication regime comprising acetaminophen, nonsteroidal anti-inflammatories, methocarbamol (Robaxin), and intravenous opioids. Regional therapies included rib block with an epidural catheter. In addition, they were randomized to placebo infusions or to 48 hours of IV ketamine at 2.5 mcg/kg per minute. “To put this in perspective, for a 70-kg patient, that is a mean of 10.5 mg/hour,” Dr. Kugler said.
The primary endpoint was a reduction of at least 2 points on an 11-point pain scale. Secondary endpoints included opioid use in oral morphine equivalents (OME); respiratory complications; and psychoactive events. The primary outcome was assessed with an area under the curve model.
In the overall group, there was no significant between-group difference in pain score. Nor were there differences in the total OME at 12-24 hours (184 mg ketamine vs. 230 mg placebo), or at 48 hours (86 vs. 113 mg).
Dr. Kugler also looked at these outcomes in patients who had only rib fractures independent of other chest injury. He saw no significant differences in pain scores or OME at 24 or 48 hours.
However, significant differences did emerge in the group of severely injured patients with an Injury Severity Score of more than 15. There were no differences in pain scores at either time point. However, ketamine allowed patients to achieve the same level of pain control with significantly less opioid medication. The OME at 12-24 hours was 50.5 mg vs 94 mg. At 24-48 hours, it was 87 mg vs. 64 mg.
This worked out to a mean OME savings of 148 mg over a patient’s entire hospitalization.
“We saw a very nice separation of opioid consumption that began early and continued to separate over the 48-hour infusion and even after it was discontinued,” Dr. Kugler said.
This benefit was achieved without any additional adverse events, he added. There were no significant differences in confusion; epidural placement; length of stay; respiratory event, sedation, hallucinations, delusions or disturbing dreams; or unplanned transfers to the ICU.
Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, also of the Medical College of Wisconsin, Milwaukee, are both paid consultants for InnoVital Systems.
SAN DIEGO – while reducing opioid consumption.
The anesthetic didn’t make much difference in pain control or opioid use overall in a randomized study of 93 patients with thoracic injury Nathan Kugler, MD, said at the annual meeting of the American Association for the Surgery of Trauma. But among severely injured patients, it cut the opioid mean equivalency dose by about 164 mg over the 48-hour infusion and by 328 mg over a mean hospital stay while maintaining pain control, said Dr. Kugler, a surgical resident at the Medical College of Wisconsin, Milwaukee.
“With increasing focus on multimodal pain strategies, opioid-based regimens continue to be the backbone of pain control,” he said. “We have used ketamine effectively for failure of maximum therapy and demonstrated an opioid-sparing effect.” This new research shows that the drug can be an effective adjunct for acute pain control for severely injured patients in the emergency setting.
The study recruited 93 patients with thoracic injury; they had a mean of six broken ribs, mostly caused by motor vehicle accidents. Most of the patients were male (75%), and their mean age was 46 years. The mean Injury Severity Score was about 15; about 30% had flail chest.
All patients received a standardized acute pain medication regime comprising acetaminophen, nonsteroidal anti-inflammatories, methocarbamol (Robaxin), and intravenous opioids. Regional therapies included rib block with an epidural catheter. In addition, they were randomized to placebo infusions or to 48 hours of IV ketamine at 2.5 mcg/kg per minute. “To put this in perspective, for a 70-kg patient, that is a mean of 10.5 mg/hour,” Dr. Kugler said.
The primary endpoint was a reduction of at least 2 points on an 11-point pain scale. Secondary endpoints included opioid use in oral morphine equivalents (OME); respiratory complications; and psychoactive events. The primary outcome was assessed with an area under the curve model.
In the overall group, there was no significant between-group difference in pain score. Nor were there differences in the total OME at 12-24 hours (184 mg ketamine vs. 230 mg placebo), or at 48 hours (86 vs. 113 mg).
Dr. Kugler also looked at these outcomes in patients who had only rib fractures independent of other chest injury. He saw no significant differences in pain scores or OME at 24 or 48 hours.
However, significant differences did emerge in the group of severely injured patients with an Injury Severity Score of more than 15. There were no differences in pain scores at either time point. However, ketamine allowed patients to achieve the same level of pain control with significantly less opioid medication. The OME at 12-24 hours was 50.5 mg vs 94 mg. At 24-48 hours, it was 87 mg vs. 64 mg.
This worked out to a mean OME savings of 148 mg over a patient’s entire hospitalization.
“We saw a very nice separation of opioid consumption that began early and continued to separate over the 48-hour infusion and even after it was discontinued,” Dr. Kugler said.
This benefit was achieved without any additional adverse events, he added. There were no significant differences in confusion; epidural placement; length of stay; respiratory event, sedation, hallucinations, delusions or disturbing dreams; or unplanned transfers to the ICU.
Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, also of the Medical College of Wisconsin, Milwaukee, are both paid consultants for InnoVital Systems.
REPORTING FROM THE AAST ANNUAL MEETING
Key clinical point: Low-dose ketamine controlled pain while reducing opioid use among patients with severe thoracic injury.
Major finding: Compared with placebo, ketamine reduced opioids conferred OME savings of 148 mg over a patient’s entire hospitalization.
Study details: The randomized study comprised 93 patients with thoracic injury.
Disclosures: Dr. Kugler disclosed that he and primary investigator Thomas Carver, MD, are both paid consultants for InnoVital Systems.
Source: Carver T et al. AAST 2018, Oral abstract 2
How effectively do ACE inhibitors and ARBs prevent migraines?
EVIDENCE SUMMARY
A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine1 headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE1). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.
Lisinopril reduces hours, days with headache and days with migraine
The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.2 Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.
Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).
Candesartan also decreases headaches and migraine
The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.3 It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.
Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.
Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).
Continue to: Overall both drugs have a significant effect on number of headaches
Overall both drugs have a significant effect on number of headaches
Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).1 (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).1
RECOMMENDATIONS
In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.4 The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”
1. Jackson JL, Cogbil E, Santana-Davila R, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS One. 2015;10:e0130733.
2. Schrader H, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo controlled, crossover study. BMJ. 2001;322:19-22.
3. Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289:65-69.
4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
EVIDENCE SUMMARY
A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine1 headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE1). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.
Lisinopril reduces hours, days with headache and days with migraine
The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.2 Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.
Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).
Candesartan also decreases headaches and migraine
The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.3 It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.
Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.
Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).
Continue to: Overall both drugs have a significant effect on number of headaches
Overall both drugs have a significant effect on number of headaches
Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).1 (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).1
RECOMMENDATIONS
In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.4 The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”
EVIDENCE SUMMARY
A network meta-analysis of 179 placebo-controlled trials of medications to treat migraine1 headache identified 3 trials involving ACE inhibitors and 3 involving ARBs (TABLE1). The authors of the meta-analysis gave 2 trials (one of lisinopril and one of candesartan) relatively high scores for methodologic quality.
Lisinopril reduces hours, days with headache and days with migraine
The first, a placebo-controlled lisinopril crossover trial, included 60 patients, 19 to 59 years of age, who experienced migraines with or without auras 2 to 6 times per month.2 Thirty patients received lisinopril 10 mg once daily for 1 week followed by 20 mg once daily (using 10-mg tablets) for 11 weeks. The other 30 patients received a similarly titrated placebo for 12 weeks. After a 2-week washout period, the groups were given the other therapy. Patients took triptan medications and analgesics as needed. Primary outcomes, extracted from headache diaries, included the number of hours and days with headache (of any type) and number of days with migraine specifically.
Out of the initial 60 participants, 47 completed the study. Using intention-to-treat analysis, lisinopril therapy resulted in fewer hours with headache (162 vs 138, a 15% difference; 95% confidence interval [CI], 0-30), fewer days with headache (25 vs 21, a 16% difference; 95% CI, 5-27), and fewer days with migraine (19 vs 15, a 22% change; 95% CI, 11-33), compared with placebo. Three patients discontinued lisinopril because of adverse events. Mean blood pressure reduction with lisinopril was 7 mm Hg systolic and 5 mm Hg diastolic more than placebo (P<.0001 for both comparisons).
Candesartan also decreases headaches and migraine
The other study given a high methodologic quality score by the network-meta-analysis authors was a placebo-controlled candesartan crossover trial.3 It enrolled 60 patients, 18 to 65 years of age, who experienced migraines with or without auras 2 to 6 times per month.
Thirty patients received 16 mg candesartan daily for 12 weeks, followed by a 4-week washout period before taking a placebo tablet daily for 12 weeks. The other 30 received placebo followed by candesartan. Patients took triptan medications and analgesics as needed. The primary outcome measure was days with headache, recorded by patients using daily diaries. Three patients didn’t complete the study.
Using intention-to-treat analysis, the mean number of days with headache was 18.5 with placebo and 13.6 with candesartan (P=.001). Secondary end points that also favored candesartan were hours with migraine (92 vs 59; P<.001), hours with headache (139 vs 95; P<.001), days with migraine (13 vs 9; P<.001), and days of sick leave (3.9 vs 1.4; P=.01). Adverse events, including dizziness, were similar with candesartan and placebo. Mean blood pressure reduction with candesartan was 11 mm Hg systolic and 7 mm Hg diastolic over placebo (P<.001 for both comparisons).
Continue to: Overall both drugs have a significant effect on number of headaches
Overall both drugs have a significant effect on number of headaches
Among all ACE inhibitor and ARB trials in the review, a network meta-analysis (designed to compare interventions never studied head-to-head) could be performed only on candesartan, which had a small effect size on headache frequency relative to placebo (2 trials, 118 patients; standardized mean difference [SMD]= −0.33; 95% CI, −0.59 to −0.7).1 (An SMD of 0.2 is considered small, 0.6 moderate, and 1.2 large). Combining data from all ACE inhibitor and ARB trials together in a standard meta-analysis yielded a large effect size on number of headaches per month compared with placebo (6 trials, 351 patients; SMD= −1.12; 95% CI, −1.97 to −0.27).1
RECOMMENDATIONS
In 2012, the American Academy of Neurology and the American Headache Society published guidelines on pharmacologic treatment for episodic migraine prevention in adults.4 The guidelines stated that lisinopril and candesartan were “possibly effective” for migraine prevention (level C recommendation based on a single lower-quality randomized clinical trial). They further advised clinicians to be “mindful of comorbid and coexistent conditions in patients with migraine to maximize potential treatment efficacy.”
1. Jackson JL, Cogbil E, Santana-Davila R, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS One. 2015;10:e0130733.
2. Schrader H, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo controlled, crossover study. BMJ. 2001;322:19-22.
3. Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289:65-69.
4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
1. Jackson JL, Cogbil E, Santana-Davila R, et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of migraine headache. PloS One. 2015;10:e0130733.
2. Schrader H, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomized, placebo controlled, crossover study. BMJ. 2001;322:19-22.
3. Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of migraine with an angiotensin II receptor blocker: a randomized controlled trial. JAMA. 2003;289:65-69.
4. Silberstein SD, Holland S, Freitag F, et al. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78:1337-1345.
EVIDENCE-BASED ANSWER:
The angiotensin-converting enzyme (ACE) inhibitor lisinopril reduces the number of migraines by about 1.5 per month in patients experiencing 2 to 6 migraines monthly (strength of recommendation [SOR]: B, small crossover trial); the angiotensin II receptor blocker (ARB) candesartan may produce a similar reduction (SOR: C, conflicting crossover trials).
Considered as a group, ACE inhibitors and ARBs have a moderate to large effect on the frequency of migraine headaches (SOR: B, meta-analysis of small clinical trials), although only lisinopril and candesartan show fair to good evidence of efficacy.
Providers may consider lisinopril or candesartan for migraine prevention, taking into account their effect on other medical conditions (SOR: C, expert opinion).
Nausea and vomiting • sensitivity to smell • history of hypertension and alcohol abuse • Dx?
THE CASE
A 57-year-old woman presented to a family physician with acute encephalopathy and complaints of recent gastritis. She reported a 2-month history of nausea, vomiting, decreased oral intake, and extreme sensitivity to smell. The patient had a history of hypertension, and a family member privately disclosed to the FP that she also had a history of alcohol abuse. The patient was taking lorazepam daily, as needed, for anxiety.
On initial assessment, the patient was alert, but not oriented to time or situation. She was ataxic and agitated but did not exhibit pupillary constriction or tremor. The FP sent her to the emergency department (ED).
After being assessed in the ED, the patient was admitted. Over the course of several days, she showed worsening mentation; she persistently believed she was in Chicago, her childhood home. On memory testing, she was unable to recall any of 3 objects after 5 minutes. She exhibited horizontal nystagmus and dysmetria bilaterally and continued to be ataxic, requiring 2-point assistance. Her agitation was managed nonpharmacologically.
A work-up was performed, which included laboratory testing, a urinalysis, and computed tomography (CT) of the head. A comprehensive metabolic panel, complete blood count, and thyroid stimulating hormone test were unremarkable except for electrolyte disturbances, with a sodium level of 158 mEq/L and a potassium level of 2.6 mEq/L (reference ranges: 135-145 mEq/L and 3.5-5 mEq/L, respectively).
Her blood alcohol level was zero, and not surprisingly given her use of lorazepam, a urine drug screen was positive for benzodiazepines. The urinalysis results were consistent with a urinary tract infection (UTI), for which she was treated with an antibiotic. A carbohydrate-deficient transferrin test may have been useful to establish chronic alcohol abuse, but was not ordered. The head CT was negative.
After a few days with fluids and electrolyte replacement, the patient’s electrolytes normalized.
THE DIAGNOSIS
The differential diagnosis included sepsis, metabolic encephalopathy, and alcoholic encephalopathy. Given that the patient’s urine drug screen was positive, benzodiazepine withdrawal was also considered a plausible explanation for her continued cognitive disturbances. (It was surmised that she had likely taken her last lorazepam several days prior.) However, the lack of other signs of withdrawal prompted further investigation.
Continue to: Since her encephalopathy...
Since her encephalopathy, ataxia, and nystagmus persisted, magnetic resonance imaging (MRI) of the brain was performed on Day 3 of hospitalization (FIGURE). A lumbar puncture and an electroencephalogram were also considered but were not performed because the MRI results revealed bilateral enhancement of the m
DISCUSSION
WKS is the concurrence of Wernicke’s encephalopathy (an acute, life-threatening condition marked by ataxia, confusion, and ocular signs) and Korsakoff’s psychosis (a long-term, debilitating amnestic syndrome). WKS is a neuropsychiatric disorder in which patients experience profound short-term amnesia; it is precipitated by thiamine deficiency (defined as a whole blood thiamine level <0.7 ng/ml1).The link to thiamine was confirmed during World War II, when thiamine treatment resolved symptoms in starving prisoners. If recognized early, treatment of thiamine deficiency can prevent long-term morbidity from WKS.
Etiology of thiamine deficiency
Our patient’s alcohol abuse placed her at risk for WKS, and her olfactory aversion to certain foods was a diagnostic clue. In this case, we inadvertently administered dextrose with antibiotics for the UTI prior to administering thiamine; this exacerbated the thiamine deficiency because glucose and thiamine compete for the same substrate.
Is alcohol abuse always to blame for WKS?
The quantity and type of alcohol that results in the development of WKS has not been well studied, but the Caine diagnostic criteria defines chronic alcoholism as the consumption of 80 g/d of ethanol (8 drinks/d).2 While WKS is commonly associated with alcoholism, other causative conditions may be overlooked. Other associated illnesses include acquired immune deficiency syndrome (AIDS), cancer, hyperemesis gravidarum, prolonged total parenteral nutrition, and psychiatric illnesses such as eating disorders and schizophrenia. Procedures such as gastric bypass and dialysis can also precipitate WKS.3
Men and women are both at risk of developing WKS. A lack of consumption of thiamine-rich sources such as cereals, rice, and legumes puts patients at risk for WKS. The recommended dietary allowance of thiamine increases with age and may be higher for obese patients.4
Continue to: Suspect thiamine deficiency and obstain a thorough history
Suspect thiamine deficiency and obtain a thorough history
A high index of suspicion for thiamine deficiency is essential for diagnosis of WKS. History of alcohol use should be obtained, including quantity, frequency, pattern, duration, and time of last use. Physicians should assess nutrition and ask about vomiting and diarrhea. It is important to collaborate with the patient’s family and friends and inquire into other substance misuse.5
Since WKS targets the dorsomedial thalamus, which is responsible for olfactory processing, patients may complain of a distorted perception of smell.6 On physical examination, look for signs of protein-calorie malnutrition, including cheilitis, glossitis, and bleeding gums; signs of alcohol abuse, such as hepatomegaly; and evidence of injuries or poor self-care.5
Varied presentation leads to under- and misdiagnosis
Diagnosis of WKS can be difficult due to the varied presentation; there is a broad spectrum of clinical features. The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases.3 Mental status changes may include a global confusional state ranging from disorientation, apathy, anxiety, fear, and mild memory impairment to pronounced amnesia. Ophthalmoplegia can include nystagmus, ocular palsies, retinal hemorrhages, scotoma, or photophobia; and ataxia can range from a mild gait abnormality to an inability to stand.7 This varied presentation ultimately leads to underdiagnosis and misdiagnosis.
MRI findings are also varied in WKS. However, the mammillary bodies are involved in many cases, where atrophy of these structures have high specificity. The dorsomedial thalamus is associated with the reported impairment in memory and can be identified antemortem on MRI.3 There is no quantifiable evidence of how much thiamine should be used to prevent WKS. However, thiamine should be given before the administration of glucose whenever WKS is considered.
Our patient. Despite the administration of thiamine (100 mg parenterally for 5 d, followed by oral thiamine 300 mg/d indefinitely), our patient’s memory and cognition remained unchanged. She underwent intensive inpatient rehabilitation for 2 months and was eventually placed in long-term nursing care.
Continue to: THE TAKEAWAY
THE TAKEAWAY
A high index of suspicion is crucial to prevent possible long-term neurologic sequelae in WKS. Appropriate care starts at the beginning, with the patient’s story.
CORRESPONDENCE
Romith Naug, MD, 15 St. Andrew Street, Unit 601, Brockville, ON Canada K6V0B8; [email protected].
1. Doshi S, Velpandian T, Seth S, et al. Prevalence of thiamine deficiency in heart failure patients on long-term diuretic therapy. J Prac Cardiovasc Sci. 2015;1:25-29.
2. Caine D, Halliday GM, Kril JJ, et al. Operational criteria for the classification of chronic alcoholics: identification of Wernicke’s encephalopathy. J Neurol Neurosurg Psychiatry. 1997;62:51-60.
3. Donnino MW, Vega J, Miller J, et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50:715-721.
4. Kerns J, Arundel C, Chawla LS. Thiamin deficiency in people with obesity. Adv Nutr. 2015;6:147-153.
5. Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern Med J. 2014;44:911-915.
