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1 October 1996 | Volume 125 Issue 7 | Pages 577-587
Purpose: To review the pathologic and clinical features of and establish the frequency of cytomegalovirus encephalitis in adults and to review the methods available for diagnosis and treatment. CLINICAL REVIEW
Cytomegalovirus Encephalitis
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Study Selection: Articles dealing with cytomegalovirus infection of the brain in adults. We also reviewed all unselected autopsies of these populations to establish the frequency of cytomegalovirus encephalitis in recipients of organ transplants and in patients infected with the human immunodeficiency virus (HIV).
Data Extraction: Epidemiologic and pathologic characteristics, clinical manifestations, diagnostic methods, pathogenetic mechanisms, and use of anticytomegalovirus treatments.
Data Synthesis: Of 676 patients receiving a diagnosis of cytomegalovirus encephalitis, 574 (85%) were infected with HIV, 81 (12%) had other causes of immunosuppression, and 21 (3%) were otherwise healthy. Cytomegalovirus encephalitis was confirmed during autopsy in 12% of HIV-infected patients and 2% of transplant recipients. The most common lesion was µglial nodule encephalitis, but the clinical findings corresponding to this pathologic entity are not well defined. In contrast, the pathologic entity of cytomegalovirus ventriculoencephalitis, found almost exclusively in patients with advanced HIV infection, has distinct clinical features that allow recognition even in patients with HIV encephalopathy. Polymerase chain reaction has been shown to be useful for diagnosis of cytomegalovirus encephalitis.
Conclusions: Cytomegalovirus encephalitis is an important opportunistic infection in HIV-infected patients but is rarely recognized in other groups. Cytomegalovirus ventriculoencephalitis has emerged as a unique entity in patients with advanced HIV infection. Recent developments in diagnostic techniques allow early recognition and may make more aggressive approaches to therapy possible.
Methods
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To compare the frequency of systemic and brain infection with cytomegalovirus in transplant recipients with that in persons infected with HIV, we searched for autopsies of these patients. We excluded series that were limited to patients who had a specific systemic or neurologic disease.
Data Synthesis
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Nonimmunocompromised Patients
We found 21 cases of cytomegalovirus encephalitis (only two of which had neuropathologic documentation) in persons who were not immunocompromised [7-22]. Nine other patients had strong evidence of cytomegalovirus infection of the central nervous system. In these patients, cytomegalovirus had been detected in the brain or cerebrospinal fluid or cytomegalovirus antibodies were produced intrathecally (Table 2). In the 10 remaining patients, cytomegalovirus encephalitis was diagnosed on the basis of 1) the association between neurologic symptoms and a blood, urine, or throat culture that was positive for cytomegalovirus or 2) serologic evidence of acute cytomegalovirus infection. We restricted our analysis to the 11 cases that showed direct evidence of cytomegalovirus infection of the central nervous system.
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The signs of cytomegalovirus encephalitis in normal hosts have been febrile illnesses with nonspecific clinical manifestations and a course that was usually self-limiting. The most commonly reported symptoms were fever and headache. Other neurologic manifestations that were reported were the confusional syndrome, seizures, coma, aphasia or dysphasia, and cranial nerve palsies. Median cerebrospinal fluid values were the following: leukocyte count, 49 cells/mm3 (range, 1 to 584 cells/mm3; most leukocytes were lymphocytes); glucose level, 3.4 mmol/L (range, 2.6 to 4.7 mmol/L in four patients; reported as normal in six other patients); protein level, 0.79 g/L (range, 0.22 to 1.25 g/L in 10 patients). Computed tomography of the head was done in seven patients. One scan showed a cerebral hemorrhage [23], and one showed areas of contrast enhancement [11]. Magnetic resonance imaging of the head was done in one patient, and the T2-weighted image showed cortical-subcortical areas of signal enhancement in the frontal and parietal regions and primarily involved the right hemisphere of the brain [11]. Six patients recovered after 1 week to 15 months; two patients recovered partially, with persistent memory deficit [9] or dysphasia [10]; and two died during the acute phase of the disease [7, 8] (one had coexisting herpes simplex encephalitis, which was suspected on the basis of results of serologic studies) [7]. Of the two patients in whom neuropathologic findings were reported, one had µglial nodule encephalitis [22] and one had necrotizing encephalitis with some features suggestive of ventriculoencephalitis [7].
