eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Vitamin B-12 Associated Neurological Diseases

Author: Niranjan N Singh, MD, DNB, Fellow in Neurophysiology, Department of Neurology, St Louis University School of Medicine
Coauthor(s): Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Associate Program Director, Associate Professor, Departments of Neurology, Molecular Virology, and Molecular Microbiology and Immunology, St Louis University School of Medicine; Alan L Diamond, DO, Movement Disorder Fellow, Department of Neurology, Baylor College of Medicine; René Diamond, DO, Resident, Internal Medicine, Saint Louis University School of Medicine
Contributor Information and Disclosures

Updated: Jan 29, 2008

Introduction

Background

The association of anemia and gastrointestinal and neurologic abnormalities referable to the brain, spinal cord, and peripheral nerves has been recognized in several clinical and postmortem case reports and series by Combe, Addison, and Fenwick since the early 19th century. In 1877, Gardner and Osler coined the term pernicious anemia (PA) to describe a patient with progressive arm numbness and difficulty with buttoning and using tools.1 Liechtenstein in 1884 reported the association of PA and spinal cord disease but attributed both to tabes dorsalis.2 Lichtheim in 18873 and Minnich in 18924 recognized the histologic differences in the spinal cord between PA and tabes dorsalis.

In 1900, Russell et al coined the term subacute combined degeneration of the spinal cord.5 In 1926, Minot and Murphy fed PA patients a half-pound of calf liver daily, for which they received the Nobel Prize.6 In 1929, Castle distinguished the role of gastric (intrinsic) and dietary (extrinsic) factors in PA.7 In 1948, cyanocobalamin was isolated from the liver. The existence of vitamin B-12 deficiency neuropathy was recognized in 1958. In 1955, Lassen et al8 noted megaloblastic anemia secondary to prolonged nitrous oxide (N2 O) exposure; the neurologic features were described in 1978 by Sahenk et al9 and Layzer et al10 .

Pathophysiology

Vitamin B-12 structure

Vitamin B-12 (cobalamin) is a complex molecule in which a cobalt atom is contained in a corrin ring. Vitamin B-12 is available in animal protein.

Body stores

Total body stores are 2-5 mg, of which half is stored in the liver. The recommended daily intake is 2 mcg/d in adults; pregnant and lactating women require 2.6 mcg/d. Children require 0.7 mcg/d and, in adolescence, 2 mcg/d. Because vitamin B-12 is highly conserved through the enterohepatic circulation, cobalamin deficiency from malabsorption develops after 2-5 years and deficiency from dietary inadequacy in vegetarians develops after 10-20 years. Its causes are mainly nutritional and malabsorptive, PA being most common.

Physiology of absorption

After ingestion, the low stomach pH cleaves cobalamin from other dietary protein. The free cobalamin binds to gastric R binder, a glycoprotein in saliva, and the complex travels to the duodenum and jejunum, where pancreatic peptidases digest the complex and release cobalamin. Free cobalamin can then bind with gastric intrinsic factor (IF), a 50-kd glycoprotein produced by the gastric parietal cells, the secretion of which parallels that of hydrochloric acid. Hence, in states of achlorhydria, IF secretion is reduced, leading to cobalamin deficiency. Importantly, only 99% of ingested cobalamin requires IF for absorption. Up to 1% of free cobalamin is absorbed passively in the terminal ileum. This why oral replacement with large vitamin B-12 doses is appropriate for PA.

Once bound with IF, vitamin B-12 is resistant to further digestion. The complex travels to the distal ileum and binds to a specific mucosal brush border receptor, cublin, which facilitates the internalization of cobalamin-IF complex in an energy-dependent process. Once internalized, IF is removed and cobalamin is transferred to other transport proteins, transcobalamin I, II, and III (TCI, TCII, TCIII). Eighty percent of cobalamin is bound to TCI/III, whose role in cobalamin metabolism is unknown. The other 20% binds with TCII, the physiologic transport protein produced by endothelial cells. Its half-life is 6-9 min, thus delivery to target tissues is rapid.

