미량원소 결핍에 의한 '감각장애" - 비타민 B1(티아민), B12(코발라민), 비타민E, B6(피리독신), B3(나이아신), 구리 결핍

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미량원소 치유의학의 세계

영양소결핍에 의한 신경병증

비타민 B1, 6, 12, E, 나이아신, 구리

Nutritional Neuropathies

Nancy Hammond, MD, Yunxia Wang, MD, Mazen Dimachkie, MD, and  Richard Barohn, MD

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Introduction

Malnutrition can affect all areas of the nervous system. Risk factors for malnutrition include alcohol abuse, eating disorders, older age, pregnancy, homelessness, and lower economic status. Any medical condition that affects the GI tract can also impair absorption of essential vitamins. Nutritional deficiencies have been described in patients with inflammatory bowel disease, fat malabsorption, chronic liver disease, pancreatic disease, gastritis, and small bowel resections. Patients receiving total parental nutrition (TPN) are also at risk for vitamin deficiency and TPN formulations should be carefully formulated to include supplemental vitamins and trace minerals. Neurological complications following gastric bypass surgery are increasingly recognized. 

영양결핍에 의한 감각장애는 알콜중독, 식이섭취장애, 고령, 임신, 가난, 기아, 위장기능장애, 염증성 장질환, 간질환, 지방섭취장애, 취장질환, 위염 등이 원인. 

Nutritional neuropathies manifest either acutely, subacutely, or chronically. They can be either demyelinating or axonal.

영양소 결핍에 의한 신경병증은 급성, 아급성, 만성적으로 나타남.

그것은 demyelinating or axonal의 형태로 구분할 수 있음. 

A unique class of peripheral neuropathy with coexistent myelopathy, also called myeloneuropathy, can also been seen with nutritional neuropathies. Myeloneuropathy has been described with deficiencies of vitamin B12 and copper.

중추신경과 말초신경병증을 동시에 일으키는 영양소 결핍은 비타민 B12, 구리 임. 

Patients with myeloneuropathy will present with both upper motor neuron and lower motor neuron signs. Peripheral neuropathy may mask the symptoms and signs of the myelopathy presenting a diagnostic challenge. Hyper reflexia may be difficult to assess in the presence of severe peripheral neuropathy and ankle jerks may be absent. Muscle weakness may impair the toe extensors, so Babinski sign may not be present. Besides spinal cord/cauda equina arteriovenous malformation, the clinician should suspect myeloneuropathy when the predominant complaint is gait impairment or bowel or bladder dysfunction in the setting of a peripheral neuropathy.

비타민 B1 티아민 결핍

Thiamine Deficiency

Pathogenesis

Thiamine (vitamin B1) is a water-soluble vitamin present in most animal and plant tissues. Neuropathy due to thiamine deficiency, known as beriberi, was the first clinically described deficiency syndrome in humans. Beriberi may manifest with heart failure (wet beriberi) or without heart failure (dry beriberi). Thiamine deficiency is also responsible for Wernicke’s encephalopathy and Korsakoff’s syndrome. Thiamine is absorbed in the small intestine by both passive diffusion and active transport and rapidly converted to thiamine diphosphate (TDP). TDP serves as an essential co-factor in cellular respiration, ATP production, synthesis of glutamate and γ-aminobutyric acid[1] and myelin sheath maintenance. Only about 20 days of thiamine are stored in the body, and thiamine deficiency can start to manifest in as little as three weeks. The recommended daily allowance (RDA) for thiamine ranges from 1.0 mg per day for young healthy adults to 1.5 mg per day for breastfeeding women[2]. Athletes and patients with higher metabolic needs as seen during pregnancy, systemic infections, and certain cancers need a higher daily intake of thiamine. Thiamine deficiency is rare in industrialized countries and is most commonly seen in the setting of chronic alcohol abuse, recurrent vomiting, AIDS, long-term total parenteral nutrition, eating disorders and weight reduction surgery.

각기병 beriberi

티아민은 약 20일치 몸에 저장되어 있음.

티아민 결핍은 드물지만 백미를 주식으로 하는 곳에서 알콜중독, 지속적인 구토, 에이즈, 영양결핍, 섭식장애 등이 있는 경우에는 티아민 결핍이 발생함. 

커피는 티아민 흡수를 방해함. 

Clinical Features

Symptoms usually develop gradually over weeks to months, but sometimes they may manifest rapidly over a few days mimicking Gullain Barré Syndrome[3, 4]. Fatigue, irritability, and muscle cramps may appear within days to weeks of nutritional deficiency[5]. Clinical features of thiamine deficiency begin with distal sensory loss, burning pain, paraesthesias or muscle weakness in the toes and feet[6]. There is often associated aching and cramping in the lower legs. Left untreated, the neuropathy will cause ascending weakness in the legs and eventually evolve to a sensorimotor neuropathy in the hands. Beriberi may include involvement of the recurrent laryngeal nerve, producing hoarseness and cranial nerve involvement manifesting as tongue and facial weakness [7]. Oculomotor muscle weakness and nystagmus have been attributed to beriberi, but these manifestations are more likely due to coexistent Wernicke’s disease. Approximately 25% of patients with thiamine deficient polyneuropathy may also have Wernicke’s encephalopathy which manifests as ophthalmoplegia, ataxia, nystagmus and encephalopathy[6].

타아민 결핍으로 인한 각기병의 신경병증은 대개는 몇주, 몇개월에 걸쳐 천천히 나타나는데 때로는 길랑바레증후군처럼 갑자기 나타나기도 함. 

피로, 흥분, 근육경련이 나타남. 

티아민 결핍으로 인한 신경병증 증상은 말초감각손실, 타는듯한 통증, 감각이상, 손발의 근력약화. 

하지의 통증과 근육경련이 흔히 나타남. 치료하지 않으면 ....

Diagnosis

Blood and urine assays for thiamine are not reliable for diagnosis of deficiency. Measurement of thiamine pyrophosphate by high-performance liquid chromatography[8] or erythrocyte transketolase activation may be preferred for assessment of thiamine status[9]. However, the precise sensitivity and specificity for those assays has not been established. Testing must be performed before thiamine supplementation is given. Electrodiagnostic testing shows an axonal sensorimotor polyneuropathy worse in the lower extremities and nerve biopsies demonstrate axonal degeneration [6].

Management

When a diagnosis of thiamine deficiency is made or suspected, thiamine replacement should be provided until proper nutrition is restored. Thiamine is usually given intravenously or intramuscularly at an initial dose of 100 mg followed by 100 mg per day. Cardiac manifestations may improve within hours to days while neurological improvement may take 3–6 months with motor manifestations responding better than sensory symptoms[10]. Some improvement is expected in most patients, but this typically occurs slowly, and in patients with severe neuropathy, there may be permanent deficits[11].

