Medical Myelopathies

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CHAPTER 37 Medical Myelopathies

Spinal cord disease may result from a variety of insults. A general classification of these various etiologies is provided in Table 37–1. This chapter addresses the “medical” causes of spinal cord dysfunction.

TABLE 37–1 Etiologies of Myelopathy

The nature of the history and the physical findings resulting from these myelopathies is very dependent on the rapidity of onset of the lesion and its specific location in the spinal cord, particularly with respect to the spinal tracts involved. Typically, the chief complaints of patients presenting with these forms of myelopathy are lower extremity weakness and gait disturbance. A sense of stiffness of the legs is common. If the cervical spinal cord is involved, upper extremity weakness is to be expected. Loss of dexterity in the fingers and hands is often perceived by the patient. Frequently, patients may complain of numbness and other sensory abnormalities.

If the illness involves the posterior columns in the cervical region, the patient may exhibit Lhermitte phenomenon, characterized by a sense of lightninglike, electric shocks that generally radiate down the spine and into the extremities on neck flexion. Variants of this phenomenon may occur, and other forms of head and neck movement may precipitate this fleeting discomfort. Spinal cord disease involving the posterior columns in the thoracic region may result in a disquieting bandlike or girdlelike sensation across the chest or abdomen. This phenomenon is a helpful localizing clue. Paresthesias of the distal extremities may also result from these lesions. Urinary urgency and frequency, incontinence of bladder and bowel, and sexual impotence are common.

Generally, but not invariably, a thorough neurologic examination allows the physician to distinguish spinal cord from other causes of these neurologic complaints. The presence of concomitant neurologic illness attributable to disease of the cerebral hemispheres or brainstem, such as hemianopsia, ophthalmoplegia, and dysarthria, does not rule out the possibility of concomitant spinal cord disease, but should suggest that the findings on neurologic examination may be ascribed to a single or multiple lesions higher in the neuraxis than the spinal cord. The physical examination of patients with spinal cord lesions that have developed gradually or who have acute lesions that have been present for several weeks typically reveals a spastic weakness of the involved extremities with associated hyperreflexia and pathologic reflexes. The latter include Hoffman sign (palmar flexion of the thumb when the distal phalanx of the middle finger of the same hand is rapidly tapped) in the upper extremities and Babinski sign (plantar extension of the hallux when the sole of the foot is stroked) in the lower extremities. Several variants of these signs have been described.1 Superficial reflexes, such as abdominal and cremasteric reflexes, are absent.

In the early period of an acutely developing spinal cord lesion, “spinal shock” is typical, in which a flaccid weakness of the extremities predominates. Although this entity is more common with traumatic lesions of the spinal cord, it may result from infectious, vascular, or other insults to the spinal cord. The presence of a flaccid weakness with areflexia may lead to a false diagnosis of an acute peripheral neuropathy as may be observed with Guillain-Barré syndrome. A careful sensory examination is crucial to distinguish appropriately between these possibilities. A sensory level is to be expected with a spinal cord lesion, but is hardly an invariable finding. Guillain-Barré syndrome is predominantly a motor neuropathy, and when it results in sensory loss, a mild decrease in vibratory sensation in distal extremities is usually observed. Although more severe forms of sensory loss may be seen with this and other causes of peripheral neuropathy, a sensory level is not present.

The appearance of Brown-Séquard syndrome is pathognomonic of spinal cord disease. This syndrome results from an injury to one half of the spinal cord and is characterized by the presence of weakness and loss of position and vibratory sensory perception ipsilateral to the side of the lesion and loss of pinprick and temperature sensory perception on the side of the body contralateral to the lesion. Incomplete forms of Brown-Séquard syndrome are commonly observed.

Acute Idiopathic Transverse Myelitis and Multiple Sclerosis

Patients with acute idiopathic transverse myelitis most often present with paresthesias of the feet, toes, or fingertips.2 Gradually developing numbness and coincident weakness of the legs follows with subsequent paralysis of the legs. The features of this illness usually evolve over 1 to 3 weeks, but they may develop abruptly. The initial symptoms may be predominantly unilateral, and asymmetrical findings are common. As the illness progresses, upper extremity numbness and weakness and bowel and bladder incontinence may ensue. In some patients, posterior column involvement (decreased vibration and position senses) is spared early but affected later. Occasionally, back (interscapular) pain and, more rarely, calf, arm, or radicular pain may accompany the progressive myelopathy suggesting other pathologic processes, such as an intraspinal neoplasm or epidural abscess. To be considered idiopathic, acute transverse myelitis should be unassociated with a known preceding or concomitant viral infection. The dominant pathologic feature of the spinal cord is demyelination.

Treatment with adrenocorticotropic hormone (ACTH) or corticosteroids has been advocated; the response to therapy may be highly variable, and some studies indicate no benefit.3 A pilot study of high-dose methylprednisolone in children with acute transverse myelitis showed a significant shortening of motor recovery compared with historical controls.4 Approximately one third of patients have a return of a normal gait and bladder function.2 When recovery to a normal or near-normal level of function occurs, it does so within 1 year of the onset of the illness. Of affected patients, 25% become wheelchair-bound or bedridden, and the remainder have varying degrees of lesser disability.2

In some instances, myelopathy develops abruptly. Frequently, a flaccid, areflexic paralysis of the affected limbs accompanies spinal shock. Loss of vision resulting from optic nerve inflammation may accompany this myelopathy. Devic disease (neuromyelitis optica [NMO]) refers to the combination of acute optic neuritis and transverse myelitis. Similar to the more slowly evolving idiopathic transverse myelitis, demyelination is a characteristic neuropathologic hallmark. The pathology has been described as a necrotizing hemorrhagic leukomyelitis. The prognosis of patients with this rapidly evolving myelopathy, particularly when it is accompanied by spinal shock, is worse than the prognosis for the more gradually developing transverse myelitis.5

The differential diagnosis of idiopathic transverse myelitis includes multiple sclerosis; infectious myelitis; postinfectious or postvaccination myelitis; and myelopathy associated with vasculitis and connective tissue diseases, such as Behçet disease, systemic lupus erythematosus (SLE), and Sjögren syndrome. Multiple sclerosis may initially manifest as a transverse myelitis; the likelihood of transverse myelitis being the presenting manifestation of multiple sclerosis was previously reported to be 5% to 15%.2,57 Since the advent of more sensitive testing (magnetic resonance imaging [MRI]), this likelihood has been estimated at 42%.8 If cranial MRI is highly suggestive of multiple sclerosis at the time of onset of myelitis, the risk of progression to clinically definite multiple sclerosis is 50% at 2 years, whereas if cranial MRI is negative, the risk is 5%.9 A temporal association with a viral illness (Table 37–2), signs and symptoms that develop over a few days, and a monophasic course should suggest the possibility of a viral myelitis.10

TABLE 37–2 Viral Etiologies of Myelitis

RNA Viruses DNA Viruses
Nonenveloped
Picornaviruses Hepatitis B
Coxsackieviruses  
Echoviruses  
Polioviruses  
Other enteroviruses  
Hepatitis A  
Encephalomyocarditis virus  
Enveloped
Togaviruses Herpesviruses
Arbovirus Herpes simplex
Rubella Varicella-zoster
Tick-borne encephalitis virus Epstein-Barr virus
Retroviruses Cytomegalovirus
Human immunodeficiency virus type 1 Herpes simiae
Human T-cell lymphotropic virus type I Poxviruses
Orthomyxoviruses Vaccinia
Influenza Variola
Paramyxoviruses  
Measles  
Mumps  
Bunyaviruses  
California encephalitis virus  
Arenavirus  
Lymphocytic choriomeningitis  
Rhabdovirus  
Rabies  

Adapted from Tyler KL, Gross RA, Cascino GD: Unusual viral causes of transverse myelitis: Hepatitis A virus and cytomegalovirus. Neurology 36:855-858, 1986.

Spinal cord disease is extremely common in the setting of multiple sclerosis and frequently is responsible for the associated extremity weakness, spasticity, gait abnormalities, and sphincter disturbances. Within 10 to 15 years of the onset of multiple sclerosis, more than 80% of patients exhibit extremity spasticity and weakness, and more than 50% have sphincter disturbances.11,12 Lhermitte sign has been reported in 38% of patients with clinically definite multiple sclerosis.13 Approximately 10% of patients with multiple sclerosis have a primary progressive form of the disease. This disorder often affects the spinal cord predominantly and most commonly develops in women older than 40 years.

NMO has been regarded as a variant of multiple sclerosis; however, the occurrence of a unique IgG antibody to the aquaporin-4 channel (NMO-IgG)14 suggests it is a distinct disorder. NMO may occur as an isolated condition or, more commonly, as recurrent spells of optic neuritis and myelitis. In contrast to the myelitis of multiple sclerosis, which seldom extends beyond two or three segments, the myelitis of NMO is often longitudinally extensive. Optic neuritis or myelitis in isolation may occur with NMO. Treatment recommendations15 include high-dose intravenous methylprednisolone; plasma exchange; intravenous immunoglobulin; and rituximab, an anti-CD20 antibody directed against B cells.

The diagnostic approach to a patient suspected to have an acute transverse myelitis should begin with a thorough history and physical examination. Evidence of a recent viral illness should be sought. A history of syphilis, connective tissue diseases, or prior neurologic illness may prove essential in arriving at the correct diagnosis. Serologic studies should always include a serum Venereal Disease Research Laboratory (VDRL) test and fluorescent treponemal antibody absorption for syphilis.

