Varicella-Zoster Myelitis
This 64 year old man with a previous episode of transverse myelitis presented with bilateral, asymmetric sensory disturbances and limb weakness, evolving over several days. His present illness occurred in the context of a segmental, vesicular skin rash and burning pain suggestive of active herpes zoster recurrence in the lumbar region. Given this temporal correlation, the possibility of a myelitis induced by varicella-zoster infection was entertained.
Examination documented evidence of the patient's chronic myelopathy, with a T9 sensory hemilevel, but suggested several additional findings. He exhibited elements of a right-sided Horner's syndrome (ptosis and miosis). New weakness was present in all major muscles of the right arm. A sensory hemilevel was present at the C4 dermatome on the right. Primary sensory modalities were asymmetrically impaired. Temperature and pinprick sensation were severely impaired in the left hand and wrist, while proprioception was absent in the right hand and wrist, and impaired at the right elbow. Tests requiring sensorimotor integration (mirroring of contralateral hand position, thumb localization in space, graphesthesia) were markedly impaired. In addition, marked dysmetria, out of proportion to weakness, and loss of the ability to rapidly check or inhibit flexion movements, were evident in the right arm.
These findings suggest dysfunction of the high cervical spinal cord, at some point between the C4 neural level and the foramen magnum. The relative dissociation of proprioceptive loss from temperature and pinprick loss, with weakness ipsilateral to the loss of proprioception, suggests a spinal cord hemisection syndrome. His Horner's syndrome could have resulted from involvement of autonomic fibers that descend laterally, or from direct involvement of intermediolateral cell columns. The patient's impairment of sensorimotor integration could reflect dorsal column nuclear dysfunction; however, the impairment of primary sensory modalities was substantial, and could have affected performance on these tests. Impairment of ascending spinocerebellar fibers in the high cervical cord is felt by many authors to account for the "cerebellar" signs occasionally seen with high cervical myelopathies.
There was no history of a fall or injury to suggest a traumatic spinal cord injury. The gradual progression of symptoms was not felt to be consistent with a typical vascular insult. MR imaging did not suggest a mass lesion, but demonstrated diffuse cervical cord enhancement, with hyperintense signal on T2-weighted sequences, and diffuse cord swelling. Signal changes were evident on axial MR images as high as the foramen magnum, but the cerebellum itself did not appear to be grossly involved on imaging studies. CSF examination showed a markedly elevated protein concentration, and a mixed pleocytosis. The differential diagnosis at this point was felt to include neoplastic, infectious, demyelinating, and inflammatory processes.
Cytologic assays of CSF, and limited screening studies of the body, did not show evidence of malignancy. A rheumatologic cause of the patient's myelitis was strongly considered, as the patient had a highly elevated antinuclear antibody (ANA) titer, both on this presentation and at previous presentations. The patient did not, however, have a history or examination findings of polyarthralgias, serositis, or rash to support a clinical diagnosis of lupus erythematosus. Likewise, an assay for anti-double-stranded DNA antibodies (anti-dsDNA) was negative, and serum complement levels were normal, arguing against a diagnosis of active lupus. There were no constitutional, respiratory, or other organ system complaints to suggest other rheumatic disorders, although a detailed search was not performed. A rheumatologic consultant reviewed the patient's case, and concurred that an active rheumatic disorder was unlikely to account for the patient's presentation. As discussed below, it is possible, although unproven, that an underlying disorder may have predisposed the patient to the outbreak of herpes zoster associated with his evolving myelitis.
Active demyelination, in rare instances, may produce spinal cord swelling with blood-brain barrier compromise. We have no histopathological evidence to conclusively rule out this possibility, but the lack of brain involvement on MRI, absence of oligoclonal banding on CSF electrophoresis, and availability of an alternate diagnosis were felt to argue against a primary demyelinating disorder.
The patient's concurrent outbreak of shingles focused attention on infectious causes of myelitis. This close temporal relationship raised the possibility of a herpes zoster myelitis, caused by recurrence of varicella-zoster virus (VZV) infection. On further questioning, the patient recollected a similar rash immediately preceding his previous bout of myelitis. Other considerations, deemed less likely, included myelitis from herpes simplex virus (HSV), acute myelitis from syphilis infection, and acute myelitis or opportunistic infection in the setting of HIV infection. A test for specific IgG antibody to VZV demonstrated detectable VZV antibody production in CSF, supporting the clinical suspicion for VZV myelitis.
Varicella-zoster virus (VZV) is an alpha-herpes virus, found exclusively in humans. Initial infection causes an acute febrile illness, usually in childhood, characterized by a widespread vesicular exanthem (chickenpox). CNS complications of acute varicella infection occur in less than 1% of cases. These neurologic sequelae most commonly present as mild meningitic symptoms. Acute cerebellitis is one of the most common neurologic abnormalities associated with varicella infection in children and adolescents. Encephalitis and myelitis have been reported as well, but are quite rare (7).
