A 73-year-old woman arrived at the emergency room (ER) because in the morning she was found unresponsive and febrile in the bed. The patient has had a fever for the 3 previous days and, in the afternoon before hospitalization, she had been seen clumsy in movement and slowed in reasoning and speech. Her sister had attributed this condition to the febrile state and a possible, yet non-testified, epileptic event, because the patient had a history of epilepsy since the age of 62; consequently, she decided not to carry the patient to ER or to call her family practitioner. The patient had been on valproic acid (VPA) 300 mg b.i.d. for the last 5 years with incomplete control of crises (a couple of episodes of generalized seizure/year). Laboratory exams, including liver function markers and VPA levels, had always been within the range of normality since then.
On ER admission, the first diagnostic hypothesis was a possible COVID-19 infection, also supported by a reduced oxygen saturation (90%) that required oxygen treatment. A nasopharyngeal swab was taken. A brain CT scan showed diffuse hypodensity of the left cerebral hemisphere (Fig. 1a) that was reported as a possible ischemic lesion. As a consequence, the patient underwent an angio-CT scan of the neck vessels and intracranial arteries which did not show any significant alteration.
Only at this time, a neurological evaluation was requested to evaluate what was advanced to be a “cerebral ischemic stroke in a possibly COVID-19 positive patient.” On the ER neurological examination, the Glasgow Coma Scale was 7 (E2, V1, M4): the patient had a response with facial grimaces to painful neck stimulus on both sides of the body. A normal flexion of lower limbs was obtained after a painful fingertip stimulus, prevalent on the left. The patient maintained her eyes opened after a painful stimulus for 20–25 s without exploring the surrounding environment. No audible verbal response was present. No difference was shown in pupil diameter and response to light. Corneal reflex was symmetrically present.
The progressive worsening of vigilance in the last 36 h before hospitalization, the absence of a manifest sudden onset, the presence of fever for a few days, the history of epilepsy, and the antiepileptic therapy currently below the therapeutic range (VPA plasmatic levels 20.8 mg/L; therapeutic range 50–100 mg/L) did not sustain the diagnosis of an acute cerebral ischemic event, while they seemed to support the hypothesis of epileptic status or, secondly, of an encephalitic process.
The electroencephalogram (EEG) showed diffuse slow activity and continuous epileptic activity on the left centrotemporal regions (Fig. 2a). A rapid, i.e., infusion of 8 mg of lorazepam induced a rapid change of EEG with the disappearance of the continuous epileptic activity, and the appearance of bilateral synchronous periodic discharges, with the highest amplitude on the left hemisphere, at about 0.2–0.3 cps, suggestive for possible limbic encephalitis, most likely herpetic (Fig. 2b). A lumbar puncture was then performed in the ER. The cerebrospinal fluid (CSF) was slightly hematic. The CSF analysis showed a high protein concentration (3380 mg/L) and an increased amount of white blood cells (108 cells/mL, of which 42% mononuclear cells and 58% polymorphonuclear cells. Herpes simplex virus-1 (HSV-1) DNA was found in CSF in large amount (142,387 copies/mL; normal < 250). The COVID-19 RT-PCR test was negative in both the CSF and the nasopharyngeal swab.
The diagnosis was that of an epileptic status caused by HSV-1 encephalitis. Therapy with intravenous acyclovir was started, and the VPA daily dose was incremented to 1300 mg/day. The patient became afebrile and partial neurological recovery was obtained after 3 days.
A few days after hospitalization, the patient underwent an MRI study which showed the extension of the cerebral damage and confirmed a distribution typical for herpetic encephalitis (Fig. 1 b, c, and d ).