6. Wilson DA, Xu W, Sadrian B, et al. Cortical odor processing in health and disease. Prog Brain Res. 2014;208:275-305.
7. Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff syndrome: under-recognized and under-treated. Psychosomatics. 2012;53:507-516.
THE CASE
A 57-year-old woman presented to a family physician with acute encephalopathy and complaints of recent gastritis. She reported a 2-month history of nausea, vomiting, decreased oral intake, and extreme sensitivity to smell. The patient had a history of hypertension, and a family member privately disclosed to the FP that she also had a history of alcohol abuse. The patient was taking lorazepam daily, as needed, for anxiety.
On initial assessment, the patient was alert, but not oriented to time or situation. She was ataxic and agitated but did not exhibit pupillary constriction or tremor. The FP sent her to the emergency department (ED).
After being assessed in the ED, the patient was admitted. Over the course of several days, she showed worsening mentation; she persistently believed she was in Chicago, her childhood home. On memory testing, she was unable to recall any of 3 objects after 5 minutes. She exhibited horizontal nystagmus and dysmetria bilaterally and continued to be ataxic, requiring 2-point assistance. Her agitation was managed nonpharmacologically.
A work-up was performed, which included laboratory testing, a urinalysis, and computed tomography (CT) of the head. A comprehensive metabolic panel, complete blood count, and thyroid stimulating hormone test were unremarkable except for electrolyte disturbances, with a sodium level of 158 mEq/L and a potassium level of 2.6 mEq/L (reference ranges: 135-145 mEq/L and 3.5-5 mEq/L, respectively).
Her blood alcohol level was zero, and not surprisingly given her use of lorazepam, a urine drug screen was positive for benzodiazepines. The urinalysis results were consistent with a urinary tract infection (UTI), for which she was treated with an antibiotic. A carbohydrate-deficient transferrin test may have been useful to establish chronic alcohol abuse, but was not ordered. The head CT was negative.
After a few days with fluids and electrolyte replacement, the patient’s electrolytes normalized.
THE DIAGNOSIS
The differential diagnosis included sepsis, metabolic encephalopathy, and alcoholic encephalopathy. Given that the patient’s urine drug screen was positive, benzodiazepine withdrawal was also considered a plausible explanation for her continued cognitive disturbances. (It was surmised that she had likely taken her last lorazepam several days prior.) However, the lack of other signs of withdrawal prompted further investigation.
Continue to: Since her encephalopathy...
Since her encephalopathy, ataxia, and nystagmus persisted, magnetic resonance imaging (MRI) of the brain was performed on Day 3 of hospitalization (FIGURE). A lumbar puncture and an electroencephalogram were also considered but were not performed because the MRI results revealed bilateral enhancement of the m
DISCUSSION
WKS is the concurrence of Wernicke’s encephalopathy (an acute, life-threatening condition marked by ataxia, confusion, and ocular signs) and Korsakoff’s psychosis (a long-term, debilitating amnestic syndrome). WKS is a neuropsychiatric disorder in which patients experience profound short-term amnesia; it is precipitated by thiamine deficiency (defined as a whole blood thiamine level <0.7 ng/ml1).The link to thiamine was confirmed during World War II, when thiamine treatment resolved symptoms in starving prisoners. If recognized early, treatment of thiamine deficiency can prevent long-term morbidity from WKS.
Etiology of thiamine deficiency
Our patient’s alcohol abuse placed her at risk for WKS, and her olfactory aversion to certain foods was a diagnostic clue. In this case, we inadvertently administered dextrose with antibiotics for the UTI prior to administering thiamine; this exacerbated the thiamine deficiency because glucose and thiamine compete for the same substrate.
Is alcohol abuse always to blame for WKS?
The quantity and type of alcohol that results in the development of WKS has not been well studied, but the Caine diagnostic criteria defines chronic alcoholism as the consumption of 80 g/d of ethanol (8 drinks/d).2 While WKS is commonly associated with alcoholism, other causative conditions may be overlooked. Other associated illnesses include acquired immune deficiency syndrome (AIDS), cancer, hyperemesis gravidarum, prolonged total parenteral nutrition, and psychiatric illnesses such as eating disorders and schizophrenia. Procedures such as gastric bypass and dialysis can also precipitate WKS.3
Men and women are both at risk of developing WKS. A lack of consumption of thiamine-rich sources such as cereals, rice, and legumes puts patients at risk for WKS. The recommended dietary allowance of thiamine increases with age and may be higher for obese patients.4
Continue to: Suspect thiamine deficiency and obstain a thorough history
Suspect thiamine deficiency and obtain a thorough history
A high index of suspicion for thiamine deficiency is essential for diagnosis of WKS. History of alcohol use should be obtained, including quantity, frequency, pattern, duration, and time of last use. Physicians should assess nutrition and ask about vomiting and diarrhea. It is important to collaborate with the patient’s family and friends and inquire into other substance misuse.5
Since WKS targets the dorsomedial thalamus, which is responsible for olfactory processing, patients may complain of a distorted perception of smell.6 On physical examination, look for signs of protein-calorie malnutrition, including cheilitis, glossitis, and bleeding gums; signs of alcohol abuse, such as hepatomegaly; and evidence of injuries or poor self-care.5
Varied presentation leads to under- and misdiagnosis
Diagnosis of WKS can be difficult due to the varied presentation; there is a broad spectrum of clinical features. The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases.3 Mental status changes may include a global confusional state ranging from disorientation, apathy, anxiety, fear, and mild memory impairment to pronounced amnesia. Ophthalmoplegia can include nystagmus, ocular palsies, retinal hemorrhages, scotoma, or photophobia; and ataxia can range from a mild gait abnormality to an inability to stand.7 This varied presentation ultimately leads to underdiagnosis and misdiagnosis.
MRI findings are also varied in WKS. However, the mammillary bodies are involved in many cases, where atrophy of these structures have high specificity. The dorsomedial thalamus is associated with the reported impairment in memory and can be identified antemortem on MRI.3 There is no quantifiable evidence of how much thiamine should be used to prevent WKS. However, thiamine should be given before the administration of glucose whenever WKS is considered.
Our patient. Despite the administration of thiamine (100 mg parenterally for 5 d, followed by oral thiamine 300 mg/d indefinitely), our patient’s memory and cognition remained unchanged. She underwent intensive inpatient rehabilitation for 2 months and was eventually placed in long-term nursing care.
Continue to: THE TAKEAWAY
THE TAKEAWAY
A high index of suspicion is crucial to prevent possible long-term neurologic sequelae in WKS. Appropriate care starts at the beginning, with the patient’s story.
CORRESPONDENCE
Romith Naug, MD, 15 St. Andrew Street, Unit 601, Brockville, ON Canada K6V0B8; [email protected].
THE CASE
A 57-year-old woman presented to a family physician with acute encephalopathy and complaints of recent gastritis. She reported a 2-month history of nausea, vomiting, decreased oral intake, and extreme sensitivity to smell. The patient had a history of hypertension, and a family member privately disclosed to the FP that she also had a history of alcohol abuse. The patient was taking lorazepam daily, as needed, for anxiety.
On initial assessment, the patient was alert, but not oriented to time or situation. She was ataxic and agitated but did not exhibit pupillary constriction or tremor. The FP sent her to the emergency department (ED).
After being assessed in the ED, the patient was admitted. Over the course of several days, she showed worsening mentation; she persistently believed she was in Chicago, her childhood home. On memory testing, she was unable to recall any of 3 objects after 5 minutes. She exhibited horizontal nystagmus and dysmetria bilaterally and continued to be ataxic, requiring 2-point assistance. Her agitation was managed nonpharmacologically.
A work-up was performed, which included laboratory testing, a urinalysis, and computed tomography (CT) of the head. A comprehensive metabolic panel, complete blood count, and thyroid stimulating hormone test were unremarkable except for electrolyte disturbances, with a sodium level of 158 mEq/L and a potassium level of 2.6 mEq/L (reference ranges: 135-145 mEq/L and 3.5-5 mEq/L, respectively).
Her blood alcohol level was zero, and not surprisingly given her use of lorazepam, a urine drug screen was positive for benzodiazepines. The urinalysis results were consistent with a urinary tract infection (UTI), for which she was treated with an antibiotic. A carbohydrate-deficient transferrin test may have been useful to establish chronic alcohol abuse, but was not ordered. The head CT was negative.
After a few days with fluids and electrolyte replacement, the patient’s electrolytes normalized.
THE DIAGNOSIS
The differential diagnosis included sepsis, metabolic encephalopathy, and alcoholic encephalopathy. Given that the patient’s urine drug screen was positive, benzodiazepine withdrawal was also considered a plausible explanation for her continued cognitive disturbances. (It was surmised that she had likely taken her last lorazepam several days prior.) However, the lack of other signs of withdrawal prompted further investigation.
Continue to: Since her encephalopathy...
Since her encephalopathy, ataxia, and nystagmus persisted, magnetic resonance imaging (MRI) of the brain was performed on Day 3 of hospitalization (FIGURE). A lumbar puncture and an electroencephalogram were also considered but were not performed because the MRI results revealed bilateral enhancement of the m
DISCUSSION
WKS is the concurrence of Wernicke’s encephalopathy (an acute, life-threatening condition marked by ataxia, confusion, and ocular signs) and Korsakoff’s psychosis (a long-term, debilitating amnestic syndrome). WKS is a neuropsychiatric disorder in which patients experience profound short-term amnesia; it is precipitated by thiamine deficiency (defined as a whole blood thiamine level <0.7 ng/ml1).The link to thiamine was confirmed during World War II, when thiamine treatment resolved symptoms in starving prisoners. If recognized early, treatment of thiamine deficiency can prevent long-term morbidity from WKS.
Etiology of thiamine deficiency
Our patient’s alcohol abuse placed her at risk for WKS, and her olfactory aversion to certain foods was a diagnostic clue. In this case, we inadvertently administered dextrose with antibiotics for the UTI prior to administering thiamine; this exacerbated the thiamine deficiency because glucose and thiamine compete for the same substrate.
Is alcohol abuse always to blame for WKS?
The quantity and type of alcohol that results in the development of WKS has not been well studied, but the Caine diagnostic criteria defines chronic alcoholism as the consumption of 80 g/d of ethanol (8 drinks/d).2 While WKS is commonly associated with alcoholism, other causative conditions may be overlooked. Other associated illnesses include acquired immune deficiency syndrome (AIDS), cancer, hyperemesis gravidarum, prolonged total parenteral nutrition, and psychiatric illnesses such as eating disorders and schizophrenia. Procedures such as gastric bypass and dialysis can also precipitate WKS.3
Men and women are both at risk of developing WKS. A lack of consumption of thiamine-rich sources such as cereals, rice, and legumes puts patients at risk for WKS. The recommended dietary allowance of thiamine increases with age and may be higher for obese patients.4
Continue to: Suspect thiamine deficiency and obstain a thorough history
Suspect thiamine deficiency and obtain a thorough history
A high index of suspicion for thiamine deficiency is essential for diagnosis of WKS. History of alcohol use should be obtained, including quantity, frequency, pattern, duration, and time of last use. Physicians should assess nutrition and ask about vomiting and diarrhea. It is important to collaborate with the patient’s family and friends and inquire into other substance misuse.5
Since WKS targets the dorsomedial thalamus, which is responsible for olfactory processing, patients may complain of a distorted perception of smell.6 On physical examination, look for signs of protein-calorie malnutrition, including cheilitis, glossitis, and bleeding gums; signs of alcohol abuse, such as hepatomegaly; and evidence of injuries or poor self-care.5
Varied presentation leads to under- and misdiagnosis
Diagnosis of WKS can be difficult due to the varied presentation; there is a broad spectrum of clinical features. The clinical triad of mental status change, ophthalmoplegia, and gait ataxia is present in as few as 10% of cases.3 Mental status changes may include a global confusional state ranging from disorientation, apathy, anxiety, fear, and mild memory impairment to pronounced amnesia. Ophthalmoplegia can include nystagmus, ocular palsies, retinal hemorrhages, scotoma, or photophobia; and ataxia can range from a mild gait abnormality to an inability to stand.7 This varied presentation ultimately leads to underdiagnosis and misdiagnosis.
MRI findings are also varied in WKS. However, the mammillary bodies are involved in many cases, where atrophy of these structures have high specificity. The dorsomedial thalamus is associated with the reported impairment in memory and can be identified antemortem on MRI.3 There is no quantifiable evidence of how much thiamine should be used to prevent WKS. However, thiamine should be given before the administration of glucose whenever WKS is considered.
Our patient. Despite the administration of thiamine (100 mg parenterally for 5 d, followed by oral thiamine 300 mg/d indefinitely), our patient’s memory and cognition remained unchanged. She underwent intensive inpatient rehabilitation for 2 months and was eventually placed in long-term nursing care.
Continue to: THE TAKEAWAY
THE TAKEAWAY
A high index of suspicion is crucial to prevent possible long-term neurologic sequelae in WKS. Appropriate care starts at the beginning, with the patient’s story.
CORRESPONDENCE
Romith Naug, MD, 15 St. Andrew Street, Unit 601, Brockville, ON Canada K6V0B8; [email protected].
1. Doshi S, Velpandian T, Seth S, et al. Prevalence of thiamine deficiency in heart failure patients on long-term diuretic therapy. J Prac Cardiovasc Sci. 2015;1:25-29.
2. Caine D, Halliday GM, Kril JJ, et al. Operational criteria for the classification of chronic alcoholics: identification of Wernicke’s encephalopathy. J Neurol Neurosurg Psychiatry. 1997;62:51-60.
3. Donnino MW, Vega J, Miller J, et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50:715-721.
4. Kerns J, Arundel C, Chawla LS. Thiamin deficiency in people with obesity. Adv Nutr. 2015;6:147-153.
5. Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern Med J. 2014;44:911-915.
6. Wilson DA, Xu W, Sadrian B, et al. Cortical odor processing in health and disease. Prog Brain Res. 2014;208:275-305.
7. Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff syndrome: under-recognized and under-treated. Psychosomatics. 2012;53:507-516.
1. Doshi S, Velpandian T, Seth S, et al. Prevalence of thiamine deficiency in heart failure patients on long-term diuretic therapy. J Prac Cardiovasc Sci. 2015;1:25-29.
2. Caine D, Halliday GM, Kril JJ, et al. Operational criteria for the classification of chronic alcoholics: identification of Wernicke’s encephalopathy. J Neurol Neurosurg Psychiatry. 1997;62:51-60.
3. Donnino MW, Vega J, Miller J, et al. Myths and misconceptions of Wernicke’s encephalopathy: what every emergency physician should know. Ann Emerg Med. 2007;50:715-721.
4. Kerns J, Arundel C, Chawla LS. Thiamin deficiency in people with obesity. Adv Nutr. 2015;6:147-153.
5. Latt N, Dore G. Thiamine in the treatment of Wernicke encephalopathy in patients with alcohol use disorders. Intern Med J. 2014;44:911-915.
6. Wilson DA, Xu W, Sadrian B, et al. Cortical odor processing in health and disease. Prog Brain Res. 2014;208:275-305.
7. Isenberg-Grzeda E, Kutner HE, Nicolson SE. Wernicke-Korsakoff syndrome: under-recognized and under-treated. Psychosomatics. 2012;53:507-516.
Office approach to small fiber neuropathy
Peripheral neuropathy is the most common reason for an outpatient neurology visit in the United States and accounts for over $10 billion in healthcare spending each year.1,2 When the disorder affects only small, thinly myelinated or unmyelinated nerve fibers, it is referred to as small fiber neuropathy, which commonly presents as numbness and burning pain in the feet.
This article details the manifestations and evaluation of small fiber neuropathy, with an eye toward diagnosing an underlying cause amenable to treatment.
OLDER PATIENTS MOST AFFECTED
The epidemiology of small fiber neuropathy is not well established. It occurs more commonly in older patients, but data are mixed on prevalence by sex.3–6 In a Dutch study,3 the overall prevalence was at least 53 cases per 100,000, with the highest rate in men over age 65.
CHARACTERISTIC SENSORY DISTURBANCES
Sensations vary in quality and time
Patients with small fiber neuropathy typically present with a symmetric length-dependent (“stocking-glove”) distribution of sensory changes, starting in the feet and gradually ascending up the legs and then to the hands.
Commonly reported neuropathic symptoms include various combinations of burning, numbness, tingling, itching, sunburn-like, and frostbite-like sensations. Nonneuropathic symptoms may include tightness, a vise-like squeezing of the feet, and the sensation of a sock rolled up at the end of the shoe. Cramps or spasms may also be reported but rarely occur in isolation.7
Symptoms are typically worse at the end of the day and while sitting or lying down at night. They can arise spontaneously but may also be triggered by something as minor as the touch of clothing or cool air against the skin. Bedsheet sensitivity of the feet is reported so often that it is used as an outcome measure in clinical trials. Symptoms can also be exacerbated by extremes in ambient temperature and are especially worse in cold weather.
Random patterns suggest an immune cause
Symptoms may also have a non–length-dependent distribution that is asymmetric, patchy, intermittent, and migratory, and can involve the face, proximal limbs, and trunk. Symptoms may vary throughout the day, eg, starting with electric-shock sensations on one side of the face, followed by perineal numbness and then tingling in the arms lasting for a few minutes to several hours. While such patterns may be seen with diabetes and other common etiologies, they often suggest an underlying immune-mediated disorder such as Sjögren syndrome or sarcoidosis.8–10 Although large fiber polyneuropathy may also be non–length-dependent, the deficits are usually fixed, with no migratory component.
Autonomic features may be prominent
Autonomic symptoms occur in nearly half of patients and can be as troublesome as neuropathic pain.3 Small nerve fibers mediate somatic and autonomic functions, an evolutionary link that may reflect visceral defense mechanisms responding to pain as a signal of danger.11 This may help explain the multisystemic nature of symptoms, which can include sweating abnormalities, bowel and bladder disturbances, dry eyes, dry mouth, gastrointestinal dysmotility, skin changes (eg, discoloration, loss of hair, shiny skin), sexual dysfunction, orthostatic hypotension, and palpitations. In some cases, isolated dysautonomia may be seen.
TARGETED EXAMINATION
History: Medications, alcohol, infections
When a patient presents with neuropathic pain in the feet, a detailed history should be obtained, including alcohol use, family history of neuropathy, and use of neurotoxic medications such as metronidazole, colchicine, and chemotherapeutic agents.
