Efficacy of clobazam as add-on therapy in brain tumor-related epilepsy.

PURPOSE: Brain tumor-related epilepsy (TRE) is often resistant to currently available antiepileptic medications (AEDs). Clobazam was initially approved as adjunctive AED for patients with Lennox Gastaut syndrome but has been used in TRE, despite limited evidence in this context. This observational study aims to examine the effect of clobazam on seizure frequency on patients who have a primary CNS tumor and continued seizures despite their current AEDs. METHODS: A retrospective review of patients with histologically-confirmed primary brain tumors seen in the neuro-oncology interdisciplinary clinic from April 2016-2019 was completed, and patients on clobazam were identified. Response to clobazam was defined as a greater than 50% reduction in seizure frequency. Additional data including patient and tumor characteristics, treatment course, tolerability, AEDs used prior to addition of clobazam, and AEDs concomitantly used with clobazam were collected. RESULTS: A total of 35 patients with TRE on clobazam were identified, with 2 patients unable to tolerate the medication due to side effects. Of the 33 remaining patients, a total of 31 (93.9%) of patients were deemed responders. Ten patients (30.3%) were seizure free within 6 months of clobazam initiation and 21 (63.6%) reported a significant reduction in seizure frequency. This reduction also allowed several patients to modify concurrent AEDs. CONCLUSIONS: Clobazam is an effective agent to use as add-on AED in TRE, with 94% of patients showing a significant response within 6 months. Furthermore, the addition of clobazam may yield a reduction in polypharmacy, as concomitant AEDs can be reduced and potentially withdrawn.

CACNA1H variants are not a cause of monogenic epilepsy.

CACNA1H genetic variants were originally reported in a childhood absence epilepsy cohort. Subsequently, genetic testing for CACNA1H became available and is currently offered by commercial laboratories. However, the current status of CACNA1H as a monogenic cause of epilepsy is controversial, highlighted by ClinGen's recent reclassification of CACNA1H as disputed. We analyzed published CACNA1H variants and those reported in ClinVar and found none would be classified as pathogenic or likely pathogenic per the American College of Medical Genetics classification criteria. Moreover, Cacna1h did not modify survival in a Dravet Syndrome mouse model. We observed a mild increase in susceptibility to hyperthermia-induced seizures in mice with reduced Cacna1h expression. Overall, we conclude that there is limited evidence that CACNA1H is a monogenic cause of epilepsy in humans and that this gene should be removed from commercial genetic testing panels to reduce the burden of variants of uncertain significance for healthcare providers, families and patients with epilepsy.

Ictal central apneas in temporal lobe epilepsies.

OBJECTIVE: The objective of the study was to examine the frequency and characteristics of ictal central apnea (ICA) in a selective cohort of patients with mesial or neocortical temporal lobe epilepsy (TLE) undergoing surface video-electroencephalography (EEG) and multimodal recording of cardiorespiratory parameters. METHODS: We retrospectively screened 453 patients who underwent EEG in a single center including nasal airflow measurements, respiratory inductance plethysmography of thoracoabdominal excursions, peripheral capillary oxygen saturation, and electrocardiography. Patients with confirmed TLE subtype, either by magnetic resonance imaging (MRI) lesions limited to the temporal neocortex or mesial structures and concordant neurophysiologic data, or patients who underwent invasive explorations were included. RESULTS: Ictal central apnea frequency and characteristics were analyzed in 41 patients with 164 seizures that had multimodal respiratory monitoring. The total occurrence of ICA in all seizures in this cohort was 79.9%. No significant difference was seen between mesial and neocortical temporal lobe seizures (79.8% and 80.0%, respectively). Ictal central apnea preceded EEG onset by 13 ±â€¯11 s in 33.3% of seizures and was the first clinical sign by 18 ±â€¯14 s in 48.7%. Longer ICA duration trended towards a more severe degree of hypoxemia. CONCLUSIONS: In a selective cohort of TLE defined by MRI lesion and/or intracranial recordings, the frequency of ICA was higher than previously reported in the literature. Multimodal respiratory monitoring has localizing value and is generally well tolerated. Ictal central apnea preceded both EEG on scalp recordings as well as clinical seizure onset in a substantial number of patients. Respiratory monitoring and ICA detection is even more paramount during invasive monitoring to confirm that the recorded seizure onset is seen before the first clinical sign.

