Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson's Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

Long-term use of rituximab increases T cell count in MS patients.

Rituximab has been used to treat MS patients in Iceland for over a decade. However, long-term effect of rituximab on leukocyte populations has not yet been elucidated. By retrospective analysis of flow cytometric data from 349 patients visiting the neurological ward at The National University Hospital of Iceland from 2012 to 2023 for rituximab treatment, the long-term effect of rituximab and whether the effect was dose dependent (1000mg vs 500mg) was evaluated. No difference was detected in efficacy of B cell depletion in patients treated with 500mg as an initial dose of rituximab when compared to 1000mg. Long-term use of rituximab led to an increase in T cell count (p=0,0015) in patients receiving 3-8 doses of rituximab (1.5-8 years of treatment). The increase occurred in both CD4+ (p=0,0028) and CD8+ T cells (p=0,0015) and led to a decrease in the CD4/CD8 ratio (p=0,004). The most notable difference lies in reshaping the balance between näive and effector CD8+ T cells. The clinical implications of long-term treatment with rituximab and its effect on the T cell pool needs to be explored further. Since no difference in B cell depletion was detected between the two patient groups, 1000mg as an initial dose might be excessive, suggesting a personalized dosing regimen might have therapeutic and financial advantages.

[The hereditary vessel disease CADASIL].

Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease of the brain characterized by progressive white matter lesions, subcortical infarcts, and cognitive decline. This autosomal dominant disorder is caused by mutations in the NOTCH3 gene located on chromosome 19, resulting in the accumulation of granular osmiophilic material within the walls of small arteries and arterioles. Clinically, CADASIL typically manifests in mid-adulthood with recurrent ischemic events, migraine with aura, mood disturbances, and cognitive impairment. Neuroimaging plays a crucial role in the diagnosis of CADASIL, with characteristic findings including white matter hyperintensities particularly in the anterior temporal lobe and external capsule.

Type, Etiology, and Duration of Epilepsy as Risk Factors for SUDEP: Further Analyses of a Population-Based Case-Control Study.

BACKGROUND AND OBJECTIVES: We conducted a nationwide case-control study in Sweden to investigate the risk of sudden unexpected death in epilepsy (SUDEP) in relation to epilepsy duration, epilepsy type, and etiology in combination with occurrence and frequency of tonic-clonic seizures (TCS) and nocturnal TCS. METHODS: The study comprised 255 SUDEP cases and 1,148 epilepsy controls. Clinical information was obtained from medical records. The association between SUDEP and risk factors was estimated by odds ratios (ORs) with 95% CIs calculated by conditional logistic regression to account for matching by sex and calendar time. RESULTS: The risk of SUDEP was elevated in people with focal (OR 1.48, 95% CI 1.00-2.20), generalized and focal (OR 3.51, 95% CI 1.55-7.96), or unknown (OR 2.43, 95% CI 1.29-4.57) vs generalized epilepsy type. Increased risk of SUDEP was also observed in relation to epilepsy with traumatic causes (OR 2.27, 95% CI 1.33-3.89 vs genetic etiology) or short duration (OR 1.71, 95% CI 1.01-2.87 for 0-5 vs 6-15 years duration). Among those with 1-3 TCS during the preceding year, structural epilepsy etiology was associated with a more than 10-fold increase 10.84 (4.85-24.27) in SUDEP risk compared with people with genetic epilepsy without TCS. The risk with ≥4 TCS the preceding year was similar among those with generalized and focal epilepsies. Those with ≥4 TCS had an OR of 210.73 (95% CI 28.40-∞) during years 0-5 compared with those free from TCS and an epilepsy duration of 6-15 years. The combination of short epilepsy duration (0-5 years) and nocturnal TCS conferred an OR of 45.99 (95% CI 12.19-173.61) compared with having longer duration (6-15 years) and being free from nocturnal TCS. DISCUSSION: Although certain etiologies, such as post-traumatic epilepsy, seem to entail a higher SUDEP risk, our data indicate that frequent and nocturnal TCS carry a similar level of risk whether focal or generalized from onset. The tonic-clonic part of the seizure seems to be decisive for the fatal outcome. SUDEP risk associated with TCS is highest during the first years after the epilepsy diagnosis which calls for effective TCS treatment and vigilance from the onset of diagnosis.