MRI of the involved area of the spinal cord is the best radiographic study. MRI may be normal or reveal cord swelling or hyperintense lesions or both on T2-weighted imaging intrinsic to the spinal cord. Miller and colleagues16 found MRI lesions at the clinically expected level in 64% of patients with a clinical syndrome suggestive of cervical involvement but in only 28% with a suspected thoracic or lumbar lesion. In patients with multiple sclerosis, most lesions are observed in the cervical spinal cord at autopsy and by MRI.17,18 Lesions on MRI are characteristically T2-weighted hyperintense signal abnormalities, generally less than 10 to 15 mm in length,18 and multiple, gapped lesions may be observed. Gadolinium enhancement with active disease is often observed.19 Generally, MRI, if available, negates the need of myelography. If MRI is unavailable, myelography should be performed with water-soluble contrast medium and computed tomography (CT) scan of the affected area. If pain is a significant component of the patient’s illness, a CT scan of the appropriate area and a bone scan may be desirable in eliminating the possibility of an epidural abscess or neoplasm.

Cerebrospinal fluid (CSF) examination typically reveals mononuclear pleocytosis, often with 100 to 200 cells, and increased protein. With necrotizing myelopathy, the spinal cord may swell sufficiently to result in a spinal block with an abnormal Queckenstedt test and an extremely high CSF protein (Froin reaction). CSF VDRL, immunoglobulins, basic myelin protein, and viral cultures should be performed.

Somatosensory evoked potentials can be very helpful in ruling in suspected cord lesions. The presence of abnormalities on brainstem auditory evoked potential and visual evoked potential testing would raise the suspicion of multifocal disease (i.e. multiple sclerosis). Absent F waves on nerve conduction testing can also support evidence of a cord lesion.20

Adrenomyeloneuropathy

Adrenomyeloneuropathy is a phenotypic variant of the genetic disorder adrenoleukodystrophy, in which myelin sheath abnormalities of the white matter are associated with adrenal insufficiency. Although adrenoleukodystrophy is a sex-linked disorder, it has variable expressions, including mild disease in heterozygous women. Pathologically, the white matter abnormality appears to be a diffuse myelinoclastic sclerosis, but it may occasionally appear as a dysmyelinating condition. The neurologic variants are explained by the degree of involvement of brain, spinal cord, and peripheral nerve. Biorefringent material in the adrenal glands and brain observed histopathologically have been shown by sequential extraction methods to be cholesterol esters with high quantities of very long chain fatty acids. Measuring fatty acids in cultured skin fibroblasts from affected individuals, Moser and colleagues21 showed abnormally large amounts of very long chain fatty acids (C24-C30) and a high ratio of C26 to C22 fatty acids. The latter has become the preferred method of diagnosing the disorder.

In patients with the spinal-neuropathic form of this disorder, adrenal insufficiency is usually present since early childhood, and a progressive spastic paraparesis and relatively mild peripheral neuropathy develop in the 3rd decade.22 Other variants affecting the spinal cord have been observed, including a progressive myelopathy in men, a mild spastic paraparesis in women, and combined cerebral and spinal involvement in children and young men. A positive family history is present in approximately 50% of affected individuals. The presence of Addison disease also provides a strong clue to the diagnosis. Addison disease, which is caused by primary adrenal failure, is often accompanied by bronzing of the skin because of excessive secretion of melanocyte-stimulating hormone in association with ACTH.

Infectious Myelopathies

Viral Myelitis

Human Immunodeficiency Virus Infection

Neurologic complications develop in 40% to 60%2325 of all patients with acquired immunodeficiency syndrome (AIDS), and neurologic disease heralds human immunodeficiency virus (HIV) infection in 10%26 to 20%25 of HIV-infected patients. In retrospective clinical series, spinal cord disease occurring in association with AIDS has been infrequently observed. Levy and colleagues24 found viral myelitis in 3 of 128 AIDS patients with neurologic symptoms, and the collective incidence of viral myelitis in AIDS was 1% when data were pooled from three different hospital series of neurologic complications of AIDS.27 The most common form of myelopathy observed with HIV infection has been a unique degeneration of the spinal cord first described by Petito and colleagues.28 In pathologic series, spinal cord degeneration has been observed in 11%29 to 22%28 of unselected cases. These pathologic series suggest that spinal cord disease occurring in association with HIV infection is common but clinically underrecognized.

The prototypic myelopathy observed with HIV infection is a unique degeneration of the spinal cord.28,30 Petito and colleagues28 observed this myelopathy in 20 of 89 consecutive autopsies of AIDS patients. Although the clinical presentation of this myelopathy may overlap with the presentation of other myelopathies associated with HIV-1 infection, the pathologic appearance is quite distinct. Clinically, patients complain of leg weakness, unsteadiness, and gait impairment. Incontinence of bladder and bowel often supervenes. In one study, incontinence was observed in 60% of patients.28 Patients with this disorder often complain of paresthesias and vague discomfort in their legs. Frequently, these complaints are attributed to the general debilitation of the patient, and the true nature of the illness remains undiagnosed until pathologic examination of the spinal cord at the time of autopsy.

On physical examination, a spastic paraparesis is detected with the degree of weakness exceeding the degree of spasticity. Rarely, marked asymmetry of the leg weakness, a monoparesis, or quadriparesis may be found. Gait ataxia is seen, and the heel-to-knee-to-toe test may reveal dysmetria and dyssynergy. Occasionally, weakness is slight or absent on confrontation testing, but hyperreflexia of the lower extremities and extensor plantar responses are noted. Muscle stretch reflexes may also be diminished or absent in this disorder, however, as a result of concomitant peripheral neuropathy. Sensory examination reveals that vibratory and position sense are disproportionately affected compared with pinprick, temperature, or light touch. A significant impairment of the latter modalities suggests the presence of a concomitant peripheral neuropathy. Electrophysiologic studies may reveal a prolonged latency of cortical evoked responses after tibial nerve stimulation. Typically, this myelopathy is seen late in the course of HIV-1 infection; however, it has been described as the presenting manifestation of infection.31

Gross examination of the spinal cord and dura is generally normal in HIV-associated myelopathy except when the myelopathy is particularly severe.28 The striking finding on histologic examination is the loss of myelin and spongy degeneration. The lateral and posterior columns are more severely affected than the anterior columns. Microvacuolization of the white matter of the spinal cord (Fig. 37–1) associated with lipid-laden macrophages bears an uncanny resemblance to the pathology of subacute combined degeneration of the spinal cord. The vacuolization seems to result from intramyelin swelling. Axons are preserved except in areas of marked vacuolization. Microglial nodules may be detected in the spinal cord gray matter, and 20% of the patients in one series also exhibited central chromatolysis of the anterior horn motor cells.28 Inflammation and intranuclear viral inclusions are generally not seen.

Although HIV has been cultured from the spinal cord, the specific role of HIV in the causation of this illness is uncertain. A similar clinicopathologic condition has been observed in patients with cancer or other immunosuppressive conditions in the absence of HIV infection.32 The spinal cord pathology is most prominent in the middle and lower thoracic regions. The cord involvement may be asymmetrical and does not seem to be confined to particular tracts.28 Goldstick and colleagues30 described involvement of the posterior columns increasing in intensity with rostral progression, whereas pyramidal tract involvement increased caudally. Petito and colleagues28 were able to correlate the frequency and severity of symptoms to the degree of spinal cord pathology in their series. A potential role of nutritional deficiency as the cause of spinal cord pathology has been suggested.33 Vacuolar myelopathy is not observed in young children with AIDS; however, pathologic abnormalities of the spinal cord are frequently seen at autopsy.34 A loss of myelin and axons in the corticospinal tracts seems to be the most common abnormality.

The diagnosis of this illness is one of exclusion. Numerous other myelopathies have been observed in association with HIV infection. An acute myelopathy of uncertain pathogenesis has been noted at the time of seroconversion.35 Table 37–3 lists other etiologies of spinal cord disease occurring in association with HIV.

TABLE 37–3 Potential Etiologies of the Myelopathies Associated with Human Immunodeficiency Virus (HIV) Infection

Infectious
Viral
Bacterial
Fungal

Parasites Noninfectious Etiologies

The most useful study is MRI of the spinal cord. The author’s practice has been generally to forego myelography if MRI of the spinal cord reveals no evidence of mass lesion. The presence of unusual features, such as back pain or radicular findings may dictate a more aggressive diagnostic approach. If MRI is negative, the CSF is examined for the presence of HIV and other pathogens. CSF examination includes viral cultures with specific emphasis on cytomegalovirus and herpes simplex virus (HSV) type 1 and HSV-2. Additionally, routine bacterial and fungal cultures and cryptococcal antigen are obtained. No treatment is known to be effective for this condition, although an aggressive antiretroviral therapy regimen should be tried.