비타민 B12 코발라민 결핍에 의한 신경병증

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Vitamin B12

Pathogenesis

Vitamin B12 (cobalamin) is present in animal and dairy products and is synthesized by specific microorganisms. Humans depend on nutritional intake for their vitamin B12 supply. Vitamin B12 deficiency has been observed in 5% to 20% of older adults and up to 40% of older adults have low serum vitamin B12 levels[12]. The RDA for vitamin B12 is 2.4 mcg daily[2].

비타민 B12 코발라민은 ...  5~20%의 노인에게서 흔히 관찰됨. 

노인의 40%이상에서 비타민 B12 혈중농도가 낮음. 

Vitamin B12 is an integral component of two biochemical reactions in human. The first is the formation of methionine by methylation of homocysteine. A byproduct of this reaction is the formation of tetrahydrofolate, an important precursor of purine and pyrimidine synthesis. The second important reaction is the conversion of L-methylmalonyl coenzyme A into succinyl coenzyme A which is essential for formation of the myelin sheath.

Vitamin B12 is liberated from food by stomach acid and pepsin. Liberated B12 then binds to R proteins secreted in the saliva and gastric secretions. Cobalamin is released from the R protein in the small intestine and binds to intrinsic factor. The vitamin B12-intrisic factor complex is then absorbed in the terminal ileum.

Cases of vitamin B12 deficiency can be due to malabsorption, pernicious anemia, gastrointestinal surgeries and weight reduction surgery. As vitamin B12 is only found in animal products strict vegan diets lack vitamin B12 and must be supplemented. Certain medications may contribute to vitamin B12 deficiency namely proton pump inhibitors[13] and metformin[14]. An underappreciated cause of Cbl deficiency is food-cobalamin malabosrption. This typically occurs in older individuals and results from an inability to adequately absorb Cbl bound in food protein. These patients can absorb free Cbl without difficulty. Therefore, Schilling tests will be normal. No apparent cause of deficiency is identified in a significant number of patients with Cbl deficiency.

The most common cause of B12 deficiency is pernicious anemia. This autoimmune disorder is characterized by destruction of the gastric mucosa, and the presence of parietal cell and intrinsic factor antibody leading to impaired B12 absorption. The disorder is more common in African-Americans and in patients with Northern European background.

Chronic exposure to nitrous oxide has been associated with subacute combined degeneration [15]. The mechanism by which nitrous oxide induces vitamin B12 deficiency is by inactivation of methyl-cobalamin thereby inhibiting the conversion of homocysteine to methionine and methyltetrahydrofolate (MTHF) and 5-methylene-tetrahydrofolate (THF), which are required for myelin sheath protein and DNA synthesis.

Clinical Features

Vitamin B12 (cobalamin) deficiency is associated with hematologic, neurologic, and psychiatric manifestations. Subacute combined degeneration, neuropsychiatric symptoms, peripheral neuropathy and optic neuropathy are the classic neurological consequences of B12 deficiency. Patients may present with neurological symptoms regardless of a normal hematological picture. The neuropathy associated with B12 deficiency usually begins with sensory symptoms in the feet.

Differentiating vitamin B12 deficiency-related polyneuropathy from cryptogenic sensory polyneuropathy (CSPN) can be difficult on clinical grounds only. Clinical features useful to identify vitamin B12 deficiency related peripheral neuropathy are the acuteness of symptoms onset, and concomitant involvement of upper and lower extremities[16]. Sometimes the sensory symptoms and signs first appear in the upper extremities or the “numb hand syndrome” [17–19]. When this occurs with other findings of a myeloneuropathy, immediately consider B12 as well as copper deficiency (see below). The myeloneuropathy findings often consist of significant proprioception and vibration, increased tone, weakness in a corticospinal tract distribution, (ex. hip and knee flexors), brisk knee and arm reflexes, Hoffman’s signs in the fingers, and extensor plantar responses in the toes.

Histopathological studies have showed breakdown and vacuolization of central nervous system myelin under B12 deficiency states [20]. In contrast to the demyelinating features seen in the spinal cord, axonal neuropathy is seen on nerve biopsies and nerve conduction studies in vitamin B12 polyneuropathy.

Diagnosis

Diagnosis of B12 deficiency is usually made in the presence of typical neurological symptoms, hematological abnormalities, and serum vitamin B12 levels less than 200 pg/ml, though a significant proportion of vitamin B12 deficiency patients may have serum levels that are within the low normal range up to 400 pg/ml. Measurement of the serum metabolites methylmalonic acid (MMA) and homocysteine (Hcy) can improve the sensitivity significantly in patients with low normal range of B12 (300–400 pg/ml) when there is high clinical suspicion [21]. Though elevated MMA and Hcy suggest B12 deficiency, it is necessary to rule out other conditions associated with such abnormal levels, such as renal insufficiency and hypovolemia. Isolated Hcy elevation may also be seen in hypothyroidism, deficiency of folic acid and pyridoxine, cigarette smoking, and advanced age.

Historically, the Schilling test was used to diagnose pernicious anemia. Today, it is difficult to obtain a Schilling test due to the unavailability of the radioisotope. Anti-intrinsic factor and anti-parietal cell antibodies can be helpful in the diagnosis of pernicious anemia with high specificity and low sensitivity for the former and high sensitivity and low specificity for the latter. In typical cases with myelopathic symptoms, increased T2 signal intensity is seen in the posterior column on magnetic resonance imaging studies (see imaging below for copper deficiency which is similar).

Treatment [17]

Early diagnosis is critical since patients with advanced disease may be left with major residual disability. Common treatment regimen includes administration of 1000 mcg intramuscularly daily for 5–7 days, followed by 1000 mcg IM monthly. Other approaches are a once-a-week injections for four weeks, and then monthly injections. Either is probably acceptable. B12 levels should be monitored occasionally to prevent inadequate treatment or non-compliance. Initial severity and duration of symptoms, and the initial hemoglobin measurements correlate with the residual neurological damage after cobalamin therapy. This inverse correlation between severity of anemia and neurologic damage is not understood. If a neurologic response occurs, it does so within the first six months of therapy, although further improvement may occur with time. On the other hand, sometimes treatment only prevents further neurologic impairment, and often patients are left with the neurologic deficits found prior to treatment.

Patients with food-cobalamin malabsorption can absorb free cobalamin and, therefore can be treated with oral cobalamin supplementation. Oral cobalamin replacement therapy may also be an option for patients with pernicious anemia. The daily requirement for cobalamin is 1 to 2 μg, and approximately 1% of orally administered cobalamin can be absorbed by patients with pernicious anemia. Therefore, theoretically, an oral cobalamin dose of 1000 mg per day should be sufficient. Although oral cobalamin may seem preferable to intramuscular injections, parenteral therapy is actually less expensive (if it is self-administered). Given the absence of convincing data regarding oral replacement in patients with neurologic deficits, the authors’ practice is to use intramuscular cobalamin therapy when the etiology is pernicious anemia. However, a reasonable compromise may be to switch to oral therapy after several months and periodically monitor MMA or Hcy levels.

