Dual Treatment of Refractory Focal Epilepsy and Obsessive-Compulsive Disorder With Intracranial Responsive Neurostimulation.

Purpose of the Review: Intracranial neurostimulation is a well-established treatment of neurologic conditions such as drug-resistant epilepsy (DRE) and movement disorders, and there is emerging evidence for using deep brain stimulation to treat obsessive-compulsive disorder (OCD) and depression. Nearly all published reports of intracranial neurostimulation have focused on implanting a single device to treat a single condition. The purpose of this review was to educate neurology clinicians on the background literature informing dual treatment of 2 comorbid neuropsychiatric conditions epilepsy and OCD, discuss ethical and logistical challenges to dual neuropsychiatric treatment with a single device, and demonstrate the promise and pitfalls of this approach through discussion of the first-in-human closed-looped responsive neurostimulator (RNS) implanted to treat both DRE (on-label) and OCD (off-label). Recent Findings: We report the first implantation of an intracranial closed-loop neurostimulation device (the RNS system) with the primary goal of treating DRE and a secondary exploratory goal of managing treatment-refractory OCD. The RNS system detects electrophysiologic activity and delivers electrical stimulation through 1 or 2 electrodes implanted into a patient's seizure-onset zones (SOZs). In this case report, we describe a patient with treatment-refractory epilepsy and OCD where the first lead was implanted in the right superior temporal gyrus to target the most active SOZ based on stereotactic EEG (sEEG) recordings and semiology. The second lead was implanted to target the right anterior peri-insular region (a secondary SOZ on sEEG) with the distal-most contacts in the right nucleus accumbens, a putative target for OCD neurostimulation treatment. The RNS system was programmed to detect and record the unique electrophysiologic signature of both the patient's seizures and compulsions and then deliver tailored electrical pulses to disrupt the pathologic circuitry. Summary: Dual treatment of refractory focal epilepsy and OCD with an intracranial closed-loop neurostimulation device is feasible, safe, and potentially effective. However, there are logistical challenges and ethical considerations to this novel approach to treatment, which require complex care coordination by a large multidisciplinary team.

Trends in management of patients with new-onset refractory status epilepticus (NORSE) from 2016 to 2023: An interim analysis.

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

Responsive neurostimulation as a therapy for epilepsy following new-onset refractory status epilepticus: Case series and review of the literature.

OBJECTIVE: To report clinical outcomes of patients who presented with new-onset refractory status epilepticus (NORSE), developed drug-resistant epilepsy (DRE), and were treated with responsive neurostimulation (RNS). METHODS: We performed a retrospective review of patients implanted with RNS at our institution and identified three who originally presented with NORSE. Through chart review, we retrieved objective and subjective information related to their presentation, workup, and outcomes including patient-reported seizure frequency. We reviewed electrocorticography (ECoG) data to estimate seizure burden at 3, 6, 12, and 24 months following RNS implantation. We performed a review of literature concerning neurostimulation in NORSE. RESULTS: Use of RNS to treat DRE following NORSE was associated with reduced seizure burden and informed care by differentiating epileptic from non-epileptic events. CONCLUSIONS: Our single-center experience of three cases suggests that RNS is a safe and potentially effective treatment for DRE following NORSE. SIGNIFICANCE: This article reports outcomes of the largest case series of NORSE patients treated with RNS. Since patients with NORSE are at high risk of adverse neuropsychiatric and cognitive sequelae beyond seizures, a unique strength of RNS over other surgical options is the ability to distinguish ictal or peri-ictal from non-epileptic events.

Comparative analysis of patients with new onset refractory status epilepticus preceded by fever (febrile infection-related epilepsy syndrome) versus without prior fever: An interim analysis.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

Responsive deep brain stimulation guided by ventral striatal electrophysiology of obsession durably ameliorates compulsion.

Treatment-resistant obsessive-compulsive disorder (OCD) occurs in approximately one-third of OCD patients. Obsessions may fluctuate over time but often occur or worsen in the presence of internal (emotional state and thoughts) and external (visual and tactile) triggering stimuli. Obsessive thoughts and related compulsive urges fluctuate (are episodic) and so may respond well to a time-locked brain stimulation strategy sensitive and responsive to these symptom fluctuations. Early evidence suggests that neural activity can be captured from ventral striatal regions implicated in OCD to guide such a closed-loop approach. Here, we report on a first-in-human application of responsive deep brain stimulation (rDBS) of the ventral striatum for a treatment-refractory OCD individual who also had comorbid epilepsy. Self-reported obsessive symptoms and provoked OCD-related distress correlated with ventral striatal electrophysiology. rDBS detected the time-domain area-based feature from invasive electroencephalography low-frequency oscillatory power fluctuations that triggered bursts of stimulation to ameliorate OCD symptoms in a closed-loop fashion. rDBS provided rapid, robust, and durable improvement in obsessions and compulsions. These results provide proof of concept for a personalized, physiologically guided DBS strategy for OCD.