Human T-Cell Lymphotropic Virus Type I

Although thought to be rare in the United States, human T-cell lymphotropic virus type I (HTLV-I) has been observed with increasing frequency in certain subpopulations. A study of volunteer blood donors by the American Red Cross revealed a seropositivity rate of 0.025% among volunteer blood donors.36 Intravenous drug abusers seem to be at particularly high risk for infection with HTLV-I. Seroprevalence rates in this population range from 7% to 49%.37,38 In a study of the seroprevalence among female prostitutes in eight areas of the United States, 6.7% were seropositive for HTLV-I and HTLV-II with prevalence rates ranging from 0% in southern Nevada to 25.4% in Newark, New Jersey.39 A case of transmission of HTLV-I by blood transfusion associated with myelopathy has been confirmed.40 In 10 native-born cases in the United States, 5 had received blood transfusions, and 6 had multiple sex partners (including one who frequented prostitution and had a history of drug abuse).41

In addition to being associated with adult T-cell leukemia/lymphoma, HTLV-I is associated with a chronic progressive myelopathy.42,43 An association between the presence of seropositivity for HTLV-I and multiple sclerosis has also been suggested,44 but this remains controversial.

The myelopathy that occurs with HTLV-I has been referred to as tropical spastic paraparesis (TSP) or HTLV-I associated myelopathy (HAM). This myelopathy is characterized on neuropathologic studies by chronic involvement of the pyramidal tracts chiefly at the thoracic level resulting in spastic lower extremity weakness and a spastic bladder. Paresthesias, pain, and sensory disturbances may also be observed. It is estimated that 1 in 250 individuals infected with HTLV-I develop this progressive myelopathy.45 The major pathologic features of HTLV-I myelopathy are long tract degeneration and demyelination affecting the pyramidal, spinocerebellar, and spinothalamic tracts associated with hyalinoid thickening of the media and adventitia of blood vessels in the brain, spinal cord, and subarachnoid space with perivascular cuffing with leukocytes, astrocytic gliosis, and foamy macrophages.46 These lesions may extend from the upper cervical cord to the lumbar regions. Vacuolization may be observed at the periphery of the lesions.

HTLV-II, a related type C retrovirus in the Oncoviridae subfamily also rarely may result in a myelopathy similar to HAM or TSP.4753 The epidemiology of this virus is different from HTLV-I because the populations principally affected are American Indians and intravenous drug abusers.54 The mode of transmission parallels that of HTLV-I and HIV. The rarity of these neurologic disorders accompanying HTLV-II has precluded meaningful analysis of treatment options. The same therapies employed in HAM or TSP have been generally recommended, however.

Herpesviruses

Varicella-zoster virus (VZV) is responsible for varicella (chickenpox) and causes shingles in adults. The virus remains latent within the dorsal root ganglia and spreads centrifugally along the corresponding nerves after reactivation resulting in a severely painful, blistering dermatomal eruption. Rarely, when the thoracic dermatomes are involved, the virus may spread centripetally and result in a necrotizing myelopathy.55 The myelitis complicating VZV infection in immunocompetent individuals typically occurs 1 to 2 weeks after the appearance of the dermatomal rash, although VZV myelitis may develop in the absence of a rash. The myelitis occurs at the level of the affected dermatome and results in paraparesis. In immunosuppressed hosts, such as AIDS patients, VZV myelopathy occurs insidiously and progresses. The disease is suspected by the close temporal relationship to the rash and is confirmed by showing the presence of VZV DNA by polymerase chain reaction in the CSF or VZV antibody in the CSF. Treatment with intravenous acyclovir (10 mg/kg every 8 hours) should be initiated.

Rarely, and usually with primary infection, HSV-2, the etiology of genital herpes, may cause a sacral radiculitis56 or an ascending myelitis.57 These neurologic complications are rarely observed with recurrent HSV-2. Epstein-Barr virus,58,59 the etiologic agent of infectious mononucleosis, and cytomegalovirus60 may also result in a transverse myelitis at the time of primary infection. In an immunocompromised host, HSV-1, HSV-2, and cytomegalovirus may result in myelitis.

Other Viruses

Many other viruses have been associated with transverse myelitis (see Table 37–2). Of patients with transverse myelitis, 20% to 40% have evidence of preceding or concurrent viral infection.2,5,7,61,62 Prompted by the increasing availability and efficacy of antiviral therapy and improved diagnostic techniques, in particular, polymerase chain reaction, these percentages are likely to increase.

Myelopathies Resulting from Bacterial Disease

Syphilis

Invasion of the central nervous system (CNS) by Treponema pallidum generally occurs within 1 year of syphilitic infection. Abnormal CSF results have been found with an incidence ranging from 13.9% to 70% in untreated patients with primary or secondary syphilis. Although CNS symptoms are infrequent at this stage of the infection, headache and meningismus can be observed during secondary syphilis, and acute meningitis complicates 1% to 2% of secondary syphilis. If left untreated, about 5% of patients with syphilis develop clinical neurosyphilis.

The spinal cord is not immune to the ravages of syphilis. Before the development of effective antibiotics, it was believed that syphilis was the most frequent cause of spinal cord disease. Historically, tabes dorsalis has been the most frequent type with a frequency that was estimated to be 10 times that of other forms of spinal syphilis. Syphilitic meningomyelitis and spinal vascular syphilis were the second and third most common forms of spinal syphilis. Spinal syphilis rarely occurs in the absence of syphilitic involvement at other sites of the neuraxis. It has been estimated that the incidence of pure spinal syphilis is approximately one fifth the incidence of cerebrospinal syphilis.

Syphilis may affect the spinal cord in various ways.25 The pathology may be predominantly meningovascular or parenchymatous in nature. Gummas may grow within the substance of the cord or compress the cord by growth from the surrounding meninges. The clinical picture of spinal cord compression in syphilis may also arise as a result of hypertrophic pachymeningitis or vertebral lesions secondary to syphilitic osteitis. Table 37–4 presents a classification based on pathology and modified after the one proposed by Adams and Merritt.63

TABLE 37–4 Syphilis of the Spinal Cord

Adapted from Adams R, Merritt H: Meningeal and vascular diseases of the spinal cord. Medicine 23:181, 1944.

Tabes Dorsalis

Tabes dorsalis is the prototypic spinal cord disorder associated with syphilis. It is characterized by incoordination, pains, anesthesia, and various visceral trophic abnormalities.64 The earliest recognized descriptions of this disorder date to the mid-18th century. By the turn of the 20th century, tabes dorsalis was recognized with increased frequency and, according to Erb, was unequaled in frequency or importance by any other chronic disease of the spinal cord.

Currently, tabes dorsalis probably accounts for no more than 5% of neurosyphilis. Approximately 65% of patients recall a prior history of venereal disease. The latency from infection to the development of tabes dorsalis averages 10 to 15 years, but it ranges from 2 to 38 years. The average age of onset is 40 years with most cases arising in the 4th and 5th decades. Tabes dorsalis is a rare complication of congenital syphilis. It exhibits an equal sex frequency, in contrast to tabes dorsalis occurring in adult syphilis, in which the incidence in men exceeds that in women by 10 : 1.

The clinical course of tabes dorsalis is typically divided into three separate phases. The initial phase is known as the preataxic phase or the “period of lightning pain.” This phase is insidious in onset and may last months to decades, although it generally averages 3 years in duration. It is characterized by various subjective complaints, the most classic being the “crisis”—a severe lancinating pain. These lightning pains are absolutely characteristic of tabes dorsalis. They occur in 90% of individuals and are the presenting manifestation in 70%. Impotence and sphincter disturbances may also be early features. Physical examination reveals loss of muscle stretch reflexes, sensory loss, a positive Romberg sign, and Argyll Robertson pupils. Argyll Robertson pupils are characterized by intact visual acuity, decreased pupillary light reaction, intact near response, miosis, and irregular pupils. It occurs in classic form in 50% of patients with tabes dorsalis.

In early tabes dorsalis, the tactile sense may be well preserved, but the pain sense is invariably disturbed. Hypalgesia, hyperalgesia, allochiria, pallesthesia, delay in pain perception of 15 seconds after the application of the stimulus, and an aftersensation lasting 30 seconds all may be detected. Loss of deep pain sensation as evidenced by diminished sensation to the application of pressure to the ulnar nerve (Biernacki sign), the Achilles tendon (Abadie sign), and the testicle (Pitres sign) may occur in the absence of significant loss of superficial sensation.

The second phase of tabes is known as the ataxic phase. It has a variable duration from 2 to 10 years and is characterized by severe ataxia, affecting the legs chiefly. Generally, the tabetic pains worsen during this period. Arthropathy develops in 5% to 10% as a result of recurrent traumatic injury resulting from loss of deep pain sensation. Proprioceptive loss that results in a slapping gait predisposes the knee joint to this injury. The tarsal joints and hip, ankle, spine, and other joints can be similarly involved.

The third phase is known as the terminal or paralytic phase. This phase also has an average duration of 2 to 10 years. In this phase of the illness, cachexia, leg stiffness and paralysis, and autonomic dysfunction typified by obstinate constipation and bladder incontinence are prominent. Sepsis from decubitus ulcers and pyelonephritis is frequently the terminal event.

The classic signs of tabes dorsalis are absent in approximately 50% of patients in the early stages of the disease. The most frequently observed findings in these patients are absent ankle jerks and impaired vibratory sensation. In 10% of cases, tabes dorsalis remains atypical throughout the course of the illness. Tabes dorsalis may also be associated with other complications of neurosyphilis, such as general paresis, syphilitic meningomyelitis, and spinal cord gummas.