Contraceptive vaginal ring reduces lamotrigine levels.

OBJECTIVE: The objective of the study was to describe the effect of the vaginal ring and transdermal patch on lamotrigine serum levels in women with epilepsy. BACKGROUND: Previous studies demonstrate that oral hormonal contraceptives containing synthetic estrogen increase lamotrigine clearance through induction of glucuronidation. This leads to variable lamotrigine serum concentrations throughout monthly cycles in women who are on combined oral contraceptives (COCs). The effects of estrogen-containing nonoral hormonal contraceptive methods, including the vaginal ring and transdermal patch, on lamotrigine pharmacokinetics are not well described. METHODS: Retrospective chart review was performed to identify serum lamotrigine levels drawn from women with epilepsy while on the active phase of vaginal ring or transdermal patch and while off contraception. Wilcoxon signed-rank tests for paired data were used to compare the difference in dose-corrected lamotrigine concentration in plasma between values while on hormonal contraception to those while off contraception in patients using a vaginal ring. RESULTS: Six patients were using the vaginal ring, and one patient was using the transdermal patch. Lamotrigine dose-corrected concentrations were decreased during the active phase of the vaginal ring compared with concentrations during the period off contraception (p = .04). There was one patient without a decrease in concentration, but the other five patients on the vaginal ring had a decrease in dose-corrected lamotrigine concentration ranging from 36 to 70% while on the vaginal ring. Similarly, one patient using the transdermal patch had a decrease of 37% in dose-corrected lamotrigine concentration while on the patch. CONCLUSIONS: The findings support that the vaginal ring contraceptive method decreases lamotrigine concentrations during the active phase of treatment. This has important implications for contraceptive counseling and maintaining therapeutic levels in women of childbearing age with epilepsy.

Continuous positive airway pressure usage in hospitalized patients with known obstructive sleep apnea: discrepancy between admission pressure settings and laboratory-determined settings.

PURPOSE: The aim of this study was to determine the frequency and predictors of correctly initiated continuous positive airway pressure (CPAP) settings on the initial night of hospitalization in patients with known obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: Hospital records of all patients who underwent an outpatient therapeutic polysomnogram (PSG) at our institution between January 2005 and December 2010 were retrospectively reviewed. Data collected included initial CPAP settings on hospital admission, latency to hospitalization (from sleep study), hospital length of stay, demographic variables, and PSG variables. RESULTS: One hundred seventy subjects were included in the analysis: 51 % were male, average age (±SD) was 55.3 ± 13.7 years, and body mass index was 43.7 ± 10.4 kg/m2. OSAHS was generally severe (apnea-hypopnea index (AHI) 52.8 ± 37.3 event/h). Mean CPAP setting during in-laboratory titration was 11.1 ± 3.1 cm H2O and during the first night of hospitalization was 9.5 ± 2.8 cm H2O (p < 0.0001). Of 170 subjects, only 71 (42 %) received the correct laboratory-derived CPAP setting on the first night of hospitalization. In a multivariable logistic regression analysis, higher body mass index (BMI), lower CPAP level determined during PSG, and shorter latency (months) between PSG and hospitalization were associated with receiving the correct CPAP setting during the first night of hospitalization: Each 1 kg/m2 increase in BMI was associated with a 7 % increase odds of receiving the correct CPAP setting during the first night of hospitalization (OR 1.07, 95 % CI 1.02-1.12), while each 1 cm H2O increase in CPAP during PSG and each 1 month longer latency between PSG and hospitalization was associated with a 15 and 7 %, respectively, decrease in the odds of receiving the correct CPAP setting during the first night of hospitalization (CPAP OR 0.85, 95 % CI 0.74-0.97 and latency OR 0.93, 95 % CI 0.90-0.97). There was no in-hospital mortality, and correct CPAP settings did not affect hospital length of stay. CONCLUSIONS: Among patients admitted to the hospital, a correct, laboratory-derived CPAP setting is infrequently prescribed during the first night of hospitalization. Predictors for correctly ordering CPAP include latency from the time of in-laboratory CPAP titration, BMI, and laboratory-derived CPAP level.

Tumor type, epilepsy burden, and seizure documentation: experiences at a single center neuro-oncology clinic.