Multigene Panel Testing in a Large Cohort of Adults With Epilepsy: Diagnostic Yield and Clinically Actionable Genetic Findings.

BACKGROUND AND OBJECTIVES: Although genetic testing among children with epilepsy has demonstrated clinical utility and become a part of routine testing, studies in adults are limited. This study reports the diagnostic yield of genetic testing in adults with epilepsy. METHODS: Unrelated individuals aged 18 years and older who underwent diagnostic genetic testing for epilepsy using a comprehensive, next-generation sequencing-based, targeted gene panel (range 89-189 genes) were included in this cross-sectional study. Clinical information, provided at the discretion of the ordering clinician, was reviewed and analyzed. Diagnostic yield was calculated for all individuals including by age at seizure onset and comorbidities based on clinician-reported information. The proportion of individuals with clinically actionable genetic findings, including instances when a specific treatment would be indicated or contraindicated due to a diagnostic finding, was calculated. RESULTS: Among 2,008 individuals, a diagnostic finding was returned for 218 adults (10.9%), with clinically actionable findings in 55.5% of diagnoses. The highest diagnostic yield was in adults with seizure onset during infancy (29.6%, 0-1 year), followed by in early childhood (13.6%, 2-4 years), late childhood (7.0%, 5-10 years), adolescence (2.4%, 11-17 years), and adulthood (3.7%, ≥18 years). Comorbid intellectual disability (ID) or developmental delay resulted in a high diagnostic yield (16.0%), most notably for females (19.6% in females vs 12.3% in males). Among individuals with pharmacoresistant epilepsy, 13.5% had a diagnostic finding, and of these, 57.4% were clinically actionable genetic findings. DISCUSSION: These data reinforce the utility of genetic testing for adults with epilepsy, particularly for those with childhood-onset seizures, ID, and pharmacoresistance. This is an important consideration due to longer survival and the complexity of the transition from pediatric to adult care. In addition, more than half of diagnostic findings in this study were considered clinically actionable, suggesting that genetic testing could have a direct impact on clinical management and outcomes.

How to Help Your Patients Enroll in the New-Onset Refractory Status Epilepticus (NORSE) and Febrile Infection-Related Epilepsy Syndrome (FIRES) Family Registry, and Other Rare Epilepsy Registries.

New-onset refractory status epilepticus (NORSE) is a rare clinical presentation of refractory status epilepticus (RSE) that occurs in people without active epilepsy or preexisting neurologic disorder. Febrile infection-related epilepsy syndrome (FIRES) is a subcategory of NORSE. New-onset refractory status epilepticus/FIRES are becoming increasingly recognized; however, information pertaining to disease course, clinical outcomes, and survivorship remains limited, and mortality and morbidity are variable, but often high. The objective of the NORSE/FIRES Family Registry is to (1) provide an easily accessible and internationally available multilingual registry into which survivors or NORSE/FIRES surrogates or family members of people affected by NORSE/FIRES or their physicians can enter data in a systematic and rigorous research study from anywhere in the world where internet is available; and (2) to examine past medical history, outcomes, and quality of life for people affected by NORSE/FIRES.

Marijuana use among patients with epilepsy at a tertiary care center.

The expansion of medical and recreational marijuana legalization facilitates patient access to cannabis, and many patients with epilepsy pursue marijuana as a treatment for seizures. We administered a nine-item survey on marijuana use to patients seen in an epilepsy clinic over a 9 month period at a tertiary care center in Oregon where recreational use was legalized in 2015. The majority of respondents (n = 39) reported cannabis use for the purpose of treating epilepsy (87.2%, n = 34), and strongly agreed (53.8%, n = 21) or agreed (28.2%, n = 11) that cannabis use improved seizure control. The most commonly selected cannabis strains were high cannabidiol (CBD) (30.8%, n = 12) or multiple types (30.8%, n = 12), with administration methods of smoking (66.7%, n = 26), edibles (48.7%, n = 19), and concentrates (43.6%, n = 17). More participants reported using marijuana with primarily CBD than primarily tetrahydrocannabinol (THC) or equal CBD:THC content, and very few women reported using marijuana with primarily THC compared with men (10% of female versus 47% of male respondents). Only 2 of 39 participants were able to give an exact dosage used in milligrams. Medical and recreational dispensaries were the most common cannabis sources, followed by homegrown and friends/family members. Although pharmaceutical CBD extract is now Food and Drug Administration (FDA)-approved for certain epilepsy types, access remains limited. Further research is needed to understand recreational cannabis use among patients with epilepsy while clinical research for pharmaceutical cannabis products continues.