There is no clear evidence that folic acid therapy precipitates or exacerbates B12 deficiency-related neuropathy, however pharmacological doses of folic acid may reverse the hematological abnormalities of cobalamin deficiency, masking early recognition of symptoms, therefore, resulting in the development or progression of neurological symptoms.

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Vitamin E Deficiency

Pathogenesis

Vitamin E is abundantly available in the diet and is present in animal fat, nuts, vegetable oils and grains. Alpha- tocopherol is the biologically active form of vitamin E in humans. The RDA of vitamin E is 15 mg per day of alpha-tocopherol[22]. Dietary vitamin E is incorporated into chylomicrons and passively absorbed in the intestines. This process requires bile acids, fatty acids, and monoglycerides for absorption[9]. Vitamin E is delivered to tissues via the chylomicrons and then chylomicron remnants when vitamin E is transferred to very low-density lipoproteins (VLDL) via alpha-tocopherol transfer protein (TTP). Most vitamin E deficiencies occur in patients with malabsorption or transport deficiencies. Patients with cystic fibrosis who have malabsorption can develop vitamin E deficiency.

The pathogenesis of vitamin E deficiency is poorly understood. Vitamin E is an antioxidant and a free radical scavenger, and it is postulated that the neurological manifestations of vitamin E deficiency are primarily related to the loss of this protective function. Fat malabsorption is the main cause of vitamin E deficiency. Isolated vitamin E deficiency is a rare autosomal recessive disorder caused by a mutation in the alpha-tocopherol transfer protein gene on chromosome 8q13 [23]. Another hereditary disorder leading to vitamin E deficiency is abetalipoproteinemia, a rare autosomal dominant disorder resulting from mutations in the microsomal triglyceride transfer protein[24]. Patients with this disorder have fat malabsorption and deficiencies of many fat soluble vitamins. If left untreated, patients with this disorder develop pigmented retinopathy, loss of vibration and proproprioception, loss of deep tendon reflexes, ataxia and cerebellar degeneration as well as generalized muscle weakness[25].

Clinical features

Because alpha- tocopherol is stored in adipose tissues, symptoms of vitamin E deficiency may take 5–10 years to manifest. The onset of symptoms is usually slow and progressive. Clinical features of vitamin E deficiency mimic that of Friederich’s ataxia and include ataxia, hyporeflexia, and loss of proprioception and vibration. Other findings on neurological examination may include dysarthria, nystagmus, ophthalmoparesis, retinopathy, head titubation, decreased sensation, and proximal muscle weakness. Pes cavus, and scoliosis may be present. Nerve conduction studies in vitamin E deficiency show a sensory predominant axonal neuropathy. Nerve biopsy shows loss of large myelinated fibers with evidence of regeneration. [26]. Electromyography is often normal, although mild signs of denervation may occur. SSEP may show abnormalities consistent with posterior column involvement [27].The principal pathologic features of vitamin E deficiency include swelling and degeneration of large myelinated axons in the posterior columns, peripheral nerves, and sensory roots[9].

Diagnosis

Diagnosis is made by measuring alpha-tocopherol levels in the serum. Serum vitamin E levels may be normal even when deficiency is present. The ratio of total serum vitamin E to the total serum lipid concentration has been suggested as a superior assessment of vitamin E status[28].

Management

Treatment of Vitamin E deficiency may reverse or halt the progression of the neurological symptoms. Treatment begins with oral supplementation of Vitamin E 400 international units twice daily, with a gradual increase in the dose until normalization of serum vitamin E levels. Patients with abetalipoprotienemia may require very large doses of vitamin E to normalize serum vitamin E levels. Malabsorption syndromes may require treatment with water-miscible or intramuscular preparations of vitamin E.

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Vitamin B6

Pathogenesis

Vitamin B6, or pyridoxine, is unique in that either a deficiency or an excess can cause a neuropathy. Pyridoxine is readily available in the diet and dietary deficiency of B6 is rare. Humans are not able to synthesize B6, so dietary intake is essential. After absorption, pyridoxine is converted into pyridoxal phosphate which is an important co-factor in numerous metabolic reactions. The RDA for pyridoxine is 1.3 mg daily with the upper limit of 100mg daily[2]. Doses of 50mg to 100mg of vitamin B6 should mainly be used in certain conditions such as pyridoxine deficient seizures and patients taking certain medications to avoid toxicity.

Vitamin B6 deficiency is most commonly seen in patients treated with the certain medications that are B6 antagonists, namely isoniazid, phenelzine [29], hydralazine [30], and penicillamine. B6 deficiency can also be seen in patients receiving chronic hemodialysis [31]. Vitamin B6 deficiency may also result from the malnutrition due to chronic alcoholism and in patients with high metabolic needs such as the pregnant or lactating woman. Risk factors for vitamin B6 toxicity are excessive intake of supplements [32,33].

Clinical Features

In infants, pyridoxine deficiency is a cause of seizures. In adults neuropathy due to B6 deficiency starts with numbness, paresthesias, or burning pain in the feet which then ascends to affect the legs and eventually the hands. Neurological examination reveals a length dependent polyneuropathy with decreased distal sensation, reduction of deep tendon reflexes, ataxia and mild distal weakness.

Vitamin B6 toxicity produces a sensory ataxia, areflexia, and impaired cutaneous sensation. Patients often complain of burning or paresthesias. Electrodiagnostic testing usually shows a sensory neuronopathy, but with severe toxicity motor nerves can be affected as well[33]. Symptoms of toxicity can be seen with doses as low as 100 mg per day[34].

Diagnosis

Vitamin B6 deficiency can be detected by direct assay of blood or urine. Pyridoxal phosphate can also be measured in the blood. Nerve conduction studies reveal severely reduced sensory nerve action potentials with preserved CMAP. Sural nerve biopsy confirm‎s axonal degeneration of small and large myelinated fibers.

Management

Vitamin B6 supplementation with 50mg per day is suggested for patients being treated with isoniazid or hydralazine. Daily B6 doses of 10 mg to 50 mg are recommended for patients undergoing hemodialysis[31].

The treatment for B6 toxicity is to stop the exogenous B6. Patients may continue to have symptom progression for 2–3 weeks following the discontinuation of vitamin B6 before a gradual improvement starts, a phenomenon known as coasting.

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Pellagra (Niacin Deficiency)

Pathogenesis

Pellagra is the clinical manifestation of nicotinic acid (niacin or B3) deficiency. The classic clinical triad of pellagra is dermatitis, dementia, and diarrhea. Pellagra was once endemic in the United States and Europe and is still occasionally encountered. Most modern patients with pellagra have other risk factors for malnutrition such as homelessness[35], anorexia[36–38], certain cancers, or malabsorption[39].

