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The release of stress hormones can lead to the production of abnormally phosphorylated tau protein, and eventually to memory loss, researchers reported. “Severity of cognitive deficits in Alzheimer’s disease correlates strongly with levels of hyperphosphorylated forms of the cytoskeletal protein tau,” the authors stated in the May 25 Journal of Neuroscience. “We thus examined whether stress, through the mediation of glucocorticoids, influences tau hyperphosphorylation, a critical and early event in the cascade of processes leading to Alzheimer’s disease pathology.” Results showed that chronic stress and hypersecretion of glucocorticoids induces abnormal hyperphosphorylation of tau in the hippocampus and prefrontal cortex, suggesting that they have a cumulative impact on the onset and progress of Alzheimer’s disease pathology.
Soluble amyloid proteins in the CSF of patients with mild cognitive impairment may be a potential biomarker for Alzheimer’s disease, according to research in the June 22 online Neurology. The investigators measured the concentrations of amyloid precursor protein, tau protein, and amyloid-beta 1-42 concentrations in the CSF of 58 patients with slight memory problems—21 of whom progressed to Alzheimer’s disease. Analysis of the samples revealed that the group that had progressed to Alzheimer’s disease had significantly higher concentrations of the soluble amyloid precursor proteins than those who reverted to normal and those who developed frontotemporal dementia. “These findings suggest that soluble amyloid precursor protein beta may be clinically useful, and superior to [amyloid-beta 1-42], in the early and differential diagnosis of Alzheimer’s disease,” the authors concluded.
Weak synchronization between brain hemispheres may be an early biomarker for autism, according to the results of a study published in the June 23 issue of Neuron. “Autism is often described as a disorder of neuronal synchronization,” the authors wrote. “However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms.” The researchers conducted an imaging study and found that toddlers with autism exhibited significantly weaker interhemispheric synchronization in putative language areas than did toddlers without the condition. In addition, toddlers with a greater strength of synchronization had higher verbal ability and lower autism severity. “Disrupted cortical synchronization, therefore, appears to be a notable characteristic of autism neurophysiology that is evident at very early stages of autism development,” they concluded.
The FDA has approved Potiga (ezogabine) tablets as an adjunctive treatment of partial-onset seizures in adults with epilepsy. It is the first neuronal potassium channel opener developed for the treatment of epilepsy. Although its mechanism of action is not firmly established, it is believed that ezogabine may act as an anticonvulsant by reducing excitability through the stabilization of neuronal potassium channels in an ‘open’ position. The FDA’s approval was based on the results of three controlled clinical studies involving 1,239 patients with epilepsy that investigated the ability of ezogabine to reduce seizure frequency during the double-blind treatment phase. The most common adverse events were dizziness, somnolence, and fatigue; approximately 2% of patients in clinical trials also experienced urinary retention. Researchers at GlaxoSmithKline and Valeant Pharmaceuticals International Inc believe that ezogabine tablets will benefit patients whose epilepsy is uncontrolled with their current medications.
Prenatal exposure to certain antiepileptic drugs has a higher risk for major congenital malformations, according to results of a study published in the July issue of Lancet Neurology. The researchers monitored pregnant women with epilepsy who were exposed to monotherapy with different doses of carbamazepine, lamotrigine, valproic acid, or phenobarbital. A total of 230 pregnancies associated with major birth defects were observed during the first year after birth; there was also an increase in malformation rates as the dose increased for each drug. The lowest rates of malformation occurred in women who took less than 300 mg per day of lamotrigine or less than 400 mg per day of carbamazepine. All doses of valproic acid and phenobarbital monotherapies had significantly higher risks for birth defects. “The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential,” the authors concluded.
Peripheral nerve stimulation delivered via an implanted medical device significantly reduces the number of days per month that patients have chronic migraine headache and pain, according to data presented at the 15th Annual International Headache Congress in Berlin. Investigators enrolled 157 patients with migraine to evaluate the safety and efficacy of the device; after 12 weeks, patients who received stimulation reported a 28% decrease in headache days per month. Sixty-seven percent also reported an improvement in their quality of life. “Many migraine patients have exhausted all current treatment options and often are disabled by the pain and frequency of migraine attacks,” the principal investigator stated. “Achieving a reduction in the number of days they suffer from headache and a significant improvement in their quality of life may be even more important than pain reduction alone.”
Researchers have identified three susceptibility loci for common migraine in the general population, according to a study published in the June 12 online Nature Genetics. In a population-based genome-wide analysis that included 5,122 patients with migraine and 18,108 patients without migraine, investigators found seven single nucleotide polymorphisms (SNPs) associated with migraine. Subsequent testing and meta-analysis confirmed that three replicating SNPs (re2651899, rs10166942, and rs11172113) were significantly associated with migraine. “The associations at r2651899 and rs10166942 were specific for migraine compared with nonmigraine headache,” the researchers reported. In addition, none of the three SNP associations was preferential for migraine with aura or without aura; there were also no associations specific for migraine features, suggesting that there is a shared pathophysiology among common types of migraine. “The three new loci identified in the present work provide hypotheses for immediate further exploration,” the authors concluded.
People who have had a herpes zoster attack may be at a higher risk for developing multiple sclerosis (MS) than people who have not had an occurrence of the virus, researchers reported in the June 7 online Journal of Infectious Diseases. “Varicella zoster virus has been proposed to be involved in the pathogenesis of MS,” the investigators wrote. In the study, they followed 315,550 patients with herpes zoster and 946,650 subjects without the virus for one year; they then calculated the one-year MS–free survival rate. “Of 1,262,200 sampled patients, 29 from the study group (.009%) and 24 from the control group (.003%) had MS during the one-year follow-up period,” the authors reported. The odds ratio of developing MS was 3.96 times greater for the study group than for the control group, supporting the notion that occurrence of the disease could be associated with herpes zoster attack.
A study published in the June 7 issue of Neurology found that patients with Parkinson’s disease have a significantly higher risk of having melanoma than do healthy controls. The researchers conducted a meta-analysis of 12 publications on melanoma and Parkinson’s disease; eight of the publications had fewer than 10 cases with both Parkinson’s disease and melanoma. The pooled odds ratio was 2.11 overall, 2.04 for men, and 1.52 for women. Melanoma occurrence was significantly higher after the diagnosis of Parkinson’s disease, but not before Parkinson’s disease was diagnosed. After analyzing the data for nonmelanoma skin cancers, the researchers found no significant relationship. “Collective epidemiologic evidence supports an association of Parkinson’s disease with melanoma,” the authors concluded. “Further research is needed to examine the nature and mechanisms of this relationship.”
At-home physical training may be just as effective as locomotor training for improving the ability to walk in patients who have had a stroke, researchers reported in the May 26 New England Journal of Medicine. The investigators randomly assigned 408 participants with stroke to one of three training groups; one group received early locomotor training on a body weight–supported treadmill two months after stroke occurred, one group received the same training six months after stroke, and the third group completed an at-home exercise program guided by a physical therapist two months after stroke. At one year of training, 52% of all participants had increased functional walking ability. The researchers observed no significant differences in improvement between early or late locomotor training and home exercise. “All groups had similar improvements in walking speed, motor recovery, balance, functional status, and quality of life,” the authors noted.
High consumption of olive oil and high plasma oleic acid are associated with lower risk for stroke in older adults, according to the results of a study published in the June 15 online Neurology. To examine this relationship, the researchers looked at 7,625 older adults; in this sample, 148 incident strokes occurred. After adjusting for demographic and dietary variables and stroke risk factors, the investigators found that “compared to those who never used olive oil, those with intensive use had a 41% lower risk of stroke.” In a secondary sample, the researchers investigated the plasma oleic acid levels of 1,245 individuals (27 had incident stroke) and found that participants in the third tertile had a 73% reduction of stroke risk. “These results suggest a protective role for high olive oil consumption on the risk of stroke in older subjects,” the authors concluded.
The release of stress hormones can lead to the production of abnormally phosphorylated tau protein, and eventually to memory loss, researchers reported. “Severity of cognitive deficits in Alzheimer’s disease correlates strongly with levels of hyperphosphorylated forms of the cytoskeletal protein tau,” the authors stated in the May 25 Journal of Neuroscience. “We thus examined whether stress, through the mediation of glucocorticoids, influences tau hyperphosphorylation, a critical and early event in the cascade of processes leading to Alzheimer’s disease pathology.” Results showed that chronic stress and hypersecretion of glucocorticoids induces abnormal hyperphosphorylation of tau in the hippocampus and prefrontal cortex, suggesting that they have a cumulative impact on the onset and progress of Alzheimer’s disease pathology.
Soluble amyloid proteins in the CSF of patients with mild cognitive impairment may be a potential biomarker for Alzheimer’s disease, according to research in the June 22 online Neurology. The investigators measured the concentrations of amyloid precursor protein, tau protein, and amyloid-beta 1-42 concentrations in the CSF of 58 patients with slight memory problems—21 of whom progressed to Alzheimer’s disease. Analysis of the samples revealed that the group that had progressed to Alzheimer’s disease had significantly higher concentrations of the soluble amyloid precursor proteins than those who reverted to normal and those who developed frontotemporal dementia. “These findings suggest that soluble amyloid precursor protein beta may be clinically useful, and superior to [amyloid-beta 1-42], in the early and differential diagnosis of Alzheimer’s disease,” the authors concluded.
Weak synchronization between brain hemispheres may be an early biomarker for autism, according to the results of a study published in the June 23 issue of Neuron. “Autism is often described as a disorder of neuronal synchronization,” the authors wrote. “However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms.” The researchers conducted an imaging study and found that toddlers with autism exhibited significantly weaker interhemispheric synchronization in putative language areas than did toddlers without the condition. In addition, toddlers with a greater strength of synchronization had higher verbal ability and lower autism severity. “Disrupted cortical synchronization, therefore, appears to be a notable characteristic of autism neurophysiology that is evident at very early stages of autism development,” they concluded.
The FDA has approved Potiga (ezogabine) tablets as an adjunctive treatment of partial-onset seizures in adults with epilepsy. It is the first neuronal potassium channel opener developed for the treatment of epilepsy. Although its mechanism of action is not firmly established, it is believed that ezogabine may act as an anticonvulsant by reducing excitability through the stabilization of neuronal potassium channels in an ‘open’ position. The FDA’s approval was based on the results of three controlled clinical studies involving 1,239 patients with epilepsy that investigated the ability of ezogabine to reduce seizure frequency during the double-blind treatment phase. The most common adverse events were dizziness, somnolence, and fatigue; approximately 2% of patients in clinical trials also experienced urinary retention. Researchers at GlaxoSmithKline and Valeant Pharmaceuticals International Inc believe that ezogabine tablets will benefit patients whose epilepsy is uncontrolled with their current medications.
Prenatal exposure to certain antiepileptic drugs has a higher risk for major congenital malformations, according to results of a study published in the July issue of Lancet Neurology. The researchers monitored pregnant women with epilepsy who were exposed to monotherapy with different doses of carbamazepine, lamotrigine, valproic acid, or phenobarbital. A total of 230 pregnancies associated with major birth defects were observed during the first year after birth; there was also an increase in malformation rates as the dose increased for each drug. The lowest rates of malformation occurred in women who took less than 300 mg per day of lamotrigine or less than 400 mg per day of carbamazepine. All doses of valproic acid and phenobarbital monotherapies had significantly higher risks for birth defects. “The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential,” the authors concluded.
Peripheral nerve stimulation delivered via an implanted medical device significantly reduces the number of days per month that patients have chronic migraine headache and pain, according to data presented at the 15th Annual International Headache Congress in Berlin. Investigators enrolled 157 patients with migraine to evaluate the safety and efficacy of the device; after 12 weeks, patients who received stimulation reported a 28% decrease in headache days per month. Sixty-seven percent also reported an improvement in their quality of life. “Many migraine patients have exhausted all current treatment options and often are disabled by the pain and frequency of migraine attacks,” the principal investigator stated. “Achieving a reduction in the number of days they suffer from headache and a significant improvement in their quality of life may be even more important than pain reduction alone.”
Researchers have identified three susceptibility loci for common migraine in the general population, according to a study published in the June 12 online Nature Genetics. In a population-based genome-wide analysis that included 5,122 patients with migraine and 18,108 patients without migraine, investigators found seven single nucleotide polymorphisms (SNPs) associated with migraine. Subsequent testing and meta-analysis confirmed that three replicating SNPs (re2651899, rs10166942, and rs11172113) were significantly associated with migraine. “The associations at r2651899 and rs10166942 were specific for migraine compared with nonmigraine headache,” the researchers reported. In addition, none of the three SNP associations was preferential for migraine with aura or without aura; there were also no associations specific for migraine features, suggesting that there is a shared pathophysiology among common types of migraine. “The three new loci identified in the present work provide hypotheses for immediate further exploration,” the authors concluded.
People who have had a herpes zoster attack may be at a higher risk for developing multiple sclerosis (MS) than people who have not had an occurrence of the virus, researchers reported in the June 7 online Journal of Infectious Diseases. “Varicella zoster virus has been proposed to be involved in the pathogenesis of MS,” the investigators wrote. In the study, they followed 315,550 patients with herpes zoster and 946,650 subjects without the virus for one year; they then calculated the one-year MS–free survival rate. “Of 1,262,200 sampled patients, 29 from the study group (.009%) and 24 from the control group (.003%) had MS during the one-year follow-up period,” the authors reported. The odds ratio of developing MS was 3.96 times greater for the study group than for the control group, supporting the notion that occurrence of the disease could be associated with herpes zoster attack.
A study published in the June 7 issue of Neurology found that patients with Parkinson’s disease have a significantly higher risk of having melanoma than do healthy controls. The researchers conducted a meta-analysis of 12 publications on melanoma and Parkinson’s disease; eight of the publications had fewer than 10 cases with both Parkinson’s disease and melanoma. The pooled odds ratio was 2.11 overall, 2.04 for men, and 1.52 for women. Melanoma occurrence was significantly higher after the diagnosis of Parkinson’s disease, but not before Parkinson’s disease was diagnosed. After analyzing the data for nonmelanoma skin cancers, the researchers found no significant relationship. “Collective epidemiologic evidence supports an association of Parkinson’s disease with melanoma,” the authors concluded. “Further research is needed to examine the nature and mechanisms of this relationship.”
At-home physical training may be just as effective as locomotor training for improving the ability to walk in patients who have had a stroke, researchers reported in the May 26 New England Journal of Medicine. The investigators randomly assigned 408 participants with stroke to one of three training groups; one group received early locomotor training on a body weight–supported treadmill two months after stroke occurred, one group received the same training six months after stroke, and the third group completed an at-home exercise program guided by a physical therapist two months after stroke. At one year of training, 52% of all participants had increased functional walking ability. The researchers observed no significant differences in improvement between early or late locomotor training and home exercise. “All groups had similar improvements in walking speed, motor recovery, balance, functional status, and quality of life,” the authors noted.
High consumption of olive oil and high plasma oleic acid are associated with lower risk for stroke in older adults, according to the results of a study published in the June 15 online Neurology. To examine this relationship, the researchers looked at 7,625 older adults; in this sample, 148 incident strokes occurred. After adjusting for demographic and dietary variables and stroke risk factors, the investigators found that “compared to those who never used olive oil, those with intensive use had a 41% lower risk of stroke.” In a secondary sample, the researchers investigated the plasma oleic acid levels of 1,245 individuals (27 had incident stroke) and found that participants in the third tertile had a 73% reduction of stroke risk. “These results suggest a protective role for high olive oil consumption on the risk of stroke in older subjects,” the authors concluded.
