Treatment of Refractory Convulsive Status Epilepticus: A Comprehensive Review by the American Epilepsy Society Treatments Committee.

PURPOSE: Established tonic-clonic status epilepticus (SE) does not stop in one-third of patients when treated with an intravenous (IV) benzodiazepine bolus followed by a loading dose of a second antiseizure medication (ASM). These patients have refractory status epilepticus (RSE) and a high risk of morbidity and death. For patients with convulsive refractory status epilepticus (CRSE), we sought to determine the strength of evidence for 8 parenteral ASMs used as third-line treatment in stopping clinical CRSE. METHODS: A structured literature search (MEDLINE, Embase, CENTRAL, CINAHL) was performed to identify original studies on the treatment of CRSE in children and adults using IV brivaracetam, ketamine, lacosamide, levetiracetam (LEV), midazolam (MDZ), pentobarbital (PTB; and thiopental), propofol (PRO), and valproic acid (VPA). Adrenocorticotropic hormone (ACTH), corticosteroids, intravenous immunoglobulin (IVIg), magnesium sulfate, and pyridoxine were added to determine the effectiveness in treating hard-to-control seizures in special circumstances. Studies were evaluated by predefined criteria and were classified by strength of evidence in stopping clinical CRSE (either as the last ASM added or compared to another ASM) according to the 2017 American Academy of Neurology process. RESULTS: No studies exist on the use of ACTH, corticosteroids, or IVIg for the treatment of CRSE. Small series and case reports exist on the use of these agents in the treatment of RSE of suspected immune etiology, severe epileptic encephalopathies, and rare epilepsy syndromes. For adults with CRSE, insufficient evidence exists on the effectiveness of brivaracetam (level U; 4 class IV studies). For children and adults with CRSE, insufficient evidence exists on the effectiveness of ketamine (level U; 25 class IV studies). For children and adults with CRSE, it is possible that lacosamide is effective at stopping RSE (level C; 2 class III, 14 class IV studies). For children with CRSE, insufficient evidence exists that LEV and VPA are equally effective (level U, 1 class III study). For adults with CRSE, insufficient evidence exists to support the effectiveness of LEV (level U; 2 class IV studies). Magnesium sulfate may be effective in the treatment of eclampsia, but there are only case reports of its use for CRSE. For children with CRSE, insufficient evidence exists to support either that MDZ and diazepam infusions are equally effective (level U; 1 class III study) or that MDZ infusion and PTB are equally effective (level U; 1 class III study). For adults with CRSE, insufficient evidence exists to support either that MDZ infusion and PRO are equally effective (level U; 1 class III study) or that low-dose and high-dose MDZ infusions are equally effective (level U; 1 class III study). For children and adults with CRSE, insufficient evidence exists to support that MDZ is effective as the last drug added (level U; 29 class IV studies). For adults with CRSE, insufficient evidence exists to support that PTB and PRO are equally effective (level U; 1 class III study). For adults and children with CRSE, insufficient evidence exists to support that PTB is effective as the last ASM added (level U; 42 class IV studies). For CRSE, insufficient evidence exists to support that PRO is effective as the last ASM used (level U; 26 class IV studies). No pediatric-only studies exist on the use of PRO for CRSE, and many guidelines do not recommend its use in children aged <16 years. Pyridoxine-dependent and pyridoxine-responsive epilepsies should be considered in children presenting between birth and age 3 years with refractory seizures and no imaging lesion or other acquired cause of seizures. For children with CRSE, insufficient evidence exists that VPA and diazepam infusion are equally effective (level U, 1 class III study). No class I to III studies have been reported in adults treated with VPA for CRSE. In comparison, for children and adults with established convulsive SE (ie, not RSE), after an initial benzodiazepine, it is likely that loading doses of LEV 60 mg/kg, VPA 40 mg/kg, and fosphenytoin 20 mg PE/kg are equally effective at stopping SE (level B, 1 class I study). CONCLUSIONS: Mostly insufficient evidence exists on the efficacy of stopping clinical CRSE using brivaracetam, lacosamide, LEV, valproate, ketamine, MDZ, PTB, and PRO either as the last ASM or compared to others of these drugs. Adrenocorticotropic hormone, IVIg, corticosteroids, magnesium sulfate, and pyridoxine have been used in special situations but have not been studied for CRSE. For the treatment of established convulsive SE (ie, not RSE), LEV, VPA, and fosphenytoin are likely equally effective, but whether this is also true for CRSE is unknown. Triple-masked, randomized controlled trials are needed to compare the effectiveness of parenteral anesthetizing and nonanesthetizing ASMs in the treatment of CRSE.