Novel Use of Responsive Neurostimulation (RNS System) in the Treatment of Super Refractory Status Epilepticus.

There are very few randomized controlled trials studying treatment of super refractory status epilepticus (SE), despite estimated occurrence in about 15% of SE cases and its association with high morbidity and mortality rates. Small case series and case reports have described use of neurostimulation, including vagal nerve stimulation, transcranial magnetic stimulation, and deep brain stimulation, to treat super refractory SE when medical interventions have failed. To our knowledge, this is the first reported case of responsive neurostimulation being used to successfully treat a case of super refractory SE. A 37-year-old man with refractory focal epilepsy and a known focal cortical dysplasia involving motor cortex was implanted with an RNS System device after being in super refractory SE for 20 days. Responsive neurostimulation strip and depth electrodes were placed targeting the cortical dysplasia. Detection and stimulation parameters were adjusted over a 14-day period, as medications were gradually weaned. Seizures abated 15 days after implant, 24 hours after stimulation parameters were configured to mimic seizure offset pattern. Seizure remission was sustained, allowing the patient to be weaned off sedating medications and discharged to a rehabilitation facility. At 6 weeks of follow-up, the patient was near his neurologic baseline with no focal deficits.

Psychogenic non-epileptic seizures among patients with functional neurological disorder: A case series from a Tanzanian referral hospital and literature review.

Objective: Functional neurological disorders (FNDs) and psychogenic nonepileptic seizures (PNES) are likely as common in Sub-Saharan Africa (SSA) as in the rest of the world, but there is a dearth of literature on the epidemiology and clinical presentation of these disorders in Africa. The purpose of this paper is to describe a case series of FNDs presenting to a referral hospital in SSA. In addition, we review the existing literature on FNDs in Africa. Methods: A hospital-based retrospective cross-sectional study was conducted to determine the prevalence, epidemiology, and clinical phenotype of FNDs and PNES in a referral hospital in Northern Tanzania over a 6-year period (2007-2013). Results: Of 2,040 patients presenting with neurological complaints, 44 (2.2%) were diagnosed with FNDs. Half (n = 22) had the clinical presentation of PNES. Age of presentation for FNDs and PNES peaked in the teen years 12-19 (n = 21 48%; and n = 14, 63%, respectively), and the majority were female (n = 30, 68%; and n = 14, 63%, respectively). The majority presented acutely with short-lived and self-limiting symptoms (only 2 recurrent cases). Literature review revealed multiple reports of "mass hysteria" in SSA often meeting the clinical criteria of epidemic FNDs. Significance: FNDs and PNES occur in Africa with age and gender distribution comparable to that found elsewhere. Although the percentage of FND cases overall was relatively low (2.2%), it is likely to be an underestimate because not all cases were recorded, and cases may be appropriately managed locally before patients are referred to a hospital. PNES was the most common phenotype of FNDs reported, and the African phenotype may be short-lived and self-limiting rather than chronic and recurrent, as reported elsewhere in the world. PNES presentations may also occur in clusters, which may have cultural significance in Africa. FNDs in Africa appear to be underreported, particularly over the last 30 years.

Neurodevelopmental Effects of Antiepileptic Drugs.

Increasing evidence suggests that exposure to certain antiepileptic drugs (AEDs) during critical periods of development may induce transient or long-lasting neurodevelopmental deficits across cognitive, motor and behavioral domains. The developing nervous system may endure prolonged chronic exposure to AEDs during pregnancy (in utero) or during childhood, which can lead to neurodevelopmental defects such as congenital neural tube defects, lower IQ, language deficits, autism and ADHD. To date, valproate is the most widely recognized AED to significantly negatively affect neurodevelopment, and demonstrates greater adverse effects than any other AEDs that have been assessed. Although some AEDs appear to have low risk (i.e., lamotrigine, levetiracetam), other AEDs have been implicated in a variety of studies detailed below, and many AEDs have not been adequately assessed. The purpose of this review article is to summarize our current understanding of the neurodevelopmental effects of AEDs.

