Roland D. Thijs

Sudden unexpected death in epilepsy: risk factors and potential pathomechanisms

Sudden unexpected death in epilepsy (SUDEP) is the most common cause of death directly related to epilepsy, and most frequently occurs in people with chronic epilepsy. The main risk factors for SUDEP are associated with poorly controlled seizures, suggesting that most cases of SUDEP are seizure-related events. Dysregulation in cardiac and respiratory physiology, dysfunction in systemic and cerebral circulation physiology, and seizure-induced hormonal and metabolic changes might all contribute to SUDEP. Cardiac factors include bradyarrhythmias and asystole, as well as tachyarrhythmias and alterations to cardiac repolarization. Altered electrolytes and blood pH, as well as the release of catecholamines, modulate cardiac excitability and might facilitate arrhythmias. Respiratory symptoms are not uncommon during seizures and comprise central apnea or bradypnea, and, less frequently, obstruction of the airways and neurogenic pulmonary edema. Alterations to autonomic function, such as a reduction in heart rate variability or disturbed baroreflex sensitivity, can impair the bodys capacity to cope with challenging situations of elevated stress, such as seizures. Here, we summarize data on the incidence of and risk factors for SUDEP, and consider the pathophysiological aspects of chronic epilepsy that might lead to sudden death. We suggest that SUDEP is caused by the fatal coexistence of several predisposing and triggering factors.

Sudden unexpected death in epilepsy: People with nocturnal seizures may be at highest risk

Purpose:  Most people with epilepsy who die suddenly and whose death is attributed to sudden unexpected death in epilepsy (SUDEP) are found in or by the bed for unknown reasons. We assessed whether those with sleep‐related SUDEP were more likely to have nocturnal seizures, and whether seizure patterns (diurnal vs. nocturnal) differed from people dying suddenly and living controls with epilepsy.

A guide to disorders causing transient loss of consciousness: focus on syncope

Episodes of transient loss of consciousness (TLOC) events pose diagnostic difficulties, as the causes are diverse, carry vastly different risks, and span various specialties. An inconsistent terminology contributes to the confusion. Here, we present a classification scheme for TLOC, based on ongoing multidisciplinary efforts including those of the Task Force on Syncope of the European Society of Cardiology. We also discuss the pathophysiology of TLOC and the key clinical features that aid diagnosis. TLOC is defined as an apparent loss of consciousness with an abrupt onset, a short duration, and a spontaneous and complete recovery. Syncope is defined as TLOC due to cerebral hypoperfusion, and is divided into reflex syncope (synonymous with neurally mediated syncope), syncope due to orthostatic hypotension, and cardiac syncope (arrhythmic or associated with structural cardiac disease). The other major groups of TLOC are generalized epileptic seizures, functional TLOC (psychogenic TLOC mimicking either epilepsy or syncope), and a further group of miscellaneous disorders. The management of patients who experience TLOC requires the recognition of the defining features of each of the major groups, and cooperation between different clinical specialties.

Anti-LGI1 encephalitis: Clinical syndrome and long-term follow-up

Objective: This nationwide study gives a detailed description of the clinical features and long-term outcome of anti–leucine-rich glioma-inactivated 1 (LGI1) encephalitis. Methods: We collected patients prospectively from October 2013, and retrospectively from samples sent to our laboratory from January 2007. LGI1 antibodies were confirmed with both cell-based assay and immunohistochemistry. Clinical information was obtained in interviews with patients and their relatives and from medical records. Initial MRI and follow-up MRI were revised blindly. Neuropsychological assessment was performed in those patients with follow-up over 2 years. Results: Annual incidence in the Netherlands was 0.83/million. A total of 34/38 patients had a limbic encephalitis. Subtle focal seizures (66%, autonomic or dyscognitive) and faciobrachial dystonic seizures (FBDS, 47%) mostly occurred before onset of memory disturbance. Later in the disease course, 63% had tonic-clonic seizures. Initial MRI showed hippocampal T2 hyperintensity in 74% of the patients. These lesions evolved regularly into mesial temporal sclerosis (44%). Substantial response to immunotherapy was seen in 80%, with early response of seizures and slow recovery of cognition. At follow-up ≥2 years, most surviving patients reported mild residual cognitive deficit with spatial disorientation. A total of 86% had persistent amnesia for the disease period. Relapses were common (35%) and presented up to 8 years after initial disease. Two-year case fatality rate was 19%. Conclusions: Anti-LGI1 encephalitis is a homogenous clinical syndrome, showing early FBDS and other focal seizures with subtle clinical manifestations, followed by memory disturbances. Better recognition will lead to earlier diagnosis, essential for prompt start of treatment. Long-term outcome of surviving patients is mostly favorable, but relapses are common.

Defining and classifying syncope.

Abstract.There is no widely adopted definition or classification of syncope and related disorders. This lack of uniformity harms patient care, research, and medical education. In this article, syncope is defined as a form of transient loss of consciousness (TLOC) due to cerebral hypoperfusion. Differences between syncope and other causes of TLOC such as epilepsy, and disorders mimicking TLOC are described. A pathophysiological classification of syncope is proposed.