The cobalamin-TCII complex is secreted into the portal blood where it is taken up mainly in the liver and bone marrow as well as other tissues. Once in the cytoplasm, cobalamin is liberated from the complex by lysosomal degradation. An enzyme-mediated reduction of the cobalt occurs by cytoplasmic methylation to form methylcobalamin or by mitochondrial adenosylation to form adenosylcobalamin, the 2 metabolically active forms of cobalamin.

Vitamin B-12 role in bone marrow function

In the cytoplasm, methylcobalamin (see Media file 1) serves as cofactor for methionine synthesis by allowing transfer of a methyl group from 5-methyl-tetrahydrofolate (5-methyl-THF) to homocysteine (HC), forming methionine and demethylated tetrahydrofolate (THF). This results in reduction in serum homocysteine, which appears to be toxic to endothelial cells. Methionine is further metabolized to S-adenosylmethionine (SAM).

THF is used for DNA synthesis. After conversion to its polyglutamate form, THF participates in purine synthesis and the conversion of deoxyuridylate (dUTP) to deoxythymidine monophosphate (dTMP), which is then phosphorylated to deoxythymidine triphosphate (dTTP). dTTP is required for DNA synthesis; therefore, in vitamin B-12 deficiency, formation of dTTP and accumulation of 5-methyl-THF is inadequate, trapping folate in its unusable form and leading to retarded DNA synthesis. RNA contains dUTP (deoxyuracil triphosphate) instead of dTTP, allowing for protein synthesis to proceed uninterrupted and resulting in macrocytosis and cytonuclear dissociation.

Because folate deficiency causes macrocytosis and cytonuclear dissociation via the same mechanisms, both deficiencies lead to megaloblastic anemia and disordered maturation in granulocytic lineages; therefore, folate supplementation can reverse the hematologic abnormalities of vitamin B-12 deficiency but has no impact on the neurologic abnormalities of vitamin B-12 deficiency, indicating both result from different mechanisms.

Vitamin B-12 role in the peripheral and central nervous systems

The neurologic manifestation of cobalamin deficiency is less well understood. CNS demyelination may play a role, but how cobalamin deficiency leads to demyelination remains unclear. Reduced SAM or elevated methylmalonic acid (MMA) may be involved.

SAM is required as the methyl donor in polyamine synthesis and transmethylation reactions. Methylation reactions are needed for myelin maintenance and synthesis. SAM deficiency results in abnormal methylated phospholipids such as phosphatidylcholine, and it is linked to central myelin defects and abnormal neuronal conduction, which may account for the encephalopathy and myelopathy. In addition, SAM influences serotonin, norepinephrine, and dopamine synthesis. This suggests that, in addition to structural consequences of vitamin B-12 deficiency, functional effects on neurotransmitter synthesis that may be relevant to mental status changes may occur. Parenthetically, SAM is being studied as a potential antidepressant.

Another possible cause of neurologic manifestations involves the other metabolically active form of cobalamin, adenosylcobalamin (see Media file 2), a mitochondrial cofactor in the conversion of L-methylmalonyl CoA to succinyl CoA. Vitamin B-12 deficiency leads to an increase in L-methylmalonyl-CoA, which is converted to D-methylmalonyl CoA and hydrolyzed to MMA. Elevated MMA results in abnormal odd chain and branched chain fatty acids with subsequent abnormal myelination, possibly leading to defective nerve transmission.

More recent studies propose a very different paradigm: B-12 and its deficiency impact a network of cytokines and growth factors, ie, brain, spinal cord, and CSF TNF-alpha; nerve growth factor (NGF), IL-6 and epidermal growth factor (EGF), some of which are neurotrophic, others neurotoxic. Vitamin B-12 regulates IL-6 levels in rodent CSF. In rodent models of B-12 deficiency parenteral EGF or anti-NGF antibody injection prevents, like B-12 itself, the SCD-like lesions.

In the same models, the mRNAs of several cell-type specific proteins (glial fibrillary acidic protein, myelin basic protein) are decreased in a region specific manner in the CNS, but, in the PNS myelin, protein zero and peripheral myelin protein 22 mRNA remain unaltered.

