Delivery problems and switch of the manufacturer of antiseizure medications - An update of an online survey of patient's experiences in Germany and other German-speaking countries.

In the last decade there is an increasing frequency of sudden generic switches of antiseizure medications (ASMs) due to delivery problems. We here explored the patient's views toward generic substitution of ASMs and their experiences with delivery problems and switches of the manufacturer. A questionnaire already used in 2011 was updateded and published on the website of a patient's organisation from March 2022 until November 2022. 54.4 % of the responders reported delivery problems. Delivery problems were reported from Germany by a higher number of responders than from Switzerland. To 83.7 % of the responders the delivery problems were communicated by the pharmacists. In 41.9 % of these the delivery problems were coped by generic substitution. In 33 % of the latter breakthrough seizures occurred. 26 % of the respondents with experience of a change of the manufacturer not due to a delivery problem reported breakthrough seizures after being substituted. The majority of patients denied having been well informed about the possible consequences of a switch of the manufacturer. A thorough counselling on the low risks caused by change of the manufacturer and the need for good adherence to further reduce the risks should be part of the general information about their treatment with ASMs for people with epilepsy.

Automated Pupillometry for Assessment of Treatment Success in Nonconvulsive Status Epilepticus.

BACKGROUND: Altered pupillary function may reflect nonconvulsive status epilepticus (NCSE). Neurological pupil index (NPi) assessed by automated pupillometry is a surrogate marker of global pupillary function. We aimed to assess NPi changes in relation to NCSE treatment response. METHODS: In this prospective observational study, serial automated pupillometry was performed in 68 NCSE episodes. In accordance with local standards, patients were treated with clonazepam (1-2 mg), levetiracetam (40 mg/kg), and lacosamide (5 mg/kg) in a stepwise approach under continuous electroencephalography monitoring until NCSE was terminated. Patients with refractory NCSE received individualized regimens. NPi was assessed bilaterally before and after each treatment step. For statistical analysis, the lower NPi of both sides (minNPi) was used. Nonparametric testing for matched samples and Cohen's d to estimate effect size were performed. Principal component analysis was applied to assess the contribution of baseline minNPi, age, sex, and NCSE duration to treatment outcome. RESULTS: In 97.1% of 68 episodes, NCSE could be terminated; in 16.2%, NCSE was refractory. In 85.3% of episodes, an abnormal baseline minNPi ≤ 4.0 was obtained. After NCSE termination, minNPi increased significantly (p < 0.001). Cohen's d showed a strong effect size of 1.24 (95% confidence interval 0.88-1.61). Baseline minNPi was higher in clonazepam nonresponders vs. responders (p = 0.008), minNPi increased in responders (p < 0.001) but not in nonresponders. NCSE refractivity was associated with normal baseline minNPi (principal component analysis, component 1, 32.6% of variance, r = 0.78), male sex, and longer NCSE duration (component 2, 27.1% of variance, r = 0.62 and r = 0.78, respectively). CONCLUSIONS: Automated pupillometry may be a helpful noninvasive neuromonitoring tool for the assessment of patients with NCSE and response to treatment.

[Self-induced epileptic seizures: Prevalence, Causes and Treatment]. / Selbstinduzierte epileptische Anfälle Prävalenz, Ursachen und Behandlung.

Self-induced seizures were first described in 1827. A majority of authors found that in unselected patients with epilepsy, the prevalence rate of these seizures was 1%. In patients with photosensitive epilepsy, there was roughly a 25% prevalence. Apart from visual stimulation, many other mechanisms of self-induction have been described. A feeling of pleasure or relaxation during seizures may be a reason for self-inductive behaviour. But often the procedure of self-induction is experienced as involuntary. Treatment is always difficult. Behavioral therapy has been proven effective in some patients. In patients with photosensitive epilepsy, sunglasses are recommended. Fenfluramine, clonazepam and valproate seem to be a bit more effective than other drugs. After all, the treatment effect depends on the motivation of the patient to change the condition.

Recognition and treatment of status epilepticus in the prehospital setting.

