Alcohol-induced polyneuropathy

Clinical manifestations. Alcohol-related peripheral neuropathy typically presents with slowly progressive sensory symptoms, including paresthesias and numbness. Symptoms most often progress over a period of months to years affecting the lower extremities initially with progression of symptoms to the upper extremities being a less frequent finding (34). On examination, patients may have sensory loss primarily of vibration and deep sensation in the distal legs, motor weakness, areflexia, calf tenderness, and, in some cases, orthostatic hypotension due to an autonomic neuropathy (32; 51). Eventually, patients may develop pain, cramps, weakness, and sensory ataxia. The legs become shiny and swollen and the skin becomes friable and subject to trauma and ulceration. Neuropathic joint degeneration may occur with bony resorption and deep tissue infection. A Guillain-Barré-like worsening of an established axonal neuropathy has been described in alcoholics with rapidly progressive weakness (74; 66), which could be associated with additional thiamine deficiency. Koike described thiamine deficiency presenting as Guillain-Barré syndrome in two patients (39).

A systematic review of 34 studies of 2590 subjects analyzed prevalence of neuropathy in chronic alcohol abusers and found a pooled prevalence of 44.2% (34). Among all patients with polyneuropathy, alcohol use is identified as the etiology in 8.7% to 10% (34). Earlier studies found a lower prevalence of alcoholic neuropathy (ranges from 9% to 30%) among hospitalized alcoholics (71). Upwards of 93% of ambulatory alcoholics may have electrophysiologic evidence of neuropathy (13). Victor found polyneuropathy in 82% of 230 patients with Wernicke-Korsakoff syndrome (71), and 84% of patients, who were able to give a dietary history, reported at least a 20-pound weight loss in the previous year. Thiamine deficiency may occur in isolation from alcohol in patients with poor or imbalanced diets.

Etiology and pathogenesis. Alcohol-related neuropathy is difficult to separate from nutritional neuropathy, specifically neuropathy that results from thiamine deficiency (12; 40), though more evidence is accruing for alcohol’s distinct toxic effect from thiamine deficiency (49). Although male gender, genetic predisposition, and type of alcohol consumed appear to be risk factors, total lifetime consumption of alcohol appears to be the greatest risk factor for development of alcohol-related peripheral neuropathy (34). Neuropathy occurs after consuming at least 100 gm of alcohol daily for several years and is made worse by a coexistent nutritional deficiency. Men outnumber women, but women may be more susceptible at lower doses than men (06). Although it is not known precisely how alcohol injures peripheral nerves, traditional theories include altered membrane lipid permeability or oxidation injury from free radical formation (08; 12; 60). Reviews suggest a complex etiology with contributions from oxidative stress, activation of matrix metalloproteinase, and blood nerve barrier disruption (05). It is uncertain how a coexistent nutritional deficiency may potentiate the toxicity of alcohol.

Attempts have been made to separate the influences of alcohol from nutrition. A group of alcoholics with neuropathy were allowed to continue drinking while receiving a nutritious diet, and all noted improvement in symptoms (67). Another study failed to produce a significant neuropathy in monkeys fed alcohol for 3 to 5 years (23). Others have found alcohol-related neuropathy in patients drinking thiamine and pyridoxine-fortified beer over many months to years.

Koike examined 18 patients with alcohol-related neuropathy and normal thiamine status. The patients demonstrated slowly progressive sensory-predominant neuropathy of the feet, axonal neurophysiology, and loss of small myelinated and unmyelinated fibers on sural nerve biopsy (40). Half the patients demonstrate autonomic dysfunction such as orthostatic hypotension. The group then did a more extensive study of 64 patients with alcoholic neuropathy and separated them into subgroups depending on measured thiamine levels (38). Both thiamine concentrations determined by high-performance liquid chromatography (normal between 20 and 50 ng/ml) and erythrocyte transketolase activity (normal between 123.8 and 206.2 U/L) were determined and applied. An additional 32 patients with nonalcoholic thiamine deficiency and neuropathy, mostly from dietary imbalance or prior gastrointestinal surgery, were also compared. Patients with prior gastric bypass for obesity or other cause for neuropathy were excluded. Based on clinical exam, electrophysiology, and sural nerve histology alcoholic neuropathy, patients with normal thiamine levels were found to have primarily slowly progressive sensory loss affecting small fiber mediated functions, especially nociception. Pain and burning paresthesias were common in this group. Primary nonalcoholic thiamine deficiency-associated neuropathy, in contrast, was found have prominent motor involvement with more acute onset in addition to large greater than small diameter fiber sensory loss. Patients with both alcohol exposure and thiamine deficiency showed a mixture of findings. This series appears to be the best evidence to date of a primary neurotoxic effect of ethanol in humans. Moreover, the group with normal thiamine levels and chronic ethanol exposure is in close keeping with traditional descriptions of alcoholic neuropathy, suggesting that thiamine deficiency is a lesser factor in most cases. Alcohol-related peripheral neuropathy is associated with small fiber sensory neuropathy on skin biopsy in heavy alcohol drinking subjects, even with normal thiamine status (50). Disulfiram neuropathy may improve on discontinuation of this potentially toxic therapy (70).

