Nutritional Neuropathy

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Background

The first study of the relationship between nutrition and peripheral neuropathy began in the 19th century, when polyneuropathy and heart failure from beriberi reached epidemic proportions. In 1897, Dr. Eijkman cured the disease in pigeons by feeding them the nutrient-rich rice husks that were stripped from the polished rice produced by the grain mills of the time. Most of the work on vitamins goes back to 1900s. The use of thiamin and its disulfide derivatives in particular is often neglected in Western medicine.

Beriberi was described in the 17th century when Brontius reported cases of sensorimotor polyneuropathy in the Dutch East Indies. The mystery ingredient was christened "vitamine" in 1911 and then changed to "thiamine" in 1936 because it is not an amine and the sulfur-containing molecular structure was characterized. Since then, outbreaks of nutritional neuropathy have occurred in World War II prisoner-of-war camps, Jamaican sugar-cane plantations, and Cuba following the collapse of Soviet food support in the 1990s. More recently, bariatric surgery has lead to increasing numbers of patients with nutritional deficiencies and consequent neurologic problems.[1, 2, 3, 4, 5, 6, 7, 8]

Pathophysiology

Neuropathies occur in 2 forms: an isolated deficiency (usually of a B vitamin) or a complex deficiency resulting from several concurrent metabolic disorders (usually including malabsorption). The mechanisms of the discrete deficiencies are described below.

Alcohol exposure

Ethanol intercalates into cell membranes, increasing membrane fluidity. Alcohol also affects many signal-transduction proteins, including ion channels, secondary messengers, neurotransmitters, neurotransmitter receptors, G proteins, chaperonins, and regulators of genetic expression.[9, 10]

Peripheral neuropathy is often the earliest symptom of chronic alcohol dependence, and generally occurs after consumption of at least 100 g/d for several years. Peripheral nerve damage results from 3 processes, and it is controversial which is the most important. The first is nutritional deficiency, especially thiamine deficiency, as ethanol interferes with thiamine absorption in the intestine. Other deficiencies may involve niacin, folate, or protein. The second is direct toxicity from abnormal products (eg, phosphatidyl ethanol, fatty acid ethyl esters) and from metabolites (eg, acetaldehyde that reacts with proteins to form adducts). The third is indirect toxicity (ie, neuropathy from hepatic dysfunction).

Likely, the direct toxic effects of ethanol and its metabolites are involved in the pathogenesis of the pure form of alcoholic neuropathy but this can be modified by a superimposed thiamine deficiency.

Thiamine deficiency

Thiamine (vitamin B 1 ) is found in wheat germ, or the outer layer of seeds, nuts, and most vegetables. Thiamine pyrophosphate is essential for the proper transfer of the aldehyde groups, and it is an essential coenzyme for glycolytic and pentose pathways of glucose metabolism. Four enzymes need thiamine: pyruvate dehydrogenase, α -ketoglutarate dehydrogenase, transketolase, and branched-chain α -ketoacid dehydrogenase.

Body tissues store about 30 mg but use about 1-2 mg daily. The United States recommended daily allowance (RDA) for men is 1.5 mg. Daily intake of less than 0.2 mg causes a discontinuous degeneration of the axonal sheath with subsequent impairment of the axon, producing a polyneuropathy in about 3 months. The vagal nerve is affected particularly, causing symptoms in the distributions of the cardiac, laryngeal, and recurrent nerves.

Thiamine deficiency can cause wet beriberi, for which congestive heart failure is the primary symptom, or dry beriberi, in which a peripheral neuropathy is the primary symptom, depending on the percentage of carbohydrates in the diet; wet beriberi is associated with high carbohydrate intake. Deficiencies preferentially affect the nervous and cardiac tissue because thiamine pyrophosphate is bound less strongly there than elsewhere. Essa et al describe a case in which cardiac MRI revealed myocardial edema associated with wet beriberi.[11]

Niacin deficiency

Niacin (vitamin B 3 ) is found in yeast, beef, pork, and chicken. The active form of this coenzyme, nicotinamide adenine dinucleotide (NAD), is essential for electron and acyl-group transfer in glycolysis. A deficiency of niacin causes pellagra. The US RDA for men is 20 mg.