Niacin is absorbed in the intestine by simple diffusion. The RDA for adults for niacin is 14mg to 16mg a day[2]. Niacin and its derivatives are important in carbohydrate metabolism

Clinical Features

Early neurological symptoms are predominantly neuropsychiatric including apathy, inattention, irritability, and depression. Without treatment symptoms can progress to stupor or coma. Isolated niacin is not known to be a cause of neuropathy and most patients deficient in niacin have other nutritional deficiencies as niacin alone will not improve neuropathy [9].

Diagnosis

There is no reliable measure of serum niacin.

Management

Oral replacement of nicotinic acid of 50 mg two or three times a day is recommended for treatment, but dose may be limited due to flushing. Nicotinamide can be used as a substitute in patients unable to tolerate nicotinic acid. Pellagra should be considered in any patient deficient in vitamin B12 or thiamine whose cognition does not improve with supplementation.

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Copper Deficiency

Pathogenesis

Copper deficiency has long been recognized as a cause of hematologic abnormalities in humans, but neurological abnormalities due to copper deficiency were not reported until 2001 [40]. Since then copper deficiency has been reported to cause either myelopathy or a myeloneuropathy[41]. Copper deficiency has also been reported in association with peripheral neuropathy[42, 43], but it is not clear from these case reports if the neuropathy was isolated or in association with other neurological manifestations. Copper sources are common in most western diets and copper rich foods include seafood, nuts, wheat and grains. The RDA for copper for adults is 900 mcg daily[44].

Copper is essential in many oxidative reactions in the body. These reactions can generate free radicals which are toxic to the cell and so both the absorption and excretion of copper are tightly regulated by cells.

Gastric acid is needed to solubilize dietary copper. Afterward, it is absorbed by both active and passive mechanisms in the intestines. The active transport mechanism predominates when dietary copper is low and augmented by passive diffusion when dietary copper is high. Gastric acid is needed to solubilize dietary copper. Once copper enters the serum it is bound to plasma proteins and transported via the portal vein to the liver. Here copper is incorporated into ceruloplasmin for delivery to cells. If copper supplies are high, the liver excretes excess copper into the bile.

The most common cause of copper deficiency is prior gastric surgery. Exogenous zinc intake from either excessive intakes of zinc supplements [45]or use of older zinc containing denture creams[46, 47]has also been postulated as a cause of copper deficiency with neurological manifestations. Both zinc and copper bind to metallothionein in the enterocytes. Excessive zinc intake leads to up regulation of these complexes and copper has a higher affinity for these receptors than zinc leading copper to displace zinc. The zinc is then absorbed into the bloodstream and the copper/metallothionein complex remains in the enterocyte and is excreted in the feces following normal sloughing of these cells. Copper deficiency can also be seen in association with excess iron consumption and malabsorption syndromes.

Clinical Features

The majority of patients present with gait difficulty and lower limb paresthesias. Neurological examination reveals loss of proprioception and vibration due to dorsal column dysfunction and sensory ataxia. Upper motor neuron signs such as bladder dysfunction, brisk knee jerks, and extensor plantar reflexes can also be elicited[41]. A motor neuron disease-like presentation has also been reported [48, 49].

MRI studies of the spinal cord are reportedly abnormal in 47% of cases showing increased T2 signal in the posterior columns in both the cervical and thoracic spinal cord[50] [Figure 1]. Neurophysiologic studies are abnormal in most patients with a copper myelopathy. Nerve conduction studies are compatible with mixed, motor and sensory axonal polyneuropathy[41].

Figure 1

Axial (A) and sagittal (B) T2 weighted MRI scans demonstrating posterior column hyperintensity (arrows).

Diagnosis

Hematologic abnormalities are common in patients with copper deficiency, particularly anemia or occasionally myelodysplastic syndrome. In copper deficiency serum copper, ceruloplasmin and urinary excretion of copper will be low, and zinc often will be high. Ceruloplasmin is an acute phase reactant, so this may not be an adequate marker in certain patients.

Management

In patients with copper deficiency due to excessive zinc intake, it is important to discontinue the exogenous zinc. Replacement with 2 mg of elemental copper three times a day orally is the preferred method of copper replacement. Our clinic combines oral replacement with a 2 mg weekly IV infusion for one month. Copper salts (copper gluconate or copper chloride) may be given intravenously. Hematologic abnormalities due to copper deficiency often respond completely and promptly. While copper replacement will stop progression of neurological abnormalities patients are often left with residual symptoms[41].

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Neuropathy Following Bariatric Surgery

Obesity is an increasing medical challenge in both developed and developing counties. In 2010, more than 35 % of Americans were obese, and 5% of Americans were morbidly obese. Bariatric surgery is an effective procedure for weight loss in morbidly obese patients refractory to a diet and exercise program. More than 200,000 bariatric surgeries were performed in 2008. The number expected to rise with the increase obesity population.

Neurological complications have gained attention in association with bariatric surgery. Neurological complications can involve the entire nervous system ranging from diffuse encephalopathy to peripheral neuropathy to myopathy. Among the neurological complications seen after bariatric surgery, peripheral neuropathies were the most common and may affect up to 16 % of operated patients[51]. There were three dominant peripheral neuropathy patterns seen after bariatric surgery: sensory-predominant polyneuropathy (acute, subacute and chronic), mononeuropathy and radiculoplexopathy, with the first two being more common than the radiculoplexopathy[51]. Onset of symptoms could be subacute to insidious; the time of onset varies from months to years, post-surgery [52,53]. Protracted vomiting and fast weight loss were risk factors to develop peripheral neuropathy after bariatric surgery[51, 54].

Malnutrition was not uncommon for morbidly obese patients prior to their bariatric surgery. Twenty nine percent patients were thiamine deficiency among 379 consecutive patients undergoing bariatric surgery reported by Flancbaum[55]. The most common nutrient deficiencies following bariatric surgery are deficiencies of thiamine, vitamin B12, vitamin E, vitamin D, and copper[56]. Bariatric procedures cause or worsen malnutrition by restriction of intake or combined restriction of intake and impaired absorption. Peripheral neurological complications after bariatric surgery are probably related to multiple nutritional deficiencies. Thiamine deficiency often was seen in painful polyneuropathy post bariatric surgery, which can present without central involvement (encephalopathy). B12 or copper deficiencies were the cause of myeloneuropathy, though data was not consistent [51].

Thiamine, B12 and copper should be a part of baseline metabolic work-up for patient undergoing bariatric surgery, especially patients who were on a diet prior to surgery. Education regarding the importance of adherence to nutritional supplements after surgery is the key to prevent peripheral neuropathy developed post bariatric surgery.

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Key Points

• Neuropathies due to nutritional problems can affect certain patient populations and have a varied presentation due to multiple co-existent nutritional deficiencies.

• Clinicians should consider nutritional neuropathies in patients presenting with neuropathies.

• Clinicians should be alert for signs and symptoms of neuropathy in patients who have had bariatric surgery.