The release of stress hormones can lead to the production of abnormally phosphorylated tau protein, and eventually to memory loss, researchers reported. “Severity of cognitive deficits in Alzheimer’s disease correlates strongly with levels of hyperphosphorylated forms of the cytoskeletal protein tau,” the authors stated in the May 25 Journal of Neuroscience. “We thus examined whether stress, through the mediation of glucocorticoids, influences tau hyperphosphorylation, a critical and early event in the cascade of processes leading to Alzheimer’s disease pathology.” Results showed that chronic stress and hypersecretion of glucocorticoids induces abnormal hyperphosphorylation of tau in the hippocampus and prefrontal cortex, suggesting that they have a cumulative impact on the onset and progress of Alzheimer’s disease pathology.
Soluble amyloid proteins in the CSF of patients with mild cognitive impairment may be a potential biomarker for Alzheimer’s disease, according to research in the June 22 online Neurology. The investigators measured the concentrations of amyloid precursor protein, tau protein, and amyloid-beta 1-42 concentrations in the CSF of 58 patients with slight memory problems—21 of whom progressed to Alzheimer’s disease. Analysis of the samples revealed that the group that had progressed to Alzheimer’s disease had significantly higher concentrations of the soluble amyloid precursor proteins than those who reverted to normal and those who developed frontotemporal dementia. “These findings suggest that soluble amyloid precursor protein beta may be clinically useful, and superior to [amyloid-beta 1-42], in the early and differential diagnosis of Alzheimer’s disease,” the authors concluded.
Weak synchronization between brain hemispheres may be an early biomarker for autism, according to the results of a study published in the June 23 issue of Neuron. “Autism is often described as a disorder of neuronal synchronization,” the authors wrote. “However, it is unknown how early in development synchronization abnormalities emerge and whether they are related to the development of early autistic behavioral symptoms.” The researchers conducted an imaging study and found that toddlers with autism exhibited significantly weaker interhemispheric synchronization in putative language areas than did toddlers without the condition. In addition, toddlers with a greater strength of synchronization had higher verbal ability and lower autism severity. “Disrupted cortical synchronization, therefore, appears to be a notable characteristic of autism neurophysiology that is evident at very early stages of autism development,” they concluded.
The FDA has approved Potiga (ezogabine) tablets as an adjunctive treatment of partial-onset seizures in adults with epilepsy. It is the first neuronal potassium channel opener developed for the treatment of epilepsy. Although its mechanism of action is not firmly established, it is believed that ezogabine may act as an anticonvulsant by reducing excitability through the stabilization of neuronal potassium channels in an ‘open’ position. The FDA’s approval was based on the results of three controlled clinical studies involving 1,239 patients with epilepsy that investigated the ability of ezogabine to reduce seizure frequency during the double-blind treatment phase. The most common adverse events were dizziness, somnolence, and fatigue; approximately 2% of patients in clinical trials also experienced urinary retention. Researchers at GlaxoSmithKline and Valeant Pharmaceuticals International Inc believe that ezogabine tablets will benefit patients whose epilepsy is uncontrolled with their current medications.
Prenatal exposure to certain antiepileptic drugs has a higher risk for major congenital malformations, according to results of a study published in the July issue of Lancet Neurology. The researchers monitored pregnant women with epilepsy who were exposed to monotherapy with different doses of carbamazepine, lamotrigine, valproic acid, or phenobarbital. A total of 230 pregnancies associated with major birth defects were observed during the first year after birth; there was also an increase in malformation rates as the dose increased for each drug. The lowest rates of malformation occurred in women who took less than 300 mg per day of lamotrigine or less than 400 mg per day of carbamazepine. All doses of valproic acid and phenobarbital monotherapies had significantly higher risks for birth defects. “The risk of major congenital malformations is influenced not only by type of antiepileptic drug, but also by dose and other variables, which should be taken into account in the management of epilepsy in women of childbearing potential,” the authors concluded.
Peripheral nerve stimulation delivered via an implanted medical device significantly reduces the number of days per month that patients have chronic migraine headache and pain, according to data presented at the 15th Annual International Headache Congress in Berlin. Investigators enrolled 157 patients with migraine to evaluate the safety and efficacy of the device; after 12 weeks, patients who received stimulation reported a 28% decrease in headache days per month. Sixty-seven percent also reported an improvement in their quality of life. “Many migraine patients have exhausted all current treatment options and often are disabled by the pain and frequency of migraine attacks,” the principal investigator stated. “Achieving a reduction in the number of days they suffer from headache and a significant improvement in their quality of life may be even more important than pain reduction alone.”
Researchers have identified three susceptibility loci for common migraine in the general population, according to a study published in the June 12 online Nature Genetics. In a population-based genome-wide analysis that included 5,122 patients with migraine and 18,108 patients without migraine, investigators found seven single nucleotide polymorphisms (SNPs) associated with migraine. Subsequent testing and meta-analysis confirmed that three replicating SNPs (re2651899, rs10166942, and rs11172113) were significantly associated with migraine. “The associations at r2651899 and rs10166942 were specific for migraine compared with nonmigraine headache,” the researchers reported. In addition, none of the three SNP associations was preferential for migraine with aura or without aura; there were also no associations specific for migraine features, suggesting that there is a shared pathophysiology among common types of migraine. “The three new loci identified in the present work provide hypotheses for immediate further exploration,” the authors concluded.
People who have had a herpes zoster attack may be at a higher risk for developing multiple sclerosis (MS) than people who have not had an occurrence of the virus, researchers reported in the June 7 online Journal of Infectious Diseases. “Varicella zoster virus has been proposed to be involved in the pathogenesis of MS,” the investigators wrote. In the study, they followed 315,550 patients with herpes zoster and 946,650 subjects without the virus for one year; they then calculated the one-year MS–free survival rate. “Of 1,262,200 sampled patients, 29 from the study group (.009%) and 24 from the control group (.003%) had MS during the one-year follow-up period,” the authors reported. The odds ratio of developing MS was 3.96 times greater for the study group than for the control group, supporting the notion that occurrence of the disease could be associated with herpes zoster attack.
A study published in the June 7 issue of Neurology found that patients with Parkinson’s disease have a significantly higher risk of having melanoma than do healthy controls. The researchers conducted a meta-analysis of 12 publications on melanoma and Parkinson’s disease; eight of the publications had fewer than 10 cases with both Parkinson’s disease and melanoma. The pooled odds ratio was 2.11 overall, 2.04 for men, and 1.52 for women. Melanoma occurrence was significantly higher after the diagnosis of Parkinson’s disease, but not before Parkinson’s disease was diagnosed. After analyzing the data for nonmelanoma skin cancers, the researchers found no significant relationship. “Collective epidemiologic evidence supports an association of Parkinson’s disease with melanoma,” the authors concluded. “Further research is needed to examine the nature and mechanisms of this relationship.”
At-home physical training may be just as effective as locomotor training for improving the ability to walk in patients who have had a stroke, researchers reported in the May 26 New England Journal of Medicine. The investigators randomly assigned 408 participants with stroke to one of three training groups; one group received early locomotor training on a body weight–supported treadmill two months after stroke occurred, one group received the same training six months after stroke, and the third group completed an at-home exercise program guided by a physical therapist two months after stroke. At one year of training, 52% of all participants had increased functional walking ability. The researchers observed no significant differences in improvement between early or late locomotor training and home exercise. “All groups had similar improvements in walking speed, motor recovery, balance, functional status, and quality of life,” the authors noted.
High consumption of olive oil and high plasma oleic acid are associated with lower risk for stroke in older adults, according to the results of a study published in the June 15 online Neurology. To examine this relationship, the researchers looked at 7,625 older adults; in this sample, 148 incident strokes occurred. After adjusting for demographic and dietary variables and stroke risk factors, the investigators found that “compared to those who never used olive oil, those with intensive use had a 41% lower risk of stroke.” In a secondary sample, the researchers investigated the plasma oleic acid levels of 1,245 individuals (27 had incident stroke) and found that participants in the third tertile had a 73% reduction of stroke risk. “These results suggest a protective role for high olive oil consumption on the risk of stroke in older subjects,” the authors concluded.
Grand Rounds: Woman, 20, With Difficulty Walking
A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.
The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.
The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.
A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.
The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.
The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.
A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm3 (normal count, 0 to 10 cells/mm3).
Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).
The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.
Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.
By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.
Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,1 manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.2,3
GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.4 In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.7 In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.8
GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 19-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.9 In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.15 Subsequently, the immune system attacks and destroys the myelin sheath.
An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.5,15,16
Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.15,17,18
The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,19 when measured two weeks after GBS onset.8,20 This score can help predict the patient’s chance of independent walking after six months.15,19
Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include21:
• Acute motor axonal neuropathy (AMAN)1,22
• Acute inflammatory demyelinating polyneuropathy (AIDP)1
• Pharyngeal-cervical-brachial variant23
• Purely sensory variant24
• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia25
• Axonal form.5,21
AMAN and AIDP are the most common subtypes of GBS.1
Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.2,15 Hughes and Cornblath26 also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.15
Cranial nerves most commonly affected are V, VI, VII, X, XI, and XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.10,15,25,27
In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10
Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.29
Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.3 Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.
Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.3,10
Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.3
Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;10 other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.30
Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 22,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 310,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.21,26,31
During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.2
MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.32 In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.33
When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.34 The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.28 Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.26 Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.35,36
The clinician cannot depend on clinical features alone to predict respiratory decline.31 Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).10 Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.31
Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).37-40 Corticosteroids do not appear to benefit patients with GBS.41,42
Several mechanisms appear to contribute to the effectiveness of immunoglobulin.38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.43 Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.15,44
In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.45,46
Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.10 Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.
Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.47 The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.10 Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al47 specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.
The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.10 According to Pandey et al,48 gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.29
More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al10 do not recommend the use of promotility drugs in patients with dysautonomia.
After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.6,49
The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.
Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.
References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.
2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.
3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.
4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.
5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.
6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.
7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.
8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.
9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.
10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.
11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.
12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.
13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.
14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.
15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.
16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.
17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.
18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.
19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.
20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neurocrit Care. 2006;5(3)235-242.
21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.
22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.
23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.
24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.
25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]
26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.
27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.
28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.
29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.
30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.
31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.
32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.
33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.
34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.
35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.
36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.
37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.
38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.
39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.
40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.
41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.
42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.
43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.
44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.
45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.
46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.
47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.
48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.
49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.
A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.
The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.
The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.
A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.
The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.
The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.
A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm3 (normal count, 0 to 10 cells/mm3).
Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).
The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.
Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.
By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.
Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,1 manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.2,3
GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.4 In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.7 In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.8
GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 19-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.9 In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.15 Subsequently, the immune system attacks and destroys the myelin sheath.
An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.5,15,16
Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.15,17,18
The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,19 when measured two weeks after GBS onset.8,20 This score can help predict the patient’s chance of independent walking after six months.15,19
Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include21:
• Acute motor axonal neuropathy (AMAN)1,22
• Acute inflammatory demyelinating polyneuropathy (AIDP)1
• Pharyngeal-cervical-brachial variant23
• Purely sensory variant24
• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia25
• Axonal form.5,21
AMAN and AIDP are the most common subtypes of GBS.1
Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.2,15 Hughes and Cornblath26 also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.15
Cranial nerves most commonly affected are V, VI, VII, X, XI, and XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.10,15,25,27
In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10
Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.29
Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.3 Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.
Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.3,10
Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.3
Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;10 other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.30
Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 22,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 310,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.21,26,31
During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.2
MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.32 In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.33
When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.34 The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.28 Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.26 Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.35,36
The clinician cannot depend on clinical features alone to predict respiratory decline.31 Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).10 Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.31
Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).37-40 Corticosteroids do not appear to benefit patients with GBS.41,42
Several mechanisms appear to contribute to the effectiveness of immunoglobulin.38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.43 Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.15,44
In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.45,46
Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.10 Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.
Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.47 The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.10 Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al47 specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.
The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.10 According to Pandey et al,48 gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.29
More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al10 do not recommend the use of promotility drugs in patients with dysautonomia.
After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.6,49
The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.
Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.
References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.
2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.
3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.
4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.
5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.
6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.
7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.
8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.
9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.
10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.
11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.
12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.
13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.
14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.
15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.
16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.
17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.
18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.
19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.
20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neurocrit Care. 2006;5(3)235-242.
21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.
22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.
23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.
24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.
25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]
26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.
27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.
28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.
29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.
30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.
31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.
32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.
33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.
34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.
35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.
36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.
37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.
38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.
39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.
40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.
41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.
42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.
43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.
44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.
45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.
46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.
47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.
48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.
49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.
A 20-year-old woman presented to her primary care clinic with a chief complaint of lower leg weakness and difficulty walking. The weakness she described had been worsening over the previous four days, with progressively worsening tingling and numbness of her toes bilaterally.
The day before the patient presented, she noticed numbness and paresthesia in both calves. At the time of her presentation to the clinic, she complained of low back ache, paresthesia of both hands, numbness bilaterally to her groin, difficulty sitting upright, ataxia, and a numb, thick-feeling tongue. She denied fever, neck stiffness, shortness of breath, headache, or visual changes.
The patient stated that 10 days earlier, she had developed an upper respiratory infection for which she was seen at the clinic and treated with a seven-day course of amoxicillin/clavulanate 875/125 mg twice daily. She said that she had recovered completely.
A review of the patient’s systems revealed proximal muscle weakness bilaterally (2/5) and loss of touch-pressure in the lower extremities. She was experiencing paresthesia of the hands and mild weakness bilaterally (4/5). She also walked with an ataxic gait and had reduced deep tendon reflexes in the lower limbs. All cranial nerves were intact, and her vital signs were stable.
The woman’s medical history was positive only for asthma. Her family history included ischemic stroke in the maternal grandfather and brain tumor in the paternal grandfather. Social history was positive for alcohol intake (ranging from four to 12 beers per week). The patient said she had never smoked or used illicit drugs. She was an unmarried college student, living in a dorm on campus. She participated in track at school.
The patient was admitted to the hospital telemetry step-down unit, and a neurology consultation was requested. Tests were ordered, among them MRI of the head and spine and comprehensive blood work, to rule out neurologic, infectious, or metabolic causes of the patient’s weakness; urinalysis was also obtained. These tests all yielded negative results.
A lumbar puncture performed the following day revealed a cerebrospinal fluid (CSF) protein level of 570 mg/L (normal range, 150 to 450 mg/L). Leukocytes numbered 2 cells/mm3 (normal count, 0 to 10 cells/mm3).
Based on the patient’s presentation, history, and symptoms, a neurologist made a diagnosis of Guillain-Barré syndrome. It was decided that no electromyographic (EMG) study was required to rule out other disease processes (eg, spinal cord disease, multiple sclerosis, tumors).
The patient underwent a five-dose course of immunomodulatory therapy with IV immunoglobulin (IVIG). In the step-down unit, she experienced one incident of sinus bradycardia (ie, resting heart rate between 40 and 50 beats/min). Her blood pressure remained stable, as did her respiratory status, according to peak expiratory flow measured frequently at her bedside.
Physical therapy was initiated, consisting of passive and active range of motion, crossovers with the patient’s feet, and stair training. This was done in response to a complaint of ankle weakness, and it helped to strengthen weakened muscles and improve alignment while the patient was bedridden and in a weakened, fatigued state. Additionally, the patient was given enoxaparin, wore antiembolic hose, and used sequential compression devices while in bed. As a result of these measures, she never experienced a pulmonary embolus or deep vein thrombosis (DVT) as a result of being immobilized.
By the seventh day of hospitalization, the patient had stable vital signs and improved lower limb strength, and numbness was resolving in her hands and lower extremities. She was discharged to home, with physical therapy to resume on an outpatient basis.