Pyridoxine deficiency and excess

Pyridoxine (vitamin B 6 ) widely occurs in plant and animal tissues, such as muscle meats, liver, vegetables, and whole-grain cereals. Vitamin B 6 consists of pyridoxine, pyridoxal, and pyridoxamine. It is involved in primary carboxylation and transamination, playing a role in metabolizing tryptophan, glycine, serotonin, and glutamate, as well as sulfur-containing amino acids. Pyridoxine is used in the synthesis of both heme and γ -aminobutyric acid (GABA). Deficiencies are usually associated with increased excretion due to isoniazid ingestion and cause a sensorimotor neuropathy and seizures. Pyridoxine deficiency is rarely associated with a vasculitic mononeuropathy multiplex. A high-protein diet increases pyridoxine requirements, for which the US RDA for men is 2 mg.

The toxic effect of long-term, excessive pyridoxine consumption on the dorsal root ganglions causes a pure sensory neuropathy. Pyridoxine inhibits methionine metabolism, causing an increase in S-adenosylmethionine, which in turn inhibits myelin synthesis. In general, exposure of 2 g/d is needed to cause the neuropathy, but cases due to longstanding use of as little as 200 mg/d have been reported. This is the only vitamin to cause a neuropathy when taken to excess.

Cyanocobalamin deficiency

Cyanocobalamin (vitamin B 12 ) is found in meats, especially liver and kidney, and in cheese, milk, eggs, and fish. This inactive precursor is converted into 2 active metabolites: methylcobalamin and adenosylcobalamin. Methylcobalamin is essential for folate metabolism and for the formation of choline-containing phospholipids, which are the building blocks of myelin. Adenosylcobalamin is required for the formation of succinyl coenzyme A, the lack of which causes impairment in the formation of neural lipids.

After its ingestion, cyanocobalamin binds with intrinsic factor secreted by parietal cells in the stomach, enabling it to resist proteolysis. Receptors in the distal ileum then facilitate digestion. The liver stores 4 mg of cyanocobalamin, representing a 3- to 6-year supply. Therefore, primary deficiencies are rare, except in strict vegetarians and nursing infants, but manifestations of cyanocobalamin deficiency occasionally complicate the presence of malabsorptive disorders. These lesions, which appear throughout the white matter, are a result of a focal disintegration of medullary sheath known as subacute combined degeneration. A single exposure to nitrous oxide may precipitate paresthesias in the hands and feet as well as features of a classic myeloneuropathy within days to weeks. The US RDA for men is 2 mg.

Pantothenic acid deficiency

Almost all foods contain this constituent of coenzyme A, the concentration of which in tissues is 10 times that of thiamine and 50% that of nicotinic acid. Deficiencies are rare because of this large amount of storage, though pantothenic acid has been implicated in the pathogenesis of burning-foot syndrome. The daily requirements are 6-10 mg.

Alpha-tocopherol deficiency

Alpha-tocopherol (vitamin E) is a lipid-soluble antioxidant. Its lack causes a syndrome resembling spinocerebellar degeneration, reversible in early stages but with devastating consequences if allowed to progress. The US RDA is 10 IU.

Gluten-sensitivity neuropathy (celiac disease)

Antibodies to gluten in wheat, barley, and oats in susceptible individuals also attack Purkinje cells and other neurons, leading to cerebellar ataxia, myoclonus, neuropathy, and neurologic symptoms. Adhering to a strict gluten-free diet may stabilize neurologic symptoms.[12, 13]

Multifactorial mechanism

This poorly characterized syndrome of neuropathy and visual and auditory deficits is common in prisoners of war camps[14] and in undernourished populations of tropical countries. Also known as "camp foot," "Jamaican neuritis," "camp dizziness," "Strachan syndrome," and other names, the neuropathy is probably due to a deficiency of B vitamins. Sensorineural deafness is postulated to result from deficiency in riboflavin or B-complex vitamins, and the amblyopia, too, may be from a complex deficiency, as it sometimes does not resolve with vitamin B 12 treatment alone.

Epidemiology

Frequency

United States

About 10,000,000 (4%) Americans are dependent on alcohol. Because of this, alcohol is the most common cause of deficiency neuropathy. About 9-30% of people with alcoholism have clinically evident neuropathy, and more than 90% have electrophysiological evidence of neuropathy.

Approximately 4-15% of ambulatory elderly people (>65 y) will have cobalamin deficiency.

Nearly 10% of people taking isoniazid will have neuropathy.

The increasing incidence of obesity in the United States has led to increased rates of bariatric surgery and consequent malabsorption neuropathies.[15] Peripheral neuropathies are the most frequent complication and can affect up to 16% of patients who have undergone bariatric surgery.[3, 4]

International

Thiamine (vitamin B 1 ) deficiency is still endemic in the Far East; nutritional deficiencies and malnutrition are common in the developing nations.