The recent report by Studahl and colleagues [10], in which cases were diagnosed while the patients were alive using polymerase chain reaction (PCR) to detect cytomegalovirus DNA in cerebrospinal fluid, suggests that cytomegalovirus encephalitis in the normal host may be more common than previously suspected. The illness was characterized by acute onset, focal neurologic findings, cerebrospinal fluid pleocytosis (in four of five patients), and spontaneous recovery after several weeks. A curious finding was that two of the patients had no serologic response to cytomegalovirus.
Transplant Recipients
The µglial nodule form of cytomegalovirus encephalitis is a well-recognized pathologic entity in organ transplant recipients, but the clinical features of the disease have never been clearly defined. The first cases were described by Schneck [24] in a review of neuropathologic findings in persons receiving kidney transplants. These findings suggested cytomegalovirus infection in 11 of 34 patients who died after kidney transplantation. The predominant neuropathologic findings were several glial nodules located primarily in gray matter. In two cases, the nodules were associated with cells containing intranuclear and intracytoplasmic inclusions. Most of the patients also had cytomegalic inclusion cells in the lungs, and cytomegalovirus was isolated from lung tissue of one patient. It was not possible to identify clinical findings associated with the pathologic evidence of cytomegalovirus encephalitis. Schober and Herman [25] reported similar findings in an early study of autopsies of persons who had received heart transplants.
We found only three reports [26-28] that described clinical features of cytomegalovirus encephalitis in five transplant recipients. One patient had received a kidney transplant and subsequently developed acute encephalitis [27]. Cytomegalovirus was implicated as the cause because cytomegalovirus DNA was found by in situ hybridization in the patient's leukocytes and by PCR in the patient's cerebrospinal fluid and because intrathecal synthesis of cytomegalovirus antibodies was evident. The patient recovered after receiving ganciclovir and intrathecal human interferon-ß. Three patients were heart transplant recipients in whom diffuse encephalopathy had been found while they were alive and µglial nodules were found in the brain at postmortem examination [26]. The fifth patient had received a bone marrow transplant and had developed an encephalitic disease 4.5 months later [28]. Cytomegalovirus encephalitis was diagnosed on the basis of seroconversion in serum and the presence of high levels of cytomegalovirus antibodies in cerebrospinal fluid. He recovered with moderate residual aphasia and amnesia after receiving vidarabine, leukocyte interferon, and acyclovir.
In our review of unselected series of general autopsies done on 552 transplant recipients (212 recipients of liver transplants, 196 recipients of bone marrow transplants, 110 recipients of heart transplants, and 34 recipients of kidney transplants) [25, 26, 27-40], we found 69 cases of cytomegalovirus encephalitis, including 11 definite cases [25-2839, 40] and 58 presumptive cases [22, 24-2629-33, 41]. The proportion of patients with µglial nodules plus cytomegalic cells ranged from 0% in bone marrow recipients to 6% in kidney recipients. The proportion of patients with µglial nodules but not cytomegalic cells ranged from 5% in bone marrow recipients to 35% in kidney recipients. The high percentage of kidney transplant recipients with evidence of cytomegalovirus encephalitis may not be representative because Schneck's study [24], which was published in 1965, was the only autopsy study of recipients of kidney transplants that included brain autopsy findings. A notable finding is that ventriculoencephalitis and focal necrosis were not described as occurring in any transplant recipient.
Immunocompromised Patients Not Receiving Transplants
We found reports of three definite cases [42-44] and one presumptive case [45] of cytomegalovirus encephalitis in immunocompromised patients who had not received transplants and did not have evidence of HIV infection. The underlying diseases and clinical findings are shown in Table 2. The case described by Suzumiya and colleagues [42] is particularly noteworthy because it is the only case in which a patient who was not infected with HIV had ventriculoencephalitis resembling the entity seen in patients with HIV infection. Interestingly, this patient was infected with human T lymphotrophic virus type 1. The pathologic manifestations of cytomegalovirus infection in the other two definite cases were focal parenchymal necrosis associated with vasculitis [43] and numerous cytomegalic inclusion cells, small hemorrhages, perivascular cuffing, and neuronal necrosis. Cytomegalovirus was confirmed in the latter case by brain biopsy rather than autopsy [44]; the reported pathologic findings were therefore subject to sampling error. Multiple cerebral infarctions and evidence of neoplastic infiltration without cytomegalic inclusion cells were found in the presumptive case [45]. The autopsy in that case was done after a prolonged course of ganciclovir; the findings thus may not have been representative of the patient's illness, which was documented while the patient was alive by detection of cytomegalovirus DNA in cerebrospinal fluid and in serum by PCR.
