Autoimmune Epilepsy in Children: Unraveling the Mystery.

Although many neurologists are familiar with the clinical presentations of anti-N-methyl-d-aspartate receptor or limbic encephalitides, there remains much mystery surrounding autoimmune etiologies of subacute and chronic epilepsies. In addition, the subtleties and differences in presentation in the pediatric population limit diagnosis and challenge clinicians. In the absence of an acute encephalitic picture, it is likely that many clinicians do not test for autoimmune disorders due to the uncertainty surrounding the selection of appropriate candidates for testing and immunomodulation. Recent developments have expanded the definition of epilepsy related to autoimmune mechanisms. Based on current knowledge, autoimmune epilepsy can best be thought of as a subset of autoimmune encephalitis where seizures and epilepsy are the primary presenting factor. Autoimmune epilepsy has been increasingly recognized as a contributor to drug-resistant epilepsies; however, identification of affected individuals remains challenging, particularly in the pediatric population. Our understanding of autoimmune epilepsy continues to evolve as more individuals with epilepsy are tested for antibodies to neuronal proteins and as additional antibodies are being identified. This article provides an overview of the clinical features most commonly associated with positive antibody testing in epilepsy and the scales that are currently available to screen patients for antibody testing and response to immunotherapy. Literature-based recommendations are presented for the modification and validation of current scales to increase applicability to children.

Adult-onset Rasmussen's Syndrome with associated cortical dysplasia.

We describe a 23-year-old woman with previous right temporal lobe surgeries for underlying cortical dysplasia, presenting with drug-resistant right hemispheric seizures and epilepsia partialis continua (EPC). After anti-seizure medication adjustments, she developed focal status epilepticus with progressive EEG and neuroimaging changes. Cerebrospinal fluid and serum autoimmune panels were negative except for an elevated serum acetylcholine-receptor antibody titer, but she underwent immunosuppressive therapy. Stereotactic-EEG evaluation demonstrated multifocal independent ictal patterns in the right hemisphere. Rasmussen's Syndrome was confirmed by brain biopsy, and a hemispherectomy was performed. This patient demonstrates the rare association of adult-onset EPC with cortical dysplasia, precipitously evolving into Rasmussen's Syndrome.

Ictal laughter and crying: Should they be classified as automatisms?

Gelastic seizures (GS) describe ictal laughter and are associated with hypothalamic lesions, as well as other cortical areas. Dacrystic seizures (DS), characterized by ictal crying, also have been reported in hypothalamic lesions and focal epilepsy. We describe a young girl with drug resistant focal dyscognitive seizures associated with gelastic and dacrystic features. However, neither laughter nor crying was correlated with a stereotyped electroencephalographic (EEG) pattern or involvement of a particular brain region. Additionally, based on the variety of epileptogenic foci associated with GS and DS in the literature, laughter and crying appear to represent ictal or peri-ictal automatisms.

Electromyography-based seizure detector: Preliminary results comparing a generalized tonic-clonic seizure detection algorithm to video-EEG recordings.

OBJECTIVE: Automatic detection of generalized tonic-clonic seizures (GTCS) will facilitate patient monitoring and early intervention to prevent comorbidities, recurrent seizures, or death. Brain Sentinel (San Antonio, Texas, USA) developed a seizure-detection algorithm evaluating surface electromyography (sEMG) signals during GTCS. This study aims to validate the seizure-detection algorithm using inpatient video-electroencephalography (EEG) monitoring. METHODS: sEMG was recorded unilaterally from the biceps/triceps muscles in 33 patients (17white/16 male) with a mean age of 40 (range 14-64) years who were admitted for video-EEG monitoring. Maximum voluntary biceps contraction was measured in each patient to set up the baseline physiologic muscle threshold. The raw EMG signal was recorded using conventional amplifiers, sampling at 1,024 Hz and filtered with a 60 Hz noise detection algorithm before it was processed with three band-pass filters at pass frequencies of 3-40, 130-240, and 300-400 Hz. A seizure-detection algorithm utilizing Hotelling's T-squared power analysis of compound muscle action potentials was used to identify GTCS and correlated with video-EEG recordings. RESULTS: In 1,399 h of continuous recording, there were 196 epileptic seizures (21 GTCS, 96 myoclonic, 28 tonic, 12 absence, and 42 focal seizures with or without loss of awareness) and 4 nonepileptic spells. During retrospective, offline evaluation of sEMG from the biceps alone, the algorithm detected 20 GTCS (95%) in 11 patients, averaging within 20 s of electroclinical onset of generalized tonic activity, as identified by video-EEG monitoring. Only one false-positive detection occurred during the postictal period following a GTCS, but false alarms were not triggered by other seizure types or spells. SIGNIFICANCE: Brain Sentinel's seizure detection algorithm demonstrated excellent sensitivity and specificity for identifying GTCS recorded in an epilepsy monitoring unit. Further studies are needed in larger patient groups, including children, especially in the outpatient setting.

Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency.

OBJECTIVE: Glucose transporter type 1 deficiency syndrome (Glut1-DS) is characterized clinically by acquired microcephaly, infantile-onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5-hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain. METHODS: Thirteen Glut1-DS patients completed a 5-hour OGTT. Six patients had prolonged electroencephalographic (EEG)/video monitoring, 10 patients had plasma glucose and serum insulin measurements, and 5 patients had repeated measures of attention, memory, fine motor coordination, and well-being. All patients had a full neuropsychological battery prior to OGTT. RESULTS: The glycemic profile and insulin response during the OGTT were normal. Following the glucose load, transient improvement of clinical seizures and EEG findings were observed, with the most significant improvement beginning within the first 30 minutes and continuing for 180 minutes. Thereafter, clinical seizures returned, and EEG findings worsened. Additionally, transient improvement in attention, fine motor coordination, and reported well-being were observed without any change in memory performance. INTERPRETATION: This study documents transient neurological improvement in Glut1-DS patients following acute hyperglycemia, associated with improved fine motor coordination and attention. Also, systemic carbohydrate homeostasis was normal, despite GLUT1 haploinsufficiency, confirming the specific role of GLUT1 as the transporter of metabolic fuel across the blood-brain barrier. The transient improvement in brain function underscores the rate-limiting role of glucose transport and the critical minute-to-minute dependence of cerebral function on fuel availability for energy metabolism.

Underlying cause of death in incident unprovoked seizures in the urban community of Northern Manhattan, New York City.

We determined underlying cause-specific mortality for incident unprovoked seizures from Northern Manhattan, New York City. We calculated the case fatality, proportionate mortality, and the underlying cause-specific standardized mortality ratios (SMRs), with U.S. death rates as the standard. Thirty-two deaths were observed between 2003 and 2007 among 209 participants. Case fatality was significantly lower for idiopathic/cryptogenic seizures versus symptomatic seizures. About 31.3% of the deaths were attributed to malignant neoplasms, 25.0% to diseases of the heart, 15.6% to influenza and pneumonia, 3.1% to cerebrovascular diseases, and 25.0% to other causes. Significant SMRs were observed for all causes (SMR = 1.6), influenza and pneumonia (SMR = 7.1), and malignant neoplasms (SMR = 2.9). Younger cases (<65 years) had increased SMRs for all causes, malignant neoplasms, and other causes. Older cases (> or =65 years) had increased SMRs for influenza and pneumonia. Underlying cause of death paralleled the underlying cause of seizure in patients with symptomatic etiologies.

The first demonstration that a subset of women with hyperemesis gravidarum has abnormalities in the vestibuloocular reflex pathway.

OBJECTIVE: The vestibular system is a major pathway to nausea and vomiting, and the vestibuloocular reflex (VOR) is a central component; its function can be studied using the vestibular autorotation test (VAT). We hypothesize that women with hyperemesis gravidarum (HG) may have VOR abnormalities. STUDY DESIGN: Women with HG were compared with women without HG using the VAT. Horizontal and vertical VOR gains and phases were evaluated at 3 frequency ranges: low (2.0 to 3.5 Hz), medium (greater than 3.5 to 5.0 Hz), and high (greater than 5.0 to 6.0 Hz) during pregnancy and postpartum. RESULTS: Twenty women with HG and 48 unaffected women were evaluated in early pregnancy. Women with HG had higher horizontal gains at all 3 frequency ranges. Horizontal phase differences were also observed at medium frequencies. No VAT differences were noted postpartum. CONCLUSION: Women experiencing HG had a higher mean VOR horizontal gain and lower horizontal phase when compared with unaffected women.