After an acute attack of chickenpox resolves, the VZ virus becomes latent in cranial and spinal ganglia, during which time the viral DNA may remain extrachromosomal but in a non-infectious state. VZV may later reactivate in a ganglion, causing a localized, usually dermatomal, eruption of zoster (shingles). Zoster infection is known to cause a wide spectrum of neurologic sequelae, including post-herpetic neuralgia, segmental sensory loss or motor paresis from radicular involvement, meningo-encephalitis, myelitis, ventriculitis, and cerebral vascular occlusion arising from vasculitic involvement (3, 7). Only 1-5% of all VZV infections leading to neurologic sequelae are felt to directly involve the central nervous system (9). Myelitis is a rare complication, most commonly occurring in the immunocompromised patient (3). Recurrent cases of myelitis are even less common. Particularly important to our understanding of this case, the spinal cord is typically affected at the level of the zoster eruption, but VZV myelitis may affect the cord diffusely rather than being limited to the site corresponding to the skin eruption. Cord tissue specimens from involved regions may show demyelination, hemorrhagic necrosis with necrotizing vasculitis and intravascular thrombosis, and Cowdry A intranuclear inclusions in nearby ganglion cells and satellite cells (3). VZ viral DNA may be demonstrated by PCR of CSF or from involved tissue. Several mechanisms could possibly lead to tissue injury, including cytotoxic or demyelinating effects of the VZ virus itself, vasculitis leading to cord ischemia, or meningitis with release of inflammatory mediators or secondary involvement of penetrating vessels.
Herpes zoster myelitis typically develops days to weeks after the development of the vesicular rash, although there are reported cases in which no dermatologic eruption was noted (6, 7). A subacute progression is characteristic, with advancing leg weakness and sensory changes being the most common presentation. Sphincter dysfunction develops in about half of patients (3). Devinsky et al, in their series of 13 patients with herpes zoster myelitis, found that the symptoms usually began unilaterally, or if bilateral, were asymmetric, with the motor and dorsal column functions altered to a greater degree on the side of the rash and spinothalamic functions altered contralaterally. In this series, spinal level to all modalities occurred in over one-third of the patients diagnosed with VZ myelitis.
MRI findings in cases of herpes zoster myelitis are usually abnormal, but non-specific. Most commonly, focal or diffusely increased intramedullary signal on T2 weighted MRI scans is found. Enhancement with contrast occurs in some cases (10).
The CSF in VZV myelitis frequently shows an elevated protein with a pleocytosis and normal glucose, as was seen in this patient. The opening pressure is usually normal or slightly elevated (3, 4). The VZ virus is rarely isolated on cell culture assays, which have little role in diagnosis of this disorder. Rapid diagnosis by PCR amplification of VZV DNA in the CSF is very helpful in making the diagnosis and can provide early support of the diagnosis of a VZV infection. There is, however, a diagnostic window for the PCR method in the early phase of the infection, after which viral DNA may disappear in the CSF. During the later stages of CNS infection, testing for CSF VZV IgG antibodies seems to the method of choice for diagnosis (1, 5). Antiviral IgG antibody is not found in cerebrospinal fluid normally, so its presence in the absence of a bloody tap is considered significant (5). The diagnosis of a VZV infection in the CNS should not be ruled out in the appropriate clinical setting even if no VZV DNA or specific IgG is detected, as it is recognized that none of the currently available assays has ideal sensitivity.
We also note that VZV DNA or specific IgG may be present in the CSF in acute herpes zoster without clinical signs or symptoms of myelopathy (11). For this reason, the diagnosis of a herpes zoster myelitis is best made by considering the appropriate clinical setting, suggestive laboratory evidence, and alternative diagnoses.
No rigorous clinical trials have been done to determine the appropriate treatment for VZV myelitis. Several case studies suggest that early intervention with antiviral therapy, particularly acyclovir, is beneficial (2, 3, 8). The use of corticosteroids in VZV myelitis is less clear. Given evidence of vascular inflammation in many tissue specimens from patients with CNS sequelae of VZV infection, a rationale exists for combining immune suppression with antiviral therapy. Corticosteroids used concomitantly with antivirals are suggested to be of benefit (2, 3, 8), but again, rigorous clinical trial evidence is lacking. Nakano et al used interferon alpha treatment in a single case of recurrent VZV myelitis with some apparent benefit in a patient who had progressed despite treatment with acyclovir and steroids (9).
The incidence of VZV infections and their neurologic sequelae will probably decline with more widespread prophylactic use of the varicella-zoster vaccine. It is unclear whether acute administration of VZ immune globulin can affect the outcome of an evolving VZ myelitis or encephalitis.
This patient was initially treated with IV methylprednisolone, together with empiric antibiotics including acyclovir. His antibiotic regimen was subsequently optimized based on culture results, and foscarnet added, to provide improved activity against VZV as well as for possible cytomegalovirus or HSV infection. Despite these treatments, his exam deteriorated over the first week to grade 1/5 strength in the right arm, and grade 2/5 strength in the right leg, with development of increased weakness in the left arm and leg, and substantially worsened neurogenic bladder dysfunction. Follow-up CSF studies done two weeks after his presentation showed normalization of CSF protein with no pleocytosis. However, the patient exhibited minimal improvement in function following his neurologic deterioration. He subsequently developed urosepsis complicated by respiratory failure, and died despite aggressive treatment. His family declined autopsy. Thus, the question of an underlying predisposition to VZV recurrence, or to development of myelitis, remains unanswered in this case.
This patient's initial presentation, as outlined by Dr. Eberle, illustrates several characteristic features of myelopathies affecting the high cervical cord, and also of the spinal cord hemisection syndrome described by Brown-Sequard. We thank the Infectious Disease and Neurology Services of the Houston Veterans Administration Medical Center for their assistance with this case.
-- Dennis R. Mosier, M.D., Ph.D.
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