Approach to a case of myeloneuropathy.

Myeloneuropathy is a frequently encountered condition and often poses a diagnostic challenge. A variety of nutritional, toxic, metabolic, infective, inflammatory, and paraneoplastic disorders can present with myeloneuropathy. Deficiencies of vitamin B12, folic acid, copper, and vitamin E may lead to myeloneuropathy with a clinical picture of subacute combined degeneration of the spinal cord. Among infective causes, chikungunya virus has been shown to produce a syndrome similar to myeloneuropathy. Vacuolar myelopathy seen in human immunodeficiency virus (HIV) infection is clinically very similar to subacute combined degeneration. A paraneoplastic myeloneuropathy, an immune-mediated disorder associated with an underlying malignancy, may rarely be seen with breast cancer. Tropical myeloneuropathies are classified into two overlapping clinical entities - tropical ataxic neuropathy and tropical spastic paraparesis. Tropical spastic paraparesis, a chronic noncompressive myelopathy, has frequently been reported from South India. Establishing the correct diagnosis of myeloneuropathy is important because compressive myelopathies may pose diagnostic confusion. Magnetic resonance imaging (MRI) in subacute combined degeneration of the spinal cord typically reveals characteristic signal changes on T2-weighted images of the cervical spinal cord. Once the presence of myeloneuropathy is established, all these patients should be subjected to a battery of tests. Blood levels of vitamin B12, folic acid, vitamins A, D, E, and K, along with levels of iron, methylmalonic acid, homocysteine, and calcium should be assessed. The pattern of neurologic involvement and results obtained from a battery of biochemical tests often help in establishing the correct diagnosis.

Introduction

Myeloneuropathy is characterized by simultaneous damage of the tracts of the spinal cord and peripheral nerves in the lower limbs. Clinical manifestations of myeloneuropathy include difficulty in walking, weakness of lower limbs, ataxic gait, and sensory manifestations in glove and stocking distribution. On examination, there are myelopathic signs such as hyperreflexia, spasticity, extensor plantar responses, and infrequently, bladder bowel disturbances. Romberg sign indicates involvement of the posterior column. Classical neuropathic signs include glove and stocking sensory loss, absent or diminished ankle jerk, and distal limb atrophy. Cognitive impairment and vision loss, because of optic nerve damage may occasionally dominate the clinical picture in a patient with myeloneuropathy. All of these patients have gait difficulty primarily due to severe sensory ataxia.[12]

In classical medicine ward teaching, four causes of an absent reflex and exaggerated knee jerks used to be enumerated; these four causes were taboparesis, subacute combined degeneration, Friedreich's ataxia, and cauda-conus syndrome. Taboparesis is a form of tertiary syphilis, which is characterized by features of both tabes dorsalis and general paralysis of the insane. Patients had upper and lower motor neuron signs in lower limbs, leading to the absence of ankle jerks along with extensor planter responses. Taboparesis is a classic example of myeloneuropathy, which is no longer seen. Now, a variety of nutritional, toxic, metabolic, infective, inflammatory, and paraneoplastic conditions are considered in the differential diagnosis of myeloneuropathy.

