Management of status epilepticus: a narrative review.

Status epilepticus causes prolonged or repetitive seizures that, if left untreated, can lead to neuronal injury, severe disability, coma and death in paediatric and adult populations. While convulsive status epilepticus can be diagnosed using clinical features alone, non-convulsive status epilepticus requires confirmation by electroencephalogram. Early seizure control remains key in preventing the complications of status epilepticus. This is especially true for convulsive status epilepticus, which has stronger evidence supporting the benefit of treatment on outcomes. When status epilepticus becomes refractory, often due to gamma-aminobutyric acid and N-methyl-D-aspartate receptor modulation, anaesthetic drugs are needed to suppress seizure activity, of which there is limited evidence regarding the selection, dose or duration of their use. Seizure monitoring with electroencephalogram is often needed when patients do not return to baseline or during anaesthetic wean; however, it is resource-intensive, costly, only available in highly specialised centres and has not been shown to improve functional outcomes. Thus, the treatment goals and aggressiveness of therapy remain under debate, especially for non-convulsive status epilepticus, where prolonged therapeutic coma can lead to severe complications. This review presents an evidence-based, clinically-oriented and comprehensive review of status epilepticus and its definitions, aetiologies, treatments, outcomes and prognosis at different stages of the patient's journey.

Subspecialty preferences among neurologists of the future.

BACKGROUND AND PURPOSE: In the era of neurological subspecialization, most neurologists will have a field of specialist interest. The aim of this cross-sectional multinational study was to identify the key areas of interest among trainees or junior specialists, assess the potential influence of an interest in research and consider the results in light of population needs. METHODS: A total of 300 residents and junior neurologists who received a bursary to attend the European Academy of Neurology conference were invited to participate in this study. Demographic and work-related characteristics, as well as main subspecialty of choice, were examined via an anonymous electronic questionnaire. Participants holding a higher degree (PhD/MD) or working in research posts were considered research oriented. RESULTS: In total, 191 neurologists in training or junior specialists responded (response rate 63.7%). Full data were available for 187 participants (59.4% females). The study sample had a mean age of 30.5 ± 3.4 (range 25-45) years. The most popular subspecialty was movement disorders (18.2%), followed by multiple sclerosis (11.2%) and epilepsy (10.2%). This did not differ significantly between the participants who were or were not research oriented. CONCLUSIONS: There is a potential mismatch between the interests of trainees and the future needs of the populations they serve, which is important to identify for workforce planning.

The effect of depression and side effects of antiepileptic drugs on injuries in patients with epilepsy.

BACKGROUND AND PURPOSE: People with epilepsy are at increased risk of accidents and injuries but, despite several studies on this subject, data regarding preventable causes are still contradictory. The aim of this study was to investigate the relationship between injuries, side effects of antiepileptic drugs (AEDs) and depression. METHODS: Data from a consecutive sample of adult patients with epilepsy attending the outpatient clinics at St George's University Hospital in London were included. All patients were asked if they had had any injury since the last clinic appointment and completed the Liverpool Adverse Event Profile (LAEP) and Neurological Disorders Depression Inventory for Epilepsy. RESULTS: Among 407 patients (243 females, mean age 43.1 years), 71 (17.4%) reported injuries since the last appointment. A two-step cluster analysis revealed two clusters with the major cluster (53.5% of the injured group) showing a total score for LAEP ≥45, a positive Neurological Disorders Depression Inventory for Epilepsy screening and presence of AED polytherapy. A total score for LAEP ≥45 was the most important predictor. CONCLUSIONS: Antiepileptic drug treatment should be reviewed in patients reporting injuries in order to evaluate the potential contribution and burden of AED side effects.

Clinical correlates of memory complaints during AED treatment.

OBJECTIVES: To investigate clinical correlates of memory complaints (MC) during anti-epileptic drug (AEDs) treatment in adults with epilepsy with special attention to the role of depression, using user-friendly standardized clinical instruments which can be adopted in any outpatient setting. MATERIALS & METHODS: Data from a consecutive sample of adult outpatients with epilepsy assessed with the Neurological Disorder Depression Inventory for Epilepsy (NDDIE), the Adverse Event Profile (AEP) and the Emotional Thermometer (ET) were analysed. RESULTS: From a total sample of 443 patients, 28.4% reported MC as 'always' a problem. These patients were less likely to be seizure free (18.3% vs 34.3%; P < 0.001), had a high number of previous AED trials (4 vs 3; P < 0.001) and high AEP total scores (49 vs 34.2; P < 0.001). There was no correlation with specific AED type or combination. Depression was the major determinant with a 2-fold increased risk (95%CI 1.15-3.86; P = 0.016). When depression was already known and under treatment, patients with MC were less likely to be in remission from depression despite antidepressant treatment (11.9% vs 1.6% P < 0.001). Among patients without depression, those reporting MC presented with significantly high scores for depression (3.3 vs 2; t = 3.07; P = 0.003), anxiety (4.5 vs 2.7; t = 4.43; P < 0.001), anger (3 vs 2; t = 2.623; P = 0.009) and distress (3.8 vs 2.2; t = 4.027; P < 0.001) than those without MC. CONCLUSIONS: Depression has to be appropriately treated and full remission from depression should represent the ultimate goal as subthreshold or residual mood and anxiety symptoms can contribute to MC.