The pathology of tabes dorsalis is characterized by changes in the posterior spinal roots and posterior spinal columns (Fig. 37–2). Shrinkage of the spinal cord may be apparent by gross inspection. Leptomeningitis is evidenced by round cell infiltration. The dorsal columns are demyelinated, particularly in the regions of the fasciculus gracilis, root entry zone, and Lissauer tract. Astrocytic proliferation in the posterior columns is accompanied by an increase in connective tissue and thickening of the blood vessel walls. The lower spinal cord bears the brunt of the damage. Nerve fibers in the posterior root are destroyed and replaced by fibrosis. Frequently, lesions are observed in the anterior horns, cranial nerves, and brainstem.

image

FIGURE 37–2 Representative cross section of lumbar vertebrae and spinal cord with its blood supply.

(From Herrick M, Mills PE Jr: Infarction of spinal cord. Arch Neurol 24:228, 1971. Copyright 1971, American Medical Association.)

Syphilitic Meningomyelitis

Syphilitic meningomyelitis occurs most commonly in individuals 25 to 40 years old, although it may arise in younger and older age groups. In most series, men predominate. The latency from the onset of the infection to the onset of symptoms with syphilitic meningomyelitis varies from 1 to 30 years with most arising within 6 years of infection.65

Typically, the patient initially notices a heavy sensation or weakness in the legs. Rarely, symptoms are confined to a single leg. Paresthesias and fleeting pain may accompany the motor disturbance. The onset is slow and gradual, and the symptoms are indistinguishable from symptoms of myelopathy associated with cervical spondylosis. Various subjective complaints have been recorded, including sensations of lower extremity numbness, cold, and tingling and girdle tightness, but objective sensory disturbances are slight. Autonomic dysfunction is also observed. It is generally characterized by precipitate frequency, hesitancy, and impotence. The predominant finding on neurologic examination is a spastic weakness in the extremities, especially the lower extremities. Muscle bulk is preserved, and the muscle stretch reflexes are exaggerated with positive Babinski signs. Sensory loss is slight. Occasionally, Brown-Séquard syndrome, significant amyotrophy, or a clinical picture of transverse myelitis may complicate syphilitic meningomyelitis.

Pathologic examination reveals thickened, inflamed meninges. The cervical region is believed to be the site at which the lesions predominate. The pathologic changes prevail in the periphery of the spinal cord, often with a symmetrical involvement of the lateral columns. The spinal cord dysfunction results from granulomatous invasion, inflammation, and vascular changes. The vascular changes are caused by Heubner and Nissl-Alzheimer endarteritis, lesions of medium and small vessels that are characterized by plasma cell and lymphocytic perivascular cuffing.

Other Forms of Spinal Syphilis

Hypertrophic pachymeningitis66 is an insidious, slowly progressive syphilitic process that results in spinal root and spinal cord dysfunction. A rare but well-recognized complication of tertiary syphilis is a gumma of the spinal cord. The clinical features of a spinal gumma are indistinguishable from an intramedullary glioma if it arises within the cord or may simulate the appearance of an extramedullary tumor if it arises from the meninges and compresses the spinal cord. Spinal cord infarction is a well-recognized complication of syphilis. Another vascular complication of syphilis is aortitis, which may eventuate in an aortic aneurysm resulting rarely in myelopathy by erosion of the vertebrae and ultimately compression of the spinal cord. Progressive spinal muscular atrophy has been observed in association with neurosyphilis, although the relationship may be coincidental. Occasionally, syphilitic caries may affect the vertebrae, particularly vertebrae of the cervical spine, resulting in pain, tenderness to palpation, and loss of mobility, and an abnormal spinal curvature in the involved area is noted. Radicular pains are observed in one third of patients. Compression of the spinal cord, although rare, has been reported.

As with other forms of neurosyphilis, the recommended treatment is 12 to 24 million U of aqueous penicillin daily in divided doses administered every 4 hours for 10 to 14 days.67 Other treatment regimens68 using doxycycline, ceftriaxone, or erythromycin may be considered if the patient cannot tolerate penicillin. These treatment regimens are not well established in treating symptomatic neurosyphilis, however.

Tuberculosis

Neurologic complications of Mycobacterium tuberculosis remain common in some parts of the world but are rare in the developed countries of the Western world. Myelopathy occurring in association with tuberculosis is usually the consequence of tuberculous spondylitis (Pott disease), which accounts for half of all skeletal tuberculosis. Typically, the anterior portion of the vertebral body is affected, with the mycobacterial spread to the vertebrae being hematogenous, lymphatic, or by direct contiguity from the lung.69 The characteristic radiographic defect is anterior wedging of two adjacent vertebrae with loss of the intervening disk space. The spine is enveloped by pus extruding anteriorly from the affected vertebrae. Myelopathy typically results from pressure on the anterior spinal cord by caseous or granulating tissue, inflammatory thrombosis of the anterior spinal artery, or injury to the cord from spinal instability. The last-mentioned may lead to complete spinal cord transection.

Myelopathy occurring in association with tuberculous infection may also occur as a consequence of intraspinal granulomatous tissue unassociated with a bony lesion and intramedullary tuberculomas. In one study of spinal tuberculosis,70 54% of patients had neurologic deficit with bony tuberculous lesions, 39% had neurologic deficit with intraspinal granulomatous tissue occurring in the absence of bony lesions, and 7% had neurologic deficit from intraspinal tuberculomas.

Therapy of patients with spinal tuberculosis requires at least 12 months of antibiotic treatment and surgical decompression in the presence of neurologic abnormalities.70 In the setting of intraspinal granulomatous disease without significant bony destruction, laminectomy and débridement is adequate70; however, more aggressive therapy is warranted when vertebral bodies are involved. A two-stage procedure comprising posterior instrumental stabilization followed by anterior radical decompression permitted earlier mobilization after neurologic recovery.71 Reports of the frequency of neurologic recovery with spinal tuberculosis vary, but functional recovery rates of 90% have been reported.71 Thoracic lesions with severe neurologic deficit show the least improvement, whereas lumbar disease has the best outcome.72

Other Forms of Bacterial Myelopathy

Numerous other bacterial infections have been associated with myelitis. Rarely, the spinal cord may be seeded by bacteria leading to a suppurative myelitis with abscess formation. In a review by Dutton and Alexander,73 direct spread for adjacent infections was most commonly observed; however, hematogenous dissemination from endocarditis, pulmonary infections, and other sites was also frequently observed. Organisms isolated in these cases have included staphylococci, streptococci, Escherichia coli, and Nocardia. Rarely, Whipple disease can manifest as a myelopathy.74,75

More often, myelopathies associated with bacterial infection are parainfectious in nature, similar clinicopathologically to myelopathies occurring after viral infection or vaccination. Potential causes76,77 include scarlet fever, pertussis, whooping cough, mycoplasmal pneumonia, and pneumococcal pneumonia. Myelitis resulting in Brown-Séquard syndrome has also been described with cat-scratch disease.78 Lyme disease, the result of infection with Borrelia burgdorferi, a treponeme, may also result in myelopathy.79

Parasitic Myelopathies

Among the most common parasites that result in spinal cord disease is Schistosoma,81,82 in particular, Schistosoma haematobium and Schistosoma mansoni. These organisms are seen only in certain geographic regions—the Far East, South America, and Africa. A history of travel to these regions and swimming or bathing in water contaminated with the cercariae that are released from certain aquatic snails may suggest the diagnosis.

Hydatid disease resulting from the larval form of the canine tapeworm, Echinococcus granulosa, may result in spinal intramedullary cysts or compress the spinal cord and roots as a consequence of bone invasion. The bone invasion by hydatid disease generally occurs in the lower thoracic region.

Cysticercosis, a particularly common disease in Mexico and Central and South American countries, is the result of infection with the larval form of pork tapeworm, Taenia solium. Spinal cord involvement may complicate 5% of cases, although the brain is the preferred site in the CNS. Cysticercosis most frequently infiltrates the subarachnoid space, but intramedullary fluid-filled cysts are also observed. A slowly progressive myelopathy implicating a lesion in the cervical or thoracic spinal cord is the typical mode of presentation for these lesions. Therapy with albendazole may be effective in eradicating the live parasite.

Paragonimiases, infection with a lung fluke acquired by eating undercooked freshwater crabs, occurs chiefly in China but may be seen in other parts of the world. Spinal cord disease results from extradural or, more rarely, intradural granuloma formation. Angiostrongylus cantonensis, the most common cause of eosinophilic meningitis and meningoencephalitis in the world, has also been reported to cause spinal cord disease.83 In patients with AIDS, toxoplasmosis has been reported in rare instances to cause an abscess of the spinal cord.

Epidural Abscesses

Spinal epidural abscess may manifest as a surgical emergency evolving rapidly over several days or may arise more indolently. Staphylococcus aureus is the etiologic agent in greater than 50% of acute spinal epidural abscesses, although a broad spectrum of other organisms may be implicated.84 The spread of infection may be directly from a focus of osteomyelitis or hematogenously from a distant site, such as skin furuncles or pulmonary infections. Trauma to the back, typically very minor in nature, has been reported by one third of individuals developing spinal epidural abscess.85 A high degree of suspicion for spinal epidural abscess should be maintained when intravenous drug abusers present with fever and back pain.