Nutritional and Metabolic

Nutritional deficiencies lead to myeloneuropathy with a clinical picture of subacute combined degeneration of the spinal cord. In subacute combined degeneration of the spinal cord, there is dysfunction of posterior and lateral columns of the spinal cord along with involvement of peripheral and optic nerves, and to some extent of the brain parenchyma. The earliest clinical feature is usually the presence of paresthesias in extremities; later sensory loss, gait ataxia, lower limb weakness, spasticity, hyperreflexia, and extensor plantar responses may evolve.[345] In a very large report that included 143 patients (153 episodes of cobalamin deficiency), paresthesia or ataxia were the initial symptoms of vitamin B12 deficiency. In this cohort, diminished vibration and proprioception in the lower limbs were the most common neurological findings. Other frequent neurologic signs were ataxia, loss of sensation, motor weakness, diminished deep tendon jerks, spasticity, urinary or fecal disturbances, postural hypotension, vision loss, dementia, psychoses, and mood changes. In many patients with subacute combined degeneration, Lhermitte's sign is present.[6] Vitamin B12 deficiency is particularly common in the elderly and after gastric surgery. Many patients with vitamin B12 deficiency have intrinsic factor-related malabsorption similar to that seen in patients with pernicious anemia. Vitamin B12 deficiency results in the failure of conversion of methyl malonyl coenzyme A to succinyl-CoA, resulting in the accumulation of methylmalonic acid. Methylmalonic acid is a neurotoxic substance that produces myelin damage in the posterior columns of the spinal cord. Lesions of the spinal cord are predominately present in the lower cervical and upper thoracic regions. The diagnosis of B12 deficiency is made in the presence of a low serum B12 level. If the blood B12 level is borderline low, increased levels of homocysteine and methylmalonic acid help in confirming the presence of B12 deficiency. Vitamin B12 deficiency is the most frequently reported cause of myeloneuropathy in India.

Copper deficiency is the next common differential diagnosis in patients with posterolateral involvement of the spinal cord presenting with myeloneuropathy. The predisposing factors for copper deficiency include enteral feeding, gastrectomy, usage of copper-chelating agents, and excessive zinc administration. Copper deficiency is treated with oral or intravenous supplementation of copper. Serum levels of copper and zinc need to be closely followed when oral replacement of copper is used, especially in patients who are also receiving supplemental zinc because zinc and copper compete for intestinal absorption. Excessive oral intake of zinc leads to copper deficiency. Zinc interferes with the absorption of copper in enterocytes of the small intestine. Additionally, excess zinc induces the synthesis of the intracellular ligand metallothionein in enterocytes, which then binds zinc. The excess zinc bound to metallothionein is then excreted in the feces through enterocyte shedding. Copper, given its higher affinity for metallothionein, displaces zinc and is also excreted excessively, leading to copper deficiency.[789101112]

Folic acid deficiency can also produce a clinical picture similar to that of subacute combined degeneration of the spinal cord. Many other deficiencies such as vitamin B12 deficiency are concomitantly present. Folic acid deficiency is usually caused by dietary deficiency, malabsorption syndromes, pregnancy and lactation, usage of anticancer, antiepileptic, or oral contraceptive drugs, and long-term alcoholism. Folic acid deficiency-associated myeloneuropathy partially responds to folic acid supplementation.[1213]

Vitamin E deficiency is classically characterized with a spinocerebellar syndrome; however, it can also present with myeloneuropathy. Ataxia with vitamin E deficiency is an autosomal recessive disorder. The clinical features of vitamin E deficiency are similar to Friedreich's ataxia. Patients present with cerebellar ataxia, loss of deep jerks, loss of vibration sense, dysarthria, and Babinski sign. Head titubation, retinopathy and dystonia are more common in these patients. Early diagnosis is crucial for successful treatment.[121314]

Toxic

Nitrous oxide-associated vitamin B12 deficiency can cause subacute combined degeneration of the spinal cord following nitrous oxide anesthesia. Nitrous oxide is a commonly used inhalational aesthetic agent. It is highly lipid soluble and rapidly crosses the blood–brain barrier. Nitrous oxide, in fact, aggravates the manifestations of vitamin B12 deficiency because it impairs the function of methylcobalamin-dependent methionine synthetase enzyme. Nitrous oxide denatures B12 molecule, making it inactive. In patients with preexisting vitamin B12 deficiency, even a single dose of nitrous oxide can produce florid neurological manifestations of vitamin B12 deficiency. High doses of vitamin B12 need to be administered to counteract the inactivating effects of the nitrous oxide. Clinical improvement is usually dramatic.[1516]

Chlorpyrifos is an organophosphate insecticide, which can cause delayed neurological toxicity following a high dose exposure. A delayed myeloneuropathy following chlorpyrifos poisoning has been reported in an isolated case.[17]

