VGKC complex antibodies in epilepsy: Diagnostic yield and therapeutic implications

PurposeIn a significant number of patients developing epilepsy in adult life, the aetiology of their seizures remains unclear. Antibodies directed against the voltage gated potassium channel complex (VGKC Ab) have been identified in various cohorts of patients with epilepsy, although the role of these antibodies in epilepsy pathogenesis is not fully known.MethodWe reviewed the notes of 144 patients with unexplained adult onset epilepsy who had been tested for VGKC Abs. We collected data on their clinical syndrome, investigation results and response to treatment.ResultsWe identified 6 (4.2%) patients who had titres of >400 pM. One of the six patients was positive for LGI1 and another for CASPR2 subunit antibodies. All patients were given immunotherapy and experienced improvement in seizure control. No patient had the clinical syndrome of limbic encephalitis.ConclusionPatients with otherwise unexplained epilepsy and positive VGKC Abs are a heterogeneous group. In our cohort there was an overall favourable response to immunotherapy but further prospective studies are needed to determine the significance of these antibodies and the optimum treatment regimen for patients.     

GABRB3-related epilepsy: novel variants,clinical features and therapeutic implications

Journal of Neurology - This study aimed to comprehensively examine the genetic and phenotypic aspects of GABRB3-related epilepsy and to explore the potential prospects of personalized medicine....     

Reflex epilepsy and nonketotic hyperglycemia in the elderly: a specific neuroendocrine syndrome

We present five elderly patients with focal reflex or posture-induced seizures and nonketotic hyperglycemia (NKH). Each patient exhibited interictal focal findings, such as hemiparesis or hemisensory or aphasic deficits. With control of the hyperglycemia, the seizures stopped, and the neurologic deficits resolved. The syndrome of focal reflex epilepsy and neurologic deficits in the elderly is transient and almost invariably related to NKH, thus representing a specific neuroendocrine syndrome.     

Neuropsychiatric issues after stroke: Clinical significance and therapeutic implications

A spectrum of neuropsychiatric disorders is a common complication from stroke. Neuropsychiatric disorders after stroke have negative effects on functional recovery, increasing the rate of mortality and disability of stroke survivors. Given the vital significance of maintaining physical and mental health in stroke patients, neuropsychiatric issues after stroke have raised concerns by clinicians and researchers. This mini-review focuses on the most common non-cognitive functional neuropsychiatric disorders seen after stroke, including depressive disorders, anxiety disorders, post-traumatic stress disorder, psychosis, and psychotic disorders. For each condition, the clinical performance, epidemiology, identification of the therapeutic implication, and strategies are reviewed and discussed; the main opinions and perspectives presented here are based on the latest controlled studies, meta-analysis, or updated systematic reviews. In the absence of data from controlled studies, consensus recommendations were provided accordingly.     

老年性癫痫的循证治疗

目的评价不同抗癫痫药物治疗方案对老年性癫痴的治疗效果及不良反应,以为老年性癫痂的循证治疗制定最佳方案。方法以elderlyepilepsy（老年性癫痫）、drugtherapy（药物治疗）、evidence．basedmedicine（循证医学）等英文词组作为检索词,分别检索PubMed、Cochrane图书馆、MEDLINE等数据库,并辅助手工检索获得临床指南、系统评价、随机对照临床试验、临床对照试验、回顾性病例分析及病例观察研究等方面的相关文献,采用Jadad量表对文献质量进行评价。结果经筛选共纳入与老年性癫痫治疗有关的临床指南1篇、系统评价14篇、随机对照临床试验1篇、临床对照试验2篇和回顾性病例分析2篇;根据Jadad量表质量评价标准,15篇为高质量文献（评分≥4分）、5篇为低质量文献（评分〈4分）。经对各项临床试验的治疗原则、不同治疗方法获得的疗效及药物安全性评价显示：（1）抗癫痂药物是治疗老年性癫痫的主要方法。（2）第二代抗癫痫药物的疗效并未优于第一代,但具有不良反应小、无药物间相互作用、安全性与耐受性高等优势。（3）一线抗癫痫药物推荐选择拉莫三嗪、左乙托西坦、加巴喷丁,其次为托吡酯和丙戊酸钠。由于受到老年性癫痫患者共患病多、长期多药治疗等因素的影响,应采取个体化治疗方案。（4）新发癫疝患者首选单药治疗,以低剂量给药、缓慢加量、延长给药间隔、改善依从性为治疗原则。结论借助循证医学的评价方法可以为老年性癫痫患者提供最佳临床证据。     

