Markus Leitinger

Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit

INTRODUCTION In refractory status epilepticus (SE), because of subcellular maladaptive changes, GABAergic drugs are no longer effective, and the excitatory neurotransmitter glutamate (Glu) plays a major role in seizure perpetuation. Perampanel (PER, licensed since 09/2012) is the first orally active noncompetitive AMPA receptor antagonist for adjunctive treatment of refractory focal epilepsy. METHODS We analyzed treatment response, seizure outcome, and adverse effects of add-on treatment with perampanel in patients with refractory status epilepticus in the Neurological Intensive Care Unit (NICU), Salzburg, Austria between 09/2012 and 11/2014 by retrospective chart review. RESULTS Twelve patients (75% women) with refractory status epilepticus were treated with PER administered per nasogastric tube between 09/2012 and 11/2014. Median age was 75 years [range: 60-91]. The most frequent SE type was nonconvulsive SE (NCSE) with (5/12, 42%) and without coma (6/12, 50%). In seven patients (58%), SE arose de novo, with an acute symptomatic cause in five patients (42%). Cerebrovascular diseases (4/12, 33%) and cerebral tumors (4/12, 33%) were the most common etiologies. Perampanel was given after a median number of four antiepileptic drugs [range: 2-7] and a median time of 1.5 days [range: 0.8-18.3]. In one patient (8%), clinical improvement was observed within 24h and EEG improvement within 60 h after administration of PER, while in another patient (8%), clinical and EEG improvement was observed more than 48 h after administration. Median initial dose was 4 mg [range: 2-12; SD: 4.11], titrated up to a median of 12 mg [range: 4-12] in steps of 2 to 4 mg per day. No adverse effects were reported regarding cardiorespiratory changes or laboratory parameters. Outcomes after SE were moderate disability in five patients (42%), death in three patients (25%), and persistent vegetative state in two patients (17%). CONCLUSION Though glutamate plays a major role in seizure perpetuation, the noncompetitive AMPA receptor antagonist PER could only ameliorate seizure activity in a few patients with refractory SE. The long duration of SE before the administration of PER via nasogastric tube, as well as relatively low doses of PER, might be responsible for the modest result. Perampanel was well tolerated, and no adverse events were reported. This article is part of a Special Issue entitled Status Epilepticus.

Diagnostic accuracy of the Salzburg EEG criteria for non-convulsive status epilepticus: a retrospective study

BACKGROUND Several EEG criteria have been proposed for diagnosis of non-convulsive status epilepticus (NCSE), but none have been clinically validated. We aimed to assess the diagnostic accuracy of the EEG criteria proposed by a panel of experts at the fourth London-Innsbruck Colloquium on Status Epilepticus in Salzburg, 2013 (henceforth called the Salzburg criteria). METHODS We did a retrospective, diagnostic accuracy study using EEG recordings from patients admitted for neurological symptoms or signs to three centres in two countries (Danish Epilepsy Centre, Dianalund, Denmark; Aarhus University Hospital, Aarhus, Denmark; and Paracelsus Medical University, Salzburg, Austria). Participants were included from the Danish centres if they were aged 4 months or older, and from the Austrian centre if aged 18 years or older. Participants were sorted into two groups: consecutive patients under clinical suspicion of having NCSE (the clinical validation group) or consecutive patients with abnormal EEG findings but no clinical suspicion of NCSE (the control group). Two raters blinded to all other patient data retrospectively analysed the EEG recordings and, using the Salzburg criteria, categorised patients as in NCSE or not in NCSE. By comparing with a reference standard inferred from all clinical and para-clinical data, therapeutic response, and the final outcome, we calculated sensitivity, specificity, overall diagnostic accuracy, positive and negative predictive values, and inter-rater agreement for the Salzburg criteria. The reference standard was inferred by two raters who were blinded to the scorings of the Salzburg criteria. FINDINGS We retrospectively reviewed EEG data from 220 patients. EEGs in the clinical validation group were recorded in 120 patients between Jan 1, and Feb 28, 2014 (Austria), and Aug 1, 2014, and Jan 31, 2015 (Denmark). EEGs in the control group were recorded in 100 patients between Jan 13 and Jan 22, 2014 (Austria) and Jan 12 and Jan 26, 2015 (Denmark). According to the reference standard, 43 (36%) of the 120 patients in the validation group had NCSE. In the validation cohort sensitivity was 97·7% (95% CI 87·9-99·6) and specificity was 89·6% (80·8-94·6); overall accuracy was 92·5% (88·3-97·5). Positive predictive value was 84·0% (95% CI 74·1-91·5) and negative predictive value was 98·6% (94·4-100). Three people in the control group (n=100) fulfilled the Salzburg criteria and were therefore false positives (specificity 97·0%, 95% CI 91·5-99·0; sensitivity not calculable). Inter-rater agreement was high for both the Salzburg criteria (k=0·87) and for the reference standard (k=0·95). Therapeutic changes occurred significantly more often in the group of patients fulfilling Salzburg criteria (42 [84%] of 50 patients) than in those who did not (11 [16%] of 70; p<0·0001). INTERPRETATION The Salzburg criteria for diagnosis of NCSE have high diagnostic accuracy and excellent inter-rater agreement, making them suitable for implementation in clinical practice. FUNDING None.

