Infantile nonconvulsive status epilepticus caused by herpes encephalitis.

Sir,

Nonconvulsive status epilepticus is a specific form of status epilepticus characterized by alteration in the mental status and persistent seizure activity on electroencephalogram (EEG), with or without motor phenomena. Herpes simplex encephalitis (HSE) is one of the causes of it.[1] Herein, we report an infant- developed nonconvulsive status epilepticus following HSE.

An 11-month-old girl, who had unremarkable medical history, was admitted to a local hospital with fever and seizure. She had otitis media and was hospitalized there for intravenous antibiotic therapy for 1 week before being referred to our hospital. She was unconscious, and responsive to only painful stimuli at admission. Left central facial paralysis was detected and she had no swallow reflex or no gag reflex. Brain computed tomography (CT) revealed a low-density lesion in the right frontal lobe. Cerebrospinal fluid (CSF) revealed 40/mm3 leukocyte (100% lymphocyte); protein was 36 mg/dl and glucose 47 mg/dl. Ceftriaxone (100 mg/kg/day) and acyclovir (30 mg/kg/day) therapies were administered to the patient on account of encephalitis or inadequately treated bacterial meningitides. An electroencephalogram (EEG) pointed out diffuse slow-wave activity without focal changes. Phenytoin and midazolam treatment were administered in order to cease right focal motor seizures. Magnetic resonance imaging (MRI) on the second day of hospitalization revealed increased signal intensity in the cortical–subcortical region of frontal lobes bilaterally on T2-weighted images and a decreased signal intensity on T1-weighted images [Figure 1]. Lesions were extended bilaterally to frontotemporal lobes on MRI in the second week of hospitalization [Figure 2]. CSF examination yielded increased herpes simplex virus (HSV) Ig M (4.7 RU/ ml, N: 01 RU/ml) and Ig G (33.7 RU/ml, N: 0–20 RU/ml) antibodies. Acyclovir therapy was administered for 3 weeks. The patient improved remarkably. Focal seizures were under control on the fifth day of therapy. She was conscious on the sixth day, and facial paralysis had disappeared. Patient was discharged on the 21st day of hospitalization with a complete recovery. Twenty days after her discharge, she was readmitted to the hospital with bizarre movements’ affecting limbs. Her parents complained about her reduced level of consciousness. CSF examination revealed 300/mm3 erythrocytes, and CSF protein and glucose levels were 40 mg/dl and 60 mg/dl, respectively. EEG pointed out a persistent epileptic activity [Figure 3]. Acyclovir readjusted for recurrent HSE over 21 days. Midasolam infusions and valproat were used in order to control the epileptic activity. There was no alteration on the MRI findings. CSF examination for HSV polymerase chain reaction (PCR) and the HSV IgM antibody was negative; besides, the HSV IgG antibody level was increased up to 92.7 RU/ml (N: 0-0.20 RU/ml). The epileptic activity was decreased during hospitalization and the patient was discharged with antiepileptic medications.

Figure 1

Cortical-subcortical increased signal intensity in bilaterally frontal lobes on T1-weighted images on cranial MRI on the second day of hospitalization

Figure 2

Extended leisons on bilaterally frontotemporal lobes on MRI on the second week of hospitalization

Figure 3

Persistent epileptic activity on EEG at the second hospitalization

HSE is one of the most devastating infections of the central nervous system (CNS). Despite specific antiviral therapies, serious neurological deficits occur in 18-42% of the survivors of HSE.[23] The common neurological sequelae include memory impairment, behavioral and cognitive abnormality, and secondary epilepsy. Besides, relapse of HSE has been reported in 3.8-26% of the patients.[4-6] The three most common clinical manifestations of HSE relapse are altered mental status, fever, and involuntary movements, usually choreo -athetoid or ballismic.[7-9] Status epilepticus may also be the first manifestation of relapsing herpes encephalitis, which is difficult to distinguish from secondary epilepsy.[2] Moreover, herpes encephalitis is one of the causes of nonconvulsive status epilepticus.[1] Our patient was readmitted to the hospital with choreiform movements and persistent seizure activity on EEG 20 days after HSE. She was conscious, but lethargic. It is difficult to differentiate that this clinical findings was due to the relapse of HSE or due to secondary epilepsy following HSE. Thirty-eight pediatric relapsing herpes encephalitis cases have been studied, and the average age at primary infection is established as 36 months (3 days-16 years), and 65.8% of the cases were under 24 months of age. A relapse occurred within 2 weeks after the end of the treatment of the initial episode in 52% of the patients reported.[7] Also our patient was 11 month old, and she had choreiform movements and status epilepticus occurred within 20 days after the end of the treatment. These findings suggest that this condition was due to the relapse of herpes encephalitis, but laboratory findings did not support the relapsing HSE diagnosis. The detection of the CSF for HSV PCR was negative and the CSF anti-HSV Ig M antibody had become negative at the second hospitalization, and MRI findings revealed no new alteration, so the status epilepticus might be a finding of secondary epilepsy. On the other hand, CSF HSV PCR positivity has been reported in only 56% of the patients with relapse encephalitis.[7] It has been reported that negative PCR results might be correlated with low CSF protein and white blood cell levels, as well as with the presence of anti-HSV antibodies in the CSF.[10] Besides, immunology-mediated mechanisms might have a major role in the pathogenesis of the relapse, and not direct viral cytotoxicity.[11]

On the other hand, should patients have chronic active encephalitis? Progressive mental and behavioral deterioration following herpes encephalitis has been reported.[2] Most of these patients developed intractable seizures, slowly progressive hemiparesis, and cognitive decline in a few years after contracting the disease, and neuropathological studies of these patients showed chronic active encephalitis.[2] We could not perform brain biopsy to our patient, and it is difficult to make a decision about the exact cause of the clinical picture.

Acyclovir therapy is suggested in patients who are presented with status epilepticus after herpes encephalitis, because the patient may be experiencing a relapse of the encephalitis, and we gave a second cycle of acyclovir therapy to the patient.[278]

The prognosis of relapsing HSE cases is poor. The outcome of the majority of patients is either death, or moderate-to-severe neurological impairment. Valencia et al.[7] reported two cases of relapse encephalitis and both of them progressed to a neurovegetative state. Some clinical improvement has been obtained in our patient, but not a complete recovery.

It has been suggested that young age (< 2 years) and a lower total dose of acyclovir treatment are the risk factors for recurrence.[27] But even in patients, who were given acyclovir treatment at a dosage of 60 mg/kg/day for 21 days, a relapse of herpes encephalitis has been reported.[12] Our patient was under 2 years and she was admitted to our hospital 2 weeks after the beginning of the symptoms.

In conclusion, herpes encephalitis should bear in mind as a cause of nonconvulsive status epilepticus. Since the recurrent or chronic infections and complications due to HSV are frequent, especially young children should be monitored carefully. A better understanding of the relapse mechanism is required in order to propose a more efficient treatment.