Estimating the incidence of first unprovoked seizure and newly diagnosed epilepsy in the low-income urban community of Northern Manhattan, New York City.

PURPOSE: To estimate the incidence and mortality associated with first unprovoked seizure or newly diagnosed epilepsy in a low-income, predominantly Hispanic community in Northern Manhattan, New York City. METHODS: We performed a population-based study to determine the incidence of first unprovoked seizure or newly diagnosed epilepsy. Participants were Northern Manhattan residents seen at area hospitals and nursing homes between 2003 and 2005. Cumulative probability of mortality and standardized mortality ratios (SMRs) were also calculated. RESULTS: Among 209 incident cases identified, 123 (58.9%) presented with an incident single unprovoked seizure. A total of 138 (66.0%) participants were Hispanic and 94 (45.0%) had a median household income under $15,000/year. The overall age and sex-adjusted incidence of all unprovoked seizures was 41.1 (95%CI = 35.4-46.8) per 100,000 person-years. Higher incidence was observed in low-income groups. Incidence among Hispanics was similar to that of non-Hispanic whites and non-Hispanic blacks. The cumulative probability of mortality was 17% (95%CI = 12-24%) by 3 years after diagnosis and was significantly greater in females and in those with an identified etiology. SMRs were significantly increased for all groups with respect to age, Hispanic ethnicity, middle and high income, partial seizure type, and remote symptomatic etiology. Idiopathic/cryptogenic and progressive symptomatic etiologies, low income, gender, and non-Hispanic ethnicity were not associated with a significantly increased SMR. CONCLUSION: Incidence of first unprovoked seizure or newly diagnosed epilepsy did not differ by race-ethnicity. Although lower income was associated with higher incidence, higher income was associated with an increased SMR. Future research should examine reasons for differential incidence by income.

Are MRI-detected brain abnormalities associated with febrile seizure type?

OBJECTIVE: Whether magnetic resonance imaging (MRI) is informative in febrile seizures (FS) is unknown. We undertook a study to determine the frequency of MRI-detected brain abnormalities and to evaluate their association with FS type and with specific features of complex FS. METHODS: A prospective cohort study, from 1999 to 2004, included children with first FS from one Pediatric Emergency Department. MRI of the brain was performed within 1 week of the seizure. FS type was categorized by experts blind to the prior clinical history and MRI results. MRI examinations were read blind to the child's clinical history and FS type, and interviewers were blind to MRI results. RESULTS: In 159 children with a first FS, imaging abnormalities occurred in 12.6% (N = 20). Eight of the 54 with complex FS had imaging abnormalities compared to 12 of the 105 with simple FS (n.s.). Compared to children with simple FS, children with both focal and prolonged FS (N = 14) were more likely to have imaging abnormality (OR = 4.3, 95% CI = 1.2-15.0), even after adjustment for abnormal neurological examination. Imaging abnormalities included those known to be associated with seizures (e.g., focal cortical dysplasia) and those not typically associated with seizures (e.g., subcortical focal hyperintensities > or = 5 mm). DISCUSSION: Our data suggest that brain abnormalities may lower seizure threshold in febrile children, predisposing to the development of FS. Clinical management was unaffected and therefore these data do not alter the recommendation that MRI is unnecessary in children with FS, without some other neurological indication.

Prevalence of self-reported epilepsy in a multiracial and multiethnic community in New York City.