Mortality/Morbidity

Morbidity and mortality rates vary by etiology.

Race

Racial differences in incidence are likely due to differing socioeconomic status and geographic location.

Sex

Alcoholic neuropathy affects men more than women, but women appear to be susceptible at lower doses.

Age

The incidence of neuropathy due to alcohol dependence peaks at the age of 40 years, although the primary disease may become established decades earlier.

Thiamine (vitamin B 1 ) deficiency predominantly occurs in adolescence and early adulthood.

Children are particularly prone to pyridoxine deficiency, which becomes apparent within a few days of birth.

History

Peripheral neuropathies due to nutritional deficiencies have few individually characteristic signs but can be differentiated by observing other symptoms of the patient's underlying systemic disease. Neuropathies mostly affect the long fibers first, starting in the feet and progressing upward. Once they have progressed to the calf, symptoms may appear in the hands. Cyanocobalamin (vitamin B12) deficiency occasionally manifests in the upper extremities.

Alcohol neuropathy

This disease is characterized by paresthesias (decreased pain and temperature sensation in a stocking-glove distribution), pain, and weakness, especially in the feet but extending proximally to the arms, causing difficulty in climbing stairs and walking.

Autonomic symptoms are less common than those listed above, but include GI dysmotility, urinary or fecal incontinence, and abnormal sweat patterns.

The neuropathy may be seen in conjunction with Wernicke encephalopathy (ie, ophthalmoplegia, ataxia, encephalopathy) or Korsakoff syndrome (ie, amnestic dementia).

Thiamine (vitamin B1) deficiency

Dry beriberi is characterized by severe burning dysesthesias (feet more than hands), weakness and wasting (distal more than proximal), trophic changes (shiny skin, hair loss), and acrodistal sensory loss in a graded fashion typical of dying-back polyneuropathies.

Some patients do not become symptomatic, possibly because they are absorbing thiamine produced by bacteria in the large intestine. However, one half become symptomatic by 7 weeks; by 15 weeks, axonal changes start to appear histologically.

The neuropathy begins with fatigue and loss of sensation, pain, and heaviness in the legs. Then, pretibial edema develops, along with glove-and-stocking paresthesias and difficulty with tasks such as climbing stairs and standing on one leg.

If the thiamine deficiency is long standing, muscles on the dorsum of the feet atrophy and paralysis can ensue.

Difficulty with talking or swallowing may also be noted.

Niacin (vitamin B3) deficiency

Pellagra is characterized by the 3 D s, which are (1) dermatitis, ie, hyperkeratotic skin lesions, particularly on hands, feet, face, and neck (sun-exposed regions); (2) diarrhea; and (3) dementia. In addition, patients may exhibit peripheral neuropathy and other CNS signs, such as depression, excitation, seizures, insomnia, dizziness, cog-wheeling of the extremities, tremor, loss of hearing, tingling fingers, muscle tenderness, and bilateral symmetric glove-and-stocking numbness.

Polyneuropathy is not always associated with pellagra and may be related to accompanying thiamine or pyridoxine deficiency. Therefore, it should be considered an accompanying rather than guiding symptom. It is characterized by acrodistal sensory excitation, the itching and burning in the hands, feet, and trunk, and it sometimes manifests as hydromania, or the compulsion to immerse oneself in cold water.

The dysesthesias progress proximally to the knees, thighs, and hips, after which weakness in the legs becomes manifest.

Paresis is rare, but bulbopontine symptoms can ensue, with abnormalities of the cranial nerves, especially the vestibular, acoustic, and ocular nerves (where symptoms manifest as optic atrophy or amblyopia), as well as seizures.

Eventually, the initial peripheral excitation, erythema, and GI distress progress to cerebral and spinal defects.

Finally, marasmus, cachexia, macrocytic anemia, and coma develop.

Pyridoxine (vitamin B 6) deficiency or excess

This deficiency must be suspected any time a sensory polyneuropathy occurs after hyperesthesia-causalgia syndrome.

First, bilateral numbness and tingling begin in the distal feet. This proceeds proximally up the feet and legs, occasionally appearing in the fingers and hands. Then pain becomes prevalent in these areas, and symptoms can include a burning sensation in the feet.

In rare cases, patients experience loss of power in the legs, in which sensory loss is greater than motor loss; the etiology is axonal loss.

