Herpes simplex virus encephalitis (HSV-E) is a rare but devastating disease with an incidence of approximately two to four people per 1 million. The initial presentation consists of subacute development of fever, altered consciousness, focal cranial nerve deficit, hemiparesis, and aphasia, but the clinical presentation is mild or atypical in as much as 20% of individuals,1 and cerebrospinal fluid (CSF) without pleocytosis has been described during the first 2 days,2 which could lead to diagnostic difficulties. In this journal, Mook-Kanamori and colleagues described an individual with a HSV encephalitis with abnormalities on the magnetic resonance imaging (MRI) scan of the brain without pleocytosis in the CSF during the initial examination.3 They concluded that normal CSF is highly unusual. We present a patient with HSV-E with MRI abnormalities but no pleocytosis on repeated lumbar punctures and would like to argue that finding no pleocytosis is not unusual. A 72-year-old man was admitted to the internal medicine department of Haga Teaching Hospital (The Hague, the Netherlands) with fever, malaise, and respiratory symptoms. He had been diagnosed with Wegener's disease with pulmonary and renal involvement 4 months earlier for which he was treated with cyclophosphamide and prednisone in combination with cotrimoxazole, resulting in partial remission of his Wegener's disease after 3 months. At that time (1 month before admission) he developed asymptomatic severe leukopenia (0.8 × 109 WBC/L), which made it necessary to interrupt his immunosuppressive treatment. The leukopenia resolved, and leukocyte number was normalized at time of admission (8.2 × 109 WBC/L). In the week before admittance, his physical condition deteriorated, and he had shortness of breath after walking short distances, although on the day of admission, he was able to drive his car. He did not complain of headache. During his first night in the hospital, he had signs of progressive respiratory distress without signs of pneumonia on chest X-ray and was admitted to the intensive care unit the next morning. Because of respiratory failure, he was mechanically ventilated. Because there was no clear focus for the fever, a lumbar puncture was done that showed no abnormalities (total white cell blood count (WBC) 1/μL (reference: <4/μL), protein 0.45 g/L (reference: 0.26–0.79 g/L), glucose 4.00 mmol/L (reference: 2.50–3.70 mmol/L)). On the third and fourth days, a computed tomography (CT) scan of the brain and lungs was performed and did not show clear abnormalities. On the fifth day, sedation was temporarily stopped and, because he did not regain consciousness, an electroencephalogram (EEG) was performed that showed generalized epileptic discharges on the right more than on the left frontal region, suggesting nonconvulsive status epilepticus. The epilepsia was treated with diphantoine, levetiracetam, and midazolam. Eight days after admittance, CT scan of the brain was repeated and showed mild hypodensity over the right temporal region, suggesting edema. HSV-E was considered, and a second lumbar puncture showed a total WBC of 3/μL, protein 0.49 g/L, and glucose 4.6 nmol/L; acyclovir was started. Polymerase chain reaction (PCR) of the second lumbar puncture was positive for HSV type 1 (cycle threshold (ct) value 30.3), and when examined, PCR of the first lumbar puncture was also positive for HSV-1 (ct value 30.7). On Day 9, a MRI scan of the brain showed extensive hyperintense lesions in both temporal regions (Figure 1). On Day 15, brainstem reflexes disappeared, and the EEG became unresponsive. On Day 17, ventilation was stopped, and the patient died shortly afterward. The CSF of this man did not show an increase in WBC, even after 7 days without treatment. It has been suggested that finding no pleocytosis is unusual,3 but in the literature, the percentage false-negative CSF findings varies depending on the criterion standard. In a cohort of 180 patients with biopsy-confirmed HSV-E, no pleocytosis was found in nine (5%).2 In another cohort of 24 patients with PCR-confirmed HSV-E, WBC counts were normal in as many as 21%.4 Whether the immune status in the current patient was of significance is unclear. One article reporting three cases suggested that there might be a relationship between abnormal presentation, normal CSF, and the immunological status of the patient.5 The PCR test for HSV-E has shown excellent specificity, probably greater than 95%, but can also be normal during the first days of HSV-E.6-8 To conclude, in a patient presenting with encephalitis, normal CSF findings (WBC and PCR) do not exclude HSV-E. Every patient suspected of having HSV-E should receive acyclovir, brain imaging, and repeat CSF examination. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: All authors contributed equally to the preparation of this manuscript, except for GG Schoonman, who also wrote the first draft. Sponsor's Role: None.
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Jul 18, 2024
Giulia De Napoli + 11
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