Barbara A. Dworetzky

Incidence and Mechanisms of Cardiorespiratory Arrests in Epilepsy Monitoring Units (MORTEMUS): A Retrospective Study.

BACKGROUND Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in people with chronic refractory epilepsy. Very rarely, SUDEP occurs in epilepsy monitoring units, providing highly informative data for its still elusive pathophysiology. The MORTEMUS study expanded these data through comprehensive evaluation of cardiorespiratory arrests encountered in epilepsy monitoring units worldwide. METHODS Between Jan 1, 2008, and Dec 29, 2009, we did a systematic retrospective survey of epilepsy monitoring units located in Europe, Israel, Australia, and New Zealand, to retrieve data for all cardiorespiratory arrests recorded in these units and estimate their incidence. Epilepsy monitoring units from other regions were invited to report similar cases to further explore the mechanisms. An expert panel reviewed data, including video electroencephalogram (VEEG) and electrocardiogram material at the time of cardiorespiratory arrests whenever available. FINDINGS 147 (92%) of 160 units responded to the survey. 29 cardiorespiratory arrests, including 16 SUDEP (14 at night), nine near SUDEP, and four deaths from other causes, were reported. Cardiorespiratory data, available for ten cases of SUDEP, showed a consistent and previously unrecognised pattern whereby rapid breathing (18-50 breaths per min) developed after secondary generalised tonic-clonic seizure, followed within 3 min by transient or terminal cardiorespiratory dysfunction. Where transient, this dysfunction later recurred with terminal apnoea occurring within 11 min of the end of the seizure, followed by cardiac arrest. SUDEP incidence in adult epilepsy monitoring units was 5·1 (95% CI 2·6-9·2) per 1000 patient-years, with a risk of 1·2 (0·6-2·1) per 10,000 VEEG monitorings, probably aggravated by suboptimum supervision and possibly by antiepileptic drug withdrawal. INTERPRETATION SUDEP in epilepsy monitoring units primarily follows an early postictal, centrally mediated, severe alteration of respiratory and cardiac function induced by generalised tonic-clonic seizure, leading to immediate death or a short period of partly restored cardiorespiratory function followed by terminal apnoea then cardiac arrest. Improved supervision is warranted in epilepsy monitoring units, in particular during night time. FUNDING Commission of European Affairs of the International League Against Epilepsy.

Differential effects of antiepileptic drugs on sexual function and hormones in men with epilepsy

Objective: To compare sexual function and reproductive hormone levels among men with epilepsy who took various antiepileptic drugs (AEDs), untreated men with epilepsy, and normal controls. Methods: Subjects were 85 men with localization-related epilepsy (25 on carbamazepine [CBZ], 25 on phenytoin [PHT], 25 on lamotrigine [LTG], and 10 untreated for at least 6 months [no AED]) and 25 controls. Sexual function scores (S-scores), hormone levels (bioactive testosterone, estradiol), hormone ratios (bioactive testosterone/bioactive estradiol), and gonadal efficiency (bioactive testosterone/luteinizing hormone) were compared among the five groups. Results: S-scores, bioactive testosterone levels, bioactive testosterone/bioactive estradiol, and bioactive testosterone/luteinizing hormone were significantly greater in the control and LTG groups than in the CBZ and PHT groups. Sex hormone binding globulin was significantly higher in the CBZ and PHT groups than in all other groups. S-scores were below the control range in 20% of the men with epilepsy, including 32.0% on CBZ, 24% on PHT, 20% on no AEDs, and 4% on LTG (χ2: p = 0.08 for all four groups; χ2: p = 0.02 for the three AED groups). Bioactive testosterone was below the control range in 28.2%, including 48% on CBZ, 28% on PHT, 20% on no AEDs, and 12% on LTG (χ2: p = 0.02). Among men with epilepsy who had low S-scores, 70.6% had bioactive testosterone levels below the control range as compared to 17.6% among men with normal S-scores (χ2: p < 0.0001). Among men with epilepsy who had abnormally low bioactive testosterone, 50.0% had low S-scores; among men with normal bioactive testosterone, 8.2% had low S-scores (χ2: p < 0.0001). Bioactive testosterone decline with age was significantly greater among men with epilepsy than among controls and notably greater in the CBZ and PHT groups than in the LTG and untreated groups. Conclusions: Sexual function, bioavailable testosterone levels, and gonadal efficiency in men with epilepsy who took lamotrigine were comparable to control and untreated values and significantly greater than with carbamazepine or phenytoin treatment.

