These myelopathies encompass a heterogeneous group of conditions that affect the spinal cord as well as the brain and peripheral nerves in many cases. Despite different etiologies underlying these conditions, they tend to have many clinical, electrophysiologic, and neuropathologic similarities. Typically, they involve the dorsal columns of the spinal cord preferentially, but also have some corticospinal tract and peripheral nerve involvement. Because of this, the term myeloneuropathy is sometimes used.
Metabolic and toxic myelopathies can be divided into the following 4 categories:
- Disorders because of an identified nutrient deficiency, such as the subacute combined degeneration of vitamin B12 deficiency.
- Disorders because of toxins without geographic predilection, such as hepatic myelopathy.
- Disorders that have a geographic predilection and are the result of suspected toxins, such as lathyrism.
- Disorders that present as a metabolic myelopathy; these include those with a defined mode of inheritance (eg, mitochondrial disorders, eg, Friedreich ataxia).
The most common and well understood of the toxic and nutritional myelopathies is vitamin B12 deficiency, which causes the syndrome of subacute combined degeneration, first described in 1884. Folate, copper, and vitamin E deficiency and consumption of large amounts of fluoride have also been shown to cause myelopathies.
Some myelopathies result from toxins independent of geography including nitrous oxide and heroin. Nitrous oxide leads to vitamin B12 deficiency and subsequent subacute combined degeneration because it inactivates vitamin B12 by oxidizing methylcobalamin, the active form of intracellular B12. The mechanism for heroin myelopathy is not well established, but several theories exist. The most promising theory is an immune-mediated hypersensitivity response as most cases of heroin myelopathy occur after a single use of heroin following a period of abstinence.
Other myelopathies are the result of toxins that have a geographic predilection, such as lathyrism. The cause of lathyrism is ingestion of a toxic amino acid contained in the grass (chickling) pea, Lathyrus sativus. It is found across India, Bangladesh, and Ethiopia. This toxin, β-N-oxalyl-L-α,β-diaminopropionic acid, a neurotoxic amino acid, causes an acute to subacute, irreversible, nonprogressive spastic paraparesis that may be preceded by a series of symptoms including lower limb weakness, myalgia and stiffness. The last recorded episode of the disease is from Ethiopia during the 1995-1997 famine and in India it has virtually disappeared during the last three decades despite its continued cultivation and consumption in several areas. Even during the recent Ethiopian famine the disease was well controlled by the timely introduction of food aid cereal supplementation. What has become abundantly clear over the years is the fact that as part of a normal diet like most legumes Lathyrus sativus appears to be well tolerated and is only an issue during times of famine as evidenced by the virtual disappearance of the disease from India during the past three decades.
Konzo is another common toxic myelopathy linked to high exposure to cyanogenic compounds in diets containing insufficiently processed bitter cassava (Manihot esculenta). It most often occurs across Africa with prolonged consumption of cassava root in conjunction with a diet deficient in protein, in particular, sulfur containing amino acids. These conditions are often precipitated by drought and famine. The result is an irreversible, nonprogressive spastic paraparesis. The onset is abrupt, less than 1 week, is symmetric and can be associated with bilaterally increased ankle jerks. Sensory loss and genitourinary impairment does not occur. Optic neuropathy occurs in about half the patients with this condition.
There are many drugs and chemical agents that cause myelopathy or myeloneuropathy. These include clioquinol, organophosphate, and chemotherapeutic agents, such as cisplatin, intrathecal methotrexate, and anti-TNF medications. Clioquinol use, mainly in Japan (removed from the market in 1970), was responsible for a disorder called subacute myelo-opticoneuropathy. This is composed of visual loss, lower limb sensory loss, bowel and bladder dysfunction and gait abnormalities.
Radiation treatment of tumors in the CNS, mediastinum or Hodgkin’s lymphoma can lead to myelopathy; the most common form occurs acutely between 6 weeks and 6 months of exposure an typically resolves over the course of several weeks to months. A delayed-onset myelopathy occurs months to years following spinal cord radiation with progressive motor and sensory loss and impairment of bowel and bladder function, but pain is uncommon. It is usually progressive and irreversible.
Hepatic dysfunction can be associated with myelopathy, particularly in those with portosystemic shunts, thought to be the result of ammonia or elevated manganese.