Discussion
Guillain-Barré syndrome (GBS), an acute immune-mediated paralytic disorder,1 manifests in the form of weakness and diminished reflexes. Affecting the peripheral nerves, GBS is characterized by progressive symmetrical ascending weakness with varying degrees of sensory complaints.2,3
GBS occurs worldwide, and incidence is estimated between 1.1 and 1.8 cases per 100,000 persons.4 In the United States, GBS can be found in all age-groups, with peak incidence noted in elderly persons and young adults.5,6 Even with treatment, 3% to 10% of patients are reported to die of this illness, and 20% cannot walk six months after symptom onset.7 In one prospective population-based study of patients with confirmed GBS, 6% of patients died within 30 days of symptom onset, often as a result of respiratory complications.8
GBS is a postinfectious disorder, with cases developing several days or weeks after a viral or bacterial illness—most commonly, an upper respiratory infection or diarrhea (see Table 19-13). The most common trigger of GBS is infection with the bacterial microorganism Campylobacter jejuni (occurring in 15% to 40% of patients with GBS),9,14 a pathogen that can produce demyelination-causing antibodies. Other responsible pathogens include cytomegalovirus and Epstein-Barr virus.9 In a process called molecular mimicry, the immune system is unable to distinguish the amino acid of an infectious organism from the proteinaceous content of the peripheral nerve.15 Subsequently, the immune system attacks and destroys the myelin sheath.
An example of this is the apparent cross-reaction of the ganglioside GM1 with C jejuni lipopolysaccharide antigens.14,15 The resulting effect is immunologic damage to the peripheral nervous system. The flaccid paralysis that occurs in patients with GBS is thought to be caused by lymphocytic infiltration and complement activation of the spinal roots and peripheral nerves, where macrophages strip the myelin.5,15,16
Stages and Variants
Three stages characterize the course of GBS. The acute phase, which lasts one to four weeks, begins with onset of symptoms and persists until the associated neurologic deterioration has ceased. During the second phase, the plateau period, symptoms persist with no further deterioration; this stage can last several days to several weeks or months. The final phase, the recovery period, can last from four months to two years after symptom onset.15,17,18
The clinical course of GBS is highly variable and in many cases difficult to predict. Certain factors have been associated with a poor outcome: advancing age, previous presence of diarrhea, need for mechanical ventilation, an extended plateau phase, and a lower patient score on the Erasmus GBS Outcome Scale,19 when measured two weeks after GBS onset.8,20 This score can help predict the patient’s chance of independent walking after six months.15,19
Although the classic presenting symptom of GBS is symmetric ascending weakness, several disease variants have been identified, with differing symptoms and degrees of recovery. These variants also differ in terms of the muscle groups affected; in some, visual defects may be present at onset. GBS variants include21:
• Acute motor axonal neuropathy (AMAN)1,22
• Acute inflammatory demyelinating polyneuropathy (AIDP)1
• Pharyngeal-cervical-brachial variant23
• Purely sensory variant24
• Miller-Fisher syndrome, which manifests with ophthalmoplegia, in addition to ataxia and areflexia25
• Axonal form.5,21
AMAN and AIDP are the most common subtypes of GBS.1
Symptoms, Signs, and Disease Manifestations
Limb weakness, the classic presenting symptom of GBS, is both symmetrical and ascending. Weakness can develop acutely and progress over days to weeks.2,15 Hughes and Cornblath26 also note pain, numbness, and paresthesias among the initial symptoms of GBS. Others include sensory changes, cranial nerve involvement, various autonomic changes, and respiratory or oropharyngeal weakness. Reflexes, particularly the tendon reflexes, may be diminished or absent.15,18,21 In many cases, sensory changes (ie, pain) may precede the onset of weakness, often making diagnosis difficult.15
Cranial nerves most commonly affected are V, VI, VII, X, XI, and XII, with manifestations that include dysphagia, dysarthria, diplopia, limitation to eye movements, and facial droop and weakness. Usually facial and oropharyngeal weakness occur after the extremities and trunk are affected. Blindness may occur if demyelination of the optic nerve occurs; this is seen in Miller-Fisher syndrome.10,15,25,27
In GBS, many patients report pain, which can present as bilateral sciatica or as throbbing or aching in the large muscles of the upper legs, flanks, or back.28 This pain, which results from the demyelination of the sensory nerve fibers, can be severe.10
Patients with GBS may experience manifestations of autonomic nervous system dysfunction—for example, arrhythmias, hypotension or hypertension, urinary retention, cardiomyopathy, and paralytic ileus.10,20 Dysautonomia often impedes patients’ progress in inpatient rehabilitation. Patients may have persistent problems involving postural hypotension, hypertension, excessive sympathetic outflow, or bladder and bowel dysfunction.29
Blood pressure fluctuations, often attributed to changes in catecholamine levels and disturbances in the baroreceptor reflex pathway, are common and are considered characteristic of GBS. Transient or persistent hypotension is caused by the dysregulation of the parasympathetic and sympathetic systems, with subsequent alterations in venomotor tone.3 Additionally, an increased sensitivity to catecholamine can lead to cardiovascular disturbances, resulting in denervation hypersensitivity and impairment of the carotid sinus reflex.
Arrhythmias occur in perhaps half of patients with GBS. The most common is sustained sinus tachycardia, which usually requires no treatment. Bradycardia leading to atrioventricular blocks and asystole is believed to result from afferent baroreceptor reflex failure. Treatment may be required—either administration of atropine or insertion of a pacemaker, depending on the severity of the arrhythmia.3,10
Myocardial involvement can range from asymptomatic mycocarditis to neurogenic stunned myocardium and heart failure. Patients with ECG abnormalities should undergo two-dimensional echocardiographic studies and other testing to explore cardiac involvement. Acute coronary syndromes, including ST-segment elevation MI, have been reported, in some cases associated with IVIG treatment. In one patient, coronary spasm was reported, with clean coronary arteries found on cardiac catheterization.3
Patients with GBS are at risk for compromised neuromuscular respiratory function; demyelination of the nerves that innervate the intercostal muscles and the diaphragm can result in respiratory failure. Key clinical indicators of respiratory muscle fatigue include tachypnea, diaphoresis, and asynchronous movements of the abdomen and chest;10 other symptoms relevant to respiratory or oropharyngeal weakness include slurred speech, dyspnea (with or without exertion), difficulty swallowing, and inability to cough.2,10 Serial respiratory function testing is advisable to detect patients at risk for respiratory failure.30
Diagnosis
Guillain-Barré is a syndrome diagnosed by a collection of symptoms (see Table 22,21,31), including subacute developing paralysis, symmetrical bilateral weakness beginning at onset, and diminishing to absent reflexes.21,31 Other causes for rapidly developing weaknesses should be ruled out (see Table 310,21,26,31). Lumbar puncture typically shows increased protein levels with a normal white cell count; however, neither this test nor electrophysiologic evaluation offers significant value for diagnosis of GBS.21,26,31
During the acute phase of GBS (within three weeks of onset), there is found an elevation of CSF protein (> 550 mg/L) without an elevation in white blood cells. This phenomenon, called albuminocytologic dissociation, reflects inflammation of the nerve roots and is considered the hallmark of GBS.2
MRI can also facilitate the diagnosis of GBS; it demonstrates anterior and posterior intrathecal spinal nerve roots and cauda equina.32 In patients with GBS, evidence supporting breakdown of the blood–nerve barrier can be seen in abnormal gadolinium enhancement of the intrathecal nerve roots on MRI.33
When electrophysiologic studies are performed, they typically reveal slowing nerve conduction, prolonged distal latencies, and partial motor conduction block.34 The characteristic finding of early demyelination is conduction block, a reduction in the amplitude of the muscle action potential after stimulation of the distal, as opposed to the proximal, nerve.28 Nerve conduction studies may help in the diagnosis and classification of GBS—and, to a limited extent, formulation of a prognosis. Such alternative diagnoses as myositis and myasthenia gravis may be excluded by neurophysiology.26 Early in GBS, neurophysiologic abnormalities may be very mild or occasionally normal; test results may not correlate with clinical disability.35,36
The clinician cannot depend on clinical features alone to predict respiratory decline.31 Frequent evaluations of respiratory effort, by measurement of maximal inspiratory pressures and vital capacity, should be performed at the bedside to monitor diaphragmatic strength. Respiratory ventilation should be initiated if the patient becomes hypoxic or experiences a rapid decline in vital capacity (ie, below 60% of predicted value).10 Mechanical ventilation is more likely to be required in patients with a negative inspiratory force of less than 30 cm H2O.31
Treatment
Guillain-Barré syndrome has an acute onset and progression. Patients quickly become nonambulatory and may require total ventilation due to paralysis. Therapeutic options are IVIG or plasmapheresis (plasma exchange).37-40 Corticosteroids do not appear to benefit patients with GBS.41,42
Several mechanisms appear to contribute to the effectiveness of immunoglobulin.38,39 Infused IVIG interferes with antigen presentation, inhibits antibody production, neutralizes pathologic autoantibodies, and modulates other immunologic events involved in the pathogenesis of autoimmune neuromuscular diseases, including GBS.43 Adverse reactions, which are usually minor, include headache, fever, chills, myalgia, and malaise. In rare instances, anaphylaxis or renal failure may occur.15,44
In plasmapheresis, blood is removed from the body and dialyzed, with circulating antibodies and immunoglobulins removed from the plasma; fresh frozen plasma, albumin, or saline is administered. This treatment, performed via central venous catheter, should be initiated as soon as possible after onset of symptoms but can be implemented as late as 30 days after GBS onset. Plasmapheresis requires personnel trained in dialysis, which may not be performed in all hospitals. Possible adverse events include infection and hemorrhage. Laboratory values must be monitored for hypokalemia and hypocalcemia.45,46
Supportive Care
Patients with GBS require intensive care and very close monitoring for complications of respiratory difficulty and autonomic dysfunction. Individualized programs should be initiated for patients in the acute phase of GBS, aimed at the prevention of contractures and skin breakdown.10 Exercise programs, as conducted with the case patient, should also help relieve the fatigue syndromes that accompany GBS.
Immobilization associated with bed rest incurs a risk for pulmonary emboli and DVT; this has been found true during the first 12 weeks after symptom onset in patients with GBS who remain immobile.47 The use of antiembolic hose and sequential compression devices can help reduce the risk for thrombotic events.10 Use of enoxaparin or heparin is recommended for nonambulating patients until they are able to walk, with Gaber et al47 specifying the use of low-molecular-weight heparin to reduce, but not eliminate, the risk for DVT.
The pain associated with GBS can be severe. Narcotic analgesics may be administered with careful monitoring of autonomic denervation. Long-term management of neuropathic pain may require adjuvant therapy, such as tricyclic antidepressants, gabapentin, or tramadol hydrochloride.10 According to Pandey et al,48 gabapentin alone may suffice for pain control in GBS, with minimal adverse effects. In certain rehabilitation facilities, tricyclic antidepressants, capsaicin, and transcutaneous nerve stimulation have been reported effective; during the early stages of treatment, until these treatments reach their full effect, pain medications such as tramadol or narcotics can provide temporary relief.29
More than one-half of patients with GBS in the acute phase can develop ileus. Constipation can also occur as a result of pain medication use, prolonged bed rest, and poor intake. Auscultation of bowel sounds and abdominal assessment should be performed daily to monitor for ileus. Hughes et al10 do not recommend the use of promotility drugs in patients with dysautonomia.
After hospital discharge, easy fatigability can affect work and social activities. With continued physical therapy, occupational therapy, and monitoring, however, patients with GBS can expect to return to an optimal level of functioning. Speed of recovery varies with these patients from a few months to several years, depending on such factors as age and the extent to which axonal degeneration has occurred.6,49
The Case Patient
For several weeks after discharge, the case patient continued to experience fatigue, low back pain, and general muscle pain. With her family’s support, she continued to receive outpatient physical therapy, and within one month she had regained her ankle strength. She was soon able to resume her classes, despite some lingering fatigue.
Conclusion
Guillain-Barré syndrome is a potentially life-threatening disease whose symptoms health care providers need to recognize quickly to provide prompt treatment. Supportive care for both patient and family is of key importance for maximum rehabilitation and return to the previous lifestyle. The clinical course of GBS is highly variable and difficult to predict. The patient’s outcome depends on several factors, including age and severity of illness. GBS patients can experience long-term psychosocial effects.
References
1. Magira EE, Papaioakim M, Nachamkin I, et al. Differential distribution of HLA-DQ beta/DR beta epitopes in the two forms of Guillain-Barré syndrome, acute motor axonal neuropathy and acute inflammatory demyelinating polyneuropathy (AIDP): identification of DQ beta epitopes associated with susceptibility to and protection from AIDP. J Immunol. 2003;170(6):3074-3080.
2. Tremblay ME, Closon A, D’Anjou G, Bussières JF. Guillain-Barré syndrome following H1N1 immunization in a pediatric patient. Ann Pharmacother. 2010;44(7-8):1330-1333.
3. Mukerji S, Aloka F, Farooq MU, et al. Cardiovascular complications of the Guillain-Barré syndrome. Am J Cardiol. 2009;104(10):1452-1455.
4. McGrogan A, Madle GC, Seaman HE, de Vries CS. The epidemiology of Guillain-Barré syndrome worldwide: a systematic literature review. Neuroepidemiology. 2009;32(2):150-163.
5. Haber P, Sejvar J, Mikaeloff Y, DeStefano F. Vaccines and Guillain-Barré syndrome. Drug Saf. 2009; 32(4):309-323.
6. van Doorn PA. What’s new in Guillain-Barré syndrome in 2007-2008? J Periph Nerv Syst. 2009;14(2):72-74.
7. van Doorn PA, Ruts L, Jacobs BC. Clinical features, pathogenesis, and treatment of Guillain-Barré syndrome. Lancet Neurol. 2008;7(10):939-950.
8. Chiò A, Cocito D, Leone M, et al; Piemonte and alle d’Aosta Register for Guillain-Barré Syndrome. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003; 60(7):1146-1150.
9. Hadden RD, Karch H, Hartung HP, et al. Preceding infections, immune factors, and outcome in Guillain-Barré syndrome. Neurology. 2001;56(6):758-765.
10. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62(8):1194-1198.
11. Aluka KJ, Turner PL, Fullum TM. Guillain-Barré syndrome and postbariatric surgery polyneuropathies. JSLS. 2009;13(2):250-253.
12. Brannagan TH 3rd, Zhou Y. HIV-associated Guillain-Barré syndrome. J Neurol Sci. 2003;208(1-2):39-42.
13. Lin WC, Lee PI, Lu CY, et al. Mycoplasma pneumoniae encephalitis in childhood. J Microbiol Immunol Infect. 2002;35(3):173-178.
14. Sivadon-Tardy V, Orlikowski D, Porcher R, et al. Detection of Campylobacter jejuni by culture and real-time PCR in a French cohort of patients with Guillain-Barre syndrome. J Clin Microbiol. 2010;48 (6):2278-2281.
15. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30 suppl 1:S74-S78.
16. Kaida K, Kusunoki S. Guillan-Barré syndrome: update on immunobiology and treatment. Expert Rev Neurother. 2009;9(9):1307-1319.
17. Forsberg A, Press R, Einarsson U, et al. Disability and health-related quality of life in Guillain-Barré syndrome during the first two years after onset: a prospective study. Clin Rehabil. 2005;19(8):900-909.
18. Criteria for diagnosis of Guillain-Barré syndrome. Ann Neurol. 1978;3(6):565-566.
19. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical progostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6(7):589-594.