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Footnotes

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Continuum (Minneap Minn). 2014 Oct; 20(5 Peripheral Nervous System Disorders): 1293–1306. 

doi: 10.1212/01.CON.0000455880.06675.5a

PMCID: PMC4208100

PMID: 25299283

Peripheral Neuropathy Due to Vitamin Deficiency, Toxins, and Medications

Nathan P. Staff, MD, PhD and  Anthony J. Windebank, MD, FAAN

Author information Copyright and License information Disclaimer

This article has been cited by other articles in PMC.

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Abstract

Purpose of Review:

Peripheral neuropathies secondary to vitamin deficiencies, medications, or toxins are frequently considered but can be difficult to definitively diagnose. Accurate diagnosis is important since these conditions are often treatable and preventable. This article reviews the key features of different types of neuropathies caused by these etiologies and provides a comprehensive list of specific agents that must be kept in mind.

Recent Findings:

While most agents that cause peripheral neuropathy have been known for years, newly developed medications that cause peripheral neuropathy are discussed.

Summary:

Peripheral nerves are susceptible to damage by a wide array of toxins, medications, and vitamin deficiencies. It is important to consider these etiologies when approaching patients with a variety of neuropathic presentations; additionally, etiologic clues may be provided by other systemic symptoms. While length-dependent sensorimotor axonal peripheral neuropathy is the most common presentation, several examples present in a subacute severe fashion, mimicking Guillain-Barré syndrome.

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INTRODUCTION

Toxins, medication side effects, and vitamin deficiencies frequently damage the peripheral nervous system. This susceptibility is likely a result of the metabolic demands of a neuron whose cell body and distal axon can be several feet apart. While the peripheral nervous system may be the primary organ system affected in these conditions, peripheral neuropathy often occurs within a multisystem constellation of dysfunction (Table 7-1). Knowledge of the syndromic presentations can facilitate prompt, accurate diagnosis and subsequent treatments.

- 독성물질, 약물의 부작용, 비타민 결핍은 흔히 말초신경손상을 초래함. 

- 비타민 B12, 3, 1 결핍, 납독성(lead), 비소독성(arsenic),  수은독성( mercury),  disulfiram 독성 등

  비타민 E 결핍,  탈륨독성(thallium) 

Table 7-1

Other Systems Involvement That May Provide Clues to Etiology of a Peripheral Neuropathy Due to Toxicity or Vitamin Deficiency

As with most types of peripheral neuropathies, acquiring a detailed history is crucial to the diagnosis of neuropathies caused by toxic agents and vitamin deficiencies. Careful attention must be paid to occupational and home exposures. In particular, asking about recent changes in exposures may provide useful information, as many of the toxic exposures result from new day-to-day habits. While most forms of malnutrition no longer plague developed societies, a history of gastric surgery, chronic malabsorption, or alcoholism may predict the presence of vitamin deficiencies. It is important to take a complete review of systems to determine whether a multisystem syndrome is present as this may lead to a correct diagnosis.

It is also important to recognize that other causes of neuropathy may mimic what is suspected to arise from a toxic source or a vitamin deficiency. For example, a patient with more sensory loss on examination than expected from considering his or her history, combined with high arches and hammertoes, may reflect a long-standing hereditary neuropathy that has finally become symptomatic (especially in the setting of a positive family history of neuropathy). Most toxic and vitamin deficiency–related neuropathies present in a length-dependent fashion with axonal pathology (apart from some notable exceptions detailed below). Therefore, in a neuropathy with significant asymmetry, polyradicular, or mononeuritis multiplex presentation, other etiologies should be explored further, even in the setting of documented toxicity or vitamin deficiency.

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NUTRITIONAL DEFICIENCIES

Vitamin B12

Causes of vitamin B12 deficiency can be organized by where the absorption defect occurs. A diet containing minimal animal products provides sufficient vitamin B12, so severe deficiency due to poor intake occurs only in the case of strict veganism. Within the stomach there are several etiologies that degrade the ability of vitamin B12 to bind with intrinsic factor, including pernicious anemia, atrophic gastritis, prolonged antacid use (proton-pump inhibitor or H2-antagonists),1 and gastric bypass. The final absorption of vitamin B12 in the terminal ileum may be interrupted by Crohn disease or surgical resection.2The main pathology of vitamin B12 deficiency is subacute combined degeneration within the spinal cord with loss of both corticospinal tracts and posterior columns with a concomitant axonal sensorimotor peripheral neuropathy. It is important to note that because of the involvement of the cervical spinal cord early in disease, sensory symptoms in both hands and feet may present simultaneously and provide a clue to etiology.3

On examination, the patient will exhibit signs of both upper and lower motor neuron dysfunction (sometimes appearing as decreased reflexes with a Babinski sign). Vitamin B12 deficiency is also associated with cognitive dysfunction. Megaloblastic anemia may be present as well, owing to the importance of vitamin B12 in DNA synthesis.

Testing to confirm‎ vitamin B12 deficiency should include both serum vitamin B12 and methylmalonic acid, which is a more accurate marker of cellular vitamin B12 levels and may be abnormal in the setting of low-normal vitamin B12 levels. Elevated levels of gastrin and intrinsic factor antibodies can also establish the diagnosis of pernicious anemia. Supplementation for vitamin B12 deficiency should be provided parenterally since poor oral absorption is usually the cause of the disease. Supplementation with vitamin B12 typically halts progression of the disease, but does not reverse it since much of the disability is secondary to the spinal cord pathology. Supplementation recommendations for vitamin B12 and other vitamin deficiencies are outlined in Table 7-2.

Table 7-2

Vitamin Supplementation Recommendations in Symptomatic Vitamin Deficiencies

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Copper

Acquired copper deficiency may look very clinically similar to vitamin B12 deficiency and should be investigated in parallel with patients presenting with a myeloneuropathy.4 Copper is absorbed in the stomach and small bowel, and gastric surgery has been associated with copper deficiency. Additionally, copper absorption is competitive with zinc absorption and reports have shown an association between use of zinc supplementation and presence of copper deficiency (Case 7-1). Therefore, it is useful to test both copper and zinc when this condition is suspected. Anemia is also a common complication of copper deficiency.

- 구리는 위와 소장에서 흡수하고 위절제술은 구리결핍의 주요 원인..

The treatment strategy for copper deficiency is to combine copper supplementation with identifying and removing excess zinc intake.5 The goal is to halt progression of the myeloneuropathy as reversibility may be limited.

Case 7-1 

A 65-year-old man with no significant past medical history developed progressive gait ataxia over a 3-month period. He had multiple falls without significant injuries. He progressed to requiring a walker for gait stability at the time of his examination. He denied any frank weakness, bowel/bladder difficulties, erectile dysfunction, orthostatism, dry eyes/dry mouth, or cognitive changes. There was no family history of neuromuscular diseases.