Pharmacologic treatment of status epilepticus

ABSTRACT Introduction: Status epilepticus (SE) requires rapid identification of its cause and urgent pharmacological treatment. Despite an estimated incidence of up to 61 per 100,000 per year, evidence from high-class clinical trials is only available for the early stages of SE. Areas covered: Following a four-stage approach of SE (early, established, refractory and super-refractory), we present pharmacological treatment options and their clinical utility. Expert opinion: Intravenous lorazepam and intramuscular midazolam appear as most effective treatments for early SE. In children, buccal midazolam has emerged as first-line non-intravenous drug with similar efficacy and safety to other intravenous or rectal benzodiazepines. In established SE intravenous antiepileptic drugs are in use. There are no double-blind, but six randomized open studies with valproate and two with levetiracetam. A meta-analysis found higher rates of seizure cessation with valproate 75.7% (95% CI 63.7–84.8) and phenobarbital 73.6%, (95% CI 58.3–84.8) than with levetiracetam (68.5%, 95% CI 56.2–78.7) or phenytoin (50.2%, 95% CI 34.2–66.1). Based on the favourable tolerability profile of levetiracetam and valproate, the authors prefer these drugs in established SE over phenytoin. Treatment options in refractory SE are intravenous anaesthetics. In super-refractory SE ketamine, magnesium, steroids and other drugs have been used with variable outcomes. At this stage therapeutic decisions are based on doctors’ preferences, patient factors such as age and comorbidity, and cause of SE, if identified.

Mortality, morbidity and refractoriness prediction in status epilepticus: Comparison of STESS and EMSE scores

PURPOSE Status epilepticus (SE) is a neurological emergency, characterized by high short-term morbidity and mortality. We evaluated and compared two scores that have been developed to evaluate status epilepticus prognosis: STESS (Status Epilepticus Severity Score) and EMSE (Epidemiology based Mortality score in Status Epilepticus). METHODS A prospective observational study was performed on consecutive patients with SE admitted between September 2013 and August 2015. Demographics, clinical variables, STESS-3 and -4, and EMSE-64 scores were calculated for each patient at baseline. SE drug response, 30-day mortality and morbidity were the outcomes measure. RESULTS 162 episodes of SE were observed: 69% had a STESS ≥3; 34% had a STESS ≥4; 51% patients had an EMSE ≥64. The 30-days mortality was 31.5%: EMSE-64 showed greater negative predictive value (NPV) (97.5%), positive predictive value (PPV) (59.8%) and accuracy in the prediction of death than STESS-3 and STESS-4 (p<0.001). At 30 days, the clinical condition had deteriorated in 59% of the cases: EMSE-64 showed greater NPV (71.3%), PPV (87.8%) and accuracy than STESS-3 and STESS-4 (p<0.001) in the prediction of this outcome. In 23% of all cases, status epilepticus proved refractory to non-anaesthetic treatment. All three scales showed a high NPV (EMSE-64: 87.3%; STESS-4: 89.4%; STESS-3: 87.5%) but a low PPV (EMSE-64: 40.9%; STESS-4: 52.9%; STESS-3: 32%) for the prediction of refractoriness to first and second line drugs. This means that accuracy for the prediction of refractoriness was equally poor for all scales. CONCLUSIONS EMSE-64 appears superior to STESS-3 and STESS-4 in the prediction of 30-days mortality and morbidity. All scales showed poor accuracy in the prediction of response to first and second line antiepileptic drugs. At present, there are no reliable scores capable of predicting treatment responsiveness.