Vascular Disease of the Spinal Cord

Paired segmental arteries arising from the aorta and branches of the subclavian and internal iliac arteries supply blood to the spinal cord (Fig. 37–3).87 The most important vascular supply to the cervical spinal cord arises from the vertebral artery, which provides the cephalad origin of the anterior median and posterior lateral spinal arteries. The blood supply to the thoracic and lumbar spinal cord arises from the aorta and internal iliac arteries, and segmental branches of the lateral sacral arteries nourish the sacral spinal cord. The segmental branches that arise from the aorta divide into anterior and posterior rami. A branch of the posterior ramus (see Fig. 37–2), the spinal artery, enters the vertebral foramen and branches at irregular intervals into anterior and posterior medullary arteries, which feed the anterior median spinal artery and the posterior spinal arteries. At regular intervals, the spinal artery also branches into the anterior and posterior radicular arteries, which supply the spinal ganglia and roots.

image

FIGURE 37–3 Anterior view of spinal cord with its segmental blood supply from aorta.

(From Herrick M, Mills PE Jr: Infarction of spinal cord. Arch Neurol 24:228, 1971. Copyright 1971, American Medical Association.)

The chief blood supply to the spinal cord comes from the 6 to 8 anterior and 10 or more posterior medullary arteries that arise from the spinal arteries. The most important anterior medullary artery is the artery of Adamkiewicz, which usually approaches the cord on the left side between the T10 and L3 cord segments. Because of the variability of the vascular anatomy of the spinal cord, however, it is impossible to predict the deficits that will occur after occlusion of a specific artery.

Although an anastomosing vascular network can be found over the surface of the spinal cord, the anterior median spinal artery is responsible for nourishing the anterior two thirds of the spinal cord. The territory in its distribution includes the anterior and lateral corticospinal tracts and the lateral spinothalamic tracts, whereas the posterior columns (fasciculus gracilis and cuneatus) are supplied by the posterior spinal arteries.

An occlusion of a dominant medullary artery or, more rarely, the anterior median spinal artery results in an ischemic softening of a variable portion of the anterior two thirds of the spinal cord. This entity is referred to as an anterior spinal artery syndrome and may arise as the consequence of thrombotic atherosclerotic disease, aortic dissection, embolization, or vasculitis (particularly polyarteritis nodosa) or as a complication of aortic angiography.88 Cross clamping of the aorta during cardiac surgery for more than 30 minutes may also result in an infarction in this territory. A clinical hallmark of this entity is a dissociated sensory loss in which position and vibratory sensory perception are maintained, but a sensory level to pinprick is present. The latter is accompanied by paralysis below the level of the lesion, which typically manifests in association with spinal shock. Rarely, anastomotic blood flow allows for the preservation of the white matter of the spinal cord, and the gray matter alone is infarcted. Painful segmental spasm and spinal myoclonus may be observed with this condition.10

An unusual and seldom clinically diagnosed etiology of vascular injury to the spinal cord results from fibrocartilaginous embolization. The embolization typically follows minor trauma to the vertebrae.89 Among the reported precipitants have been lifting heavy weights, prolonged coughing, stooping, or falling.90 Valsalva maneuver has been suggested as a possible contributing factor resulting in the retrograde flow of fibrocartilaginous emboli to the spinal cord. Some investigators have suggested that the fibrocartilaginous debris is forced into the vessels of the spinal leptomeninges and spinal cord through the valveless Batson venous plexus.91 Minor trauma to the vertebrae before onset was noted in most cases with the time to maximum neurologic deficit ranging from minutes to 24 to 48 hours.89 Death typically supervenes within 11 months of onset (median 2.5 to 4 months).89 Multiple emboli have been postulated to occur in some of these instances.92 Involvement of the anterior spinal artery has also been observed.93 Spinal MRI reveals characteristics indicative of vascular lesions.92

Hemorrhage may occur within the epidural or subdural space or directly into the spinal cord. Trauma, hemorrhagic disorders (particularly administration of anticoagulant therapy), and bleeding from vascular malformations may lead to these complications. These events are usually apoplectic in nature with rapidly developing paralysis and sensory loss. Immediate radiographic demonstration of the region of the hemorrhage and surgical evacuation are indicated.

Vascular malformations are another etiology of hemorrhage into or around the spinal cord. One type of spinal cord vascular malformation is venous angioma, which is found most often on the dorsal portion of the spinal cord. Middle-aged and elderly men are chiefly affected. The slow and temporally irregular development of symptoms resulting from this lesion is believed to be secondary to ischemic compromise and compression of the spinal cord. Another type of spinal cord vascular malformation is arteriovenous malformation, which predominately affects younger patients. It is most often located on the dorsal thoracic or upper lumbar spinal cord. With this lesion, symptoms may be slowly progressive or may appear suddenly. Rapidly developing symptoms may result from occlusion of a key nutrient vessel or hemorrhage. The association of a cutaneous vascular nevus with a vascular malformation of the spinal cord has been referred to as Klippel-Trenaunay-Weber syndrome. The syndrome of Alajouanine94 or angiodyskinetic myelomalacia is a necrotic myelopathy resulting in a slowly evolving amyotrophic paraplegia in men that has been attributed to spinal venous thrombosis. In the absence of a spinal dural arteriovenous fistula, it is likely to be impossible to distinguish this entity from tumor on radiographic imaging.95 Although its exact nature remains controversial, some investigators have proposed that the lesions are probably acquired rather than congenital.96

Venous infarction of the spinal cord can also occur in the absence of an arteriovenous malformation. This spinal cord disorder may be extremely difficult to identify in light of the absence of specific clinical, laboratory, or radiographic findings short of spinal angiography. For this reason, it is likely seldom recognized and underreported. Kim and colleagues97 classified venous spino-occlusive disease into three types: nonhemorrhagic infarction, hemorrhagic infarction, and embolic infarction. Any region of the spinal cord may be affected, but involvement of the thoracic cord seems to predominate.

Nonhemorrhagic infarction is protracted, seldom accompanied by back pain, evolves slowly, and has survivals averaging approximately 4 years.97 Hemorrhagic infarction is generally sudden in onset and rapidly progressive. Back pain is observed. The full extent of the spinal cord may be affected.98 Survival averages approximately 1 month.97 Hemorrhagic infarction has been reported in association with hypercoagulable syndromes (e.g., Trousseau phenomenon) complicating pancreatic adenocarcinoma.99 Embolic venous infarction was initially reported by Feigin and colleagues91 in 1965. This disorder begins precipitously often with pain in the back and extremities. Asymmetrical and dissociated loss of function occurs more commonly in this form of venous spino-occlusive disease.97

Myelopathy Secondary to Connective Tissue Diseases

Rheumatoid Arthritis

Rheumatoid arthritis may result in myriad complications involving the spinal cord. Among the major abnormalities of the spine and spinal cord in rheumatoid arthritis are vertebral body erosion,100 discitis,101 and spinal cord compression102 that may be secondary to pannus formation. The most dramatic and frequent abnormality occurs at the atlantoaxial region.103 Cervical subluxation may assume many forms in this disorder,103,104 including anterior subluxation, posterior subluxation, vertical subluxation with protrusion of the odontoid, and rotational atlantoaxial subluxation. Other abnormalities include ligamentous calcification, erosion, cystic changes, and spinous process erosion.104 Cervical subluxation may be asymptomatic, although neck pain is common. Lower extremity weakness and spasticity, sensory loss, and sphincter disturbances are seen with lesser degrees of frequency. Hyperextension of the cervical spine, such as may occur with endotracheal intubation, in the face of cervical instability secondary to rheumatoid arthritis may cause severe displacement with rapidly evolving myelopathy.

Unusual causes of myelopathy in a patient with rheumatoid arthritis include “epidural lipomatosis” in patients on high-dose corticosteroid therapy105 and progressive cervical osteomyelitis.106 Rarely, these patients may develop pseudoaneurysm of the vertebral artery or anterior spinal artery occlusion secondary to compression. Marked C1-2 abnormalities seem to be more frequent in young women with severe, long-standing, seropositive rheumatoid arthritis.107 MRI may be useful in identifying pannus formation and craniovertebral involvement in rheumatoid arthritis.108 Many patients stabilize with conservative therapy,109 and the presence of cervical subluxation does not correlate with decreased survival from rheumatoid arthritis. Surgical craniocervical decompression can be helpful in early cases in which the patients remain ambulatory and are medically stable110 but is probably not helpful in advanced nonambulatory cases.111

Sjögren Disease

Sjögren disease is typically a disease of women 30 to 50 years old characterized by dry eyes (xerophthalmia), dry mouth (xerostomia), and noninflammatory arthritis. Neurologic manifestations are diverse and may reflect peripheral nervous system and CNS involvement. Spinal cord involvement includes progressive myelopathy, acute transverse myelitis, and intraspinal hemorrhage.112 Recurrent transverse myelitis may be observed. Pathologic examination revealed angiitis and necrotizing myelitis in one instance.113 Myelopathy related to Sjögren disease can be associated with optic neuropathy or cutaneous vasculopathy.114,115 The evaluation of Sjögren disease includes Schirmer test, serologic testing for anti-Ro (SSa) and anti-La (SSb) antibodies, and labial biopsy. Anecdotal reports have suggested improvement with corticosteroids and plasma exchange.116

Systemic Lupus Erythematosus and Antiphospholipid Antibody Syndrome

Myelopathy is an uncommon manifestation of SLE.117 In one series of 315 patients with SLE, acute transverse myelopathy was observed in 10 (3.2%).118 Most patients have evidence of other systemic disease at the time of diagnosis; however, this and other features of CNS lupus may lead to confusion with multiple sclerosis.119 In a large series of lupus myelopathy, optic neuritis was observed in 48% of patients.120 The association of optic neuritis and myelopathy may be particularly difficult to distinguish from multiple sclerosis. Typically, patients complain of numbness and weakness of the lower extremities manifesting in a subacute fashion, although in one series the cervical cord was involved in 50%.118