The value of multichannel MEG and EEG in the presurgical evaluation of 70 epilepsy patients

OBJECTIVE To evaluate the sensitivity of a simultaneous whole-head 306-channel magnetoencephalography (MEG)/70-electrode EEG recording to detect interictal epileptiform activity (IED) in a prospective, consecutive cohort of patients with medically refractory epilepsy that were considered candidates for epilepsy surgery. METHODS Seventy patients were prospectively evaluated by simultaneously recorded MEG/EEG. All patients were surgical candidates or were considered for invasive EEG monitoring and had undergone an extensive presurgical evaluation at a tertiary epilepsy center. MEG and EEG raw traces were analysed individually by two independent reviewers. RESULTS MEG data could not be evaluated due to excessive magnetic artefacts in three patients (4%). In the remaining 67 patients, the overall sensitivity to detect IED was 72% (48/67 patients) for MEG and 61% for EEG (41/67 patients) analysing the raw data. In 13% (9/67 patients), MEG-only IED were recorded, whereas in 3% (2/67 patients) EEG-only IED were recorded. The combined sensitivity was 75% (50/67 patients). CONCLUSION Three hundred and six-channel MEG has a similarly high sensitivity to record IED as EEG and appears to be complementary. In one-third of the EEG-negative patients, MEG can be expected to record IED, especially in the case of lateral neocortical epilepsy and/or cortical dysplasia.

Phonological processing and lexical access in aphasia

This study explored the relationship between on-line processing of phonological information and lexical access in aphasic patients. A lexical decision paradigm was used in which subjects were presented auditorily with pairs of words or word-like stimuli and were asked to make a lexical decision about the second stimulus in the pair. The initial phonemes of the first word primes, which were semantically related to the real word targets, were systematically changed by one or more than one phonetic feature, e.g., cat-dog, gat-dog, wat-dog. Each of these priming conditions was compared to an unrelated word baseline condition, e.g., nurse-dog. Previous work with normals showed that even a nonword stimulus receives a lexical interpretation if it shares a sufficient number of phonetic features with an actual word in the listeners lexicon. Results indicated a monotonically decreasing degree of facilitation as a function of phonological distortion. In contrast, fluent aphasics showed priming in all phonological distortion conditions relative to the unrelated word baseline. Nonfluent aphasics showed priming only in the undistorted, related word condition relative to the unrelated word baseline. Nevertheless, in a secondary task requiring patients to make a lexical decision on the nonword primes presented singly, all aphasics showed phonological feature sensitivity. These results suggest deficits for aphasic patients in the various processes contributing to lexical access, rather than impairments at the level of lexical organization or phonological organization.

SUDDEN UNEXPECTED NEAR DEATH IN EPILEPSY: MALIGNANT ARRHYTHMIA FROM A PARTIAL SEIZURE

Cardiac arrhythmias are a well-described complication of partial seizures.1 During epileptic seizures, the most common finding is sinus tachycardia, found in up to 99% of patients in one series.2 More concerning rhythm disturbances such as bradycardia, asystole, and conduction abnormalities, while less common, have been reported in 13% of patients.2 The degree to which these rhythm disturbances contribute to sudden unexpected death in epilepsy (SUDEP) is unknown.3 We report a patient electively admitted for video-EEG monitoring who developed ventricular fibrillation requiring cardiopulmonary resuscitation (CPR) as a result of a seizure. ### Case report. A 51-year-old right-handed woman with a history of epilepsy since childhood was admitted for elective long-term video-EEG monitoring. Seizures began at age 3 and became refractory to medical treatment. At the time of admission, she reported cognitive decline and 2–3 seizures per week characterized by staring, head deviation rightward, and unresponsiveness lasting 10–15 seconds. She was taking four anticonvulsants (carbamazepine [serum level, 6.2 μg/dL], phenytoin [serum level, 15.5 μg/dL], zonisamide [serum level, 17 μg/dL], and topiramate [serum level, 0.7 μg/dL]). Past medical history …

A randomized trial of polyunsaturated fatty acids for refractory epilepsy

OBJECTIVE Though polyunsaturated fatty acids (PUFA) reduce seizures in several animal models, results have been inconsistent in humans. The goal of the present study was to assess the effectiveness of a PUFA supplement as adjunctive treatment for intractable focal or generalized epilepsy in humans. METHODS Adults with uncontrolled epilepsy were randomized to either mineral oil placebo or a PUFA supplement (eicosapentanoic acid (EPA) plus docosahexanoic acid (DHA), 2.2 mg/day in a 3:2 ratio). Following a 4-week prospective baseline and 1-week titration, subjects entered a 12-week treatment period, followed by an optional 4-week open-label phase. RESULTS Of 21 subjects (12 PUFA and 9 placebo), 0 on PUFA versus 2 on placebo had at least a 50% decrease in seizure frequency from baseline (P=0.17). Overall, seizure frequency increased 6% on PUFA and decreased 12% on placebo (P=0.21). During optional open-label administration, however, 15 of 19 subjects had fewer seizures than during baseline (P=0.02). CONCLUSIONS Based on the randomized, blinded portion of this study, the PUFA preparation used was not superior to placebo as adjunctive treatment for intractable epilepsy. It is not known whether different doses or different EPA:DHA ratios would be effective.