Two-year real-world experience with perampanel in patients with refractory focal epilepsy: Austrian data

Background: The aim of this study was to analyse registry data of seizure outcome and adverse events (AEs) for perampanel as add-on therapy in patients with focal epilepsy since its approval in 2012 for adjunctive treatment of focal epilepsy in patients ⩾12 years. Method: A retrospective 2-year chart review of all patients receiving perampanel was carried out. Results: A total of 122 patients received perampanel [median treatment length: 20.1 (range: 3.4–26.8) months]; 71 (58%) remained on treatment at last follow up. Overall, 33 patients (27%) were seizure-free for ⩾3 months at last follow up; of these, eight were seizure free for ⩾3 times the longest interictal interval before perampanel therapy; 18 (15%) had reduced seizure frequency ⩾50%. A total of 58 (47%) had an AE and 34 (28%) withdrew from treatment because of AEs. AEs included dizziness (33%), fatigue (12%), psychiatric symptoms (8%), cognitive deficits (7%), speech problems (5%), nausea (4%) and gait problems (4%). AEs subsided in 17/18 patients (94%) following a 2 mg dose reduction. A total of 43 (35%) took a concomitant enzyme inducer. Patients not taking enzyme inducers were more likely to be seizure free (p = 0.002); there were no other between-group differences. Conclusions: Perampanel was well tolerated and improved seizure control in 42% of patients (50– 100% reduction), with higher rates in those not receiving a concomitant enzyme inducer. AEs, particularly dizziness, were common but often disappeared with a slight dose reduction. The results are consistent with those from randomized controlled trials.

Perampanel for the treatment of primary generalized tonic-clonic seizures in idiopathic generalized epilepsy

ABSTRACT Introduction: The non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) – receptor antagonist perampanel (PER) was approved in 2015 for treatment of primary generalized tonic-clonic seizures (pGTCS). The aim of this narrative review is to summarize available data on pharmacological properties, efficacy and tolerability of PER in pGTCs. Areas covered: Data sources included MEDLINE, EMBASE, Google Scholar and ClinicalTrials.gov, conference proceedings of the ILAE congresses and the most recent conference proceedings of the American Epilepsy Society (2013 to 2015). Expert opinion: A placebo-controlled clinical phase III study including 164 patients (≥ 12 years) with pGTCS in idiopathic generalized epilepsies (IGE) demonstrated efficacy of PER in reducing pGTCS with good tolerability profile, and without aggravating absence seizures or myoclonic seizures. Dizziness, the main adverse event (AE), can be avoided by bedtime administration. Psychiatric AEs ranging from mild depression to aggression and suicidal attempts should be especially monitored in patients with a history of psychiatric disorders. Co-administration of enzyme inducing antiepileptic drugs (AEDs) might decrease PER plasma levels and make dose adjustment necessary. A reduced efficacy of progesterone-containing oral contraceptives should be considered when administering PER to young women. There is lack of evidence on PER treatment in pregnancy. Although no teratogenic effects were observed in animal models, PER is not recommended for women of childbearing age without contraception.