Human immunodeficiency virus (HIV) and hepatitis C infection are well known to be associated with small fiber neuropathy, so relevant risk factors (eg, blood transfusions, sexual history, intravenous drug use) should be asked about. Recent illnesses and vaccinations are another important line of questioning, as a small-fiber variant of Guillain-Barré syndrome has been described.12
Assess reflexes, strength, sensation
On physical examination, particular attention should be focused on searching for abnormalities indicating large nerve fiber involvement (eg, absent deep tendon reflexes, weakness of the toes). However, absent ankle deep tendon reflexes and reduced vibratory sense may also occur in healthy elderly people.
Similarly, proprioception, motor strength, balance, and vibratory sensation are functions of large myelinated nerve fibers, and thus remain unaffected in patients with only small fiber neuropathy.
Evidence of a systemic disorder should also be sought, as it may indicate an underlying etiology.
DIAGNOSTIC TESTING
Although patients with either large or small fiber neuropathy may have subjective hyperesthesia or numbness of the distal lower extremities, the absence of significant abnormalities on neurologic examination should prompt consideration of small fiber neuropathy.
Electromyography worthwhile
Nerve conduction studies and needle electrode examination evaluate only large nerve fiber conditions. While electromyographic results are normal in patients with isolated small fiber neuropathy, the test can help evaluate subclinical large nerve fiber involvement and alternative diagnoses such as bilateral S1 radiculopathy. Nerve conduction studies may be less useful in patients over age 75, as they may lack sural sensory responses because of aging changes.13
Skin biopsy easy to do
Skin biopsy for evaluating intraepidermal nerve fiber density is one of the most widely used tests for small fiber neuropathy. This minimally invasive procedure can now be performed in a primary care office using readily available tools or prepackaged kits and analyzed by several commercial laboratories.
Reduced intraepidermal nerve fiber density on skin biopsy has been described in various other conditions such as fibromyalgia and chronic pain syndromes.16,17 The clinical significance of these findings remains uncertain.
Quantitative sudomotor axon reflex testing
Quantitative sudomotor axon reflex testing (QSART) is a noninvasive autonomic study that assesses the volume of sweat produced by the limbs in response to acetylcholine. A measure of postganglionic sympathetic sudomotor nerve function, QSART has a sensitivity of up to 80% and can be used to diagnose small fiber neuropathy.18 In a series of 115 patients with sarcoidosis small fiber neuropathy,9 the QSART and skin biopsy findings were concordant in 17 cases and complementary in 29, allowing for confirmation of small fiber neuropathy in patients whose condition would have remained undiagnosed had only one test been performed. QSART can also be considered in cases where skin biopsy may be contraindicated (eg, patient use of anticoagulation). Of note, the study may be affected by a number of external factors, including caffeine, tobacco, antihistamines, and tricyclic antidepressants; these should be held before testing.
Other diagnostic studies
Other tests may be helpful, as follows:
Tilt-table and cardiovagal testing may be useful for patients with orthostasis and palpitations.
Thermoregulatory sweat testing can be used to evaluate patients with abnormal patterns of sweating, eg, hyperhidrosis of the face and head.
INITIAL TESTING FOR AN UNDERLYING CAUSE
Glucose tolerance test for diabetes
Diabetes is the most common identifiable cause of small fiber neuropathy and accounts for about a third of all cases.5 Impaired glucose tolerance is also thought to be a risk factor and has been found in up to 50% of idiopathic cases, but the association is still being debated.21
While testing for hemoglobin A1c is more convenient for the patient, especially because it does not require fasting, a 2-hour oral glucose tolerance test is more sensitive for detecting glucose dysmetabolism.22
Lipid panel for metabolic syndrome
Small fiber neuropathy is associated with individual components of the metabolic syndrome, which include obesity, hyperglycemia, and dyslipidemia. Of these, dyslipidemia has emerged as the primary factor involved in the development of small fiber neuropathy, via an inflammatory pathway or oxidative stress mechanism.23,24
Vitamin B12 deficiency testing
Vitamin B12 deficiency, a potentially correctable cause of small fiber neuropathy, may be underdiagnosed, especially as values obtained by blood testing may not reflect tissue uptake. Causes of vitamin B12 deficiency include reduced intake, pernicious anemia, and medications that can affect absorption of vitamin B12 (eg, proton pump inhibitors, histamine 2 receptor antagonists, metformin).
Testing should include:
- Complete blood cell count to evaluate for vitamin B12-related macrocytic anemia and other hematologic abnormalities
- Serum vitamin B12 level
- Methylmalonic acid or homocysteine level in patients with subclinical or mild vitamin B12 deficiency, manifested as low to normal vitamin B12 levels (< 400 pg/mL); methylmalonic acid and homocysteine require vitamin B12 as a cofactor for enzymatic conversion, and either or both may be elevated in early vitamin B12 deficiency.
Celiac antibody panel
Celiac disease, a T-cell mediated enteropathy characterized by gluten intolerance and a herpetiform-like rash, can be associated with small fiber neuropathy.25 In some cases, neuropathy symptoms are preceded by the onset of gastrointestinal symptoms, or they may occur in isolation.25
Inflammatory disease testing
Sjögren syndrome accounts for nearly 10% of cases of small fiber neuropathy. Associated neuropathic symptoms are often non–length-dependent, can precede sicca symptoms for up to 6 years, and in some cases are the sole manifestation of the disease.10 Small fiber neuropathy may also be associated with vasculitis, systemic lupus erythematosus, and other connective tissue disorders.
Testing should include:
- Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodies: though these are nonspecific markers of inflammation, they may support an immune-mediated etiology if positive
- Extractable nuclear antigen panel: Sjögren syndrome A and B autoantibodies are the most important components in this setting5,11
- The Schirmer test or salivary gland biopsy should be considered for seronegative patients with sicca or a suspected immune-mediated etiology, as the sensitivity of antibody testing ranges from only 10% to 55%.10
Thyroid function testing
Hypothyroidism, and less commonly hyperthyroidism, are associated with small fiber neuropathy.
Metabolic tests for liver and kidney disease
Renal insufficiency and liver impairment are well-known causes of small nerve fiber dysfunction. Testing should include:
- Comprehensive metabolic panel
- Gamma-glutamyltransferase if alcohol abuse is suspected, since heavy alcohol use is one of the most common causes of both large and small fiber neuropathy.
HIV and hepatitis C testing
For patients with relevant risk factors, HIV and hepatitis C testing should be part of the initial workup (and as second-tier testing for others). Patients who test positive for hepatitis C should undergo further testing for cryoglobulinemia, which can present with painful small fiber neuropathy.26
Serum and urine immunoelectrophoresis
Paraproteinemia, with causes ranging from monoclonal gammopathy of uncertain significance to multiple myeloma, has been associated with small fiber neuropathy. An abnormal serum or urine immunoelectrophoresis test warrants further investigation and possibly referral to a hematology-oncology specialist.
SECOND-TIER TESTING
Less common treatable causes of small fiber neuropathy may also be evaluated.
Copper, vitamin B1 (thiamine), or vitamin B6 (pyridoxine) deficiency testing. Although vitamin B6 toxicity may also result in neuropathy due to its toxic effect on the dorsal root ganglia, the mildly elevated vitamin B6 levels often found in patients being evaluated for neuropathy are unlikely to be the primary cause of symptoms. Many laboratories require fasting samples for accurate vitamin B6 levels.
Angiotensin-converting enzyme levels for sarcoidosis. Small fiber neuropathy is common in sarcoidosis, occurring in more than 30% of patients with systemic disease.27 However, screening for sarcoidosis by measuring serum levels is often falsely positive and is not cost-effective. In a study of 195 patients with idiopathic small fiber neuropathy,11 44% had an elevated serum level, but no evidence of sarcoidosis was seen on further testing, which included computed tomography of the chest in 29 patients.12 Thus, this test is best used for patients with evidence of systemic disease.
Amyloid testing for amyloidosis. Fat pad or bone marrow biopsy should be considered in the appropriate clinical setting.
Paraneoplastic autoantibody panel for occult cancer. Such testing may also be considered if clinically warranted. However, if a patient is found to have low positive titers of paraneoplastic antibodies and suspicion is low for an occult cancer (eg, no weight loss or early satiety), repeat confirmatory testing at another laboratory should be done before embarking on an extensive search for malignancy.
Ganglionic acetylcholine receptor antibody testing for autoimmune autonomic ganglionopathy. This should be ordered for patients with prominent autonomic dysfunction. The antibody test can be ordered separately or as part of an autoantibody panel. The antibody may indicate a primary immune-mediated process or a paraneoplastic disease.28
Genetic mutation testing. Recent discoveries of gene mutations leading to peripheral nerve hyperexcitability of voltage-gated sodium channels have elucidated a hereditary cause of small fiber neuropathy in nearly 30% of cases that were once thought to be idiopathic.29,30 Genetic testing for mutations in SCN9A and SCN10 (which code for the Nav1.7 and Nav1.8 sodium channels, respectively) is commercially available and may be considered for those with a family history of neuropathic pain in the feet or for young, otherwise healthy patients.
Fabry disease is an X-linked lysosomal disorder characterized by angiokeratomas, cardiac and renal impairment, and small fiber neuropathy. Treatment is now available, but screening is not cost-efficient and should only be pursued in patients with other symptoms of the disease.31,32
OTHER POSSIBLE CAUSES
Guillain-Barré syndrome
A Guillain-Barré syndrome variant has been reported that is characterized by ascending limb paresthesias and cerebrospinal fluid albuminocytologic dissociation in the setting of preserved deep tendon reflexes and normal findings on EMG.12 The clinical course is similar to that of typical Guillain-Barré syndrome, in that symptoms follow an upper respiratory or gastrointestinal tract infection, reach their nadir at 4 weeks, and then gradually improve. Some patients respond to intravenous immune globulin.
Vaccine-associated
Postvaccination small fiber neuropathy has also been reported. The nature of the association is unclear.33
Parkinson disease
Small fiber neuropathy is associated with Parkinson disease. It is attributed to a number of proposed factors, including neurodegeneration that occurs parallel to central nervous system decline, as well as intestinal malabsorption with resultant vitamin deficiency.34,35
Rapid glycemic lowering
Aggressive treatment of diabetes, defined as at least a 2-point reduction of serum hemoglobin A1c level over 3 months, may result in acute small fiber neuropathy. It manifests as severe distal extremity pain and dysautonomia.
In a retrospective study,36 104 (10.9%) of 954 patients presenting to a tertiary diabetic clinic developed treatment-induced diabetic neuropathy with symptoms occurring within 8 weeks of rapid glycemic control. The severity of neuropathy correlated with the degree and rate of glycemic lowering. The condition was reversible in some cases.
TREATING SPECIFIC DISORDERS
For patients with an identified cause of neuropathy, targeted treatment offers the best chance of halting progression and possibly improving symptoms. Below are recommendations for addressing neuropathy associated with the common diagnoses.
Diabetes, impaired glucose tolerance, and metabolic syndrome. In addition to glycemic- and lipid-lowering therapies, lifestyle modifications with a specific focus on exercise and nutrition are integral to treating diabetes and related disorders.
In the Look AHEAD (Action for Health in Diabetes) study,37 which evaluated the effects of intensive lifestyle intervention on neuropathy in 5,145 overweight patients with type 2 diabetes, patients in the intervention group had lower pain scores and better touch sensation in the toes compared with controls at 1 year. Differences correlated with the degree of weight loss and reduction of hemoglobin A1c and lipid levels.
As running and walking may not be feasible for many patients owing to pain, stationary cycling, aqua therapy, and swimming are other options. A stationary recumbent bike may be useful for older patients with balance issues.
Vitamin B12 deficiency. As reduced absorption rather than low dietary intake is the primary cause of vitamin B12 deficiency for many patients, parenteral rather than oral supplementation may be best. A suggested regimen is subcutaneous or intramuscular methylcobalamin injection of 1,000 µg given daily for 1 week, then once weekly for 1 month, followed by a maintenance dose once a month for at least 6 to 12 months. Alternatively, a daily dose of vitamin B12 1,000 µg can be taken sublingually.
Sjögren syndrome. According to anecdotal case reports, intravenous immune globulin, corticosteroids, and other immunosuppressants help painful small fiber neuropathy and dysautonomia associated with Sjögren syndrome.10
Sarcoidosis. Sarcoidosis-associated small fiber neuropathy may also respond to intravenous immune globulin, as well as infliximab and combination therapy.9 Culver et al38 found that cibinetide, an experimental erythropoetin agonist, resulted in improved corneal nerve fiber measures in patients with small fiber neuropathy associated with sarcoidosis.
Celiac disease. A gluten-free diet is the treatment for celiac disease and can help some patients.
GENERAL MANAGEMENT
For all patients, regardless of whether the cause of small fiber neuropathy has been identified, managing symptoms remains key, as pain and autonomic dysfunction can markedly impair quality of life. A multidisciplinary approach that incorporates pain medications, physical therapy, and lifestyle modifications is ideal. Integrative holistic treatments such as natural supplements, yoga, and other mind-body therapies may also help.
Pain control
Mexiletine, a voltage-gated sodium channel blocker used as an antiarrhythmic, may help refractory pain or hereditary small fiber neuropathy related to sodium channel dysfunction. However, it is not recommended for diabetic neuropathy.39
Combination regimens that use drugs with different mechanisms of action can be effective. In one study, combined gabapentin and nortriptyline were more effective than either drug alone for neuropathic pain.40
Inhaled cannabis reduced pain in patients with HIV and diabetic neuropathy in a number of studies. Side effects included euphoria, somnolence, and cognitive impairment.41,42 The use of medical marijuana is not yet legal nationwide and may affect employability even in states in which it has been legalized.
Owing to the opioid epidemic and high addiction potential, opioids are no longer a preferred recommendation for chronic treatment of noncancer-related neuropathy. A population-based study of 2,892 patients with neuropathy found that those on chronic opioid therapy (≥ 90 days) had worse functional outcomes and higher rates of addiction and overdose than those on short-term therapy.43 However, the opioid agonist tramadol was found to be effective in reducing neuropathic pain and may be a safer option for patients with chronic small fiber neuropathy.44
Integrative, holistic therapies
PROGNOSIS
For many patients, small fiber neuropathy is a slowly progressive disorder that reaches a clinical plateau lasting for years, with progression to large fiber involvement reported in 13% to 36% of cases; over half of patients in one series either improved or remained stable over a period of 2 years.5,57 Long-term studies are needed to fully understand the natural disease course. In the meantime, treating underlying disease and managing symptoms are imperative to patient care.
- Burke JF, Skolarus LE, Callaghan BC, Kerber KA. Choosing Wisely: highest-cost tests in outpatient neurology. Ann Neurol 2013; 73(5):679–683. doi:10.1002/ana.23865
- Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003; 26(6):1790–1795. pmid:12766111
- Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology 2013; 81(15):1356–1360. doi:10.1212/WNL.0b013e3182a8236e
- Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999; 53(8):1641–1647. pmid:10563606
- Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008; 131(pt 7):1912–1925. doi:10.1093/brain/awn093
- Lacomis D. Small-fiber neuropathy. Muscle Nerve 2002; 26(2):173–188. doi:10.1002/mus.10181
- Lopate G, Streif E, Harms M, Weihl C, Pestronk A. Cramps and small-fiber neuropathy. Muscle Nerve 2013; 48(2):252–255. doi:10.1002/mus.23757
- Khan S, Zhou L. Characterization of non-length-dependent small-fiber sensory neuropathy. Muscle Nerve 2012; 45(1):86–91. doi:10.1002/mus.22255
- Tavee JO, Karwa K, Ahmed Z, Thompson N, Parambil J, Culver DA. Sarcoidosis-associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med 2017; 126:135–138. doi:10.1016/j.rmed.2017.03.011
- Berkowitz AL, Samuels MA. The neurology of Sjogren’s syndrome and the rheumatology of peripheral neuropathy and myelitis. Pract Neurol 2014; 14(1):14–22. doi:10.1136/practneurol-2013-000651
- Lang M, Treister R, Oaklander AL. Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy. J Neurol 2016; 263(12):2515–2527. doi:10.1007/s00415-016-8270-5
- Seneviratne U, Gunasekera S. Acute small fibre sensory neuropathy: another variant of Guillain-Barré syndrome? J Neurol Neurosurg Psychiatry 2002; 72(4):540–542. pmid:11909922
- Tavee JO, Polston D, Zhou L, Shields RW, Butler RS, Levin KH. Sural sensory nerve action potential, epidermal nerve fiber density, and quantitative sudomotor axon reflex in the healthy elderly. Muscle Nerve 2014; 49(4):564–569. doi:10.1002/mus.23971
- Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med 2009; 76(5):297–305. doi:10.3949/ccjm.76a.08070
- Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 1999; 53(8):1634–1640. pmid:10563605
- Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 2013; 154(11):2310–2316. doi:10.1016/j.pain.2013.06.001
- Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136(pt 6):1857–1867. doi:10.1093/brain/awt053
- Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve 1992; 15(6):661–665. doi:10.1002/mus.880150605
- Malik RA, Kallinikos P, Abbott CA, et al. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 2003; 46(5):683–688. doi:10.1007/s00125-003-1086-8
- de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy—a large cohort study and review of the literature. Eur J Neurol 2018; 25(2):348–355. doi:10.1111/ene.13508
- Smith AG. Impaired glucose tolerance and metabolic syndrome in idiopathic neuropathy. J Peripher Nerv Syst 2012; 17(suppl 2):15–21. doi:10.1111/j.1529-8027.2012.00390.x
- Hoffman-Snyder C, Smith BE, Ross MA, Hernandez J, Bosch EP. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol 2006; 63(8):1075–1079. doi:10.1001/archneur.63.8.noc50336
- Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst 2009; 14(4):257–267. doi:10.1111/j.1529-8027.2009.00237.x
- Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA, Feldman EL. Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes 2009; 58(7):1634–1640. doi:10.2337/db08-1771
- Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy. Neurology 2003; 60(10):1581–1585. pmid:12771245
- Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry 2005; 76(10):1410–1414. doi:10.1136/jnnp.2004.057620
- Bakkers M, Merkies IS, Lauria G, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 2009; 73(14):1142–1148. doi:10.1212/WNL.0b013e3181bacf05
- Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343(12):847–855. doi:10.1056/NEJM200009213431204
- Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012; 71(1):26–39. doi:10.1002/ana.22485
- Brouwer BA, Merkies IS, Gerrits MM, Waxman SG, Hoeijmakers JG, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst 2014; 19(2):53–65. doi:10.1111/jns5.12071
- Samuelsson K, Kostulas K, Vrethem M, Rolfs A, Press R. Idiopathic small fiber neuropathy: phenotype, etiologies, and the search for Fabry disease. J Clin Neurol 2014; 10(2):108–118. doi:10.3988/jcn.2014.10.2.108
- de Greef BT, Hoeijmakers JG, Wolters EE, et al. No Fabry disease in patients presenting with isolated small fiber neuropathy. PLoS One 2016; 11(2):e0148316. doi:10.1371/journal.pone.0148316
- Souayah N, Ajroud-Driss S, Sander HW, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 2009; 27(52):7322–7325. doi:10.1016/j.vaccine.2009.09.077
- Nolano M, Provitera V, Manganelli F, et al. Loss of cutaneous large and small fibers in naive and l-dopa–treated PD patients. Neurology 2017; 89(8):776–784. doi:10.1212/WNL.0000000000004274
- Zis P, Grünewald RA, Chaudhuri RK, Hadjivassiliou M. Peripheral neuropathy in idiopathic Parkinson’s disease: a systematic review. J Neurol Sci 2017; 378:204–209. doi:10.1016/j.jns.2017.05.023
- Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain 2015; 138(pt 1):43–52. doi:10.1093/brain/awu307
- Look AHEAD Research Group. Effects of a long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study. Diabetologia 2017; 60(6):980–988. doi:10.1007/s00125-017-4253-z
- Culver DA, Dahan A, Bajorunas D, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci 2017; 58(6):BIO52–BIO60. doi:10.1167/iovs.16-21291
- Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R 2011; 3(4):345–352.e21. doi:10.1016/j.pmrj.2011.03.008
- Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009; 374(9697):1252–1261. doi:10.1016/S0140-6736(09)61081-3
- Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34(3):672–680. doi:10.1038/npp.2008.120
- Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 2015; 16(7):616–627. doi:10.1016/j.jpain.2015.03.008
- Hoffman EM, Watson JC, St Sauver J, Staff NP, Klein CJ. Association of long-term opioid therapy with functional status, adverse outcomes, and mortality among patients with polyneuropathy. JAMA Neurol 2017; 74(7):773–779. doi:10.1001/jamaneurol.2017.0486
- Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50(6):1842–1846. pmid:9633738
- Sima AA, Calvani M, Mehra M, Amato A; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005; 28(1):89–94. pmid:15616239
- Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995; 38(12):1425–1433. pmid:8786016
- Scarpini E, Sacilotto G, Baron P, Cusini M, Scarlato G. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst 1997; 2(3):250-252. pmid: 10975731
- Hershman DL, Unger JM, Crew KD, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 2013; 31(20):2627-2633. doi:10.1200/JCO.2012.44.8738
- Amara S. Oral glutamine for the prevention of chemotherapy-induced peripheral neuropathy. Ann Pharmacother 2008; 42(10):1481-1485. doi:10.1345/aph.1L179
- Huang JS, Wu CL, Fan CW, Chen WH, Yeh KY, Chang PH. Intravenous glutamine appears to reduce the severity of symptomatic platinum-induced neuropathy: a prospective randomized study. J Chemother 2015; 27(4):235-240. doi:10.1179/1973947815Y.0000000011
- Banafshe HR, Hamidi GA, Noureddini M, Mirhashemi SM, Mokhtari R, Shoferpour M. Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system. Eur J Pharmacol 2014; 723:202-206. doi:10.1016/j.ejphar.2013.11.033
- Mendonça LM, da Silva Machado C, Teixeira CC, de Freitas LA, Bianchi MD, Antunes LM. Curcumin reduces cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells. Neurotoxicology 2013; 34:205-211. doi:10.1016/j.neuro.2012.09.011
- Wagner K, Lee KS, Yang J, Hammock BD. Epoxy fatty acids mediate analgesia in murine diabetic neuropathy. Eur J Pain 2017; 21(3):456-465. doi:10.1002/ejp.939
- Lewis EJ, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: a 12-month pilot trial. Neurology 2017; 88(24):2294–2301. doi:10.1212/WNL.0000000000004033
- Hu D, Wang C, Li F, et al. A combined water extract of frankincense and myrrh alleviates neuropathic pain in mice via modulation of TRPV1. Neural Plast 2017; 2017:3710821. doi:10.1155/2017/3710821
- Tavee J, Rensel M, Planchon SM, Butler RS, Stone L. Effects of meditation on pain and quality of life in multiple sclerosis and peripheral neuropathy: a pilot study. Int J MS Care 2011; 13(4):163–168. doi:10.7224/1537-2073-13.4.163
- Khoshnoodi MA, Truelove S, Burakgazi A, Hoke A, Mammen AL, Polydefkis M. Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy. JAMA Neurol 2016; 73(6):684–690. doi:10.1001/jamaneurol.2016.0057
Peripheral neuropathy is the most common reason for an outpatient neurology visit in the United States and accounts for over $10 billion in healthcare spending each year.1,2 When the disorder affects only small, thinly myelinated or unmyelinated nerve fibers, it is referred to as small fiber neuropathy, which commonly presents as numbness and burning pain in the feet.