One week after the removal of vitamin B6 from the diet, levels of xanthurenic acid increase and levels of pyridoxine decrease in the urine. At 3 weeks, EEG abnormalities manifest, and tonic-clonic seizures refractory to anticonvulsants may follow.

The 4 main symptoms and signs are as follows:

Neuropathy due to toxicity occurs 1 month to 3 years after the individual starts excessive consumption.

Cyanocobalamin (vitamin B12) deficiency

About 80% of all cases are due to pernicious anemia, and another 10% are due to achlorhydria. Exposure to nitrous oxide can suddenly precipitate the deficiency, which should be considered in any patient who develops postoperative paresthesias.

The disease predominantly affects the spinal cord; therefore, separating the painful sensory and sensorimotor paresthesias of the peripheral neuropathy from the symptoms of spinal cord involvement is difficult.

Presentations vary greatly among patients.

The symmetric glove-and-stocking paresthesias, or tingling in the distal aspect of the toes, numbness, coldness, a pins-and-needles feeling, and occasional feelings of swelling or constriction, are slowly progressive and insidious. Symptoms progress up the legs, occasionally affect the fingers, and culminate in weakness and spasticity.

In late stages, manifestations include moderate muscular wasting, optic atrophy, sphincter dysfunction, and mental disturbances. Examples of these disturbances are mild dementia (which is often the first symptom and clinically indistinguishable from other dementias), disorientation, depression, psychosis, and persecutory delusions.

The hematologic manifestation of anemia, if present, can cause weakness, light-headedness, vertigo, tinnitus, palpitations, angina, heart failure, cardiomegaly, pallor, tachycardia, and hepatosplenomegaly.

GI symptoms include a sore, beefy red tongue and anorexia.

If left untreated, the gait becomes ataxic, followed by paraplegia with spasticity and contractures.

The subacute combined degeneration that develops results in a severe myelopathy, involving posterior columns and lateral corticospinal tracts, with other manifestations including optic (retrobulbar) neuropathy[16] , sensorimotor polyneuropathy, and dementia.

Pantothenic acid deficiency

This manifests as painful burning paresthesias in the feet, ataxia, and hyperreflexia, followed by weakness, fatigue, apathy, and psychiatric disturbances 5-8 weeks later.

Alpha-tocopherol (vitamin E) deficiency

This syndrome resembles Friedreich ataxia. Symptoms include hyporeflexia progressing to areflexia, decreased proprioception and vibration sense with preserved pain and temperature senses, distal muscular weakness progressing to ataxia, dysphagia, and cardiac problems, and nyctalopia (night blindness). Nystagmus, ophthalmoplegia, and blindness, and dementia follow.

Symptoms vary with etiology. Patients with isolated vitamin E deficiency syndrome tend to present without the hyporeflexia, and deficiency from abetalipoproteinemia manifests as increased eye problems, in contrast with deficiency from cholestatic disease, which tends to spare the eye but causes increased psychiatric and behavioral problems.

Folate deficiency

The symptoms of folate deficiency are indistinguishable from those of cobalamin (vitamin B12) deficiency, though the dementia tends to be more prominent.

Hypophosphatemia

Invariably found in patients on total parenteral nutrition, this deficiency causes tingling paresthesias in the tongue, fingers, and toes but can progress to severe weakness and areflexia, sensory loss, and cranial neuropathies.

It can resemble Guillain-Barré syndrome.

Patients may have gluten sensitivity.

Neurologic manifestations can include ataxia, myoclonus, myopathy, myelopathy, dementia, and a peripheral neuropathy that can include sensorimotor axonal neuropathy, axonal motor and mononeuropathy multiplex.

Copper deficiency (usually following bariatric surgery) is commonly associated with myelopathy and spastic gait. Other features can include peripheral neuropathy, myeloneuropathy, optic neuropathy[17] , CNS demyelination, myopathy, myelo-opticoneuropathy, and motor neuron disease. Clinically and radiologically it can appear similar to B12 deficiency.[2]

Bariatric surgery

History is generally sufficient to establish the diagnosis. Three distinctive patterns are most common: sensory polyneuropathy, mononeuropathies, and radiculoplexopathy.

Sensory neuropathies tend to present with symmetrical numbness, burning, sharp pain, and tingling. Some also have distal motor weakness, commonly foot drop. Cramping, autonomic and bulbar symptoms, and involvement of trunk nerves may also occur.