Phonological factors in lexical access: Evidence from an auditory lexical decision task

A group of subjects performed a lexical decision task in which target words were preceded by a number of different prime types: semantically related words, nonwords in which the initial phoneme of the semantically related word was distorted by one phonetic feature, nonwords in which the initial phoneme of the related word was distorted by more than one phonetic feature, and unrelated words. The results showed a monotonic relationship between phonetic distortion and lexical decision facilitation. Lexical access appears to take into account possible noise or distortion of the speech signal, so that a nonword stimulus that is phonetically related to an actual lexical entry is, in some sense, “normalized” and processed as an actual lexical entry.

Valproate and lamotrigine level variation with menstrual cycle phase and oral contraceptive use

Objective: To determine whether 1) combined oral contraceptive (COC) use affects serum levels of valproate (VPA) as well as lamotrigine (LTG) and 2) the naturally occurring high (mid-luteal) and low (early-mid follicular) reproductive steroid level phases of the menstrual cycle might affect antiepileptic drug levels as well. Methods: This investigation compared serum antiepileptic drug levels at two timepoints during a single menstrual cycle in four groups of women with epilepsy: 12 on VPA, 12 on VPA plus COC (VPA-COC), 12 on LTG, and 12 on LTG plus COC (LTG-COC). Results: Both VPA and LTG levels were lower (p < 0.01) on active COC than on inactive pill with median declines of 23.4% for the VPA-COC group and 32.6% for the LTG-COC group. Serum LTG levels showed a notable but not significant 31.3% median decline during the mid-luteal phase compared to the early-mid follicular phase in the non-COC group. The non-COC valproate group showed the least change of any group between the two measured timepoints with a decline of 8.3% (p = NS). Conclusions: The findings suggest that valproate (VPA), like lamotrigine (LTG), has substantially and significantly lower serum levels while women take active combined oral contraceptives as compared to inactive pills. Larger sample sizes will be required to determine whether LTG levels may drop significantly also during the luteal (high steroid) phase of natural menstrual cycles and whether VPA levels may show greater stability in levels across the phases of the menstrual cycle. AED = antiepileptic drug; BMI = basal metabolic index; COC = combined oral contraceptive; EIAED = enzyme-inducing antiepileptic drug; IGE = idiopathic generalized epilepsy; LRE = localization-related epilepsy; LTG = lamotrigine; VPA = valproate.

Progesterone vs placebo therapy for women with epilepsy: A randomized clinical trial

Objective: To assess progesterone treatment of intractable seizures in women with partial epilepsy. Methods: This randomized, double-blind, placebo-controlled, phase III, multicenter, clinical trial compared the efficacy and safety of adjunctive cyclic natural progesterone therapy vs placebo treatment of intractable seizures in 294 subjects randomized 2:1 to progesterone or placebo, stratified by catamenial and noncatamenial status. It compared treatments on proportions of ≥50% responders and changes in seizure frequency from 3 baseline to 3 treated menstrual cycles. Results: There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation (C1 level) was a significant predictor of responders for progesterone but not placebo. With increasing C1 levels, responders increased from 21% to 57% with progesterone vs 19% to 20% with placebo. Reductions in seizure frequency correlated with increasing C1 levels for progesterone but not placebo, progressing from 26% to 71% for progesterone vs 25% to 26% for placebo. A prespecified clinically important separation between progesterone and placebo responders (37.8% vs 11.1%; p = 0.037) was realized among 21.4% of women who had C1 level ≥3. Conclusion: There was no difference in the primary outcome of ≥50% responder rates between progesterone vs placebo for catamenial or noncatamenial groups. Post hoc findings suggest that the level of perimenstrual seizure exacerbation is a significant predictor of responder rate with progesterone and that progesterone may provide clinically important benefit for a subset of women with perimenstrually exacerbated seizures. Classification of evidence: This study provides Class III evidence that cyclic progesterone is ineffective in women with intractable partial epilepsy. Post hoc analysis identified a subset of women with higher levels of perimenstrual seizure exacerbation that were responsive to treatment.

Artifact and recording concepts in EEG.

Summary: Artifact is present when electrical potentials that are not brain derived are recorded on the EEG and is commonly encountered during interpretation. Many artifacts obscure the tracing, while others reflect physiologic functions that are crucial for routine visual analysis. Both physiologic and nonphysiologic sources of artifact may act as source of confusion with abnormality and lead to misinterpretation. Identifying the mismatch between potentials that are generated by the brain from activity that does not conform to a realistic head model is the foundation for recognizing artifact. Electroencephalographers are challenged with the task of correct interpretations among the many artifacts that could potentially be misleading, resulting in an incorrect diagnosis and treatment that may adversely impact patient care. Despite advances in digital EEG, artifact identification, recognition, and elimination are essential for correct interpretation of the EEG. The authors discuss recording concepts for interpreting EEG that contains artifact.