Patients with AIDS
We identified 574 HIV-infected patients who had cytomegalovirus encephalitis (Table 1). Of 144 patients in whom sex was identified, 137 (95%) were male. Presence of risk factors for HIV infection was identified in 68 patients; of these patients, 55 (81%) were homosexual or bisexual, 5 (7%) used injection drugs, and 3 (4%) had received blood products. Three patients (4%) were thought to have become infected by heterosexual intercourse, and 2 patients (3%) had no risk factors identified. The median CD4 count, determined from data from 37 patients, was 16 cells/mm3 (range, 1 to 94 cells/mm3).
According to the autopsies reviewed, cytomegalovirus encephalitis was common but not universal in patients who had been infected with HIV and was considerably more common in HIV-infected patients than in transplant recipients. In patients with AIDS, cytomegalic cells were detected in 12% (316 of 2603 autopsies) of brains and 55% (854 of 1553) of organs outside of the central nervous system [2-5, 46-57]; in transplant recipients, the respective percentages were 2% (11 of 552) and 18% (97 of 522) [25, 30, 32, 32, 36-3840, 58]. Studies using immunocytochemical [59] or nucleic acid detection [60] techniques suggest that these frequencies are underestimates. Descriptions of coexisting diseases were included for 173 autopsies in which the brains of HIV-infected patients were examined [47, 61-90]; 94 (54%) of these brains had one or more coexisting processes, including 34 (20%) with HIV encephalopathy, 26 (15%) with toxoplasmic encephalitis, 16 (9%) with lymphoma of the central nervous system, and 9 (5%) with herpes simplex infection.
Cytomegalovirus encephalitis usually occurred in the context of systemic cytomegalovirus infection. We found 212 autopsies of HIV-infected patients that contained data on systemic pathology [47, 51, 62, 63, 66, 68, 70-7276, 78-8084, 85, 87-97]. Of these autopsies, 183 (86%) had evidence of cytomegalovirus in extraneural sites. Conversely, of the 640 patients with AIDS and systemic cytomegalovirus infection for whom data were available on neuropathologic findings [3-546-4850-54, 98], only 135 (21%) had cytomegalic cells found in their brains.
Pathologic Findings
Cytomegalovirus has been identified in astrocytes, neurons, oligodendroglia, and capillary endothelia [59, 63, 88, 99]. Morgello and colleagues [63] described four pathologic lesions associated with cytomegalovirus encephalitis in patients with AIDS. The four lesions are shown in Figure 1 and described as follows.
1. Isolated cytomegalic cells: cytomegalic cells without associated µglial nodules or inflammation.
2. Microglial nodules: dense cellular aggregates of macrophages, rod cells, or both, typically well demarcated from the adjacent parenchyma and more common in gray matter than in white matter. Few µglial nodules (only 7% to 12%) contain cytomegalic inclusions [63, 88, 98, 100], but cytomegalovirus DNA has been shown by in situ hybridization in one third of these nodules [99] and by PCR in two thirds [60].
3. Focal parenchymal necrosis: discrete foci of parenchymal necrosis with cytomegalic cells and macrophages.
4. Cytomegalovirus ventriculoencephalitis: focal or diffuse destruction of the ependymal lining and necrosis of periventricular parenchymal tissue associated with dense accumulation of cytomegalic cells in the ependymal and periependymal areas. Ventriculomegaly, necrosis, and hemorrhage or fibrinous exudates covering the ventricular system may be evident on gross inspection [63, 70, 79, 88]. Diffuse and uniform infection of ependymal and subependymal lining cells by cytomegalovirus has been shown by in situ hybridization [79, 90].