PURPOSE: We performed this retrospective data bank analysis to evaluate the management of status epilepticus (SE) in the prehospital setting and the possible association of treatment delay or insufficient treatment approach with outcome. METHOD: We evaluated all treatment episodes of a prehospital SE according to our hospital record system between January 1st 2014 and December 31st 2018. Classification according to the ILAE classification of 2015, Status Epilepticus Severity Score (STESS), Charlson Comorbidity Index (CCI) at admission and the Modified Rankin Scale (mRS) at discharge or in hospital death were recorded or calculated. Statistical analysis was performed with the Mann-Withney-U test, the Chi-Square test and corrections of Yates and Bonferroni-Holmes where appropriate. RESULTS: There were 331 treatment episodes in 282 patients with a fatality rate of 7.6 %. Median age at treatment was 72 years. Patients who died were significantly older and had a higher STESS and CCI than patients who survived. SE was recognised in the prehospital setting in only 56.8 % of treatment episodes. Patients in treatment episodes with recognized SE were significantly younger than the others. Status epilepticus was more often recognized, when epilepsy was known. Overall in 48 % of treatment episodes with another SE type than generalized convulsive SE the diagnosis was missed. CCI was significantly higher in the episodes without recognized SE. Patients were more often discharged from hospital with a new deficit, when the SE was not recognized in the prehospital setting. In treatment episodes with initiation of a benzodiazepine (BZD) the patients were more likely to be discharged without a new deficit than others. After excluding cases with insufficient documentation of treatment steps 273 treatment episodes remained. In 178 of these treatment episodes epilepsy was known before, but in only 11.2 % of them a rescue medication was given by bystanders. In only 6.7 % of treatment episodes of SE in patients with known epilepsy a BZD was given in an appropriate way by bystanders. In nearly all treatment episodes with lorazepam (88.9 %) or midazolam (97.8 %) the dosage was below the recommended level. CONCLUSIONS: Missing the SE in the prehospital setting was frequent and associated with a higher risk of developing a new neurological deficit. Treatment with BZD was associated with a lower risk of developing a new neurological deficit, but was underdosed in the vast majority of situations.

Quantitative Infrared Pupillometry in Nonconvulsive Status Epilepticus.

BACKGROUND: Nonconvulsive status epilepticus (NCSE) is a frequent disorder in neurocritical care and diagnosing it can be challenging. NCSE patients often show altered pupil function, but nature and extent may vary. Infrared pupillometry allows detection of subtle changes of pupil function. The neurological pupil index (NPi) is considered a surrogate marker of global pupil function which is supposed to be independent of absolute parameters such as the pupil diameter. OBJECTIVE: Cross-sectional observational study to assess whether NPi is altered in NCSE. METHODS: 128 consecutive adult emergency patients who had experienced a suspected seizure, have not reached their prior functional level regarding level of consciousness, mental status or focal deficits, had no obvious clinical signs of status epilepticus and had an EEG indication as determined by the treating clinician for exclusion of NCSE were examined by routine EEG and pupillometry. Exclusion criteria were ocular comorbidity (n = 21) and poor EEG quality (n = 4). Pupillometry was performed once directly before the beginning of EEG recording. NCSE diagnosis (no NCSE, possible NCSE and confirmed NCSE) was established according to Salzburg consensus criteria blinded to pupillometry results. Group comparison was performed for right NPi, left NPi, lowest NPi of both sides (minNPi) and the absolute difference of both sides (diffNPi) applying non-parametric testing. In post-hoc analysis, receiver operating characteristics (ROC) of NCSE diagnosis (combined confirmed NCSE and possible NCSE) were performed for minNPi and diffNPi. RESULTS: From 103 patients included in the final analysis, 5 (4.9%) had confirmed NCSE, 7 (6.8%) had possible NCSE. Right NPi (p = 0.002), left NPi (p < 0.001) and minNPi (p < 0.001) were significantly lower in "confirmed NCSE" and "possible NCSE" compared to "no NCSE"; diffNPi was significantly higher in "confirmed NCSE" and "possible NCSE" compared to "no NCSE" (p < 0.001). There was no significant difference of minNPi and diffNPi between "confirmed NCSE" and "possible NCSE". ROC analysis showed an optimal cut-off of minNPi for NCSE diagnosis of 4.0 (AUC = 0.93, 95% CI 0.86-0.99). Optimal ROC analysis cut-off of diffNPi for NCSE diagnosis was 0.2 (AUC = 0.89, 95% CI 0.80-0.99). CONCLUSIONS: NPi was significantly reduced and the difference between left and right NPi was significantly higher in confirmed NCSE. An NPi < 4.0 on either side as well as an NPi difference of both sides > 0.2 may be potential indicators of NCSE. Infrared pupillometry may be a helpful diagnostic tool in the assessment of NCSE and should be studied further in larger populations.

Breach Rhythm May Be Suppressed as a Form of Todd's Paralysis.