SLE-related myelopathy disables two thirds of affected individuals, but the other one third may recover significantly.121 Sedimentation rate and complement levels seem to be insensitive as markers of disease activity for this condition,122 and myelopathy is not associated with anti–ribosomal P, anti-ENA, or antiphospholipid antibodies.118 CSF abnormalities are seen in more than 60% of cases,118 including increased protein, pleocytosis, and even mildly decreased glucose. MRI may reveal prolongation of T1 or T2 signal in the affected cord, spinal cord enlargement, and contrast enhancement.123 The presence of a “longitudinal myelitis,” characterized by increased signal on T2-weighted imaging over many continuous segments has been suggested as a diagnostic clue, particularly for SLE-related myelopathy associated with antiphospholipid antibody.124

Aggressive treatment with intravenous high-dose steroids within 1 week of onset of symptoms has been associated with better outcomes.125 Other treatment modalities have included cyclophosphamide120 and plasmapheresis; however, the relative rarity of the syndrome has precluded rational clinical trials, and the effects of these and other therapeutic options remain uncertain. Subarachnoid spinal hemorrhage may occur in association with SLE.112 Because some cases of SLE-related myelopathy are associated with antiphospholipid antibodies, hypercoagulability or vasculopathy may be partly responsible for the pathogenesis of the disorder.126

Isolated myelopathy127130 and optic neuropathy associated with myelopathy131 have been reported to accompany antiphospholipid antibody syndrome. Recurrent transverse myelitis has also been reported.132,133 Antiphospholipid antibody syndrome is a disorder in which hypercoagulability is associated with antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and antibodies directed against β2-glycoprotein I).134 A wide variety of neurologic disorders may be associated with this disorder.135 The myelopathy of antiphospholipid antibody syndrome may be recurrent in nature136 making it difficult to distinguish from multiple sclerosis, particularly when associated with optic neuritis. The disorder may be a variant of SLE. Response to treatment seems to be inconsistent. Recommended therapies have included methylprednisolone, intravenous immunoglobulin, and measures to reduce the antibodies.

Sarcoid Myelopathy

Sarcoidosis is a chronic idiopathic granulomatous disease that may involve multiple organ systems. Bilateral hilar adenopathy and pulmonary infiltrates are the most common manifestations of the disease. Skin, eyes, heart, bone, and kidney may also be involved. Sarcoid involves the nervous system in only 5% of patients. This involvement may take the form of CNS mass lesions, hydrocephalus, recurrent aseptic meningitis, cranial neuropathies, myopathy, neuropathy, or mononeuropathy multiplex. Granulomatous infiltrates may appear in nearly any structure of the spine and cause arachnoiditis, cauda equina syndrome, intradural and extradural extramedullary granulomas, and intramedullary spinal sarcoidosis.

In the study by Junger and colleagues,141 the patients were noted to have paraparesis, urinary bladder dysfunction, radiculopathies, chest wall numbness, gait problems, Brown-Séquard syndrome, or limb numbness or pain. The mean age of onset of neurologic symptoms was 35. Evaluation of the CSF revealed mild or moderate pleocytosis (1 to 200 cells/mm3 [mean 36 cells/mm3]) and elevated protein (52 to 568 mg/dL [mean 162 mg/dL]).

Definitive diagnostic testing requires biopsy showing noncaseating epithelioid granulomas. As intramedullary biopsy is rarely desirable; biopsy material may be obtained from safer sites (e.g., the lungs) if available. MRI can be normal in some suspected cases of spinal sarcoidosis.142 Observed changes in spinal sarcoidosis include gadolinium-enhancing nerve roots, enhancing parenchymal spinal cord masses,143 diffuse spinal cord enlargement, spinal cord atrophy, or focal or diffuse areas of increased T2-weighted signals.141 Gallium scanning may show uptake in the lungs or parotid, salivary, or lacrimal glands. Systemic disease can be detected by increased serum angiotensin-converting enzyme levels. It is unclear at present whether measurements of CSF angiotensin-converting enzyme levels are helpful in diagnosing nervous system involvement. Serum angiotensin-converting enzyme levels are not informative with respect to CNS involvement.

Spontaneous recovery over months or years can occur in 60% to 80% of patients with isolated pulmonary disease, but very little is known about the natural history of CNS disease. Most authorities proceed aggressively with steroids if neurologic involvement becomes symptomatic. If sarcoidosis is refractory to corticosteroids, cyclosporine, cyclophosphamide, chlorambucil, methotrexate, and radiation therapy have been applied in combinations with steroid with some success.144,145

Nutritional Myelopathies

Vitamin B12 Deficiency

Vitamin B12 deficiency may result from an inadequate dietary intake or from an inability to absorb vitamin B12 from the small intestine because of a lack of intrinsic factor. The latter condition is referred to as pernicious anemia, although the effects of vitamin B12 deficiency on the CNS may occur in the absence of the characteristic megaloblastic anemia. The neurologic disease may occur even in the absence of pathologically abnormal serum levels of vitamin B12. A Schilling test or measurements of methylmalonic acid are warranted when the illness is clinically suspected.

The brain, spinal cord, optic nerve, and peripheral nerves may be adversely affected by the absence of vitamin B12. Typically, the patient comments on a sense of weakness and easy fatigability of the lower extremities that is accompanied by paresthesias. Occasionally, Lhermitte phenomenon is noted. With progression of the disease, a spastic-ataxic gait and loss of vibratory and position sense ensue. The limbs are symmetrically affected. Cognitive and behavioral abnormalities, decreasing visual acuity, and a peripheral neuropathy may be superimposed on the spinal cord symptoms. Physical examination may reveal areas of vitiligo. Hyperpigmentation of the palms and soles is observed in blacks.

The myelopathy that results from vitamin B12 deficiency (subacute combined degeneration) is chiefly characterized neuropathologically by foci of demyelination in the posterior and lateral columns of the cervical and upper thoracic spinal cord. The earliest changes of demyelination are fusiform expansions of the myelin sheaths. Subsequently, the myelin degenerates, and if the process is uninterrupted, gliosis and involvement of the axons eventually ensue. Clinical remissions are anticipated when this myelopathy is treated expeditiously with hydroxycobalamin or cyanocobalamin. The mechanism by which vitamin B12 deficiency results in demyelination is unknown. It is a cofactor in choline synthesis and important in the conversion of methylmalonyl-CoA to succinyl CoA, both important to the myelin sheath.146 Fusiform expansion of the myelin sheaths is followed by myelin degeneration.146,147 If the process is uninterrupted, gliosis and involvement of the axons eventually ensue.146 After effective therapy, the myelopathy of vitamin B12 deficiency not only may resolve clinically, but also radiographically.

Pernicious anemia is treated by intramuscular injection of cyanocobalamin. For the first week, 1000 µg daily is administered, followed by one injection weekly for the next 1 to 3 months and one injection monthly thereafter.

Myelopathy Complicating Copper Deficiency

Copper deficiency may result in spinal cord disease that can be clinically reminiscent of the neurologic manifestations of vitamin B12 deficiency.148 Sensory ataxia with a spastic gait and marked ataxia coupled with a distal axonal sensorimotor neuropathy can be observed.149 Causes of copper deficiency include prior gastric surgery, excessive zinc ingestion, and malabsorption; however, an underlying cause is not always uncovered.150 Anemia and neutropenia are often present. Spinal cord disease and peripheral neuropathy developing after gastric bypass surgery should always raise concern about the presence of either vitamin B12 deficiency or copper deficiency.151,152

Metabolic Myelopathies

Myelopathy Resulting from Portosystemic Shunts

A progressive myelopathy has been observed in association with portosystemic shunting.153 Although the illness generally accompanies alcoholic cirrhosis, it may arise secondary to other causes of portosystemic shunting. A selective demyelination predominates in the posterior and lateral funiculi of the spinal cord. Hepatic encephalopathy often accompanies the myelopathy. Myelopathy is manifested by an insidiously developing spastic paraparesis and gait with relative preservation of sensory and sphincter function. Hyperparathyroidism and hyperthyroidism have been rarely associated with cervical myelopathies that remit when the endocrinologic derangement is removed.154156

Paraneoplastic Myelopathies

Paraneoplastic syndromes are syndromes associated with underlying malignancies not caused by direct tumoral invasion or macroscopic metastatic disease. These remote effects of cancer are usually without an identifiable etiology, although some syndromes are associated with circulating antibodies to nervous system tissue or are the result of a presumptive concomitant viral infection. These syndromes generally are uncommon. Approximately 50% of all paraneoplastic syndromes are associated with small cell carcinoma of the lung.157 The prototypic paraneoplastic syndrome is subacute cerebellar degeneration, which is associated with loss of Purkinje cells in the cerebellar cortex and various circulating antibodies directed against these cells. Paraneoplastic myelopathy is rare158—much less common than myelopathy resulting from metastatic epidural spinal cord compression. Myelopathy occurring in association with malignancy can also be secondary to radiation therapy or the result of the combined effects of radiation therapy and intrathecal chemotherapy, especially methotrexate chemotherapy,159,160 herpes zoster,161 abscess, or hematoma. These myelopathies may occur in isolation or as part of a syndrome in which encephalomyelitis,162 cerebellar degeneration, or peripheral radiculoneuropathies are also observed.

