Abstract
Background
Refractory status epilepticus carries a high risk of morbidity and mortality despite, and at times as a result of, aggressive pharmacologic interventions. Dietary therapies have been used for almost a century in children for controlling medically refractory seizures and status epilepticus and recent studies suggest efficacy and safety in adults as well.
Methods
Case report and literature review.
Results
We describe a case of medically and surgically refractory status epilepticus that was controlled after initiation of the ketogenic diet and maintenance with the modified Atkins diet in an adult in the neurocritical care unit.
Conclusions
Dietary therapy should be considered as a treatment option in adult patients with refractory status epilepticus.
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Introduction
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 [1]. 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.
Discussion
Mortality rates with refractory status epilepticus have been reported as high as 17–57% despite aggressive pharmacologic intervention [2, 3]. We present a patient with inflammatory encephalitis and status epilepticus whose seizures did not respond to conventional medical or surgical measures, but who achieved seizure freedom following initiation of the ketogenic diet in the neurointensive care unit and maintained seizure control after transitioning to the modified Atkins diet. Care and close monitoring of this patient required a coordinated multidisciplinary approach between neurointensivists, neuroimmunologists, and neurological infectious disease experts, epileptologists, nurse practitioners, nursing staff, electroencephalography technicians, dietitians, and pharmacists for work up and successful initiation and maintenance of dietary therapy.
Dietary therapies have been described in the treatment of epilepsy since 1921 [4]. These include high fat, low carbohydrate diets such as the traditional ketogenic diet [5–7], the modified Atkins diet [1, 8–14], as well as the low-glycemic index treatment [15], and all three have been used primarily in the treatment of children. However, even as long ago as 1930, these treatments have been recognized as beneficial for adults [16]. In recent years, there has been renewed interest in using dietary treatments for adults with epilepsy as well [1, 17–19].
Although typically used for patients with chronic yet intractable epilepsy, there has been interest in the past several years in the use of the diet as an emergent, acute therapy [13, 20–22]. Unlike some medications and the vagus nerve stimulator, dietary treatment appears to work quite rapidly, with large series reporting seizure reduction within typically 2 weeks [23] and sometimes even during the first few days. Retrospective case series have described the use of dietary therapies in refractory status epilepticus. The ketogenic diet was shown to be effective in a case series of 9 pediatric patients with fever induced refractory epileptic encephalopathy in school aged children (FIRES) [22]. Kumada et al. [13] also described two children who had daily nonconvulsive status epilepticus for months to years with resolution of SE within 10 days of initiating a 10 gram per day modified Atkins diet. One recent case report and a case series of two patients have described efficacy of the ketogenic diet in adult patients, a 54-year-old man with refractory partial status epilepticus [24], a 29-year-old with Parry Romberg and Rasmussen’s syndrome presenting with prolonged simple partial status epilepticus, and a 34-year-old man with presumed viral encephalitis and convulsive seizures that progressed into status epilepticus [20].
The argument could be made in this case that the seizures ceased as part of the natural evolution of the underlying inflammatory process, independent of treatment or as a result of “burn-out” following prolonged status epilepticus. However, prior to initiation of the diet, cortical inflammation appeared to worsen despite conventional anti-inflammatory treatments and there was no clear improvement in seizure control, as described. Ketogenic diets may have potential anti-inflammatory properties that may have contributed to the patient’s recovery. By 4 weeks, ketogenic diet pretreatment decreases paw swelling and plasma extravasation after injection of complete Freund’s adjuvant into rat paws [25]. The anti-inflammatory response was suggested by the authors to be mediated by an adenosinergic mechanism. Alternative explanations have been provided by others. In a murine Parkinson disease model, 1 week pretreatment with a ketogenic diet appeared to prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced microglia activation in the substantia nigra (although the analysis was not quantitative) [26]. In that model, a ketogenic diet decreased levels of interleukin-1β, interleukin-6, and tumor necrosis-α, which had been increased by MPTP. The clinical relevance of an effect on IL-6 is unclear, as ketogenic diet consumption for 7 days had no effect on serum levels of interleukin-6 in patients with rheumatoid arthritis [27]. In terms of cellular immunity, these patients had no change in early T lymphocyte activation or absolute numbers of CD4+ or CD8+ cells (although there was a decrease in blood total lymphocyte count) [28]. Further investigation into the ketogenic diet’s anti-inflammatory properties may provide additional insights into the role of inflammation in epilepsy.
In the pediatric population, reported side effects of the ketogenic diet have included hypoglycemia, constipation, and hyperlipidemia, however, more severe side effects such as nephrolithiasis, pancreatitis, and cardiomyopathy have also been reported [29]. A 10-year-old boy suffered fatal propofol infusion syndrome when administered the ketogenic diet [30]. In this patient, propofol was believed to impair fatty acid oxidation, a necessary step in long chain fatty acid metabolism. Therefore, authors of current protocols for the treatment of status epilepticus in children recommend avoiding administration of propofol and the ketogenic diet simultaneously in the pediatric population [31, 32]. Other concerns in the critically ill population include worsening nutritional status and worsening acidosis that can impact critical care physiology. In the critical care setting, prolonged use of anesthetics can inhibit gastrointestinal motility and prevent effective administration of the ketogenic diet, and this should be taken under consideration before initiating the diet. In this patient, the diet was initiated late in their hospital course as a “last resort” but perhaps could be considered sooner in the course of treatment.
Screening laboratory studies are crucial to monitor for potential side effects and the level of ketosis achieved with the diet. Current recommended studies include daily urine ketone levels, dexsticks, and weights, and long-term monitoring of fasting lipids, liver studies, and electrolytes during initiation of the diet [6]. Care should be taken to avoid carbohydrates in intravenous fluids and medications with close monitoring by a dietitian and pharmacy team. Successful implementation involves continued follow-up with a dietitian beyond transfer out of the intensive care unit and patient and family education regarding selecting and measuring foods, measuring urine ketones at home, and identifying side effects should they occur. Consideration should be given to discontinuing the diet if no seizure improvement is seen in 2 weeks following initiation [23].
In conclusion, this case illustrates that once comprehensive anticonvulsant management has failed to control status epilepticus in the adult population, consideration should be made to initiating the ketogenic diet with the goals of lowering seizure frequency and reducing medication burden. The patient can be transitioned safely to a modified Atkins diet while maintaining seizure control and minimizing medical comorbidities to facilitate recovery.
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Acknowledgments
We wish to thank the multidisciplinary team that collaborated in the care of this patient including the neurocritical care, epilepsy, neuroimmunology, and neurological infectious disease faculty, and the Johns Hopkins Neurosciences Critical Care Unit fellows, nurse practitioners, nurses, dietitians, pharmacists, and epilepsy fellows, especially Batya Radzik, Filissa Caserta, Marie Depew, Lourdes James, Juan Ricardo Carhuapoma, Michael Levy, Vinay Chaudhry, Frederick Lenz, Navaz Karanjia, Tung Tran, and Taryn Fortune.
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Cervenka, M.C., Hartman, A.L., Venkatesan, A. et al. The Ketogenic Diet for Medically and Surgically Refractory Status Epilepticus in the Neurocritical Care Unit. Neurocrit Care 15, 519–524 (2011). https://doi.org/10.1007/s12028-011-9546-3
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DOI: https://doi.org/10.1007/s12028-011-9546-3