This case report will provide further evidence for the fact that breach rhythm is not the effect of a bone abnormality only. We present the case of an 84-year-old woman, who had a craniotomy 14 month before admission to our emergency department with a focal inhibitory status epilepticus. Even after clinical recovery, electroencephalography revealed frequent subclinical seizure patterns. When seizure activity was suppressed by anticonvulsive medication with levetiracetam, breach rhythm appeared. Breach rhythm develops usually some months after craniotomy and therefore should have been established in our patient at the time of admission. Therefore, it is reasonable to assume that it was in some way suppressed by the seizure activity in our primary EEG recordings. The appearance of the breach rhythm after the complete suppression of seizure activity by antiepileptic drug treatment shows that breach rhythm is not purely the result of a skull defect but is related to the functional state of the brain tissue beneath.

[Levetiracetam for treatment of status epilepticus - an update]. / Levetiracetam in der Behandlung des Status epilepticus ­ ein update.

Since 2004 several reports on the treatment of status epilepticus with levetiracetam have been published. In this review, the results of a PubMed-based search of publications December 12, 2011 - July 6, 2018 are summarized and compared to those of earlier publications. In total, 28 treatment episodes in case reports, each on one or two cases of treatment episodes, and 412 treatment episodes in case series and prospective studies were analyzed. Case series and prospective studies reported an average success rate for termination of status probably of 55,0 %-59,4 %. Since preclinical data suggest a delayed effect of levetiracetam, its use in the treatment of generalized convulsive status epilepticus appears still questionable. A loading dose of 30 mg / kg seems to be reasonable.

Pregnancy-related knowledge of women with epilepsy - An internet-based survey in German-speaking countries.

There are several issues, which have to be acknowledged, when treating women with epilepsy (WWE). The need for counseling WWE in Germany with epilepsy on pregnancy-related matters was stressed in several papers and medical guidelines. Physicians treating WWE in Germany therefore should be aware of the information needs of their patients. We aimed to determine the level of pregnancy-related knowledge of WWE and their informational needs concerning pregnancy and childbirth issues in German-speaking countries by an internet-based survey. The questionnaire consisted of 18 questions addressing the characteristics of the epilepsy syndromes, the patients' experience with pregnancy, and the sources of their pregnancy-related knowledge. Another 20 items addressed the level of pregnancy-related knowledge. One hundred ninety-two women (179 patients, 13 relatives; age: 30.5±10.8years) participated. Most of the women got information and advice on the treatment of epilepsy from a neurologist (81%). Most of the women had obtained information concerning driving license (72%) followed by information about pregnancy and delivery (60%). The women, who remembered being counseled about pregnancy-related matters gave more correct answers to the pregnancy-related questions than the others (51±17% vs. 38±24%, p<0.011). Thirty-eight percent of WWE taking enzyme inducing antiepileptic drugs (AEDs) were unaware of the interaction with oral contraception. Forty-one percent of WWE taking valproate were unaware of its high teratogenicity, and 89% of WWE had not been counseled about potentially reduced bone mineral density. Forty-six percent of participants did not believe that the majority of WWE have healthy children. The findings of this survey reveal considerable information needs of WWE concerning pregnancy-related matters in German-speaking countries.

The efficacy of different kinds of intravenously applied antiepileptic drugs in the treatment of status epilepticus. How can it be determined?

We explored the influence of four different efficacy criteria on the results of observational studies concerning the treatment of status epilepticus (SE) and its subtypes. We compared and contrasted the results of four different efficacy criteria for the effectiveness of phenytoin, valproate, levetiracetam, and lacosamide. Criterion 1=the last antiepileptic drug (AED) administered before SE termination. Criterion 2=the last drug introduced into the antiepileptic therapy within 72h before the cessation of SE and without changes in dosage or number of the co-medication. Criterion 3=the last drug introduced into the antiepileptic therapy or increased in dose within 24h before termination of the SE without changes in the co-medication. Criterion 4=the last drug introduced into the antiepileptic therapy within 72h before the cessation of SE even allowing changes in the co-medication. We used two-tailed χ2-tests with the Yates adjustment for small samples to evaluate statistical differences between efficacy rates of different AEDs in the entire group and in subgroups of SE according to the second level of subdivisions in axis 1 and according to axis 2 of the new ILAE classification. A total of 145 treatment episodes in 124 patients (47 male, 77 female) were evaluated. There were 23 significant differences in efficacy according to the different criteria. Only criteria 1 and 3 led to significant results in our analysis. When incorporating theoretical considerations and the results of this study, criterion 3 seems to be the most appropriate measure for the evaluation of efficacy of an AED in the treatment of SE, because it seems to be more reasonable than criterion 1.

The impact of anxiety, seizure severity, executive dysfunction, subjectively perceived psychological deficits, and depression on social function in patients with epilepsy.