This article details the manifestations and evaluation of small fiber neuropathy, with an eye toward diagnosing an underlying cause amenable to treatment.
OLDER PATIENTS MOST AFFECTED
The epidemiology of small fiber neuropathy is not well established. It occurs more commonly in older patients, but data are mixed on prevalence by sex.3–6 In a Dutch study,3 the overall prevalence was at least 53 cases per 100,000, with the highest rate in men over age 65.
CHARACTERISTIC SENSORY DISTURBANCES
Sensations vary in quality and time
Patients with small fiber neuropathy typically present with a symmetric length-dependent (“stocking-glove”) distribution of sensory changes, starting in the feet and gradually ascending up the legs and then to the hands.
Commonly reported neuropathic symptoms include various combinations of burning, numbness, tingling, itching, sunburn-like, and frostbite-like sensations. Nonneuropathic symptoms may include tightness, a vise-like squeezing of the feet, and the sensation of a sock rolled up at the end of the shoe. Cramps or spasms may also be reported but rarely occur in isolation.7
Symptoms are typically worse at the end of the day and while sitting or lying down at night. They can arise spontaneously but may also be triggered by something as minor as the touch of clothing or cool air against the skin. Bedsheet sensitivity of the feet is reported so often that it is used as an outcome measure in clinical trials. Symptoms can also be exacerbated by extremes in ambient temperature and are especially worse in cold weather.
Random patterns suggest an immune cause
Symptoms may also have a non–length-dependent distribution that is asymmetric, patchy, intermittent, and migratory, and can involve the face, proximal limbs, and trunk. Symptoms may vary throughout the day, eg, starting with electric-shock sensations on one side of the face, followed by perineal numbness and then tingling in the arms lasting for a few minutes to several hours. While such patterns may be seen with diabetes and other common etiologies, they often suggest an underlying immune-mediated disorder such as Sjögren syndrome or sarcoidosis.8–10 Although large fiber polyneuropathy may also be non–length-dependent, the deficits are usually fixed, with no migratory component.
Autonomic features may be prominent
Autonomic symptoms occur in nearly half of patients and can be as troublesome as neuropathic pain.3 Small nerve fibers mediate somatic and autonomic functions, an evolutionary link that may reflect visceral defense mechanisms responding to pain as a signal of danger.11 This may help explain the multisystemic nature of symptoms, which can include sweating abnormalities, bowel and bladder disturbances, dry eyes, dry mouth, gastrointestinal dysmotility, skin changes (eg, discoloration, loss of hair, shiny skin), sexual dysfunction, orthostatic hypotension, and palpitations. In some cases, isolated dysautonomia may be seen.
TARGETED EXAMINATION
History: Medications, alcohol, infections
When a patient presents with neuropathic pain in the feet, a detailed history should be obtained, including alcohol use, family history of neuropathy, and use of neurotoxic medications such as metronidazole, colchicine, and chemotherapeutic agents.
Human immunodeficiency virus (HIV) and hepatitis C infection are well known to be associated with small fiber neuropathy, so relevant risk factors (eg, blood transfusions, sexual history, intravenous drug use) should be asked about. Recent illnesses and vaccinations are another important line of questioning, as a small-fiber variant of Guillain-Barré syndrome has been described.12
Assess reflexes, strength, sensation
On physical examination, particular attention should be focused on searching for abnormalities indicating large nerve fiber involvement (eg, absent deep tendon reflexes, weakness of the toes). However, absent ankle deep tendon reflexes and reduced vibratory sense may also occur in healthy elderly people.
Similarly, proprioception, motor strength, balance, and vibratory sensation are functions of large myelinated nerve fibers, and thus remain unaffected in patients with only small fiber neuropathy.
Evidence of a systemic disorder should also be sought, as it may indicate an underlying etiology.
DIAGNOSTIC TESTING
Although patients with either large or small fiber neuropathy may have subjective hyperesthesia or numbness of the distal lower extremities, the absence of significant abnormalities on neurologic examination should prompt consideration of small fiber neuropathy.
Electromyography worthwhile
Nerve conduction studies and needle electrode examination evaluate only large nerve fiber conditions. While electromyographic results are normal in patients with isolated small fiber neuropathy, the test can help evaluate subclinical large nerve fiber involvement and alternative diagnoses such as bilateral S1 radiculopathy. Nerve conduction studies may be less useful in patients over age 75, as they may lack sural sensory responses because of aging changes.13
Skin biopsy easy to do
Skin biopsy for evaluating intraepidermal nerve fiber density is one of the most widely used tests for small fiber neuropathy. This minimally invasive procedure can now be performed in a primary care office using readily available tools or prepackaged kits and analyzed by several commercial laboratories.
Reduced intraepidermal nerve fiber density on skin biopsy has been described in various other conditions such as fibromyalgia and chronic pain syndromes.16,17 The clinical significance of these findings remains uncertain.
Quantitative sudomotor axon reflex testing
Quantitative sudomotor axon reflex testing (QSART) is a noninvasive autonomic study that assesses the volume of sweat produced by the limbs in response to acetylcholine. A measure of postganglionic sympathetic sudomotor nerve function, QSART has a sensitivity of up to 80% and can be used to diagnose small fiber neuropathy.18 In a series of 115 patients with sarcoidosis small fiber neuropathy,9 the QSART and skin biopsy findings were concordant in 17 cases and complementary in 29, allowing for confirmation of small fiber neuropathy in patients whose condition would have remained undiagnosed had only one test been performed. QSART can also be considered in cases where skin biopsy may be contraindicated (eg, patient use of anticoagulation). Of note, the study may be affected by a number of external factors, including caffeine, tobacco, antihistamines, and tricyclic antidepressants; these should be held before testing.
Other diagnostic studies
Other tests may be helpful, as follows:
Tilt-table and cardiovagal testing may be useful for patients with orthostasis and palpitations.
Thermoregulatory sweat testing can be used to evaluate patients with abnormal patterns of sweating, eg, hyperhidrosis of the face and head.
INITIAL TESTING FOR AN UNDERLYING CAUSE
Glucose tolerance test for diabetes
Diabetes is the most common identifiable cause of small fiber neuropathy and accounts for about a third of all cases.5 Impaired glucose tolerance is also thought to be a risk factor and has been found in up to 50% of idiopathic cases, but the association is still being debated.21
While testing for hemoglobin A1c is more convenient for the patient, especially because it does not require fasting, a 2-hour oral glucose tolerance test is more sensitive for detecting glucose dysmetabolism.22
Lipid panel for metabolic syndrome
Small fiber neuropathy is associated with individual components of the metabolic syndrome, which include obesity, hyperglycemia, and dyslipidemia. Of these, dyslipidemia has emerged as the primary factor involved in the development of small fiber neuropathy, via an inflammatory pathway or oxidative stress mechanism.23,24
Vitamin B12 deficiency testing
Vitamin B12 deficiency, a potentially correctable cause of small fiber neuropathy, may be underdiagnosed, especially as values obtained by blood testing may not reflect tissue uptake. Causes of vitamin B12 deficiency include reduced intake, pernicious anemia, and medications that can affect absorption of vitamin B12 (eg, proton pump inhibitors, histamine 2 receptor antagonists, metformin).
Testing should include:
- Complete blood cell count to evaluate for vitamin B12-related macrocytic anemia and other hematologic abnormalities
- Serum vitamin B12 level
- Methylmalonic acid or homocysteine level in patients with subclinical or mild vitamin B12 deficiency, manifested as low to normal vitamin B12 levels (< 400 pg/mL); methylmalonic acid and homocysteine require vitamin B12 as a cofactor for enzymatic conversion, and either or both may be elevated in early vitamin B12 deficiency.
Celiac antibody panel
Celiac disease, a T-cell mediated enteropathy characterized by gluten intolerance and a herpetiform-like rash, can be associated with small fiber neuropathy.25 In some cases, neuropathy symptoms are preceded by the onset of gastrointestinal symptoms, or they may occur in isolation.25
Inflammatory disease testing
Sjögren syndrome accounts for nearly 10% of cases of small fiber neuropathy. Associated neuropathic symptoms are often non–length-dependent, can precede sicca symptoms for up to 6 years, and in some cases are the sole manifestation of the disease.10 Small fiber neuropathy may also be associated with vasculitis, systemic lupus erythematosus, and other connective tissue disorders.
Testing should include:
- Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodies: though these are nonspecific markers of inflammation, they may support an immune-mediated etiology if positive
- Extractable nuclear antigen panel: Sjögren syndrome A and B autoantibodies are the most important components in this setting5,11
- The Schirmer test or salivary gland biopsy should be considered for seronegative patients with sicca or a suspected immune-mediated etiology, as the sensitivity of antibody testing ranges from only 10% to 55%.10
Thyroid function testing
Hypothyroidism, and less commonly hyperthyroidism, are associated with small fiber neuropathy.
Metabolic tests for liver and kidney disease
Renal insufficiency and liver impairment are well-known causes of small nerve fiber dysfunction. Testing should include:
- Comprehensive metabolic panel
- Gamma-glutamyltransferase if alcohol abuse is suspected, since heavy alcohol use is one of the most common causes of both large and small fiber neuropathy.
HIV and hepatitis C testing
For patients with relevant risk factors, HIV and hepatitis C testing should be part of the initial workup (and as second-tier testing for others). Patients who test positive for hepatitis C should undergo further testing for cryoglobulinemia, which can present with painful small fiber neuropathy.26
Serum and urine immunoelectrophoresis
Paraproteinemia, with causes ranging from monoclonal gammopathy of uncertain significance to multiple myeloma, has been associated with small fiber neuropathy. An abnormal serum or urine immunoelectrophoresis test warrants further investigation and possibly referral to a hematology-oncology specialist.
SECOND-TIER TESTING
Less common treatable causes of small fiber neuropathy may also be evaluated.
Copper, vitamin B1 (thiamine), or vitamin B6 (pyridoxine) deficiency testing. Although vitamin B6 toxicity may also result in neuropathy due to its toxic effect on the dorsal root ganglia, the mildly elevated vitamin B6 levels often found in patients being evaluated for neuropathy are unlikely to be the primary cause of symptoms. Many laboratories require fasting samples for accurate vitamin B6 levels.
Angiotensin-converting enzyme levels for sarcoidosis. Small fiber neuropathy is common in sarcoidosis, occurring in more than 30% of patients with systemic disease.27 However, screening for sarcoidosis by measuring serum levels is often falsely positive and is not cost-effective. In a study of 195 patients with idiopathic small fiber neuropathy,11 44% had an elevated serum level, but no evidence of sarcoidosis was seen on further testing, which included computed tomography of the chest in 29 patients.12 Thus, this test is best used for patients with evidence of systemic disease.
Amyloid testing for amyloidosis. Fat pad or bone marrow biopsy should be considered in the appropriate clinical setting.
Paraneoplastic autoantibody panel for occult cancer. Such testing may also be considered if clinically warranted. However, if a patient is found to have low positive titers of paraneoplastic antibodies and suspicion is low for an occult cancer (eg, no weight loss or early satiety), repeat confirmatory testing at another laboratory should be done before embarking on an extensive search for malignancy.
Ganglionic acetylcholine receptor antibody testing for autoimmune autonomic ganglionopathy. This should be ordered for patients with prominent autonomic dysfunction. The antibody test can be ordered separately or as part of an autoantibody panel. The antibody may indicate a primary immune-mediated process or a paraneoplastic disease.28
Genetic mutation testing. Recent discoveries of gene mutations leading to peripheral nerve hyperexcitability of voltage-gated sodium channels have elucidated a hereditary cause of small fiber neuropathy in nearly 30% of cases that were once thought to be idiopathic.29,30 Genetic testing for mutations in SCN9A and SCN10 (which code for the Nav1.7 and Nav1.8 sodium channels, respectively) is commercially available and may be considered for those with a family history of neuropathic pain in the feet or for young, otherwise healthy patients.
Fabry disease is an X-linked lysosomal disorder characterized by angiokeratomas, cardiac and renal impairment, and small fiber neuropathy. Treatment is now available, but screening is not cost-efficient and should only be pursued in patients with other symptoms of the disease.31,32
OTHER POSSIBLE CAUSES
Guillain-Barré syndrome
A Guillain-Barré syndrome variant has been reported that is characterized by ascending limb paresthesias and cerebrospinal fluid albuminocytologic dissociation in the setting of preserved deep tendon reflexes and normal findings on EMG.12 The clinical course is similar to that of typical Guillain-Barré syndrome, in that symptoms follow an upper respiratory or gastrointestinal tract infection, reach their nadir at 4 weeks, and then gradually improve. Some patients respond to intravenous immune globulin.
Vaccine-associated
Postvaccination small fiber neuropathy has also been reported. The nature of the association is unclear.33
Parkinson disease
Small fiber neuropathy is associated with Parkinson disease. It is attributed to a number of proposed factors, including neurodegeneration that occurs parallel to central nervous system decline, as well as intestinal malabsorption with resultant vitamin deficiency.34,35
Rapid glycemic lowering
Aggressive treatment of diabetes, defined as at least a 2-point reduction of serum hemoglobin A1c level over 3 months, may result in acute small fiber neuropathy. It manifests as severe distal extremity pain and dysautonomia.
In a retrospective study,36 104 (10.9%) of 954 patients presenting to a tertiary diabetic clinic developed treatment-induced diabetic neuropathy with symptoms occurring within 8 weeks of rapid glycemic control. The severity of neuropathy correlated with the degree and rate of glycemic lowering. The condition was reversible in some cases.
TREATING SPECIFIC DISORDERS
For patients with an identified cause of neuropathy, targeted treatment offers the best chance of halting progression and possibly improving symptoms. Below are recommendations for addressing neuropathy associated with the common diagnoses.
Diabetes, impaired glucose tolerance, and metabolic syndrome. In addition to glycemic- and lipid-lowering therapies, lifestyle modifications with a specific focus on exercise and nutrition are integral to treating diabetes and related disorders.
In the Look AHEAD (Action for Health in Diabetes) study,37 which evaluated the effects of intensive lifestyle intervention on neuropathy in 5,145 overweight patients with type 2 diabetes, patients in the intervention group had lower pain scores and better touch sensation in the toes compared with controls at 1 year. Differences correlated with the degree of weight loss and reduction of hemoglobin A1c and lipid levels.