Acute nutritional axonal neuropathy is well described in the context of alcohol use, with thiamine deficiency being a common finding. In a 2023 series of 40 patients with acute nutritional axonal neuropathy, 21 were secondary to alcohol intake, 10 were secondary to anorexia, and nine were in the context of bariatric surgery (25). Low thiamine levels were seen in 85% of patients. There are sparse data in the literature to guide prognostication, though persistent deficits appear common. At the final follow-up visit, an average of 22 months after the onset of neuropathy, only 35% were able to ambulate independently. In a series of 13 patients with acute axonal nutritional neuropathy from either bariatric surgery, alcohol abuse, or chronic vomiting, all 13 were found to have low thiamine levels (24). All patients experienced some improvement from treatment with greater improvement in motor than sensory deficits.

Diagnostic workup. The diagnosis of thiamin deficiency neuropathy is typically clinical. Approximately 80% of thiamine is present as thiamine diphosphate present in erythrocytes. Measurement of whole blood thiamine diphosphate provides a reasonable measure of total thiamine status. Direct measurement of plasma or whole blood thiamine levels are unreliable and poor indicators of overall thiamin status. Erythrocyte transketolase is a functional measurement of thiamine activity that may serve as an indirect measure of thiamine status; however, this assay is technically challenging and infrequently available. MRI of the brain may show symmetric T2 signal abnormalities in periaqueductal gray matter, basal ganglia, and mamillary bodies (73).

Prevention. Although fortification of liquor with thiamine and pyridoxine may help prevent certain complications such as Wernicke-Korsakoff syndrome, the neuropathy associated with alcohol is not necessarily prevented by fortification. Abstinence and good nutrition appear to be the only prevention.

Management. Treatment of suspected thiamine deficiency in the setting of Wernicke encephalopathy begins with the immediate administration of intravenous thiamine. Recommended doses vary from 200 mg three times daily to 500 mg three times daily for a period of 3 to 5 days, followed by long-term oral replacement with 50 to 100 mg daily. This should be done before the administration of dextrose-containing intravenous fluids (20).

Cobalamin deficiency neuropathy (vitamin B12 deficiency neuropathy)

Clinical manifestations and pathology. The myelopathic and cognitive defects of cobalamin deficiency have been well described. However, its neuropathic symptoms may be easily confused with those of a myelopathy, namely paresthesias of the hands and feet with vibration and position sense impairment and a variable degree of cutaneous sensory loss. Whether cobalamin deficiency causes a separate neuropathy, therefore, has a controversial history, but it is said that this can occur in 5% of deficient cases. Early studies failed to document much involvement of the peripheral nerves; however, pathologic study of the peripheral nerves was limited (55). Electrophysiologic data and pathologic evidence have clearly demonstrated peripheral neuropathy and may occur in isolation or prior to the emergence of spinal cord abnormalities. The peripheral neuropathy is usually axonal and sensorimotor; however, demyelinating physiology with conduction block has been described (48; 27; 02; 28). Isolated sensory axonal peripheral neuropathy from cobalamin deficiency may be reversible, at least partially (11).

