Intravenous brivaracetam in status epilepticus: A multicentric retrospective study in Italy.

PURPOSE: to evaluate the use, effectiveness, and adverse events of intravenous brivaracetam (BRV) in status epilepticus (SE). METHODS: a retrospective multicentric study involving 24 Italian neurology units was performed from March 2018 to June 2020. A shared case report form was used across participating centres to limit biases of retrospective data collection. Diagnosis and classification of SE followed the 2015 ILAE proposal. We considered a trial with BRV a success when it was the last administered drug prior the clinical and/or EEG resolution of seizures, and the SE did not recur during hospital observation. In addition, we considered cases with early response, defined as SE resolved within 6 h after BRV administration. RESULTS: 56 patients were included (mean age 62 years; 57 % male). A previous diagnosis of epilepsy was present in 21 (38 %). Regarding SE etiology classification 46 % were acute symptomatic, 18 % remote and 16 % progressive symptomatic. SE episodes with prominent motor features were the majority (80 %). BRV was administered as first drug after benzodiazepine failure in 21 % episodes, while it was used as the second or the third (or more) drug in the 38 % and 38 % of episodes respectively. The median loading dose was 100 mg (range 50-300 mg). BRV was effective in 32 cases (57 %). An early response was documented in 22 patients (39 % of the whole sample). The use of the BRV within 6 h from SE onset was independently associated to an early SE resolution (OR 32; 95 % CI 3.39-202; p = 0.002). No severe treatment emergent adverse events were observed. CONCLUSION: BRV proved to be useful and safe for the treatment of SE. Time to seizures resolution appears shorter when it is administered in the early phases of SE.

Clinical pathways of epileptic seizures and status epilepticus: results from a survey in Italy.

OBJECTIVE: Patients with seizures or status epilepticus (SE) access the hospital through emergency departments and may be admitted into different wards according to the level of care required. Clinicians with different expertise are in charge of taking critical therapeutic decisions. To date, very few studies have investigated the stage at which these patients are referred to neurologists or epileptologists and how guideline recommendations are applied in clinical practice. METHODS: A survey was used to investigate how patients with epileptic seizures or SE are managed in emergency and in subsequent hospital pathways in Italy. RESULTS: One hundred and seventy-seven physicians (mainly neurologists) from all parts of Italy filled in a questionnaire. Less than half of the participants (35%) answered that, in their hospital, patients with epilepsy were managed by epileptologists. The percentages were lower for patients presenting with acute seizures (21%) or SE (16%). Diagnostic, therapeutic, and assistance pathways (PDTA) for patients presenting with seizure(s) or SE were available for both conditions in about 50% of cases, while, in the rest of the hospitals, participants indicated informal agreements (about 25% of cases) or lack of any agreement (about 25% of cases) between clinicians. Professionals more often involved in PDTA were epileptologists/neurologists, emergency physicians, and intensivists. More than half ot the participants (55%) thought that organizational issues are the most important criticalities for such patients and need to be improved (61%). SIGNIFICANCE: There is a high variability in hospital clinical pathways for epilepsy in Italy.

Management of status epilepticus in adults. Position paper of the Italian League against Epilepsy.

Since the publication of the Italian League Against Epilepsy guidelines for the treatment of status epilepticus in 2006, advances in the field have ushered in improvements in the therapeutic arsenal. The present position paper provides neurologists, epileptologists, neurointensive care specialists, and emergency physicians with updated recommendations for the treatment of adult patients with status epilepticus. The aim is to standardize treatment recommendations in the care of this patient population.

The anesthetic drug treatment of refractory and super-refractory status epilepticus around the world: Results from a global audit.

Multinational and multicenter registries collecting cases of refractory and super-refractory status epilepticus help to understand what the current practice in the treatment of such conditions is and can improve the rational therapy. We prospectively collected 776 cases of refractory status epilepticus requiring continuous intravenous anesthetic drugs in an intensive care unit setting, through online questionnaires compiled by the treating physicians in 50 countries. Initiation of an intravenous anaesthetic drug was relatively delayed in middle-income compared with high-income countries. There were marked regional differences in the choice of initial intravenous anaesthetic drug. Generally, midazolam was the most commonly used initial anesthetic drug (56%), followed by propofol (35%), in Europe, propofol was preferred over midazolam. In addition to anesthesia, 26% of cases received some form of immunosuppression (with corticosteroids and/or intravenous immunoglobulin). In this observational study, outcome was not affected by choice or sequence of anesthetic drugs, and nor was the use of barbiturate anesthetics associated with poorer outcome. The proportion of patients responding to cycles of different anaesthetic drugs was high even after failure of the earlier anesthetics, but the neurological outcome progressively worsened the longer anaesthetic drugs were needed and the longer the status epilepticus continued. However, even in the 158 patients who required three or more different anaesthetic trials, 49% had seizure control on tapering the third anesthetic, and 20% had a good neurological outcome anywhere. For these reasons we believe that it is important to persist with therapy in patients who are intractable initially, especially as etiology, not the number of duration of anesthesia, is the primary determinant of prognosis. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Etiologies and characteristics of refractory status epilepticus cases in different areas of the world: Results from a global audit.