In human and rodent serum and CSF, concomitantly with a vitamin B-12 decrease, EGF levels are decreased, while at the same time, TNF-alpha increases in step with homocysteine levels. These observations provide evidence that the clinical and histological changes of vitamin B-12 deficiency may result from up-regulation of neurotoxic cytokines and down-regulation of neurotrophic factors.

N2 O pathomechanisms in vitamin B-12 deficiency

N2 O can oxidize the cobalt core of vitamin B-12 from a 1+ to 3+ valance state, rendering methylcobalamin inactive, inhibiting HC conversion to methionine and depleting the supply of SAM. Patients with sufficient vitamin B-12 body stores can maintain cellular functions after N2 O exposure, but in patients with borderline or low vitamin B-12 stores, this oxidation may be sufficient to precipitate clinical manifestations.

Frequency

United States

The prevalence of vitamin B-12 deficiency is difficult to ascertain because of diverse etiologies and different assays, ie, radioassay or chemiluminescence. Affected individuals may number 300,000 to 3 million in the United States.

Using the radioassay and a value less than 200 pg/mL, the prevalence of vitamin B-12 deficiency is 3-16%. In a geriatric population using a radioassay cutoff of 300 pg/mL and elevated HC and MMA levels, a prevalence of 21% was reported.

Of HIV-seropositive individuals, 11% are vitamin B-12 deficient; another 12% have levels of 200-240 pg/mL. In a subgroup with chronic diarrhea, the rate reaches 39%. However, the importance for vitamin B-12 deficiency in the development of neurologic disease in these patients remains unclear.

International

In Europe, the prevalence of vitamin B-12 deficiency is 1.6-10%.

In India, a hospital population radioassay study with a cutoff of 200 pg/mL found a vitamin B-12 deficiency in 0.88% of patients, with borderline values in 3.8%.

Mortality/Morbidity

  • Vitamin B-12 deficiency is associated with an elevated HC.
  • The prevalence of hyperhomocysteinemia in the general population is 5-10%; in people older than 65 years it may reach 30-40%. Elevated HC is a risk factor for coronary artery, cerebrovascular, and peripheral vascular diseases and venous thrombosis. About 10% of the vascular disease risk in the general population is linked to HC.
  • Case-control studies have reported a correlation between multi-infarct dementia or dementia of the Alzheimer type and elevated HC; vitamin B-12 supplementation had no clinical benefit.
  • Neural tube defects are associated with low folate and vitamin B-12.
  • PA patients have a 3 times and 13 times increased risk of gastric carcinoma and gastric carcinoid tumors, respectively.
  • Patients with diabetes mellitus type 1 and autoimmune thyroid diseases are at higher risk of developing PA.
  • Multifactorial abnormalities of vitamin B-12 metabolism and absorption occur in HIV infection.

Race

  • PA prevalence may be higher in white people and lower in Hispanic and black people.
  • No known relationship exists between neurologic symptoms and race.
  • Studies in Africa and the United States have shown higher vitamin B-12 and transcobalamin II levels in black than in white individuals. Additionally, blacks have lower HC levels and metabolize it more efficiently than whites.

Sex

  • In Europe and Africa, the prevalence of PA is higher in elderly women than men (1.5:1), while in the United States no differences exist.
  • Men have higher HC levels at all ages.
  • Pregnancy and estrogen replacement in postmenopausal women lower HC levels.

Age

  • PA occurs in people of all ages, but it is more common in people older than 40-70 years and, in particular, in people older than 65 years.
  • In white people, the mean age of onset is 60; in black people, the mean age is 50 years.
  • Congenital PA manifests in children aged 9 months to 10 years; the mean age is 2 years.

Clinical

History

Clinical course

The neurologic features are attributable to pathology in the peripheral and optic nerves, posterior and lateral columns of the spinal cord (subacute combined degeneration), and in the brain. Interestingly, hematologic and neurologic manifestations are occasionally dissociated. An inverse correlation in the severity of both manifestations has been suggested. In patients with neuropsychiatric abnormalities, 28% lack anemia or macrocytosis.