As running and walking may not be feasible for many patients owing to pain, stationary cycling, aqua therapy, and swimming are other options. A stationary recumbent bike may be useful for older patients with balance issues.
Vitamin B12 deficiency. As reduced absorption rather than low dietary intake is the primary cause of vitamin B12 deficiency for many patients, parenteral rather than oral supplementation may be best. A suggested regimen is subcutaneous or intramuscular methylcobalamin injection of 1,000 µg given daily for 1 week, then once weekly for 1 month, followed by a maintenance dose once a month for at least 6 to 12 months. Alternatively, a daily dose of vitamin B12 1,000 µg can be taken sublingually.
Sjögren syndrome. According to anecdotal case reports, intravenous immune globulin, corticosteroids, and other immunosuppressants help painful small fiber neuropathy and dysautonomia associated with Sjögren syndrome.10
Sarcoidosis. Sarcoidosis-associated small fiber neuropathy may also respond to intravenous immune globulin, as well as infliximab and combination therapy.9 Culver et al38 found that cibinetide, an experimental erythropoetin agonist, resulted in improved corneal nerve fiber measures in patients with small fiber neuropathy associated with sarcoidosis.
Celiac disease. A gluten-free diet is the treatment for celiac disease and can help some patients.
GENERAL MANAGEMENT
For all patients, regardless of whether the cause of small fiber neuropathy has been identified, managing symptoms remains key, as pain and autonomic dysfunction can markedly impair quality of life. A multidisciplinary approach that incorporates pain medications, physical therapy, and lifestyle modifications is ideal. Integrative holistic treatments such as natural supplements, yoga, and other mind-body therapies may also help.
Pain control
Mexiletine, a voltage-gated sodium channel blocker used as an antiarrhythmic, may help refractory pain or hereditary small fiber neuropathy related to sodium channel dysfunction. However, it is not recommended for diabetic neuropathy.39
Combination regimens that use drugs with different mechanisms of action can be effective. In one study, combined gabapentin and nortriptyline were more effective than either drug alone for neuropathic pain.40
Inhaled cannabis reduced pain in patients with HIV and diabetic neuropathy in a number of studies. Side effects included euphoria, somnolence, and cognitive impairment.41,42 The use of medical marijuana is not yet legal nationwide and may affect employability even in states in which it has been legalized.
Owing to the opioid epidemic and high addiction potential, opioids are no longer a preferred recommendation for chronic treatment of noncancer-related neuropathy. A population-based study of 2,892 patients with neuropathy found that those on chronic opioid therapy (≥ 90 days) had worse functional outcomes and higher rates of addiction and overdose than those on short-term therapy.43 However, the opioid agonist tramadol was found to be effective in reducing neuropathic pain and may be a safer option for patients with chronic small fiber neuropathy.44
Integrative, holistic therapies
PROGNOSIS
For many patients, small fiber neuropathy is a slowly progressive disorder that reaches a clinical plateau lasting for years, with progression to large fiber involvement reported in 13% to 36% of cases; over half of patients in one series either improved or remained stable over a period of 2 years.5,57 Long-term studies are needed to fully understand the natural disease course. In the meantime, treating underlying disease and managing symptoms are imperative to patient care.
Peripheral neuropathy is the most common reason for an outpatient neurology visit in the United States and accounts for over $10 billion in healthcare spending each year.1,2 When the disorder affects only small, thinly myelinated or unmyelinated nerve fibers, it is referred to as small fiber neuropathy, which commonly presents as numbness and burning pain in the feet.
This article details the manifestations and evaluation of small fiber neuropathy, with an eye toward diagnosing an underlying cause amenable to treatment.
OLDER PATIENTS MOST AFFECTED
The epidemiology of small fiber neuropathy is not well established. It occurs more commonly in older patients, but data are mixed on prevalence by sex.3–6 In a Dutch study,3 the overall prevalence was at least 53 cases per 100,000, with the highest rate in men over age 65.
CHARACTERISTIC SENSORY DISTURBANCES
Sensations vary in quality and time
Patients with small fiber neuropathy typically present with a symmetric length-dependent (“stocking-glove”) distribution of sensory changes, starting in the feet and gradually ascending up the legs and then to the hands.
Commonly reported neuropathic symptoms include various combinations of burning, numbness, tingling, itching, sunburn-like, and frostbite-like sensations. Nonneuropathic symptoms may include tightness, a vise-like squeezing of the feet, and the sensation of a sock rolled up at the end of the shoe. Cramps or spasms may also be reported but rarely occur in isolation.7
Symptoms are typically worse at the end of the day and while sitting or lying down at night. They can arise spontaneously but may also be triggered by something as minor as the touch of clothing or cool air against the skin. Bedsheet sensitivity of the feet is reported so often that it is used as an outcome measure in clinical trials. Symptoms can also be exacerbated by extremes in ambient temperature and are especially worse in cold weather.
Random patterns suggest an immune cause
Symptoms may also have a non–length-dependent distribution that is asymmetric, patchy, intermittent, and migratory, and can involve the face, proximal limbs, and trunk. Symptoms may vary throughout the day, eg, starting with electric-shock sensations on one side of the face, followed by perineal numbness and then tingling in the arms lasting for a few minutes to several hours. While such patterns may be seen with diabetes and other common etiologies, they often suggest an underlying immune-mediated disorder such as Sjögren syndrome or sarcoidosis.8–10 Although large fiber polyneuropathy may also be non–length-dependent, the deficits are usually fixed, with no migratory component.
Autonomic features may be prominent
Autonomic symptoms occur in nearly half of patients and can be as troublesome as neuropathic pain.3 Small nerve fibers mediate somatic and autonomic functions, an evolutionary link that may reflect visceral defense mechanisms responding to pain as a signal of danger.11 This may help explain the multisystemic nature of symptoms, which can include sweating abnormalities, bowel and bladder disturbances, dry eyes, dry mouth, gastrointestinal dysmotility, skin changes (eg, discoloration, loss of hair, shiny skin), sexual dysfunction, orthostatic hypotension, and palpitations. In some cases, isolated dysautonomia may be seen.
TARGETED EXAMINATION
History: Medications, alcohol, infections
When a patient presents with neuropathic pain in the feet, a detailed history should be obtained, including alcohol use, family history of neuropathy, and use of neurotoxic medications such as metronidazole, colchicine, and chemotherapeutic agents.
Human immunodeficiency virus (HIV) and hepatitis C infection are well known to be associated with small fiber neuropathy, so relevant risk factors (eg, blood transfusions, sexual history, intravenous drug use) should be asked about. Recent illnesses and vaccinations are another important line of questioning, as a small-fiber variant of Guillain-Barré syndrome has been described.12
Assess reflexes, strength, sensation
On physical examination, particular attention should be focused on searching for abnormalities indicating large nerve fiber involvement (eg, absent deep tendon reflexes, weakness of the toes). However, absent ankle deep tendon reflexes and reduced vibratory sense may also occur in healthy elderly people.
Similarly, proprioception, motor strength, balance, and vibratory sensation are functions of large myelinated nerve fibers, and thus remain unaffected in patients with only small fiber neuropathy.
Evidence of a systemic disorder should also be sought, as it may indicate an underlying etiology.
DIAGNOSTIC TESTING
Although patients with either large or small fiber neuropathy may have subjective hyperesthesia or numbness of the distal lower extremities, the absence of significant abnormalities on neurologic examination should prompt consideration of small fiber neuropathy.
Electromyography worthwhile
Nerve conduction studies and needle electrode examination evaluate only large nerve fiber conditions. While electromyographic results are normal in patients with isolated small fiber neuropathy, the test can help evaluate subclinical large nerve fiber involvement and alternative diagnoses such as bilateral S1 radiculopathy. Nerve conduction studies may be less useful in patients over age 75, as they may lack sural sensory responses because of aging changes.13
Skin biopsy easy to do
Skin biopsy for evaluating intraepidermal nerve fiber density is one of the most widely used tests for small fiber neuropathy. This minimally invasive procedure can now be performed in a primary care office using readily available tools or prepackaged kits and analyzed by several commercial laboratories.
Reduced intraepidermal nerve fiber density on skin biopsy has been described in various other conditions such as fibromyalgia and chronic pain syndromes.16,17 The clinical significance of these findings remains uncertain.
Quantitative sudomotor axon reflex testing
Quantitative sudomotor axon reflex testing (QSART) is a noninvasive autonomic study that assesses the volume of sweat produced by the limbs in response to acetylcholine. A measure of postganglionic sympathetic sudomotor nerve function, QSART has a sensitivity of up to 80% and can be used to diagnose small fiber neuropathy.18 In a series of 115 patients with sarcoidosis small fiber neuropathy,9 the QSART and skin biopsy findings were concordant in 17 cases and complementary in 29, allowing for confirmation of small fiber neuropathy in patients whose condition would have remained undiagnosed had only one test been performed. QSART can also be considered in cases where skin biopsy may be contraindicated (eg, patient use of anticoagulation). Of note, the study may be affected by a number of external factors, including caffeine, tobacco, antihistamines, and tricyclic antidepressants; these should be held before testing.
Other diagnostic studies
Other tests may be helpful, as follows:
Tilt-table and cardiovagal testing may be useful for patients with orthostasis and palpitations.
Thermoregulatory sweat testing can be used to evaluate patients with abnormal patterns of sweating, eg, hyperhidrosis of the face and head.
INITIAL TESTING FOR AN UNDERLYING CAUSE
Glucose tolerance test for diabetes
Diabetes is the most common identifiable cause of small fiber neuropathy and accounts for about a third of all cases.5 Impaired glucose tolerance is also thought to be a risk factor and has been found in up to 50% of idiopathic cases, but the association is still being debated.21
While testing for hemoglobin A1c is more convenient for the patient, especially because it does not require fasting, a 2-hour oral glucose tolerance test is more sensitive for detecting glucose dysmetabolism.22
Lipid panel for metabolic syndrome
Small fiber neuropathy is associated with individual components of the metabolic syndrome, which include obesity, hyperglycemia, and dyslipidemia. Of these, dyslipidemia has emerged as the primary factor involved in the development of small fiber neuropathy, via an inflammatory pathway or oxidative stress mechanism.23,24
Vitamin B12 deficiency testing
Vitamin B12 deficiency, a potentially correctable cause of small fiber neuropathy, may be underdiagnosed, especially as values obtained by blood testing may not reflect tissue uptake. Causes of vitamin B12 deficiency include reduced intake, pernicious anemia, and medications that can affect absorption of vitamin B12 (eg, proton pump inhibitors, histamine 2 receptor antagonists, metformin).
Testing should include:
- Complete blood cell count to evaluate for vitamin B12-related macrocytic anemia and other hematologic abnormalities
- Serum vitamin B12 level
- Methylmalonic acid or homocysteine level in patients with subclinical or mild vitamin B12 deficiency, manifested as low to normal vitamin B12 levels (< 400 pg/mL); methylmalonic acid and homocysteine require vitamin B12 as a cofactor for enzymatic conversion, and either or both may be elevated in early vitamin B12 deficiency.
Celiac antibody panel
Celiac disease, a T-cell mediated enteropathy characterized by gluten intolerance and a herpetiform-like rash, can be associated with small fiber neuropathy.25 In some cases, neuropathy symptoms are preceded by the onset of gastrointestinal symptoms, or they may occur in isolation.25
Inflammatory disease testing
Sjögren syndrome accounts for nearly 10% of cases of small fiber neuropathy. Associated neuropathic symptoms are often non–length-dependent, can precede sicca symptoms for up to 6 years, and in some cases are the sole manifestation of the disease.10 Small fiber neuropathy may also be associated with vasculitis, systemic lupus erythematosus, and other connective tissue disorders.
Testing should include:
- Erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodies: though these are nonspecific markers of inflammation, they may support an immune-mediated etiology if positive
- Extractable nuclear antigen panel: Sjögren syndrome A and B autoantibodies are the most important components in this setting5,11
- The Schirmer test or salivary gland biopsy should be considered for seronegative patients with sicca or a suspected immune-mediated etiology, as the sensitivity of antibody testing ranges from only 10% to 55%.10
Thyroid function testing
Hypothyroidism, and less commonly hyperthyroidism, are associated with small fiber neuropathy.
Metabolic tests for liver and kidney disease
Renal insufficiency and liver impairment are well-known causes of small nerve fiber dysfunction. Testing should include:
- Comprehensive metabolic panel
- Gamma-glutamyltransferase if alcohol abuse is suspected, since heavy alcohol use is one of the most common causes of both large and small fiber neuropathy.
HIV and hepatitis C testing
For patients with relevant risk factors, HIV and hepatitis C testing should be part of the initial workup (and as second-tier testing for others). Patients who test positive for hepatitis C should undergo further testing for cryoglobulinemia, which can present with painful small fiber neuropathy.26
Serum and urine immunoelectrophoresis
Paraproteinemia, with causes ranging from monoclonal gammopathy of uncertain significance to multiple myeloma, has been associated with small fiber neuropathy. An abnormal serum or urine immunoelectrophoresis test warrants further investigation and possibly referral to a hematology-oncology specialist.
SECOND-TIER TESTING
Less common treatable causes of small fiber neuropathy may also be evaluated.
Copper, vitamin B1 (thiamine), or vitamin B6 (pyridoxine) deficiency testing. Although vitamin B6 toxicity may also result in neuropathy due to its toxic effect on the dorsal root ganglia, the mildly elevated vitamin B6 levels often found in patients being evaluated for neuropathy are unlikely to be the primary cause of symptoms. Many laboratories require fasting samples for accurate vitamin B6 levels.
Angiotensin-converting enzyme levels for sarcoidosis. Small fiber neuropathy is common in sarcoidosis, occurring in more than 30% of patients with systemic disease.27 However, screening for sarcoidosis by measuring serum levels is often falsely positive and is not cost-effective. In a study of 195 patients with idiopathic small fiber neuropathy,11 44% had an elevated serum level, but no evidence of sarcoidosis was seen on further testing, which included computed tomography of the chest in 29 patients.12 Thus, this test is best used for patients with evidence of systemic disease.
Amyloid testing for amyloidosis. Fat pad or bone marrow biopsy should be considered in the appropriate clinical setting.
Paraneoplastic autoantibody panel for occult cancer. Such testing may also be considered if clinically warranted. However, if a patient is found to have low positive titers of paraneoplastic antibodies and suspicion is low for an occult cancer (eg, no weight loss or early satiety), repeat confirmatory testing at another laboratory should be done before embarking on an extensive search for malignancy.
Ganglionic acetylcholine receptor antibody testing for autoimmune autonomic ganglionopathy. This should be ordered for patients with prominent autonomic dysfunction. The antibody test can be ordered separately or as part of an autoantibody panel. The antibody may indicate a primary immune-mediated process or a paraneoplastic disease.28
Genetic mutation testing. Recent discoveries of gene mutations leading to peripheral nerve hyperexcitability of voltage-gated sodium channels have elucidated a hereditary cause of small fiber neuropathy in nearly 30% of cases that were once thought to be idiopathic.29,30 Genetic testing for mutations in SCN9A and SCN10 (which code for the Nav1.7 and Nav1.8 sodium channels, respectively) is commercially available and may be considered for those with a family history of neuropathic pain in the feet or for young, otherwise healthy patients.
Fabry disease is an X-linked lysosomal disorder characterized by angiokeratomas, cardiac and renal impairment, and small fiber neuropathy. Treatment is now available, but screening is not cost-efficient and should only be pursued in patients with other symptoms of the disease.31,32
OTHER POSSIBLE CAUSES
Guillain-Barré syndrome
A Guillain-Barré syndrome variant has been reported that is characterized by ascending limb paresthesias and cerebrospinal fluid albuminocytologic dissociation in the setting of preserved deep tendon reflexes and normal findings on EMG.12 The clinical course is similar to that of typical Guillain-Barré syndrome, in that symptoms follow an upper respiratory or gastrointestinal tract infection, reach their nadir at 4 weeks, and then gradually improve. Some patients respond to intravenous immune globulin.
Vaccine-associated
Postvaccination small fiber neuropathy has also been reported. The nature of the association is unclear.33
Parkinson disease
Small fiber neuropathy is associated with Parkinson disease. It is attributed to a number of proposed factors, including neurodegeneration that occurs parallel to central nervous system decline, as well as intestinal malabsorption with resultant vitamin deficiency.34,35
Rapid glycemic lowering
Aggressive treatment of diabetes, defined as at least a 2-point reduction of serum hemoglobin A1c level over 3 months, may result in acute small fiber neuropathy. It manifests as severe distal extremity pain and dysautonomia.
In a retrospective study,36 104 (10.9%) of 954 patients presenting to a tertiary diabetic clinic developed treatment-induced diabetic neuropathy with symptoms occurring within 8 weeks of rapid glycemic control. The severity of neuropathy correlated with the degree and rate of glycemic lowering. The condition was reversible in some cases.
TREATING SPECIFIC DISORDERS
For patients with an identified cause of neuropathy, targeted treatment offers the best chance of halting progression and possibly improving symptoms. Below are recommendations for addressing neuropathy associated with the common diagnoses.
Diabetes, impaired glucose tolerance, and metabolic syndrome. In addition to glycemic- and lipid-lowering therapies, lifestyle modifications with a specific focus on exercise and nutrition are integral to treating diabetes and related disorders.
In the Look AHEAD (Action for Health in Diabetes) study,37 which evaluated the effects of intensive lifestyle intervention on neuropathy in 5,145 overweight patients with type 2 diabetes, patients in the intervention group had lower pain scores and better touch sensation in the toes compared with controls at 1 year. Differences correlated with the degree of weight loss and reduction of hemoglobin A1c and lipid levels.
As running and walking may not be feasible for many patients owing to pain, stationary cycling, aqua therapy, and swimming are other options. A stationary recumbent bike may be useful for older patients with balance issues.
Vitamin B12 deficiency. As reduced absorption rather than low dietary intake is the primary cause of vitamin B12 deficiency for many patients, parenteral rather than oral supplementation may be best. A suggested regimen is subcutaneous or intramuscular methylcobalamin injection of 1,000 µg given daily for 1 week, then once weekly for 1 month, followed by a maintenance dose once a month for at least 6 to 12 months. Alternatively, a daily dose of vitamin B12 1,000 µg can be taken sublingually.
Sjögren syndrome. According to anecdotal case reports, intravenous immune globulin, corticosteroids, and other immunosuppressants help painful small fiber neuropathy and dysautonomia associated with Sjögren syndrome.10
Sarcoidosis. Sarcoidosis-associated small fiber neuropathy may also respond to intravenous immune globulin, as well as infliximab and combination therapy.9 Culver et al38 found that cibinetide, an experimental erythropoetin agonist, resulted in improved corneal nerve fiber measures in patients with small fiber neuropathy associated with sarcoidosis.