老年性癫痫的循证治疗

目的评价不同抗癫癎药物治疗方案对老年性癫癎的治疗效果及不良反应,以为老年性癫癎的循证治疗制定最佳方案。方法以elderly epilepsy(老年性癫癎)、drug therapy(药物治疗)、evidence-based medicine(循证医学)等英文词组作为检索词,分别检索PubMed、Cochrane图书馆、MEDLINE等数据库,并辅助手工检索获得临床指南、系统评价、随机对照临床试验、临床对照试验、回顾性病例分析及病例观察研究等方面的相关文献,采用Jadad量表对文献质量进行评价。结果经筛选共纳入与老年性癫癎治疗有关的临床指南1篇、系统评价14篇、随机对照临床试验Ⅰ篇、临床对照试验2篇和回顾性病例分析2篇;根据Jadad量表质量评价标准,15篇为高质量文献(评分≥4分)、5篇为低质量文献(评分<4分)。经对各项临床试验的治疗原则、不同治疗方法获得的疗效及药物安全性评价显示:(1)抗癫癎药物是治疗老年性癫癎的主要方法。(2)第二代抗癫癎药物的疗效并未优于第一代,但具有不良反应小、无药物间相互作用、安全性与耐受性高等优势。(3)一线抗癫癎药物推荐选择拉莫三嗪、左乙拉西坦、加巴喷丁,其次为托吡酯和丙戊酸钠。由于受到老年性癫癎患者共患病多、长期多药治疗等因素的影响,应采取个体化治疗方案。(4)新发癫癎患者首选单药治疗,以低剂量给药、缓慢加量、延长给药间隔、改善依从性为治疗原则。结论借助循证医学的评价方法可以为老年性癫癎患者提供最佳临床证据。     

Epileptic drop attacks in partial epilepsy: clinical features, evolution, and prognosis

OBJECTIVES—Sudden falls have been described inpatients with partial epilepsy. However, no study has detailed theclinical, EEG, and evolutive features of partial epilepsies with drop attacks.
METHODS—In a consecutive series of 222 patientswith partial epilepsy admitted for uncontrolled seizures over a 10 yearperiod, 31patients presented with epileptic drop attacks duringevolution of their illness. Twenty two patients had frontal, fivetemporal, and four multifocal or undefinable lobe epilepsy; 74% of thecases showed an EEG pattern of secondary bilateral synchrony during evolution. A statistical comparison of some clinical and EEG features between the patients with epileptic drop attacks and patients withpartial epilepsy without drop attacks (control group of 191patients)was carried out.
RESULTS—Seventy four per cent of patients had apoor prognosis and 45% were mentally retarded; 52% of patients withepileptic drop attacks continued to have epileptic falls associatedwith partial seizures and mental deterioration at the end of the followup. These characteristics of patients with epileptic drop attacks weresignificantly different from the control group.
CONCLUSION—Almost all literature reports concurthat the physiopathogenetic substrate of epileptic drop attacks is amechanism of secondary bilateral synchrony. A localised epileptic focusmay lead to a process of secondary epileptogenesis involving the wholebrain, causing a progressive cerebral disturbance with worsening of the epileptic seizures and higher cerebral functions.