Clinical manifestations due to vitamin B-12 deficiency are unrelated to etiology. In a prospective comparative study between antiparietal cell antibody positive and negative patients, no significant difference was shown in clinical, electrodiagnostic, and radiological features.11

Although the clinical features of vitamin B-12 deficiency may consist of a classic triad of weakness, sore tongue, and paresthesias, these are not usually the chief symptoms.

Onset is subacute or gradual, although more acute courses have been described, in particular after N 2 O exposure. In 1986, Schilling described 2 patients with unrecognized vitamin B-12 deficiency who developed paresthesias and poor manual dexterity 1-3 months after brief N 2 O exposure.102 In 1995, Kinsella and Green described a 70-year-old man with paresthesias and hand clumsiness after 2 exposures to N 2 O over 3 months.12

Onset is often with a sensation of cold, numbness, or tightness in the tips of the toes and then in the fingertips, rarely with lancinating pains. Simultaneous involvement of arms and legs is uncommon, and onset in the arms is even rarer.

Paresthesias are ascending and occasionally involve the trunk, leading to a sensation of constriction in the abdomen and chest.

Untreated patients may develop limb weakness and ataxia.

In 1991, Healton et al performed detailed neurologic evaluations of 143 patients with vitamin B-12 deficiency; 74% presented with neurologic symptoms.13

  • Isolated numbness or paresthesias were present in 33%.
  • Gait abnormalities occurred in 12%.
  • Psychiatric or cognitive symptoms were noted in 3%.
  • Visual symptoms were reported in 0.5%. Symptoms include subacute progressive decrease in visual acuity, usually caused by bilateral optic neuropathy and rarely pseudotumor cerebri or optic neuritis.
  • Rare autonomic features include orthostasis, sexual dysfunction, and bowel and bladder incontinence.
  • Other symptoms include lightheadedness and impaired taste and smell.
  • Asymptomatic neurologic manifestations can be detected using somatosensory evoked potentials (SSEP); see below.
  • Nonneurologic symptoms, some of which may also reflect autonomic nervous system involvement, were present in 26%.
    • Constitutional symptoms, including anorexia and weight loss occurred in 50%. Low-grade fever that resolves with treatment occurred in 33% of cases. Other symptoms include fatigue and malaise.
    • Cardiovascular symptoms include syncope, dyspnea, orthopnea, palpitations, and angina.
    • Gastrointestinal symptoms include heartburn, flatulence, constipation, diarrhea, sore tongue, and early satiety.

In a prospective study of 57 patients with vitamin B-12 deficiency neurological syndrome, common presenting syndromes included myeloneuropathy (25), myelopathy (14), myeloneuroencephalopathy (13), myeloencephalopathy (4), and behavioral (1).{Ref126}

Physical

Most patients exhibit signs of peripheral nervous system (PNS) or spinal cord involvement, but the extent of PNS involvement remains unclear, in part because both neuropathy and myelopathy can cause impaired vibration sense, ataxia, and paresthesias. Either can be affected first in the early stages. Objective sensory abnormalities usually result from posterior column involvement and less often from PNS disease.

In 1919, Woltmann found features of PNS disease in 4.9% of patients with PA, including distal hyporeflexia or areflexia; 80% of these also had evidence of cord involvement.14