On neurologic examination, the patient had normal mentation and cranial nerves. He exhibited mild weakness in toe extensors, but strength was otherwise intact. Tone was normal and no tremor was present. He had decreased sensory perception to light touch, vibration, and joint position sense up to the ankles, and heat-pain sensation was normal. Reflexes were brisk at the knees and reduced at the ankles, and Babinski sign was present bilaterally. There were no abnormalities on finger-to-nose or heel-to-shin testing when allowing visual cues. He exhibited a wide-based gait, but was able to rise on his toes and heels. He was unable to tandem walk and had a positive Romberg sign.

MRI of the cervical spine demonstrated nonenhancing, mild T2 hyperintensity of the dorsal columns from C3 to C6 without any spinal canal stenosis. Nerve conduction study showed reduced amplitudes of lower extremity compound muscle action potentials and absent sural sensory nerve action potentials. Conduction velocities, distal latencies, and F waves were normal. On EMG, long-duration motor unit potentials were observed in distal musculature. The study was interpreted as consistent with an axonal sensorimotor peripheral neuropathy.

Laboratory studies were notable for a microcytic anemia, reduced serum copper level, and increased serum zinc level.

On further review of systems, the patient endorsed taking megadoses of zinc supplementation, and was treated with oral supplementation of 2 mg elemental copper daily. His symptoms stabilized, and he noted some functional improvement after intensive physical therapy.

Comment. This case illustrates a copper deficiency myeloneuropathy, which presents in a similar fashion to subacute combined degeneration and may be associated with excessive exogenous zinc supplementation (either through supplements or zinc-containing dental cream). Copper supplementation stabilizes neurologic deficits, but reversibility is minimal.

The treatment strategy for copper deficiency is to combine copper supplementation with identifying and removing excess zinc intake.5 The goal is to halt progression of the myeloneuropathy as reversibility may be limited.

Vitamin E

While the primary neurologic deficit in vitamin E deficiency is a spinocerebellar syndrome, there is often a concomitant large fiber sensory-predominant axonal peripheral neuropathy. Vitamin E deficiency occurs in the setting of severe fat malabsorption (eg, biliary dysfunction, cystic fibrosis) or genetic disorders (eg, ataxia with vitamin E deficiency or abetalipoproteinemia). Strategies to treat vitamin E deficiency include improving fat absorption and oral vitamin E supplementation.

Vitamin B6

Vitamin B6 is unusual in that it is associated with peripheral neuropathy either when deficient or in excess. Vitamin B6 deficiency-related peripheral neuropathy primary occurs in the setting of isoniazid treatment for tuberculosis, which can be prevented with concurrent supplementation with vitamin B6. Excess of vitamin B6 can lead to a sensory neuropathy or neuronopathy, which most obviously occurs with megadoses of vitamin B6 (greater than 2 g/d), but has also been reported in patients taking lower doses (50 mg/d) over long periods.6 Since many patients with neuropathy take B-vitamin supplementation, it is worthwhile to ensure they are not taking high doses of vitamin B6 and worsening their disease.

Vitamin B1 (Thiamine)

A progressive axonal sensorimotor peripheral neuropathy due to vitamin B1 (thiamine) deficiency is a part of beriberi syndrome. Atrophic skin changes are also commonly present. The neuropathic presentation of thiamine deficiency is quite varied and may precede the systemic and cognitive symptoms. When thiamine deficiency occurs due to strict malnutrition, there is often involvement of cranial nerves (tongue, facial, and laryngeal weakness), but progressive motor-predominant neuropathy mimicking Guillain-Barré syndrome has also been reported.7 Classic beriberi is very rare in developed countries, where it is often precipitated by gastrectomy; however, neuropathy occurring in severe alcoholics often shares qualities with beriberi (see discussion below). Finally, Wernicke-Korsakoff syndrome in alcoholics is due to thiamine deficiency, and administration of parenteral thiamine supplementation prior to glucose-containing IV solutions can help prevent onset of this condition.

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TOXIC NEUROPATHIES

Alcohol

Alcoholism is one of the most common associations with the development of a progressive axonal sensorimotor peripheral neuropathy. In 2012, 6.5% of Americans age 12 or older self-reported to having five or more drinks on each of 5 or more days in the past 30 days.8 Therefore, it is very important to take a careful history of alcohol use in all patients presenting with neuropathy. Underreporting of alcohol consumption is very common, and approaching this questioning in a nonjudgmental fashion is key. If alcoholism is suspected, it is helpful to have early involvement of trained chemical dependency personnel.

Because alcoholism is common and often has associated malnutrition, it has been difficult to epidemiologically determine whether this association is a direct toxic effect of alcohol,9 a secondary effect of chronic malnutrition and multiple vitamin deficiencies,10 or both. Treatment of alcoholism-associated peripheral neuropathy requires abstinence and a return to a well-balanced diet, which thus treats both possible etiologies. Furthermore, given that alcohol is a known neurotoxin in laboratory studies,11 it is appropriate to counsel any patient with an established peripheral neuropathy, regardless of etiology, on the moderation of alcohol intake. For further information on the neuromuscular complications of alcohol, refer to the article “Neurologic Complications of Alcoholism” by James M. Noble, MD, and Louis H. Weimer, MD, FAAN, in the June 2014 issue of CONTINUUM.

Renal Failure

Chronic renal failure has long been associated with a length-dependent axonal sensorimotor peripheral neuropathy. Referred to as uremic neuropathy, this condition occurs irrespective of the cause of renal failure (eg, diabetes mellitus, glomerulonephritis), and increasing evidence suggests that chronic hyperkalemia may play a role in the development of this neuropathy.12 The pathologic features of uremic neuropathy on nerve biopsy are distinctive, and the characteristic axonal atrophy and secondary segmental demyelination are not associated with underlying conditions that cause renal failure.13 Fortunately, the more severe forms of this condition are rare today, presumably due to early and aggressive dialysis and kidney transplantation. Because of the current rarity of this condition, it is important that other causes of neuropathy be explored in the setting of a patient with neuropathy on chronic dialysis.

Heavy Metals

Exposure to several metals has been shown to cause peripheral neuropathy and may be discovered on laboratory testing of a 24-hour urine sample.14 Lead neurotoxicity may present as a combination of motor-predominant peripheral neuropathy (classically described as wrist-drop) and encephalopathy. There is often concomitant systemic disease, including constipation (likely secondary to autonomic nerve involvement) and microcytic anemia. Fortunately, the incidence of overt lead toxicity with peripheral neuropathy has substantially declined with changes in lead mining practices and decreased human exposure to the major sources in the environment, such as lead-based paint and lead supplements in gasoline. In cases of lead-induced peripheral neuropathy, chelation therapy should be used.15

Inorganic arsenic neurotoxicity may occur from well water contamination, accidental exposure to industrial or agricultural agents, or in the setting of homicidal/suicidal intent. This is to be distinguished from the non-neurotoxic organic arsenic found in some fish and crustaceans, which is often found on urine heavy metal screening. Arsenic neurotoxicity from acute poisoning often occurs 1 to 2 weeks after a severe acute systemic syndrome characterized by nausea, vomiting, and diarrhea. The neuropathy often starts as a length-dependent sensory-predominant painful neuropathy, but in severe forms it may progress to a diffuse sensorimotor polyradiculoneuropathy mimicking Guillain-Barré syndrome (Case 7-2).16 Chronic arsenic exposure can cause an indolent sensory-predominant peripheral neuropathy. Nerve conduction studies in both settings are characterized by slowed conduction velocities. While 24-hour urine sampling will reveal chronic arsenic poisoning, it may not disclose late effects of single or repeated exposures, in which case, it is important to sample hair and nails for arsenic levels.