Mononeuropathies are usually asymmetric and have been described in the radial, sensory radial, ulnar, greater occipital, and fibular nerves, as well as carpal tunnel syndrome, and meralgia paresthetica. The last 2 are the most common, and the carpal tunnel syndrome is usually symmetrical.

Radiculoplexopathies affect the cervical and lumbosacral regions, and are usually unilateral, causing pain and numbness followed by limb weakness but usually no autonomic or bulbar symptoms.

In 2017, researchers described three cases post-bariatric surgery where patients developed acute polyneuropathy and were responsive to aggressive parenteral Vitamin B1 and B12 replacement therapy.[18, 19]

Multifactorial disease

This paresthesia-causalgia syndrome (ie, acrodynia or burning-foot syndrome) escalates from a mild paresthesia to painful burning and freezing sensations in the feet, prominent at night, relieved with exercise. This disease may mask sensory deficits, especially those on the soles of the feet.

Tobacco-alcohol amblyopia is a slowly progressive symmetrical visual field loss often described as a central haze or cloud. There is no pain, photopsia, or other positive symptoms, but loss of color vision (especially red) is more profound than the loss of visual acuity. It presents clinically as a characteristic retrobulbar optic neuropathy with slow evolution and a classical cecocentral scotoma with an appearance of "champagne cork" and red-green dyschromatopsia.[20]

Less common is mild-to-moderate unilateral or bilateral hearing loss with tinnitus or vertigo.

Hoarseness and other laryngeal symptoms are equally rare.

Physical

Several physical findings can provide clues to the etiology of the nutritional neuropathy.

Findings in specific syndromes include the following:

Causes

See the list below:

Laboratory Studies

The neuropathy first must be characterized as a polyneuropathy, mononeuropathy, mononeuropathy multiplex disease, or plexopathy; motor, sensory, sensorimotor, motor-sensory, or autonomic; acute or chronic; and of demyelinating or axonal pathophysiology. Readily apparent clues in the history can often suggest that the peripheral neuropathy might be secondary to nutritional problems; they are as follows:

Once the neuropathy is suspected to be nutritional in origin, the physician should first assess a possible vitamin B 12 deficiency (remembering that a CBC is not a good indicator). Documenting other B vitamin deficiencies is not as important because treatment replaces these vitamins anyway.

If history—which is the key to diagnosing a nutritional neuropathy—and physical are unrevealing, check CBC, urinalysis, thyroid-stimulating hormone (TSH), glucose, renal and hepatic functions, vitamin B 12 level, erythrocyte sedimentation rate (ESR), and serum protein electrophoresis, then order other tests, such as copper, as needed. Electrophysiologic findings can confirm the impression of polyneuropathy but rarely provide the diagnosis.

Imaging Studies

Imaging studies are generally not useful. In thiamine deficiency, MRIs occasionally show abnormal signal intensity in periaqueductal gray matter and midline structures.

Radiographs of chronic peripheral neuropathies are often consistent with the picture of a diabetic foot.

Other Tests

Axonal loss manifests as a mild slowing of the nerve conduction velocity (NCV) with a disproportionate loss of amplitude. Demyelination, on the other hand, produces mild loss of amplitude with a disproportionate slowing of the NCV. In affected motor fibers, electromyography (EMG) shows fibrillations, positive sharp waves, and decreased motor unit potentials. EMG and NCV are useful to assess the degree of damage and monitor progression of the neuropathy.

Sensorineural hearing loss: Audiometry shows high-tone hearing loss.

Alcohol: The CSF protein level on lumbar puncture is normal or slightly elevated.

Histologic Findings

A biopsy is not indicated unless the diagnosis is in doubt. If so, biopsy is indicated only if the neuropathy is multifocal or asymmetric, or if the patient has multiple mononeuropathies. The best nerve to biopsy is the sural nerve, lateral to the lateral malleolus. In general, sural nerve biopsy is of limited use in differentiating various types of nutritional neuropathy, but it can help in distinguishing hereditary neuropathy, neuropathy caused by organic solvents, leprosy, amyloidosis, polyarteritis nodosa, or sarcoidosis, and it is occasionally useful in evaluating Guillain-Barré syndrome. Nutritional neuropathies can result in either demyelinating or axonal peripheral nerve pathology.

Medical Care

If the neuropathy is due to thiamine deficiency in an alcohol-dependent patient, consider instituting an alcohol-withdrawal protocol and providing seizure prophylaxis if indicated.