We categorized pathologic changes associated with cytomegalovirus encephalitis by using descriptions of 137 autopsies [47, 63, 68, 71, 88, 92, 96, 101, 102]. The most common lesion was µglial nodules, described in 118 autopsies (86%). Ventriculoencephalitis was described in 42 autopsies (31%), focal parenchymal necrosis in 22 (16%), isolated cytomegalic cells in 18 (13%), vasculitis in 13 (10%), and demyelinization in 4 (3%). The brains of two patients with cerebral masses [103] and one patient with vasculopathy [104] were recently proven by biopsy to contain cytomegalic cells.
Clinical Findings
Because of the possibility that cytomegalovirus brain lesions (especially µglial nodule encephalitis and ventriculoencephalitis) have different natural histories and clinical manifestations, we attempted to correlate clinical and pathologic findings. However, few reports describe the clinical findings associated with isolated cytomegalic cells, µglial nodules, or focal parenchymal necrosis [91, 96]. Accordingly, the following discussion is limited to patients with ventriculoencephalitis.
We found reports of 32 patients with ventriculoencephalitis shown at autopsy who had no coexisting neuropathologic process involving the brain other than HIV encephalopathy (which was present in 7 patients). Eight patients had coexisting cytomegalovirus radiculomyelitis. The clinical findings are summarized in Table 3. The clinical picture was typically dominated by confusion and lethargy, and the course was relatively rapid with subacute progression to coma and death. All patients had advanced HIV infection, and most had a diagnosis of another disease related to cytomegalovirus, most commonly retinitis. Nineteen (59%) of the 32 patients were receiving maintenance doses of ganciclovir or foscarnet at the time of presentation with neurologic signs. Nystagmus, ataxia, and unilateral or bilateral cranial nerve palsies usually involving oculomotor or facial nerves were the most characteristic neurologic signs. Although one or more of the characteristic focal neurologic findings were present in half of the 32 patients, it is important to recognize that the other patients presented with an encephalopathic illness without focal neurologic findings. Eight patients [68, 69, 74, 81, 94, 106, 107] developed evidence of encephalitis shortly after presenting with lower-extremity weakness from radiculomyelitis.
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Cerebrospinal fluid findings were available from 19 of the 32 patients [68-7073, 79, 81, 94, 106-109], including 7 with coexisting radiculomyelitis [68, 69, 81, 94, 100, 107]. The median leukocyte counts and protein levels were lower in patients with isolated ventriculoencephalitis (leukocyte count, 4 cells/mm3; protein level, 1.22 g/L) than in those with coexisting radiculomyelitis (leukocyte count, 520 cells/mm3; protein level, 4.70 g/L). Pleocytosis in patients with radiculomyelitis was predominantly polymorphonuclear (median, 70%); in patients with isolated ventriculoencephalitis, it was predominantly mononuclear (median, 8% polymorphonuclear). Cytomegalovirus was isolated from cultures of cerebrospinal fluid from only 1 of 12 patients with isolated ventriculoencephalitis and from 2 of 3 with coexisting radiculomyelitis.
Computed tomography of the brain in 16 patients showed atrophy in 10, enlarged ventricles in 3, periventricular enhancement in 1, subarachnoid hemorrhage in 1, and no abnormalities in 6. Magnetic resonance images of 14 patients showed periventricular enhancement with or without enlarged ventricles in 7, enlarged ventricles alone in 1, atrophy in 3, and no abnormal findings in 3. Figure 2 shows magnetic resonance images from a patient cared for by one of the authors.
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A recent prospective series [110] showed that ventriculoencephalitis can often be recognized while the patient is alive. In that series, Gozlan and colleagues followed 164 consecutive patients with HIV who were having lumbar puncture for evaluation of neurologic symptoms. Of the 12 patients who had ventriculoencephalitis, 8 had received an accurate diagnosis before death on the basis of characteristic clinical findings in the setting of advanced HIV infection.