More than seizures: improving the lives of people with refractory epilepsy.

As captured by the proposed new definition, epilepsy is increasingly recognized as a disorder characterized not only by an enduring predisposition to recurrent seizures but explicitly also by the neurobiological, cognitive, psychological and social consequences of this condition. Further, both in the estimated 15 million people worldwide who have ongoing seizures despite optimal management and in a substantial proportion of those in remission, the consequences and comorbidities of epilepsy are the major determinants of quality of life. These include mood disorders such as anxiety and depression, dose related and longer term effects of antiepileptic drugs, including on prenatal development and bone health, and neurobehavioural effects. Whilst separating those that are part of an underlying condition or have unrelated contributors from those that are potentially remediable can be difficult, given the range of tools now available to assist with screening and management there is no excuse for not at least trying as part of standard care for people with epilepsy. Managing epilepsy well is about much more than controlling seizures and this needs to be recognized in planning and delivering services, as well as in prioritizing research.

Administration of levetiracetam after prolonged status epilepticus does not protect from mitochondrial dysfunction in a rodent model.

Neuronal death and dysfunction occur after status epilepticus (SE), and is associated with mitochondrial enzyme damage. We previously showed, using the rat perforant pathway stimulation model, that levetiracetam administration (LEV; 1000 mg/kg intraperitoneal) during established SE reduces seizure severity and prevents mitochondrial dysfunction. We now show that administration of the same dose of LEV after 5h SE, does not protect from mitochondrial dysfunction.

The antioxidant N-acetyl-L-cysteine does not prevent hippocampal glutathione loss or mitochondrial dysfunction associated with status epilepticus.

Hippocampal reduced glutathione (GSH) levels diminish after status epilepticus (SE), which precedes damage to mitochondrial enzymes, which is associated with cell death. The rat perforant pathway stimulation model was used to assess whether intraperitoneal administration of the GSH precursor N-acetyl-L-cysteine (NAC) protected against these changes. NAC (300 mg/kg) treated animals exhibited the same GSH decrease post SE as vehicle treated. Furthermore, NAC treatment had no protective effects on mitochondrial dysfunction.

An audit of electroencephalography requests: use and misuse.

OBJECTIVE: To investigate whether electroencephalogram (EEG) requests at St George's Hospital (SGH) are being made according to clinical guideline recommendations. METHODS: A retrospective audit at a regional neurology and neurosurgery referral centre, also serving a district population. All adult National Health Service patients undergoing standard EEG between 1st November 2003 and 31st January 2004, for whom the request originated within the hospital, were identified. Data was collected from each subject's case notes, request form and EEG report and compared to predetermined criteria. RESULTS: Fifty sets of notes from ninety patients meeting the inclusion criteria were available for review. Twenty-six percent of requests were considered 'inappropriate', with respect to clinical guidelines, of which 92% were for 'funny turns' where there appeared to be insufficient clinical evidence to justify the request. The EEG contributed to diagnosis or management in only 22% of cases, all of which had been appropriately requested. Neurologists/epileptologists appeared better than non-specialists in terms of appropriateness of referrals, though the numbers were too small to reach significance (p = 0.173, Fisher's exact). Forty-two percent of all patients, and less than 10% of outpatients, had their EEG within the guideline target wait of 4 weeks. CONCLUSIONS: Over a quarter of EEG referrals are not being made in accordance with guidelines, mainly because of the misconception that an EEG can confirm or exclude a diagnosis of epilepsy in patients with "funny turns". In addition, less than 10% of out patient requests are being met within 4 weeks. Strategies to maximise service utilisation are discussed.

The -1021C->T DBH gene variant is not associated with epilepsy or antiepileptic drug response.

Dopamine beta-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE). Animal studies show that genes in the NE pathway are candidates for susceptibility to epilepsy and antiepileptic drug (AED) response. The authors genotyped the -1021C-->T major functional polymorphism in the DBH gene in 675 patients with epilepsy and 1,087 controls. The authors found no association with epilepsy, several epilepsy subtypes, or AED response. The results suggest that the -1021C-->T variant does not contribute to epilepsy.

A comparison of lorazepam and diazepam as initial therapy in convulsive status epilepticus.

