PRIMARY MYELOPATHIES (DEGENERATIVE, INFECTIVE, METABOLIC)

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CHAPTER 39 PRIMARY MYELOPATHIES (DEGENERATIVE, INFECTIVE, METABOLIC)

A number of conditions may selectively involve the spinal cord; some of these conditions also involve other neural tissues, to a lesser extent. The spinal cord neurons are relatively extensive, and as a result, they may be particularly susceptible to defects, which impair intraneuronal transport mechanisms. This chapter covers primary disorders of the spinal cord, excluding spinal cord trauma, spinal cord compression, and developmental spinal disorders; those topics are covered in Chapters 38, 40, and 99. For discussion, it is convenient to divide the primary myelopathies into acute (including subacute) and chronic clinical manifestations.

ACUTE MYELOPATHIES

Acute myelopathy, or acute transverse myelopathy, is a disorder of acute or subacute spinal cord dysfunction resulting from a variety of causes, as listed in Table 39-1. In a clinical study, de Seze and colleagues (2001) found the commonest cause to be multiple sclerosis (43%); other causes included systemic disease (16.5%), spinal cord infarction (14%), infectious or parainfectious conditions (6%), and radiation myelopathy (4%). No underlying cause was found in the remaining 16.5%, despite an average of 29 months’ follow-up. The criteria for the clinical diagnosis of acute transverse myelopathy include (1) acute/subacute onset of sensory and motor symptoms, including symptoms of sphincter dysfunction; (2) spinal segmental level of sensory disturbance with a well-defined upper limit; (3) occurrence of symptoms over no more than 3 weeks and sustained for a period of at least 48 hours; (4) no clinical or radiological evidence of spinal cord compression; and (5) no known history of neurological disease or neurological symptoms.

TABLE 39-1 Causes of Acute Transverse Myelopathy

Demyelination	Multiple sclerosis, acute disseminated encephalomyelitis, neuromyelitis optica
Systemic disorders	Systemic lupus erythematosus, sarcoid, Sjögren’s syndrome, Behçet’s syndrome, antiphospholipid syndrome, mixed connective tissue disease
Infectious/parainfectious	Herpes simplex viruses 1 and 2, herpes zoster virus, Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, enterovirus, human immunodeficiency virus, human T cell lymphotrophic virus type 1, mycoplasma, Lyme disease, syphilis
Vascular	Arterial, venous, watershed, arteriovenous malformation, fibrocartilaginous embolism
Miscellaneous Idiopathic	Radiation myelopathy, epidural lipomatosis

New cases of acute transverse myelopathy occur at a rate of 1 to 4 per million people per year. There is no gender predisposition, in contrast to the predominant female predisposition in multiple sclerosis. Fifty percent of patients develop almost complete paraparesis, most have bladder dysfunction, and 80% to 94% have sensory disturbance. The recovery of the neurological deficit is somewhat variable: One third of patients recover with little or no deficit, one third have moderate disability, and one third have severe disability.

Acute transverse myelopathy may be an initial presenting feature of multiple sclerosis. Typically, such patients who ultimately go on to develop multiple sclerosis have an asymmetrical partial transverse myelitis: that is, predominant sensory disturbance with relative motor sparing. Magnetic resonance imaging (MRI) of the spine characteristically shows lesions extending over less than two spinal segments. MRI of the brain may show characteristic demyelinating lesions (in up to 50% of cases manifesting as a clinically isolated syndrome). The cerebrospinal fluid may reveal unmatched oligoclonal bands (in up to 50% of cases manifesting as a clinically isolated syndrome).

The diagnostic evaluation of a patient with suspected acute transverse myelopathy initially involves neuroimaging of the spine (usually MRI with gadolinium) to rule out a compressive myelopathy. After a compressive spinal lesion is ruled out, a lumbar puncture helps distinguish an inflammatory myelopathy from a noninflammatory myelopathy. The cerebrospinal fluid analysis includes a cell count determination and differential, protein and glucose level measurements, oligoclonal band analysis, and cytologic studies. If an inflammatory myelopathy is suspected, brain MRI and evoked potentials may indicate whether there is a multifocal inflammatory process, suggestive of multiple sclerosis, acute disseminated encephalomyelitis or neuromyelitis optica (also known as Devic’s syndrome). In the case of neuromyelitis optica, patients may be tested for a specific neuromyelitis optica-immunoglobulin G autoantibody, as recently described by Lennon and associates.