  • In 1991, Healton summarized his experience with a large group of patients as follows:13
    • Isolated neuropathy was reported in 25% of patients.
    • Myelopathy occurred in 12% of cases.
    • A combination of neuropathy and myelopathy was noted in 41%.
    • Neuropsychiatric manifestations, such as recent memory loss with reduced attention span and otherwise normal cognition, depression, hypomania, paranoid psychosis with auditory or visual hallucinations (megaloblastic madness), violent behavior, personality changes, blunted affect, and emotional liability, were reported in 8% of patients.
    • Ocular findings included a cecocentral scotoma and occurred in 0.5% of cases. Others have described optic atrophy, nystagmus, small reactive pupils, and chiasmatic lesion causing bitemporal hemianopia.
    • Normal findings were noted on neurologic examination in 14% of patients despite paresthetic symptoms.
  • Early in the course, poor joint position and vibration sense predominate. Typically, the legs are affected before the arms. Rarely are all limbs affected simultaneously. A Romberg sign is commonly found. The gait may be wide based.
  • On presentation, 50% of patients have absent ankle reflexes with relative hyperreflexia at the knees. Plantars are initially flexor and later extensor. A Hoffman sign may be found.
  • As the disease progresses, ascending loss of pinprick, light touch, and temperature sensation occurs. Later, depending on the predominance of posterior column versus cortical spinal tract involvement, ataxia or spastic paraplegia predominates. Then, PNS involvement causes distal limb atrophy.
  • Cognitive testing may reveal mild impairment or frank dementia.
  • Nonneurologic manifestations include the following:
    • General - Lemon-yellow waxy pallor, premature whitening of hair, flabby bulky frame, mild icterus, and blotchy skin pigmentation in dark-skinned patients
    • Cardiovascular - Tachycardia, congestive heart failure
    • Gastrointestinal - Beefy, red, smooth, and sore tongue with loss of papillae that is more pronounced along edges
  • Abnormal vitamin B-12 metabolism occurs in infants born to vitamin B-12–deficient mothers or those with hereditary diseases, including the Imerslünd-Grasbeck syndrome (cublin mutation resulting in decreased cobalamin transport from the intestinal lumen), transcobalamin II deficiency, and intracellular cobalamin abnormalities (classified as Cbl A though G with neurologic features in Cbl C and Cbl D, see below). Symptoms become prominent after exhaustion of vitamin B-12 stores acquired in utero. Infants present with developmental delay, failure to thrive, lethargy, poor feeding, mental retardation, seizures, listlessness, irritability, ataxia, hyporeflexia, hypotonia, pathologic reflexes, coma, tremor, and myoclonus. The latter may worsen transiently upon initiation of treatment.

Causes

Inadequate vitamin B-12 absorption is the major pathomechanism and may result from several factors.

  • Intrinsic factor deficiency
    • PA accounts for 75% of cases of vitamin B-12 deficiency. It is an autoimmune attack on gastric IF. Antibodies are present in 70% of patients. They may block the formation of the cobalamin-IF complex or block its binding with cublin. Other antibodies are directed at parietal cell hydrogen-potassium adenosine triphosphatase (ATPase).
    • Juvenile PA results from inability to secrete IF. Secretion of hydrogen ions and the gastric mucosa are normal. Transmittance is autosomal recessive inheritance of abnormal GIF on chromosome arm 11q13.
    • Destruction of gastric mucosa can occur from gastrectomy or Helicobacter pylori infection. A Turkish study found endoscopic evidence of H pylori infection in more than 50% of vitamin B-12–deficient patients. Antibiotics alone eradicated H pylori in 31 patients, with resolution of vitamin B-12 deficiency.
  • Deficient vitamin B-12 intake: Intake may be inadequate because of strict vegetarianism (rare), breastfeeding of infants by vegan mothers, alcoholism, or following dietary fads.
  • Disorders of terminal ileum: Tropical sprue, celiac disease, enteritis, exudative enteropathy, intestinal resection, Whipple disease, ileal tuberculosis, and cublin gene mutation on chromosome arm 10p12.1 in the region designated MGA 1, which affects binding of the cobalamin-IF complex to intestinal mucosa (Imerslünd-Grasbeck syndrome), are disorders that affect the terminal ileum.
  • Competition for cobalamin: Competition for cobalamin may occur in blind loop syndrome or with fish tapeworm (Diphyllobothrium latum).
  • Abnormalities related to protein digestion related to achlorhydria: Abnormalities include atrophic gastritis, pancreatic deficiency, proton pump inhibitor use, and Zollinger-Ellison syndrome, in which the acidic pH of the distal small intestine does not allow the cobalamin-IF complex to bind with cublin.
  • Medications: Medications include colchicine, neomycin, and p -aminosalicylic acid.
  • Transport protein abnormality: Abnormalities include transcobalamin II deficiency (autosomal recessive inheritance of an abnormal TCN2 gene on chromosome arm 22q11.2-qter resulting in failure to absorb and transport cobalamin) and deficiency of R-binder cobalamin enzyme.
  • Disorders of intracellular cobalamin metabolism: These disorders result in methylmalonic aciduria and homocystinuria in infants.
    • Isolated methylmalonic aciduria
      • Cbl A is due to deficiency of mitochondrial cobalamin reductase resulting in deficiency of adenosylcobalamin.
      • Cbl B is due to deficiency of adenosylcobalamin transferase resulting in deficiency of adenosylcobalamin.
    • Methylmalonic aciduria and homocystinuria
      • Cbl C is a combined deficiency of methylmalonyl CoA mutase and homocysteine:methyltetrahydrofolate methyltransferase. Patients have prominent neurologic features and megaloblastic anemia.
      • Cbl D is a deficiency of cobalamin reductase. Patients have prominent neurologic features.
      • Cbl F is a defect in lysosomal release of cobalamin.
    • Isolated homocystinuria
      • Cbl E is due to a defect in methionine synthase reductase located on chromosome arm 5p15.3-p15.2.
      • Cbl G is due to a defect in methyltetrahydrofolate homocysteine methyltransferase located on chromosome arm 1q43.
  • Increased vitamin B-12 requirement: Requirement is increased in hyperthyroidism and alpha thalassemia.
  • Other causes
    • In AIDS, vitamin B-12 deficiency is not infrequent. Although the exact etiology remains obscure, it is likely a multimodal process involving poor nutrition, chronic diarrhea, ileal dysfunction, and exudative enteropathy. Low vitamin B-12 levels may be more common in late than in early HIV disease.
    • N 2 O exposure can occur iatrogenically (ie, anesthesia) or through abuse ("whippets").