BACKGROUND: Previous trials have suggested lorazepam may be superior to diazepam as first-line treatment of convulsive status epilepticus (CSE), with improved seizure outcome, and a lower incidence of side-effects. Many published guidelines however still recommend diazepam. AIM: To compare the efficacy, safety and cost of lorazepam compared to diazepam, in adults with CSE. DESIGN: Retrospective case note audit. METHODS: Cases of CSE were retrospectively identified over two 18-month periods either side of the introduction of a new management protocol in May 1997, in which lorazepam 4 mg i.v. was substituted for diazepam 10 mg i.v. as first-line treatment for CSE. Diagnostic codes for all admissions and casualty presentations of patients over 16 years of age were examined for primary or secondary codes including 'epilepsy', 'fits' or 'status epilepticus'. Medical records and casualty notes were reviewed to identify CSE cases. Treatment groups were compared using ANOVA and a Tukey post hoc analysis. Treatment success was defined as cessation of seizures without recurrence in the subsequent 12 h. RESULTS: In both premonitory and established CSE, both drugs were equally effective at terminating seizures, but significantly fewer seizure recurrences followed lorazepam, and fewer repeat doses were needed. There were no differences in reported adverse events or in drug costs. DISCUSSION: We recommend that lorazepam be the first-line therapy in preference to diazepam in adults with CSE.

Mitochondrial myopathies and encephalomyopathies.

Defects of mitochondrial metabolism result in a wide variety of human disorders, which can present at any time from infancy to late adulthood and involve virtually any tissue either alone or in combination. Abnormalities of the electron transport and oxidative phosphorylation (OXPHOS) system are probably the most common cause of mitochondrial diseases. Thirteen of the protein subunits of OXPHOS are encoded by mitochondrial DNA (mtDNA) and mutations of this genome are important causes of OXPHOS deficiency. The link between genotype and phenotype with respect to mtDNA mutations is not clear: the same mutation may result in a variety of phenotypes, and the same phenotype may be seen with a variety of different mtDNA mutations. The pathogenesis of mtDNA mutations is unclear although OXPHOS and ATP deficiency, and free radical generation, are thought to contribute to tissue dysfunction. There is now strong evidence for mitochondrial dysfunction in neurodegenerative disorders. In some cases, e.g. Friedreich's ataxia, hereditary spastic paraplegia, this is a result of a mutation of a nuclear gene encoding a mitochondrial protein, whilst in others, e.g. Huntington's disease, amyotrophic lateral sclerosis, the OXPHOS defect is secondary to events induced by a mutation in a nuclear gene encoding a non-mitochondrial protein. In yet a third group, e.g. Parkinson's disease, Alzheimer's disease, the relationship of the mitochondrial defect to aetiology and pathogenesis is unclear.

Functional consequences of the 3460-bp mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy.

Complex I is the largest of the mitochondrial respiratory chain proteins, and contains subunits encoded by both mitochondrial and nuclear genomes. Leber's hereditary optic neuropathy has been clearly linked to mutations of mitochondrial DNA complex I genes, and variable complex I functional defects have been reported. We have confirmed an approximate 60% defect in mitochondrial NADH CoQ1 reductase activity in cultured fibroblasts bearing the 3460-bp G to A mutation within the ND1 gene. However complex I-linked ATP synthesis was found to be normal in these fibroblasts. A 60% rotenone-induced decrease in complex I activity was shown to reduce ATP synthesis in normal fibroblasts, indicating that this level of complex I activity was below the threshold required to affect ATP synthesis. Although 3460 LHON mitochondria were less sensitive to rotenone inhibition, this did not explain the decreased complex I activity as the rotenone insensitive activity was not increased, nor did the inhibitor diphenyleneiodonium inhibit the NADH CoQ1 reductase activity to a greater extent. Decreased NADH cytochrome c reductase activity in cybrids homoplasmic for the 3460 LHON mtDNA mutation confirmed that the decrease in complex I activity was not specific to the assay used and was not caused by inhibitory effects of ubiquinone analogues used in the NADH CoQ1 reductase assay. These findings have important implications for our understanding of complex I dysfunction in the pathogenesis of 3460 Leber's hereditary optic neuropathy.

The influence of nuclear background on the biochemical expression of 3460 Leber's hereditary optic neuropathy.

The role of mitochondrial DNA (mtDNA) mutations in the pathogenesis of Leber's hereditary optic neuropathy (LHON) has yet to be characterized. Several clinical features of the disease imply that nuclear genes might also be involved in its expression. We have confirmed the presence of a severe NADH:coenzyme Q1 reductase (complex I) defect in association with the A3460G mtDNA LHON mutation in cultured fibroblasts compared with age-matched controls. This defect was not seen in clonal fibroblasts with 0% mutant mtDNA developed from a heteroplasmic A3460G LHON subject, confirming the association between the A3460G mutation and the complex I defect. Cybrids prepared from the fusion of enucleated fibroblasts homoplasmic for the A3460G mutation with 206 (osteosarcoma) cells lacking mtDNA (p0) also had a severe deficiency of complex I activity. However, in A3460G LHON fusion cybrids containing a different nuclear background, A549 p0 (lung derived), this biochemical defect was not apparent in all the clones studied. These results suggest that the nuclear environment can influence the expression of the biochemical defect in LHON patients with the A3460G mutation.