Etiology and pathogenesis. Cobalamin deficiency is associated with a variety of disorders, most commonly pernicious anemia. Approximately 78% of patients with cobalamin deficiency will be found to have a proven or probable defect of intrinsic factor production from the gastric parietal cell (pernicious anemia). Perhaps 10% of patients have food-cobalamin malabsorption due to hypochlorhydria or achlorhydria, a disorder that affects 16% to 40% of the elderly (29). The rest result from a variety of causes, including bacterial overgrowth, tape worm infestation, blind loop syndrome, gastric bypass, serum binding protein abnormalities, and malabsorption from Crohn disease, and ulcerative colitis (19; 62). Patients that adhere to vegetarian or vegan diets are at higher risk of B12 deficiency (15). Long-term use of medications such as metformin and agents that alter gastric acidity, such as proton pump inhibitors and H2 blockers, may predispose to B12 deficiency (46).

Cobalamin deficiency probably causes neuropathy and myelopathy through its effects on homocysteine and methylmalonic acid metabolism. Homocysteine is converted to methionine, which is important in the methylation of myelin basic protein. Methylmalonic acid is important for the production of succinate and other long-chain fatty acids. Cobalamin deficiency leads to an accumulation of methylmalonic acid causing synthesis of “funny fatty acids,” which are then incorporated into a dysfunctional myelin membrane, potentially leading to defects in nerve transmission. There is a genetic component to cobalamin deficiency, and it is not uncommon for multiple autoimmune syndromes to coexist, such as thyroid disease, Addison disease, vitiligo, and myasthenia gravis (the so-called polyglandular autoimmune syndromes) (19).

Diagnostic workup. In a patient with signs and symptoms of cobalamin deficiency, one should begin with a cobalamin assay. If the serum cobalamin assay result is less than the lower normal limit, a measurement of intrinsic factor antibodies may be obtained if there is concern for pernicious anemia. In pernicious anemia, laboratory evidence of an autoimmune process may be found. Antiparietal cell antibodies are present in 90% and intrinsic factor antibodies in 60% of patients with pernicious anemia. Antiparietal cell antibodies have a 10% false-positive rate. Though it lacks sensitivity, the test for intrinsic factor antibodies is much more specific. The Schilling test, which attempted to measure absorption of cobalamin, is infrequently performed and of largely historical interest. Gastrointestinal evaluation, including endoscopy, may be warranted in patients diagnosed with malabsorption syndromes. MRI of the spine may reveal T2 hyperintensity in the dorsal columns.

In patients with serum cobalamin levels in the lower normal range (200 to 400), but in whom one still suspects clinical cobalamin deficiency, one should measure levels of homocysteine and particularly methylmalonic acid (19; 64). Methylmalonic acid may be measured in serum or urine. The urinary assay is more specific in patients with renal insufficiency. If either metabolite is elevated, then serum intrinsic factor antibodies and gastrin may be measured. The serum gastrin level is often elevated in pernicious anemia and is a marker for achlorhydria, a cause of food-cobalamin malabsorption.

Management. For cobalamin deficiency, the total body store of cobalamin is 2000 to 5000 µg, half of which is stored in the liver. The recommended daily allowance is 6 µg/day, and the average diet provides 20 µg/day. Recommendations for treatment suggest 1 to 2 mg/day vitamin B12 orally or intramuscular injections of 0.1 to 1 mg/month (46). Because 1% of all ingested cobalamin may be absorbed by passive diffusion, cobalamin requirements can be satisfied with oral therapy, even in patients with pernicious anemia (45). A daily dose of 1000 µg/day orally will yield 10 µg of absorbed cobalamin, which exceeds the recommended daily allowance. Sublingual cobalamin 2000 µg/day is also effective and may be superior to intramuscular injections for some patients (16). A randomized, double-blind, controlled, parallel intervention trial evaluated high (2000 µg/week) and low dose (350 µg/week) sublingual B12 replacement in 40 patients with marginal B12 levels, and both supplements were able to adequately restore serum B12 levels (15). It may be practical to replenish cobalamin stores first using injections of cyanocobalamin for 1 week, and then to maintain patients using a 1000 µg daily oral supplement. The effectiveness of treatment, regardless of route, can be confirmed by demonstrating normal serum or urine methylmalonic acid levels 3 to 4 weeks after beginning B12 replacement.

Patients undergoing anesthesia. Patients with subclinical cobalamin deficiency may experience an acute syndrome of myeloneuropathy after receiving nitrous oxide anesthesia. If suspected, serum B12 and metabolite assays should be measured prior to surgery to avoid this complication. The recreational use of “laughing gas” (nitrous oxide) may also provoke a functional B12 deficiency.