Ergänzungen zur prächirurgischen Diagnostik bei Epilepsiepatienten

Mit großer Freude und hohem Interesse haben wir die Schwerpunktausgabe „Epilepsiechirurgie“ der Zeitschrift für Epileptologie (Bd. 29, Heft 3 September 2016) gelesen. Insbesondere zu den praxisrelevanten Aspektenmöchten wir herzlich gratulieren. Dennoch waren wir erstaunt, dass im Artikel über die aktuelle prächirurgische Diagnostik 3 wesentliche Dinge aus unserer Sicht völlig unerwähnt geblieben sind. 1. Seit 16 Jahren gibt es konsensbasierte Qualitätsleitlinien für prächirurgische Epilepsiediagnostik und operative Epilepsietherapie, die auch international publiziert wurden. Diese trinationalen Leitlinien finden auch international große Beachtung [7, 8]. Darin werden nicht nur die Anzahl der Eingriffe und die Mindestausstattung an Personal definiert, sondern auch die technische Ausstattung, die an epilepsiechirurgisch tätigen Zentren vorgehalten werden muss, um die nötigen Qualitätskriterien, aber auch die Sicherheitsaspekte zu erfüllen. In Österreich wurden diese Kennzahlen sogar in die Neufassung des Strukturplans Gesundheit 2016/17 mit einbezogen. In den Qualitätsleitlinien wird auch ganz wesentlich auf den Sicherheitsaspekt in Epilepsiemonitoringeinheiten hingewiesen. Diesen relevanten Aspekt der Patientensicherheit haben wir im Artikel von G. Leonhardt völlig vermisst. 2. In Epilepsiemonitoringeinheiten werden die Patienten bewusst aufgenommen, um, meist unter Medikamentenreduktion, Anfälle zu erzielen, aufzunehmen und zu analysieren. Dabei kann es nicht nur zu Verletzungen und Stürzen führen, sondern auch zu Stati epileptici oder periiktalen Psychosen. Somit hat das Video-EEG-Monitoring auch erhebliche Nebenwirkungen. Die Nebenwirkungsrate lag in einer Innsbrucker Untersuchung bei 9% [3]. Leider wird dieser Aspekt viel zu wenig berücksichtigt, was sich in einer rezenten Erhebung an europäischen Referenzzentren (E-PILEPSY; [10]) für prächirurgische Epilepsiediagnostik zeigt. Dabei war in 19% der 25 Zentren keine kontinuierliche 24/7-Überwachung vorhanden, 44% der Zentren erheben keine schriftliche Einverständniserklärung der Patienten und spezifische Sicherheitsprotokolle lagen nur in etwas mehr als der Hälfte der Zentren vor [4]. Es ist nicht nur der Patientensicherheit sondern auch den Qualitätsstandards einer leistungsorietierten Krankenhausfinanzierung (DRG oder LKF) geschuldet, entsprechende Strukturqualitätskriterien einzuhalten und an die Refundierung zu binden. Eine Diskussion dieses wichtigen Aspektes hätten wir für angebracht erachtet. 3. In der Auflistung der Untersuchungstechniken haben wir die mittlerweile gut etablierte Magnetenzephalographie und die damit durchgeführte Quellenlokalisation vermisst. Die MEG ist bereits in den Qualitätsleitlinien angeführt [7, 8]. Bereits ein Drittel aller europäischen Referenzzentren im Epilepsienetzwerk verwenden die MEG mit Quellenlokalisation als Standarduntersuchung im Rahmen der prächirurgischen Diagnostik [6]. Die in dem Positionspapier der American Clinical MEGSociety [1, 2] und in rezenten Übersichtsarbeiten zusammengefassten Daten über die klinische Wertigkeit des MEG (z. B. [5, 9]) in der prächirurgischen Diagnostik sollten daher in einer Übersichtsarbeit in der Zeitschrift für Epileptologie auf keinen Fall fehlen.

Ictal unilateral eye blinking and contralateral blink inhibition — A video-EEG study and review of the literature

Introduction There is limited information on ictal unilateral eye blinking (UEB) as a lateralizing sign in focal seizures. We identified two patients with UEB and propose a novel mechanism of UEB based on a review of the literature. Materials and methods We report on two patients with intractable focal epilepsy showing UEB among 269 consecutive patients undergoing noninvasive video-EEG monitoring from October 2011 to May 2013. Results Unilateral eye blinking was observed in 0.7% (two of 269) of our patients. Patient one had four focal seizures. Semiological signs in all of her seizures were impaired consciousness, bilateral eye blinking (BEB), and UEB on the right. During one seizure, BEB recurred after UEB with a higher blink frequency on the right. Patient two had ten focal seizures. Among them were one electrographic seizure and nine focal seizures with BEB (in 3/10) and UEB on the left (in 1/10 seizures, respectively). Both patients did not display any clonic activity of the face. In seizures with UEB, ictal EEG onset was observed over the ipsilateral frontotemporal region in both of the patients (over F8 in 2/4, Fp2-F8 in 1/4, Sp2-T2 in 1/4, and F7 in 1/1 seizures, respectively). Ictal pattern during UEB showed bilateral ictal activity (in 4/4) and ictal discharges over the ipsilateral frontal region (maximum over F3 in 1/1 seizure). Interictal EEG showed sharp waves over the same regions. Discussion Unilateral eye blinking was ipsilateral to the frontotemporal ictal EEG pattern in both patients. The asymmetric blink frequency during BEB in patient one leads to the hypothesis that ictal UEB is caused by contralateral blink inhibition due to activation in frontotemporal cortical areas and mediated by trigeminal fibers.