Infective

Among infective causes, chikungunya virus in India has been shown to produce a syndrome similar to myeloneuropathy. A study during a chikungunya epidemic noted that among 90 laboratory-confirmed cases, 12 patients had myeloneuropathy, with or without encephalitis. The outcome of the neurological complications was good. In an another report of 300 patients with chikungunya, in 2006, 14% (7/49) patients had myeloneuropathy.[1819]

Vacuolar myelopathy in HIV infection is clinically very similar to subacute combined degeneration. Vacuolar myelopathy manifests with a posterolateral spinal cord syndrome with bladder and bowel disturbances. HIV myelopathy appears in the late stages of HIV infection when CD4+ cell counts are very low. Most of these patients concomitantly have other complications of HIV infection such as encephalopathy, opportunistic infections, or malignancies. Spinal cord pathology, including vacuolar myelopathy, has rarely been reported in Indian HIV-infected patients.[2021]

Inflammatory

A paraneoplastic myeloneuropathy is an infrequent immune-mediated disorder that is associated with an underlying malignancy. In some case reports, paraneoplastic myeloneuropathy has been reported with carcinoma of the breast. Antineuronal nuclear antibody 1 (anti-Hu) is frequently positive in these patients and they respond well to corticosteroids.[2223] Reports on paraneoplastic myelopathies have demonstrated a characteristic magnetic resonance imaging (MRI) pattern of longitudinally extensive signal changes in the spinal cord.

Another inflammatory condition, Sjögren's syndrome, can manifest with myeloneuropathy. Sjögren's syndrome is an autoimmune disorder characterized by decreased secretions of lacrimal and salivary glands (sicca symptoms). The central and peripheral nervous systems' involvement in Sjögren's syndrome is a result of vasculitis as well as direct immunological injury to neurons. Clinical spectrum of Sjögren's syndrome-associated neuropathy includes sensory ataxic neuropathy, trigeminal neuropathy, multiple mononeuropathy, radiculoneuropathy, painful sensory neuropathy without sensory ataxia, autonomic neuropathy with anhidrosis, and multiple cranial neuropathy. Neurological symptoms occur in approximately 20% of patients with Sjögren's syndrome, and may be the presenting manifestations of the disease.[24]

In Hashimoto's disease, antithyroid antibodies can also be associated with acute myeloneuropathy or myelopathy. The exact role of antithyroid antibodies in the pathogenesis of the myelopathy is not precisely clear; however, a vasculitic process has been suggested. There is often a good response to corticosteroids.[2526]

Sarcoidosis is a granulomatous disorder that can affect virtually any organ of the human body and nearly any component of the nervous system. A variety of neurological manifestations are possible including myelopathic signs and symptoms, and signs of segmental radiculopathy at the affected levels. Polyradiculopathy, including cauda equina syndrome and peripheral neuropathy, may accompany myelopathic finding. The diagnosis of sarcoidosis is quite challenging in such patients.

Tropical Myeloneuropathies

Tropical myeloneuropathies are classified into two overlapping clinical entities — tropical spastic paraparesis and tropical ataxic neuropathy. Tropical spastic paraparesis, a chronic cause of myeloneuropathy, has frequently been reported from South India. It is caused by an infection with human T-cell lymphotropic virus-1. Tropical ataxic neuropathy is a slowly progressive cause of myeloneuropathy seen in cassava-eating countries. This disease characteristically occurs in an endemic form and is clinically characterized by sensory polyneuropathy, gait ataxia, optic atrophy, and nerve deafness. Tropical ataxic neuropathy often starts with dysesthesias in the lower limbs followed by unsteadiness of the gait. Romberg test is characteristically present. Reflexes in the lower limbs are either diminished or absent. Plantar response is usually flexor. Tropical ataxic neuropathy is seen in populations that use large quantities of cassava in their diets for very long periods. This syndrome has not been reported from India.[2728]