A possible infectious/parainfectious cause may manifest with certain clinical features: fever, rash, meningismus, concurrent systemic infection, immunocompromised state, recurrent genital infection, radicular burning pain with vesicles (suggestive of herpes zoster), and lymphadenopathy. In such cases, further investigation includes serum and cerebrospinal fluid viral and bacterial cultures, cerebrospinal fluid viral and bacterial polymerase chain reaction studies, and acute and convalescent serum antibody studies for the infectious agents listed in Table 39-1.

Alternatively, certain clinical features such as arthritis, erythema nodosum, xerostomia, Raynaud’s phenomenon, rash, and ulcers may be suggestive of an underlying systemic disease, such as systemic lupus erythematosus, Sjögren’s syndrome, sarcoidosis, mixed connective tissue disease, Behçet’s disease, or antiphospholipid antibody syndrome. If a systemic autoimmune disease is suspected, serum should be analyzed for antinuclear antibodies, double-stranded DNA antibodies, Ro and La antibodies, cardiolipin antibodies, lupus anticoagulant, angiotensin-converting enzyme level, β₂-glycoprotein level, and complement levels. Schirmer’s test, lip/salivary gland biopsy, and chest computed tomographic scan should also be considered.

CHRONIC MYELOPATHIES

The commonest causes of chronic myelopathy seen in neurological practice include spinal multiple sclerosis, cervical spondylitic radiculomyelopathy, and sporadic motor neuron disease. These topics are covered in more detail elsewhere in the book. Patients with chronic myelopathy typically present with gradually progressive spastic paraparesis and varying spastic paresis of the upper limbs. The extent of sensory loss varies according to the nature of the underlying neuropathology. Sphincter dysfunction is also commonly seen. Causes of chronic myelopathy are listed in Table 39-2.

TABLE 39-2 Causes of Chronic Myelopathy

Hereditary Spastic Paraplegia

Hereditary spastic paraplegia is a rare, genetically determined degenerative disorder affecting predominantly corticospinal neurons. The condition is outlined in more detail in Chapter 69. Hereditary spastic paraplegia was first described by Adolf von Strümpell and M. Lorrain during the late 19th century. Although the phenotypic variants are well described elsewhere, knowledge of the genetic basis of this condition has undergone vast changes since the mid-1990s. At the time of this writing, more than 20 genetic loci (labeled SPG1 to SPG23) and nine defined gene products have been discovered. These gene products include spastin (which accounts for 40% of dominantly inherited hereditary spastic paraplegia cases), atlastin, NIPA1, kinesin heavy chain, heat shock protein 60, seipin, paraplegin, spartin, L1 cell adhesion molecule, and proteolipid protein. The precise functions of these gene proteins are not well understood; however, knowledge in this area is rapidly expanding.

Hereditary spastic paraplegia displays marked phenotypic and genotypic variabilities. The inheritance may be autosomal dominant, autosomal recessive, or X-linked. The disorder has traditionally been divided clinically into pure and complicated forms; the latter has been associated with additional neurological features such as amyotrophy, dementia, epilepsy, optic atrophy, retinopathy, extrapyramidal disease, ataxia, mental retardation, deafness, ichthyosis, and peripheral neuropathy.

Patients present at any age, typically with gait disturbance. A patient may present with toe walking, with a tendency to trip because the feet catch on uneven ground, or with premature wear on footwear. In childhood cases, walking may be delayed. Spasticity predominates over weakness, particularly in the lower limbs. The upper limbs are rarely affected. Brisk tendon reflexes with extensor plantar responses are found. Sensory loss, if present, involves mild impairment of vibration sense. Similarly, sphincter involvement is usually mild and results in urinary urgency, frequency, and hesitancy. Some affected patients may be so severely disabled by spasticity that they require a walking aid or wheelchair, despite having normal performance on muscle testing. Some affected family members may be minimally affected or even asymptomatic. The prognosis is highly variable; however, early-onset cases (manifesting before age 35 years) may have a very slowly progressive course with ambulation remaining, whereas later onset cases (after age 35 years) may progress rapidly, rendering patients nonambulatory. The diagnosis is usually made by exclusion of alternative causes, although gene testing is available for some cases.

Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a hereditary degenerative disorder involving the anterior horn cells, spinal interneurons, and, in some cases, the bulbar nuclei. The childhood-onset, autosomal recessive, proximal form is the commonest variation of the disorder. The incidence ranges from 1 per 6000 to 1 per 10,000. It is a common genetic cause of death and disability in childhood. The disorder has traditionally been classified into types I, II, and III by age at onset and by severity. Type I, also known as Werdnig-Hoffman disease, is characterized by early age at onset (before 6 months of age) and severe muscle weakness, muscle wasting, and hypotonia. Death from respiratory failure often occurs before the age of 2 years. Type III, also known as Kugelberg-Welander disease, begins after the age of 18 months and is of milder severity. Affected patients usually survive into adulthood, and many can walk or stand without assistance. Type II is an intermediate form. Additional clinical features of SMA include hyporeflexia, tongue fasciculations, and hand tremor. Sensory loss and sphincter disturbance are absent. The electrophysiological investigations reveal changes in denervation on electromyography and normal sensory/motor conduction velocities. Muscle biopsy also reveals denervative changes with hypertrophic fibers.

Genetic linkage analysis has linked SMA types I, II, and III to defects on chromosome 5q11.2-13.3. A mutation in the survival motor neurone gene (SMN1) was discovered as the causative factor. A copy gene, SMN2, acts as a modifier gene, possibly rescuing the phenotype. The SMN1 gene codes for a 38-kD protein, which plays a multifunctional role in ribonucleoprotein metabolism and premessenger RNA splicing. There appears to be a dose effect of the SMN protein, which determines the clinical subtype and therefore the severity of the condition.

A number of less common variants of SMAs also occur. A rare subtype of SMA type I, SMARD1, constitutes 1% of cases of infantile SMA. This variant is characterized by severe diaphragmatic weakness with eventration of abdominal contents, which results in respiratory distress. The muscle weakness is usually predominantly distal rather than proximal, as opposed to the more commonly occurring SMA type I. Another subtype is dominant distal SMA, also known as “spinal CMT 2D.” In this variant, there is a predominance for upper limb weakness; the condition is linked to chromosome 7p and has been found to be caused by a mutation in the glycyl transfer RNA synthetase gene. A further variant is X-linked severe SMA with arthrogryposis and bone fractures.

Cobalamin Deficiency Myelopathy or Subacute Combined Degeneration

Neurological disorders associated with pernicious anemia were first identified in the late 19th century. Although the myelopathy associated with cobalamin deficiency is the predominant neurological manifestation, other recognized features include dementia, neuropathy, and, in rare cases, optic neuropathy. A more comprehensive discussion of the cobalamin deficiency is presented in Chapter 109; however, the myelopathy is briefly described here. Classically, a patient presenting with numbness and weakness in the legs is found to have macrocytic anemia. The examination reveals a smooth tongue, prematurely graying hair, and yellow skin. The diagnosis is then confirmed by demonstration of a low serum cobalamin level. Frequently, however, affected patients present with atypical clinical or laboratory features, such as neurological manifestations without anemia, macrocytosis, or depressed serum cobalamin level. In the last situation, elevated levels of cobalamin metabolites (methylmalonic acid and homocystine) may provide a clue to the diagnosis.

Healton and colleagues reported the first large series of patients with neurological manifestations from cobalamin deficiency since the introduction of modern diagnostic techniques and therapeutic measures. Of 369 patients with cobalamin deficiency, 189 (51%) had neurological symptoms and 114 (31%) had neurological symptoms as their presenting symptom. Of those with neurological manifestations, paresthesias occurred in 70% and were disabling in 10%. Twenty-one percent had neurological symptoms but with normal findings on neurological examination. On examination, impaired lower limb vibration sense (88%) and diminished proprioception in the toes and ankles (59%) were the predominant findings. Other findings included impaired touch/pain sensation (30%), gait ataxia (23%), limb weakness (13%), positive Romberg test results (11%), absent or reduced deep tendon reflexes (33%), and exaggerated deep tendon reflexes (11%). Brisk deep tendon reflexes with extensor plantar responses and lower limb spasticity were found in just 6%.