To describe the demographics, etiologies, types of status epilepticus (SE), and outcomes in people with refractory and super-refractory SE from around the world, we prospectively collected cases of refractory SE (RSE) treated with continuous intravenous anesthetic drugs in an intensive care unit setting through online questionnaires using "active surveillance." We collected information about 776 cases of RSE in 50 countries over 4 years. Control of SE was achieved in 74% of the cases. Neurologic outcomes were poor in 41% of patients, and 24% died. Good outcome was associated with younger age and a history of epilepsy. Etiology strongly influenced the outcome. Patients from Asia were younger, more frequently presented with convulsive SE, and were more frequently affected by infectious etiologies when compared with patients from Europe and the Americas. Despite these differences, outcomes were similar in all countries. Demographics of patients with RSE in a global audit are similar to those in prior single center series, providing evidence of generalizability of those studies. Important differences exist among patients with RSE from different regions of the world, but these do not seem to significantly influence patient outcomes.

A case of epilepsy in multiple sclerosis: Three-dimensional double inversion recovery sequences revealed cortical dysplasia.

In epileptic patients with multiple sclerosis (MS), cortical lesions have been suggested to cause seizures. In brain magnetic resonance imaging (MRI), double inversion recovery (DIR) sequences are generally used to evaluate MS cortical disease burden. We present the case of a woman, diagnosed with MS, suffering from drug-resistant partial seizures initially attributed to MS. The patient underwent many MRI exams, but only by means of high-resolution three-dimensional DIR sequences was a focal cortical dysplasia discovered. The MRI findings and FDG-PET/CT supported the diagnosis. This case recommends the use of DIR sequences both in patients with suspect epileptogenic lesions not detected with routine MRI protocols and in epileptic patient with MS, before ascribing seizures to MS.

Seizure precipitants (triggering factors) in patients with epilepsy.

AIM: adult epilepsy clinic population: (a) to identify the frequency of seizure precipitants (triggering factors) and their relative frequency in those with psychiatric disorders, and in those in remission or with active epilepsy, differences in frequency with regard to gender, seizure duration, number of drugs taken; (b) to determine which precipitants patients most commonly report; and (c) to identify differences in the distribution of precipitants among generalized, temporal, and extratemporal epilepsies. METHODS: Consecutive patients attending a tertiary-care epilepsy clinic were prospectively and an open personal interview to identify and characterize seizure precipitants. Information about the epilepsy and clinical characteristics of patients was collected during the interview and from medical records. RESULTS: Of 104 patients, 97% cited at least one precipitant. Stress, sleep deprivation, and fatigue were the most frequently reported precipitants. Patients with psychological comorbidities reported a greater percentage of seizures with seizure precipitants. Patients with idiopathic generalized epilepsy seemed to be more sensitive to seizures during awakening and sleep deprivation, patients with extratemporal epilepsy reported more frequent seizures during sleep. There were no differences in frequency or type of seizure precipitants with regard to gender, seizure duration or frequency, and the number of antiepileptic drugs taken. CONCLUSION: The findings may have implications for the better management of epilepsy by increasing a focus on nonpharmacological therapy. The implications of the findings for nosology and causation of epilepsy are also briefly discussed.

What can we learn from status epilepticus registries?

There is a remarkable dearth of information about the various therapies used, often widely so, to control refractory or super-refractory status epilepticus despite its high mortality and morbidity. As pointed out by recent literature reviews, there are no controlled studies, and information is based almost entirely on open, often small and retrospective, case series or case reports. Randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available. For this reason, we proposed an international case registry of therapies used in refractory and super-refractory cases and their outcome. Clinicians from different countries will be asked to complete an online questionnaire when they treat a patient with refractory or super-refractory status epilepticus. Information gathered from this database will summarize the spectrum of etiologies, treatments, and outcomes of this challenging condition and may even form the bases for treatment guidelines or future targeted treatment trials.

A randomized controlled trial of IV immunoglobulin in patients with postpolio syndrome.