Neuropathy associated with bariatric surgery

Clinical manifestations. Neuropathy seen after bariatric surgery can present with slow progressive sensory loss or, less frequently, may present with acute or subacute sensory loss, weakness, and areflexia in the limbs. Acute neuropathy is more closely associated with significant weight loss or protracted nausea or vomiting, which results in a malnourished state (59; 17; 61; 58; 65; 26; 36). Peripheral neuropathy after bariatric surgery is very common; a 2004 Mayo Clinic retrospective review of 435 patients showed a frequency of 16% (69).

The clinical spectrum is predominantly that of neuropathy, but encephalopathy, clinically indistinguishable from Wernicke-Korsakoff syndrome, and a combination of neuropathy and encephalopathy may also occur. An association with vomiting has been recognized. Wernicke and Korsakoff separately described young women with intractable vomiting. Korsakoff described a pregnant woman with intractable vomiting from hyperemesis gravidarum (71).

Of 37 cases reviewed (36), 26 developed neuropathy alone, two had encephalopathy and nine had features of both. One patient developed blindness and optic neuropathy. Intractable vomiting was almost always present. This syndrome presented suddenly several months after surgical procedures that included gastrojejunostomy, gastric stapling, vertical banded gastroplasty, and gastrectomy with Roux-en-Y anastomosis. Following a period of recurrent vomiting and precipitous weight loss, patients felt numbness and tingling in the soles of their feet, calves, and thighs. Distal or proximal weakness developed, and the patient had difficulty rising from a chair or climbing stairs. Pain was not a dominant feature, unlike the exquisitely tender calves often seen in thiamine-deficient neuropathy. Examination showed symmetric sensory loss with muscle weakness and areflexia in the legs more than in the arms. Patients developed quadriparesis and prolonged or permanent disability. When associated with an encephalopathy, patients demonstrated confusion, memory loss, and disturbances of affect. Some were mistakenly diagnosed early in their course as conversion disorders (58).

Etiology and pathogenesis. The etiology of neuropathy after bariatric surgery is unknown but probably polynutritional, with thiamine deficiency playing a major role and B12 and copper deficiency to a lesser extent. Thiamine deficiency has been proposed as the cause, though it is not confirmed. A 2022 systematic review and meta-analysis that included 11 studies of 1494 patients showed that 27% of patients who had bariatric surgery experienced thiamine deficiency (04). A toxic hypothesis is supported by the fact that some have reported a resolution of the symptoms following reversal of the surgical procedure, whereas nutritional replacement alone does not have the same result. The pathology of peripheral nerves has been studied in a few cases. Axonal neuropathy predominates, yet one case was unlike any known nutritional neuropathy. Feit and colleagues demonstrated lipid deposition within the nerve cell bodies, suggesting that the pathophysiology may have been related to the rapid mobilization of lipids in the surgically starved (17).

Thaisetthawatkul and colleagues compared 435 patients who had bariatric surgery with controls having gallbladder surgery. They found that 16% developed some form of neuropathy, compared with 3% in the gallbladder group. Of the 71 included, more than half had entrapment neuropathy, mostly carpal tunnel syndrome. Twenty-seven had a polyneuropathy, and five had a radiculoplexus neuropathy. Sural nerve biopsies in five patients (four polyneuropathy, one radiculoplexus neuropathy) showed prominent axonal degeneration with variable degrees of perivascular mononuclear cell infiltration. No definite vasculitis was seen. Risk factors identified for neuropathic complications of bariatric surgery were acute weight loss, excessive vomiting, postoperative complications, poor vitamin supplementation, and jejunoileal bypass procedure (69).

Diagnostic workup. Evaluation includes laboratory studies to assess for secondary causes of neuropathy. Levels of vitamins (cobalamin, thiamine, folate) and minerals (copper) may be obtained as well to provide additional information.

Prevention. Neuropathy after bariatric surgery is best prevented by strict adherence to dietary regimen and vitamin supplementation. Total parenteral nutrition and supplementary parenteral vitamins should be considered during episodes of recurrent vomiting.

