Human Immunodeficiency Virus Infection

Neurologic complications develop in 40% to 60%^23–25 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.

FIGURE 37–1 Microvacuolization of posterior columns of thoracic spinal cord in a patient with HIV-1–related myelopathy.

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

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.^47–53 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.

Enteroviruses

Enteroviruses, particularly poliovirus, can affect the spinal cord. Effective vaccination has made this illness very rare in the Western world. In the United States in the recent past, there were approximately 10 to 15 cases of polio reported yearly; most of these were vaccine associated, although several were imported by immigrants. Paralytic poliomyelitis is a rare complication of poliovirus infection (1% to 2%); most infections result in inapparent infection (90% to 95%) or a minor illness with mild systemic symptoms (5% to 10%). The poliovirus has a unique predilection to affect the anterior horn cells of the spinal cord and results in a lower motor neuron type of weakness; this is characterized by a flaccid weakness with wasting, fasciculations, and areflexia. Sensory and sphincter functions are spared. After infection, weakness may arise rapidly over 48 hours or occur in a delayed fashion over weeks. The risk of paralysis increases with age: Infants are rarely paralyzed, adults are paralyzed much more frequently, and risks for children are in between. Other enteroviruses, including coxsackieviruses and echoviruses, may also result in myelitis.

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.

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

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.

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.)

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 causes^76,77 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