Fluorosis occurs when large amounts of fluoride are consumed. This usually occurs when it is naturally present in the earth and water. Deposition of the floride occurs in bones with a predilection for the vertebral column. Neurologic symptoms are delayed and are seen in ~ 10% of patients with skeletal fluorosis with cord compression and less often radiculopathy.
Genetic conditions, which may present as a metabolic myelopathy, often with other central nervous system involvement, include adult polyglucosan body disease, adrenomyeloneuropathy and other leukodystrophies, spinal xanthomatosis, biotinidase deficiency, arginase deficiency, mitochondrial disorders, and hexosaminidase A deficiency.
Epidemiology including risk factors and primary prevention
Risk factors for these conditions are as diverse as the conditions themselves. Primary prevention consists of maintaining normative levels of key nutrients, and avoiding drugs and other toxins if possible. For vitamin B12 deficiency with subacute combined degeneration, risk factors include malabsorptive disorders, such as poor nutrition, atrophic gastritis, celiac sprue, gastric or ileal resections, overgrowth of intestinal bacteria in blind loops, anastomoses, diverticula, use of drugs, such as H2 antagonists and metformin, and infestation with cobalamin-metabolizing fish tapeworm. It is less commonly seen in lactovegetarians, infants nursed by mothers deficient in vitamin B12, and individuals exposed to excessive amounts of nitrous oxide.
Folate deficiency is caused by alcoholism, gastrointestinal disease, folate antagonists (eg, methotrexate), or errors of folate metabolism. Cooper is an ubiquitous element present in most diets. However, copper deficiency can be seen in zinc excess, gastric bypass surgery, total parenteral nutrition, or enteral feeding. It is important to note that denture adhesive and topical zinc products may be an overlooked source of zinc excess in some patients. Vitamin E deficiency can be caused by chronic cholestasis, pancreatic insufficiency, gastrointestinal disease, or lipoprotein disorders; it is rarely as a result of dietary inadequacy. Hereditary disorders of vitamin E metabolism should especially be on the differential in children without signs of GI disease.
Epidemiology varies with the toxins as previously described. Risk factors for toxic myelopathies are exposures to the etiologic toxin. In the case of nitrous oxide toxicity, pre-existing B12 deficiency increases the risk of nitrous oxide myelopathy with exposure. For radiation myelopathy, increased risk may be dose dependent and increase with higher doses and previous exposures as well as with age.
The most common and well-studied pathology is that of subacute combined degeneration. The pathologic process is diffuse, uneven degeneration of the white matter of the spinal cord (and occasionally the brain). The earliest histologic event is swelling of the myelin sheaths, followed by a coalescence of small foci of tissue destruction into larger ones, imparting a vacuolated, sieve-like appearance to the tissue. Gliosis becomes pronounced in chronic lesions. These changes begin in the posterior columns of the lower cervical and upper thoracic segments and spread throughout the white matter.
The biochemical pathways in which vitamin B12 (cobalamin) are involved are complex. The neurologic manifestations are thought to be the result of impairment in the methylation of homocysteine to methionine, a reaction which depends on a cobalamin-dependent enzyme.
Although the pathophysiology of the other toxic and metabolic myelopathies have not been as well described, some distinguishing factors do exist to help differentiate between the causes. Copper deficiency myelopathy, for example, which causes a sensory ataxia similar to subacute combined degeneration can also be accompanied by an optic neuropathy.
Vitamin E deficiency myelopathy causes a spinocerebellar syndrome and peripheral neuropathy. It is also associated with ophthalmoplegia, myopathy and retinopathy.
Heroin myelopathy causes a transverse myelitis and is often associated with rhabdomyolysis and urinary retention.
Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)
Most of these conditions have a subacute symptom onset; the exceptions include nitrous oxide toxicity and heroin myelopathy. Cassava toxicity, a result of weeks or even years of ingestion of cassava, can result in either an acute nonprogressive myelopathy or a slowly progressive disease characterized by ataxia, peripheral neuropathy, and optic atrophy.
Generally, although there may be improvement of these conditions with treatment, a more common outcome is cessation of progression. The exception to this is the slow progression in neurologic deficits in the genetic disorders.