The most typical myelopathy is a necrotizing myelopathy. It is a rare entity associated with lymphoma, leukemia, and small cell lung cancer. Myelopathy may manifest before, concomitant with, or after the initial tumor presentation. Clinically, it is characterized by a rapidly ascending spinal cord dysfunction leading to a flaccid areflexic paraplegia. Myelopathy may manifest asymmetrically and often results in Brown-Séquard syndrome163; however, eventually it becomes bilateral and symmetrical. The brainstem may also be involved. There is no effective treatment. One patient with Hodgkin disease and a paraneoplastic myelopathy was believed to respond favorably to intrathecal corticosteroids.164 CSF usually shows an elevated protein and a mild pleocytosis. Pathologically, there is widespread necrosis of the cord, mostly in the thoracic region.165 Gray and white matter are involved, and lesions may be identified elsewhere in the CNS. In two cases of “paraneoplastic” necrotizing myelopathy, immunohistochemical studies and electron microscopy revealed convincing evidence of infection with HSV-2.166

Other, less common syndromes include a subacute motor neuropathy associated with Hodgkin disease and other malignant lymphomas.167 It is typically diagnosed at a later stage and sometimes after radiation therapy. The motor weakness is clinically of the lower motor neuron type and involves the legs more than the arms. Sensory loss is mild. The course is benign and may stabilize or improve with specific therapy. Pathologically, neuropathy shows degeneration of the anterior horn cells and resembles an indolent poliomyelitis.167

A syndrome of paraneoplastic myelopathy with limbic encephalitis is associated with the antineuronal autoantibody anti-Hu.168 This syndrome is almost always related to small cell lung cancer, and the presence of anti-Hu should lead to aggressive workup for neoplasms. This antibody is also associated with a subacute generalized sensory neuronopathy.

Although not truly a paraneoplastic disorder, intravascular lymphomatosis should be considered in the differential diagnosis of a patient presenting with an unexplained myelopathy. Spinal cord involvement occurs in approximately one third of patients. Although myelopathy, including conus involvement,169 may be the heralding feature of the disorder, it seldom remains the only neurologic manifestation.170 The spinal cord disorder may be indolent or rapidly progressive and may mimic multiple sclerosis or idiopathic transverse myelitis. An initially favorable but incomplete response to corticosteroids may be observed. Damage to the nervous system results from ischemia secondary to occlusion of small-caliber vessels. This disorder is most often the consequence of a clonal expansion of CD20+ B lymphocytes, although T cells and natural killer cells have also been reported. In most cases, the diagnosis remains a conundrum and is established at autopsy.171 Aggressive therapy with CHOP (cyclophosphamide, hydroxydaunomycin, vincristine [Oncovin], and prednisone) has been associated with long-term survival, but the disease is generally fatal.

Myelopathy Secondary to Radiation Therapy

Myelopathy secondary to radiation therapy is an iatrogenic illness. The incidence is affected by the total dose of radiation delivered, the dose per fraction, and the total volume of tissue irradiated.172 In a large study by Kagen and colleagues,173 it was determined that spinal cord injury could be avoided if the total dose delivered was kept to 6000 rads and given over a 30- to 70-day period at a rate not exceeding 200 rads/day or 900 rads/wk.

Two pathophysiologic mechanisms are proposed for this myelopathy: direct damage to the nervous tissue of the spinal cord by irradiation and damage to the vascular supply of the spinal cord. The effects of radiation take the form of an early delayed and late delayed myelopathy. There are no acute effects of radiation on the spinal cord.172 The incidence of this complication is 2% to 3%174 but is substantially higher when radiation therapy is combined with hyperthermia.175

The early delayed radiation myelopathy usually manifests several weeks after radiation therapy as sensory symptoms and paresthesias. These symptoms may be exacerbated by neck flexion, and a typical Lhermitte phenomenon may be detected. These symptoms are believed to be secondary to demyelination and depletion of oligodendrocytes.10 The presence of this early delayed myelopathy does not predict the development of a late delayed radiation injury.176

Late delayed radiation myelopathy may evolve in two distinct forms: (1) a progressive myelopathy that usually occurs 12 to 15 months after radiation therapy and never before 6 months and (2) a progressive lower motor neuron weakness that occurs 3 to 14 months after radiation. The former is characterized by sensory symptoms similar to early delayed myelopathy, but it is accompanied by an asymmetrical weakness. Frequently, the initial picture is that of Brown-Séquard syndrome, which often progresses to complete transverse myelopathy with spastic paraplegia; truncal sensory level; and bowel, bladder, and sexual dysfunction. The CSF profile is unremarkable except for the frequent presence of a slightly elevated protein. Pathologic changes include areas of necrosis that affect gray and white matter, but white matter seems to be preferentially affected. The posterior columns and posterolateral columns may be especially involved.172

There is no specific therapy, although steroids may slow the tempo of the illness. The differential diagnosis includes recurrent tumor or epidural spinal cord compression. The painless nature of the radiation damage is a useful diagnostic clue, particularly when MRI is indeterminate.

Not unexpectedly, the progressive lower motor neuron weakness after radiation therapy is accompanied by pathologic alterations in the anterior horn cells. There is an asymmetrical atrophy with fasciculations and areflexia.177,178 No sensory or sphincter disturbances are noted. This peculiar myelopathy resembles a paraneoplastic subacute motor neuropathy described in patients with lymphoma.167

Toxins

Several agents with industrial, pharmaceutical, and medical applications have been identified as toxins capable of producing myelopathy. Toxic iatrogenic causes of myelopathy include spinal anesthesia and exposure to contrast agents used with myelography and angiography. Spinal anesthesia, with the epidural or intrathecal administration of local anesthetics, has been reported to produce myelopathy.179,180 Although an extremely rare occurrence, myelopathy following spinal anesthesia may be permanent and includes frank paraplegia, sensory loss, and loss of sphincter function.181,182

Some investigators contend that the true incidence of these complications is underreported for medicolegal reasons.183 In a review of 32,718 cases of epidural or spinal anesthesia,184 transient paralysis was observed in 48 (0.1%), and permanent paralysis was observed in 7 (0.02%). Similarly, only 3 of 50,000 patients were reported to have permanent lower extremity weakness in a combined series.185 The first case report of paraplegia after epidural anesthesia was by Davies and colleagues in 1958.186 The mechanisms of spinal anesthesia–induced myelopathy, particularly myelopathy induced by epidural anesthesia, remain elusive. Possible etiologies187 include direct neurotoxicity of these agents, toxicity of drug diluents or contaminants, hypotension leading to spinal cord infarction (typically from anterior spinal artery syndrome), epidural hematoma, epidural abscess, trauma from the epidural needle, and exacerbation of an underlying process. In some instances, a surgical procedure, such as renal transplantation, may be contributory or causative. In the latter example, the artery of Adamkiewicz may be inadvertently traumatized. Cases of myelopathy after spinal anesthesia in the setting of spinal cord tumors or herniated discs have been reported.188

Although oil-soluble and water-soluble myelographic contrast agents may induce arachnoiditis, which may lead to spinal cord dysfunction, these agents may themselves produce a toxic myelopathy. Although the use of modern contrast agents has essentially eliminated this complication, nearly 6% of patients had permanent myelopathic findings after myelography in early reports.189 Transient myelopathic symptoms lasting 24 hours have also been reported after administration of water-soluble contrast agents.77

Myelopathy as a complication of spinal angiography has been well recognized.190 Although this complication is most often ascribed to the induction of vasospasm or embolic thrombosis of spinal vessels resulting in ischemic infarction, a direct neurotoxic effect of the angiographic agents has been implicated in some instances.191,192 Patients may develop pain and spasms immediately on contrast agent injection, or this may be delayed by several hours. Subsequently, patients progress to flaccid paraplegia with frequent sensory and sphincter dysfunction. Partial recovery occurs in about half of the patients, and complete recovery occurs in about 20% within weeks.77 Many patients are left with a spastic paraplegia.

Although an extremely safe agent when used according to recommendations, nitrous oxide can manifest neurotoxicity when abused or under conditions of chronic exposure.193,194 Usually long delayed after nitrous oxide exposure, the resulting myeloneuropathy syndrome may include sensory dysesthesias, leg weakness, spasticity, sphincter dysfunction, and ataxia. Thought to result from a nitrous oxide–induced inhibition of vitamin B12 use, the symptoms tend to resolve after exposure is discontinued.

Intrathecal administration of antineoplastic agents, such as methotrexate or cytosine arabinoside, has been reported to produce transient and permanent myelopathy.195197 Intrathecal steroid administration may initiate an acute meningeal reaction, probably secondary to polyethylene glycol detergent included in the preparation.198,199 Distinct from problems that are due to a secondary arachnoiditis, this acute syndrome may result in back and leg pain, paresthesias, and sphincter dysfunction. Intravenous heroin administration may also cause an acute transverse myelitis. This syndrome may result from direct drug toxicity, a systemic reaction to the drug itself or to quinine or another drug diluent, a hypersensitivity reaction, or transient spinal cord ischemia.200

Iodochlorohydroxyquinolone, a drug used in the treatment of infectious diarrheas, has been reported to cause a syndrome of myeloneuropathy sometimes accompanied by optic atrophy.201 Seen most frequently in Japan, this syndrome usually follows an episode of abdominal pain or diarrhea and therapy with iodochlorhydroxyquinoline. Although apparently related to the total accumulated dose of the drug, this syndrome might also be related to an enteric virus associated with the patients’ initial abdominal symptoms. Patients initially complain of ascending numbness and paresthesias, which develop into a profound sensory loss. Gait ataxia, leg weakness, and sphincter dysfunction are frequent concomitants; optic atrophy and visual loss are seen in about 25% of patients. After discontinuing the drug, complete or near-complete recovery is the rule.