PURPOSE: To estimate the prevalence of epilepsy in a racially and ethnically diverse neighborhood in New York City. METHODS: We used random-digit dialing to identify people with a history of epilepsy. We estimated the prevalence of active epilepsy and lifetime epilepsy. RESULTS: The age-adjusted prevalence of active epilepsy was 5.0 per 1000, and that of lifetime epilepsy was 5.9 per 1000. Prevalence appeared higher in Hispanics (active prevalence: 6.3 per 1000; lifetime prevalence: 7.5 per 1000) than in non-Hispanics (active prevalence: 4.1 per 1000; lifetime prevalence: 4.7 per 1000). Blacks appeared to have a lower prevalence of active epilepsy (5.2 per 1000) than whites (5.9 per 1000), but a higher lifetime prevalence (7.5 per 1000 vs. 5.9 per 1000). Ethnic and racial differences in access to epilepsy care were evident both in terms of drug treatment and use of emergency departments for care. CONCLUSIONS: The prevalence of epilepsy in this predominantly minority urban community is similar to that reported in other contemporary studies. Less access to health care for black and Hispanic respondents, compared with white respondents, may have influenced self-reported active epilepsy prevalence estimates since the definition includes recent use of antiseizure medication.

Nonconvulsive status epilepticus in children: clinical and EEG characteristics.

BACKGROUND: Nonconvulsive status epilepticus (NCSE) is a highly heterogeneous clinical condition that is understudied in the pediatric population. OBJECTIVE: To analyze the epidemiological, clinical, and electroencephalograpic features in pediatric patients with NCSE. METHODS: We identified 19 pediatric patients with NCSE from the epilepsy database of the Comprehensive Epilepsy Center at, Columbia University between June 2000 and December 2003. Continuous electroencephalographic (EEG) monitoring was analyzed and chart review was performed. RESULTS: The patients ranged from 1 month old to 17 years of age. Five patients developed NCSE following convulsive status epilepticus (CSE), and a further 12 patients developed NCSE after brief convulsions. Two developed NCSE as the first manifestation during a comatose state following hypoxic events. Acute hypoxic-ischemic injury was the most frequent etiology of NCSE in our population (5 of 19; 26%), followed by exacerbation of underlying neurometabolic disease (4 of 19; 21%), acute infection (3 of 19; 16%), change in antiepileptic drug regimen (3 of 19;16%), refractory epilepsy (2 of 19; 11%) and intracranial hemorrhage (2 of 19; 11%). Six patients had associated periodic lateralized epileptiform discharges (PLEDs), one had generalized periodic epileptiform discharges (GPEDs). Five (5 of 19; 26%) patients died of the underlying acute medical illness. Periodic discharges were associated with worse outcome. CONCLUSION: The majority of our patients with NCSE had preceding seizures in the acute setting prior to the diagnosis of NCSE, though most of these seizures were brief, isolated convulsions (12 patients) rather than CSE (five patients). Prolonged EEG monitoring to exclude NCSE may be warranted in pediatric patients even after brief convulsive seizures. Prompt recognition and treatment may be necessary to improve neurological outcome.

Risk of intracranial pathologic conditions requiring emergency intervention after a first complex febrile seizure episode among children.

OBJECTIVE: To determine the likelihood of intracranial pathologic conditions requiring emergency neurosurgical or medical intervention among children without meningitis who presented to the pediatric emergency department after a first complex febrile seizure. METHODS: We performed a retrospective review of prospectively collected data for children in neurologically normal condition who presented to a single pediatric emergency department after a first complex febrile seizure (focal, multiple, or prolonged). The complex febrile seizure classification was determined independently by 2 epileptologists. The presence of intracranial pathologic conditions was determined through review of neuroimaging results, telephone interviews, or medical record review. RESULTS: Data for 71 children with first complex febrile seizures were analyzed. Fifty-one (72%) had a single complex feature (20 focal, 22 multiple, and 9 prolonged), and 20 (28%) had multiple complex features. None of the 71 patients (1-sided 95% confidence interval: 4%) had intracranial pathologic conditions that required emergency neurosurgical or medical intervention. CONCLUSIONS: For children with first complex febrile seizures, the risk of intracranial pathologic conditions that require emergency neurosurgical or medical intervention is low, which suggests that routine emergency neuroimaging for this population is unnecessary.

Seizure characterization and electroencephalographic features in Glut-1 deficiency syndrome.