Celiac disease. A gluten-free diet is the treatment for celiac disease and can help some patients.
GENERAL MANAGEMENT
For all patients, regardless of whether the cause of small fiber neuropathy has been identified, managing symptoms remains key, as pain and autonomic dysfunction can markedly impair quality of life. A multidisciplinary approach that incorporates pain medications, physical therapy, and lifestyle modifications is ideal. Integrative holistic treatments such as natural supplements, yoga, and other mind-body therapies may also help.
Pain control
Mexiletine, a voltage-gated sodium channel blocker used as an antiarrhythmic, may help refractory pain or hereditary small fiber neuropathy related to sodium channel dysfunction. However, it is not recommended for diabetic neuropathy.39
Combination regimens that use drugs with different mechanisms of action can be effective. In one study, combined gabapentin and nortriptyline were more effective than either drug alone for neuropathic pain.40
Inhaled cannabis reduced pain in patients with HIV and diabetic neuropathy in a number of studies. Side effects included euphoria, somnolence, and cognitive impairment.41,42 The use of medical marijuana is not yet legal nationwide and may affect employability even in states in which it has been legalized.
Owing to the opioid epidemic and high addiction potential, opioids are no longer a preferred recommendation for chronic treatment of noncancer-related neuropathy. A population-based study of 2,892 patients with neuropathy found that those on chronic opioid therapy (≥ 90 days) had worse functional outcomes and higher rates of addiction and overdose than those on short-term therapy.43 However, the opioid agonist tramadol was found to be effective in reducing neuropathic pain and may be a safer option for patients with chronic small fiber neuropathy.44
Integrative, holistic therapies
PROGNOSIS
For many patients, small fiber neuropathy is a slowly progressive disorder that reaches a clinical plateau lasting for years, with progression to large fiber involvement reported in 13% to 36% of cases; over half of patients in one series either improved or remained stable over a period of 2 years.5,57 Long-term studies are needed to fully understand the natural disease course. In the meantime, treating underlying disease and managing symptoms are imperative to patient care.
- Burke JF, Skolarus LE, Callaghan BC, Kerber KA. Choosing Wisely: highest-cost tests in outpatient neurology. Ann Neurol 2013; 73(5):679–683. doi:10.1002/ana.23865
- Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003; 26(6):1790–1795. pmid:12766111
- Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology 2013; 81(15):1356–1360. doi:10.1212/WNL.0b013e3182a8236e
- Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999; 53(8):1641–1647. pmid:10563606
- Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008; 131(pt 7):1912–1925. doi:10.1093/brain/awn093
- Lacomis D. Small-fiber neuropathy. Muscle Nerve 2002; 26(2):173–188. doi:10.1002/mus.10181
- Lopate G, Streif E, Harms M, Weihl C, Pestronk A. Cramps and small-fiber neuropathy. Muscle Nerve 2013; 48(2):252–255. doi:10.1002/mus.23757
- Khan S, Zhou L. Characterization of non-length-dependent small-fiber sensory neuropathy. Muscle Nerve 2012; 45(1):86–91. doi:10.1002/mus.22255
- Tavee JO, Karwa K, Ahmed Z, Thompson N, Parambil J, Culver DA. Sarcoidosis-associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med 2017; 126:135–138. doi:10.1016/j.rmed.2017.03.011
- Berkowitz AL, Samuels MA. The neurology of Sjogren’s syndrome and the rheumatology of peripheral neuropathy and myelitis. Pract Neurol 2014; 14(1):14–22. doi:10.1136/practneurol-2013-000651
- Lang M, Treister R, Oaklander AL. Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy. J Neurol 2016; 263(12):2515–2527. doi:10.1007/s00415-016-8270-5
- Seneviratne U, Gunasekera S. Acute small fibre sensory neuropathy: another variant of Guillain-Barré syndrome? J Neurol Neurosurg Psychiatry 2002; 72(4):540–542. pmid:11909922
- Tavee JO, Polston D, Zhou L, Shields RW, Butler RS, Levin KH. Sural sensory nerve action potential, epidermal nerve fiber density, and quantitative sudomotor axon reflex in the healthy elderly. Muscle Nerve 2014; 49(4):564–569. doi:10.1002/mus.23971
- Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med 2009; 76(5):297–305. doi:10.3949/ccjm.76a.08070
- Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 1999; 53(8):1634–1640. pmid:10563605
- Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 2013; 154(11):2310–2316. doi:10.1016/j.pain.2013.06.001
- Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136(pt 6):1857–1867. doi:10.1093/brain/awt053
- Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve 1992; 15(6):661–665. doi:10.1002/mus.880150605
- Malik RA, Kallinikos P, Abbott CA, et al. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 2003; 46(5):683–688. doi:10.1007/s00125-003-1086-8
- de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy—a large cohort study and review of the literature. Eur J Neurol 2018; 25(2):348–355. doi:10.1111/ene.13508
- Smith AG. Impaired glucose tolerance and metabolic syndrome in idiopathic neuropathy. J Peripher Nerv Syst 2012; 17(suppl 2):15–21. doi:10.1111/j.1529-8027.2012.00390.x
- Hoffman-Snyder C, Smith BE, Ross MA, Hernandez J, Bosch EP. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol 2006; 63(8):1075–1079. doi:10.1001/archneur.63.8.noc50336
- Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst 2009; 14(4):257–267. doi:10.1111/j.1529-8027.2009.00237.x
- Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA, Feldman EL. Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes 2009; 58(7):1634–1640. doi:10.2337/db08-1771
- Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy. Neurology 2003; 60(10):1581–1585. pmid:12771245
- Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry 2005; 76(10):1410–1414. doi:10.1136/jnnp.2004.057620
- Bakkers M, Merkies IS, Lauria G, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 2009; 73(14):1142–1148. doi:10.1212/WNL.0b013e3181bacf05
- Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343(12):847–855. doi:10.1056/NEJM200009213431204
- Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012; 71(1):26–39. doi:10.1002/ana.22485
- Brouwer BA, Merkies IS, Gerrits MM, Waxman SG, Hoeijmakers JG, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst 2014; 19(2):53–65. doi:10.1111/jns5.12071
- Samuelsson K, Kostulas K, Vrethem M, Rolfs A, Press R. Idiopathic small fiber neuropathy: phenotype, etiologies, and the search for Fabry disease. J Clin Neurol 2014; 10(2):108–118. doi:10.3988/jcn.2014.10.2.108
- de Greef BT, Hoeijmakers JG, Wolters EE, et al. No Fabry disease in patients presenting with isolated small fiber neuropathy. PLoS One 2016; 11(2):e0148316. doi:10.1371/journal.pone.0148316
- Souayah N, Ajroud-Driss S, Sander HW, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 2009; 27(52):7322–7325. doi:10.1016/j.vaccine.2009.09.077
- Nolano M, Provitera V, Manganelli F, et al. Loss of cutaneous large and small fibers in naive and l-dopa–treated PD patients. Neurology 2017; 89(8):776–784. doi:10.1212/WNL.0000000000004274
- Zis P, Grünewald RA, Chaudhuri RK, Hadjivassiliou M. Peripheral neuropathy in idiopathic Parkinson’s disease: a systematic review. J Neurol Sci 2017; 378:204–209. doi:10.1016/j.jns.2017.05.023
- Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain 2015; 138(pt 1):43–52. doi:10.1093/brain/awu307
- Look AHEAD Research Group. Effects of a long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study. Diabetologia 2017; 60(6):980–988. doi:10.1007/s00125-017-4253-z
- Culver DA, Dahan A, Bajorunas D, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci 2017; 58(6):BIO52–BIO60. doi:10.1167/iovs.16-21291
- Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R 2011; 3(4):345–352.e21. doi:10.1016/j.pmrj.2011.03.008
- Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009; 374(9697):1252–1261. doi:10.1016/S0140-6736(09)61081-3
- Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34(3):672–680. doi:10.1038/npp.2008.120
- Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 2015; 16(7):616–627. doi:10.1016/j.jpain.2015.03.008
- Hoffman EM, Watson JC, St Sauver J, Staff NP, Klein CJ. Association of long-term opioid therapy with functional status, adverse outcomes, and mortality among patients with polyneuropathy. JAMA Neurol 2017; 74(7):773–779. doi:10.1001/jamaneurol.2017.0486
- Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50(6):1842–1846. pmid:9633738
- Sima AA, Calvani M, Mehra M, Amato A; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005; 28(1):89–94. pmid:15616239
- Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995; 38(12):1425–1433. pmid:8786016
- Scarpini E, Sacilotto G, Baron P, Cusini M, Scarlato G. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst 1997; 2(3):250-252. pmid: 10975731
- Hershman DL, Unger JM, Crew KD, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 2013; 31(20):2627-2633. doi:10.1200/JCO.2012.44.8738
- Amara S. Oral glutamine for the prevention of chemotherapy-induced peripheral neuropathy. Ann Pharmacother 2008; 42(10):1481-1485. doi:10.1345/aph.1L179
- Huang JS, Wu CL, Fan CW, Chen WH, Yeh KY, Chang PH. Intravenous glutamine appears to reduce the severity of symptomatic platinum-induced neuropathy: a prospective randomized study. J Chemother 2015; 27(4):235-240. doi:10.1179/1973947815Y.0000000011
- Banafshe HR, Hamidi GA, Noureddini M, Mirhashemi SM, Mokhtari R, Shoferpour M. Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system. Eur J Pharmacol 2014; 723:202-206. doi:10.1016/j.ejphar.2013.11.033
- Mendonça LM, da Silva Machado C, Teixeira CC, de Freitas LA, Bianchi MD, Antunes LM. Curcumin reduces cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells. Neurotoxicology 2013; 34:205-211. doi:10.1016/j.neuro.2012.09.011
- Wagner K, Lee KS, Yang J, Hammock BD. Epoxy fatty acids mediate analgesia in murine diabetic neuropathy. Eur J Pain 2017; 21(3):456-465. doi:10.1002/ejp.939
- Lewis EJ, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: a 12-month pilot trial. Neurology 2017; 88(24):2294–2301. doi:10.1212/WNL.0000000000004033
- Hu D, Wang C, Li F, et al. A combined water extract of frankincense and myrrh alleviates neuropathic pain in mice via modulation of TRPV1. Neural Plast 2017; 2017:3710821. doi:10.1155/2017/3710821
- Tavee J, Rensel M, Planchon SM, Butler RS, Stone L. Effects of meditation on pain and quality of life in multiple sclerosis and peripheral neuropathy: a pilot study. Int J MS Care 2011; 13(4):163–168. doi:10.7224/1537-2073-13.4.163
- Khoshnoodi MA, Truelove S, Burakgazi A, Hoke A, Mammen AL, Polydefkis M. Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy. JAMA Neurol 2016; 73(6):684–690. doi:10.1001/jamaneurol.2016.0057
- Burke JF, Skolarus LE, Callaghan BC, Kerber KA. Choosing Wisely: highest-cost tests in outpatient neurology. Ann Neurol 2013; 73(5):679–683. doi:10.1002/ana.23865
- Gordois A, Scuffham P, Shearer A, Oglesby A, Tobian JA. The health care costs of diabetic peripheral neuropathy in the US. Diabetes Care 2003; 26(6):1790–1795. pmid:12766111
- Peters MJ, Bakkers M, Merkies IS, Hoeijmakers JG, van Raak EP, Faber CG. Incidence and prevalence of small-fiber neuropathy: a survey in the Netherlands. Neurology 2013; 81(15):1356–1360. doi:10.1212/WNL.0b013e3182a8236e
- Periquet MI, Novak V, Collins MP, et al. Painful sensory neuropathy: prospective evaluation using skin biopsy. Neurology 1999; 53(8):1641–1647. pmid:10563606
- Devigili G, Tugnoli V, Penza P, et al. The diagnostic criteria for small fibre neuropathy: from symptoms to neuropathology. Brain 2008; 131(pt 7):1912–1925. doi:10.1093/brain/awn093
- Lacomis D. Small-fiber neuropathy. Muscle Nerve 2002; 26(2):173–188. doi:10.1002/mus.10181
- Lopate G, Streif E, Harms M, Weihl C, Pestronk A. Cramps and small-fiber neuropathy. Muscle Nerve 2013; 48(2):252–255. doi:10.1002/mus.23757
- Khan S, Zhou L. Characterization of non-length-dependent small-fiber sensory neuropathy. Muscle Nerve 2012; 45(1):86–91. doi:10.1002/mus.22255
- Tavee JO, Karwa K, Ahmed Z, Thompson N, Parambil J, Culver DA. Sarcoidosis-associated small fiber neuropathy in a large cohort: clinical aspects and response to IVIG and anti-TNF alpha treatment. Respir Med 2017; 126:135–138. doi:10.1016/j.rmed.2017.03.011
- Berkowitz AL, Samuels MA. The neurology of Sjogren’s syndrome and the rheumatology of peripheral neuropathy and myelitis. Pract Neurol 2014; 14(1):14–22. doi:10.1136/practneurol-2013-000651
- Lang M, Treister R, Oaklander AL. Diagnostic value of blood tests for occult causes of initially idiopathic small-fiber polyneuropathy. J Neurol 2016; 263(12):2515–2527. doi:10.1007/s00415-016-8270-5
- Seneviratne U, Gunasekera S. Acute small fibre sensory neuropathy: another variant of Guillain-Barré syndrome? J Neurol Neurosurg Psychiatry 2002; 72(4):540–542. pmid:11909922
- Tavee JO, Polston D, Zhou L, Shields RW, Butler RS, Levin KH. Sural sensory nerve action potential, epidermal nerve fiber density, and quantitative sudomotor axon reflex in the healthy elderly. Muscle Nerve 2014; 49(4):564–569. doi:10.1002/mus.23971
- Tavee J, Zhou L. Small fiber neuropathy: a burning problem. Cleve Clin J Med 2009; 76(5):297–305. doi:10.3949/ccjm.76a.08070
- Herrmann DN, Griffin JW, Hauer P, Cornblath DR, McArthur JC. Epidermal nerve fiber density and sural nerve morphometry in peripheral neuropathies. Neurology 1999; 53(8):1634–1640. pmid:10563605
- Oaklander AL, Herzog ZD, Downs HM, Klein MM. Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 2013; 154(11):2310–2316. doi:10.1016/j.pain.2013.06.001
- Üçeyler N, Zeller D, Kahn AK, et al. Small fibre pathology in patients with fibromyalgia syndrome. Brain 2013; 136(pt 6):1857–1867. doi:10.1093/brain/awt053
- Stewart JD, Low PA, Fealey RD. Distal small fiber neuropathy: results of tests of sweating and autonomic cardiovascular reflexes. Muscle Nerve 1992; 15(6):661–665. doi:10.1002/mus.880150605
- Malik RA, Kallinikos P, Abbott CA, et al. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia 2003; 46(5):683–688. doi:10.1007/s00125-003-1086-8
- de Greef BTA, Hoeijmakers JGJ, Gorissen-Brouwers CML, Geerts M, Faber CG, Merkies ISJ. Associated conditions in small fiber neuropathy—a large cohort study and review of the literature. Eur J Neurol 2018; 25(2):348–355. doi:10.1111/ene.13508
- Smith AG. Impaired glucose tolerance and metabolic syndrome in idiopathic neuropathy. J Peripher Nerv Syst 2012; 17(suppl 2):15–21. doi:10.1111/j.1529-8027.2012.00390.x
- Hoffman-Snyder C, Smith BE, Ross MA, Hernandez J, Bosch EP. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol 2006; 63(8):1075–1079. doi:10.1001/archneur.63.8.noc50336
- Vincent AM, Hinder LM, Pop-Busui R, Feldman EL. Hyperlipidemia: a new therapeutic target for diabetic neuropathy. J Peripher Nerv Syst 2009; 14(4):257–267. doi:10.1111/j.1529-8027.2009.00237.x
- Wiggin TD, Sullivan KA, Pop-Busui R, Amato A, Sima AA, Feldman EL. Elevated triglycerides correlate with progression of diabetic neuropathy. Diabetes 2009; 58(7):1634–1640. doi:10.2337/db08-1771
- Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy. Neurology 2003; 60(10):1581–1585. pmid:12771245
- Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry 2005; 76(10):1410–1414. doi:10.1136/jnnp.2004.057620
- Bakkers M, Merkies IS, Lauria G, et al. Intraepidermal nerve fiber density and its application in sarcoidosis. Neurology 2009; 73(14):1142–1148. doi:10.1212/WNL.0b013e3181bacf05
- Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343(12):847–855. doi:10.1056/NEJM200009213431204
- Faber CG, Hoeijmakers JG, Ahn HS, et al. Gain of function Nav1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol 2012; 71(1):26–39. doi:10.1002/ana.22485
- Brouwer BA, Merkies IS, Gerrits MM, Waxman SG, Hoeijmakers JG, Faber CG. Painful neuropathies: the emerging role of sodium channelopathies. J Peripher Nerv Syst 2014; 19(2):53–65. doi:10.1111/jns5.12071
- Samuelsson K, Kostulas K, Vrethem M, Rolfs A, Press R. Idiopathic small fiber neuropathy: phenotype, etiologies, and the search for Fabry disease. J Clin Neurol 2014; 10(2):108–118. doi:10.3988/jcn.2014.10.2.108
- de Greef BT, Hoeijmakers JG, Wolters EE, et al. No Fabry disease in patients presenting with isolated small fiber neuropathy. PLoS One 2016; 11(2):e0148316. doi:10.1371/journal.pone.0148316
- Souayah N, Ajroud-Driss S, Sander HW, Brannagan TH, Hays AP, Chin RL. Small fiber neuropathy following vaccination for rabies, varicella or Lyme disease. Vaccine 2009; 27(52):7322–7325. doi:10.1016/j.vaccine.2009.09.077
- Nolano M, Provitera V, Manganelli F, et al. Loss of cutaneous large and small fibers in naive and l-dopa–treated PD patients. Neurology 2017; 89(8):776–784. doi:10.1212/WNL.0000000000004274
- Zis P, Grünewald RA, Chaudhuri RK, Hadjivassiliou M. Peripheral neuropathy in idiopathic Parkinson’s disease: a systematic review. J Neurol Sci 2017; 378:204–209. doi:10.1016/j.jns.2017.05.023
- Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain 2015; 138(pt 1):43–52. doi:10.1093/brain/awu307
- Look AHEAD Research Group. Effects of a long-term lifestyle modification programme on peripheral neuropathy in overweight or obese adults with type 2 diabetes: the Look AHEAD study. Diabetologia 2017; 60(6):980–988. doi:10.1007/s00125-017-4253-z
- Culver DA, Dahan A, Bajorunas D, et al. Cibinetide improves corneal nerve fiber abundance in patients with sarcoidosis-associated small nerve fiber loss and neuropathic pain. Invest Ophthalmol Vis Sci 2017; 58(6):BIO52–BIO60. doi:10.1167/iovs.16-21291
- Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM R 2011; 3(4):345–352.e21. doi:10.1016/j.pmrj.2011.03.008
- Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL. Nortriptyline and gabapentin, alone and in combination for neuropathic pain: a double-blind, randomised controlled crossover trial. Lancet 2009; 374(9697):1252–1261. doi:10.1016/S0140-6736(09)61081-3
- Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 2009; 34(3):672–680. doi:10.1038/npp.2008.120
- Wallace MS, Marcotte TD, Umlauf A, Gouaux B, Atkinson JH. Efficacy of inhaled cannabis on painful diabetic neuropathy. J Pain 2015; 16(7):616–627. doi:10.1016/j.jpain.2015.03.008
- Hoffman EM, Watson JC, St Sauver J, Staff NP, Klein CJ. Association of long-term opioid therapy with functional status, adverse outcomes, and mortality among patients with polyneuropathy. JAMA Neurol 2017; 74(7):773–779. doi:10.1001/jamaneurol.2017.0486
- Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998; 50(6):1842–1846. pmid:9633738
- Sima AA, Calvani M, Mehra M, Amato A; Acetyl-L-Carnitine Study Group. Acetyl-L-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005; 28(1):89–94. pmid:15616239
- Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995; 38(12):1425–1433. pmid:8786016
- Scarpini E, Sacilotto G, Baron P, Cusini M, Scarlato G. Effect of acetyl-L-carnitine in the treatment of painful peripheral neuropathies in HIV+ patients. J Peripher Nerv Syst 1997; 2(3):250-252. pmid: 10975731
- Hershman DL, Unger JM, Crew KD, et al. Randomized double-blind placebo-controlled trial of acetyl-L-carnitine for the prevention of taxane-induced neuropathy in women undergoing adjuvant breast cancer therapy. J Clin Oncol 2013; 31(20):2627-2633. doi:10.1200/JCO.2012.44.8738
- Amara S. Oral glutamine for the prevention of chemotherapy-induced peripheral neuropathy. Ann Pharmacother 2008; 42(10):1481-1485. doi:10.1345/aph.1L179
- Huang JS, Wu CL, Fan CW, Chen WH, Yeh KY, Chang PH. Intravenous glutamine appears to reduce the severity of symptomatic platinum-induced neuropathy: a prospective randomized study. J Chemother 2015; 27(4):235-240. doi:10.1179/1973947815Y.0000000011
- Banafshe HR, Hamidi GA, Noureddini M, Mirhashemi SM, Mokhtari R, Shoferpour M. Effect of curcumin on diabetic peripheral neuropathic pain: possible involvement of opioid system. Eur J Pharmacol 2014; 723:202-206. doi:10.1016/j.ejphar.2013.11.033
- Mendonça LM, da Silva Machado C, Teixeira CC, de Freitas LA, Bianchi MD, Antunes LM. Curcumin reduces cisplatin-induced neurotoxicity in NGF-differentiated PC12 cells. Neurotoxicology 2013; 34:205-211. doi:10.1016/j.neuro.2012.09.011
- Wagner K, Lee KS, Yang J, Hammock BD. Epoxy fatty acids mediate analgesia in murine diabetic neuropathy. Eur J Pain 2017; 21(3):456-465. doi:10.1002/ejp.939
- Lewis EJ, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: a 12-month pilot trial. Neurology 2017; 88(24):2294–2301. doi:10.1212/WNL.0000000000004033
- Hu D, Wang C, Li F, et al. A combined water extract of frankincense and myrrh alleviates neuropathic pain in mice via modulation of TRPV1. Neural Plast 2017; 2017:3710821. doi:10.1155/2017/3710821
- Tavee J, Rensel M, Planchon SM, Butler RS, Stone L. Effects of meditation on pain and quality of life in multiple sclerosis and peripheral neuropathy: a pilot study. Int J MS Care 2011; 13(4):163–168. doi:10.7224/1537-2073-13.4.163
- Khoshnoodi MA, Truelove S, Burakgazi A, Hoke A, Mammen AL, Polydefkis M. Longitudinal assessment of small fiber neuropathy: evidence of a non-length-dependent distal axonopathy. JAMA Neurol 2016; 73(6):684–690. doi:10.1001/jamaneurol.2016.0057
KEY POINTS
- Patients typically develop a symmetric “stocking-glove” pattern of sensory loss in the feet and hands.