BACKGROUND: Patients with both primary and metastatic brain tumors have significant seizure burden due to their tumor. The management of tumor-related epilepsy (TRE) and optimizing antiepileptic drug (AED) regimens requires collaboration between neurologists and seizure specialists, which is facilitated by seizure documentation in clinic notes. We aim to describe seizure incidence in patients seen in neuro-oncology clinical practice. Further, in the subset of those patients with TRE, we aim to analyze seizure documentation. METHODS: This is a retrospective review of patients with a primary or metastatic brain tumor seen in a neuro-oncology clinic in October 2019. Patients with TRE were included in the analysis of seizure documentation. These notes were analyzed for inclusion of seizure descriptors, terminology, AED regimens, and changes in management. RESULTS: Of the full cohort of 356 patients, 199 (55.9%) had TRE. Anaplastic astrocytomas had the highest percentage of patients with TRE. The analysis of seizure documentation in patients with TRE revealed that the majority of notes (90.9%) mentioned seizures. Fewer notes (39.6%) provided additional descriptions of the seizures or commented on AED regimens (58.3%). In notes for patients who had seizures within the previous 6 months, seizure descriptors were more likely. CONCLUSIONS: This study defines the TRE burden in a cohort of patients seen in neuro-oncology clinic. Among patients with TRE, our study shows that documentation of many aspects of the characteristics and management of patient seizures can be improved, which would facilitate further analysis of impact on patient care as well as future research.

Indications and yield of ambulatory EEG recordings.

To study the yield of prolonged ambulatory electroencephalogram (aEEG). A retrospective chart review of all patients who underwent aEEG studies between 2013 and 2017 was performed. Reasons for aEEG were classified into five categories: detection of interictal epileptiform discharges (IEDs), capturing clinical events, detection of unrecognized seizures, monitoring IEDs during treatment, and unclassifiable. Ambulatory EEG reports were reviewed to evaluate whether the study answered the clinical question. A total of 1,264 patients were included. Forty studies were excluded for incomplete data and 234 for being a repeat study. The average number of recording days was 1.57 ± 0.73. Based on initial clinical evaluation, patients carried the following presumptive diagnosis: 61% epilepsy, 11% single unprovoked or acute symptomatic seizure and 28% non-epileptic paroxysmal events (PEs). Overall, focal IEDs were seen in 16.1% of studies, generalized IEDs in 10.8%, focal seizures in 4.1%, and generalized seizures in 1.9%. The most frequent reason for ordering aEEG was to detect IEDs for diagnostic purposes (48.1%). For this indication, additional information was provided by the aEEG in 19.1% of cases (58.6% focal IEDs, 33.5% generalized IEDs, 7.9% seizures without IEDs). Ambulatory EEG was ordered with the intent to capture and characterize clinical events in 18.9%, mostly in patients who reported daily or weekly events. In these, aEEG captured either epileptic seizures or PEs in 102 (42.7%) of the studies (83.3% PEs, 16.7% epileptic seizures). Ambulatory EEG was ordered to evaluate unrecognized seizures in 17.8% of patients, and electrographic seizures were identified in 13.3% of these studies. The yield of aEEG varies based on the indication for the study. Ambulatory EEG can be a useful tool for recording IEDs in the outpatient setting and in a select group of patients to capture clinical events or unrecognized seizures.

Paraclinical serum markers as aids in the diagnosis of autoimmune encephalitis.

Expert opinion suggests the presence ANA and thyroid antibodies may be helpful to diagnosis autoimmune encephalitis (AE). This study investigates the sensitivity of these serum markers in a cohort of 26 patients with AE. TPO-Ab, TG-Ab and ANA (titer ≥1:320) were present in 45%, 35% and 32% of patients tested, respectively. The prevalence of TPO-Ab (11.3%), TG-Ab (10.4%) and ANA ≥1:320 (3.3%) has been previously reported in disease-free populations. Although these antibodies represent non-specific markers of autoimmunity, this study demonstrated that TPO-Ab, TG-Ab and ANA were significantly elevated in AE compared to disease-free populations (p < .001, p = .003, p < .001, respectively).

Automated seizure detection accuracy for ambulatory EEG recordings.