20. Koeppen S, Kraywinkel K, Wessendorf TE, et al. Long-term outcome of Guillain-Barré syndrome. Neurocrit Care. 2006;5(3)235-242.
21. Sheridan JM, Smith D. Atypical Guillain-Barré in the emergency department. West J Emerg Med. 2010;11(1):80-82.
22. Ogawara K, Kuwabara S, Koga M, et al. Anti-GM1b IgG antibody is associated with acute motor axonal neuropathy and Campylobacter jejuni infection. J Neurol Sci. 2003;210(1-2):41-45.
23. Nagashima T, Koga M, Odaka M, et al. Continuous spectrum of pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. Arch Neurol. 2007;64(10):1519-1523.
24. Oh SJ, LaGanke C, Claussen GC. Sensory Guillain-Barré syndrome. Neurology. 2001;56(1):82-86.
25. Aráranyi Z, Kovács T, Sipos I, Bereczki D. Miller Fisher syndrome: brief overview and update with a focus on electrophysiological findings. Eur J Neurol. 2011 Jun 1. [Epub ahead of print]
26. Hughes RA, Cornblath, DR. Guillain-Barré syndrome. Lancet. 2005;366(9497):1653-1666.
27. Snyder LA, Rismondo V, Miller NR. The Fisher variant of Guillain-Barré syndrome (Fisher syndrome). J Neuroophthalmol. 2009;29(4):312-324.
28. Ropper AH. The Guillain-Barré syndrome. N Engl J Med.1992;326(17):1130-1136.
29. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil.1997;78(8):872-879.
30. Sharshar T, Chevret S, Bourdain F, et al; French Cooperative Group on Plasma Exchange in Guillain-Barré syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003; 31(1):278-283.
31. McGillicuddy DC, Walker O, Shapiro NI, et al. Guillain-Barré syndrome in the emergency department. Ann Emerg Med. 2006;47(4):390-393.
32. Yikilmaz A, Doganay S, Gumus H, et al. Magnetic resonance imaging of childhood Guillain-Barré syndrome. Childs Nerv Syst. 2010;26(8):1103-1108.
33. Gonzalez-Quevedo A, Carriera RF, O’Farrill ZL, et al. An appraisal of blood-cerebrospinal fluid barrier dysfunction during the course of Guillain-Barré syndrome. Neurol India. 2009;57(3):288-294.
34. Abai S, Kim SB, Kim JP, Lim YJ. Guillan-Barré syndrome combined with acute cervical myelopathy. J Korean Neurosurg Soc. 2010;48(3):298-300.
35. Uncini A, Yuki N. Electrophysiologic and immunopathologic correlates in Guillain-Barré syndrome subtypes. Expert Rev Neurother. 2009;9(6):869-884.
36. Hadden RD, Hughes RA. Management of inflammatory neuropathies. J Neurol Neurosurg Psychiatry. 2003;74 suppl 2:ii9-ii14.
37. Raphaël JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2):CD001798.
38. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Jun 16; (6):CD002063.
39. Human immunoglobulin and the Guillain-Barré syndrome: new indication. An alternative to plasmapheresis. Prescrire Int. 2000;9(49):142-143.
40. van der Meché FG, Schmitz PI; Dutch Guillain-Barré Study Group. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. N Engl J Med. 1992;327(17):1123-1129.
41. Hughes RA, Swan AV, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2010 Feb 16;(2):CD001446.
42. Hahn AF. Guillain-Barré syndrome. Lancet. 1998; 352(9128):635-641.
43. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291(19):2367-2375.
44. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokenetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Ann Neurol. 2009;66(5):597-603.
45. Atkinson SB, Carr RL, Maybee P, Haynes D. The challenges of managing and treating Guillain-Barré syndrome during the acute phase. Dimens Crit Care Nurs. 2006;25(6):256-263.
46. van Doorn PA. Treatment of Guillain-Barré syndrome and CIDP. J Periph Nerv Syst. 2005;10(2):113-127.
47. Gaber TA, Kirker SGB, Jenner JR. Current practice of prophylactic anticoagulation in Guillain-Barré syndrome. Clin Rehabil. 2002;16(2):190-193.
48. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a double-blinded, placebo-controlled, crossover study. Anesth Analg. 2002;95(6):1719-1723.
49. de Vries JM, Hagemans ML, Bussmann JB, et al. Fatigue in neuromuscular disorders: focus on Guillain-Barré syndrome and Pompe disease. Cell Mol Life Sci. 2010;67(5):701-713.
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Missed aortic aneurysm proves fatal ... Too-late cancer Dx blamed on neglected x-ray findings... More
Missed dissecting aortic aneurysm proves fatal
A 43-YEAR-OLD MAN was admitted to the hospital complaining of severe chest pain, shortness of breath, sweating, and dry mouth. After being seen by several physicians, the patient suffered an aortic dissection, which caused bleeding in the wall of the aorta, an aortic rupture, and bleeding into the pericardium. He died 2 days later.
PLAINTIFF’S CLAIM The defendants failed to order tests to rule out a dissecting aortic aneurysm and did not include aortic dissection in the differential diagnosis. They failed to provide appropriate drug therapy to decrease cardiac impulse and lower the systolic blood pressure. They did not obtain an emergency cardiac consultation or admit the patient to a cardiovascular surgical intensive care unit.
THE DEFENSE The defendants denied negligence and claimed that nothing they did or failed to do contributed to the patient’s death.
VERDICT $250,000 Michigan settlement.
COMMENT Just yesterday, a malpractice lawyer presented me with a case very similar to this one: a patient with unexplained chest pain who died of a dissecting aneurysm. Remember, not all chest pain is caused by coronary artery disease.
Too-late cancer Dx blamed on neglected x-ray findings
A LONG-TERM CIGARETTE SMOKER IN HER 50s saw a physician in 2001 for symptoms of pneumonia. The doctor prescribed antibiotics and referred her to another facility for a chest radiograph.
Five days later, she returned to the physician’s office, where she was seen by another internist in the practice. The internist noted that the chest radiograph showed parenchymal densities in the right lung. Parenchymal densities had also showed up on 2 previous chest radiographs, but were more prevalent on the latest film. The internist advised the patient to finish her antibiotic regimen; he did not prescribe further tests or treatment.
Over the following 40 months, doctors in the patient’s medical group examined her 8 times. Each time she complained of impaired respiration. The internist believed that the symptoms were caused by asthma.
In 2004, the patient was diagnosed with stage IV cancer of the right lung, which had spread to her bones and was untreatable. She died several weeks later.
PLAINTIFF’S CLAIM A proper diagnosis in 2001 would have allowed the cancer to be cured. A computed tomography scan should have been performed and a pulmonologist consulted at that time.
THE DEFENSE Findings from the radiograph from 2001 did not necessitate further action. Because the patient’s cancer had metastasized before that radiograph, treatment then (or later) would not have changed the outcome.
VERDICT $850,000 New York verdict.
COMMENT Careful follow-up and diagnosis of chest radiograph abnormalities is paramount.
Yes, it was a stroke
WEAKNESS, NUMBNESS, AND TINGLING IN HIS RIGHT ARM prompted a 56-year-old man to visit his primary care physician. The physician sent the patient to the emergency department (ED) for testing because he believed the man was experiencing stroke-like symptoms. As the patient and his wife drove to the hospital, the physician faxed the patient’s medical records to the ED.
When the patient’s wife tried to give ED employees the physician’s orders for tests and tell them of the doctor’s concern about a stroke, they told her that all the beds were full and she should sit down and wait.
The patient was eventually evaluated as a low-priority patient with numbness in his right hand. The examining doctor ordered radiographs of the right wrist and discharged the patient with a diagnosis of carpal tunnel syndrome.
Twenty minutes later, a nurse left a message telling the patient to return to the hospital for the stroke-related tests that had been ordered by his primary care physician. An ED physician other than the one who first examined the patient performed the tests—except for a test of blood flow to the brain. The physician diagnosed stroke-like symptoms and requested a consultation with another physician, which never happened. The patient was discharged about 6 hours after his first discharge.
About 16 hours later, the patient suffered a stroke. Subsequent testing revealed an obstruction in the left carotid artery. The stroke resulted in permanent neurologic injury.
PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.
THE DEFENSE The defendants denied negligence and disputed the extent of the patient’s injuries.
VERDICT $1.123 million Maryland verdict.
COMMENT Coordination of care remains critical, particularly between our outpatient offices and the busy ED.
Missed dissecting aortic aneurysm proves fatal
A 43-YEAR-OLD MAN was admitted to the hospital complaining of severe chest pain, shortness of breath, sweating, and dry mouth. After being seen by several physicians, the patient suffered an aortic dissection, which caused bleeding in the wall of the aorta, an aortic rupture, and bleeding into the pericardium. He died 2 days later.
PLAINTIFF’S CLAIM The defendants failed to order tests to rule out a dissecting aortic aneurysm and did not include aortic dissection in the differential diagnosis. They failed to provide appropriate drug therapy to decrease cardiac impulse and lower the systolic blood pressure. They did not obtain an emergency cardiac consultation or admit the patient to a cardiovascular surgical intensive care unit.
THE DEFENSE The defendants denied negligence and claimed that nothing they did or failed to do contributed to the patient’s death.
VERDICT $250,000 Michigan settlement.
COMMENT Just yesterday, a malpractice lawyer presented me with a case very similar to this one: a patient with unexplained chest pain who died of a dissecting aneurysm. Remember, not all chest pain is caused by coronary artery disease.
Too-late cancer Dx blamed on neglected x-ray findings
A LONG-TERM CIGARETTE SMOKER IN HER 50s saw a physician in 2001 for symptoms of pneumonia. The doctor prescribed antibiotics and referred her to another facility for a chest radiograph.
Five days later, she returned to the physician’s office, where she was seen by another internist in the practice. The internist noted that the chest radiograph showed parenchymal densities in the right lung. Parenchymal densities had also showed up on 2 previous chest radiographs, but were more prevalent on the latest film. The internist advised the patient to finish her antibiotic regimen; he did not prescribe further tests or treatment.
Over the following 40 months, doctors in the patient’s medical group examined her 8 times. Each time she complained of impaired respiration. The internist believed that the symptoms were caused by asthma.
In 2004, the patient was diagnosed with stage IV cancer of the right lung, which had spread to her bones and was untreatable. She died several weeks later.
PLAINTIFF’S CLAIM A proper diagnosis in 2001 would have allowed the cancer to be cured. A computed tomography scan should have been performed and a pulmonologist consulted at that time.
THE DEFENSE Findings from the radiograph from 2001 did not necessitate further action. Because the patient’s cancer had metastasized before that radiograph, treatment then (or later) would not have changed the outcome.
VERDICT $850,000 New York verdict.
COMMENT Careful follow-up and diagnosis of chest radiograph abnormalities is paramount.
Yes, it was a stroke
WEAKNESS, NUMBNESS, AND TINGLING IN HIS RIGHT ARM prompted a 56-year-old man to visit his primary care physician. The physician sent the patient to the emergency department (ED) for testing because he believed the man was experiencing stroke-like symptoms. As the patient and his wife drove to the hospital, the physician faxed the patient’s medical records to the ED.
When the patient’s wife tried to give ED employees the physician’s orders for tests and tell them of the doctor’s concern about a stroke, they told her that all the beds were full and she should sit down and wait.
The patient was eventually evaluated as a low-priority patient with numbness in his right hand. The examining doctor ordered radiographs of the right wrist and discharged the patient with a diagnosis of carpal tunnel syndrome.
Twenty minutes later, a nurse left a message telling the patient to return to the hospital for the stroke-related tests that had been ordered by his primary care physician. An ED physician other than the one who first examined the patient performed the tests—except for a test of blood flow to the brain. The physician diagnosed stroke-like symptoms and requested a consultation with another physician, which never happened. The patient was discharged about 6 hours after his first discharge.
About 16 hours later, the patient suffered a stroke. Subsequent testing revealed an obstruction in the left carotid artery. The stroke resulted in permanent neurologic injury.
PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.
THE DEFENSE The defendants denied negligence and disputed the extent of the patient’s injuries.
VERDICT $1.123 million Maryland verdict.
COMMENT Coordination of care remains critical, particularly between our outpatient offices and the busy ED.
Missed dissecting aortic aneurysm proves fatal
A 43-YEAR-OLD MAN was admitted to the hospital complaining of severe chest pain, shortness of breath, sweating, and dry mouth. After being seen by several physicians, the patient suffered an aortic dissection, which caused bleeding in the wall of the aorta, an aortic rupture, and bleeding into the pericardium. He died 2 days later.
PLAINTIFF’S CLAIM The defendants failed to order tests to rule out a dissecting aortic aneurysm and did not include aortic dissection in the differential diagnosis. They failed to provide appropriate drug therapy to decrease cardiac impulse and lower the systolic blood pressure. They did not obtain an emergency cardiac consultation or admit the patient to a cardiovascular surgical intensive care unit.
THE DEFENSE The defendants denied negligence and claimed that nothing they did or failed to do contributed to the patient’s death.
VERDICT $250,000 Michigan settlement.
COMMENT Just yesterday, a malpractice lawyer presented me with a case very similar to this one: a patient with unexplained chest pain who died of a dissecting aneurysm. Remember, not all chest pain is caused by coronary artery disease.
Too-late cancer Dx blamed on neglected x-ray findings
A LONG-TERM CIGARETTE SMOKER IN HER 50s saw a physician in 2001 for symptoms of pneumonia. The doctor prescribed antibiotics and referred her to another facility for a chest radiograph.
Five days later, she returned to the physician’s office, where she was seen by another internist in the practice. The internist noted that the chest radiograph showed parenchymal densities in the right lung. Parenchymal densities had also showed up on 2 previous chest radiographs, but were more prevalent on the latest film. The internist advised the patient to finish her antibiotic regimen; he did not prescribe further tests or treatment.
Over the following 40 months, doctors in the patient’s medical group examined her 8 times. Each time she complained of impaired respiration. The internist believed that the symptoms were caused by asthma.
In 2004, the patient was diagnosed with stage IV cancer of the right lung, which had spread to her bones and was untreatable. She died several weeks later.
PLAINTIFF’S CLAIM A proper diagnosis in 2001 would have allowed the cancer to be cured. A computed tomography scan should have been performed and a pulmonologist consulted at that time.
THE DEFENSE Findings from the radiograph from 2001 did not necessitate further action. Because the patient’s cancer had metastasized before that radiograph, treatment then (or later) would not have changed the outcome.
VERDICT $850,000 New York verdict.
COMMENT Careful follow-up and diagnosis of chest radiograph abnormalities is paramount.
Yes, it was a stroke
WEAKNESS, NUMBNESS, AND TINGLING IN HIS RIGHT ARM prompted a 56-year-old man to visit his primary care physician. The physician sent the patient to the emergency department (ED) for testing because he believed the man was experiencing stroke-like symptoms. As the patient and his wife drove to the hospital, the physician faxed the patient’s medical records to the ED.
When the patient’s wife tried to give ED employees the physician’s orders for tests and tell them of the doctor’s concern about a stroke, they told her that all the beds were full and she should sit down and wait.
The patient was eventually evaluated as a low-priority patient with numbness in his right hand. The examining doctor ordered radiographs of the right wrist and discharged the patient with a diagnosis of carpal tunnel syndrome.
Twenty minutes later, a nurse left a message telling the patient to return to the hospital for the stroke-related tests that had been ordered by his primary care physician. An ED physician other than the one who first examined the patient performed the tests—except for a test of blood flow to the brain. The physician diagnosed stroke-like symptoms and requested a consultation with another physician, which never happened. The patient was discharged about 6 hours after his first discharge.
