Multiple drugs

Abstract

Lack of efficacy: case report A 13-year-old boy exhibited lack of efficacy during treatment with valproate, levetiracetam, midazolam, lidocaine, ketamine carbamazepine, clobazam, phenytoin, topiramate, perampanel, lacosamide, phenobarbital and unspecified benzodiazepines for focal status epilepsy [dosages not stated; not all routes stated]. The boy woke-up in the morning with the right facial jerks after a mild cough, involving also his right arm at evening with clumsiness and progressive aphasia. He tried communicating by writing, but progressive impairment of consciousness resulted in coma. He was admitted to the ICU without any response to unspecified benzodiazepines, valproate and levetiracetam. MRI demonstrated a region pf cortical swelling in his left precentral gyrus and restricted diffusion, which was consistent with acute injury. His parents reported recent history of oppositive behavior and anxiety, leading to psychodiagnostic evaluation 4 months prior. The psychodiagnostic evaluation revealed normal IQ and specific learning disorder. He arrived to an institution 5 days later on spontaneous ventilation and with persistent right-sided focal myoclonic jerks and focal clonic seizures along with discharges arising from the left central areas. EEG demonstrated rhythmic high-amplitude delta and superimposed burst of spikes (RHADS), which was mostly observed on the left fronto-central region. Due to no response to IV infusion of thiopental sodium [thiopental] and midazolam, ventilation was started. CSF analysis was insignificant, except mild blood-brain barrier damage with increased CSF albumin and IgG. Metabolic and infectious aetiologies were excluded. CSF and serum lactate was normal. Fifteen days later, brain MRI was performed, which demonstrated involvement of the superior, precentral and middle frontal convolutions with signs of hyperperfusion on the arterial spin labeling (ASL) sequence and less pronounced diffusion restriction, which was interpreted as postictal. EEG changes were observed in relation to thiopental sodium with persistent polyspikes and spikes over the left central regions on thiopental sodium tapering, followed by reappearance of the right-sided jerks after some days. Treatment with carbamazepine, clobazam, levetiracetam, valproate, phenytoin, topiramate, phenobarbital, perampanel, lacosamide and ketogenic diet had no effect. Autoimmune encephalitis (AE) was suspected due to the EEG pattern, clinical presentation and recent history of behavioural abnormalities. The first-line empiric immunomodulatory therapy was started with unspecified immunoglobulins and steroids along with plasmapheresis. Second-line therapy consisted of rituximab, anakinra, sirolimus and bortezomib. His superrefractory status epilepticus was controlled only on thiopental sodium, and continuous IV infusion of either midazolam, ketamine and lidocaine did not allow thiopental sodium tapering. His focal status epilepsy was thought to be refractory to valproate, levetiracetam, midazolam, lidocaine, ketamine carbamazepine, clobazam, phenytoin, topiramate, perampanel, lacosamide, phenobarbital and unspecified benzodiazepines (lack of efficacy). Over the next 6 months, brain MRI demonstrated a progressive and marked decrease in the cortical abnormalities with the development of diffuse cortical atrophy. Four months later, the involved left central area was surgically excised to stop or reduce seizures and to obtain histological verification. Subsequent genetic analysis of blood DNA using a customised multigene next-generation sequencing panel for mitochondrial diseases identified a de novo c.1207C>T (p.Arg403Cys) mutation in DNM1L (NM_005690.4). Focal status epilepsy and acute encephalopathy was thought to be related to the mutation in DNM1L. Futher, his disease course was complicated by severe sacral pressure ulcer, for which debridement and skin graft was performed. Then, he developed septic shock and necrotising enterocolitis. Six months later, he died. Autopsy was not done [cause of death not stated].