Summary Refractory status epilepticus (RSE) is defined as status epilepticus that continues despite treatment with benzodiazepines and one antiepileptic drug. RSE should be treated promptly to prevent morbidity and mortality; however, scarce evidence is available to support the choice of specific treatments. Major independent outcome predictors are age (not modifiable) and cause (which should be actively targeted). Recent recommendations for adults suggest that the aggressiveness of treatment for RSE should be tailored to the clinical situation. To minimise intensive care unit-related complications, focal RSE without impairment of consciousness might initially be approached conservatively; conversely, early induction of pharmacological coma is advisable in generalised convulsive forms of the disorder. At this stage, midazolam, propofol, or barbiturates are the most commonly used drugs. Several other treatments, such as additional anaesthetics, other antiepileptic or immunomodulatory compounds, or non-pharmacological approaches (eg, electroconvulsive treatment or hypothermia), have been used in protracted RSE. Treatment lasting weeks or months can sometimes result in a good outcome, as in selected patients after encephalitis or autoimmune disorders. Well designed prospective studies of RSE are urgently needed.

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Management of refractory status epilepticus in adults: still more questions than answers

Status epilepticus (SE) represents the most severe form of epilepsy. It is one of the most common neurologic emergencies, with an incidence of up to 61 per 100,000 per year and an estimated mortality of 20 %. Clinically, tonic-clonic convulsive SE is divided into four subsequent stages: early, established, refractory, and super-refractory. Pharmacotherapy of status epilepticus, especially of its later stages, represents an “evidence-free zone,” due to a lack of high-quality, controlled trials to inform clinical decisions. This comprehensive narrative review focuses on the pharmacotherapy of SE, presented according to the four-staged approach outlined above, and providing pharmacological properties and efficacy/safety data for each antiepileptic drug according to the strength of scientific evidence from the available literature. Data sources included MEDLINE and back-tracking of references in pertinent studies. Intravenous lorazepam or intramuscular midazolam effectively control early SE in approximately 63–73 % of patients. Despite a suboptimal safety profile, intravenous phenytoin or phenobarbital are widely used treatments for established SE; alternatives include valproate, levetiracetam, and lacosamide. Anesthetics are widely used in refractory and super-refractory SE, despite the current lack of trials in this field. Data on alternative treatments in the later stages are limited. Valproate and levetiracetam represent safe and effective alternatives to phenobarbital and phenytoin for treatment of established SE persisting despite first-line treatment with benzodiazepines. To date there are no class I data to support recommendations for most antiepileptic drugs for established, refractory, and super-refractory SE. Limiting the methodologic heterogeneity across studies is required and high-class randomized, controlled trials to inform clinicians about the best treatment in established and refractory status are needed.

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Pharmacotherapy for Status Epilepticus

Prognostic factors, morbidity and mortality in tonic–clonic status epilepticus: A review

HLA-G is a HLA-class Ib molecule with potent immunomodulatory activities, which is expressed in physiological conditions, where modulation of the immune response is required to avoid allograft recognition (i.e., maternal-fetal interface or transplanted patients). However, HLA-G can be expressed de novo at high levels in several pathological conditions, including solid and hematological tumors and during microbial or viral infections, leading to the impairment of the immune response against tumor cells or pathogens, respectively. On the other hand, the loss of HLA-G mediated control of the immune responses may lead to the onset of autoimmune/inflammatory diseases, caused by an uncontrolled activation of the immune effector cells. Here, we have reviewed novel findings on HLA-G functions in different physiological and pathological settings, which have been published in the last two years. These studies further confirmed the important role of this molecule in the modulation of the immune system.

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Recent Advances in Our Understanding of HLA-G Biology: Lessons from a Wide Spectrum of Human Diseases.

Status epilepticus (SE) prognosis is related to nonmodifiable factors (age, etiology), but the exact role of drug treatment is unclear. This study was undertaken to address the prognostic role of treatment adherence to guidelines (TAG). We prospectively studied over 26 months a cohort of adults with incident SE (excluding postanoxic). TAG was assessed in terms of drug doses (± 30 % of recommendations) and medication sequence; its prognostic impact on mortality and return to baseline conditions was adjusted for etiology, SE severity [Status Epilepticus Severity Score (STESS)], and comorbidities. Of 225 patients, 26 (12 %) died and 82 (36 %) were discharged with a new handicap; TAG was observed in 142 (63 %). On univariate analysis, age, etiology, SE severity, and comorbidities were significantly related to outcome, while TAG was associated with neither outcome nor likelihood of SE control. Logistic regression for mortality identified etiology [odds ratio (OR) 18.8, 95 % confidence interval (CI) 4.3-82.8] and SE severity (STESS ≥ 3; OR 1.7, 95 % CI 1.2-2.4) as independent predictors, and for lack of return to baseline, again etiology (OR 7.4, 95 % CI 3.9-14.0) and STESS ≥ 3 (OR 1.7, 95 % CI 1.4-2.2). Similar results were found for the subgroup of 116 patients with generalized-convulsive SE. Receiver operator characteristic (ROC) analyses confirmed that TAG did not improve outcome prediction. This study of a large SE cohort suggests that treatment adherence to recommendations using current medications seems to play a negligible prognostic role (class III), confirming the importance of the biological background. Awaiting further treatment trials, it appears mandatory to apply resources towards identification of new therapeutic approaches.

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Treatment deviating from guidelines does not influence status epilepticus prognosis.

Purpose 
Epidemiological surveys on status epilepticus (SE) in adults in two Italian areas (Bologna and Lugo di Romagna) disclosed a major difference in 30-day case fatality (33% versus 7 %). Since suboptimal management was hypothesised in the first site, we compared the quality of treatment in the two cohorts and examined its contribution to prognosis.

Impact of treatment on the short-term prognosis of status epilepticus in two population-based cohorts.

BACKGROUND The relevance of human leukocyte antigen (HLA)-G in dimeric form in multiple sclerosis (MS) is still unknown. OBJECTIVE To investigate the contribution of cerebrospinal fluid (CSF) HLA-G dimers in MS pathogenesis. METHODS CSF amounts of 78-kDa HLA-G dimers were measured by western blot analysis in 80 MS relapsing-remitting MS (RRMS) patients and in 81 inflammatory and 70 non-inflammatory controls. RESULTS CSF amounts of 78 kDa HLA-G dimers were more frequent in RRMS than in inflammatory (p<0.01) and non-inflammatory controls (p<0.001) and in magnetic resonance imaging (MRI) inactive than in MRI active RRMS (p<0.00001). CONCLUSION Our findings suggest that HLA-G dimers may be implicated in termination of inflammatory response occurring in MS.

M. Galeotti

Papers

Impact of treatment on the short-term prognosis of status epilepticus in two population-based cohorts.

Cerebrospinal fluid amounts of HLA-G in dimeric form are strongly associated to patients with MRI inactive multiple sclerosis.