Acute encephalopathy after intravenous administration of valproate in non‐convulsive status epilepticus

Sir, We report a 45-year-old woman suffering from intractable generalized epilepsy (GE). She had absence seizures and former rare generalized tonic clonic seizures (GTCS) since the age of 10 years with an actual frequency of 1–3 absence seizures per month. Previous CT or MRI-scans were normal, interictal electroencephalograms (EEGs) showed generalized fast spike wave activity without any focal abnormalities concordant with the diagnosis of primary GE. She presented in our outpatient clinic in a state of psychomotor slowing, diminished responsiveness, slurred speech and eyelid blinking. An immediately performed video-EEG revealed continuous generalized spike wave and poly spike wave activity (see Fig. 1). Neuropsychological bedside testing showed extended psychomotor slowing and impairment of attention and auditory short-term memory. At the time of admission, the patient was treated with phenytoin 250 mg/day (serum level 16.5 μg/ml) and topiramate 300 mg/day (serum level 4.1 μg/ml). A non-convulsive status epilepticus (NCSE) was diagnosed and treated with 8 mg Lorazepam IV followed by 1000 mg valproat (VPA) IV within 30 min and a maintenance dose of 2000 mg VPA IV per day. Phenytoin was reduced to 100 mg/day, topiramate was continued with 250 mg/day. Patients behaviour and EEG returned back to normal within 1 h. Subsequently, over the next 24 h, the patient developed a stuporous state with repeated vomiting and occurrence of GTCS followed by coma on day 2 of IV VPA treatment. EEG recording showed diffuse generalized slowing with high amplitude delta waves predominantly over the frontal regions (see Fig. 2). Serum levels of VPA and phenytoin were 29.0 and 8.8 μg/ml, respectively. The CT-scan revealed diffuse swelling (data not shown). Cerebrospinal fluid (CSF) analysis revealed an elevated lactate level of 29.6 μg/ml (normal range 13–18.9 μg/ml) and no signs of infection. Serum analysis exhibited slightly elevated liver enzyme levels (GOT 97 U/l, range 10–35 U/l; γ-GT 69 U/l, range 5–39 U/l; GPT was normal; myoglobin 446 μg/l, range 0–116 μg/l) and creatininkinase (1397 U/l, range 24–140 U/l) were elevated, but ammonium was within the normal range. Neurological findings in the stuporous patient were bilateral Babinski signs and synergistic stretching of the upper and – less pronounced – of the lower limbs but no focal signs. An acute IV VPA induced encephalopathy was diagnosed. Thus, administration of the drug was stopped immediately and the patient was transferred to the neurological intensive care unit. Due to elevated CSF and serum lactate levels a possible mitochondriopathy was suspected and 3 g l-carnitine was administered once daily. An aspiration pneumonia was treated with 1800 mg clindamycin IV and 6 g cefotiam IV daily. No further intervention was necessary, and the patient recovered completely within 48 h with normalized EEG and cerebral CT-scan (data not shown). Electroencephalogram (EEG) on admission. Generalised spike wave activity clinically concordant with absence status or non-convulsive status epilepticus (NCSE). Electroencephalogram (EEG) on day 2 of intravenous valproat (IV VPA) therapy. EEG exhibits diffuse generalized slowing with high amplitude delta activity predominantly over the frontal regions as a consequence of VPA induced encephalopathy clinically presenting with a stuporous state, occurrence of generalized tonic clonic seizures (GTCS), repeated vomiting followed by coma. VPA rarely induces encephalopathy after initiating VPA therapy as well as after long-term oral administration [1]. The cause of acute encephalopathy is yet to be elucidated, however, metabolic, toxic or intrinsic effects of VPA were accused as well as hyperammonemia [2,3]. Moreover, a few reports suggest, that patients are more vulnerable when VPA is added to premedication with topiramate, phenytoin, phenobarbital, lamotirigin or lorazepam [1]. Neurotoxicity was reported in three patients on lamotrigin after adding IV VPA for treatment of frequent absences seizures [4]. At the time our patient became stuporous after successful termination of NCSE, a CT scan revealed a diffuse oedema of the brain. To date, the exact mechanism leading to brain swelling in VPA encephalopathy are not known. Several authors discuss a mechanism triggered by elevated ammonium levels [5]. However, the serum ammonium level in our patient was normal, thus other mechanisms may be involved in the development of cerebral oedema. Another cause for VPA induced encephalopathy might be an underlying mitochondriopathy such as MELAS (myopathy–encephalopathy–lactate acidosis and stroke like episodes) or MERRF (myoclonus epilepsy and ragged red fibres) syndrome. Elevated CSF lactate levels and serum myoglobine levels, together with the seizure type of the patient lead to the assumption of an underlying hitherto unknown MERRF-syndrome and therefore prompted the treatment with l-carnitine. However, 6 weeks after the acute phase a muscle biopsy and consecutive immunocytochemical and genetic screening was performed and a mitochondryo(myo)pathy was excluded in our patient. Thus, the increase of myoglobine and creatininkinase was most likely related to the two previously experienced GTCS. At day two of IV VPA treatment the EEG showed a diffuse, highamplitude theta-delta slowing over the fronto-central regions which is in line with previous findings [6]. The diffuse slowing was not attributable to hepatic encephalopathy since signs of hepatic failure were absent. In conclusion, encephalopathy should be kept in mind as a rare side effect of VPA and has to be distinguished from relapse of NCSE which might also present with obtundation and stupor. EEG monitoring is essential in establishing the differential diagnosis showing early changes with high amplitude delta activity over the frontal regions and probably triphasic waves differing clear cut from relapse of NCSE. In these cases acute withdrawal of VPA leads to complete resolution of the symptoms.