Identifying patients with epilepsy at high risk of cardiac death: signs,risk factors and initial management of high risk of cardiac death

People with epilepsy have a three‐fold increased risk of dying prematurely, and a significant proportion is due to sudden cardiac death or acute myocardial infarctions. The causes of increased cardiovascular morbidity and mortality in epilepsy are manifold and include acute or remote effects of epileptic seizures, the longstanding epilepsy itself or antiseizure treatments. Seizure‐related cardiac arrhythmias are common and comprise bradyarrhythmia and asystole, atrial fibrillation and ventricular tachycardia. The most frequent clinically relevant seizure‐related arrhythmia is ictal asystole that may require implantation of a cardiac pacemaker, whereas seizure‐related ventricular tachycardias are only rarely reported. Takotsubo cardiomyopathy and myocardial infarction are rare complications and predominantly described in association with tonic‐clonic seizures. Epilepsy‐related cardiac complications include a disturbed cardiac autonomic nervous system and acquired dysfunction of the heart (recently defined as ‘epileptic heart’), probably contributing to the abnormalities of cardiac repolarisation and elevated risk of sudden cardiac death in people with epilepsy. If successful, the use of antiseizure medication prevents seizure‐related cardiac arrhythmias and remote cardiac complications. However, enzyme‐inducing antiseizure medications have a negative impact on cardiovascular risk factors, which may further be aggravated by weight gain linked to specific antiseizure drugs. Given the severe consequences of cardiac risks, the aim of this educational review is to explain the many facets of cardiac complications and their underlying causes, and to enable the reader to recognize and manage these risks with the goal to mitigate the cardiac risks in people with epilepsy. Features of syncope are explained in detail, as syncope of all origins can be mistaken as epileptic seizures in people with or without epilepsy, and ictal syncope (i.e. seizure‐induced syncope) can easily be ignored.     

Setting standards for severity of common symptoms in oncology using the PROMIS item banks and expert judgment

Background

Although the use of patient-reported outcome measures (PROs) has increased markedly, clinical interpretation of scores remains lacking. We developed a method to identify clinical severity thresholds for pain, fatigue, depression, and anxiety in people with cancer.

Methods

Using available Patient-Reported Outcomes Measurement Information System (PROMIS) item bank response data collected on 840 cancer patients, symptom vignettes across a range of symptom severity were developed and placed on index cards. Cards represented symptom severity at five-point intervals differences on the T score metric [mean = 50; standard deviation (SD) = 10]. Symptom vignettes for each symptom were anchored on these standardized scores at 0.5 SD increments across the full range of severity. Clinical experts, blind to the PROMIS score associated with each vignette, rank-ordered the vignettes by severity, then arrived at consensus regarding which two vignettes were at the upper and lower boundaries of normal and mildly symptomatic for each symptom. The procedure was repeated to identify cut scores separating mildly from moderately symptomatic, and moderately from severely symptomatic scores. Clinician severity rankings were then compared to the T scores upon which the vignettes were based.

Results

For each of the targeted PROs, the severity rankings reached by clinician consensus perfectly matched the numerical rankings of their associated T scores. Across all symptoms, the thresholds (cut scores) identified to differentiate normal from mildly symptomatic were near a T score of 50. Cut scores differentiating mildly from moderately symptomatic were at or near 60, and those separating moderately from severely symptomatic were at or near 70.

Conclusions

The study results provide empirically generated PROMIS T score thresholds that differentiate levels of symptom severity for pain interference, fatigue, anxiety, and depression. The convergence of clinical judgment with self-reported patient severity scores supports the validity of this methodology to derive clinically relevant symptom severity levels for PROMIS symptom measures in other settings.     

Complex visual hallucinations (Charles Bonnet syndrome) in visual field defects following cerebral surgery. Report of four cases

The development of visual hallucinations after loss of vision is known as the Charles Bonnet syndrome. This phenomenon was first described in 1760 by Charles Bonnet and others during their observations of elderly patients with degeneration of the retina or cornea. To date a clear association between visual hallucinations and neurosurgical procedures has not been reported. Because of their clear demarcation, however, surgical lesions in the cerebrum offer a unique opportunity to determine the pathoanatomical aspects of visual hallucinations. During a 3-year period, 41 consecutive patients who acquired visual field defects after neurosurgery were examined for the occurrence of visual hallucination. Postoperatively, four of these patients experienced visual hallucinations. In two of them an upper quadrantanopia developed after the patients had undergone selective amygdalohippocampectomy. In the other two patients a complete hemianopia developed, in one case after resection of a parietal astrocytoma and in the other after resection of an occipital glioblastoma multiforme. The visual hallucinations were transient and gradually disappeared between 4 days and 6 months postoperatively. The patients were aware of the fact that their hallucinations were fictitious and displayed no psychosis. Electroencephalographic recordings were obtained in only two patients and epileptic discharges were found. Deafferentiation of cortical association areas may lead to the spontaneous generation of complex visual phenomena. In the present series this phenomenon occurred in approximately 10% of patients with postoperative visual field defects. In all four cases the central optic radiation was damaged between the lateral geniculate nucleus and the primary visual cortex. The complex nature of the visual hallucination indicates that they were generated in visual association areas.     