Fatal Necrotizing Encephalopathy after Treatment with Nivolumab for Squamous Non-Small Cell Lung Cancer: Case Report and Review of the Literature

Immune checkpoint inhibitors are antibodies, which enhance cellular and humoral immune responses and are approved for the treatment of various tumors. Immune-related adverse events (irAE) involving different organs and systems are, however, among the side-effects. Recent reports of severe persistent neurological deficits and even fatal cases underpin the need for better understanding of the exact pathomechanisms of central nervous system (CNS) toxicity. To our knowledge, we report the first biopsy-proven case of fatal necrotizing encephalopathy after treatment with nivolumab. Nivolumab targets the immune-check point inhibitor programmed cell death-1 and was used for squamous non-small cell lung cancer. Partly reversible neurologic and psychiatric symptoms and unremarkable brain magnetic resonance imaging (MRI) were observed after the first course. Neurological symptoms progressed and recurrent seizures developed after the second course. Brain MRI disclosed multiple edematous and confluent supra- and infratentorial lesions, partly with contrast-enhancement. We excluded autoimmune and paraneoplastic causes and performed ancillary investigations to rule out common and opportunistic infections. Eventually, postmortem histopathological analysis of the brain revealed a necrotizing process, which contrasts previous cases reporting parenchymal immune cell infiltration or demyelination. Appropriate diagnostic pathways and treatment algorithms need to be implemented for the work-up of CNS toxicity and irAEs related to immune checkpoint inhibitor treatment.

Perampanel in patients with refractory and super-refractory status epilepticus in a neurological intensive care unit: A single-center audit of 30 patients

In refractory status epilepticus (SE), γ‐aminobutyric acidergic drugs become less effective and glutamate plays a major role in seizure perpetuation. Data on the efficacy of perampanel (PER) in treatment of refractory SE in humans are limited. Here, we present a single‐center case series of patients with refractory SE who received PER orally in an intensive care unit. We retrospectively analyzed treatment response, outcome, and adverse effects of all patients with refractory SE in our Neurological Intensive Care Unit who received add‐on PER between September 2012 and February 2018. Thirty patients with refractory SE (median = 72 years, range = 18‐91, 77% women) were included. In 14 patients (47%), a high‐dose approach was used, with a median initial dose of 24 mg (range = 16‐32). In five patients (17%), SE could be terminated after PER administration (median dose = 6 mg, range = 6‐20 mg, 2/5 patients in high‐dose group). Clinical response was observed after a median of 24 hours (range = 8‐48 hours), whereas electroencephalogram resolved after a median of 60 hours (range = 12‐72 hours). Time to treatment response tended to be shorter in patients receiving high‐dose PER (median clinical response = 16 hours vs 18 hours; electroencephalographic response = 24 hours vs 72 hours), but groups were too small for statistical analysis. Continuous cardiorespiratory monitoring showed no changes in cardiorespiratory function after “standard” and “high‐dose” treatment. Elevated liver enzymes without clinical symptoms were observed after a median of 6 days in seven of 30 patients (23%; 57% high dose vs 43% standard dose), of whom six also received treatment with phenytoin (PHT). Outcome was unfavorable (death, persistent vegetative state) in 13 patients (43%; 39% high dose vs 61% standard dose), and good recovery (no significant disability, moderate disability) was achieved in nine patients (56% high dose vs 44% standard dose). Oral PER in loading doses up to 32 mg were well tolerated but could terminate SE only in a few patients (5/30; 17%). Long duration of SE, route of administration, and severe underlying brain dysfunction might be responsible for the modest result. An intravenous formulation is highly desired to explore the full clinical utility in the treatment of refractory SE.