More on Vitamin B-12 Associated Neurological Diseases

Overview: Vitamin B-12 Associated Neurological Diseases
Differential Diagnoses & Workup: Vitamin B-12 Associated Neurological Diseases
Treatment & Medication: Vitamin B-12 Associated Neurological Diseases
Follow-up: Vitamin B-12 Associated Neurological Diseases
Multimedia: Vitamin B-12 Associated Neurological Diseases
References
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Further Reading

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Keywords

vitamin B-12 deficiency, cobalamin deficiency, subacute combined spinal degeneration, pernicious anemia, PA, vitamin B-12 associated neurologic diseases, vitamin B-12 associated neurological diseases

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Contributor Information and Disclosures

Author

Niranjan N Singh, MD, DNB, Fellow in Neurophysiology, Department of Neurology, St Louis University School of Medicine
Niranjan N Singh, MD, DNB is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Coauthor(s)

Florian P Thomas, MD, MA, PhD, Drmed, Director, Spinal Cord Injury Unit, St Louis Veterans Affairs Medical Center; Associate Program Director, Associate Professor, Departments of Neurology, Molecular Virology, and Molecular Microbiology and Immunology, St Louis University School of Medicine
Florian P Thomas, MD, MA, PhD, Drmed is a member of the following medical societies: American Academy of Neurology and National Multiple Sclerosis Society
Disclosure: Nothing to disclose.

Alan L Diamond, DO, Movement Disorder Fellow, Department of Neurology, Baylor College of Medicine
Alan L Diamond, DO is a member of the following medical societies: American Academy of Neurology, American Medical Association, American Osteopathic Association, and American Society of Neuroimaging
Disclosure: Nothing to disclose.

René Diamond, DO, Resident, Internal Medicine, Saint Louis University School of Medicine
René Diamond, DO is a member of the following medical societies: American Medical Student Association/Foundation and American Osteopathic Association
Disclosure: Nothing to disclose.

Medical Editor

Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

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Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
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Nestor Galvez-Jimenez, MD, Program Director of Movement Disorders, Department of Neurology, Division of Medicine, Director of Neurology Residency Training Program, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
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