Cytomegalovirus-associated acute transverse myelitis in immunocompetent adults
Corresponding author and reprint requests: S. Zimmerli, Institute for Infectious Diseases, University of Bern, Friedbuehlstrasse 51, PO Box 61, CH-3010 Bern, Switzerland
Tel: +41 31 632 32 58
Fax: +41 31 632 35 50
We report a case of transverse myelitis as a complication of acute cytomegalovirus (CMV) infection in immunocompetent patients; and review the literature on the entity. Primary CMV infection was documented by CMV antigenemia and high serum titers of CMV IgM and IgG antibodies. Cerebrospinal fluid (CSF) pleocytosis indicated central nervous system inflammation; CSF polymerase chain reaction (PCR) for CMV, however, was negative. The results of magnetic resonance imaging of the myelon were normal. Although CMV-associated transverse myelitis has been well described in HIV-positive individuals, but is very rare in immunocompetent individuals. It remains unclear whether the neuronal damage is immune mediated or due to a cytotoxic effect of viral infection. The outcome is mainly favorable.
Acute transverse myelitis (ATM) is an uncommon syndrome characterized by segmental motor, sensory and autonomic dysfunction of the spinal cord [1,2]. Larger retrospective series have revealed an incidence of 1.3–4.6 cases per million per year [1,3]. The disease usually begins with back pain, and this is followed by the onset of acute or subacute paraparesis, an ascending sensory level, and disturbed sphincter functions. Approximately 50% of patients temporarily lose all movement in their legs, 80–94% have paresthesias, and almost all have bladder dysfunction . Possible causes include (para)infectious or post-vaccinial states, multiple sclerosis, or autoimmune disorders. Mechanical myelon compression, metastasis and vascular insufficiency must be ruled out in the diagnosis.
Cytomegalovirus (CMV) is a common opportunistic pathogen in severely immunocompromised patients. It may cause transverse myelitis and other central and peripheral neurologic affections . CMV radiculomyelitis was found in 3.4% of autopsies of patients with AIDS . In contrast, CMV-induced myelitis is very rare in immunocompetent patients.
We report on a healthy man developing transverse myelitis as a complication of acute CMV infection.
A 31-year-old man was admitted to our hospital because of progressive proximal leg weakness and a sensory level ascending to T6. The neurologic symptoms had begun 4 days earlier, with numbness in the feet. The patient had suffered from a high fever, intermittent chills and a dry cough for 2 weeks before admission.
On examination, we found hypesthesia below T12 and hyperesthesia/paresthesia between T12 and T6. Proximal muscle strength in the legs was M2 on the left and M3 on the right. Muscle strength below the knee was M3 on the left and M4 on the right. Tendon reflexes of the lower extremities were increased, and right and left plantar responses became extensor within a week. There was hepatosplenomegaly, but no lymphadenopathy or pharyngitis. In addition, the patient had urinary retention, obstipation, and increased sweating.
Laboratory examination showed a normal total leukocyte count, with 7.5% atypical lymphocytes. Lactate dehydrogenase and transaminases were elevated to two times the upper limit of normal. Antinuclear antibodies, antineutrophil cytoplasmic antibodies and rheumatoid factor were negative. CMV antigen pp65 was detected in 2/200 000 blood leukocytes. Both anti-CMV IgM and IgG were elevated in the serum (Table 1), but there was no production of CMV-specific antibodies within the cerebrospinal fluid (CSF). Serologic tests ruled out an acute infection with HIV, varicella-zoster virus (VZV), tick-borne encephalitis virus, measles and mumps viruses, Mycoplasma pneumoniae, Toxoplasma gondii, Borrelia, Rickettsia, and Treponema pallidum. Findings on lumbar puncture included 29 cells/mm3 (95% mononuclear cells), protein 0.48 g/L, lactate 2.8 mmol/L, and glucose 3.0 mmol/L. CSF PCR was negative for herpes simplex virus (HSV), VZV, CMV and Epstein–Barr virus (EBV). Repeated magnetic resonance imaging (MRI) examinations of the central nervous system (CNS) and spinal cord were normal.
Table 1. CMV antibody response over time
Under combined treatment with ganciclovir (5 mg/kg twice daily for 14 days) and methylprednisolone (500 mg once daily for 5 days), CMV antigenemia became negative within 7 days, and the neurologic symptoms improved gradually over weeks. After 4 months, slight weakness of the proximal leg muscles and dysesthesia below the knees persisted. In contrast, the extrapyramidal signs and the alterations of the autonomous nervous system had reverted to normal.
Discussion and review of the literature
The findings in our patient are highly suggestive of ATM involving segments T6–T12. Diagnostic criteria for acute transverse myelitis, as proposed in , are summarized in Table 2: The diagnosis of ATM requires evidence of inflammation within the spinal cord demonstrated by CSF pleocytosis, an elevated IgG index, or inflammatory signs on spinal MRI. In the published literature, both MRI and CSF examination were normal in 40–50% of patients with transverse myelitis [2,3,8]. Our patient had CSF pleocytosis, a normal IgG index, and normal myelon imaging results. The proposed diagnostic criteria set a time limit of 4 h to 21 days between the onset and the maximum neurologic deficit. This is intended to exclude both faster-developing vascular myelopathies and slower-occurring neurodegenerative or neoplastic disorders.