In a recent study, Holland and colleagues [96] described differences in the clinical manifestations of cytomegalovirus encephalitis compared with HIV dementia. They compared 14 patients who had AIDS and cytomegalovirus encephalitis with 17 controls who had HIV dementia and no pathologic evidence of cytomegalovirus encephalitis. Some neurologic findings (impaired memory, psychomotor retardation, and impaired attention) were similar in both groups, but confusion and disorientation, apathy and withdrawal, cranial nerve palsies, and serum electrolyte abnormalities were statistically significantly more common in patients with cytomegalovirus encephalitis. All 14 patients had µglial nodules; 5 (36%) also had focal parenchymal necrosis in periventricular areas, and 3 (21%) had severe ventriculoencephalitis. The format of the report did not allow us to determine whether the clinical manifestations differed among patients with various cytomegalovirus-related brain lesions.
Reports from the beginning of the AIDS epidemic found cytomegalovirus so frequently in the brains of HIV-infected patients that cytomegalovirus was implicated as a cause of HIV dementia [59]. However, our review of the literature found no direct evidence to support a causal relation between cytomegalovirus encephalitis and dementia other than the rapidly progressive deterioration of cognition that is a part of the clinical syndrome corresponding with ventriculoencephalitis. In a study of autopsies of patients with AIDS, including 46 patients with dementia, Navia and colleagues [91] found no correlation between the severity of dementia and the presence of abundant µglial nodules or cytomegalovirus inclusions. Although a link between the µglial nodule form of cytomegalovirus encephalitis and dementia has been postulated [111], this issue has not been definitively resolved.
Diagnosis
Viral Culture
With few exceptions [76, 110, 112], viral cultures of cerebrospinal fluid have been negative in patients with AIDS and cytomegalovirus encephalitis [63, 70, 79, 90, 96, 97, 100, 108, 113, 114]. Some evidence suggests a correlation between the number of nucleated cells in cerebrospinal fluid and the ability to recover virus [76, 112].
Polymerase Chain Reaction
This assay has become an important tool for recognizing cytomegalovirus encephalitis before death. To evaluate its performance, we reviewed all studies of PCR reported to date [68, 71, 74, 76, 77, 93, 96, 101] and extracted data on the 123 patients in whom the histopathologic findings of the brain were reported and from whom cerebrospinal fluid samples were obtained during life. In these patients, sensitivity of PCR for the detection of cytomegalovirus encephalitis was 79% and specificity was 95%. It should be noted that the relatively low sensitivity is attributable to the inclusion of results from one study [96] that reported a sensitivity (33%) much lower than those reported by the others (range, 79% to 100%).
A potential pitfall of PCR as a diagnostic test for cytomegalovirus encephalitis is that it might be too sensitive, detecting cytomegalovirus encephalitis that is not clinically significant. In three series [68, 71, 101], cytomegalovirus DNA was found in the cerebrospinal fluid of patients with AIDS whose postmortem examination showed only isolated cytomegalic cells in areas of normal brain parenchyma, a lesion of dubious clinical relevance. Recent studies [68, 115] have suggested that a high level of cytomegalovirus DNA in the cerebrospinal fluid is a marker for clinically significant cytomegalovirus encephalitis. Arribas and colleagues [68] found that patients with ventriculoencephalitis, radiculomyelitis, or both had high levels of cytomegalovirus DNA in cerebrospinal fluid (as many as 106 genomes per 8 µL of cerebrospinal fluid). In that series and in one reported by Cinque and colleagues [115], patients with less severe lesions had lower levels of cytomegalovirus DNA. Arribas and colleagues cautioned that the implication of low levels of cytomegalovirus DNA in cerebrospinal fluid is still unknown.
Other Diagnostic Methods
Other methods have been described as potentially useful for diagnosis of cytomegalovirus encephalitis. These methods (which have been tested on a small number of patients) are detection of pp65 antigen in cerebrospinal fluid leukocytes [115, 116], increased ratios of cytomegalovirus antibodies in cerebrospinal fluid and serum [73, 117, 118], and in situ hybridization of cerebrospinal fluid leukocytes [119].
Treatment
Antiviral therapy that is currently available for cytomegalovirus disease includes the nucleoside analogue ganciclovir and the pyrophosphate analogue foscarnet. Most clinical studies involving these agents have been done in patients with cytomegalovirus retinitis, and published information about the response of cytomegalovirus encephalitis to anticytomegalovirus therapy is limited. Several reports document the development of cytomegalovirus encephalitis in patients receiving maintenance doses of ganciclovir [70, 76, 79, 85, 87] or foscarnet [76, 79] for cytomegalovirus retinitis.