Specific secondary or associated conditions and complications
Gait abnormalities include a sensory ataxia, which may occur in association with spasticity, loss of joint position sense, and pathologic reflexes. Bowel, bladder, and sexual dysfunction may occur. Optic neuritis may also be associated with some types of myelopathy, such as copper deficiency.
2. ESSENTIALS OF ASSESSMENT
History should be comprehensive and include recent illnesses, dietary habits, occupational and environmental exposures, and a general medical and surgical history. Neurologic symptoms should be elucidated, including motor and sensory abnormalities, problems with balance, proprioception and coordination, cognitive difficulties, spasticity, and other symptoms, such as bladder, bowel, and sexual dysfunction. Time course and speed of progression of symptoms should be noted.
In addition to a general physical examination, a complete neurologic examination should be performed, including assessment of cognition, cranial nerves, motor, sensory (light touch, pinprick, vibration, joint position sense), reflexes, range of motion, spasticity, and coordination. Skin should be examined to look for pressure sores, and rectal examination should be performed to guide in assessment of injury and bowel/bladder management. Gait should also be assessed.
Assessment of function, including activities of daily living (ADLs), mobility, and cognitive function should be similar to other types of nontraumatic myelopathy. A variety of scales can be used, including the Functional Independence Measure, the WeeFIM for children, the Spinal Cord Independence Measure, and/or the Walking Index for Spinal Cord Injury. Cognition can be screened using the Mini-Mental Status Examination.
Tests may include the following:
- Vitamin B12 deficiency: serum vitamin B12 (cobalamin), serum methylmalonic acid, plasma total homocysteine, hematologic tests, Schilling test, serum gastrin, intrinsic factor, and parietal cell antibodies.
- Folate deficiency: serum folate, red blood cell folate (measures tissue stores), and plasma total homocysteine.
- Copper deficiency: serum and urine copper, serum ceruloplasmin, serum and urine zinc, and hematologic tests.
- Vitamin E deficiency: serum vitamin E and ratio of serum vitamin E to sum of serum cholesterol and triglycerides.
- Nitrous oxide toxicity: low serum B12 in the setting of nitrous oxide exposure.
- Cassava toxicity: serum thiocyanate as a biomarker for dietary cyanide exposure.
- Hepatic myelopathy: elevated serum manganese.
- Fluorosis: osteosclerosis and ligamentous calcification seen on xray with elevated alkaline phosphatase with normal calcium and phosphorus levels. Urinary fluoride levels are not reliable.
- Genetic tests when appropriate.
Magnetic resonance imaging (MRI) findings are similar in many of the nutritional myelopathies, including vitamin B12 deficiency myelopathy, nitrous oxide intoxications, and copper deficiency myelopathy. Typically, T2 signal hyperintensities are seen in the posterior and lateral columns, especially the cervical and upper thoracic extending over several segments. This signal has been referred to as an “inverted V sign”. Nitrous oxide toxicity will result in the same pattern. In copper deficiency, lumbar involvement can also be seen, with spinal cord atrophy in severe cases. In vitamin E deficiency, the T2 signal hyperintensities are seen in the posterior columns as well as the cerebellar atrophy.
In hepatic myelopathy, there is an increased pallidal signal on the T1 cranial MRI and, rarely, also, increased cervical cord signal on the T2 images. Symmetric demyelination of the lateral corticospinal tracts, posterior columns, and spinocerebellar tracts may be seen.
Heroin myelopathy can show selective involvement of the lateral and posterior columns with T2, with evidence of cord swelling with gadolinium enhancement resembling transverse myelitis. Conversely, MR imaging in acute heroin myelopathy may be normal. MRI can also be normal with radiation myelopathy. Over time, MR imaging may reveal spinal cord swelling with T2 hypersensitivity and variable gadolinium enhancement.
Fluorosis shows osteosclerosis and ligamentous calcification and calcification of the interosseous membrane of the forearm on xray.
Supplemental assessment tools
Additional testing is done, as indicated by neurologic impairment, including urodynamics for neurogenic bladder dysfunction and spirometry for respiratory dysfunction. In the case of EMG, studies of vitamin B12, copper, and vitamin E deficiency myelopathy have demonstrated patterns of predominantly axonal peripheral neuropathy with somatosensory evoked potential showing slowing of central somatosensory pathways.