The impact of anxiety, seizure severity, executive dysfunction, subjectively perceived psychological deficits, and depression on social function in patients with epilepsy (PWE) was analyzed. A brief cognitive screening test (EpiTrack) and an estimation of the last 6 months' cumulative seizure severity (Chalfont seizure severity scale) were performed, and questionnaires on subjectively perceived cognitive deficits (c.I.-Skala), anxiety (State-Trait Anxiety Inventory, STAIX1 and STAIX2), depression (Self Rating Depression Scale, SDS), and social function (Soziale Aktivität Selbstbeurteilungsskala, SASS) were completed. Forty PWE (aged 41.8 years, SD 16; 24 female, 16 male) were analyzed. Thirty-eight point 5 percent had a score signifying depression in the SDS; 20% had a pathological result in at least one of the anxiety scores. The ANOVA revealed that only anxiety as a trait symptom (STAIX2) had a significant influence on social function apart from the other factors (p<0.004). Additionally there was a trend for a significant influence of depressive symptoms (SDS) on social functioning (p=0.093). Symptoms of anxiety impair the social function of patients with epilepsy apart from depression, cognitive function, and seizure severity. They should be taken into account in the treatment of patients with epilepsy.

Magnetic resonance-transcranial ultrasound fusion imaging: A novel tool for brain electrode location.

BACKGROUND: A combination of preoperative magnetic resonance imaging (MRI) with real-time transcranial ultrasound, known as fusion imaging, may improve postoperative control of deep brain stimulation (DBS) electrode location. Fusion imaging, however, employs a weak magnetic field for tracking the position of the ultrasound transducer and the patient's head. Here we assessed its feasibility, safety, and clinical relevance in patients with DBS. METHODS: Eighteen imaging sessions were conducted in 15 patients (7 women; aged 52.4 ± 14.4 y) with DBS of subthalamic nucleus (n = 6), globus pallidus interna (n = 5), ventro-intermediate (n = 3), or anterior (n = 1) thalamic nucleus and clinically suspected lead displacement. Minimum distance between DBS generator and magnetic field transmitter was kept at 65 cm. The pre-implantation MRI dataset was loaded into the ultrasound system for the fusion imaging examination. The DBS lead position was rated using validated criteria. Generator DBS parameters and neurological state of patients were monitored. RESULTS: Magnetic resonance-ultrasound fusion imaging and volume navigation were feasible in all cases and provided with real-time imaging capabilities of DBS lead and its location within the superimposed magnetic resonance images. Of 35 assessed lead locations, 30 were rated optimal, three suboptimal, and two displaced. In two cases, electrodes were re-implanted after confirming their inappropriate location on computed tomography (CT) scan. No influence of fusion imaging on clinical state of patients, or on DBS implantable pulse generator function, was found. CONCLUSIONS: Magnetic resonance-ultrasound real-time fusion imaging of DBS electrodes is safe with distinct precautions and improves assessment of electrode location. It may lower the need for repeated CT or MRI scans in DBS patients.

Comparison of the effectiveness of four antiepileptic drugs in the treatment of status epilepticus according to four different efficacy criteria.

The preliminary data presented here shall give an impression on how different criteria for the identification of an antiepileptic drug (AED) with a possible or certain treatment effect can have an influence on the results of retrospective case series. We present a data subset from a large retrospective study which, when completed, will cover all treatment episodes of status epilepticus (SE) at the neurological department of the Universitätsmedizin Rostock from January 2010 to June 2013. We compare and contrast the results of four different efficacy criteria for the effectiveness of phenytoin (PHT), valproate (VPA), levetiracetam (LEV), and lacosamide (LCM): criterion 1 = the last AED administered before SE termination; criterion 2 = the last drug introduced into the antiepileptic therapy within 72 h before SE termination and without changes in the comedication; criterion 3 = the last drug introduced into the antiepileptic therapy or increased in dose within 24h before SE termination without changes in the comedication; and criterion 4 = the last drug introduced into the antiepileptic therapy within 72 h before SE termination, even allowing changes in the comedication. Thirty-seven treatment episodes in 32 patients (13 male and 19 female, mean age at first episode: 68 years, SD: 17) could be analyzed. In 31 episodes, at least one AED was given intravenously. Efficacy rates in the whole case series according to all four criteria were not significantly different between the four AEDs, but there was a considerable difference in the efficacy rates of each AED when evaluating them with the different efficacy criteria. Our data show that statistically significant results concerning the efficacy of different AEDs in different subtypes of SE may depend on the outcome criteria. Therefore, efficacy criteria for the effectiveness of AEDs in the treatment of SE should be standardized. This article is part of a Special Issue entitled Status Epilepticus.

