A 49-year-old right-handed Asian man presented in the fall of 2010 with status epilepticus. He reported one day of right hand clumsiness and weakness followed by trembling of the fingers, then two generalized tonic-clonic seizures. At a local emergency room, he received intravenous lorazepam and phenytoin. Seizures persisted and he was admitted to the neurology service at the outside hospital for observation with gradual titration of phenytoin to 200 mg t.i.d. Ten years prior, the patient had the sudden onset of simple partial motor seizures involving the left face, arm, and leg and was found to have a right frontoparietal nonenhancing T2-intense lesion of unknown etiology despite biopsy. At that time, he was treated empirically with corticosteroids, a 3 month course of antibiotics, carbamazepine, and valproic acid with complete resolution of seizures and no residual neurologic deficits.
A CT scan and MRI of the head during the present admission in 2010 showed gliosis and encephalomalacia in the region of the right supramarginal gyrus. A routine EEG was normal. The patient was discharged on oral phenytoin and presented the following day to another hospital with recurrent complex partial seizures consisting of rightward head and eye deviation, right hand posturing and altered awareness. He received intravenous lorazepam. The total phenytoin level was 34.1 mg/l (free level 2.9 mg/l). Initial screening laboratory studies were remarkable only for a CK of 538 U/l and a mild elevation of liver enzymes by serology. Cerebrospinal fluid analysis revealed 10 white blood cells/mm3 (3 polymorphonuclear cells and 7 mononuclear cells), 341 red blood cells/mm3, glucose 49 mg/dl (simultaneous serum glucose 94 mg/dl), protein 8 mg/dl, and an IgG index 0.6. Bacterial, mycobacterial, and fungal studies were negative. Negative viral investigations included West Nile virus, enterovirus, Epstein–Barr virus, cytomegalovirus, varicella zoster virus, herpes simplex virus, and JC virus. Cytopathology was negative and flow cytometry revealed no evidence of malignancy. GAD antibodies and a paraneoplastic antibody panel including Anti-Hu, Ma1, Ma2, Yo, Ri, CAR, LEMS, CV2, Zic4, VGKC, Amphiphysin, G-AChR, and NMDA receptor antibodies were negative. Underlying metabolic or mitochondrial etiologies were thought to be unlikely based on the patient’s age at the time of initial presentation and normal laboratory studies. An MRI revealed T2 hyperintensity involving the left precentral gyrus and superior frontal gyrus in addition to the region of encephalomalacia seen previously on the right (Fig. 1a, b). The patient was treated empirically with vancomycin, ceftriaxone, cefazolin, ampicillin/sulbactam, and acyclovir for presumed viral or bacterial encephalitis.
Over the next 2 days, he continued to have frequent complex partial seizures without recovery to baseline mental status between seizures despite multiple doses of intravenous lorazepam and addition of levetiracetam (1500 mg b.i.d.) and valproic acid (1000 mg b.i.d.). A routine EEG showed periodic epileptiform discharges over the left central head region and occasional sharp waves over the right temporal head region. He was transferred to the neurointensive care unit for continuous EEG monitoring, aggressive seizure management, and critical care support. Frequent clinical and electrographic seizures were noted which originated from the left central head region (Fig. 2).
Seizure suppression was attempted with maximal doses of phenobarbital, lacosamide, topiramate, lidocaine, and ketamine. Attempted induction of burst suppression was unsuccessful with continuous infusions of midazolam and propofol, and then was finally achieved with pentobarbital titrated up to 5 mg/kg per hour, with highest serum level 50.8 mg/l. However, when attempting to wean the pentobarbital, frequent electrographic and clinical seizures recurred and were often noted to be stimulus-provoked. With persisting unresponsiveness and need for prolonged mechanical ventilation and nutritional support, the patient ultimately required placement of tracheostomy and gastrostomy tubes.
On hospital day 12, the patient underwent a biopsy of the affected region of the left frontal cortex and surrounding dura which showed only a chronic lymphoplasmacytic infiltrate. Based on the suspected diagnosis of inflammatory cerebritis, the patient received an empiric trial of methylprednisolone and five courses of plasmapheresis over the next month followed by mycophenolate mofetil. Repeated attempts at weaning pentobarbital resulted in continued seizure recurrence. The patient suffered hematochezia from a rectal ulcer, urinary tract infections, bladder rupture, acute respiratory distress syndrome, and hypotensive episodes despite aggressive medical management.
On hospital day 38, the patient returned to the operating room and received intraoperative electrocorticography that revealed widespread left hemisphere epileptiform activity, maximal over the portion of the left precentral gyrus that was abnormal on MRI. This region was resected but seizures persisted, at times originating over the left or right hemisphere. Pentobarbital was weaned again while the patient was on high doses of phenobarbital (highest level 136.8 mg/l) as well as high doses of topiramate, lacosamide, and levetiracetam. The patient had no clinical seizures but no improvement in level of arousal and phenobarbital was gradually tapered as well. Once the phenobarbital level was weaned near 60 mg/l, electrographic and clinical seizures re-emerged but the patient did not regain awareness, so higher doses were continued to achieve both high serum concentrations and seizure control. A postoperative MRI revealed increased T2 hyperintensity surrounding the operative site 4 weeks after surgery (Fig. 1c).
On hospital day 58, the patient was tolerating tube feeds well via percutaneous endoscopic gastrostomy tube and the ketogenic diet was introduced via gastrostomy tube with intravenous hydration and no dextrose following extensive discussion between the neurocritical care team and the epilepsy team. His current formula was substituted immediately, without a fasting period, using KetoCal© (Nutricia, North America) and a ketogenic ratio (grams of fat to protein and carbohydrates combined) of 4:1, beginning with half of the recommended daily allowance of calories for 24 h then advancing to full calories. There was no hypoglycemia or acidosis and within 11 days he was producing large urine ketones. Phenobarbital was gradually weaned again and all other antiepileptic medications (phenobarbital, topiramate, and levetiracetam) remained unchanged, this time without resultant electrographic or clinical seizures. The patient then began following commands. Follow-up routine EEGs showed intermittent sharp waves and a routine EEG on hospital day 81 showed focal slowing over the left anterior head region but no epileptiform discharges (Fig. 3). The patient was discharged to rehabilitation on hospital day 80 on a 4:1 ketogenic diet via gastrostomy tube. One week after transfer to rehabilitation, the patient was tolerating oral feeding and was transitioned to a 20 g/day carbohydrate modified Atkins diet with no calorie restrictions . At follow-up 1 month later and again after 3 months, the patient remained seizure-free with residual weakness in the right hand and difficulty performing fine fractionated movements but was otherwise grossly neurologically intact.