     

Glutamic acid decarboxylase (GAD) antibodies in epilepsy: Diagnostic yield and therapeutic implications

PurposeThe aetiology of adult onset epilepsy remains unascertained in a significant proportion of patients. Antibodies directed against neuronal antigens have been suggested to have a potential pathogenic role in some cases of epilepsy. We describe a series of patients with adult onset epilepsy in whom antibodies to glutamic acid decarboxylase (GAD Abs) have been identified.MethodsAll patients attending a regional epilepsy service with unexplained adult onset epilepsy’ were tested for the presence of GAD Abs. Those with high serum titres underwent CSF analysis, and were offered additional treatment with immunotherapy. Those who underwent immunotherapy were monitored by monthly review. Clinical details and response to treatment was collated by review of notes.ResultsOf 112 patients tested, high serum titres were found in 6 (5.4%) patients. These patients had clinical and electroencephalographic evidence of focal epilepsy. CSF analysis revealed oligoclonal bands and intrathecal GAD Abs in all patients. Five patients received immunotherapy. No improvement in seizures was observed in any. One patient with equivocal MRI evidence of hippocampal sclerosis and concordant video EEG and PET scan, achieved 12 months seizure freedom following temporal lobectomy.ConclusionsThe relevance of GAD Abs to epilepsy remains uncertain. Our experience does not support the routine use of immunotherapy in patients with epilepsy and GAD Abs. Larger studies enrolling greater numbers of patients are required to identify sufficient numbers of patients for controlled treatment trials.     

Emergency psychiatry in the general hospital: Staffing, training, and leadership issues

Psychiatric services in general medical hospitals have increased in the past two decades. More and more, emergency services are being used for less urgent problems, and have created difficulties in health care delivery for all physicians. This is especially true for psychiatrists, since emergency psychiatric care is more time- and staff-intensive, and the need for it is unpredictable. The important issues of staffing, training, and the need for creative leadership for emergency psychiatric services are discussed.     

Understanding hippocampal sclerosis in the elderly: Epidemiology,characterization, and diagnostic issues

Hippocampal sclerosis (HS) is a pathologic term used to describe severe loss of neurons and reactive gliosis without cystic cavitation in the CA1 sector of the hippocampus. In late life, HS is associated with hippocampal atrophy, severe amnesia, and slowly progressive dementia without clinical seizure activity. HS is difficult to distinguish clinically from Alzheimer’s disease and is often diagnosed postmortem. In autopsy series, HS may be found without significant other pathology (2%–4% of cases), but it occurs frequently in combination with other vascular and neurodegenerative disorders (12%–20% of cases). HS is found bilaterally in 50% of cases and unilaterally in 50% of cases, with similar predilection for the right versus left hemisphere. The pathogenesis of HS is unknown and may be multifactorial in origin, possibly due to anoxic/ischemic injury or TDP-43-related neurodegeneration. Little is known about the prevention and treatment of late-life HS, although circumstantial evidence suggests the importance of identifying and treating vascular risk factors.     

Cytokines and depression: findings, issues, and treatment implications

Depression has traditionally been classified as a disorder of the brain and CNS, with behavioural manifestations which comprise its symptomatology. That symptomatology includes a range of behaviours that also occur during certain immunological responses to pathogens, and this relationship has engendered a large research literature focussed upon the links between cell messenger cytokines and depression. However, despite many studies of those links, the precise contribution that cytokines make to the development of depression remains unclear. In order to explicate the current state of knowledge of this contribution, a review of literature reviews reported during the last five years, plus a sample of empirical studies reported during the last three years, was conducted. Results indicate that there are many plausible pathways between cytokine responses to pathogens and depression, most notably via 'sickness behaviour', which supports a model of depression as withdrawal behaviour instigated by the brain and that is based upon primitive responses to uncontrollable and life-threatening environmental challenges. However, the precise nature of the mechanisms by which various cytokines communicate with brain regions and influence functions that are trophic to depressive symptomatology remains to be explicated.     

Pharmacotherapy of epilepsy: new armamentarium, new issues.