About 16 hours later, the patient suffered a stroke. Subsequent testing revealed an obstruction in the left carotid artery. The stroke resulted in permanent neurologic injury.
PLAINTIFF’S CLAIM No information about the plaintiff’s claim is available.
THE DEFENSE The defendants denied negligence and disputed the extent of the patient’s injuries.
VERDICT $1.123 million Maryland verdict.
COMMENT Coordination of care remains critical, particularly between our outpatient offices and the busy ED.
CVD prevention in women: A practice update
Nearly 3 out of 4 (71.9%) US women (and 72.6% of men) ages 60 to 79 years have cardiovascular disease (CVD)—the leading cause of death despite marked improvement in mortality rates in the last 4 decades. In that same age group, the prevalence of cerebral vascular disease is 8.2% in women and 7.2% in men.1
The age-adjusted death rate for all adults is 135.1 in 100,000 for coronary heart disease (CHD) and 44.1 in 100,000 for cerebral vascular disease. In 2007, CVD caused 34.5% of deaths in women and 32.7% of deaths in men.1
Evidence that CVD frequently manifests differently in women than in men led the American Heart Association (AHA) to issue recommendations for the prevention of CVD in women in 1999, and to follow with guidelines in 2004 and an update in 2007.2-4 However, the recommended interventions were, with a few exceptions, the same as the recommendations for men. But that’s changed.
The latest update of the guidelines, published earlier this year, focuses more on sex-based differences, with the addition of pregnancy complications as a major risk factor, for example. (See “AHA’s 2011 CVD guideline update: What’s new?”.) Highlights of the guidelines,5 including the recommended interventions for all women (TABLE 1) and a comparison of its recommendations with those of the US Preventive Services Task Force (USPSTF)6 (TABLE 2)—are detailed here.
The updated guidelines for prevention of CVD in women give more weight to conditions that increase risk for heart disease and stroke primarily or exclusively in women, including gestational diabetes and other complications of pregnancy, lupus, and rheumatoid arthritis. Some of the changes include:
- adding a history of preeclampsia, gestational diabetes, and pregnancy-induced hypertension as criteria for the "at risk" classification
- revising the criterion for "high risk" classification based on risk calculation to ≥10% 10-year predicted risk of CVD (it was previously ≥20%)
- addressing the challenges of diversity, including recommendations that providers develop cultural competence and become aware of, and take steps to reduce, CVD health disparities
- redefining the lowest risk category as "ideal cardiovascular health," for women who have ideal blood pressure, cholesterol, and fasting glucose levels, and adhere to optimal lifestyle/behavioral recommendations.
The AHA indicates that it has changed from evidence-based to effectiveness-based guidelines;5 however, the practical implications within the guidelines themselves are unclear.
TABLE 1
AHA recommends these interventions for all women5
| Avoid smoking (incorporates smoking prevention and cessation advice and assistance, including nicotine replacement, pharmacotherapy, and formal smoking cessation programs) and environmental tobacco smoke |
| Exercise (≥150 minutes of moderate exercise or ≥75 minutes of vigorous exercise per week, with additional benefit gained by more time and higher-level exercise) |
| Consume a healthy diet, rich in fruits and vegetables; whole-grain, high-fiber foods; and fish (at least twice a week); limit intake of saturated fat, cholesterol, alcohol, sodium, and sugar and avoid trans-fatty acids |
| Control your weight (maintain a BMI of <25 kg/m2) |
| Keep blood pressure <120/mm Hg through diet, exercise, and weight control; take medication for BP ≥140/90 mm Hg (or ≥130/80 mm Hg for women with diabetes or chronic kidney disease) |
| Maintain healthy lipid levels (LDL-C <100 mg/dL, HDL-C >50 mg/dL, triglycerides <150 mg/dL, and non-HDL-C [total cholesterol minus HDL] <130 mg/dL) through lifestyle and diet; consider medication for hyperlipidemia based on CVD risk and lipid levels |
| BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. |
TABLE 2
CVD prevention in women: Comparing AHA1and USPSTF recommendations5,6
| AHA | USPSTF | |
|---|---|---|
| Screening for CVD risks | ||
| Hypertension | Implied, but no specific recommendation | Recommends screening for high BP in women ≥18 y |
| Lipid disorders | Implied, but no specific recommendation | Recommends screening women ≥20 y for lipid disorders if they are at increased risk for CHD (evidence is stronger for women ≥45 y) No recommendation for or against routine screening for lipid disorders in women who are not at increased risk for CHD |
| Obesity | Implied, but no specific recommendation | Recommends screening all adult patients for obesity |
| Diabetes | Implied, but no specific recommendation | Recommends screening for asymptomatic adults with sustained BP (treated or untreated) >135/80 mm Hg Insufficient evidence to assess the balance of benefits and harms of screening asymptomatic adults with BP ≤135/80 mm Hg |
| Tobacco use | Implied, but no specific recommendation | Recommends asking all adults about tobacco use and providing tobacco cessation interventions for those who use tobacco products |
| Nontraditional risk factors | The role that novel CVD risk biomarkers (hs-CRP and advanced lipid testing) and imaging technologies (coronary calcium scoring assessment) is not yet well defined | Insufficient evidence to assess the balance of benefits and harms of using nontraditional risk factors* to screen asymptomatic women with no history of CHD |
| Screening for CVD | ||
| Carotid artery stenosis | Not addressed, but implies it might be useful for classification | Recommends against screening for asymptomatic carotid artery stenosis in the general adult population |
| Peripheral artery disease | Not addressed, but implies it might be useful for classification | Recommends against routine screening for peripheral arterial disease |
| CHD or prediction of CHD | Not addressed, but implies it might be useful for classification | Recommends against routine screening with resting EKG, ETT, or EBCT scanning for coronary calcium for the presence of severe carotid artery stenosis or the prediction of CHD events in adults at low risk for CHD events Insufficient evidence to recommend for or against routine screening with EKG, ETT, or EBCT scanning for coronary calcium for the presence of severe carotid artery stenosis or the prediction of CHD events in adults at increased risk for CHD events |
| Behavioral counseling to reduce risk | ||
| To promote physical activity | Sets physical activity targets but does not address how to achieve them | Insufficient evidence to recommend for or against behavioral counseling in primary care settings to promote physical activity |
| To promote weight loss | Sets ideal weight targets but does not address how to achieve them | Recommends intensive counseling and behavioral interventions+ to promote sustained weight loss for obese adults Insufficient evidence to recommend for or against the use of moderate (monthly) or low-intensity (less than once a month) counseling together with behavioral interventions to promote sustained weight loss in obese adults Insufficient evidence to recommend for or against the use of counseling of any intensity and behavioral interventions to promote sustained weight loss in overweight adults |
| Tobacco use | Recommends smoking prevention and cessation advice and assistance, including nicotine replacement, pharmacotherapy, and formal smoking cessation programs | Recommends tobacco cessation interventions for those who use tobacco products |
| Risk reduction interventions | ||
| Aspirin | Recommends the use of aspirin in women with CHD unless it is contraindicated Says use of aspirin is reasonable in women with diabetes, unless it is contraindicated If aspirin is indicated but not tolerated, clopidogrel should be substituted. Aspirin may be reasonable for women <65 years for stroke prevention, but is not recommended for MI prevention. Aspirin can be useful for women >65 years if BP is controlled; benefit for stroke and MI prevention is likely to outweigh risk of GI bleeding and hemorrhagic stroke | Recommends the use of aspirin for women ages 55 to 79 years when the potential benefit of a reduction in ischemic stroke outweighs the potential harm of an increased risk of GI hemorrhage Insufficient evidence to assess aspirin for cardiovascular disease prevention in women ≥80 years Recommends against the use of aspirin for stroke prevention in women ≤55 years |
| Beta-carotene | Should not be used for prevention of CVD | Recommends against the use of beta-carotene supplements, either alone or in combination, for the prevention of cancer or cardiovascular disease |
| Antioxidants and vitamins | Vitamins E, C, B6, B12, and folic acid should not be used for CVD prevention. | Insufficient evidence to recommend for or against the use of supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or cardiovascular disease |
| Hormonal therapy | Hormone therapy and selective estrogen-receptor modulators should not be used for CVD prevention. | Recommends against the routine use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women Recommends against the routine use of unopposed estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy |
| †;Defined by the USPSTF as >1 individual or group session per month for ≥3 months. *Nontraditional risk factors included in this recommendation are high-sensitivity C-reactive protein, ankle-brachial index, leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness, coronary artery calcification score on electron-beam computed tomography, homocysteine level, and lipoprotein(a) level. AHA, American Heart Association; BP, blood pressure; CHD, coronary heart disease; CVD, cardiovascular disease; EBCT, electron-beam computed tomography; EKG, electrocardiography; ETT, exercise treadmill test; GI, gastrointestinal; hs-CRP, high-sensitivity C-reactive protein; MI, myocardial infarction; USPSTF, US Preventive Services Task Force. | ||
The AHA’s assessment of risk
The new guideline update recommends assessing each woman’s CVD risk and placing her into one of 3 risk groups—high risk, at risk, and ideal cardiovascular health (TABLE 3)—then using an algorithm to determine which preventive interventions to recommend based on her risk level.
This classification approach is challenging, for several reasons. It lumps women with markedly different risk profiles into the “at risk” group, a category that will likely apply to a high proportion of women. It also appears to encourage the use of diagnostic tests for subclinical vascular disease, for which there is no evidence of effectiveness. In addition, some of the terms used in the at-risk criteria, such as ”physical inactivity” and “poor diet,” are vague.
TABLE 3
Cardiovascular disease: How the AHA classifies women’s risk5
High risk ≥1 of the following: Documented CVD Diabetes Chronic or end-stage renal disease 10-year predicted risk of CVD ≥10%* |
At risk ≥1 of the following major risk factors: Smoking Hypertension (BP ≥120/80 mm Hg, or treated hypertension) Hyperlipidemia (total cholesterol ≥200 mg/dL, HDL cholesterol <50 mg/dL, or treated dyslipidemia) Obesity Poor diet Physical inactivity Premature CVD in a first-degree relative (<55 years for men and <65 for women) Metabolic syndrome Subclinical atherosclerosis Poor exercise tolerance on a treadmill test Systemic autoimmune disease A history of preeclampsia, gestational diabetes, or PIH |
Ideal cardiovascular health All of the following: Total cholesterol <200 mg/dL, untreated BP <120/80 mm Hg, untreated Fasting blood glucose <100 mg/dL, untreated BMI <25 mm/kg2 Nonsmoking Healthy diet (rich in fruits and vegetables; whole-grain, high-fiber foods; and fish, especially oily fish such as salmon and mackerel, at least twice a week; with limited intake of saturated fat, cholesterol, alcohol, sodium, and sugar; and avoidance of trans-fatty acids) Physical activity (≥150 minutes per week at moderate intensity or ≥75 minutes per week at vigorous intensity) |
| *Calculation tools can be found at http://hp2010.nhlbihin.net/atpiii/calculator.asp (for CHD) and at http://www.westernstroke.org/PersonalStrokeRisk1.xls (for stroke). AHA, American Heart Association; BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein, PIH, pregnancy-induced hypertension. |
Some recommendations apply to all women, regardless of risk
The AHA recommendations for all women (TABLE 1) include smoking prevention or cessation, maintenance of optimal weight, regular physical activity, and a diet aimed at preventing CVD. The guidelines also emphasize that major CVD risks should be controlled, with either lifestyle and diet modifications (preferably) or pharmacotherapy. The aggressiveness of control targets depends on the level of risk and the presence of other risk factors.
The guidelines recommend against some interventions that are often used for CVD prevention, based on a high level of evidence that they are ineffective. These include estrogen or selective estrogen receptor modulators, antioxidant vitamins (vitamins E and C, and beta-carotene), folic acid with or without vitamins B6 and B12, and aspirin (for CHD prevention) for healthy women <65 years old.
The AHA does not take a position for or against several diagnostic and risk classification tools because of a lack of evidence of usefulness. These include CVD risk biomarkers such as high sensitivity C-reactive protein and imaging technologies such as coronary calcium scoring assessment.
AHA and USPSTF diverge, but not by much
Screening for conditions that increase CVD risk is not explicitly addressed in the AHA guidelines. Screening is implied by the proposed classification scheme, which includes the presence or absence of smoking, obesity, diabetes, hypertension, and dyslipidemia, but there is no guidance on when to start or stop screening for these conditions. The AHA and the USPSTF diverge on screening women for dyslipidemia, with the USPSTF recommending screening for lipid disorders only in women at increased risk for CHD.
The recommendations for optimal weight and activity levels in the AHA guidelines do not include advice on how to achieve them, nor do they call for an assessment of the effectiveness of behavioral counseling in the clinical setting. Because the USPSTF includes an assessment of, and recommendations for, asymptomatic patients in primary care settings, its recommendations do not address women with conditions such as established CVD, heart failure, or atrial fibrillation—which the AHA guidelines do.
Overall, the AHA and USPSTF agree more than they disagree, and each covers some areas that the other does not (TABLE 2). Family physicians can use the information provided by both entities to ensure that their female patients receive high-quality preventive care that will minimize their risk for CVD.
1. American Heart Association. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18-e209.
2. Mosca L, Grundy SM, Judelson D, et al. Guide to preventive cardiology for women. AHA/ACC scientific statement, consensus panel statement. Circulation. 1999;99:2480-2484.
3. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-693.
4. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481-1501.
5. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011;123:1243-1262.
6. United States Preventive Services Task Force. USPSTF A-Z guide. Available at: www.uspreventiveservicestaskforce.org/uspstopics.htm. Accessed June 7, 2011.
Nearly 3 out of 4 (71.9%) US women (and 72.6% of men) ages 60 to 79 years have cardiovascular disease (CVD)—the leading cause of death despite marked improvement in mortality rates in the last 4 decades. In that same age group, the prevalence of cerebral vascular disease is 8.2% in women and 7.2% in men.1
The age-adjusted death rate for all adults is 135.1 in 100,000 for coronary heart disease (CHD) and 44.1 in 100,000 for cerebral vascular disease. In 2007, CVD caused 34.5% of deaths in women and 32.7% of deaths in men.1
Evidence that CVD frequently manifests differently in women than in men led the American Heart Association (AHA) to issue recommendations for the prevention of CVD in women in 1999, and to follow with guidelines in 2004 and an update in 2007.2-4 However, the recommended interventions were, with a few exceptions, the same as the recommendations for men. But that’s changed.
The latest update of the guidelines, published earlier this year, focuses more on sex-based differences, with the addition of pregnancy complications as a major risk factor, for example. (See “AHA’s 2011 CVD guideline update: What’s new?”.) Highlights of the guidelines,5 including the recommended interventions for all women (TABLE 1) and a comparison of its recommendations with those of the US Preventive Services Task Force (USPSTF)6 (TABLE 2)—are detailed here.
The updated guidelines for prevention of CVD in women give more weight to conditions that increase risk for heart disease and stroke primarily or exclusively in women, including gestational diabetes and other complications of pregnancy, lupus, and rheumatoid arthritis. Some of the changes include:
- adding a history of preeclampsia, gestational diabetes, and pregnancy-induced hypertension as criteria for the "at risk" classification
- revising the criterion for "high risk" classification based on risk calculation to ≥10% 10-year predicted risk of CVD (it was previously ≥20%)
- addressing the challenges of diversity, including recommendations that providers develop cultural competence and become aware of, and take steps to reduce, CVD health disparities
- redefining the lowest risk category as "ideal cardiovascular health," for women who have ideal blood pressure, cholesterol, and fasting glucose levels, and adhere to optimal lifestyle/behavioral recommendations.