Input resistance is voltage dependent due to activation of Ih channels in rat CA1 pyramidal cells

The contribution of the hyperpolarization-activated cation current (I(h)) to input resistance (R(N)) and resting potential (RP) was investigated during whole-cell patch-clamp recordings in CA1 pyramidal cells of rat hippocampal slices. In current-clamp mode, R(N) was determined at different membrane potentials. R(N) decreased with increasing hyperpolarization, from about 260 Momega to 140 Momega at potentials of about -60 mV and -110 mV, respectively. Both the potential of half-maximal reduction of R(N) and the potential of half-maximal I(h) activation (determined in voltage-clamp mode) were approximately -90 mV. The analysis of the voltage sag indicative of I(h) activation revealed a preferential activity of I(h) channels in a voltage range between -70 and -95 mV. ZD7288 (50 microM), a specific I(h) blocker, led to a hyperpolarization by about 4.8 mV, increased R(N) by approximately 45% within a potential range between -65 and -80 mV, and abolished the voltage dependence of R(N). Gabapentin (GBP, 100 microM), an I(h) channel agonist, led to a depolarization by about 2.4 mV and reduced R(N) by about 20% within a potential range between -65 and -80 mV. In conclusion, our data show that R(N) is voltage dependent due to I(h) channel activation and that I(h) channels are preferentially active at voltages between -70 and -95 mV. Furthermore, we demonstrated that R(N) can be modulated by antiepileptic drugs such as GBP, which may partly explain its antiepileptic effect as due to decreasing the sensitivity to excitatory input.     

Postictal increase in T-wave alternans after generalized tonic-clonic seizures

Purpose: Sudden unexpected death in epilepsy (SUDEP) occurs most frequently in people with chronic uncontrolled epilepsy. Tonic–clonic seizures are a well‐recognized risk factor for SUDEP. T‐wave alternans (TWA) is a novel independent marker of risk of sudden cardiac death and cardiovascular mortality. The aim of this study was to determine if the level of TWA in patients with epilepsy differed after complex‐partial and secondary generalized tonic–clonic seizures (sGTCS). Methods: Electrocardiography (ECG) and electroencephalography (EEG) data from patients with drug‐resistant focal epilepsy who had both complex partial and sGTCS during video‐EEG telemetry were retrospectively reviewed. Periictal TWA, heart rate (HR), and heart rate variability (HRV) were analyzed. Key Findings: ECG and EEG data of 16 patients (31.6 ± 8.7 years, nine male) with focal epilepsies were analyzed. sGTCS led to a postictal increase in TWA for 15 min as well as a higher postictal HR and decreased postictal HRV for the whole observation time of 30 min. There was no significant association between postictal TWA or HR and seizure duration or duration of the tonic–clonic phase. Significance: Our study demonstrates that derangements in autonomic function and TWA are highly prevalent after sGTCS in patients with chronic uncontrolled epilepsy. Further studies are warranted to investigate the value of TWA for risk stratification in epilepsy patients for sudden cardiac death and SUDEP.     

K(+)-evoked [(3)H]-norepinephrine release in human brain slices from epileptic and non-epileptic patients is differentially modulated by gabapentin and pinacidil

The modulation of K(+)-evoked [(3)H]-norepinephrine ([(3)H]-NE) release by gabapentin (GBP) and pinacidil (PIN), a known K(ATP) agonist, was examined in human brain slices. We compared the pharmacological effects on NE-release in human epileptic neocortex and epileptic hippocampus to non-epileptic neocortex. GBP (100 microM) decreased [(3)H]-NE release by 22% in non-epileptic neocortical slices, whereas this inhibition was absent in slices from epileptic hippocampus and epileptic neocortex. PIN (10 microM) also reduced [(3)H]-NE release by 30% in non-epileptic neocortical slices and only by 5% in epileptic hippocampal slices. The blockade of voltage-gated calcium channels by omega-conotoxins MVIIA and MVIIC (0.1 microM) reduced [(3)H]-NE release in epileptic and non-epileptic neocortical slices to the same extend. The data show a marked reduction in K(+)-evoked [(3)H]-NE release by GBP and PIN in epileptic hippocampus and neocortex, suggesting an alteration of K(ATP) channel function, whereas the effects of the calcium channel modulators omega-conotoxins MVIIA and MVIIC are similar in both epileptic and non-epileptic neocortex.     

K(+)-induced changes in the properties of the hyperpolarization-activated cation current I(h) in rat CA1 pyramidal cells

The effects of rises in external K(+) (K(ext)) on I(h) were investigated in CA1 pyramidal cells of rat hippocampal slices using the whole-cell patch clamp technique. At the basal K(ext) level (2.5 mM), hyperpolarization-activated cation current (I(h)) had a maximal amplitude of -350+/-60 pA which was enhanced by approximately 60 and approximately 95% at 5 and 7.5 mM K(ext), respectively. The midpoint activation voltage was significantly shifted from -80 mV in the negative direction to about -87 mV at both 5 and 7.5 mM K(ext), without appreciable alterations of the current kinetics. The maximal conductance was approximately 2.4 nS under control conditions and significantly increased to approximately 3.3 and approximately 5.6 nS at 5 and 7.5 mM K(ext), respectively. The reversal potential was shifted in the positive direction, from a control value of approximately -30 mV by approximately 6 and approximately 14 mV at 5 and 7.5 mM K(ext), respectively. Our data demonstrate that even moderate changes in K(ext) have a substantial effect on the properties of I(h).