OBJECTIVE: To investigate the accuracy of preselected software automatic seizure files to detect at least one seizure per study in prolonged ambulatory EEG recording. METHODS: All the prolonged ambulatory EEG recordings (>24 hours) read at the Northwestern Memorial Hospital from January 2013 to October 2017 were included. We selected only the first study of each patient. We reviewed the studies entirely, and processed the recordings through 1 of 3 different detection software that are commercially available (Persyst 11, Persyst 12, and Gotman TM Event Detection). The proportion of patients with at least one electrographic seizure (≥10 seconds) correctly identified by a seizure detector was calculated. Finally, we evaluated whether the type of seizure (focal vs generalized) may affect the chances of being automatically detected. RESULTS: We read 1,478 ambulatory EEG studies entirely (2,323 days of EEG recording; average 1.6 d/study). From the first study of each patient (1,257 studies), we found electrographic seizures in 70 (5.6%) studies. In 37 of 70 patients (53%), the automatic detectors correctly identified at least one seizure. Detections happened slightly more frequently in generalized seizures (14/20, 70%) compared to focal seizures (23/50, 46%) (p = 0.06). CONCLUSION: Seizures were found in 5.6% of the studies. Automatic seizure detectors identified at least one electrographic seizure in only 53% of the studies. They performed slightly better detecting generalized than focal seizures. Therefore, the review of only automatically selected segments may be of decreased value to identify seizures, in particular when focal seizures are suspected.

Positive Expiratory Pressure Therapy With And Without Oscillation And Hospital Length Of Stay For Acute Exacerbation Of Chronic Obstructive Pulmonary Disease.

Introduction: Pharmacologic management of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is well-established. Our aim in the current study is to determine if therapy with a positive expiratory pressure (PEP) device with or without an oscillatory mechanism (OM) in addition to standard care results in a reduction in hospital length of stay (LOS) among patients hospitalized for AECOPD. Methods: Two studies were performed and are reported here. Study 1: Patients admitted with AECOPD and sputum production were enrolled in a prospective trial comparing PEP therapy versus Oscillatory PEP (OPEP) therapy. Study 2: A retrospective historical cohort, matched in a 2 to 1 manner by age, gender, and season of admission, was compared with the prospectively collected data to determine the effect of PEP ± OM versus standard care on hospital LOS. Results: In the prospective trial (Study 1; 91 subjects), median hospital LOS was 3.2 (95% CI 3.0-4.3) days in the OPEP group and 4.8 (95% CI 3.9-6.1) days in the PEP group (p=0.16). In fully adjusted models comparing the prospective trial data with the retrospective cohort (Study 2; 182 subjects), cases had a median hospital LOS of 4.2 days (95% CI 3.8-5.1) versus 5.2 days (95% CI 4.4-6.0) in controls, consistent with a shorter hospital LOS with adjunctive PEP±OM therapy versus standard care (p=0.04). Conclusion: Adjunctive therapy with a PEP device versus standard care may reduce hospital LOS in patients admitted for AECOPD. Although the addition of an OM component to PEP therapy suggests a further reduction in hospital LOS, comprehensive multicenter randomized controlled trials are needed to confirm these findings. Clinical trial registration number: NCT03094806.

Use of high speed stereo radiography to assess the foot orthoses effectiveness in controlling midfoot posture during walking: A pilot study.

BACKGROUND: The intent of this pilot study was to determine the feasibility of using high-speed stereo radiography (HSSR) to assess the effectiveness of footwear and foot orthoses in controlling the change in the position of the midfoot during walking in individuals with a flexible pes planus foot type. METHODS: Four individuals (1 female; 3 male) with a mean age of 25 years (range 22-29) and a bilateral flexible pes planus foot type participated in the study. The HSSR system was used to measure 3-dimensional changes in the longitudinal arch angle (LAA) with each participant walking barefoot, shoe only and shoes with orthoses. RESULTS: The HSSR system was found to be highly effective in measuring the change in the position of the midfoot, as measured using the LAA, when wearing footwear with or without foot orthoses. Based on an assessment of mean values, three out of the four participants demonstrated a change in the LAA as a result of using either shoes only or shoes with orthoses. The methodology used in this pilot study for assessing the effect of footwear and foot orthoses on the posture of the midfoot was highly effective with no side-effects noted by any of the study participants. CONCLUSIONS: Future studies using the HSSR will require modifications to participant inclusion criteria as well as alterations to the data collection methodology. The HSSR system used in this study is feasible for use in larger cohort studies assessing footwear and foot orthosis effectiveness with the described modifications.