Few studies of cerebrospinal fluid pharmacokinetics for either drug have been done. One study [120] that included four cerebrospinal fluid samples from two patients (who were receiving ganciclovir at a dosage of 2.5 mg/kg of body weight every 8 or 12 hours) found cerebrospinal fluid levels of ganciclovir of 0.50 to 0.68 µg/mL, corresponding to 24% to 67% of plasma levels. These concentrations are below the median infective dose of some ganciclovir-sensitive cytomegalovirus strains, which have been reported to range from 0.26 to 1.28 µg/mL [121]. It should be noted that the dosages of ganciclovir used in that study were lower than those currently recommended for induction therapy for cytomegalovirus retinitis (5 mg/kg every 12 hours). One autopsy study [122] showed that ganciclovir concentrations in the brain were 38% of the levels in the blood.
Three studies [123-125] of foscarnet pharmacokinetics have reported that although cerebrospinal fluid penetration of foscarnet greatly varied, most of the cerebrospinal fluid concentrations achieved were sufficient for inhibition of cytomegalovirus replication. In one study [124], the mean concentrations of foscarnet in the cerebrospinal fluid of HIV-infected patients were 437 µmol/L 1 hour after a single dose of 90 mg/kg and 308 µmol/L under steady-state conditions (4 weeks of therapy with 90 mg/kg every 12 hours). This is higher than the 90% inhibitory dose of wild-type isolates of cytomegalovirus, which has been reported as 270 µmol [126]. That study found no relation between blood-brain barrier defects and foscarnet penetration into the cerebrospinal fluid, but another study [123] did find higher cerebrospinal fluid penetration when the meninges were inflamed. Ganciclovir and foscarnet have been found to be synergistic against cytomegalovirus [127], and patients in whom monotherapy for systemic or ocular cytomegalovirus infection has failed have responded to combination therapy [128]. No reports on the efficacy of combination therapy for cytomegalovirus encephalitis have been published to date.
Prognosis
Ventriculoencephalitis was a complication of HIV infection that caused death in reported cases. In the 32 patients with cytomegalovirus ventriculoencephalitis and no coexisting central nervous system disorder other than HIV encephalitis, the median survival from the onset of neurologic symptoms was 42 days (Table 3). In a recent prospective study of 146 HIV-infected patients who had lumbar puncture for evaluation of neurologic symptoms [110], the median survival time after puncture was significantly shorter in the 42 patients with cytomegalovirus DNA present in cerebrospinal fluid (50 days) than in the 125 patients whose cerebrospinal fluid was negative by PCR (205 days) (P < 0.001). In another recent report [68], patients with high levels of cytomegalovirus DNA in cerebrospinal fluid (103 cytomegalovirus genomes per 8 µL of cerebrospinal fluid) had a median survival of 19 days.
Discussion
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Because of the HIV epidemic, cytomegalovirus encephalitis has emerged as an important clinical entity in adults. Our review of the literature shows two main forms of cytomegalovirus encephalitis: µglial nodule encephalitis and ventriculoencephalitis. Microglial nodule encephalitis consists of diffuse µglial nodules and few cytomegalic cells. Ventriculoencephalitis is a necrotizing infection of the ependyma and subependyma that resembles the findings in congenital cytomegalovirus infection of the central nervous system [129]. Microglial nodule encephalitis occurs in recipients of organ transplants and in patients with HIV infection. Ventriculoencephalitis occurs almost exclusively in patients with advanced HIV infection and CD4 counts less than 100 cells/mm3. Ventriculoencephalitis was unknown in adults before the AIDS epidemic.
The characteristics of cytomegalovirus ventriculoencephalitis are sufficiently distinct that the disorder can often be recognized clinically, even when HIV dementia is present [79, 96]. The disease begins with cognitive loss, often with apathy, flat affect, and withdrawal, progressing within a few days or weeks to a state of withdrawn mutism and brain stem involvement, including ocular motor and other cranial nerve palsies, nystagmus, and ataxia. Serum electrolyte levels may be abnormal. The cerebrospinal fluid may show neutrophilic pleocytosis, hypoglycorrhachia, and increased protein, but it can also be unremarkable. Magnetic resonance imaging may show enlarged ventricles, periventricular enhancement, or both. Cytomegalovirus retinitis is often present, and encephalitis may occur during maintenance therapy for the retinitis. Results of viral cerebrospinal fluid cultures are usually negative, but cytomegalovirus DNA can be detected in cerebrospinal fluid by PCR.