Table 2. Diagnostic criteria for acute transverse myelitis 
|Sensorimotor and autonomic dysfunction |
attributable to the spinal cord
|Findings compatible with causative vasculopathy|
|Bilateral manifestation||History of spinal radiation|
|Clearly defined sensory level||Compressive myelopathy|
|Inflammation within the spinal cord|
|Progression to nadir between 4 h and 21 days|
Symptomatic primary CMV infection is rare in immunocompetent subjects. The clinical and laboratory findings in our patient are compatible with acute CMV infection. His anti-CMV antibody response over time (Table 1) and his CMV antigenemia further support this diagnosis. PCR is the most reliable method for the detection of CMV-related CNS disorders in vivo. CSF tested positive in 62% of patients with AIDS and suspected CMV-associated neurologic disease . In patients with suspected CMV-associated transverse myelitis, CMV DNA has been detected in some patients with AIDS, but, up to this time, never in immunocompetent patients.
Approximately 40% of ATM cases are reported to be preceded by infection with a wide range of pathogens, including herpesviruses (HSV, VZV, CMV, EBV), enterovirus, hepatitis viruses, measles and mumps viruses, or Mycoplasma pneumoniae[1,3]. In addition to direct infection of neural cells, autoimmune mechanisms requiring only peripheral immune activation may be involved. Kerr and Ayetey  reviewed a variety of immunologic mechanisms postulated to cause myelitis: In ATM associated with systemic disease (i.e. systemic lupus erythematosus or sarcoidosis), vasculitis or a granulomatous process can often be identified. Histologic evaluation of idiopathic ATM revealed intraparenchymal or perivascular cellular infiltrations of the spinal cord, resulting in demyelination and neuronal injury. Pathophysiologic mechanisms include molecular mimicry and the fulminant activation of lymphocytes by microbial superantigens. In addition, high levels of circulating antibodies may cause ATM by immune complex deposition, as shown in a patient with ATM following hepatitis B booster immunization .
CMV-associated transverse myelitis in immunocompetent subjects is extremely rare. We are aware of only eight cases reported in the literature (Table 3). The clinical presentations were very similar to those of our patient. Three patients had additional sensorimotor deficits of cerebral nerves and/or the upper extremities [11–13]. There are, however, substantial differences in findings regarding CSF and MRI. The published literature demonstrates that both alterations on MRI (normal in three of six patients evaluated) and CSF pleocytosis (normal in two of nine patients) are lacking in a substantial proportion of immunocompetent patients with CMV-associated ATM. The paucity of case reports does not allow the correlation of initial findings or therapeutic approaches with final outcome. Rapid progression of symptoms, back pain and spinal shock have been associated with poor recovery [2,14]. The detection of the neuronal 14-3-3 protein in the CSF, indicating axonal destruction, was postulated to herald poor prognosis .
Table 3. Published cases of CMV-associated acute transverse myelitis in immunocompetent adults: compilation of CSF and MRI findings
|||202 (68% PMNa)||0.43||–||–|
|||3200 (100% PMN)||7.2||–||–|
|||226 (76% monocytes)||1.4||–||–|
|||200 (62% PMN)||1.7||–||Normal|
|||104 (monocytes)||1||?b||Lesions with T2 hyperintensity|
|||230 (95% monocytes)||1.65||–||Normal|
|||3||1.24||Negative||Lesions with T2 hyperintensity|
|||0||0.15||Negative||Lesions with T2 hyperintensity|
|Our patient||29 (95% monocytes)||0.48||Negative||Normal|
In our patient, the absence of detectable CMV DNA in the CSF might argue in favor of immune-mediated—rather than directly virus-induced—nerve damage. This hypothesis is supported by the absence of intrathecal production of specific CMV antibodies. Pathologic studies in a case of presumed CMV myelitis in an immunocompromised individual indicated that the spinal cord injury was due to both direct viral infection of the spinal cord and virus-induced vasculitis . Kabins et al.  described concomitant non-thrombocytopenic purpura suggestive of CMV-triggered vasculitis.
The uncertainty about the pathophysiology of myelon damage is reflected by the published therapeutic approaches in immunocompetent patients. Purely antiviral  and exclusively anti-inflammatory [13,18] treatments have been reported, as well as combinations of these . Methylprednisolone has been beneficial in some , but not all,  studies. A beneficial effect was reported for lupus myelitis . Plasma exchange was effective in patients with severe isolated CNS demyelination . We combined ganciclovir (given until clearance of pp65 antigenemia was documented) with a 5-day course of methylprednisolone.
In immunocompetent patients, the prognosis of CMV-associated myelitis is quite favorable. All but one patient regained normal gait after months of rehabilitation . Some degree of incontinence and hyperreflexia, however, persisted in most patients .
This case strongly suggests that primary CMV infection can cause transverse myelitis in immunocompetent persons. It remains unclear whether the neuronal damage is immune mediated or due to a cytotoxic effect of viral infection. The variability of CSF and imaging findings in reported cases stresses the importance of clinical data for the diagnosis of transverse myelitis.