Surgical Care

See the list below:

Consultations

Refer the patient to an orthopedic surgeon for evaluation of osseous deformities.

Diet

Establishing an exact nutritional deficiency is often difficult. Many etiologies are often present simultaneously, especially in patients with malnutrition. Nutritional supplements are relatively innocuous. Therefore, for many nutritional neuropathies, the treatment is empirical and establishes the diagnosis. The further the disease has progressed, the lower the likelihood of reversing the symptoms.

Activity

Physical therapy is recommended to prevent joint contractures. Therapy consists of daily exercises though full range of motion, the use of splints to prevent foot drop, and the use of orthotics to minimize ulceration at denervated pressure points.

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Thiamine (Thiamilate)

Clinical Context:  For thiamine deficiency syndromes.

Niacin (Vitamin B 3 )

Clinical Context:  Source of niacin used in tissue respiration, lipid metabolism, and glycogenolysis.

Cyanocobalamin (Crystamine)

Clinical Context:  Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B 12 in humans. Vitamin B 12 synthesized by microbes but not humans or plants. Vitamin B 12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of distal ileum.

Folate (Folvite)

Clinical Context:  Important cofactor for enzymes used to produce RBCs.

Alpha-tocopherol (Vita-Plus E Softgels, Vitec, Aquasol E)

Clinical Context:  Protects polyunsaturated fatty acids in membranes from attack by free radicals and protects RBCs against hemolysis.

Multivitamins (MVI-12, Cernevit-12)

Clinical Context:  Dietary supplement.

Class Summary

To treat a nutritional neuropathy, replacing the deficient nutrients is necessary. This may involve administration of folate, thiamine (vitamin B 1 ), nicotinamide, pyridoxine (vitamin B 6 ), cyanocobalamin (vitamin B 12 ), alpha-tocopherol (vitamin E), vitamin A, or protein.

Further Outpatient Care

After the diagnosis is made and treatment is initiated, the primary care physician can follow up with the patient.

Deterrence/Prevention

See the list below:

Prognosis

An acute decrease in vitamin levels causes acute symptoms of vitamin deficiency but few morphologic changes. However, as the deficiency becomes chronic over months to years, such changes eventually take place.

In severe chronic deficiency states, response to pharmacologic treatment may be partial or nonexistent, as axonal degeneration can be halted but sometimes not reversed.

Improvement is always slow and, although peripheral nerves regenerate at a rate of 1 mm/d, full recovery cannot occur if the neuronal cell body or proximal neuron is damaged or if central pathways have been damaged.

Patient Education

See the list below:

Author

Jasvinder Chawla, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Glenn Lopate, MD, Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University in St Louis School of Medicine; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD, MHA, CPE, Co-Founder and Former Chief Publishing Officer, eMedicine and eMedicine Health, Founding Editor-in-Chief, eMedicine Neurology; Founder and Former Chairman and CEO, Pearlsreview; Founder and CEO/CMO, PHLT Consultants; Chief Medical Officer, MeMD Inc; Chief Strategy Officer, Discourse LLC

Disclosure: Nothing to disclose.

Additional Contributors

Milind J Kothari, DO, Professor, Department of Neurology, Pennsylvania State University College of Medicine; Consulting Staff, Department of Neurology, Penn State Milton S Hershey Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Lawrence D Recht, MD Professor of Neurology and Neurosurgery, Department of Neurology and Clinical Neurosciences, Stanford University Medical School

Lawrence D Recht, MD is a member of the following medical societies: American Academy of Neurology, American Association for Cancer Research, American Neurological Association, and Society for Neuroscience

Disclosure: Nothing to disclose.

R Andrew Sewell, MD Associate Research Scientist in Psychiatry and Mental Illness Research, Education,Veterans Affairs Connecticut Health Care System, Yale University School of Medicine

R Andrew Sewell, MD is a member of the following medical societies: American Academy of Neurology, American Headache Society, American Pain Society, and American Psychiatric Association

Disclosure: Nothing to disclose.

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Pernicious anemia. Characteristic lemon-yellow–tinged pallor with raw-beef tongue lacking filiform papillae. Used with permission from Forbes and Jackson.

Ischemic retinopathy caused by severe megaloblastic anemia.

Pernicious anemia. Characteristic lemon-yellow–tinged pallor with raw-beef tongue lacking filiform papillae. Used with permission from Forbes and Jackson.

Ischemic retinopathy caused by severe megaloblastic anemia.