The AHA indicates that it has changed from evidence-based to effectiveness-based guidelines;5 however, the practical implications within the guidelines themselves are unclear.
TABLE 1
AHA recommends these interventions for all women5
| Avoid smoking (incorporates smoking prevention and cessation advice and assistance, including nicotine replacement, pharmacotherapy, and formal smoking cessation programs) and environmental tobacco smoke |
| Exercise (≥150 minutes of moderate exercise or ≥75 minutes of vigorous exercise per week, with additional benefit gained by more time and higher-level exercise) |
| Consume a healthy diet, rich in fruits and vegetables; whole-grain, high-fiber foods; and fish (at least twice a week); limit intake of saturated fat, cholesterol, alcohol, sodium, and sugar and avoid trans-fatty acids |
| Control your weight (maintain a BMI of <25 kg/m2) |
| Keep blood pressure <120/mm Hg through diet, exercise, and weight control; take medication for BP ≥140/90 mm Hg (or ≥130/80 mm Hg for women with diabetes or chronic kidney disease) |
| Maintain healthy lipid levels (LDL-C <100 mg/dL, HDL-C >50 mg/dL, triglycerides <150 mg/dL, and non-HDL-C [total cholesterol minus HDL] <130 mg/dL) through lifestyle and diet; consider medication for hyperlipidemia based on CVD risk and lipid levels |
| BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. |
TABLE 2
CVD prevention in women: Comparing AHA1and USPSTF recommendations5,6
| AHA | USPSTF | |
|---|---|---|
| Screening for CVD risks | ||
| Hypertension | Implied, but no specific recommendation | Recommends screening for high BP in women ≥18 y |
| Lipid disorders | Implied, but no specific recommendation | Recommends screening women ≥20 y for lipid disorders if they are at increased risk for CHD (evidence is stronger for women ≥45 y) No recommendation for or against routine screening for lipid disorders in women who are not at increased risk for CHD |
| Obesity | Implied, but no specific recommendation | Recommends screening all adult patients for obesity |
| Diabetes | Implied, but no specific recommendation | Recommends screening for asymptomatic adults with sustained BP (treated or untreated) >135/80 mm Hg Insufficient evidence to assess the balance of benefits and harms of screening asymptomatic adults with BP ≤135/80 mm Hg |
| Tobacco use | Implied, but no specific recommendation | Recommends asking all adults about tobacco use and providing tobacco cessation interventions for those who use tobacco products |
| Nontraditional risk factors | The role that novel CVD risk biomarkers (hs-CRP and advanced lipid testing) and imaging technologies (coronary calcium scoring assessment) is not yet well defined | Insufficient evidence to assess the balance of benefits and harms of using nontraditional risk factors* to screen asymptomatic women with no history of CHD |
| Screening for CVD | ||
| Carotid artery stenosis | Not addressed, but implies it might be useful for classification | Recommends against screening for asymptomatic carotid artery stenosis in the general adult population |
| Peripheral artery disease | Not addressed, but implies it might be useful for classification | Recommends against routine screening for peripheral arterial disease |
| CHD or prediction of CHD | Not addressed, but implies it might be useful for classification | Recommends against routine screening with resting EKG, ETT, or EBCT scanning for coronary calcium for the presence of severe carotid artery stenosis or the prediction of CHD events in adults at low risk for CHD events Insufficient evidence to recommend for or against routine screening with EKG, ETT, or EBCT scanning for coronary calcium for the presence of severe carotid artery stenosis or the prediction of CHD events in adults at increased risk for CHD events |
| Behavioral counseling to reduce risk | ||
| To promote physical activity | Sets physical activity targets but does not address how to achieve them | Insufficient evidence to recommend for or against behavioral counseling in primary care settings to promote physical activity |
| To promote weight loss | Sets ideal weight targets but does not address how to achieve them | Recommends intensive counseling and behavioral interventions+ to promote sustained weight loss for obese adults Insufficient evidence to recommend for or against the use of moderate (monthly) or low-intensity (less than once a month) counseling together with behavioral interventions to promote sustained weight loss in obese adults Insufficient evidence to recommend for or against the use of counseling of any intensity and behavioral interventions to promote sustained weight loss in overweight adults |
| Tobacco use | Recommends smoking prevention and cessation advice and assistance, including nicotine replacement, pharmacotherapy, and formal smoking cessation programs | Recommends tobacco cessation interventions for those who use tobacco products |
| Risk reduction interventions | ||
| Aspirin | Recommends the use of aspirin in women with CHD unless it is contraindicated Says use of aspirin is reasonable in women with diabetes, unless it is contraindicated If aspirin is indicated but not tolerated, clopidogrel should be substituted. Aspirin may be reasonable for women <65 years for stroke prevention, but is not recommended for MI prevention. Aspirin can be useful for women >65 years if BP is controlled; benefit for stroke and MI prevention is likely to outweigh risk of GI bleeding and hemorrhagic stroke | Recommends the use of aspirin for women ages 55 to 79 years when the potential benefit of a reduction in ischemic stroke outweighs the potential harm of an increased risk of GI hemorrhage Insufficient evidence to assess aspirin for cardiovascular disease prevention in women ≥80 years Recommends against the use of aspirin for stroke prevention in women ≤55 years |
| Beta-carotene | Should not be used for prevention of CVD | Recommends against the use of beta-carotene supplements, either alone or in combination, for the prevention of cancer or cardiovascular disease |
| Antioxidants and vitamins | Vitamins E, C, B6, B12, and folic acid should not be used for CVD prevention. | Insufficient evidence to recommend for or against the use of supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or cardiovascular disease |
| Hormonal therapy | Hormone therapy and selective estrogen-receptor modulators should not be used for CVD prevention. | Recommends against the routine use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women Recommends against the routine use of unopposed estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy |
| †;Defined by the USPSTF as >1 individual or group session per month for ≥3 months. *Nontraditional risk factors included in this recommendation are high-sensitivity C-reactive protein, ankle-brachial index, leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness, coronary artery calcification score on electron-beam computed tomography, homocysteine level, and lipoprotein(a) level. AHA, American Heart Association; BP, blood pressure; CHD, coronary heart disease; CVD, cardiovascular disease; EBCT, electron-beam computed tomography; EKG, electrocardiography; ETT, exercise treadmill test; GI, gastrointestinal; hs-CRP, high-sensitivity C-reactive protein; MI, myocardial infarction; USPSTF, US Preventive Services Task Force. | ||
The AHA’s assessment of risk
The new guideline update recommends assessing each woman’s CVD risk and placing her into one of 3 risk groups—high risk, at risk, and ideal cardiovascular health (TABLE 3)—then using an algorithm to determine which preventive interventions to recommend based on her risk level.
This classification approach is challenging, for several reasons. It lumps women with markedly different risk profiles into the “at risk” group, a category that will likely apply to a high proportion of women. It also appears to encourage the use of diagnostic tests for subclinical vascular disease, for which there is no evidence of effectiveness. In addition, some of the terms used in the at-risk criteria, such as ”physical inactivity” and “poor diet,” are vague.
TABLE 3
Cardiovascular disease: How the AHA classifies women’s risk5
High risk ≥1 of the following: Documented CVD Diabetes Chronic or end-stage renal disease 10-year predicted risk of CVD ≥10%* |
At risk ≥1 of the following major risk factors: Smoking Hypertension (BP ≥120/80 mm Hg, or treated hypertension) Hyperlipidemia (total cholesterol ≥200 mg/dL, HDL cholesterol <50 mg/dL, or treated dyslipidemia) Obesity Poor diet Physical inactivity Premature CVD in a first-degree relative (<55 years for men and <65 for women) Metabolic syndrome Subclinical atherosclerosis Poor exercise tolerance on a treadmill test Systemic autoimmune disease A history of preeclampsia, gestational diabetes, or PIH |
Ideal cardiovascular health All of the following: Total cholesterol <200 mg/dL, untreated BP <120/80 mm Hg, untreated Fasting blood glucose <100 mg/dL, untreated BMI <25 mm/kg2 Nonsmoking Healthy diet (rich in fruits and vegetables; whole-grain, high-fiber foods; and fish, especially oily fish such as salmon and mackerel, at least twice a week; with limited intake of saturated fat, cholesterol, alcohol, sodium, and sugar; and avoidance of trans-fatty acids) Physical activity (≥150 minutes per week at moderate intensity or ≥75 minutes per week at vigorous intensity) |
| *Calculation tools can be found at http://hp2010.nhlbihin.net/atpiii/calculator.asp (for CHD) and at http://www.westernstroke.org/PersonalStrokeRisk1.xls (for stroke). AHA, American Heart Association; BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein, PIH, pregnancy-induced hypertension. |
Some recommendations apply to all women, regardless of risk
The AHA recommendations for all women (TABLE 1) include smoking prevention or cessation, maintenance of optimal weight, regular physical activity, and a diet aimed at preventing CVD. The guidelines also emphasize that major CVD risks should be controlled, with either lifestyle and diet modifications (preferably) or pharmacotherapy. The aggressiveness of control targets depends on the level of risk and the presence of other risk factors.
The guidelines recommend against some interventions that are often used for CVD prevention, based on a high level of evidence that they are ineffective. These include estrogen or selective estrogen receptor modulators, antioxidant vitamins (vitamins E and C, and beta-carotene), folic acid with or without vitamins B6 and B12, and aspirin (for CHD prevention) for healthy women <65 years old.
The AHA does not take a position for or against several diagnostic and risk classification tools because of a lack of evidence of usefulness. These include CVD risk biomarkers such as high sensitivity C-reactive protein and imaging technologies such as coronary calcium scoring assessment.
AHA and USPSTF diverge, but not by much
Screening for conditions that increase CVD risk is not explicitly addressed in the AHA guidelines. Screening is implied by the proposed classification scheme, which includes the presence or absence of smoking, obesity, diabetes, hypertension, and dyslipidemia, but there is no guidance on when to start or stop screening for these conditions. The AHA and the USPSTF diverge on screening women for dyslipidemia, with the USPSTF recommending screening for lipid disorders only in women at increased risk for CHD.
The recommendations for optimal weight and activity levels in the AHA guidelines do not include advice on how to achieve them, nor do they call for an assessment of the effectiveness of behavioral counseling in the clinical setting. Because the USPSTF includes an assessment of, and recommendations for, asymptomatic patients in primary care settings, its recommendations do not address women with conditions such as established CVD, heart failure, or atrial fibrillation—which the AHA guidelines do.
Overall, the AHA and USPSTF agree more than they disagree, and each covers some areas that the other does not (TABLE 2). Family physicians can use the information provided by both entities to ensure that their female patients receive high-quality preventive care that will minimize their risk for CVD.
Nearly 3 out of 4 (71.9%) US women (and 72.6% of men) ages 60 to 79 years have cardiovascular disease (CVD)—the leading cause of death despite marked improvement in mortality rates in the last 4 decades. In that same age group, the prevalence of cerebral vascular disease is 8.2% in women and 7.2% in men.1
The age-adjusted death rate for all adults is 135.1 in 100,000 for coronary heart disease (CHD) and 44.1 in 100,000 for cerebral vascular disease. In 2007, CVD caused 34.5% of deaths in women and 32.7% of deaths in men.1
Evidence that CVD frequently manifests differently in women than in men led the American Heart Association (AHA) to issue recommendations for the prevention of CVD in women in 1999, and to follow with guidelines in 2004 and an update in 2007.2-4 However, the recommended interventions were, with a few exceptions, the same as the recommendations for men. But that’s changed.
The latest update of the guidelines, published earlier this year, focuses more on sex-based differences, with the addition of pregnancy complications as a major risk factor, for example. (See “AHA’s 2011 CVD guideline update: What’s new?”.) Highlights of the guidelines,5 including the recommended interventions for all women (TABLE 1) and a comparison of its recommendations with those of the US Preventive Services Task Force (USPSTF)6 (TABLE 2)—are detailed here.
The updated guidelines for prevention of CVD in women give more weight to conditions that increase risk for heart disease and stroke primarily or exclusively in women, including gestational diabetes and other complications of pregnancy, lupus, and rheumatoid arthritis. Some of the changes include:
- adding a history of preeclampsia, gestational diabetes, and pregnancy-induced hypertension as criteria for the "at risk" classification
- revising the criterion for "high risk" classification based on risk calculation to ≥10% 10-year predicted risk of CVD (it was previously ≥20%)
- addressing the challenges of diversity, including recommendations that providers develop cultural competence and become aware of, and take steps to reduce, CVD health disparities
- redefining the lowest risk category as "ideal cardiovascular health," for women who have ideal blood pressure, cholesterol, and fasting glucose levels, and adhere to optimal lifestyle/behavioral recommendations.
The AHA indicates that it has changed from evidence-based to effectiveness-based guidelines;5 however, the practical implications within the guidelines themselves are unclear.