The importance of PCR for confirming the diagnosis of cytomegalovirus infection of the central nervous system has been documented [68, 71, 76, 101, 110]. If the PCR assay used has a high sensitivity (for example, the ability to detect 10 to 50 copies of cytomegalovirus DNA), a negative result provides strong evidence that cytomegalovirus is not the cause of the neurologic illness. The interpretation of a positive result is more problematic because low-grade cytomegalovirus infection of the central nervous system, although it may not be responsible for the neurologic illness, may be detected by PCR. Nevertheless, a positive result in the appropriate clinical setting strongly supports the diagnosis of cytomegalovirus encephalitis. Recent research [68] suggests that a high level of cytomegalovirus DNA in cerebrospinal fluid may indicate clinically significant cytomegalovirus encephalitis. Quantitative PCR assays will probably be valuable for following the course of disease and response to treatment as well as for characterizing the clinical significance of the process [115]. Recent studies have also provided encouraging evidence that PCR can be used to detect resistance to antiviral drugs [130, 131].
Further clarification of the relation between the pathologic lesions that are associated with cytomegalovirus encephalitis and their clinical manifestations is required. Most cases of the rapidly progressive form of cytomegalovirus encephalitis appear to manifest as ventriculoencephalitis. A relation between µglial nodule encephalitis and HIV dementia has been suggested [111], but another study [91] showed no correlation between the two conditions.
The literature has shown a lack of sustained response to treatment of cytomegalovirus encephalitis—most patients die within weeks of diagnosis. Aggressive treatment regimens, including combination therapy with ganciclovir and foscarnet, may improve survival. The experience with cytomegalovirus radiculomyelitis may be relevant; in that disease, prognosis has improved because greater awareness has led to earlier clinical recognition and prompt institution of antiviral therapy [132, 133]. Development of new antiviral agents that have activity against cytomegalovirus may also lead to improved results. Exploration of new approaches is important because the occurrence of cytomegalovirus encephalitis is likely to increase as the duration of survival in patients with advanced HIV infection increases.
Recommendations
Diagnosis of cytomegalovirus encephalitis should be considered in patients with advanced HIV infection (CD4 count <100 cells/mm3) who develop rapidly progressive generalized brain dysfunction (which may include focal neurologic findings). A history of cytomegalovirus infection involving sites other than the central nervous system should increase clinical suspicion. Magnetic resonance imaging should be done because it is more sensitive than computed tomography. Characteristic periventricular enhancement is diagnostic, but this sign is not always found. A lumbar puncture should be done to identify neutrophilic pleocytosis, elevated protein levels, and low glucose levels (some or all of these findings are frequently absent). Polymerase chain reaction should be done on cerebrospinal fluid for cytomegalovirus DNA; detection of cytomegalovirus DNA strongly supports the diagnosis of cytomegalovirus encephalitis. Antiviral therapy would be considered once the diagnosis is established, but therapy with ganciclovir or foscarnet does not usually result in prolonged survival. Combined therapy is being used by some experts, but no data on efficacy are currently available. Studies to assess the safety and effectiveness of aggressive antiviral therapy are currently being planned.
Dr. Storch: Department of Pediatrics, Washington University School of Medicine at St. Louis Children's Hospital, One Children's Place, St. Louis, MO 63110.
Dr. Clifford: Department of Neurology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.
Dr. Tselis: Department of Neurology, 6E-UHC, Wayne State University School of Medicine, 4201 St. Antoine, Detroit, MI 48201.
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Article
and pyramid (asterisk). (Luxol fast blue stain with hematoxylin and eosin counterstain; original magnification, x 2.5.) D. Magnified view of the edge of the lesion seen in part C. Numerous cytomegalic inclusion cells (arrows) can be seen. (Original magnification, x 40.) E. Cytomegalovirus ventriculitis. Several cytomegalic inclusion cells can be seen at the aqueduct. The ependyma is disrupted with cytomegalic cells (arrows). (Hematoxylin and eosin stain; original magnification, x 25.).