- The diagnosis may be confirmed with skin biopsy for nerve fiber density, which can easily be done in a clinic setting with commercially available kits.
- Diabetes is the most common identifiable cause of small fiber neuropathy.
- Serologic testing can help uncover a vitamin deficiency or other potentially treatable condition.
- Antiepileptics, antidepressants, and topical agents are first-line drugs for managing pain.
Small fibers, large impact
The details about an individual’s search for information tell us a lot about healthcare concerns and uncertainty across the medical universe. For nearly a decade, one of the most “clicked on” papers we have published in the Journal has been a review of small fiber neuropathy—a clinical entity with a prevalence of perhaps 1 in 1,000 to 2,000 people and, to my knowledge, no associated walkathons or arm bracelets. Yet it certainly piques the interest of clinicians from many specialties far broader than neurology. In this issue of the Journal, Dr. Jinny Tavee updates her 2009 review and provides us with a clinical overview of the disorder and the opportunity to assess how much further we need to more fully understand its management and associated comorbid conditions.
The wide interest in this disorder plugs into our current seeming epidemic of patients with chronic pain. It seems that almost half of my new patients have issues related to chronic pain that are not directly explained by active inflammation or anatomic damage. Many of these patients have diffuse body pains with associated fatigue and sleep disorders and are diagnosed with fibromyalgia. But others describe pain with a burning and tingling quality that seems of neurologic origin, yet their neurologic examination is normal. A few describe a predominantly distal symmetric stocking-and-glove distribution, but most do not. In some patients these pains are spatially random and evanescent, which to me are usually the hardest to fathom. Nerve conduction studies, when performed, are unrevealing.
A number of systemic autoimmune disorders, as discussed by Dr. Tavee in her article, are suggested to have an association with these symptoms. Given the chronicity and the frustrating nature of the symptoms, it is no surprise that a panoply of immune serologies are frequently ordered. Invariably, since serologies (eg, ANA, SSA, SSB, rheumatoid factor) are not specific for any single entity, some will return as positive. The strength of many of these associations is weak; even when the clinical diagnosis of lupus, for example, is definite, treatment of the underlying disease does not necessarily improve the dysesthetic pain. In an alternative scenario, the small fiber neuropathy is ascribed to a systemic autoimmune disorder that has been diagnosed because an autoantibody has been detected, but this rarely helps the patient and may in fact worsen symptoms by increasing anxiety and concern over having a systemic disease such as Sjögren syndrome or lupus (both of which sound terrible when reviewed on the Internet).
Some patients describe autonomic symptoms. Given the biologic basis that has been defined for this entity, it is no surprise that some patients have marked symptoms of decreased exocrine gland function, gastrointestinal dysmotility, and orthostasis. These symptoms may not be recognized unless specifically sought out when interviewing the patient.
Given the chronicity and sometimes the vagaries of symptoms, it is often comforting for patients to get an actual diagnosis. Dr. Tavee notes the relative simplicity of diagnostic procedures. But determining the clinical implications of the results may not be straightforward, and devising a fully and uniformly effective therapeutic approach eludes us still. As she points out, a multidisciplinary approach to therapy and diagnosis can be quite helpful.
The details about an individual’s search for information tell us a lot about healthcare concerns and uncertainty across the medical universe. For nearly a decade, one of the most “clicked on” papers we have published in the Journal has been a review of small fiber neuropathy—a clinical entity with a prevalence of perhaps 1 in 1,000 to 2,000 people and, to my knowledge, no associated walkathons or arm bracelets. Yet it certainly piques the interest of clinicians from many specialties far broader than neurology. In this issue of the Journal, Dr. Jinny Tavee updates her 2009 review and provides us with a clinical overview of the disorder and the opportunity to assess how much further we need to more fully understand its management and associated comorbid conditions.
The wide interest in this disorder plugs into our current seeming epidemic of patients with chronic pain. It seems that almost half of my new patients have issues related to chronic pain that are not directly explained by active inflammation or anatomic damage. Many of these patients have diffuse body pains with associated fatigue and sleep disorders and are diagnosed with fibromyalgia. But others describe pain with a burning and tingling quality that seems of neurologic origin, yet their neurologic examination is normal. A few describe a predominantly distal symmetric stocking-and-glove distribution, but most do not. In some patients these pains are spatially random and evanescent, which to me are usually the hardest to fathom. Nerve conduction studies, when performed, are unrevealing.
A number of systemic autoimmune disorders, as discussed by Dr. Tavee in her article, are suggested to have an association with these symptoms. Given the chronicity and the frustrating nature of the symptoms, it is no surprise that a panoply of immune serologies are frequently ordered. Invariably, since serologies (eg, ANA, SSA, SSB, rheumatoid factor) are not specific for any single entity, some will return as positive. The strength of many of these associations is weak; even when the clinical diagnosis of lupus, for example, is definite, treatment of the underlying disease does not necessarily improve the dysesthetic pain. In an alternative scenario, the small fiber neuropathy is ascribed to a systemic autoimmune disorder that has been diagnosed because an autoantibody has been detected, but this rarely helps the patient and may in fact worsen symptoms by increasing anxiety and concern over having a systemic disease such as Sjögren syndrome or lupus (both of which sound terrible when reviewed on the Internet).
Some patients describe autonomic symptoms. Given the biologic basis that has been defined for this entity, it is no surprise that some patients have marked symptoms of decreased exocrine gland function, gastrointestinal dysmotility, and orthostasis. These symptoms may not be recognized unless specifically sought out when interviewing the patient.
Given the chronicity and sometimes the vagaries of symptoms, it is often comforting for patients to get an actual diagnosis. Dr. Tavee notes the relative simplicity of diagnostic procedures. But determining the clinical implications of the results may not be straightforward, and devising a fully and uniformly effective therapeutic approach eludes us still. As she points out, a multidisciplinary approach to therapy and diagnosis can be quite helpful.
The details about an individual’s search for information tell us a lot about healthcare concerns and uncertainty across the medical universe. For nearly a decade, one of the most “clicked on” papers we have published in the Journal has been a review of small fiber neuropathy—a clinical entity with a prevalence of perhaps 1 in 1,000 to 2,000 people and, to my knowledge, no associated walkathons or arm bracelets. Yet it certainly piques the interest of clinicians from many specialties far broader than neurology. In this issue of the Journal, Dr. Jinny Tavee updates her 2009 review and provides us with a clinical overview of the disorder and the opportunity to assess how much further we need to more fully understand its management and associated comorbid conditions.
The wide interest in this disorder plugs into our current seeming epidemic of patients with chronic pain. It seems that almost half of my new patients have issues related to chronic pain that are not directly explained by active inflammation or anatomic damage. Many of these patients have diffuse body pains with associated fatigue and sleep disorders and are diagnosed with fibromyalgia. But others describe pain with a burning and tingling quality that seems of neurologic origin, yet their neurologic examination is normal. A few describe a predominantly distal symmetric stocking-and-glove distribution, but most do not. In some patients these pains are spatially random and evanescent, which to me are usually the hardest to fathom. Nerve conduction studies, when performed, are unrevealing.
A number of systemic autoimmune disorders, as discussed by Dr. Tavee in her article, are suggested to have an association with these symptoms. Given the chronicity and the frustrating nature of the symptoms, it is no surprise that a panoply of immune serologies are frequently ordered. Invariably, since serologies (eg, ANA, SSA, SSB, rheumatoid factor) are not specific for any single entity, some will return as positive. The strength of many of these associations is weak; even when the clinical diagnosis of lupus, for example, is definite, treatment of the underlying disease does not necessarily improve the dysesthetic pain. In an alternative scenario, the small fiber neuropathy is ascribed to a systemic autoimmune disorder that has been diagnosed because an autoantibody has been detected, but this rarely helps the patient and may in fact worsen symptoms by increasing anxiety and concern over having a systemic disease such as Sjögren syndrome or lupus (both of which sound terrible when reviewed on the Internet).
Some patients describe autonomic symptoms. Given the biologic basis that has been defined for this entity, it is no surprise that some patients have marked symptoms of decreased exocrine gland function, gastrointestinal dysmotility, and orthostasis. These symptoms may not be recognized unless specifically sought out when interviewing the patient.
Given the chronicity and sometimes the vagaries of symptoms, it is often comforting for patients to get an actual diagnosis. Dr. Tavee notes the relative simplicity of diagnostic procedures. But determining the clinical implications of the results may not be straightforward, and devising a fully and uniformly effective therapeutic approach eludes us still. As she points out, a multidisciplinary approach to therapy and diagnosis can be quite helpful.
When stroke runs in the family
A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.
He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.
On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.
We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.
Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.
STROKE AND HEREDITY
CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.
The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.1 Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.
Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.2 Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.1,2
There is no known treatment for CADASIL.
- Davous P. CADASIL: a review with proposed diagnostic criteria. Eur J Neurol 1998; 5(3):219–233. pmid:10210836
- Stojanov D, Vojinovic S, Aracki-Trenkic A, et al. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Bosn J Basic Med Sci 2015; 15(1):1–8. doi:10.17305/bjbms.2015.247
A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.
He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.
On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.
We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.
Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.
STROKE AND HEREDITY
CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.
The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.1 Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.
Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.2 Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.1,2
There is no known treatment for CADASIL.
A 54-year-old man presented to our hospital with acute-onset left-sided weakness and right facial droop. Three days earlier he had also had migraine-like headaches, which he had never experienced before. He also reported a change in behavior during the past week, which his family had described as inappropriate laughter.
He had no history of hypertension, diabetes, or dyslipidemia. He did not smoke or drink alcohol. However, he had an extensive family history of stroke. His mother had a stroke at age 50, his brother a stroke at age 57, and his sister had been admitted for a stroke 1 month earlier at the age of 52.
On examination, he had weakness of the left arm and leg, right facial droop, and hyperactive reflexes on the left side. He had no sensory or cerebellar deficits. He had episodes of laughter during the examination.
We learned that the patient’s sister had undergone a workup showing mutations in the NOTCH3 gene and a skin biopsy study consistent with CADASIL.
Our patient was started on antiplatelet and high-intensity statin therapy. His symptoms improved, and he was discharged to an acute inpatient rehabilitation facility. He was referred to a CADASIL registry.
STROKE AND HEREDITY
CADASIL is a rare hereditary vascular disorder inherited in an autosomal dominant manner. It is the most common inherited form of small-vessel disease and results from a mutation in the NOTCH3 gene that leads to degeneration of smooth muscle in cerebral blood vessels. It can manifest as migraine with aura, vascular dementia, cognitive impairment, or ischemic stroke.
The diagnosis is based on a clinical picture that typically includes stroke at a young age (age 40 to 50) in the absence of stroke risk factors, or frequent lacunar infarction episodes that can manifest as migraine, lacunar infarct, or dementia.1 Some patients, such as ours, may have subtle nonspecific behavioral changes such as inappropriate laughter, which may herald the development of an infarct.
Characteristic findings on MRI are white matter hyperintensities that tend to be bilateral and symmetrical in the periventricular areas. Symmetrical involvement in the temporal lobes has high sensitivity and specificity for CADASIL.2 Biopsy study of the skin, muscle, or sural nerve shows small-vessel changes that include thickening of the media, granular material positive on periodic acid-Schiff staining, and narrowing of the lumen. However, the gold standard for diagnosis is confirmation of the NOTCH3 mutation on chromosome 19.1,2
There is no known treatment for CADASIL.
- Davous P. CADASIL: a review with proposed diagnostic criteria. Eur J Neurol 1998; 5(3):219–233. pmid:10210836
- Stojanov D, Vojinovic S, Aracki-Trenkic A, et al. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Bosn J Basic Med Sci 2015; 15(1):1–8. doi:10.17305/bjbms.2015.247
- Davous P. CADASIL: a review with proposed diagnostic criteria. Eur J Neurol 1998; 5(3):219–233. pmid:10210836
- Stojanov D, Vojinovic S, Aracki-Trenkic A, et al. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Bosn J Basic Med Sci 2015; 15(1):1–8. doi:10.17305/bjbms.2015.247
Postsurgical hypoparathyroidism is not primary hypoparathyroidism
To the Editor: I read with interest the case of a 67-year-old woman with bilateral hand numbness, published in the March 2018 issue of the Journal, and I would like to suggest 2 important corrections to this article.1
The authors present a case of hypocalcemia secondary to postsurgical hypoparathyroidism but describe it as due to primary hypoparathyroidism. The patient had undergone thyroidectomy 10 years earlier and since then had hypocalcemia, secondary to postsurgical hypoparathyroidism, that was treated with calcium and vitamin D, until she stopped taking these agents. Postsurgical hypothyroidism is the most common cause of acquired or secondary hypoparathyroidism and is not primary hypoparathyroidism. I strongly feel that this requires an update or correction to the article. This patient may have associated malabsorption, as the authors alluded to, as the cause of her “normal” serum parathyroid hormone level.
The patient also had hypomagnesemia, which the authors state could have been due to furosemide use and “uncontrolled” diabetes mellitus. Diabetes doesn’t need to be uncontrolled to cause hypomagnesemia. Hypomagnesemia is common in patients with type 2 diabetes mellitus, with a prevalence of 14% to 48% in patients with diabetes compared with 2.5% to 15% in the general population.2 It is often multifactorial and may be secondary to one or more of the following factors: poor dietary intake, autonomic dysfunction, altered insulin resistance, glomerular hyperfiltration, osmotic diuresis (uncontrolled diabetes), recurrent metabolic acidosis, hypophosphatemia, hypokalemia, and therapy with drugs such as metformin and sulfonylureas.
Patients with type 2 diabetes and hypomagnesemia often enter a vicious cycle in which hypomagnesemia worsens insulin resistance and insulin resistance, by reducing the activity of renal magnesium channel transient receptor potential melastatin (TRPM) type 6, perpetuates hypomagnesemia.3
- Radwan SS, Hamo KN, Zayed AA. A 67-year-old woman with bilateral hand numbness. Cleve Clin J Med 2018; 85(3):200–208. doi:10.3949/ccjm.85a.17026
- Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol 2007; 2(2):366–373. doi:10.2215/CJN.02960906
- Gommers LM, Hoenderop JG, Bindels RJ, de Baaij JH. Hypomagnesemia in type 2 diabetes: a vicious circle? Diabetes 2016; 65(1):3–13. doi:10.2337/db15-1028
To the Editor: I read with interest the case of a 67-year-old woman with bilateral hand numbness, published in the March 2018 issue of the Journal, and I would like to suggest 2 important corrections to this article.1
The authors present a case of hypocalcemia secondary to postsurgical hypoparathyroidism but describe it as due to primary hypoparathyroidism. The patient had undergone thyroidectomy 10 years earlier and since then had hypocalcemia, secondary to postsurgical hypoparathyroidism, that was treated with calcium and vitamin D, until she stopped taking these agents. Postsurgical hypothyroidism is the most common cause of acquired or secondary hypoparathyroidism and is not primary hypoparathyroidism. I strongly feel that this requires an update or correction to the article. This patient may have associated malabsorption, as the authors alluded to, as the cause of her “normal” serum parathyroid hormone level.