TABLE 1
AHA recommends these interventions for all women5
| Avoid smoking (incorporates smoking prevention and cessation advice and assistance, including nicotine replacement, pharmacotherapy, and formal smoking cessation programs) and environmental tobacco smoke |
| Exercise (≥150 minutes of moderate exercise or ≥75 minutes of vigorous exercise per week, with additional benefit gained by more time and higher-level exercise) |
| Consume a healthy diet, rich in fruits and vegetables; whole-grain, high-fiber foods; and fish (at least twice a week); limit intake of saturated fat, cholesterol, alcohol, sodium, and sugar and avoid trans-fatty acids |
| Control your weight (maintain a BMI of <25 kg/m2) |
| Keep blood pressure <120/mm Hg through diet, exercise, and weight control; take medication for BP ≥140/90 mm Hg (or ≥130/80 mm Hg for women with diabetes or chronic kidney disease) |
| Maintain healthy lipid levels (LDL-C <100 mg/dL, HDL-C >50 mg/dL, triglycerides <150 mg/dL, and non-HDL-C [total cholesterol minus HDL] <130 mg/dL) through lifestyle and diet; consider medication for hyperlipidemia based on CVD risk and lipid levels |
| BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. |
TABLE 2
CVD prevention in women: Comparing AHA1and USPSTF recommendations5,6
| AHA | USPSTF | |
|---|---|---|
| Screening for CVD risks | ||
| Hypertension | Implied, but no specific recommendation | Recommends screening for high BP in women ≥18 y |
| Lipid disorders | Implied, but no specific recommendation | Recommends screening women ≥20 y for lipid disorders if they are at increased risk for CHD (evidence is stronger for women ≥45 y) No recommendation for or against routine screening for lipid disorders in women who are not at increased risk for CHD |
| Obesity | Implied, but no specific recommendation | Recommends screening all adult patients for obesity |
| Diabetes | Implied, but no specific recommendation | Recommends screening for asymptomatic adults with sustained BP (treated or untreated) >135/80 mm Hg Insufficient evidence to assess the balance of benefits and harms of screening asymptomatic adults with BP ≤135/80 mm Hg |
| Tobacco use | Implied, but no specific recommendation | Recommends asking all adults about tobacco use and providing tobacco cessation interventions for those who use tobacco products |
| Nontraditional risk factors | The role that novel CVD risk biomarkers (hs-CRP and advanced lipid testing) and imaging technologies (coronary calcium scoring assessment) is not yet well defined | Insufficient evidence to assess the balance of benefits and harms of using nontraditional risk factors* to screen asymptomatic women with no history of CHD |
| Screening for CVD | ||
| Carotid artery stenosis | Not addressed, but implies it might be useful for classification | Recommends against screening for asymptomatic carotid artery stenosis in the general adult population |
| Peripheral artery disease | Not addressed, but implies it might be useful for classification | Recommends against routine screening for peripheral arterial disease |
| CHD or prediction of CHD | Not addressed, but implies it might be useful for classification | Recommends against routine screening with resting EKG, ETT, or EBCT scanning for coronary calcium for the presence of severe carotid artery stenosis or the prediction of CHD events in adults at low risk for CHD events Insufficient evidence to recommend for or against routine screening with EKG, ETT, or EBCT scanning for coronary calcium for the presence of severe carotid artery stenosis or the prediction of CHD events in adults at increased risk for CHD events |
| Behavioral counseling to reduce risk | ||
| To promote physical activity | Sets physical activity targets but does not address how to achieve them | Insufficient evidence to recommend for or against behavioral counseling in primary care settings to promote physical activity |
| To promote weight loss | Sets ideal weight targets but does not address how to achieve them | Recommends intensive counseling and behavioral interventions+ to promote sustained weight loss for obese adults Insufficient evidence to recommend for or against the use of moderate (monthly) or low-intensity (less than once a month) counseling together with behavioral interventions to promote sustained weight loss in obese adults Insufficient evidence to recommend for or against the use of counseling of any intensity and behavioral interventions to promote sustained weight loss in overweight adults |
| Tobacco use | Recommends smoking prevention and cessation advice and assistance, including nicotine replacement, pharmacotherapy, and formal smoking cessation programs | Recommends tobacco cessation interventions for those who use tobacco products |
| Risk reduction interventions | ||
| Aspirin | Recommends the use of aspirin in women with CHD unless it is contraindicated Says use of aspirin is reasonable in women with diabetes, unless it is contraindicated If aspirin is indicated but not tolerated, clopidogrel should be substituted. Aspirin may be reasonable for women <65 years for stroke prevention, but is not recommended for MI prevention. Aspirin can be useful for women >65 years if BP is controlled; benefit for stroke and MI prevention is likely to outweigh risk of GI bleeding and hemorrhagic stroke | Recommends the use of aspirin for women ages 55 to 79 years when the potential benefit of a reduction in ischemic stroke outweighs the potential harm of an increased risk of GI hemorrhage Insufficient evidence to assess aspirin for cardiovascular disease prevention in women ≥80 years Recommends against the use of aspirin for stroke prevention in women ≤55 years |
| Beta-carotene | Should not be used for prevention of CVD | Recommends against the use of beta-carotene supplements, either alone or in combination, for the prevention of cancer or cardiovascular disease |
| Antioxidants and vitamins | Vitamins E, C, B6, B12, and folic acid should not be used for CVD prevention. | Insufficient evidence to recommend for or against the use of supplements of vitamins A, C, or E; multivitamins with folic acid; or antioxidant combinations for the prevention of cancer or cardiovascular disease |
| Hormonal therapy | Hormone therapy and selective estrogen-receptor modulators should not be used for CVD prevention. | Recommends against the routine use of combined estrogen and progestin for the prevention of chronic conditions in postmenopausal women Recommends against the routine use of unopposed estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy |
| †;Defined by the USPSTF as >1 individual or group session per month for ≥3 months. *Nontraditional risk factors included in this recommendation are high-sensitivity C-reactive protein, ankle-brachial index, leukocyte count, fasting blood glucose level, periodontal disease, carotid intima-media thickness, coronary artery calcification score on electron-beam computed tomography, homocysteine level, and lipoprotein(a) level. AHA, American Heart Association; BP, blood pressure; CHD, coronary heart disease; CVD, cardiovascular disease; EBCT, electron-beam computed tomography; EKG, electrocardiography; ETT, exercise treadmill test; GI, gastrointestinal; hs-CRP, high-sensitivity C-reactive protein; MI, myocardial infarction; USPSTF, US Preventive Services Task Force. | ||
The AHA’s assessment of risk
The new guideline update recommends assessing each woman’s CVD risk and placing her into one of 3 risk groups—high risk, at risk, and ideal cardiovascular health (TABLE 3)—then using an algorithm to determine which preventive interventions to recommend based on her risk level.
This classification approach is challenging, for several reasons. It lumps women with markedly different risk profiles into the “at risk” group, a category that will likely apply to a high proportion of women. It also appears to encourage the use of diagnostic tests for subclinical vascular disease, for which there is no evidence of effectiveness. In addition, some of the terms used in the at-risk criteria, such as ”physical inactivity” and “poor diet,” are vague.
TABLE 3
Cardiovascular disease: How the AHA classifies women’s risk5
High risk ≥1 of the following: Documented CVD Diabetes Chronic or end-stage renal disease 10-year predicted risk of CVD ≥10%* |
At risk ≥1 of the following major risk factors: Smoking Hypertension (BP ≥120/80 mm Hg, or treated hypertension) Hyperlipidemia (total cholesterol ≥200 mg/dL, HDL cholesterol <50 mg/dL, or treated dyslipidemia) Obesity Poor diet Physical inactivity Premature CVD in a first-degree relative (<55 years for men and <65 for women) Metabolic syndrome Subclinical atherosclerosis Poor exercise tolerance on a treadmill test Systemic autoimmune disease A history of preeclampsia, gestational diabetes, or PIH |
Ideal cardiovascular health All of the following: Total cholesterol <200 mg/dL, untreated BP <120/80 mm Hg, untreated Fasting blood glucose <100 mg/dL, untreated BMI <25 mm/kg2 Nonsmoking Healthy diet (rich in fruits and vegetables; whole-grain, high-fiber foods; and fish, especially oily fish such as salmon and mackerel, at least twice a week; with limited intake of saturated fat, cholesterol, alcohol, sodium, and sugar; and avoidance of trans-fatty acids) Physical activity (≥150 minutes per week at moderate intensity or ≥75 minutes per week at vigorous intensity) |
| *Calculation tools can be found at http://hp2010.nhlbihin.net/atpiii/calculator.asp (for CHD) and at http://www.westernstroke.org/PersonalStrokeRisk1.xls (for stroke). AHA, American Heart Association; BMI, body mass index; BP, blood pressure; CVD, cardiovascular disease; HDL, high-density lipoprotein, PIH, pregnancy-induced hypertension. |
Some recommendations apply to all women, regardless of risk
The AHA recommendations for all women (TABLE 1) include smoking prevention or cessation, maintenance of optimal weight, regular physical activity, and a diet aimed at preventing CVD. The guidelines also emphasize that major CVD risks should be controlled, with either lifestyle and diet modifications (preferably) or pharmacotherapy. The aggressiveness of control targets depends on the level of risk and the presence of other risk factors.
The guidelines recommend against some interventions that are often used for CVD prevention, based on a high level of evidence that they are ineffective. These include estrogen or selective estrogen receptor modulators, antioxidant vitamins (vitamins E and C, and beta-carotene), folic acid with or without vitamins B6 and B12, and aspirin (for CHD prevention) for healthy women <65 years old.
The AHA does not take a position for or against several diagnostic and risk classification tools because of a lack of evidence of usefulness. These include CVD risk biomarkers such as high sensitivity C-reactive protein and imaging technologies such as coronary calcium scoring assessment.
AHA and USPSTF diverge, but not by much
Screening for conditions that increase CVD risk is not explicitly addressed in the AHA guidelines. Screening is implied by the proposed classification scheme, which includes the presence or absence of smoking, obesity, diabetes, hypertension, and dyslipidemia, but there is no guidance on when to start or stop screening for these conditions. The AHA and the USPSTF diverge on screening women for dyslipidemia, with the USPSTF recommending screening for lipid disorders only in women at increased risk for CHD.
The recommendations for optimal weight and activity levels in the AHA guidelines do not include advice on how to achieve them, nor do they call for an assessment of the effectiveness of behavioral counseling in the clinical setting. Because the USPSTF includes an assessment of, and recommendations for, asymptomatic patients in primary care settings, its recommendations do not address women with conditions such as established CVD, heart failure, or atrial fibrillation—which the AHA guidelines do.
Overall, the AHA and USPSTF agree more than they disagree, and each covers some areas that the other does not (TABLE 2). Family physicians can use the information provided by both entities to ensure that their female patients receive high-quality preventive care that will minimize their risk for CVD.
1. American Heart Association. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18-e209.
2. Mosca L, Grundy SM, Judelson D, et al. Guide to preventive cardiology for women. AHA/ACC scientific statement, consensus panel statement. Circulation. 1999;99:2480-2484.
3. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-693.
4. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481-1501.
5. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011;123:1243-1262.
6. United States Preventive Services Task Force. USPSTF A-Z guide. Available at: www.uspreventiveservicestaskforce.org/uspstopics.htm. Accessed June 7, 2011.
1. American Heart Association. Heart disease and stroke statistics—2011 update: a report from the American Heart Association. Circulation. 2011;123:e18-e209.
2. Mosca L, Grundy SM, Judelson D, et al. Guide to preventive cardiology for women. AHA/ACC scientific statement, consensus panel statement. Circulation. 1999;99:2480-2484.
3. Mosca L, Appel LJ, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation. 2004;109:672-693.
4. Mosca L, Banka CL, Benjamin EJ, et al. Evidence-based guidelines for cardiovascular disease prevention in women: 2007 update. Circulation. 2007;115:1481-1501.
5. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of cardiovascular disease in women—2011 update: a guideline from the American Heart Association. Circulation. 2011;123:1243-1262.
6. United States Preventive Services Task Force. USPSTF A-Z guide. Available at: www.uspreventiveservicestaskforce.org/uspstopics.htm. Accessed June 7, 2011.
Which smoking cessation interventions work best?
NICOTINE REPLACEMENT THERAPY (NRT), bupropion, nortriptyline, clonidine, and varenicline are all effective, although insufficient evidence exists to recommend one intervention over another (SOR: A, systematic reviews).
Effective nonpharmacologic interventions include brief physician advice and more intensive counseling, such as proactive telephone counseling, group and individual counseling, and use of quit lines (SOR: A, systematic reviews).
Evidence summary
NRT. A Cochrane review of 111 randomized controlled trials (RCTs) with a total of >40,000 subjects evaluated abstinence rates after 6 months of NRT and placebo or no treatment.1 All forms of NRT increased abstinence vs placebo or no treatment, independent of setting, duration of treatment, and intensity of nonpharmacologic therapies. Overlapping confidence intervals suggested that no one form of NRT was superior. (The TABLE summarizes all the studies discussed here.)
Bupropion. A Cochrane review of 36 RCTs (N=11,140) showed higher abstinence rates with bupropion than placebo after ≥6 months of follow-up (average quit rate 17% vs 9%). Duration (6 vs 12 months) and intensity (150 vs 300 mg) of therapy didn’t influence the results.2 Six separate RCTs comparing bupropion plus NRT with NRT alone showed significant heterogeneity, but found no significant differences using a mixed-effects model.2
Nortriptyline. A Cochrane review that pooled results from 6 RCTs (N=975) showed superior 6-month abstinence rates for nortriptyline compared with placebo.2 Adding nicotine patches in other RCTs (N=1219) didn’t change abstinence rates.2 No long-term studies have examined other tricyclic antidepressants.
Clonidine. A pooled analysis of 6 RCTs found clonidine superior to placebo after ≥12 weeks of follow-up.3 Results were heavily influenced by one trial limited to heavy smokers and poor tolerability due to adverse effects of therapy, especially sedation and dry mouth.
Nicotine receptor partial agonists and antagonists. Standard dose varenicline was more than twice as likely as placebo to produce abstinence at 6 months in a Cochrane review of 10 RCTs.4 Lower doses were slightly less effective, but had fewer side effects. Adverse effects included mild to moderate nausea and sleep disorders; causation has not been established between varenicline and rare postmarketing reports of severe psychiatric disturbances.4,5
The pooled results of 3 RCTs suggested that varenicline was superior to bupropion, but different abstinence rates for bupropion users in other placebo-controlled trials necessitate caution in interpreting these results.4 Varenicline was not superior to NRT.4
One RCT (N=48) comparing nicotine patches plus the nicotine antagonist mecamylamine with patches plus placebo found improved abstinence rates at 6 and 12 months; a larger RCT didn’t support these findings.6
Table
How effective are smoking cessation interventions?
| Intervention | No. of studies | Effect size* (95% confidence interval) | Total N |
|---|---|---|---|
| NRT vs placebo or no treatment1 | 111 | 1.58 (1.50-1.66) | >40,000 |
| Bupropion vs placebo2 | 36 | 1.69 (1.53-1.85) | 11,140 |
| Bupropion 300 mg/d vs 150 mg/d2 | 3 | 1.08 (0.93-1.26) | 2042 |
| Bupropion + NRT vs NRT2 | 6 | 1.23 (0.67-2.26) | 1106 |
| Nortriptyline vs placebo2 | 6 | 2.03 (1.48-2.78) | 975 |
| Nortriptyline + NRT vs NRT2 | 4 | 1.29 (0.97-1.72) | 1219 |
| Clonidine vs placebo3 | 6 | 1.63 (1.22-2.18) | 776 |
| Varenicline vs placebo, standard dose4 Varenicline vs placebo, low dose4 Varenicline vs bupropion4 Varenicline vs NRT4 | 10 4 3 2 | 2.31 (2.01-2.66) 2.09 (1.56-2.78) 1.52 (1.22-1.88) 1.13 (0.94-1.35) | 4443 1272 1622 778 |
| Mecamylamine + NRT vs NRT+ placebo6 | 1 | 37.5% vs 12.5% | 48 |
| Simple advice vs usual care10-13 | 17 | 1.66 (1.42-1.94) | 15,930 |
| Patient-initiated telephone quit line vs usual care14 | 9 | 1.37 (1.26-1.50) | 24,000 |
| NRT, nicotine replacement therapy. *An effect size >1.0 means that patients using this intervention are more likely not to smoke at 6 to 12 months; larger numbers correlate with greater effectiveness | |||
These interventions are not supported
A review of placebo-controlled RCTs found no evidence of improved abstinence at 6 to 12 months with fluoxetine, paroxetine, sertraline, venlafaxine, citalopram, or monoamine oxidase inhibitors, alone or as adjuncts to NRT.2
No good evidence supports using anxiolytics, silver acetate, Nicobrevin (a nicotine-free smoking cessation aid), lobeline, or naltrexone for smoking cessation.7-9
Simple advice and quit lines help
A Cochrane review of 17 RCTs found that simple advice improved quit rates and maintenance of abstinence at 12 months.10-13
A review of 9 RCTs (N>24,000). found that telephone quit lines increased abstinence, particularly after more than 2 sessions.14
No high-quality studies demonstrate the effectiveness of acupuncture, hypnotherapy, or acupressure for smoking cessation.15,16
Recommendations
The Agency for Health Care Research and Quality recommends counseling (including individual, group, and telephone sessions and brief physician advice) in addition to sustained-release bupropion, NRT, and varenicline as first-line agents. It considers clonidine and nortriptyline second-line therapies.17
1. Silagy C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000146.-
2. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2010;(4):CD000031.-
3. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000058.-
4. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.-
5. Product Information for Chantix. New York, NY: Pfizer; 2006.
6. Lancaster T, Stead LF. Mecamylamine for smoking cessation. Cochrane Database Syst Rev. 2009;(1):CD001009.-
7. Hughes JR, Stead LF, Lancaster T. Anxiolytics for smoking cessation. Cochrane Database Syst Rev. 2010;(1):CD002849.-
8. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD000191.-
9. David S, Lancaster T, Stead LF, et al. Opioid antagonists for smoking cessation. Cochrane Database Syst Rev. 2009;(4):CD003086.-
10. Lancaster T, Stead LF. Self-help interventions for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001118.-
11. Lancaster T, Stead LF. Physician advice for smoking cessation. Cochrane Database Syst Rev 2008;(2):CD000165.-
12. Lancaster T, Stead LF. Individual behavioral counseling for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD001292.-
13. Stead LF, Lancaster T. Group behavior therapy programs for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001007.-
14. Stead LF, Perera R, Lancaster T. Telephone counseling for smoking cessation. Cochrane Database Syst Rev. 2009;(3):CD002850.-
15. White AR, Rampes H, Campbell JL. Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD000009.-
16. Abbot NC, Stead LF, White AR, et al. Hypnotherapy for smoking cessation. Cochrane Database Syst Rev. 2010;(10):CD001008.-
17. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Rockville, MD: US Department of Health and Human Services, Public Health Service; May 2008.