OBJECTIVE: To investigate in a single-center randomized control trial whether a single IVIg course improves short-term outcome in patients with postpolio syndrome (PPS). METHODS: Fifty-one patients with PPS were randomly allocated to receive 2g/kg IVIg body weight or placebo infused over 5 consecutive days. The primary endpoint was health-related quality of life (HRQoL) limited to the physical component score (PCS) in the Short-Form-36 (SF-36). Secondary endpoints included the SF-36 mental component score (MCS), 6-minute walk test, visual analog scale, 101-numeric rating, and fatigue severity scale. Muscle strength was graded according to the Medical Research Council scale and by dynamometer. Primary and secondary outcome variables were tested double-blind at baseline, 2months, and 4months. RESULTS: At two months, although SF-36 PCS scores were similar in both arms, the role physical (RP) domain improved significantly in the treatment arm (p=0.05) and so did the composite MCS (p=0.015), and role emotional (RE) subscale (p=0.02). No differences were found in the remaining outcome measures. At 4months, none of the outcome variables differed significantly between groups. CONCLUSIONS: Although the study did not reach the primary endpoint, we showed that a single IVIg course improves HRQoL related to mental activity, as measured by the SF-36 composite MCS, and role limitations including RP and RE SF-36 subscales at 2months, in patients with PPS. A single IVIg course leaves, gait, muscle strength, fatigue and bodily pain unchanged in patients with PPS. CLASSIFICATION OF EVIDENCE: Class I evidence indicates that IVIg did not change SF-36 PCS, and Class II evidence indicates that IVIg improved scores on the SF-36 MCS, RP, and RE.

The outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy.

In a previous paper, we reviewed the range of therapies available for the treatment of super-refractory status epilepticus. Here we report a review of the outcome of therapies in refractory and super-refractory status epilepticus. Patients (n = 1168) are reported who had therapy with: thiopental, pentobarbital, midazolam, propofol, ketamine, inhalational anaesthetics (isoflurane, desflurane), antiepileptic drugs (topiramate, lacosamide, pregabalin, levetiracetam), hypothermia, magnesium, pyridoxine, immunotherapy, ketogenic diet, emergency neurosurgery, electroconvulsive therapy, cerebrospinal fluid drainage, vagal nerve stimulation and deep brain stimulation. The outcome parameters reported include control of status epilepticus, relapse on withdrawal, breakthrough seizures and mortality. Where reported (596 cases), the long-term outcome was found to be death (35%), severe neurological deficit (13%), mild neurological deficit (13%), undefined deficit (4%) and recovery to baseline (35%). The quality of reported outcome data is generally poor and the number of cases reported for all non-anaesthetic therapies is low. Outcome assessment is complicated by changes in co-medication, delay in response and publication bias. Given these deficits, only broad recommendations can be made regarding optimal therapy. An approach to therapy, divided into first-line, second-line and third-line therapy, is suggested on the basis of this outcome evaluation. The importance of treatments directed at the cause of the status epilepticus, and of supportive ITU care is also emphasized.

Risk factors for post-polio syndrome among an Italian population: a case-control study.

Post-polio syndrome (PPS) is a clinical syndrome of new weakness, fatigue and musculoskeletal pain occurring in a variable proportion of polio survivors decades after acute disease. To date, several risk factors for PPS development have been reported, although the etiology of this disorder remains elusive. Using a case-control design, we aimed to assess risk indicators for PPS in a group of Italian polio survivors. Subjects with prior poliomyelitis attending the rehabilitation hospital of Malcesine, Italy, were the target population. Patients with PPS, diagnosed according to the European Federation of Neurological Societies criteria, served as cases, while patients not meeting diagnostic criteria for PPS were used as controls. All subjects were assessed through a structured questionnaire made of 82 questions and neurological examination. The association with investigated risk factors (sex, age at polio onset, age at onset of symptoms, extension and severity of polio, employment) was analyzed by the calculation of the odds ratio. A total of 161 out of 391 eligible patients met the adopted diagnostic criteria for PPS, giving a frequency of 41.2%. Symptoms most frequently complained by PPS patients were loss of muscle strength, loss of resistance, loss of muscle volume and generalized fatigue. Female gender, the presence of respiratory disturbance during the acute phase of polio and the use of orthoses and aids during the recovery and stabilization represented independent risk factors for PPS in the studied population.

Vincristine-related neuropathy versus acute inflammatory demyelinating polyradiculoneuropathy in children with acute lymphoblastic leukemia.