Management. Treatment of suspected thiamine deficiency begins with the immediate administration of 100 mg thiamine intravenously followed by 100 mg intramuscularly daily for 3 to 5 days and parenteral multivitamins. Patients are then maintained on 50 mg thiamine orally daily. Guidelines also suggest supplementation of fat-soluble vitamins, B complex vitamins, iron, calcium, zinc, copper, and, additionally, a multivitamin in patients at risk for nutrient absorption, including those who have undergone bariatric surgery (46). Controversy exists whether vitamin and nutritional supplementation alone or the reversal of the surgical procedure is more helpful in resolving the neuropathy (47). Improvement has been noted after vitamin supplementation, IVIG, nutritional support, and reversal of the surgical bypass (01; 33). If vomiting develops following bariatric surgery, patients should receive parenteral nutrition, multiple vitamins, and thiamine. Most patients make some recovery if the neuropathy is discovered early; however, many have residual weakness and sensory loss. The degree of disability appears to depend on the duration and severity of symptoms prior to diagnosis and treatment.

Gluten-sensitive neuropathy

This is a proposed autoimmune disorder that occurs in celiac disease. Wheat, barley, and rye are composed of gluten that may induce an antibody reaction in susceptible individuals. These antibodies are thought to be directed against Purkinje cells and other nervous system tissue leading to a variety of disorders, including cerebellar ataxia, neuropathy, and myoclonus. Oat consumption may also lead to gluten sensitivity neuropathy, even though oats are gluten free, as farming practices may lead to contamination of oats by gluten-containing cereals. Moreover, many patients with celiac disease are intolerant of oat proteins in addition to gluten. Hadjivassiliou reviewed 35 reports of neurologic disorders associated with celiac disease in 83 patients (mean age 48 years of age, male=female). These included ataxia (29), peripheral neuropathy (29), myopathy (13), ataxia with myoclonus (9), myelopathy (4), and dementia (6). The same author has reported up to 40% of patients with idiopathic peripheral neuropathy have antigliadin antibodies (21), which has not been replicated.

The neuromuscular manifestations include sensorimotor axonal neuropathy, axonal motor, sensory ganglionitis, and mononeuropathy multiplex. All patients were found to have antigliadin antibodies, either IgG or IgA. Of all patients with positive antibodies, only 35% have an abnormal intestinal biopsy, suggesting that neurologic symptoms may occur without GI symptoms. HLA DQ2 is found in 90% of patients with celiac disease so this offers an additional confirmatory test. Further study is needed of this potentially important, but unproven, cause of neurologic illness (09; 10). Hadjivassiliou and colleagues described associated sensory ganglionopathy responsive to a strict gluten-free diet (22).

Patterson showed no correlation between celiac neuropathy and copper levels in a cohort of 18 patients with celiac disease, as none had hypocupremia (57).

The management of gluten-sensitive neuropathy is not well established, but avoidance of gluten is often advised; there appears to be sparse literature to guide optimal treatment. A study of 60 patients with gluten neuropathy observed that pain was a feature in 55% of patients. Patients with painless gluten neuropathy were more likely to comply with strict avoidance of gluten (55.6% vs. 21.2%) (75).

Pyridoxine (vitamin B-6) deficiency neuropathy

Pyridoxine is unique because both a deficiency and an overdose will produce sensory neuropathy/neuronopathy (36). It was first discovered among patients receiving isoniazid and later hydralazine. Deficiency affects the blood, skin, and nervous system. Skin changes may be indistinguishable from pellagra, which may be due to the close interaction of niacin and pyridoxine. It is characterized by sensory loss in the distal limbs, weakness, and reflex changes. Patients describe burning feet and painful paresthesias.

Central nervous system manifestations of pyridoxine deficiency include depression, irritability, and confusion. It may also present as pyridoxine-responsive seizures in neonates. Up to 10% of patients with tuberculosis on isoniazid may develop a peripheral sensory neuropathy from secondary deficiency due to increased pyridoxine excretion in the urine. Phenytoin, hydralazine, and phenelzine also interfere with B6 metabolism to a lesser degree.

Pyridoxine produces neuropathy both in its deficient and toxic states at a dosage at or above 200 mg per day, which exemplifies the ubiquitous nature of this compound and its importance in amino acid metabolism, particularly tryptophan and methionine. By inhibiting methionine metabolism, excessive S-adenosylmethionine accumulates, which inhibits nerve lipid and myelin synthesis. A daily dosage of vitamin B6 at or below 50 mg is felt to be safe.

