Epilepsy in KCNH1‐related syndromes

Aim. KCNH1 mutations have been identified in patients with Zimmermann‐Laband syndrome and Temple‐Baraitser syndrome, as well as patients with uncharacterized syndromes with intellectual disability and overlapping features. These syndromes include dysmorphic facial features, nail hypo/aplasia, thumb and skeletal anomalies, intellectual disability, and seizures. We report the epilepsy phenotype in patients with KCNH1 mutations. Methods. Demographic data, electroclinical features, response to antiepileptic drugs, and results of significant diagnostic investigations of nine patients carrying mutations in KCNH1 were obtained from referring centres. Results. Epilepsy was present in 7/9 patients. Both generalized and focal tonic‐clonic seizures were observed. Complete seizure control was achieved with pharmacological treatment in 2/7 patients; polytherapy was required in 4/7 patients. Status epilepticus occurred in 4/7 patients. EEG showed a diffusely slow background in 7/7 patients with epilepsy, with variable epileptiform abnormalities. Cerebral folate deficiency and an increase in urinary hypoxanthine and uridine were observed in one patient. Conclusions. Epilepsy is a key phenotypic feature in most individuals with KCNH1‐related syndromes, suggesting a direct role of KCNH1 in epileptogenesis, although the underlying mechanism is not understood.     

Fast Ca2+ responses in astrocyte end‐feet and neurovascular coupling in mice

Cerebral blood flow (CBF) is regulated by the activity of neurons and astrocytes. Understanding how these cells control activity‐dependent increases in CBF is crucial to interpreting functional neuroimaging signals. The relative importance of neurons and astrocytes is debated, as are the functional implications of fast Ca²⁺ changes in astrocytes versus neurons. Here, we used two‐photon microscopy to assess Ca²⁺ changes in neuropil, astrocyte processes, and astrocyte end‐feet in response to whisker pad stimulation in mice. We also developed a pixel‐based analysis to improve the detection of rapid Ca²⁺ signals in the subcellular compartments of astrocytes. Fast Ca²⁺ responses were observed using both chemical and genetically encoded Ca²⁺ indicators in astrocyte end‐feet prior to dilation of arterioles and capillaries. A low dose of the NMDA receptor antagonist (5R,10s)‐(+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine‐hydrogen‐maleate (MK801) attenuated fast Ca²⁺ responses in the neuropil and astrocyte processes, but not in astrocyte end‐feet, and the evoked CBF response was preserved. In addition, a low dose of 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP), an agonist for the extrasynaptic GABA_A receptor (GABA_AR), increased CBF responses and the fast Ca²⁺ response in astrocyte end‐feet but did not affect Ca²⁺ responses in astrocyte processes and neuropil. These results suggest that fast Ca²⁺ increases in the neuropil and astrocyte processes are not necessary for an evoked CBF response. In contrast, as local fast Ca²⁺ responses in astrocyte end‐feet are unaffected by MK801 but increase via GABA_AR‐dependent mechanisms that also increased CBF responses, we hypothesize that the fast Ca²⁺ increases in end‐feet adjust CBF during synaptic activity.     

Epilepsy surgery in China: past,present, and future

Since the 1990s, China has experienced a boom in epilepsy surgery. Five cities have established epilepsy centers, and at least one hospital in each of the 32 provinces provides epilepsy surgical services. Epilepsy surgery in China has benefited from the availability of advanced non‐invasive diagnostic tools to delineate epileptogenic lesions and epilepsy functional deficits, increased medical and social acceptance of epilepsy surgery, and collaborations with the International League Against Epilepsy, the International Bureau for Epilepsy, and international epilepsy centers. However, national demand for epilepsy surgery still far exceeds supply, and epilepsy surgery is underutilized in many economically underdeveloped provinces. This paper analyzes the current progress of epilepsy surgery in China and details necessary steps for future development. Specifically, the growing need for standardized quality control, multidisciplinary research, and continued worldwide collaboration is addressed. Surgical therapy for epilepsy has experienced rapid growth in recent years, but many patients with active epilepsy did not receive appropriate treatment in China. Improved epilepsy education remains an important tool to correct the treatment gap. Epilepsy surgery has rapidly grown in China. The establishment of additional epilepsy centers, enhancement of multidisciplinary cooperation, standardization of surgical indications and techniques, increased public education, and government recognition of epilepsy treatment as a medical priority are interventions that will improve the surgical treatment of people with epilepsy in China.     