The evaluation of a patient with suspected cobalamin deficiency should begin with a serum cobalamin level measurement, and if the level is in the low normal range and the clinical index of suspicion is high, then serum methylmalonic acid and homocystine levels should be measured. If the serum cobalamin level is reduced, measurement of intrinsic factor antibodies and parietal cell antibodies may be useful in diagnosing autoimmune pernicious anemia. Schilling’s test may then be helpful in determining the cause of cobalamin deficiency. Spinal MRI may show characteristic T2 signal changes in the posterior and lateral columns, and somatosensory evoked potentials may demonstrate impairment of central conduction defects. Treatment of cobalamin deficiency requires 1000 μg of intramuscular cobalamin daily for 5 days, followed by monthly doses of similar amount.

Exposure to nitrous oxide, either through its use as an anesthetic or through recreational use, may trigger an acute or subacute myelopathy by interfering with cobalamin metabolism. The treatment is the same as for subacute combined degeneration as described previously.

Copper Deficiency Myelopathy

A progressive myelopathy/myeloneuropathy associated with copper deficiency has been recognized. The condition may have been hitherto underrecognized. Kumar and associates (2004) reported a series of such cases with a clinical syndrome resembling subacute combined degeneration. The patients typically presented with a spastic ataxic gait and marked posterior column sensory deficits. MRI may demonstrate posterior column signal changes, and somatosensory evoked potentials may show evidence of central proprioceptive pathway conduction defects. Reduced ceruloplasmin levels were the initial clue to the diagnosis. The cause of reduced levels of serum copper was not known in most cases. Copper supplementation restores the serum copper levels and may prevent further neurological deterioration. Some cases of copper deficiency were associated with elevated zinc levels. As with subacute combined degeneration from cobalamin deficiency, copper deficiency-related myelopathy occurred in the absence of hematological manifestations.

Paraneoplastic Myelopathy

Progressive myelopathy has rarely been reported in the context of systemic cancer. Mancall and Rosales reported cases of subacute necrotizing myelopathy associated with visceral carcinoma. Subacute ascending flaccid areflexic paraplegia with sphincter paresis and sensory involvement was the characteristic presentation. The cerebrospinal fluid analysis shows pleocytosis and elevated protein. MRI of the spine shows spinal cord enlargement and T2 signal abnormalities. There is no specific cancer described with the syndrome, and there are no recognized testable autoantibodies that can serve as a marker for a paraneoplastic process.

Hepatic Myelopathy

A rare progressive myelopathy may occur in the setting of chronic liver disease and may be part of the clinical spectrum, which includes acquired hepatocerebral degeneration. Patients typically have spastic paraparesis with minimal sensory involvement. Pathologically, there is symmetrical demyelination of the lateral pyramidal tracts with a degree of axonal loss. Differential effects of the exposure to toxic metabolic substances that bypass the liver may explain the resultant neurological manifestations (i.e., hepatic myelopathy versus acquired hepatocerebral degeneration).