Pyridoxine deficiency is primarily seen in chronic alcoholics and in patients taking isoniazid or hydralazine. Pyridoxine deficiency will cause elevations in serum homocysteine and cystathionine, and assays are commercially available. Urinary assays for xanthurenic acid and other pyridoxine metabolites may be performed following tryptophan loading.

Pyridoxine excess neuropathy

Toxic doses of pyridoxine may also result in a large fiber sensory peripheral neuropathy/neuronopathy (63; 56; 14; 44). Mega doses of pyridoxine may produce sensory neuropathy after several weeks of use, generally in excess of 2 grams per day. It has also been reported with chronic use of as little as 200 mg a day. Symptoms of paresthesias, ataxia, and burning feet occur 1 month to 3 years after starting pyridoxine.

Axonal degeneration, reduced myelin fiber density, and myelin debris have all been demonstrated in sural nerve biopsies. After cessation of pyridoxine, few patients entirely resolved, but most improved. Individuals who use large doses of B-complex vitamins are under the false impression that, because B-complex vitamins are water soluble and, therefore, are excreted in the urine, it is not possible to take too much. In fact, 200 mg doses of pyridoxine are commonly found as single tablets in pharmacies and are sufficient to cause sensory neuropathy after many months of exposure.

The pathogenesis and pathophysiology by which pyridoxine excess causes neuropathy are not understood. Pyridoxine excess should be suspected in any individual with neuropathic symptoms who takes dietary supplements. A careful dietary history needs to be obtained in all such patients.

Vitamin E deficiency neuropathy

Vitamin E is fat soluble and found in abundance in vegetable oils and wheat germ. It is carried in portal blood to the liver, and alpha-tocopherol transfer protein binds it and recycles vitamin E in the liver for incorporation into low density and very low density lipoproteins. The patients at risk for development of vitamin E deficiency include those with rare hereditary conditions such as hypo- or abetalipoproteinemia, and even more rarely, with other disorders of the pancreas and liver, such as cystic fibrosis, protein-calorie malnutrition, familial vitamin E deficiency, and other malabsorption states (31). Symptoms include areflexia, cerebellar ataxia, cutaneous sensory impairment, position and vibratory sense abnormalities, and, less commonly, ophthalmoplegia, muscle weakness, nystagmus, extensor plantar responses, ptosis, and dysarthria. The peripheral neuropathy in abetalipoproteinemia is usually limited to the legs and is mild, axonal, and sensorimotor in nature (07). Vitamin E supplementation may have a possible protective role in chemotherapy-induced neuropathy when administered prior to receiving cisplatin or paclitaxel (03). Vitamin E supplementation’s protective effect was confirmed for cisplatin chemotherapy (54) but has been questioned in paclitaxel therapy (53).

Vitamin E deficiency may be acquired in adulthood in patients with a defect of alpha-tocopherol transfer protein. It is indistinguishable phenotypically from Friedreich ataxia. Vitamin E deficiency can be reliably investigated using the serum alpha-tocopherol level. Adult patients without malabsorption and a clinical picture consistent with Friedrich ataxia and neuropathy should be investigated for an autosomal recessive defect in the tocopherol transporter protein gene of chromosome 8. Tocopherol transporter protein incorporates tocopherol into chylomicrons. The serum tocopherol levels in these patients may be in the normal range; however, they respond to high dose supplementation.

Copper deficiency myeloneuropathy and folate deficiency neuropathy

Copper deficiency myeloneuropathy. Subacute myelopathy and neuropathy have been reported in patients with copper deficiency. Clinically, this may occur in the context of malabsorption from bariatric surgery, primary gastrointestinal pathology, or from secondary malabsorption of copper from excessive zinc consumption. Deficiency due to zinc consumption has occurred with use of remedies for prevention of colds and upper respiratory infections as well as excessive ingestion of denture adhesives containing high zinc amounts (52). Based on an early series of 25 patients with copper deficiency myelopathy, the most common presenting symptom was gait difficulty, which resulted from sensory ataxia and spasticity. Hyperreflexia at the knees was seen in 21, reduced ankle jerks in 15, and extensor plantar response in 12 of 25 subjects. A history of gastric surgery was noted in 10, and anemia was seen in 20 of 25. Data for treatment response were only available in 20 subjects, of which 18 had normalization of serum copper. All 20 patients had residual neurologic deficits whereas hematologic abnormalities were completely reversible (41). In a series of 34 patients with copper deficiency neuropathy, a length-dependent sensory predominant neuropathy was found to be most common in 71% of subjects. Additionally, 21 of 34 subjects had myelopathy (68). Copper may now be added to the list of other nutrient deficiencies that may cause a myeloneuropathy (vitamin B12, E, and copper) (43; 42). The combination of pancytopenia and neuropathy raises the possibility of copper deficiency (30).