Topiramate and Metabolic Acidosis in Pediatric Epilepsy

PURPOSE: Topiramate (TPM) has been widely used as an adjunctive therapy for treating epilepsy. TPM is reported to have multiple mechanisms of action, including inhibition of carbonic anhydrase, which may result in metabolic acidosis from decreased serum bicarbonate (HCO3-). METHODS: Clinical data from 30 children who received TPM as adjunctive therapy for medically refractory epilepsy were reviewed at Children's Hospital, Boston. Serum HCO3- levels were assessed before, during, and after discontinuing TPM (n = 9). When multiple data were available, mean values were used for analysis. RESULTS: Of the 30 patients, 21 had a >10% decrease in HCO3- levels. The mean decrease in HCO3- among the 21 patients was 4.7 mEq/L, and maximum was 10 mEq/L. No clinical symptoms occurred, and HCO3- supplement was not needed, except for one patient who developed tachypnea from worsened acidosis after prolonged status epilepticus during a suspected viral illness. Among the 21 patients, TPM was discontinued in seven children because of a lack of efficacy, and in two because of anorexia. After discontinuing TPM, the serum HCO3- returned to the previous level before starting TPM in all nine. CONCLUSIONS: Decreased HCO3- levels occurred in the majority of patients reviewed, usually only to a small to moderate extent, but by 8 and 10 mEq/L in two cases. In patients at risk for acidosis, the decrease in HCO3- may cause significant consequences, such as severe acidosis or renal calculi. Monitoring HCO3- levels before and during TPM therapy may be indicated, especially with conditions that predispose to acidosis.     

Epilepsy‐related mortality is low in children: A 30‐year population‐based study in Olmsted County,MN

Purpose: Epilepsy is a common childhood neurologic disorder, affecting 0.5–1% of children. Increased mortality occurs due to progression of underlying disease, seizure‐related accidents, suicide, status epilepticus, aspiration during seizures, and sudden unexplained death in epilepsy (SUDEP). Previous studies show mortality rates of 2.7–6.9 per 1,000 person‐years. Potential risk factors include poor seizure control, intractable epilepsy, status epilepticus, tonic–clonic seizures, mental retardation, and remote symptomatic cause of epilepsy. Few population‐based studies of mortality and SUDEP in childhood‐onset epilepsy have been published. The purpose of this study is to report mortality and SUDEP from a 30‐year population‐based cohort of children with epilepsy. Methods: The Medical Diagnostic Index of the Rochester Epidemiology Project was searched for all codes related to seizure and convulsion in children living in Olmsted County, Minnesota and of ages birth through 17 years from 1980 through 2009. The medical records of these children were reviewed to identify all those with new‐onset epilepsy, and to abstract other baseline and follow‐up information. Potential risk factors including seizure type, epilepsy syndrome, history of status epilepticus, the presence and severity of neurologic impairment, and epilepsy outcome was reviewed. Epilepsy outcome was characterized by seizure frequency, number of antiseizure medications (antiepileptic drugs, AEDs) used, and number of AEDs failed due to lack of efficacy, and epilepsy intractability at 1 year and 2, 3, 5, 10, 15, and 20 years after epilepsy onset. We followed all children through their most recent visit to determine vital status, cause of death, and whether autopsy was performed. Key Findings: From 1980 to 2009, there were 467 children age birth through 17 years diagnosed with epilepsy while residents of Olmsted County, Minnesota, and who had follow‐up beyond the time of epilepsy diagnosis. Children were followed for a median of 7.87 years after the time of diagnosis (range 0.04–29.49 years) for a total of 4558.5 person‐years. Sixteen (3.4%) of the children died, or 3.51 deaths per 1,000 person‐years. Two deaths were epilepsy related (12.5%) for a rate of 0.44 per 1,000 person‐years. One of these children died of probable SUDEP and one died of aspiration during a seizure. The remaining 14 deaths (87.5%) were caused by other complications of underlying disease. Several risk factors for mortality were found, including abnormal cognition, abnormal neurologic examination, structural/metabolic etiology for epilepsy, and poorly controlled epilepsy. Significance: Although mortality in children with epilepsy was higher than what would be expected in the general pediatric population, death occurred significantly more in children with neurologic impairment and poorly controlled epilepsy. Epilepsy‐related death, including SUDEP, was rare and mortality due to epilepsy alone was similar to the expected mortality in the general population (observed deaths = 2, expected deaths = 1.77; standardized mortality ratio 1.13, 95% confidence interval 0.19–3.73, p = 0.86). By contrast, most children died of complications of the underlying neurologic disease or unrelated disease rather than the epilepsy.     