Thallium was previously used in pesticides and rodenticides, but this has been removed in most Western countries, which, fortunately, has dramatically decreased the frequency of poisoning. Thallium poisoning begins with a severe gastrointestinal illness. In surviving patients, a painful sensory followed by motor neuropathy mimicking Guillain-Barré syndrome occurs within 1 to 2 days, similar to that seen in arsenic poisoning.17 Of note, alopecia, which is a hallmark of thallium intoxication, usually does not occur until 2 to 3 weeks after intoxication. Prussian blue is approved as an oral agent to prevent absorption of thallium.15

The main sources of mercury poisoning come from contaminated fish (organic mercury), industrial mercury salts (inorganic mercury), and vaporized metallic mercury. Organic mercury affects the dorsal root and trigeminal ganglia, causing paresthesia, often before causing widespread CNS dysfunction. Inorganic mercury poisoning primarily causes renal disease, but psychiatric manifestations also commonly occur (eg, Alice in Wonderland’s Mad Hatter was exposed to inorganic mercury in the production of felt hats). Chelation therapy with British anti-Lewisite (BAL) or penicillamine should be tried in patients with nervous system involvement.15

Case 7-2

A 47-year-old woman was transferred to a tertiary medical center for progressive weakness and sensory loss. She was initially hospitalized with severe nausea, vomiting, and dehydration requiring intensive care unit–level treatment. During her recovery from gastrointestinal illness, she began to develop ascending sensory loss and weakness. She was diagnosed with Guillain-Barré syndrome and given a 5-day course of IV immunoglobulin. Unfortunately, she continued to progress and was transferred for further workup and treatment. She had a history of irritable bowel syndrome and reported some baseline numbness in her toes, but otherwise had been healthy. There was no family history of neuromuscular diseases.

Examination was notable for moderate-to-severe length-dependent weakness, multimodal sensory loss, and areflexia. Extensive blood work and CSF analysis was normal (at 3 weeks out from her original illness). Nerve conduction studies and EMG showed a severe length-dependent axonal peripheral neuropathy. Twenty-four-hour urine heavy metals showed detectable levels of arsenic, but were within normal limits. Due to clinical suspicion, hair samples were sent for testing for inorganic arsenic levels, which were found to be very elevated.

Comment. Arsenic neurotoxicity may mimic Guillain-Barré syndrome and is usually associated with severe gastrointestinal symptoms. Urine levels may be normal if tested weeks after acute poisoning, therefore, hair or nail samples may be required for diagnosis when there is clinical suspicion. While cases of arsenic neurotoxicity secondary to groundwater occur, intentional poisoning should be considered when making a diagnosis.

Industrial Agents

Peripheral neuropathy arising from exposure to industrial agents is uncommon in developed worlds,18primarily due to the restricted (or banned) use of these agents once clear neurotoxicity is established. Where these agents are still used in industrial processes, strict exposure precautions have also reduced the incidence of neurotoxicity. A careful history is warranted as exposure to organic solvents (eg, diketone degreasing agents used in engine shops) is now more commonly encountered in the setting of either personal use or within small businesses that are less carefully regulated than larger industries. Table 7-3delineates the neuropathies secondary to industrial agents.

Table 7-3

Occupational Exposures of Specific Toxins

Medications

Many drugs within a variety of medication classes are associated with peripheral neuropathy. It is important to note that before discontinuing a medication thought to be causing a neuropathy, the patient should discuss the need for the medication and reasonable alternatives with the prescriber. Often, the need for the medication may outweigh the desire to stop it (especially if the association with the neuropathy is in doubt). A list of medications most prominently associated with the development of peripheral neuropathy is included in Table 7-4; for most of these agents, the incidence of peripheral neuropathy is rare.19 Medications causing neuropathy that are no longer in general use have been omitted from this table. Because of the common occurrence of peripheral neuropathy as a dose-limiting side effect of certain chemotherapeutic agents, these are discussed in more detail next in this article.

Table 7-4

Medications Associated With the Development of Peripheral Neuropathy

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Chemotherapy

Peripheral neuropathy secondary to chemotherapy treatments for cancers affect approximately 30% of patients receiving one of the neurotoxic agents.20 Peripheral neuropathy is one of the major dose-limiting toxicities and frequently decreases the amount of chemotherapy available to treat the underlying cancers. While much of the toxicity relates to dose (and is managed by oncologists), growing evidence also argues for contribution of the patient’s genetics and type of cancer.21–23 Therefore, in patients who develop severe neuropathies in the setting of chemotherapy (especially if not in a classic stocking-glove distribution), it is important to rule out other causes of neuropathy. For example, it has been reported that patients with underlying hereditary neuropathies likely develop more severe chemotherapy-induced peripheral neuropathy.24 Also, there are many reports in the literature about immune-mediated neuropathies in the setting of chemotherapy, which may be a paraneoplastic process or triggered by chemotherapeutic agents.25 Direct compression or invasion of nerve by the underlying malignancy should be considered as well.

Platinum-based compounds (cisplatin, carboplatin, and oxaliplatin) primarily produce a sensory neuropathy/neuronopathy (Case 7-3). Oxaliplatin also has a specific neuropathic syndrome in which patients develop a temporary, but very uncomfortable, cold-induced neuropathic pain in the hands and face. These neuropathic symptoms from oxaliplatin arise from direct interaction with voltage-gated sodium channels leading to altered nerve excitability.26–28 More generally, the platinum-based compounds are thought to cause neuropathy by binding to nuclear and mitochondrial DNA, leading to apoptosis. Neuropathies from platinum-based compounds are also notorious for progressing for several weeks following medication discontinuation, a phenomenon called coasting.

The microtubule toxins, taxanes and vinca alkaloids, produce a length-dependent sensorimotor peripheral neuropathy, likely by disruption of microtubule-dependent axonal transport. Taxanes (paclitaxel, docetaxel) cause stabilization of microtubules, whereas vinca alkaloids (vincristine, vinblastine) destabilize microtubules.