Early predictions of outcomes
Because of the diverse nature of these conditions, prognostication is difficult. Generally, the more rapid the onset and more severe the neurologic deficits, the poorer the prognosis is for complete recovery. Extent of MRI involvement in vitamin B12 has not been shown to correlate with degree of recovery.
In addition to the usual assessment of environment that is appropriate for persons with functional deficits as a result of spinal cord injury, these conditions are often characterized by loss of proprioception. Thus, environmental assessment should include focus on reducing fall risk, including lights for nighttime, grab bars in the bath (where eyes must be closed and impaired proprioception becomes more noticeable), among others.
3. REHABILITATION MANAGEMENT AND TREATMENTS
Available or current treatment guidelines
Specific interventions to address the underlying cause depend on the specific etiology, and include the following:
- Vitamin B12 deficiency: intramuscular vitamin B12 1000 µg daily for 14 days, then monthly thereafter.
- Folate deficiency: oral folate 1 mg 3 times a day until hematologic values normalize, followed by 1 mg daily as maintenance. Increase dietary intake of green, leafy vegetables and citrus fruits.
- Copper deficiency: oral copper 8 mg daily for 1 week, then 6 mg daily for 1 week, then 4 mg daily for 1 week, then 2 mg daily. Discontinue intake of exogenous zinc in patients with excess zinc as a cause.
- Vitamin E deficiency: vitamin E 200 to 1000 mg daily (may be oral or intramuscular).
- Nitrous oxide toxicity: cessation of chronic exposure. Give intramuscular vitamin B12 with acute nitrous oxide poisoning. There may be a role for methionine supplementation. Consider prophylactic vitamin B12 prior to surgery in individuals with a borderline vitamin B12, if expected to get nitrous oxide anesthesia.
- Cassava toxicity: “wetting method” involving mixing cassava with flour and letting it sit has greatly reduced incidence in areas of Africa.
- Lathyrism: preventable by mixing grass pea with cereals, or detoxification through aqueous leaching.
- Hepatic myelopathy: possible benefit of early liver transplantation.
- Organophosphate toxicity: pralidoxime and atropine for acute toxicity. Prevention by use of gloves and protective clothing.
- Fluorosis: surgery may be required for evidence of cord compression.
- The radiation dose to limit the risk of radiation myelopathy is 45 Gy, administered over 22-25 fractions.
In addition to these specific treatments, rehabilitative strategies should focus on addressing the associated impairments. This will include therapy for transfers, strengthening, gait training with a device as needed, and evaluation of ADLs needs with provision of appropriate equipment. Patients with proprioceptive deficits will need to be trained in accommodative techniques, such as the use of visual feedback, to compensate for loss of joint position sense.
Patient & family education
For conditions caused by toxins, especially as a result of dietary exposure, education will be key to preventing future exposure. Many of the nutrient deficiencies require lifelong supplementation, and patient education regarding this will be key.
Similar to other nontraumatic myelopathies.
Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills
These conditions should be in the differential diagnosis of unexplained weakness, sensory impairment, or gait disturbance, because they are uncommon yet often treatable.
4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE
5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE
Gaps in the evidence-based knowledge
It is possible that other myelopathies may also be the result of impaired vitamin B12 metabolism, though the precise role may not be fully defined. For example, the vacuolar myelopathy associated with acquired immunodeficiency syndrome is thought to possibly be because of a metabolic disorder of the vitamin B12-dependent transmethylation pathway, induced by the human immunodeficiency virus or cytokine activation.
Further study into the mechanism and treatment of heroin myelopathy is needed. Several proposed mechanisms exist including the immune-mediated response previously mentioned as well as a direct toxic effect of heroin on the CNS and vasculitis. This research may become increasingly important given the current epidemic of heroin use.
Clioquinol was used as a topical and intestinal antiseptic and to treat acrodermatitis enteropathica until it was banned after epidemiological studies identified it as the cause of subacute myelo-opticoneuropathy in 1970. It acts as a zinc chelator in the intestine and causes an increase in systemic zinc absorption. Therefore, it is hypothesized that copper deficiency may have been the cause of this disorder.
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Original Version of the Topic
Susan V. Garstang, MD. Metabolic / Nutritional / Toxic / Radiation myelopathies. 09/20/2013.
Thomas Kiser, MD
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Noel Brown, MD
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