Folate deficiency neuropathy. Folate deficiency-related neuropathy is not as well established, and it is probably very rare in developed countries given the ubiquity of folic acid–enriched foods. Koike and colleagues described a case of a chronically malnourished alcoholic with otherwise idiopathic neuropathy and anemia who responded to folic acid supplementation (37).

Clinical vignette

Case 1. A 75-year-old man fainted in the elevator after leaving his dentist's office following a dental extraction under nitrous oxide anesthesia. The following week, he returned for a second extraction, again receiving nitrous oxide. He fainted a second time and had a transient sensation of vertigo. Two weeks later, he underwent a resection of a rectal adenoma under nitrous oxide anesthesia, as well as enflurane. Three days after surgery, he noted numbness and tingling in the hands and feet and a sandpaper feeling in the hands, limiting his dexterity. He was unsteady on his feet and had orthostatic hypotension that corrected with intravenous fluids. Sensation to light touch, pin, and vibration was diminished in the hands and feet. Reflexes were 2+ and plantar responses were extensor.

A serum vitamin B12 level was found to be 32 (normal is greater than 220 ng/dl). He received intramuscular replacement and noted some improvement in his lightheadedness and unsteadiness but no improvement in the paresthesias of the hands and feet and hand clumsiness. Romberg was positive. A Schilling test was abnormal in parts I, II, and III. Serum gastrin was markedly elevated, and intrinsic factor antibodies were absent. Hematocrit was normal, and mean corpuscular volume was 101. The patient was given a diagnosis of pernicious anemia as well as B12 malabsorption syndrome, secondary to Crohn disease, which was discovered some months later. An EMG and nerve conduction study demonstrated lumbosacral radiculopathy and carpal tunnel syndrome bilaterally. Motor and sensory conductions in the legs were normal. There was no evidence of amyloidosis on biopsy of the flexor retinaculum during carpal tunnel release. He was managed with intramuscular B12 1000 mcg monthly for the first year, followed by oral cobalamin 1000 mcg daily, thereafter, maintaining normal serum B12 levels. Paresthesias in the feet and the clumsiness of the hands improved minimally 3 years later.

This patient demonstrated several important issues relating to B12 deficiency:

Case 2. A 28-year-old woman with morbid obesity underwent vertical-banded gastroplasty for weight reduction. Her postoperative course was complicated by recurrent admissions for intractable vomiting, requiring total parenteral nutrition. She was instructed on the use of dietary supplements and vitamins as an outpatient. After 4 months of recurrent intractable vomiting, the patient fell on the bathroom floor and was unable to get up. She complained of numbness on the inner thighs down to the feet bilaterally. Examination demonstrated give-way weakness in proximal leg muscles, normal position sense and reflexes, and normal sensation to light touch, temperature, and vibration. She could not rise from a deep-knee bend. An MRI of the lumbosacral spine and an EMG were recommended, but the patient declined, stating that she felt better by the time the tests were scheduled. She was discharged home. Several weeks later, she was again admitted with intractable vomiting and developed persistent paresthesias and weakness in both legs. She was found to have diminished reflexes, proximal and distal weakness of the legs, and diminished sensation to light touch, temperature, and vibration. Nerve conduction studies and electromyography demonstrated a severe axonal polyneuropathy worse in the legs than the arms. MRI scan of the brain and spine were unrevealing. Spinal fluid analysis showed no elevation in protein. The surgical procedure was reversed, but the operative course was complicated by splenic rupture necessitating splenectomy and a prolonged intensive care stay for hypovolemic shock. The patient was discharged and, because of prolonged weakness in both legs, required a wheelchair. After 1.5 years, the patient could walk but complained of short-term memory loss and persistent paresthesias in the legs.

This case study demonstrates an acute presentation of a nutritional syndrome in an obese patient, not the typical individual in whom one expects to find dietary deficiencies. A high index of suspicion and the early use of large doses of thiamine, as well as other multivitamins may prevent longstanding complications and disability.