Efficacy of perampanel in refractory nonconvulsive status epilepticus and simple partial status epilepticus.

We provide some evidence concerning the efficacy of perampanel (PER) in refractory status epilepticus (SE). We retroactively identified patients with SE treated in our department by searching for the term "status epilepticus" in the electronic archive of medical records. We present and analyze in this paper the subset of data of the patients treated with PER. We analyzed ten episodes of SE in nine patients. At the first administration, PER was given in a dosage of 6mg to most of our patients (7 of 10). On average, PER was administered as the 6th antiepileptic drug (AED) (range: 2-10). Depending on the criterion for efficacy, PER appears effective for the termination of SE in 2 to 6 (of 10) episodes. Unfortunately, safety data for the administration of PER with loading doses needed for the treatment of SE are lacking. Because of this, PER should be used very carefully in refractory SE and only after first-line treatment options have failed.

Creutzfeldt-Jakob-Like Syndrome due to Hypercalcemic Encephalopathy.

Hypercalcemia can cause a subacute syndrome of progressive dementia and marked changes in the electroencephalogram (EEG). We report a case of iatrogenic hypercalcemia with a close correlation between the clinical course and the EEG changes. A 73-year-old woman presented with a subacute syndrome of progressive dementia and bursts of 1.5 to 2 Hz intermittent rhythmic delta activity superimposed on a low-voltage background activity in the EEG. Clinical and EEG abnormalities rapidly resolved after normalization of serum calcium levels. As part of the diagnostic workup of a subacute progressive dementia, a serum calcium level and an EEG should be obtained to detect a Creutzfeldt-Jakob like syndrome in hypercalcemia. Unlike in Creutzfeldt-Jakob disease, and Creutzfeldt-Jakob-like syndrome induced by lithium intoxication, there are rarely myoclonic jerks and periodic discharges in hypercalcemic encephalopathy.

Neuropsychological deficits after a first unprovoked seizure and depressive symptoms in the week before.

This prospective study was performed to investigate whether verbal memory deficits are present in patients with a first unprovoked seizure irrespective of significant lesions in the brain and whether symptoms of depression were experienced by those patients in the week before the seizure. After having given informed consent, patients who presented with a first unprovoked seizure were investigated with a psychometric battery consisting of a verbal memory test, a figural memory test, a test following the Stroop paradigm, and a self-rating scale for depression in addition to the routine diagnostic work-up with EEG and MRI. The data of 53 patients aged 45years on average (33 males and 20 females) were available. Verbal memory deficits were present in 60% of the patients, and 21% of the patients delivered a self-rating that was suggestive of at least minor depression in the week before the seizure. Neither verbal memory deficits nor symptoms of depression were associated with a significant lesion of the brain. There was a significant negative correlation between immediate recall in the verbal memory test and the score in the self-rating scale for depression. Our data suggest that even at the time of the first unprovoked seizure, there is an epileptic condition of the brain, which facilitates the occurrence of verbal memory deficits and depression in the presence of an epileptogenic focus irrespective of its localization.

Treatment and course of different subtypes of status epilepticus.

Since randomized controlled trials are difficult to perform for ethical reasons in a potentially deadly condition like status epilepticus (SE), a retrospective database analysis may be welcome to broaden the evidence for the treatment of SE. In this retrospective study we evaluated every SE treatment at the neurological department of the University of Rostock from January 2000 to December 2009 in order to determine the efficacy of different antiepileptic drugs (AEDs) in terminating different kinds of SE. We analyzed the frequency of refractory courses in different types of SE, at which time which AED was administered and at which time which AED was effective to terminate the different epileptic conditions. A second aim of this study was to evaluate the course and the outcome of different kinds of SE. Statistical comparisons were performed with the χ(2)-test. 167 episodes of SE in 118 patients could be evaluated. The efficacy rates of AEDs differed significantly, mainly due to the superior efficacy of clonazepam (CZP). CZP seemed to be more effective than DZP, LEV, MDM and VPA in terminating generalized convulsive status epilepticus (GCSE), whereas there was no significant difference in the efficacy for terminating nonconvulsive status epilepticus (NCSE) and epilepsia partialis continua (EPC) between the used AEDs. Anaesthesia and CZP both terminated GCSE more effectively than NCSE and EPC. Concerning the course of the different kinds of SE the following results were obtained: 13 patients died during hospital treatment. Treatment in NCSE and EPC started significantly later than in GCSE. There was no significant difference in mortality between the types of SE. However the frequency of refractory courses differed between the types of SE. At the time of SE termination without the administration of anaesthesia a combination therapy using 2 or more AEDs was established in most episodes.