Newer chemotherapy agents approved by the US Food and Drug Administration over the past several years continue to have a frequent side effect of peripheral neuropathy. The proteasome inhibitor bortezomib, used primarily in multiple myeloma, causes a sensory-predominant axonal neuropathy that is frequently dose-limiting. Carfilzomib, a newer-generation proteasome inhibitor, is reported to produce less peripheral neuropathy than bortezomib.29 Both brentuximab vedotin (for refractory large cell lymphoma) and ado-trastuzumab emtansine (for HER2 positive breast cancer) are antibody-drug conjugations where the antibody is cancer specific (anti-CD20 and HER2, respectively), but also have a drug that targets microtubules (vedotin and mertansine), which likely cause the associated peripheral neuropathy.30,31Likewise, the breast cancer chemotherapeutics ixabepilone and eribulin mesylate, both of which act on microtubules, have been shown to cause a dose-limiting sensory-predominant peripheral neuropathy.32

Case 7-3 

A 39-year-old man with a history of testicular cancer presented with new-onset numbness and paresthesia in his hands and feet over the past 2 weeks. He denied any weakness or autonomic symptoms. He completed his final course of cisplatin-based chemotherapy 2 weeks prior to the onset of symptoms, but otherwise had been well.

Neurologic examination was notable for reduced perception of all sensory modalities in the hands and feet (up to the ankles) and areflexia.

His symptoms progressed over the next 2 weeks with sensory loss to the knees and forearms with some gait instability. Extensive blood work and CSF analysis was normal. Nerve conduction study was notable for absent sural sensory nerve action potentials and reduced amplitude median and ulnar sensory nerve action potentials with borderline slow conduction velocities.

A diagnosis of cisplatin-induced peripheral neuropathy was made. The patient had continued mild progression over the next month, which then stabilized. He reported modest improvement 1 year later, but was cured from his cancer.

Comment. Cisplatin-induced peripheral neuropathy usually develops within days of infusion, but may present up to 4 weeks after the last dose of cisplatin. Unlike most other types of chemotherapy-induced peripheral neuropathy, which tend to be length-dependent axonal sensorimotor neuropathies, platinum primarily causes a sensory neuronopathy. This likely contributes to the relative lack of reversibility of the neuropathy after cisplatin discontinuation. Additionally, platinum-based chemotherapy-induced peripheral neuropathies are known to develop the “coasting phenomenon,” wherein symptoms may progress for months after chemotherapy has stopped. Patients may also experience late progression of symptoms when positive painful dysesthesia replace previous negative symptoms of loss of feeling. Typically, even though symptoms have worsened, the clinical examination and electrophysiologic changes are stable. These patients may need to be followed to establish that neuropathy due to a different underlying progressive problem is not present.

Biological Toxins

There are several toxins produced by biological agents that affect the peripheral nervous system, some of which will be covered in the article “Infectious Neuropathies” by Eric L. Logigian, MD, FAAN, and Michael K. Hehir II, MD, in this issue of CONTINUUM.

Ingestion of toxic seafood may be associated with peripheral nerve disorders, often presenting as a syndrome of gastroenteritis and perioral paresthesia. In more severe cases, paresthesia is more widespread with concomitant weakness and occasional cardiovascular collapse. The mechanism of action for all of these toxins is binding of the voltage-gated sodium channel, and symptoms typically resolve within days to months. Ciguatera toxin is produced within dinoflagellate plankton, which then accumulates within fish that consume the plankton up the food chain, which leads to prominent perioral paresthesia, metallic taste, and temperature-related dysesthesia.33 Saxitoxin and brevetoxin B are also produced by dinoflagellate plankton, which are associated with “red tides,” and tend to concentrate in bivalve mollusks and cause more paralysis than ciguatera toxicity.34 Tetrodotoxin is produced within the puffer fish (fugu) ovaries. It is consumed in Japanese sushi, which must be carefully prepared to avoid the potentially fatal toxin.

In addition to neuropathies caused by Lyme disease (carried by Ixodes genus ticks), ticks can produce a “tick paralysis” syndrome that usually affects children under 6. The saliva of three female ticks (Dermacentor andersoni, Dermacentor variabilis, and Ixodes holocyclus) contains a neurotoxin that can lead to a rapidly progressive paralysis, which may include bulbar and respiratory muscles and associated dysautonomia, although sensory systems are spared. Treatment involves supportive care and removal of the offending tick, which leads to rapid reversal of symptoms.

Ingestion of the fruit from the buckthorn plant (Karwinskia humbodtiana), which grows throughout the southwest United States and Mexico, produces a rapidly progressive sensorimotor demyelinating peripheral neuropathy that is very clinically similar to Guillain-Barré syndrome.35 The neurologic symptoms develop 5 to 20 days after fruit ingestion, which may make diagnosis challenging, especially in small children, who are most commonly affected. Of note, the CSF should remain normal in buckthorn neuropathy, and treatment is supportive with slow recovery over many months.

CONCLUSION

The wide array of deficiencies and toxins that damage the peripheral nervous system highlight its vulnerability, and as illustrated with chemotherapy-induced peripheral neuropathies, even newer agents continue to frequently cause this unwanted problem. While many of these syndromes present as a length-dependent sensorimotor peripheral neuropathy, the more rare presentations with asymmetry and radicular localization require that these peripheral neuropathy causes should be considered in the differential diagnosis of most cases of neuropathy. Fortunately, a thorough history that includes a review of systemic illness, medication changes, and exposures will provide etiological clues in most cases of neuropathy due to vitamin deficiency, toxins, and medications.

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KEY POINTS

• Acquiring a detailed history is crucial to diagnosis of neuropathies caused by toxic agents and vitamin deficiencies.

• In a neuropathy with significant asymmetry, polyradicular, or mononeuritis multiplex presentation, other etiologies should be explored further, even in the setting of documented toxicity or vitamin deficiency.

• Causes for vitamin B12 deficiency include pernicious anemia, strict veganism, gastric bypass, prolonged antacid use, atrophic gastritis, or diseases of the terminal ileum (eg, resection, Crohn disease).

• Copper deficiency may look very clinically similar to vitamin B12 deficiency and should be investigated in parallel in patients with a myeloneuropathy presentation.

• Vitamin B6 is unusual in that it is associated with peripheral neuropathy either when deficient or in excess.

• Neuropathy due to thiamine deficiency has many presentations, including length-dependent sensorimotor, cranial nerve, and motor-predominant polyneuropathy, all of which may precede cognitive and systemic symptoms.

• It has been difficult to determine whether alcohol directly causes neuropathy or if its association with neuropathy is due more to chronic malnutrition and vitamin deficiencies in alcoholics.

• Intoxication from arsenic or thallium is preceded by severe gastrointestinal illness, and the neuropathy may mimic Guillain-Barré syndrome.

• Toxic exposure from industrial agents may be more likely to occur in people using these agents for personal use or in small businesses.

• Newer chemotherapy agents approved over the past several years continue to have frequent side effects of peripheral neuropathy.

• Ingestion of toxic seafood may be associated with peripheral nerve disorders, which often present as a syndrome of gastroenteritis and perioral paresthesia.

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