Patients can develop neuropathies due to inadequate nutrition and subsequent vitamin deficiency (Table 18-1). Nutritional deficiency-related polyneuropathies are currently uncommon, especially in developed countries. However, these neuropathies do occur and are important because they are potentially treatable. Malnutrition may occur in chronic alcoholics and in patients with chronic illness, unusual diets, and obesity surgery. Some vitamin deficiencies (e.g., vitamins B12 and E) often occur because of impaired gastrointestinal absorption rather than poor dietary intake. In other cases, neuropathy may develop secondary to the effects of medications (e.g., isoniazid causing vitamin B6 deficiency). The clinical and laboratory features of most nutritional polyneuropathies are similar to those of the more common polyneuropathies. Timely and accurate diagnosis is important because patients can improve with replacement therapy.

CLINICAL FEATURES

Thiamine deficiency or beriberi is uncommon nowadays and primarily occurs as a consequence of chronic alcohol abuse, recurrent vomiting, total parenteral nutrition, inappropriately restrictive diets, and perhaps bariatric surgery.¹ The symptoms arising from insufficient dietary intake of thiamine are known as beriberi and may present in two forms: dry beriberi and wet beriberi. The difference between these two types of beriberi is simply the presence (wet beriberi) or absence (dry beriberi) of congestive heart failure and lower limb edema. Affected individuals usually present with numbness, tingling, and burning in the distal lower extremities, which subsequently spread to involve the proximal legs and upper extremities.² On examination, a mild-to-moderate reduction in all sensory modalities is noted in a stocking distribution along with diminished muscle stretch reflexes. Mild, predominantly distal weakness may be appreciated. Congestive heart failure with edema of the lower legs is seen in the so-called wet beriberi.

LABORATORY FEATURES

Measuring thiamine concentration in serum and urine is not very reliable.³ Assay of erythrocyte transketolase activity and the increase in activity after adding thiamine pyrophosphate (TPP) appears to be more accurate and reliable.^4–7 Sensory nerve conduction studies (NCS) reveal reduced or absent sensory nerve action potentials (SNAPs) amplitudes with relative preservation of distal sensory latencies and conduction velocities.² The motor NCS may be normal or demonstrate slightly reduced amplitudes.

HISTOPATHOLOGY

Sural nerve biopsies reveal loss of primarily large myelinated axons.^1,8 Necropsy studies have demonstrated chromatolysis of the anterior horn cells and dorsal root ganglia cells along with axonal degeneration and secondary demyelination of the posterior columns.

PATHOGENESIS

Most meats and vegetables contain adequate amounts of thiamine, in particular unrefined cereal grains, wheat germ, yeast, soybean flour, and pork.³ It is absorbed in the small intestine by both passive diffusion and active transport. Here, thiamine is converted to TPP.³ Because stores of thiamine in the body are limited and its half-life is only 10–14 days, 1–1.5 mg daily of thiamine should be part of any routine diet else deficiency can arise.³

Thiamine and TPP catalyze the decarboxylation of alpha-ketoacids to coenzyme A moieties, an important process in ATP synthesis in mitochondria.³ TPP plays a role in the formation of myelin.⁹ Thiamine may also affect neuronal conduction by altering membrane sodium channel function.^10,11

TREATMENT

Thiamine 100 mg/d should be given intravenously or intramuscularly in deficient patients. In patients with thiamine deficiency secondary to alcohol use, discontinuation of alcohol is imperative. In addition to the likely direct toxic influences on Schwann cells and peripheral nerves, ethanol is likely to impair thiamine utilization even when blood levels are normal.¹² Cardiomyopathy usually is quite responsive to thiamine replacement, although improvement in neurologic function is more variable and less dramatic.¹³ Motor deficits appear to improve more so than sensory.¹⁴ Some improvement is expected in most patients, but this typically occurs slowly over 6–12 months. In patients with severe neuropathy permanent deficits are typical.²