Adrenomyeloneuropathy

Adrenomyeloneuropathy is regarded as a milder variant of adrenoleukodystrophy. Adrenoleukodystrophy is discussed in greater detail in Chapter 80. It is an X-linked disorder caused by a mutation in the Xq28 gene, which codes for a peroxisomal membrane transporter protein (ALDP). The precise role of ALDP is unknown; however, the ALDP mutation leads to the accumulation of very-long-chain fatty acids, particularly tetracosanoic acid (C24:0) and hexacosanoic acid (C26:0) in neural tissue, adrenal glands, and testes. A typical patient with adrenomyeloneuropathy presents with a slowly progressive spastic paraparesis during the third to fourth decades of life. Early sphincter involvement and defects in posterior column sensory function are characteristic. Signs of adrenal and testicular insufficiency may precede, occur synchronously with, or follow the onset of the neurological manifestations. Nevertheless, 15% of affected male patients and 99% of affected female patients (symptomatic carriers) do not develop adrenal insufficiency. Of all patients with adrenomyeloneuropathy, 40% to 50% have cerebral white matter lesions on MRI (“cerebral” adrenomyeloneuropathy). Those without such cerebral white matter lesions (i.e., “pure” adrenomyeloneuropathy) have a better prognosis, whereas 25% of patients with “cerebral” adrenomyeloneuropathy develop a catastrophic course like that of childhood cerebral adrenoleukodystrophy. Pathological studies of adrenomyeloneuropathy suggest a noninflammatory distal axonopathy involving the spinal cord tracts and, to a lesser extent, peripheral nerves. The diagnosis is based on the demonstration of increased levels of serum very-long-chain fatty acids and mutation analysis. In other inborn errors of metabolism (e.g., globoid leukodystrophy and metachromatic leukodystrophy), myelopathy may be part of the clinical manifestation; however, such conditions produce not isolated myelopathy but rather a multisystem neurological disorder.

• Acute transverse myelopathy can result from a variety of inflammatory processes, including idiopathic transverse myelitis, multiple sclerosis, and neuromyelitis optica; a variety of infectious/parainfectious disorders; and systemic autoimmune disorders such as systemic lupus erythematosus.

• The syndrome of acute transverse myelopathy may also result from noninflammatory processes such as spinal cord infarction and radiation myelopathy.

• Myelopathy resembling subacute combined degeneration can be caused by cobalamin deficiency and also copper deficiency.

• Advances in molecular genetics are rapidly expanding knowledge of the hereditary degenerative myelopathies such as hereditary spastic paraplegia and spinal muscular atrophy.

Suggested Reading

De Seze J, Stojkovic T, Breteau G, et al. Acute myelopathies: clinical, laboratory and outcome profiles in 79 cases. Brain. 2001;124:1509-1521.

Green R, Kinsella L. Current concepts in the diagnosis of cobalamin deficiency. Neurology. 1995;45:1435-1440.

Kumar N, Gross JB, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology. 2004;63:33-39.

Miller AE, editor. Spinal cord disorders [June issue]. Continuum: Lifelong Learning in Neurology. 2005;11(3).

Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59:499-505.

Anderson K, Talbot K. Spinal muscular atrophies reveal motor neuron vulnerability to defects in ribonucleoprotein handling. Curr Opin Neurol. 2003;16:595-599.

Elliott JL. Beginning to understand hereditary spastic paraplegia atlastin. Arch Neurol. 2004;61:1842-1843.

Fink JK. The hereditary spastic paraplegias: nine genes and counting. Arch Neurol. 2003;60:1045-1049.

Fink JK, Rainier S. Hereditary spastic paraplegia: spastin phenotype and function. Arch Neurol. 2004;61:830-833.

Healton EB, Savage DG, Brust JCM, et al. Neurologic aspects of cobalamin deficiency. Medicine. 1991;70:229-244.

Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364:2106-2112.

Lewis M, Howdle PD. The neurology of liver failure. Q J Med. 2003;96:623-633.

McDermott CJ, White K, Bushby K, et al. Hereditary spastic paraparesis: a review of new developments. J Neurol Neurosurg Psychiatry. 2000;69:150-160.

Mancall EL, Rosales RK. Necrotizing myelopathy associated with visceral carcinoma. Brain. 1964;87:639-656.

Moser H, Dubey P, Fatemi A. Progress in X-linked adrenoleukodystrophy. Curr Opin Neurol. 2004;17:263-269.

Nicole S, Diaz CC, Frugier T, et al. Spinal muscular atrophy: recent advances and future prospects. Muscle Nerve. 2002;26:4-13.

Powers JM, DeCierco DP, Ito M, et al. Adrenomyeloneuropathy: a neuropathologic review featuring its noninflammatory myelopathy. J Neuropathol Exp Neurol. 2000;59:89-102.

Rudnicki SA, Dalmau J. Paraneoplastic syndromes of the spinal cord, nerve and muscle. Muscle Nerve. 2000;23:1800-1818.

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