Effects of Meteorological Variables on the Incidence of Rupture of Intracranial Aneurysms in Central New Jersey.

Introduction Previous studies have suggested relationships between the rupture of intracranial aneurysms and meteorological variables such as season, barometric pressure, and temperature. Our objective was to examine the relationship between the incidence of hospital admissions secondary to aneurysmal subarachnoid hemorrhage (aSAH) and meteorological variables in central New Jersey. Methods The study population consisted of 312 patients who presented to University Hospital in Newark, New Jersey, between January 1, 2003, and December 31, 2008, with aSAH. Days in the 6-year period were classified as nonbleed days (no aSAH), bleed days (one or more aSAHs within 1 calendar day), cluster days (two or more aSAHs within 2 calendar days), and multiple-bleed days (two or more aSAHs within 1 calendar day). Results The only significant meteorological risk factor for the occurrence of multiple-bleed days was high barometric pressure (1018.5 versus 1016.5 millibars [mbars]; p < 0.04), but an increase in barometric pressure (+ 2.8 mbars) over the 2 days prior to the multiple-bleed day, although not statistically significant, may be a risk factor (p < 0.09). Barometric pressure was also noted to be increased on bleed days (1017.2 versus 1016.5 mbars) and cluster days (1017.7 versus 1016.5 mbars), but this relationship was not significant (p < 0.1 and p < 0.1, respectively). Although aSAH days demonstrated consistently lower temperatures than non-aSAH days and dropping temperatures were consistently found in the days preceding the aSAH, these relationships were not significant. Conclusion Among meteorological factors, high barometric pressure and low temperature may be risk factors for the onset of aSAH.

Sudden neurologic deficit.

Clinicians treating sudden neurologic deficit are being faced with an increasing number of available imaging modalities. In this chapter we discuss a general approach to acute neuroimaging and weigh the considerations that determine which modality or modalities should be utilized.

Health care utilization following diagnosis of psychogenic nonepileptic seizures.

OBJECTIVES: The long-term outcome of patients with psychogenic nonepileptic seizures (PNES) is of importance given the disabling symptoms and tendency to affect patients early in their productive years. Health care utilization (HCU) is an important outcome measure reflecting overall health status and costs. There is little information regarding long-term HCU following diagnosis of PNES. METHODS: We retrospectively reviewed records of Veterans diagnosed with PNES during epilepsy monitoring unit (EMU) evaluation. For the three-year period following diagnosis of PNES, we reviewed emergency department (ED) visits, hospitalizations, outpatient clinic visits, and radiology procedures. We compared the three years following PNES diagnosis with the three years preceding diagnosis. We also compared patients with PNES and patients with epileptic seizures (ES). RESULTS: Emergency department visits and hospitalizations were more frequent in patients with PNES compared with those in patients with ES (p=0.01). There was no overall improvement in HCU during the three-year interval following diagnosis of PNES. A transient decrease during the year following diagnosis was not sustained over three-year follow-up. Pain complaints rather than seizures were the most common reason for presentation, whereas the opposite was true for patients with ES (p<0.01). There was a sharp decrease in neurology outpatient visits (p<0.001) and a decrease in primary care visits (p<0.05) after PNES was diagnosed. Total outpatient visits were unchanged. CONCLUSIONS: Overall HCU did not improve during the three years following diagnosis of PNES, compared with three years preceding diagnosis. The results add to studies documenting poor seizure outcomes following diagnosis of PNES and underscore the need for more effective and comprehensive treatments, addressing comorbid symptoms.

Secondary Myelitis in Dermal Sinus Causing Paraplegia in a Child with Previously Normal Neurological Function.

Neural tube defects result from failure of neural tube fusion during early embryogenesis, the fourth week after conception. The spectrum of severity is not uniform across the various forms of this congenital anomaly as certain presentations are not compatible with extrauterine life (anencephaly) while, on the other hand, other defects may remain undiagnosed as they are entirely asymptomatic (occult spina bifida). We report a child with previously normal neurological development, a devastating clinical course following superinfection of a subtle spina bifida defect which resulted in a flaccid paralysis below the level of the lesion and permanent neurological deficits following resolution of the acute infection and a back closure surgery.