The objective of this study was to evaluate whether electroneurography could help in differentiating between vincristine-induced neuropathy and acute inflammatory demyelinating polyradiculoneuropathy. We performed electroneurography in 7 children from September 2006 to March 2009 admitted to receive chemotherapy including vincristine for acute lymphoblastic leukemia, in whom severe acute limb weakness developed, suggesting vincristine-induced neuropathy. Three of 7 patients had electroneurography, suggesting acute inflammatory demyelinating polyradiculoneuropathy. They received intravenous immunoglobulins without discontinuing chemotherapy, and within 10 days their electroclinical conditions improved. Although electroneurography showed only absent F waves, preventing us from reaching a definitive neurophysiological diagnosis of acute inflammatory demyelinating polyradiculoneuropathy, children's presenting clinical manifestations, their disease course, and rapid and complete recovery after intravenous immunoglobulins argued strongly in its favor. A prompt, correct differential diagnosis of vincristine neuropathy and acute inflammatory demyelinating polyradiculoneuropathy in patients with acute lymphoblastic leukemia receiving vincristine is essential to improve disease outcome and prolong life expectancy.

The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol.

Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset of anaesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia. It is an uncommon but important clinical problem with high mortality and morbidity rates. This article reviews the treatment approaches. There are no controlled or randomized studies, and so therapy has to be based on clinical reports and opinion. The published world literature on the following treatments was critically evaluated: anaesthetic agents, anti-epileptic drugs, magnesium infusion, pyridoxine, steroids and immunotherapy, ketogenic diet, hypothermia, emergency resective neurosurgery and multiple subpial transection, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, electroconvulsive therapy, drainage of the cerebrospinal fluid and other older drug therapies. The importance of treating the identifying cause is stressed. A protocol and flowchart for managing super-refractory status epilepticus is suggested. In view of the small number of published reports, there is an urgent need for the establishment of a database of outcomes of individual therapies.

Fear as the only clinical expression of affective focal status epilepticus.

Affective seizures consist of fear, depression, joy, and (rarely) anger. A correct diagnosis is often delayed as the behavioral features, like fear, are interpreted as psychiatric disorders. We describe a patient with affective focal status epilepticus (AFSE) in which fear was the only clinical manifestation. We present electroencephalographic correlates and discuss the diagnostic difficulties that can be encountered in similar cases. AFSE with fear as the only clinical expression may represent a diagnostic challenge. When fear is the only or the prominent behavioral feature, seizures may be diagnosed as panic attacks, leading to erroneous therapy. In such situations, electroencephalography is an essential tool in differentiating between psychiatric disorders and epileptic events.

Sleep disturbance and daytime sleepiness in patients with cirrhosis: a case control study.

Sleep disturbance and excessive daytime sleepiness have been reported in patients with hepatic cirrhosis. The objective of this study was to evaluate daytime somnolence and sleep complaints in a group of 178 patients with cirrhosis compared to a control group. Sleep features and excessive daytime sleepiness were evaluated by the Basic Nordic Sleep Questionnaire (BNSQ) and the Epworth Sleepiness Scale (ESS). We collected clinical and laboratory data, neurological assessment and EEG recordings in cirrhotic patients. Patients with cirrhosis complained of more daytime sleepiness (p<0.005), sleeping badly at least three times a week (p<0.005), difficulties falling asleep (p<0.01) and frequent nocturnal awakening (p<0.005) than controls. We found a poor correlation between sleep disorders and clinical or laboratory parameters. Our results confirm previous literature reports suggesting a high prevalence of sleep disturbance in patients with cirrhosis. Insomnia and daytime sleepiness are the main complaints. Sleep disorders are probably a multifactorial phenomenon.

Daytime driving simulation performance and sleepiness in obstructive sleep apnoea patients.

BACKGROUND: Sleepiness related car accidents are common in obstructive sleep apnoea syndrome (OSAS) patients. The objective measurements of sleepiness used in clinical setting quantify the tendency to fall asleep in quiet situations that are completely different from driving. METHODS: We studied 30 OSAS patients with subjective (subjective sleepiness scales) and objective (multiple sleep latency test, MSLT) sleepiness measurements, associated with driving simulation test (DST), previously validated in young healthy subjects. The results of subjective and objective sleepiness tests were compared with simulated driving performance in order to evaluate the suitability of our DST for measuring alertness. RESULTS: Subjective and objective sleepiness measurements were significantly correlated with driving performance on the simulator. The most significant correlates of sleepiness were the measures of the primary vehicle control task on the simulator: lane position variability and crash data. The comparison of DST and MSLT results suggested our driving simulated approach could be used to evaluate daytime sleepiness in the clinical setting of OSAS patients. CONCLUSIONS: Our DST is a suitable objective tool to detect sleepiness in OSAS patients, and could be useful in the clinical setting of sleep medicine and research.