PURPOSE: To characterize seizure types and electroencephalographic features of glucose transporter type 1 deficiency syndrome (Glut-1 DS). METHODS: Twenty children with clinical and laboratory features of Glut-1 DS were evaluated. Age at seizure diagnosis, seizure classification, and response to treatment were determined by chart review. Thirty-two continuous 24-h EEG monitoring sessions and reports of 42 routine EEG studies were assessed. RESULTS: Age at seizure diagnosis was between 4 weeks and 18 months (mean, 5 months). Seizure types were generalized tonic or clonic (14), absence (10), partial (nine), myoclonic (six), or astatic (four). During 24-h EEGs, background activity showed generalized 2.5- to 4-Hz spike-wave discharges (41%), generalized slowing or attenuation (34%), no abnormalities (34%), focal epileptiform discharges (13%), or focal slowing or attenuation (9%). No seizures were captured during 69% of the studies; the remainder had absence (19%), myoclonic (9%), or partial seizures (3%). On evaluation of routine and 24-h EEG studies, focal epileptiform discharges (24%) and slowing (11%) were more frequent in ages 0-24 months. In older children (2-8 years), generalized epileptiform discharges (37.5%) and slowing (21%) were more common. CONCLUSIONS: In all ages, a normal interictal EEG was the most common EEG finding. When abnormalities occurred, focal slowing or epileptiform discharges were more prevalent in the infant. In older children (2 years or older), a generalized 2.5- to 4-Hz spike-wave pattern emerged. Seizure types observed included, absence, myoclonic, partial, and astatic.

Treatment for latent TB in correctional facilities: a challenge for TB elimination.

BACKGROUND: To eliminate tuberculosis (TB) in the United States, more information is needed on how to gain access to difficult-to-reach, high-risk populations to evaluate people who would benefit from treatment for latent TB infection (LTBI). METHODS: A field study was conducted of people at risk for co-infection with TB and the human immunodeficiency virus (HIV) and to demonstrate that treating LTBI in inmates is feasible. Inmates were tested for LTBI using the Mantoux tuberculin skin test (TST). Outcomes measured were skin test results and the start and completion of treatment for LTBI. RESULTS: In 49 correctional facilities in 12 states, 198102 inmates had a skin test read. The mean skin test positivity rate among inmates was 17.0%. Of those who had a known HIV test result, 14.5% tested HIV positive. Inmates with a positive TST were 4.2 times more likely than those with a negative TST to be HIV infected (95% confidence interval [CI]=3.9-4.4). Therapy for LTBI was completed in 55.9% of patients started on treatment. Patients who were HIV positive and started on a 12-month treatment regimen were less likely than HIV-negative patients (40.0% vs 68.1%, respectively) to complete treatment (odds ratio [OR]=0.24, 95% CI=0.20-0.28). Patients treated in jails were less likely than those treated in prisons (33.6% vs 57.7%, respectively) to complete treatment (OR=0.29, 95% CI=0.26-0.32). CONCLUSIONS: Correctional facilities offer a venue for identifying and treating high-risk individuals for LTBI. However, completing treatment is more problematic in jails than in prisons.

Glucose transporter 1 deficiency syndrome and other glycolytic defects.

Glucose transporter 1 deficiency syndrome is emblematic of a brain energy failure syndrome. Energy failure also results from other genetically determined metabolic disorders, such as hypoglycemic syndromes, hypoketonemic syndromes associated with fatty acid oxidation defects, glycolytic enzymopathies, and mitochondrial defects. Glucose transporter 1 deficiency syndrome is particularly illustrative of this group of disorders and produces an infantile-onset epileptic encephalopathy that responds to a ketogenic diet. The electroencephalographic correlate is distinctive and emerges as a 2.5- to 4-Hz spike-wave discharge in late infancy to early childhood. Infantile apnea and oscillatory eye movements reminiscent of opsoclonus may be the earliest signs of this condition. Mutations of the GLUT1 gene are causative and transmitted as an autosomal dominant trait. Thioctic acid is a glucose transporter 1 activator, whereas barbiturates and methylxanthines are glucose transporter 1 inhibitors. The ketogenic diet is effective treatment for glucose transporter 1 deficiency syndrome and pyruvate dehydrogenase deficiency. It also should benefit patients with neurologic symptoms resulting from a glycolytic enzymopathy.