Triorthocresyl phosphates, used as industrial lubricating oils and solvents, are highly neurotoxic. Although accidental occupational exposure is rare, patients are often exposed by ingesting triorthocresyl phosphates in lieu of ethanol or by ingesting cooking oils contaminated with these compounds. Although the most profound neurologic complication of triorthocresyl phosphate ingestion is an acute peripheral neuritis, clinical signs of spinal cord degeneration can be seen in patients with persistent symptoms. Wallerian degeneration of the pyramidal tract and chromatolytic changes in dorsal and ventral horn cells has been identified.202,203 In patients developing findings of myelopathy, the clinical syndrome is usually permanent.

A peculiar myelopathy seen in India and certain parts of Africa is believed to be the result of a neurotoxin (β-N-oxalylaminoalanine) found in chickpeas, Lathyrus sativus. It is most often observed with prolonged consumption of flour made from chickpeas in times of famine when sources of other grains are scarce. Patients complain of the gradual onset of leg weakness, stiffness, and cramping. Paresthesias, formication, and numbness of the legs are frequent. Sphincter disturbances, impotence, and variable involvement of the arms and hands are observed. The prognosis for recovery is poor.

Electrical Injury

Electrical injury of the nervous system results most frequently from accidental exposure to high-tension currents, although lightning and complication of electroshock therapy have also been reported to cause neurologic injury. Although current sufficient to cause damage to the nervous system is usually fatal, individuals who survive such injuries are subject to damage throughout the neuraxis.77,204 Acutely, patients may have neurologic symptoms referable to cerebral anoxia secondary to cardiac arrhythmias or respiratory arrest. Neural tissue examined shortly after electrical injury shows petechial and perivascular hemorrhages and severe ganglion cell changes. The most abnormal areas of the spinal cord are in the path of the electrical current. Short-term survivors of this acute phase may show focal myelomalacia and mild gliosis on autopsy. Although the pathophysiology is not fully understood, the injury most probably reflects a direct vascular injury to spinal cord vessels, an indirect vascular injury to spinal vasomotor nerves, or a direct effect of current on spinal cord tissue. Pathologic changes noted in long-term survivors postmortem have included demyelination with preservation axons, anterior horn cell loss, and necrosis.

Permanent neurologic manifestations of electrical injury are uncommon. The most characteristic neurologic effect of electrical injury is delayed myelopathy, occurring in 1% to 6% of victims.205,206 Immediately after electrical injury, patients may complain of paresthesias, pain, urinary dysfunction, or impotence. These symptoms tend to improve rapidly. Occasionally, delays in the onset of neurologic symptoms of up to 6 weeks (averaging 1 week) may be observed. Neurologic signs may worsen over 2 to 14 days.207 According to Winkelman,207 one third of patients recover fully, one third have partial recovery, and one third experience no recovery. The last-mentioned is the rule in patients with a complete spinal cord lesion or progression of spinal symptoms over a prolonged period. Rarely, delayed neurologic deficits can appear after a latency of several months.208,209 The symptoms of delayed myelopathy after electrical injury are typically permanent, but rapid recovery has also been reported.210

A cervical myelopathy with atrophic quadriparesis is the most frequent complication; this myelopathy results from current passing from hand to hand.211,212 With low-voltage injuries (<1000 volts), muscular atrophy from anterior horn cell damage is most common.77 With higher voltages, more profound injuries occur to the lateral and posterior columns.77 Pyramidal signs, including spastic weakness, hyperreflexia, and Babinski signs, predominate regardless of the location of the lesion. Sensory findings are less prominent with posterior column dysfunction predominating. Lhermitte phenomenon has been reported rarely.213 Other forms of electrical injury to the spinal cord result in spinal atrophic paralysis, a syndrome of focal muscular atrophy that typically follows low-tension electrical injury that has a predilection to involve gray rather than white matter and, questionably, amyotrophic lateral sclerosis.

Barotrauma

Spinal cord injury following rapid changes in atmospheric pressure, such as can occur in caisson work, scuba diving, and flying, has been well documented.214216 Spinal cord damage results from too-rapid decompression after exposure to significant increases in atmospheric pressure. At higher atmospheric pressures, increasing amounts of gas are dissolved into tissue. The higher tissue concentration of oxygen is used in oxidative metabolism, whereas nitrogen gas, which is inert, remains dissolved only by virtue of the hyperbaric condition. With decompression, the nitrogen is released; when decompression is too rapid, nitrogen bubbles may form and occlude the spinal cord vasculature.

Symptoms tend to develop during or immediately after decompression. Patients frequently complain of interscapular pain followed by lower extremity paresthesias, frank leg weakness, and sphincter disturbances within hours. Examination usually reveals a flaccid paraplegia with loss of pain and temperature sensation and frequent sparing of proprioceptive sensation. In most cases, the thoracic spinal cord is the major site of involvement, whereas combined lesions in the lower cervical and lumbar cord may occur less commonly. Pathologic examination of the cord shows early white matter hemorrhages followed by perivascular demyelination. These changes tend to be most extensive in the posterior and lateral columns, and secondary ascending and descending tract degeneration may be seen over time.

Therapy for decompression myelopathy is recompression followed by controlled slow decompression. If treatment is instituted rapidly, complete recovery is possible. If it is delayed more than a few hours, the chances of recovery are remote.215,217

Heredofamilial Degenerations

Numerous genetic neurodegenerative diseases can include spasticity attributable in part or total to spinal cord involvement in their complex of multiple signs and symptoms, but two disorders have quite prominent spastic paraparesis. Hereditary spastic paraplegia appears in autosomal recessive, autosomal dominant, and X-linked forms. A locus for the autosomal recessive form has been found on chromosome 8q; loci for the dominant form have been found at 2p, 14q, and 15q; and a locus for the X-linked form has been found at Xq22. In one family with the X-linked form, this has been shown to be due to a mutation in a proteolipoprotein.218 There is spastic weakness in the legs, gait difficulties, hyperactive reflexes, and extensor plantar signs. The course is one of slow but relentless progression. There are rare variants with other associated degenerations, such as optic neuropathy. The diagnosis is made by family history and excluding any other causes.10

Patients with Friedreich ataxia begin having problems in childhood. There is spastic quadriparesis owing to upper motor neuron degeneration, ataxia from cerebellar degeneration, numbness and foot deformity from neuropathy, nystagmus, tremor, and other problems. There is degeneration of the posterior columns, corticospinal tracts, spinocerebellar tracts, dentate nuclei, cranial nerve nuclei, and myocardial muscle fibers. There is no treatment, and death occurs in young adulthood. It has been found more recently that most cases of the illness are due to trinucleotide repeat expansion in the gene X25, which codes for a protein frataxin, on chromosome 9q13. A few cases are due to point mutations in the same gene.219

Key Points

Key References

1 Adams RD, Merritt HH. Meningeal and vascular diseases of the spinal cord. Medicine. 1944;23:181.

Although published in the middle of the past century, this is the classic work on the spectrum of vascular diseases of the spinal cord. The authors describe in detail the vascular network that supplies the cord and ganglia and address the numerous fashions by which the circulation can be impaired.

2 Kovacs B, Lafferty TL, Brent LH, et al. Transverse myelopathy in systemic lupus erythematosus: An analysis of 14 cases and review of the literature. Ann Rheum Dis. 2000;59:120-124.

Distinguishing the myelopathy accompanying SLE from idiopathic transverse myelitis is occasionally difficult. A high index of suspicion is necessary. The authors present 14 cases and provide an excellent review of the literature on this important topic.

3 McLean JM, Palagallo GL, Henderson JP, et al. Myelopathy associated with fibrocartilaginous emboli (FE): Review and two suspected cases. Surg Neurol. 1995;44:228-235.

Fibrocartilaginous embolization with infarction of the spinal cord is often overlooked as a diagnostic entity. The authors present two cases of their own and provide an excellent review of the literature on this topic.

4 Petito CK, Navia BA, Cho ES, et al. Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1985;312:874.

This is the initial description of the entity referred to as HIV-associated vacuolar myelopathy. The authors address the clinical presentation and the pathologic findings. They show the similarities to subacute combined degeneration of the spinal cord from vitamin B12 deficiency and, in a subsequent publication, suggest that this myelopathy is not unique to HIV infection.

5 Vernant JC, Maurs L, Gessain A, et al. Endemic tropical spastic paraparesis associated with human T-lymphotropic virus type I: A clinical and seroepidemiological study of 25 cases. Ann Neurol. 1987;21:123.

Building on their earlier observations on the association of a unique myelopathy in the setting of HTLV-I seropositivity in a Caribbean population, the authors expand their series and describe in detail the clinical presentation of HAM or TSP.

6 Weinshenker BG, Wingerchuk DM. Neuromyelitis optica: Clinical syndrome and the NMO-IgG autoantibody marker. Curr Top Microbiol Immunol. 2008;318:343-356.

This is a review of the latest understanding of NMO, or Devic syndrome, with an emphasis on the role of the newly discovered aquaporin-4 antibody in pathogenesis and diagnosis of the disorder.

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