The patient also had hypomagnesemia, which the authors state could have been due to furosemide use and “uncontrolled” diabetes mellitus. Diabetes doesn’t need to be uncontrolled to cause hypomagnesemia. Hypomagnesemia is common in patients with type 2 diabetes mellitus, with a prevalence of 14% to 48% in patients with diabetes compared with 2.5% to 15% in the general population.2 It is often multifactorial and may be secondary to one or more of the following factors: poor dietary intake, autonomic dysfunction, altered insulin resistance, glomerular hyperfiltration, osmotic diuresis (uncontrolled diabetes), recurrent metabolic acidosis, hypophosphatemia, hypokalemia, and therapy with drugs such as metformin and sulfonylureas.
Patients with type 2 diabetes and hypomagnesemia often enter a vicious cycle in which hypomagnesemia worsens insulin resistance and insulin resistance, by reducing the activity of renal magnesium channel transient receptor potential melastatin (TRPM) type 6, perpetuates hypomagnesemia.3
To the Editor: I read with interest the case of a 67-year-old woman with bilateral hand numbness, published in the March 2018 issue of the Journal, and I would like to suggest 2 important corrections to this article.1
The authors present a case of hypocalcemia secondary to postsurgical hypoparathyroidism but describe it as due to primary hypoparathyroidism. The patient had undergone thyroidectomy 10 years earlier and since then had hypocalcemia, secondary to postsurgical hypoparathyroidism, that was treated with calcium and vitamin D, until she stopped taking these agents. Postsurgical hypothyroidism is the most common cause of acquired or secondary hypoparathyroidism and is not primary hypoparathyroidism. I strongly feel that this requires an update or correction to the article. This patient may have associated malabsorption, as the authors alluded to, as the cause of her “normal” serum parathyroid hormone level.
The patient also had hypomagnesemia, which the authors state could have been due to furosemide use and “uncontrolled” diabetes mellitus. Diabetes doesn’t need to be uncontrolled to cause hypomagnesemia. Hypomagnesemia is common in patients with type 2 diabetes mellitus, with a prevalence of 14% to 48% in patients with diabetes compared with 2.5% to 15% in the general population.2 It is often multifactorial and may be secondary to one or more of the following factors: poor dietary intake, autonomic dysfunction, altered insulin resistance, glomerular hyperfiltration, osmotic diuresis (uncontrolled diabetes), recurrent metabolic acidosis, hypophosphatemia, hypokalemia, and therapy with drugs such as metformin and sulfonylureas.
Patients with type 2 diabetes and hypomagnesemia often enter a vicious cycle in which hypomagnesemia worsens insulin resistance and insulin resistance, by reducing the activity of renal magnesium channel transient receptor potential melastatin (TRPM) type 6, perpetuates hypomagnesemia.3
- Radwan SS, Hamo KN, Zayed AA. A 67-year-old woman with bilateral hand numbness. Cleve Clin J Med 2018; 85(3):200–208. doi:10.3949/ccjm.85a.17026
- Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol 2007; 2(2):366–373. doi:10.2215/CJN.02960906
- Gommers LM, Hoenderop JG, Bindels RJ, de Baaij JH. Hypomagnesemia in type 2 diabetes: a vicious circle? Diabetes 2016; 65(1):3–13. doi:10.2337/db15-1028
- Radwan SS, Hamo KN, Zayed AA. A 67-year-old woman with bilateral hand numbness. Cleve Clin J Med 2018; 85(3):200–208. doi:10.3949/ccjm.85a.17026
- Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol 2007; 2(2):366–373. doi:10.2215/CJN.02960906
- Gommers LM, Hoenderop JG, Bindels RJ, de Baaij JH. Hypomagnesemia in type 2 diabetes: a vicious circle? Diabetes 2016; 65(1):3–13. doi:10.2337/db15-1028
In reply: Postsurgical hypoparathyroidism is not primary hypoparathyroidism
In Reply: We thank Dr. Parmar and appreciate his important comments.
Regarding the difference between primary and secondary hypoparathyroidism, the definition varies among investigators. Some define primary hypoparathyroidism as a condition characterized by primary absence or deficiency of parathyroid hormone (PTH), which results in hypocalcemia and which can be congenital or acquired, including postsurgical hypoparathyroidism.1–4 In principle, this is similar to the classification of disorders affecting other endocrine glands as primary and secondary. For example, primary hypothyroidism refers to a state of low thyroid hormones resulting from impairment or loss of function of the thyroid gland itself, such as in Hashimoto thyroiditis, radioactive iodine therapy, or thyroidectomy, among others.5 We adopted this definition in our article. In contrast, secondary hypoparathyroidism is characterized by low PTH secretion in response to certain conditions that cause hypercalcemia. Non-PTH-mediated hypercalcemia is a more common term used to describe this state of secondary hypoparathyroidism.
Other investigators restrict the term “primary hypoparathyroidism” to nonacquired (congenital or hereditary) etiologies, while applying the term “secondary hypoparathyroidism” to acquired etiologies.6
Concerning the association between diabetes mellitus and hypomagnesemia, we agree that diabetes does not need to be uncontrolled to cause hypomagnesemia. However, the patient described in our article presented with severe hypomagnesemia (serum level 0.6 mg/dL), which is not commonly associated with diabetes. Most cases of hypomagnesemia in patients with type 2 diabetes mellitus are mild and asymptomatic, whereas severe manifestations including seizures, cardiac arrhythmias, and acute tetany are rarely encountered in clinical practice.7 Furthermore, numerous studies have shown a negative correlation between serum magnesium level and glycemic control.7–11 A recent study reported that plasma triglyceride and glucose levels are the main determinants of the plasma magnesium concentration in patients with type 2 diabetes.12
Our patient’s diabetes was uncontrolled, as evidenced by her hemoglobin A1c level of 9.7% and her random serum glucose level of 224 mg/dL. Therefore, it is more likely that “uncontrolled diabetes mellitus” (in addition to diuretic use) was the cause of her symptomatic severe hypomagnesemia rather than controlled diabetes mellitus.
- Mendes EM, Meireles-Brandão L, Meira C, Morais N, Ribeiro C, Guerra D. Primary hypoparathyroidism presenting as basal ganglia calcification secondary to extreme hypocalcemia. Clin Pract 2018; 8(1):1007. doi:10.4081/cp.2018.1007
- Vadiveloo T, Donnan PT, Leese GP. A population-based study of the epidemiology of chronic hypoparathyroidism. J Bone Miner Res 2018; 33(3):478-485. doi:10.1002/jbmr.3329
- Hendy GN, Cole DEC, Bastepe M. Hypoparathyroidism and pseudohypoparathyroidism. In: De Groot LJ, Chrousos G, Dungan K, et al, eds. Endotext [Internet], South Dartmouth (MA): MDText.com, Inc.; 2017. www.ncbi.nlm.nih.gov/books/NBK279165. Accessed August 20, 2018.
- Rosa RG, Barros AJ, de Lima AR, et al. Mood disorder as a manifestation of primary hypoparathyroidism: a case report. J Med Case Rep 2014; 8:326. doi:10.1186/1752-1947-8-326
- Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am 2012; 96(2):203–221. doi:10.1016/j.mcna.2012.01.005
- Fouda UM, Fouda RM, Ammar HM, Salem M, Darouti ME. Impetigo herpetiformis during the puerperium triggered by secondary hypoparathyroidism: a case report. Cases J 2009; 2:9338. doi:10.1186/1757-1626-2-9338
- Tosiello L. Hypomagnesemia and diabetes mellitus. A review of clinical implications. Arch Intern Med 1996; 156(11):1143–1148. pmid: 8639008
- Pham PC, Pham PM, Pham PA, et al. Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2. Clin Nephrol 2005; 63(6):429–436. pmid:15960144
- Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20(1):3–17. doi:10.1177/0885066604271539
- Resnick LM, Altura BT, Gupta RK, Laragh JH, Alderman MH, Altura BM. Intracellular and extracellular magnesium depletion in type 2 (non-insulin-independent) diabetes mellitus. Diabetologia 1993; 36(8):767–770. pmid:8405745
- Pun KK, Ho PW. Subclinical hyponatremia, hyperkalemia and hypomagnesemia in patients with poorly controlled diabetes mellitus. Diabetes Res Clin Pract 1989; 7(3)163–167. pmid: 2605984
- Kurstjens S, de Baaij JH, Bouras H, Bindels RJ, Tack CJ, Hoenderop JG. Determinants of hypomagnesemia in patients with type 2 diabetes mellitus. Eur J Endocrinol 2017; 176(1):11–19. doi:10.1530/EJE-16-0517
In Reply: We thank Dr. Parmar and appreciate his important comments.
Regarding the difference between primary and secondary hypoparathyroidism, the definition varies among investigators. Some define primary hypoparathyroidism as a condition characterized by primary absence or deficiency of parathyroid hormone (PTH), which results in hypocalcemia and which can be congenital or acquired, including postsurgical hypoparathyroidism.1–4 In principle, this is similar to the classification of disorders affecting other endocrine glands as primary and secondary. For example, primary hypothyroidism refers to a state of low thyroid hormones resulting from impairment or loss of function of the thyroid gland itself, such as in Hashimoto thyroiditis, radioactive iodine therapy, or thyroidectomy, among others.5 We adopted this definition in our article. In contrast, secondary hypoparathyroidism is characterized by low PTH secretion in response to certain conditions that cause hypercalcemia. Non-PTH-mediated hypercalcemia is a more common term used to describe this state of secondary hypoparathyroidism.
Other investigators restrict the term “primary hypoparathyroidism” to nonacquired (congenital or hereditary) etiologies, while applying the term “secondary hypoparathyroidism” to acquired etiologies.6
Concerning the association between diabetes mellitus and hypomagnesemia, we agree that diabetes does not need to be uncontrolled to cause hypomagnesemia. However, the patient described in our article presented with severe hypomagnesemia (serum level 0.6 mg/dL), which is not commonly associated with diabetes. Most cases of hypomagnesemia in patients with type 2 diabetes mellitus are mild and asymptomatic, whereas severe manifestations including seizures, cardiac arrhythmias, and acute tetany are rarely encountered in clinical practice.7 Furthermore, numerous studies have shown a negative correlation between serum magnesium level and glycemic control.7–11 A recent study reported that plasma triglyceride and glucose levels are the main determinants of the plasma magnesium concentration in patients with type 2 diabetes.12
Our patient’s diabetes was uncontrolled, as evidenced by her hemoglobin A1c level of 9.7% and her random serum glucose level of 224 mg/dL. Therefore, it is more likely that “uncontrolled diabetes mellitus” (in addition to diuretic use) was the cause of her symptomatic severe hypomagnesemia rather than controlled diabetes mellitus.
In Reply: We thank Dr. Parmar and appreciate his important comments.
Regarding the difference between primary and secondary hypoparathyroidism, the definition varies among investigators. Some define primary hypoparathyroidism as a condition characterized by primary absence or deficiency of parathyroid hormone (PTH), which results in hypocalcemia and which can be congenital or acquired, including postsurgical hypoparathyroidism.1–4 In principle, this is similar to the classification of disorders affecting other endocrine glands as primary and secondary. For example, primary hypothyroidism refers to a state of low thyroid hormones resulting from impairment or loss of function of the thyroid gland itself, such as in Hashimoto thyroiditis, radioactive iodine therapy, or thyroidectomy, among others.5 We adopted this definition in our article. In contrast, secondary hypoparathyroidism is characterized by low PTH secretion in response to certain conditions that cause hypercalcemia. Non-PTH-mediated hypercalcemia is a more common term used to describe this state of secondary hypoparathyroidism.
Other investigators restrict the term “primary hypoparathyroidism” to nonacquired (congenital or hereditary) etiologies, while applying the term “secondary hypoparathyroidism” to acquired etiologies.6
Concerning the association between diabetes mellitus and hypomagnesemia, we agree that diabetes does not need to be uncontrolled to cause hypomagnesemia. However, the patient described in our article presented with severe hypomagnesemia (serum level 0.6 mg/dL), which is not commonly associated with diabetes. Most cases of hypomagnesemia in patients with type 2 diabetes mellitus are mild and asymptomatic, whereas severe manifestations including seizures, cardiac arrhythmias, and acute tetany are rarely encountered in clinical practice.7 Furthermore, numerous studies have shown a negative correlation between serum magnesium level and glycemic control.7–11 A recent study reported that plasma triglyceride and glucose levels are the main determinants of the plasma magnesium concentration in patients with type 2 diabetes.12
Our patient’s diabetes was uncontrolled, as evidenced by her hemoglobin A1c level of 9.7% and her random serum glucose level of 224 mg/dL. Therefore, it is more likely that “uncontrolled diabetes mellitus” (in addition to diuretic use) was the cause of her symptomatic severe hypomagnesemia rather than controlled diabetes mellitus.
- Mendes EM, Meireles-Brandão L, Meira C, Morais N, Ribeiro C, Guerra D. Primary hypoparathyroidism presenting as basal ganglia calcification secondary to extreme hypocalcemia. Clin Pract 2018; 8(1):1007. doi:10.4081/cp.2018.1007
- Vadiveloo T, Donnan PT, Leese GP. A population-based study of the epidemiology of chronic hypoparathyroidism. J Bone Miner Res 2018; 33(3):478-485. doi:10.1002/jbmr.3329
- Hendy GN, Cole DEC, Bastepe M. Hypoparathyroidism and pseudohypoparathyroidism. In: De Groot LJ, Chrousos G, Dungan K, et al, eds. Endotext [Internet], South Dartmouth (MA): MDText.com, Inc.; 2017. www.ncbi.nlm.nih.gov/books/NBK279165. Accessed August 20, 2018.
- Rosa RG, Barros AJ, de Lima AR, et al. Mood disorder as a manifestation of primary hypoparathyroidism: a case report. J Med Case Rep 2014; 8:326. doi:10.1186/1752-1947-8-326
- Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am 2012; 96(2):203–221. doi:10.1016/j.mcna.2012.01.005
- Fouda UM, Fouda RM, Ammar HM, Salem M, Darouti ME. Impetigo herpetiformis during the puerperium triggered by secondary hypoparathyroidism: a case report. Cases J 2009; 2:9338. doi:10.1186/1757-1626-2-9338
- Tosiello L. Hypomagnesemia and diabetes mellitus. A review of clinical implications. Arch Intern Med 1996; 156(11):1143–1148. pmid: 8639008
- Pham PC, Pham PM, Pham PA, et al. Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2. Clin Nephrol 2005; 63(6):429–436. pmid:15960144
- Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20(1):3–17. doi:10.1177/0885066604271539
- Resnick LM, Altura BT, Gupta RK, Laragh JH, Alderman MH, Altura BM. Intracellular and extracellular magnesium depletion in type 2 (non-insulin-independent) diabetes mellitus. Diabetologia 1993; 36(8):767–770. pmid:8405745
- Pun KK, Ho PW. Subclinical hyponatremia, hyperkalemia and hypomagnesemia in patients with poorly controlled diabetes mellitus. Diabetes Res Clin Pract 1989; 7(3)163–167. pmid: 2605984
- Kurstjens S, de Baaij JH, Bouras H, Bindels RJ, Tack CJ, Hoenderop JG. Determinants of hypomagnesemia in patients with type 2 diabetes mellitus. Eur J Endocrinol 2017; 176(1):11–19. doi:10.1530/EJE-16-0517
- Mendes EM, Meireles-Brandão L, Meira C, Morais N, Ribeiro C, Guerra D. Primary hypoparathyroidism presenting as basal ganglia calcification secondary to extreme hypocalcemia. Clin Pract 2018; 8(1):1007. doi:10.4081/cp.2018.1007
- Vadiveloo T, Donnan PT, Leese GP. A population-based study of the epidemiology of chronic hypoparathyroidism. J Bone Miner Res 2018; 33(3):478-485. doi:10.1002/jbmr.3329
- Hendy GN, Cole DEC, Bastepe M. Hypoparathyroidism and pseudohypoparathyroidism. In: De Groot LJ, Chrousos G, Dungan K, et al, eds. Endotext [Internet], South Dartmouth (MA): MDText.com, Inc.; 2017. www.ncbi.nlm.nih.gov/books/NBK279165. Accessed August 20, 2018.
- Rosa RG, Barros AJ, de Lima AR, et al. Mood disorder as a manifestation of primary hypoparathyroidism: a case report. J Med Case Rep 2014; 8:326. doi:10.1186/1752-1947-8-326
- Almandoz JP, Gharib H. Hypothyroidism: etiology, diagnosis, and management. Med Clin North Am 2012; 96(2):203–221. doi:10.1016/j.mcna.2012.01.005
- Fouda UM, Fouda RM, Ammar HM, Salem M, Darouti ME. Impetigo herpetiformis during the puerperium triggered by secondary hypoparathyroidism: a case report. Cases J 2009; 2:9338. doi:10.1186/1757-1626-2-9338
- Tosiello L. Hypomagnesemia and diabetes mellitus. A review of clinical implications. Arch Intern Med 1996; 156(11):1143–1148. pmid: 8639008
- Pham PC, Pham PM, Pham PA, et al. Lower serum magnesium levels are associated with more rapid decline of renal function in patients with diabetes mellitus type 2. Clin Nephrol 2005; 63(6):429–436. pmid:15960144
- Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intensive Care Med 2005; 20(1):3–17. doi:10.1177/0885066604271539
- Resnick LM, Altura BT, Gupta RK, Laragh JH, Alderman MH, Altura BM. Intracellular and extracellular magnesium depletion in type 2 (non-insulin-independent) diabetes mellitus. Diabetologia 1993; 36(8):767–770. pmid:8405745
- Pun KK, Ho PW. Subclinical hyponatremia, hyperkalemia and hypomagnesemia in patients with poorly controlled diabetes mellitus. Diabetes Res Clin Pract 1989; 7(3)163–167. pmid: 2605984
- Kurstjens S, de Baaij JH, Bouras H, Bindels RJ, Tack CJ, Hoenderop JG. Determinants of hypomagnesemia in patients with type 2 diabetes mellitus. Eur J Endocrinol 2017; 176(1):11–19. doi:10.1530/EJE-16-0517