NICOTINE REPLACEMENT THERAPY (NRT), bupropion, nortriptyline, clonidine, and varenicline are all effective, although insufficient evidence exists to recommend one intervention over another (SOR: A, systematic reviews).
Effective nonpharmacologic interventions include brief physician advice and more intensive counseling, such as proactive telephone counseling, group and individual counseling, and use of quit lines (SOR: A, systematic reviews).
Evidence summary
NRT. A Cochrane review of 111 randomized controlled trials (RCTs) with a total of >40,000 subjects evaluated abstinence rates after 6 months of NRT and placebo or no treatment.1 All forms of NRT increased abstinence vs placebo or no treatment, independent of setting, duration of treatment, and intensity of nonpharmacologic therapies. Overlapping confidence intervals suggested that no one form of NRT was superior. (The TABLE summarizes all the studies discussed here.)
Bupropion. A Cochrane review of 36 RCTs (N=11,140) showed higher abstinence rates with bupropion than placebo after ≥6 months of follow-up (average quit rate 17% vs 9%). Duration (6 vs 12 months) and intensity (150 vs 300 mg) of therapy didn’t influence the results.2 Six separate RCTs comparing bupropion plus NRT with NRT alone showed significant heterogeneity, but found no significant differences using a mixed-effects model.2
Nortriptyline. A Cochrane review that pooled results from 6 RCTs (N=975) showed superior 6-month abstinence rates for nortriptyline compared with placebo.2 Adding nicotine patches in other RCTs (N=1219) didn’t change abstinence rates.2 No long-term studies have examined other tricyclic antidepressants.
Clonidine. A pooled analysis of 6 RCTs found clonidine superior to placebo after ≥12 weeks of follow-up.3 Results were heavily influenced by one trial limited to heavy smokers and poor tolerability due to adverse effects of therapy, especially sedation and dry mouth.
Nicotine receptor partial agonists and antagonists. Standard dose varenicline was more than twice as likely as placebo to produce abstinence at 6 months in a Cochrane review of 10 RCTs.4 Lower doses were slightly less effective, but had fewer side effects. Adverse effects included mild to moderate nausea and sleep disorders; causation has not been established between varenicline and rare postmarketing reports of severe psychiatric disturbances.4,5
The pooled results of 3 RCTs suggested that varenicline was superior to bupropion, but different abstinence rates for bupropion users in other placebo-controlled trials necessitate caution in interpreting these results.4 Varenicline was not superior to NRT.4
One RCT (N=48) comparing nicotine patches plus the nicotine antagonist mecamylamine with patches plus placebo found improved abstinence rates at 6 and 12 months; a larger RCT didn’t support these findings.6
Table
How effective are smoking cessation interventions?
| Intervention | No. of studies | Effect size* (95% confidence interval) | Total N |
|---|---|---|---|
| NRT vs placebo or no treatment1 | 111 | 1.58 (1.50-1.66) | >40,000 |
| Bupropion vs placebo2 | 36 | 1.69 (1.53-1.85) | 11,140 |
| Bupropion 300 mg/d vs 150 mg/d2 | 3 | 1.08 (0.93-1.26) | 2042 |
| Bupropion + NRT vs NRT2 | 6 | 1.23 (0.67-2.26) | 1106 |
| Nortriptyline vs placebo2 | 6 | 2.03 (1.48-2.78) | 975 |
| Nortriptyline + NRT vs NRT2 | 4 | 1.29 (0.97-1.72) | 1219 |
| Clonidine vs placebo3 | 6 | 1.63 (1.22-2.18) | 776 |
| Varenicline vs placebo, standard dose4 Varenicline vs placebo, low dose4 Varenicline vs bupropion4 Varenicline vs NRT4 | 10 4 3 2 | 2.31 (2.01-2.66) 2.09 (1.56-2.78) 1.52 (1.22-1.88) 1.13 (0.94-1.35) | 4443 1272 1622 778 |
| Mecamylamine + NRT vs NRT+ placebo6 | 1 | 37.5% vs 12.5% | 48 |
| Simple advice vs usual care10-13 | 17 | 1.66 (1.42-1.94) | 15,930 |
| Patient-initiated telephone quit line vs usual care14 | 9 | 1.37 (1.26-1.50) | 24,000 |
| NRT, nicotine replacement therapy. *An effect size >1.0 means that patients using this intervention are more likely not to smoke at 6 to 12 months; larger numbers correlate with greater effectiveness | |||
These interventions are not supported
A review of placebo-controlled RCTs found no evidence of improved abstinence at 6 to 12 months with fluoxetine, paroxetine, sertraline, venlafaxine, citalopram, or monoamine oxidase inhibitors, alone or as adjuncts to NRT.2
No good evidence supports using anxiolytics, silver acetate, Nicobrevin (a nicotine-free smoking cessation aid), lobeline, or naltrexone for smoking cessation.7-9
Simple advice and quit lines help
A Cochrane review of 17 RCTs found that simple advice improved quit rates and maintenance of abstinence at 12 months.10-13
A review of 9 RCTs (N>24,000). found that telephone quit lines increased abstinence, particularly after more than 2 sessions.14
No high-quality studies demonstrate the effectiveness of acupuncture, hypnotherapy, or acupressure for smoking cessation.15,16
Recommendations
The Agency for Health Care Research and Quality recommends counseling (including individual, group, and telephone sessions and brief physician advice) in addition to sustained-release bupropion, NRT, and varenicline as first-line agents. It considers clonidine and nortriptyline second-line therapies.17
NICOTINE REPLACEMENT THERAPY (NRT), bupropion, nortriptyline, clonidine, and varenicline are all effective, although insufficient evidence exists to recommend one intervention over another (SOR: A, systematic reviews).
Effective nonpharmacologic interventions include brief physician advice and more intensive counseling, such as proactive telephone counseling, group and individual counseling, and use of quit lines (SOR: A, systematic reviews).
Evidence summary
NRT. A Cochrane review of 111 randomized controlled trials (RCTs) with a total of >40,000 subjects evaluated abstinence rates after 6 months of NRT and placebo or no treatment.1 All forms of NRT increased abstinence vs placebo or no treatment, independent of setting, duration of treatment, and intensity of nonpharmacologic therapies. Overlapping confidence intervals suggested that no one form of NRT was superior. (The TABLE summarizes all the studies discussed here.)
Bupropion. A Cochrane review of 36 RCTs (N=11,140) showed higher abstinence rates with bupropion than placebo after ≥6 months of follow-up (average quit rate 17% vs 9%). Duration (6 vs 12 months) and intensity (150 vs 300 mg) of therapy didn’t influence the results.2 Six separate RCTs comparing bupropion plus NRT with NRT alone showed significant heterogeneity, but found no significant differences using a mixed-effects model.2
Nortriptyline. A Cochrane review that pooled results from 6 RCTs (N=975) showed superior 6-month abstinence rates for nortriptyline compared with placebo.2 Adding nicotine patches in other RCTs (N=1219) didn’t change abstinence rates.2 No long-term studies have examined other tricyclic antidepressants.
Clonidine. A pooled analysis of 6 RCTs found clonidine superior to placebo after ≥12 weeks of follow-up.3 Results were heavily influenced by one trial limited to heavy smokers and poor tolerability due to adverse effects of therapy, especially sedation and dry mouth.
Nicotine receptor partial agonists and antagonists. Standard dose varenicline was more than twice as likely as placebo to produce abstinence at 6 months in a Cochrane review of 10 RCTs.4 Lower doses were slightly less effective, but had fewer side effects. Adverse effects included mild to moderate nausea and sleep disorders; causation has not been established between varenicline and rare postmarketing reports of severe psychiatric disturbances.4,5
The pooled results of 3 RCTs suggested that varenicline was superior to bupropion, but different abstinence rates for bupropion users in other placebo-controlled trials necessitate caution in interpreting these results.4 Varenicline was not superior to NRT.4
One RCT (N=48) comparing nicotine patches plus the nicotine antagonist mecamylamine with patches plus placebo found improved abstinence rates at 6 and 12 months; a larger RCT didn’t support these findings.6
Table
How effective are smoking cessation interventions?
| Intervention | No. of studies | Effect size* (95% confidence interval) | Total N |
|---|---|---|---|
| NRT vs placebo or no treatment1 | 111 | 1.58 (1.50-1.66) | >40,000 |
| Bupropion vs placebo2 | 36 | 1.69 (1.53-1.85) | 11,140 |
| Bupropion 300 mg/d vs 150 mg/d2 | 3 | 1.08 (0.93-1.26) | 2042 |
| Bupropion + NRT vs NRT2 | 6 | 1.23 (0.67-2.26) | 1106 |
| Nortriptyline vs placebo2 | 6 | 2.03 (1.48-2.78) | 975 |
| Nortriptyline + NRT vs NRT2 | 4 | 1.29 (0.97-1.72) | 1219 |
| Clonidine vs placebo3 | 6 | 1.63 (1.22-2.18) | 776 |
| Varenicline vs placebo, standard dose4 Varenicline vs placebo, low dose4 Varenicline vs bupropion4 Varenicline vs NRT4 | 10 4 3 2 | 2.31 (2.01-2.66) 2.09 (1.56-2.78) 1.52 (1.22-1.88) 1.13 (0.94-1.35) | 4443 1272 1622 778 |
| Mecamylamine + NRT vs NRT+ placebo6 | 1 | 37.5% vs 12.5% | 48 |
| Simple advice vs usual care10-13 | 17 | 1.66 (1.42-1.94) | 15,930 |
| Patient-initiated telephone quit line vs usual care14 | 9 | 1.37 (1.26-1.50) | 24,000 |
| NRT, nicotine replacement therapy. *An effect size >1.0 means that patients using this intervention are more likely not to smoke at 6 to 12 months; larger numbers correlate with greater effectiveness | |||
These interventions are not supported
A review of placebo-controlled RCTs found no evidence of improved abstinence at 6 to 12 months with fluoxetine, paroxetine, sertraline, venlafaxine, citalopram, or monoamine oxidase inhibitors, alone or as adjuncts to NRT.2
No good evidence supports using anxiolytics, silver acetate, Nicobrevin (a nicotine-free smoking cessation aid), lobeline, or naltrexone for smoking cessation.7-9
Simple advice and quit lines help
A Cochrane review of 17 RCTs found that simple advice improved quit rates and maintenance of abstinence at 12 months.10-13
A review of 9 RCTs (N>24,000). found that telephone quit lines increased abstinence, particularly after more than 2 sessions.14
No high-quality studies demonstrate the effectiveness of acupuncture, hypnotherapy, or acupressure for smoking cessation.15,16
Recommendations
The Agency for Health Care Research and Quality recommends counseling (including individual, group, and telephone sessions and brief physician advice) in addition to sustained-release bupropion, NRT, and varenicline as first-line agents. It considers clonidine and nortriptyline second-line therapies.17
1. Silagy C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000146.-
2. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2010;(4):CD000031.-
3. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000058.-
4. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.-
5. Product Information for Chantix. New York, NY: Pfizer; 2006.
6. Lancaster T, Stead LF. Mecamylamine for smoking cessation. Cochrane Database Syst Rev. 2009;(1):CD001009.-
7. Hughes JR, Stead LF, Lancaster T. Anxiolytics for smoking cessation. Cochrane Database Syst Rev. 2010;(1):CD002849.-
8. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD000191.-
9. David S, Lancaster T, Stead LF, et al. Opioid antagonists for smoking cessation. Cochrane Database Syst Rev. 2009;(4):CD003086.-
10. Lancaster T, Stead LF. Self-help interventions for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001118.-
11. Lancaster T, Stead LF. Physician advice for smoking cessation. Cochrane Database Syst Rev 2008;(2):CD000165.-
12. Lancaster T, Stead LF. Individual behavioral counseling for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD001292.-
13. Stead LF, Lancaster T. Group behavior therapy programs for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001007.-
14. Stead LF, Perera R, Lancaster T. Telephone counseling for smoking cessation. Cochrane Database Syst Rev. 2009;(3):CD002850.-
15. White AR, Rampes H, Campbell JL. Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD000009.-
16. Abbot NC, Stead LF, White AR, et al. Hypnotherapy for smoking cessation. Cochrane Database Syst Rev. 2010;(10):CD001008.-
17. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Rockville, MD: US Department of Health and Human Services, Public Health Service; May 2008.
1. Silagy C, et al. Nicotine replacement therapy for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000146.-
2. Hughes JR, Stead LF, Lancaster T. Antidepressants for smoking cessation. Cochrane Database Syst Rev. 2010;(4):CD000031.-
3. Gourlay SG, Stead LF, Benowitz NL. Clonidine for smoking cessation. Cochrane Database Syst Rev. 2008;(3):CD000058.-
4. Cahill K, Stead LF, Lancaster T. Nicotine receptor partial agonists for smoking cessation. Cochrane Database Syst Rev. 2011;(2):CD006103.-
5. Product Information for Chantix. New York, NY: Pfizer; 2006.
6. Lancaster T, Stead LF. Mecamylamine for smoking cessation. Cochrane Database Syst Rev. 2009;(1):CD001009.-
7. Hughes JR, Stead LF, Lancaster T. Anxiolytics for smoking cessation. Cochrane Database Syst Rev. 2010;(1):CD002849.-
8. Lancaster T, Stead LF. Silver acetate for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD000191.-
9. David S, Lancaster T, Stead LF, et al. Opioid antagonists for smoking cessation. Cochrane Database Syst Rev. 2009;(4):CD003086.-
10. Lancaster T, Stead LF. Self-help interventions for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001118.-
11. Lancaster T, Stead LF. Physician advice for smoking cessation. Cochrane Database Syst Rev 2008;(2):CD000165.-
12. Lancaster T, Stead LF. Individual behavioral counseling for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD001292.-
13. Stead LF, Lancaster T. Group behavior therapy programs for smoking cessation. Cochrane Database Syst Rev. 2009;(2):CD001007.-
14. Stead LF, Perera R, Lancaster T. Telephone counseling for smoking cessation. Cochrane Database Syst Rev. 2009;(3):CD002850.-
15. White AR, Rampes H, Campbell JL. Acupuncture and related interventions for smoking cessation. Cochrane Database Syst Rev. 2008;(4):CD000009.-
16. Abbot NC, Stead LF, White AR, et al. Hypnotherapy for smoking cessation. Cochrane Database Syst Rev. 2010;(10):CD001008.-
17. Fiore MC, Jaén CR, Baker TB, et al. Treating Tobacco Use and Dependence: 2008 Update. Rockville, MD: US Department of Health and Human Services, Public Health Service; May 2008.
Evidence-based answers from the Family Physicians Inquiries Network