Gene Mapping in the Idiopathic Generalized Epilepsies: Juvenile Myoclonic Epilepsy, Childhood Absence Epilepsy, Epilepsy with Grand Mai Seizures, and Early Childhood Myoclonic Epilepsy

Summary: Idiopathic generalized epilepsies, i.e., juvenile myoclonic epilepsy (JME), childhood absence epilepsy, and epilepsy with grand mal [generalized tonic-clonic seizures (GTCS)], are the most common genetic epilepsies. Linkage studies using Bf, HLA serologic, and DNA markers by three independent investigators, one from Los Angeles and two from Berlin, have localized the JME locus to the short arm of chromosome 6 (6p). Because members of the same JME family have the same JME phenotype of childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or early childhood myoclonic epilepsy (ECME), our observations give evidence for a single-locus etiology in 6p for JME and for at least some of the childhood absence seizures, epilepsy with grand mal (GTCS) seizures, and ECME. Studies should now address whether locus heterogeneity exists within childhood absence epilepsy, epilepsy with grand mal (GTCS) seizures, or ECME. Markers linked to JME (Bf, HLA serologic, and DNA markers in the DQ region) can be used to resolve etiologic heterogeneity. Using such markers, both linked and unlinked forms of phenotypes that are clinically indistinguishable may be detected and provide evidence for etiologic heterogeneity. Studies should also concentrate on narrowing the JME locus to 2 to 3 cm by screening families with recombinant events using RFLPs, candidate genes, and new expressed sequences on chromosome 6.     

Presidential Oration: The 18th Annual Conference of the Indian Academy of Neurology, Trichi, Tamil Nadu, September 24-26, 2010, Epilepsy Care in Developing Countries

Nearly 80% of the 50 million people with epilepsy worldwide reside in developing countries that are least equipped to tackle the enormous medical, social and economic challenges posed by epilepsy. These include widespread poverty, illiteracy, inefficient and unevenly distributed health care systems, and social stigma and misconceptions associated with epilepsy. Several studies have reported that a large proportion of patients with epilepsy in developing countries never receive appropriate treatment for their condition, and many, though diagnosed and initiated on treatment, soon discontinue treatment. Unaffordable cost of treatment, unavailability of antiepileptic drugs, and superstitious and cultural beliefs contribute to high epilepsy treatment gap in resource-poor countries. A significant proportion of the current burden of epilepsy in developing countries can be minimized by educating the public about the positive aspects of life with epilepsy and the primary and secondary physicians about current trends in the management of epilepsies, scaling up routine availability of low-cost antiepileptic drugs, and developing cost-effective epilepsy surgery programs.     

Surgery for drug‐resistant tuberous sclerosis complex‐associated epilepsy: who,when, and what

Objective: Tuberous sclerosis complex (TSC) is a multisystem genetic disorder associated with refractory early‐onset epilepsy. Current evidence supports surgery as the intervention most likely to achieve long‐term seizure freedom, but no specific guidelines are available on TSC pre‐surgical workup. This critical review assesses which TSC patients are suitable for surgical treatment, when pre‐surgical evaluation should start, and what degree of surgical resection is optimal for postsurgical outcome. Methods: We searched for publications from 2000 to 2020 in Pubmed and Embase using the terms “tuberous sclerosis,” “epilepsy,” and “epilepsy surgery”. To evaluate postsurgical seizure outcome, we selected only studies with at least one year of follow‐up. Results: Overall, we collected data on 1,026 patients from 34 studies. Age at surgery ranged from one month to 54 years. Mean age at surgery was 8.41 years. Of the diagnostic non‐invasive pre‐surgical tools, MRI and video‐EEG were considered most appropriate. Promising data for epileptogenic tuber detection is provided from invasive SEEG studies. Data on surgery and related outcome were available for 769 patients. Seizure freedom was seen in 64.4% of patients who underwent tuberectomy, 68.9% treated with lobectomy and 65.1% with multilobar resection. The most effective surgical approach was lobectomy, even though more recently tuberectomy associated with the resection of the perituberal area seems to be the best approach to reach seizure freedom. Published postsurgical seizure freedom rates in patients with TSC were between 65% and 75%, but reduced to 48%‐57% over longer follow‐up periods. Early surgery might positively affect neurodevelopmental trajectory in some patients, even though data on cognitive outcome are still to be confirmed with longitudinal studies. Significance: Considering the strong correlation between epilepsy duration and neurocognitive outcome, all patients with TSC ought to be referred early to a dedicated epilepsy centre for individually tailored pre‐surgical evaluation by a multi‐disciplinary epilepsy surgery team.     

AEEG、MRI与MRS对非惊厥发作癫((癎))的诊断价值

目的探讨动态脑电图(AEEG)和头颅MRI与磁共振波谱分析(MRS)检查对临床非惊厥发作癫癎的诊断和和鉴别诊断意义。方法对76例临床拟诊非惊厥发作癫癎患者行AEEG、MRI与MRS检查,并将检查结果进行分析。结果确诊癫癎56例,其中MRI异常57.1%、~1HMRS异常76.8%。结论AEEG、头颅MRI与MRS对非惊厥发作癫癎的诊断和鉴别诊断有重要意义。