The relevance of VGKC positivity in the absence of LGI1 and Caspr2 antibodies

Objective: To assess the clinical relevance of a positive voltage-gated potassium channel (VGKC) test in patients lacking antibodies to LGI1 and Caspr2. Methods: VGKC-positive patients were tested for LGI1 and Caspr2 antibodies. Patients lacking both antibodies were matched (1:2) to VGKC-negative patients. Clinical and paraclinical criteria were used to blindly determine evidence for autoimmune inflammation in both groups. Patients with an inconclusive VGKC titer were analyzed in the same way. Results: A total of 1,455 patients were tested by VGKC radioimmunoassay. Fifty-six patients tested positive, 50 of whom were available to be included. Twenty-five patients had antibodies to LGI1 (n = 19) or Caspr2 (n = 6) and 25 patients lacked both antibodies. Evidence for autoimmune inflammation was present in 7 (28%) of the VGKC-positive patients lacking LGI1 and Caspr2, compared to 9 (18%) of the VGKC-negative controls (p = 0.38). Evidence for autoimmune inflammation was mainly found in patients with limbic encephalitis/encephalomyelitis (57%), but not in other clinical phenotypes (5%, p < 0.01). VGKC titers were significantly higher in patients with antibodies to LGI1 or Caspr2 (p < 0.001). However, antibodies to Caspr2 could also be detected in patients with inconclusive low VGKC titer, while many VGKC-positive patients had no evidence for autoimmune inflammation. Conclusions: VGKC positivity in the absence of antibodies to LGI1 and Caspr2 is not a clear marker for autoimmune inflammation and seems not to contribute in clinical practice. No cutoff value for the VGKC titer was appropriate to discriminate between patients with and without autoimmune inflammation.

Falls, faints, fits and funny turns

In this practically oriented review, we will outline the clinical approach of patients with falls due to an impairment or loss of consciousness. Following a set of definitions, we describe the salient clinical features of disorders leading to such falls. Among falls caused by true loss of consciousness, we separate the clinical characteristics of syncopal falls (due to reflex syncope, hypovolemia, orthostatic hypotension or cardiac syncope) from falls due to other causes of transient unconsciousness, such as seizures. With respect to falls caused by an apparent loss of consciousness, we discuss the presentation of cataplexy, drop attacks, and psychogenic falls. Particular emphasis will be laid upon crucial features obtained by history taking for distinguishing between the various conditions that cause or mimic a transient loss of consciousness.In this practically oriented review, we will outline the clinical approach of patients with falls due to an impairment or loss of consciousness. Following a set of definitions, we describe the salient clinical features of disorders leading to such falls. Among falls caused by true loss of consciousness, we separate the clinical characteristics of syncopal falls (due to reflex syncope, hypovolemia, orthostatic hypotension or cardiac syncope) from falls due to other causes of transient unconsciousness, such as seizures. With respect to falls caused by an apparent loss of consciousness, we discuss the presentation of cataplexy, drop attacks, and psychogenic falls. Particular emphasis will be laid upon crucial features obtained by history taking for distinguishing between the various conditions that cause or mimic a transient loss of consciousness.

Epilepsy is a risk factor for sudden cardiac arrest in the general population.

Background People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study. Methods and Results This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1–8.0.], p = 0.034). The risk for SCA in epilepsy was particularly increased in young and females. Conclusion Epilepsy in the general population seems to be associated with an increased risk for SCA.

Physiologic strategies to prevent fainting responses during or after whole blood donation.

Vasovagal syncope (VVS) is a consistent, but infrequent (0.1%‐0.3%) complication of volunteer, whole blood donation. Given the large number of blood donations, a significant number of donors is involved. Syncope occasionally leads to injury. Recent rigorous data collection and analysis have led to the association of a small number of donor and donation factors with the risk of syncope. An analysis of the time course of syncope reactions among approximately 500,000 whole blood donors suggests that there are three distinct periods of risk for vasovagal reactions before, during, and after phlebotomy. This review examines the physiologic mechanisms that contribute to these periods of increased risk including the direct effects of removal of approximately 500 mL of whole blood, the psychological stress of instrumentation and giving blood (i.e., fear of needles, pain, and the sight of blood), and the orthostatic effects superimposed on a hypovolemic state after the donation. Specifically, we describe interventions that have been useful in controlling VVS in patients with fainting syndromes and we examine the potential of these interventions in the blood donation context, based on the physiologic principles involved. Finally, we propose an intervention (dietary replacement of salt lost with blood donation) that has not been applied in transfusion medicine previously but which has the potential to reduce risk.

Unconscious Confusion: A literature search for definitions of syncope and related disorders

BackgroundImprecise definitions of syncope and related conditions appear common in the medical literature. To investigate the scope of the problem we systematically searched for definitions in high-ranking medical journals.MethodsLiterature review of articles on ‘syncope’, ‘neurocardiogenic syncope’, ‘neurally mediated syncope’, ‘orthostatic intolerance’, and ‘orthostatic hypotension’ with these keywords in the title, mainly published in the ten journals with the highest impact in the fields of cardiology, internal medicine, and neurology.ResultsSyncope, neurocardiogenic syncope, neurally mediated syncope, orthostatic intolerance, and orthostatic hypotension were defined in only 41%, 34%, 26%, 38%, and 48% of papers respectively. Definitions, when given, differed considerably among papers. Orthostatic hypotension was most frequently defined, with an increase in number and consistency of definitions after publication of a consensus in 1996.ConclusionsSyncope and related conditions proved to be infrequently and inconsistently defined in current medical literature. The lack of consistent terminology is likely to harm medical education, research, and patient care. There is a strong need for a systematic terminology for syncope and related conditions.