Pyridoxine not only is neurotoxic when taken in large dosages (see Chapter 20),^15–18 but can also be associated with a sensorimotor polyneuropathy when deficient. Pyridoxine deficiency is usually associated with isoniazid and hydralazine treatment.^19–21 Pyridoxine deficiency may also result from malnutrition (e.g., chronic alcoholism) or in patients receiving chronic peritoneal dialysis.²² The symptoms of vitamin B6 deficiency are nonspecific. Affected individuals manifest with a sensory greater than motor polyneuropathy similar to most idiopathic neuropathies. The electrophysiology studies reflect an axonal sensorimotor polyneuropathy.^19,20 Vitamin B6 levels can be measured in blood. Deficient patients should be treated with 50–100 mg/d of vitamin B6.^23,24 This should also be given prophylactically in patients being treated with isoniazid or hydralazine.²⁵

CLINICAL FEATURES

Patients with vitamin B12 deficiency can present with central nervous system (CNS) or peripheral nervous system (PNS) abnormalities with or without hematologic findings (megaloblastic anemia).^26–34 Those affected may manifest with numbness and sensory ataxia due to posterior column dysfunction and spastic weakness due to pyramidal tract insult (subacute combined degeneration). In addition, they may have altered mental status. Most patients have signs and symptoms of both CNS and PNS involvement, with reduction of vibratory perception and proprioception, positive Romberg sign, sensory ataxia, decreased or absent reflexes at the ankles, and brisk reflexes elsewhere. Plantar responses can be either extensor or flexor. Because of the myelopathy, patients may present with numbness restricted to the hands potentially mimicking carpal tunnel syndrome. A subacute onset and constant, rather than intermittent numbness would favor vitamin B12 deficiency. A positive Lhermitte’s sign may be present owing to swelling in the cervical spinal cord.

LABORATORY FEATURES

Serum vitamin B12 assays are not sensitive, as many symptomatic patients may have serum vitamin B12 levels that are within the normal range.^35,36 Serum levels of the vitamin B12 metabolites, methylmalonic acid (MMA) and homocysteine (Hcy), are much more sensitive in detecting deficiency of B12.^36,37 MMA and Hcy levels are increased (i.e., evidence of B12 deficiency) in 5–10% of patients with serum vitamin B12 levels less than 300 pg/mL and in 0.1–1% of those with levels greater than 300 pg/mL.³⁷ We measure MMA and Hcy levels in patients with polyneuropathy who are suspected of having vitamin B12 deficiency (e.g., those with a sudden onset of symptoms, symptoms beginning in the hands, findings suggestive of myelopathy, or risk factors for vitamin B12 malabsorption). In addition, we routinely measure copper, ceruloplasmin, and zinc levels in the same group of patients as copper deficiency manifests in a virtually identical manner.

In the absence of symptomatic gastrointestinal disease, it probably is not necessary to seek a diagnosis of pernicious anemia in a patient with vitamin B12 deficiency because this information will not alter management.³⁸ A Schilling test can be done to diagnose pernicious anemia.³⁹ It is a multistep and therefore inconvenient test which is now uncommonly utilized. Anti-intrinsic factor antibodies are specific for pernicious anemia but are found in only 50% of patients.⁴⁰ The combination of elevated gastrin and antiparietal cell antibodies is more sensitive and specific for pernicious anemia.⁴¹

NCS reveal absent or reduced SNAP amplitudes with CMAPs amplitudes that are normal or slightly reduced. Motor and sensory distal latencies and conduction velocities are essentially normal or only mildly abnormal.^{26–30,34,42} Somatosensory-evoked potentials and magnetic stimulation studies may reveal prolongation of central conduction time.^29,32 Magnetic resonance imaging (MRI) scans of the cervical cord can reveal increased signal on T2 images in the posterior columns (Fig. 18-1).⁴³

HISTOPATHOLOGY

Degeneration of the posterior columns and corticospinal tracts has been found at autopsies. Nerve biopsies reveal loss of large myelinated fibers, axonal degeneration, and secondary segmental demyelination.^31,34,44

