Helmut F. Novak

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.

Critical Illness in Patients with Multiple Sclerosis: A Matched Case-Control Study.

Background Over the course of multiple sclerosis (MS) several conditions may arise that require critical care. We aimed to study the reasons for admission and outcome in patients with MS admitted to a neuro-intensive care unit (NICU). Methods We retrospectively searched the electronic charts of a 9-bedded NICU in a tertiary hospital for patients with a diagnosis of multiple sclerosis (MS) from 1993–2015, and matched them to NICU controls without MS based on age and gender. Conditional logistic regression was used to compare admission causes, Charlson’s Comorbidity Index, indicators of disease severity, and survival between MS and non-MS patients. Results We identified 61 MS patients and 181 non-MS controls. Respiratory dysfunction was the most frequent reason for NICU admission among MS patients (34.4%), having infectious context as a rule. In a matched analysis, after adjusting for co-morbidities and immunosuppressive medications, patients with MS were more likely to be admitted to the NICU because of respiratory dysfunction (OR = 7.86, 95% CI 3.02–20.42, p<0.001), non-respiratory infections (OR = 3.71, 95% CI 1.29–10.68, p = 0.02), had a higher rate of multiple NICU admissions (OR = 2.53, 95% CI 1.05–6.05, p = 0.04) than non-MS patients. Mortality after NICU admission at a median follow-up time of 1 year was higher in MS than control patients (adjusted OR = 4.21, 95% CI 1.49–11.85, p = 0.04). Conclusion The most common reason for NICU admission in MS patients was respiratory dysfunction due to infection. Compared to non-MS patients, critically ill MS patients had a higher NICU re-admission rate, and a higher mortality.

Nontraumatic spinal cord injury at the neurological intensive care unit: spectrum, causes of admission and predictors of mortality

Objective: Nontraumatic spinal cord injuries (NTSCIs) form a heterogeneous group of diseases, which may evolve into a life-threatening condition. We sought to characterize spectrum, causes of admission and predictors of death in patients with NTSCI treated at the neurological intensive care unit (NICU). Methods: We performed a retrospective observational analysis of NTSCI cases treated at a tertiary care center between 2001 and 2013. Among the 3937 NICU admissions were 93 patients with NTSCI (2.4%). Using multivariate logistic regression analysis, we examined predictors of mortality including demographics, etiology, reasons for admission and GCS/SAPS (Glasgow Coma Scale/Simplified Acute Physiology Score) scores. Results: Infectious and inflammatory/autoimmune causes made up 50% of the NTSCI cases. The most common reasons for NICU admission were rapidly progressing paresis (49.5%) and abundance of respiratory insufficiency (26.9%). The mortality rate was 22.6% and 2.5-fold higher than in the cohort of all other patients treated at the NICU. Respiratory insufficiency as the reason for NICU admission [odds ratio (OR) 4.97, 95% confidence interval (CI) 1.38–17.9; p < 0.01], high initial SAPS scores (OR 1.04; 95% CI 1.003–1.08; p = 0.04), and the development of acute kidney injury throughout the stay (OR 7.25, 1.9–27.5; p = 0.004) were independent risk factors for NICU death. Conclusions: Patients with NTSCI account for a subset of patients admitted to the NICU and are at risk for adverse outcome. A better understanding of predisposing conditions and further knowledge of management of critically ill patients with NTSCI is mandatory.

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.

Intravenous brivaracetam in status epilepticus: A retrospective single-center study

Brivaracetam (BRV) is a high‐affinity synaptic vesicle glycoprotein 2A ligand that is structurally related to levetiracetam (LEV). Compared to LEV, its affinity to the ligand is >10%‐30% higher. Due to its more lipophilic characteristics, it might have a quicker penetration across the blood‐brain barrier and potentially also a stronger anticonvulsant effect. Thus, we aimed to explore its usefulness in the treatment of status epilepticus (SE). We retrospectively assessed treatment response and adverse events in adjunctive treatment with intravenous BRV in patients with SE from January 2016 to July 2017 at our institution. Seven patients aged median 68 years (range = 29‐79) were treated with intravenous BRV. Three patients had SE with coma and four without. SE arose de novo in two patients; etiology was remote symptomatic in four patients and progressive symptomatic in one patient. The most frequent etiology was remote vascular in two patients. BRV was administered after median four antiepileptic drugs (range = 2‐11). Time of treatment initiation ranged from 0.5 hours to 105 days (median = 10.5 hours). Immediate clinical and electrophysiological improvement was observed in two patients (29%). Median loading dose was 100 mg intravenously over 15 minutes (range = 50‐200 mg), titrated up to a median dose of 100 mg/d (range = 100‐300). Median Glasgow Outcome Scale score was 3 (range = 3‐5), with an improvement in 86% of patients compared to admission. We observed no adverse events regarding cardiorespiratory function. BRV might have potential as a novel antiepileptic drug in early stages of SE. Its potential may lie its ability to cross the blood‐brain barrier more quickly than LEV and its favorable safety profile. Prospective studies for the use of BRV in SE are required.

Risk Factors for Intensive Care Unit Admission in Patients with Autoimmune Encephalitis

Background Prevention and early recognition of critical illness in patients with autoimmune encephalitis (AE) is essential to achieve better outcome. Aim of the study To evaluate risk factors for intensive care unit (ICU) admission and its prognostic impact in patients with AE. Patients and methods A reclassification of patients hospitalized between 2011 and 2016 revealed 17 “definite” and 15 “probable” AE cases. Thirteen patients (41%) developed critical illness and required ICU admission. The underlying conditions were intractable seizures or status epilepticus (54%), altered mental state (39%), and respiratory failure (8%). Results ICU admission was associated with longer time from first symptoms to hospitalization (p = 0.046). Regression analysis revealed that anemia on hospital admission and definite diagnosis of AE was associated with a higher risk of acquiring critical illness. At last follow-up after a median of 31 months (range 2.5–52.4), seven patients had died (23%) and 63% had a good outcome [modified Rankin Scale (mRS) 0–3]. Anemia was associated with poor prognosis (p = 0.021), whereas development of critical illness did not impact mortality and functional outcome. Conclusion We confirmed the need for ICU care in a subgroup of patients and the prevailing objective is improved seizure control, and definite diagnosis of AE and anemia were identified as risk factors for development of critical illness. However, prognosis was not affected by ICU admission.

Proximal flow to middle cerebral artery is associated with higher thrombus density in terminal internal carotid artery occlusion

Proximal collaterals may determine the composition of occluding thrombi in acute ischemic stroke (AIS) in addition to source, hematocrit, time, and medication. Here, we performed a retrospective study of 39 consecutive patients with radiological evidence of I‐, L‐, and T‐type terminal internal carotid artery occlusion. Middle cerebral artery (MCA) thrombus density was assessed on noncontrast enhanced CT and proximal collaterals on CT angiography. In patients with presence of proximal collaterals to the MCA we detected more hyperdense clots (P = 0.003) and a higher frequency of leptomeningeal collaterals (P = 0.008). We expand the spectrum of factors that potentially determine clot perviousness and evolution of ischemic stroke.