The clinical diagnosis of meningitis was raised in a 67-year-old farmer when he presented with headaches, fever, nausea, and vomiting. The symptoms started 1 day prior to presentation. He was treated intravenously with ceftriaxone, amoxicillin, and acyclovir. His laboratory studies revealed an elevated white blood cell (WBC) count of 15,600/muL with 4.5% bands. His C-reactive protein level was 19.2 mg/L, and his erythrocyte sedimentation rate was 13 mm/h. Blood and urine culture yielded no growth of microorganisms. A computed tomography (CT) scan of the head showed no pathologic findings. CSF analysis revealed a WBC count of 244/muL (46/muL neutrophils and 198/muL lymphocytes), a protein level of 0.38 g/L and a glucose level of 3.86 mmol/L (in comparison to glucose in serum of 6.51 mmol/L and a CSF-serum ratio of 0.6). The results of a CSF culture for bacteria, fungi, and mycobacteria were negative. Polymerase chain reaction (PCR) analyses for herpes simplex virus (HSV) 1 and 2 and varicella zoster virus (VZV) in CSF were negative. Serological tests were negative for Borrelia burgdorferi, but reactive for TBEV (IgG positive, IgM negative). The results were consistent with his vaccine status, as he had been vaccinated against TBEV at 19, 18, and 5 months prior to referral. During the next 3 days, his encephalitic symptoms progressed. The patient showed persistent fever and was then transferred to our tertiary care hospital for further treatment.
The patient had a medical history of rheumatoid arthritis, for which he was treated with prednisone (5 mg once daily) and methotrexate (20 mg once weekly). These compounds were not continued after first presentation. Of note, only the last vaccine against TBEV was administered while he was under immunosuppressive treatment. He had no significant family history, recent travel, or allergies.
On admission to our hospital, his body temperature was 38.8 C, he was disoriented and somnolent [Glasgow Coma Score (GCS) 12], and he showed neck stiffness, increased tonicity of the upper and lower extremities, increased jerks of the lower limbs, and myoclonic movements.
Repeated CSF analysis revealed a WBC count of 36/muL (99% lymphocytes) and repeated PCR tests for HSV 1, HSV 2, VZV, cytomegalovirus, enterovirus, and cryptococcal antigen remained negative. Screening for Mycoplasma antibodies and for vasculitis via multiple blood tests was negative, and a search for paraneoplastic causes by a CT scan of the chest and abdomen showed no pathologic results. Antimicrobial agents were stopped after microbiological investigations returned negative results.
Multiple electroencephalograms (EEGs) showed generalized slow-wave activity (Figure 1A). Within 3 days, the patient became comatose and his GCS fell to 4. He developed a syndrome of inappropriate antidiuretic hormone secretion and severe peripheral axonal neuropathy. The initially preserved oculocephalic reflex with positive doll's eye phenomenon was soon abolished, and his GCS decreased to 3. The initial cranial magnetic resonance imaging (MRI) scan demonstrated no abnormal findings (Figure 2A) nor did the subsequent cranial CT scan on days 7 and 10. On day 9, periods of rhythmic epileptiform signal transients occurred with bifrontal localization. Antiepileptic medication was started with levetiracetam. Subsequent EEGs showed further slowing of background activity, with the appearance of triphasic signals (Figure 1B). Electroneuromyography demonstrated the absence of motor responses, even upon maximal electrical nerve stimulation, but the presence of somatosensory evoked potentials. The cranial MRI scan on day 16 showed slight hyperintensity in the region of the left lateral thalamus (Figures 2B-D).
An open brain biopsy on day 15 showed scant infiltration of the cerebral cortex by CD3-positive T-lymphocytes and microglial activation (Figure 3). Immunostaining for HSV 1 and HSV 2 was negative. The findings were consistent with viral encephalitis with consecutive immune response or cellular infiltration in cerebral parenchyma due to an autoimmune disease. However, neither treatment with corticosteroids nor with plasmapheresis resulted in significant improvement of brain function or peripheral nerve function.
On the basis of a high risk for persistent tetraplegia (extensive axonal peripheral motor denervation on electromyography with absence of motor responses on electrical stimulation) and for lifelong ventilator dependence and a poor cerebral prognosis, his family elected to provide comfort measures only. Four weeks after the onset of symptoms, the patient died. Shortly before the patient's demise, IgM antibodies against West Nile virus (WNV) were detected in the serum.