Since 1990 there have been over ten antiepileptic drugs (AEDs) approved for the therapy of epilepsy. These agents have a new spectrum of efficacy and novel adverse effects, some totally unexpected. They also represent an enormous escalation of costs. Few have been subjected to head-to-head comparisons in monotherapy against established AEDs. The aim of therapy is to eliminate rather than to reduce seizure manifestations. Many traditional agents have been phased out due to poor tolerability. New epilepsy syndromes and genetic contributions to epilepsy have been refined. Special considerations apply to various classes of sufferers such as the elderly, women of childbearing age, and sufferers with concomitant disorders, treated with medications capable of drug interactions. There is a recognition of the value of slow introduction, a preference for monotherapy, recognition of the effects of AEDs on hormones and reproductive function and effects on the fetus exposed to AEDs in utero, comprising physical malformations and effects on cognitive development. A balance between efficacy and safety is pivotal, as every preference about the initial pharmacotherapy of epilepsy and subsequent polytherapy has its protagonists. With improvement in diagnostic techniques and new therapeutic modalities it is likely that in the future, pharmacogenomics and an understanding of pharmacoresistance may influence drug selection for individual patients with epilepsy.     

Intractable epilepsy: management and therapeutic alternatives

More than half of patients with newly diagnosed epilepsy achieve complete seizure control without major side-effects. Patients who continue to have seizures after initial medical therapy should have an early and detailed assessment to confirm the diagnosis, to determine the underlying cause and epilepsy syndrome, and to choose an adequate treatment strategy. The risks and potential benefits of surgical procedures or experimental therapy have to be weighed against the chance of improvement and the potential side-effects of additional medical therapy. Surgery for temporal lobe epilepsy, the most common cause of focal epilepsy, can control seizures and improve quality of life in appropriately selected patients. However, around 20-30% of patients do not respond to medical or surgical treatment. The management of chronic intractable epilepsy requires comprehensive care to address the adverse events of medical treatment, quality of life issues, and comorbid disorders. Much research focuses on the experimental treatment options that offer hope of seizure reduction or cure.     

Atherosclerosis in epilepsy: Its causes and implications

Evidence from epidemiological, longitudinal, prospective, double-blinded clinical trials as well as case reports documents age-accelerated atherosclerosis with increased carotid artery intima media thickness (CA–IMT) in patients with epilepsy. These findings raise concern regarding their implications for age-accelerated cognitive and behavioral changes in midlife and risk of later age-related cognitive disorders including neurodegenerative processes such as Alzheimer's disease (AD). Chronic epilepsy, cerebral atherosclerosis, and age-related cognitive disorders including AD share many clinical manifestations (e.g. characteristic cognitive deficits), risk factors, and structural and pathological brain abnormalities. These shared risk factors include increased CA–IMT, hyperhomocysteinemia (HHcy), lipid abnormalities, weight gain and obesity, insulin resistance (IR), and high levels of inflammatory and oxidative stresses. The resulting brain structural and pathological abnormalities include decreased volume of the hippocampus, increased cortical thinning of the frontal lobe, ventricular expansion and increased white matter ischemic disease, total brain atrophy, and β-amyloid protein deposition in the brain. The knowledge that age-accelerated atherosclerosis may contribute to age-accelerated cognitive and behavioral abnormalities and structural brain pathologies in patients with chronic epilepsy represents an important research path to pursue future clinical and management considerations.     

Management of epilepsy in the elderly

Epilepsy among the elderly is a frequently occurring pathology, differing in etiology, clinical presentation and prognosis from those of young people. In addition, beyond a certain age, physiological modifications are produced in the metabolism which alter the pharmacokinetics of antiepileptic drugs (AEDs), increasing the risk of pharmacological interactions, already greater in these patients due to the frequency of polypharmacy. Furthermore, elderly patients are particularly sensitive to certain secondary effects of AEDs, as for example, cognitive disturbances, osteoporosis or weight increase. Given that the efficacy of the major AEDs is a priori quite similar, and that the epilepsies occurring in this age-group generally have a good prognosis, the selection of an AED will depend more upon its pharmacokinetics and ability to induce certain secondary effects than on its efficacy. In this respect, levetiracetam and pregabalin, followed by oxcarbazepine and lamotrigine have the most favorable pharmocokinetical profile. Moreover, on the whole these drugs have very few cognitive effects, do not induce osteoporosis and, with the exception of pregabalin, do not affect weight, making them the first selection for use in the treatment of epilepsy in the elderly.