PATHOGENESIS

Cobalamin is found in meat, fish, and dairy products but is not present in fruits, vegetables, and grains. Vitamin B12 requires a transport molecule, intrinsic factor, which is synthesized and secreted by gastric parietal cells. Vitamin B12 deficiency can result from lack of dietary intake (strict vegetarian diet), lack of intrinsic factor (pernicious anemia with autoimmune destruction of parietal cells or gastrectomy), malabsorption syndromes (sprue or lower ileum resection), genetic defects in methionine synthetase, and bacteria (blind-loop syndrome) or bacterial or parasitic consumption prior to its absorption. Cobalamin functions as an enzyme necessary for demethylation of methyltetrahydrofolate.⁴⁵ Tetrahydrofolate, in turn, is required for the production of folate coenzymes that are necessary for DNA synthesis. The pathogenic mechanism for the neuropathy/myelopathy associated with cobalamin deficiency is not known but may be related to impairment in DNA synthesis, decreased methylation of myelin phospholipids, or buildup of methylmalonic and propionic acids that serve as abnormal substrates for fatty acid synthesis, leading to aberrant myelination.⁴⁵

TREATMENT

We generally treat deficient patients with B12 1,000 μg IM/week for 1 month, followed by 1,000 μg IM/month thereafter. It may be possible to treat vitamin B12 deficiency with oral replacement. A randomized trial comparing treatment with 2,000-mg oral vitamin B12/day to 1,000-mg intramuscular vitamin B12/month showed similar improvements in hematologic indices, serum MMA and Hcy, and neurologic symptoms.⁴⁶ However, a minority of subjects had neurologic symptoms, and the methods by which clinical efficacy was assessed were lacking.

Approximately 2% of patients experience worsening sensory symptoms for unclear reasons during the first month of treatment.⁴⁷ The response to treatment of vitamin B12 deficiency polyneuropathy, separate from other neurologic complications of vitamin B12, has not been well studied. Patients with vitamin B12 deficiency polyneuropathy/myelopathy probably do not show an immediate response to treatment and may not respond at all.^34,48 The duration of symptoms is an important determinant of treatment response.^47,49,50

Nitrous oxide can inactivate methylcobalamin, leading to neuropathy and subacute combine degeneration in individuals with low or borderline vitamin B12 levels, euphemistically referred to as “anesthetica paresthetica.”^51–54 Physical examination, electrodiagnostic findings, and nerve biopsies are similar to that seen in B12 deficiency, as described in the previous section.

CLINICAL FEATURES

Folate deficiency is associated with neurologic abnormalities similar to those complicating B12 deficiency.^55,56 Subacute combined degeneration of the posterior columns and corticospinal tracts, sensorimotor peripheral neuropathy, and altered mental status can develop.

LABORATORY FEATURES

Serum folate levels should be reduced. It is necessary to measure both serum folate and vitamin B12 levels to define a pure folic acid deficiency. Megaloblastic anemia may be evident on a complete blood count and smear. Sensory and motor NCS are similar to those seen with B12 deficiency.

PATHOGENESIS

Folate is found in fruit and vegetables and in liver. It is primarily absorbed in the proximal jejunum. Isolated folic acid deficiencies are extremely rare but can occur in the elderly on poor diets, alcoholics, young persons’ consuming only snack foods, partial gastrectomies, duodenojejunal resections, celiac disease, and disorders of the jejunal mucosa.^55,56 Several drugs (e.g., phenytoin, phenobarbital, sulfasalazine, and colchicine) can also interfere with the optimal utilization of folic acid. The mechanism by which folic acid deficiency results in a polyneuropathy is not known; however, folic acid is required in DNA synthesis.

TREATMENT

Administration of folic acid usually results in good clinical recovery.

CLINICAL FEATURES

Vitamin E or alpha-tocopherol is a lipid-soluble antioxidant vitamin that is present in the lipid bilayer constituting the cell membrane.^57,58 There is a close relationship between the metabolism of lipids and that of vitamin E. There are three major mechanisms associated with vitamin E deficiency: (1) deficient fat absorption (e.g., cystic fibrosis, chronic cholestasis, short-bowel syndrome, and intestinal lymphangiectasia), (2) deficient fat transport (abetalipoproteinemia, hypobetalipoproteinemia, normotriglyceridemic abetalipoproteinemia, and chylomicron retention disease), and (3) a genetically based abnormality of vitamin E metabolism. Patients with vitamin E deficiency usually present with progressive difficulty ambulating and impaired coordination of the hands.^59–62 Some individuals complain of weakness and sensory loss. Dysarthria can also occur.