Hereditary

A variety of hereditary myeloneuropathies have been described. Adrenomyeloneuropathy, a variant of adrenoleukodystrophy, is a noninflammatory involvement of the spinal cord that involves the descending corticospinal tracts, dominantly in the thoracic and lumbosacral regions, and the posterior columns, in the cervical spinal segments. The clinical features of adrenomyeloneuropathy include a slowly progressive spastic paraparesis and mild polyneuropathy in adult men, with or without sensory manifestations and sphincter disturbances.[29]

Recently, Motley et al. from Belgium described five siblings in a family with dominantly inherited myeloneuropathy. All affected family members had a mild axonal neuropathy and three out of four family members had lower extremity hyperreflexia, suggestive of a superimposed myelopathy. A nerve biopsy showed evidence of chronic axonal loss. All affected family members had a heterozygous missense mutation in the alanyl-tRNA synthetase gene.[30]

Neuroimaging

MRI in subacute combined degeneration of the spinal cord usually reveals signal changes on T2-weighted images of the cervical spinal cord. Classically, there are symmetric bilateral hyperintense signals in the posterior and lateral columns. Imaging findings may involve the posterior column of thoracic segments as well. Some amount of cord expansion and enhancement may be present. On sagittal images, longitudinal signal changes are noted along the dorsal columns of the spinal cord. A characteristic pattern of symmetric bilateral hyperintense signals in the dorsal columns has been described as “inverted V” or “inverted rabbit ears” appearance. These changes are partially or completely reversible following treatment[31] [Figure 1].

Figure 1

MRI of a patient presenting with subacute combined degeneration secondary to vitamin B12 deficiency depicts hyperintensity involving the posterior part of the cervical spinal cord on T2-W sagittal (A) image and inverted “V” sign on T2-W axial section (B, arrow)

The myelopathies that often need to be considered in the differential diagnosis of subacute combined degeneration of the spinal cord include spondylotic myelopathy, infectious or postinfectious myelitis, multiple sclerosis, vascular malformations of the spinal cord, spinal cord infarction, and many connective tissue diseases such as systemic lupus erythematosus. In most of these conditions, MRI reveals T2 hyperintensity in the dorsal columns.

Approach to a Case of Myeloneuropathy

Establishing the correct diagnosis of myeloneuropathy is important because compressive myelopathies may pose diagnostic confusion. An asymmetrical onset of neurological manifestations and progression, a definite upper level of involvement, Brown-Séquard syndrome like picture, or early bladder and bowel involvement, indicate a possible compressive cause for myelopathy [Figure 2].

Figure 2

Summary of the important clinical, laboratory, and imaging details of various etiologies associated with myeloneuropathy

Once the presence of myeloneuropathy is established, all these patients should be subjected to a battery of tests. Blood levels of vitamin B12, folic acid, methylmalonic acid, homocysteine, vitamins A, D, E, and K, iron, and calcium should be assessed to detect other nutritional deficiencies. Imaging of the brain and spinal cord, with contrast, is always needed. Electromyography and nerve conduction study results are often consistent with axonal sensorimotor polyneuropathy in the legs; somatosensory evoked potentials may provide an electrophysiological evidence of dysfunction in the central pathways.

Various conditions causing dietary and nutritional deficiencies should be recognized early. A history of malabsorption, gastrointestinal surgery, pregnancy and lactation, usage of anticancer, antiepileptic, or oral contraceptive drugs and long-term alcoholism hold the key to a proper diagnosis of nutritional deficiency myeloneuropathies [Table 1].

Table 1

Common nutritional, metabolic, and toxic causes of myeloneuropathy: Etiology, diagnosis, and treatment

Conclusion

A correct diagnosis of myeloneuropathy is often challenging. Vitamin B12, folate, copper, and vitamin E deficiencies lead to myeloneuropathy. The clinical picture in all these conditions is similar to that of mimics subacute combined degeneration of the spinal cord. The pattern of neurologic involvement and results obtained from a battery of biochemical tests help in establishing the correct diagnosis.

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