Genetic testing in children with epilepsy.

Genetic testing is now available clinically for several epilepsies. Neurologists increasingly face decisions about diagnostic testing in affected patients and should carefully deliberate the ethical considerations associated with genetic testing. The merits of ordering a genetic test are largely based on the utility for guiding clinical care, providing a prognosis, estimating recurrence risk, and identifying comorbidities. At the same time, a decision to pursue any genetic testing also requires evaluation of associated ethical concerns. This case illustrates ethical challenges that arise when considering genetic testing for a pediatric patient with epilepsy.

Detection of seizure-like movements using a wrist accelerometer.

Caregivers of people with epilepsy are commonly concerned about unwitnessed seizures causing injury and even death. The goal of this study was to determine if a wrist-worn motion detector could detect tonic-clonic seizures. Individuals admitted for continuous video/EEG monitoring wore a wristwatch-size device that was programmed to detect rhythmic movements such as those that occur during tonic-clonic seizures. When such movement was detected, the device sent a Bluetooth signal to a computer that registered the time and duration of the movements. Recorded detections were compared with the routinely recorded video/EEG data. Six of 40 patients had a total of eight tonic-clonic seizures. Seven of the eight seizures were detected. Nonseizure movements were detected 204 times, with opportunity for canceling transmission by the patient. Only one false detection occurred during sleep. In principle, this device should allow caregivers of people with tonic-clonic seizures to be alerted when a seizure occurs.

Epilepsy surgery following brain tumor resection in children.

OBJECT: Intractable epilepsy following successful brain tumor surgery in children may have several underlying causes such as residual tumor, cortical dysplasia, and gliosis. The authors reviewed the cases of children who had previously undergone resection of a brain tumor only to have medically refractory seizures postoperatively. METHODS: The authors performed a retrospective case review of 9 children who underwent brain tumor surgery 2-13 years before undergoing a second surgery to try and control their seizures. RESULTS: Eight of 9 children had seizures at the time of tumor presentation. Tumor types included ganglioglioma, dysembryoplastic neuroepithelial tumor, pilocytic astrocytoma, oligodendroglioma, ependymoma, and choroid plexus papilloma. All patients achieved a seizure-free interval before intractable seizures recurred. After the second operation, 3 children were seizure free, 1 only had auras, 2 had rare complex partial seizures, and 3 continued to have relatively frequent seizures, although the frequency and severity were reduced. Seven of 9 patients had pathology showing residual tumor. CONCLUSIONS: Epilepsy surgery following earlier brain tumor surgery can provide substantial benefit with reduced seizure number and severity. Despite reassuring brain imaging results, residual tumor was present more often than expected in pathological specimens.

Pediatric psychogenic nonepileptic seizures: a study of assessment tools.

The goal of this study was to identify assessment tools and associated behavioral domains that differentiate children with psychogenic nonepileptic seizures (PNES) from those with epilepsy. A sample of 24 children with PNES (mean age 14.0 years, 14 female), 24 children with epilepsy (mean age 13.6 years, 13 female), and their parents were recruited from five epilepsy centers in the United States. Participants completed a battery of behavioral questionnaires including somatization, anxiety, and functional disability symptoms. Children with PNES had significantly higher scores on the Childhood Somatization and Functional Disability Inventories, and their parents reported more somatic problems on the Child Behavior Checklist (CBCL). Depression, anxiety, and alexithymia instruments did not differentiate the groups. Measures of somatization and functional disability may be promising tools for differentiating the behavioral profile of PNES from that of epilepsy. Increased somatic awareness and perceived disability emphasize the similarity of PNES to other pediatric somatoform disorders.

Hypnosis-provoked nonepileptic events in children.

OBJECTIVE: The purpose of this study was to describe the use of hypnotic suggestion as a means of precipitating nonepileptic events in children while they are undergoing video electroencephalographic monitoring (VEEG) for differential diagnosis of seizurelike behavior. METHODS: Nine children aged 8-16 years were referred for VEEG to differentiate between epileptic seizures and nonepileptic events. All subjects underwent psychiatric consultation. Hypnosis was attempted in all subjects to try to provoke typical seizurelike events. RESULTS: In eight of nine patients, their typical seizurelike events were provoked by hypnosis. In all eight children, video and EEG analysis of the provoked events demonstrated them to be nonepileptic. No epileptiform abnormalities were present on interictal EEGs. No epileptic seizures occurred. CONCLUSION: Hypnosis is a useful and ethical means of provoking psychogenic nonepileptic events in children. Hypnotic suggestion should be considered as a provocative method when possibly psychogenic nonepileptic events have not occurred spontaneously during diagnostic evaluation.

Electroencephalography in holoprosencephaly: findings in children without epilepsy.

OBJECTIVE: To evaluate the electroencephalographic characteristics of patients with holoprosencephaly (HPE) without epilepsy. METHODS: We evaluated the electroencephalograms (EEGs) of 18 children with HPE who lacked a history of seizures. Neuroimaging studies were assessed for severity of HPE and thalamic non-separation and the presence of dorsal cysts and cortical malformations. RESULTS: Hypersynchronous theta activity occurred in 50 and 60% of EEGs during wakefulness or drowsiness/sleep, respectively, and correlated with the grade of thalamic non-separation (p<0.05). Hypersynchronous beta activity during sleep occurred in 41% of EEGs. Posterior amplitude attenuation occurred in 33% of EEGs and correlated with the presence of a dorsal cyst (p

Short duration of benign partial epilepsy in infancy.

It has previously been reported that benign partial epilepsy in infancy constitutes up to 29% of the epilepsies presenting in the first 2 years of life. To determine the proportion of benign partial epilepsy in our epilepsy population, we retrospectively reviewed 331 patients with greater than two afebrile seizures in the first 2 years of life between 1993 and 2000. Inclusion criteria were (1) partial seizures with or without secondary generalization, (2) normal development, (3) no other neurologic abnormalities, (4) normal interictal electroencephalograms (EEGs), and (5) good response to treatment. Exclusion criteria included seizures that (1) were caused by acute central nervous system insult, (2) occurred only within the first month of life, and (3) lasted longer than 30 minutes. Of 331 patients, 22 (6.6%) fulfilled the criteria with a minimum of 2 years and a mean of 4 years of follow-up off antiepilepsy drug treatment. Six (27%) had complex partial seizures, and 16 (73%) had complex partial seizures with secondary generalization. Neuroimaging studies were normal in all patients. Of the 6 patients with ictal EEGs, 3 had a temporal lobe focus, 1 had an occipital lobe focus, and the remaining 2 had dual foci. Median onset was 4.0 months (range 0.8-9.3). Seizures remitted within 4 months in 20 (91%). Mean duration of seizure persistence was 2.1 months (range 0-8.3) and was longer in treated patients. Median age at last seizure was 6.4 months (range 2-18). Nineteen were treated with antiepilepsy drugs. At last follow-up (mean duration of 52.2 months), all patients were seizure free and off antiepilepsy drugs. Benign partial epilepsy in infancy is an epilepsy syndrome of short duration and is easily recognized using accepted classification criteria. Benign partial epilepsy in infancy appears to be an idiopathic localization-related epilepsy with a favorable prognosis. The incidence in our population is not as common as previously reported. Based on our findings, we suggest weaning of antiepilepsy drugs 6 months after seizure onset.

Type 1 diabetes mellitus and epilepsia partialis continua in a 6-year-old boy with elevated anti-GAD65 antibodies.

A 6-year-old boy presented with epilepsia partialis continua 6 months after diagnosis of type 1 diabetes. Anti-glutamic acid decarboxylase 65 antibodies were found in his serum and cerebrospinal fluid. Anti-epileptic agents did not improve his seizures. High-dose steroids, plasmapheresis, and intravenous immunoglobulin resulted in decreased anti-glutamic acid decarboxylase 65 antibody levels and resolution of his seizures.

Treatment considerations: role of surgery.

Patients with developmental disabilities, including retardation and global developmental delay, are not ideal candidates for epilepsy surgery. Because they have an increased likelihood of diffuse brain dysfunction and multifocal or generalized epileptogenic zones, there is an increased chance that a focal cortical resection will not confer a major improvement in their seizure frequency and severity. There is also increased concern that cortical resection will lead to increase in the patient's disability. However, by applying the basic principles of epilepsy surgery selection (i.e., convergence of multiple lines of localizing evidence) to this population, patients with a reasonable likelihood of good seizure control can be identified. Various means of localizing seizure onset are reviewed, including history and examination, electroencephalography, magnetic resonance imaging, position emission tomography, single-photon-emission tomography, and magnetoencephalography.