Long-term Outcomes After Periprocedural and Spontaneous Spinal Cord Infarctions: A Population-Based Cohort Study.

BACKGROUND AND OBJECTIVES: Spinal cord infarction (SCInf) is a rare condition where consensus regarding diagnostic criteria is lacking, and misdiagnosis or delayed diagnosis can be detrimental. The aim of this study was to describe baseline findings and predictors of long-term functional outcome in a population-based cohort of patients with SCInf. METHODS: All adult patients (aged 18 years or older) treated at the spinal cord injury unit of the study center, between 2006 and 2019, and discharged with a G95 diagnosis (other and unspecified disease of the spinal cord) were screened for inclusion. The diagnostic criteria proposed by Zalewski et al. were retrospectively applied to evaluate the certainty of the SCInf diagnosis. RESULTS: A total of 270 patients were screened and 57 were included in the study, of whom 30 had a spontaneous SCInf and 27 had a periprocedural SCInf. The median American Spinal Cord Injury Association Impairment Scale (AIS) on admission was C, which at a median follow-up of 2.1 years had improved to D (p = 0.002). Compared with periprocedural cases, those with spontaneous SCInf showed significantly better admission AIS (median AIS D vs B, p < 0.001), fewer multilevel SCInf (27% vs 59%, p = 0.029), shorter hospital stay (median 22 vs 44 days, p < 0.001), and better AIS (median AIS D vs C, p < 0.001) and ambulatory status on long-term follow-up (66% vs 1%, p < 0.001). Regression analyses revealed that spontaneous SCInfs (odds ratio [OR] 5.91 [1.92-18.1], p = 0.002) and more favorable admission AIS (OR 33.6 [7.72-146], p < 0.001) were significant predictors of more favorable AIS at follow-up, with admission AIS demonstrating independent predictive ability (OR 35.9 [8.05-160], p < 0.001). DISCUSSION: SCInf is a rare neurologic emergency lacking specific management guidelines. While the presumptive diagnosis is based on the typical presentation and clinical findings, T2-weighted and diffusion-weighted MRI were the most useful diagnostic tools in establishing a definitive diagnosis. Our data show that spontaneous SCInf mostly affected a single spinal cord segment, whereas periprocedural cases were more extensive, had poorer AIS on admission, poorer ambulatory function, and longer hospital stays. Regardless of the etiology, significant neurologic improvements were seen at long-term follow-up, highlighting the importance of active rehabilitation.

[Transient Global Amnesia in the Reykjavik area].

BACKGROUND: Transient Global Amnesia (TGA) is a benign syndrome characterized by sudden anterograde memory loss, that resolves spontaneously within 24 hours. TGA appears without other focal neurological symptoms. The aim of this study was to study TGA in the greater Reykjavik-area. METHODS: We retrospectively analysed the medical history of patients with a diagnosis of TGA (ICD-10 G45.4) at the University Hospital in Iceland in 2010-2021. Medical records were reviewed, and information about year and age at diagnosis, sex, symptoms, precipitating events, imaging results and risk factors were collected. Statistical processing was performed with Excel and Rstudio. RESULTS: Overall, 348 attacks of TGA were identified with a mean frequency of 29 attacks/year, where 9.9% had an earlier history of TGA. The mean age was 64.1, with 50% of subjects between 58-70 years old. The sex distribution was equal (49.9% female). Possible precipitating events were found in 53.7% of cases, with physical activity being the most common one (24.4%), followed by sudden temperature change and emotional stress. In 96% of patients a computerized tomography was performed (no sign of acute changes were found), and magnetic resonance imaging (MRI) in 36.2% of cases. MRI showed restricted diffusion in the hippocampal area in 10.3% of cases. DISCUSSION: TGA is not a rare but a benign syndrome. Our findings regarding age, sex distribution and precipitating events were in accordance with other studies. TGA is thought to result from a temporary hippocampal dysfunction supported by the clinical presentation and MRI findings. The cause of TGA is however still unknown.

Perinatal risk factors for SUDEP: A population-based case-control study.

Sudden unexpected death in epilepsy (SUDEP) is a leading epilepsy-related cause of death. Researchers have highlighted the similarities between SUDEP and sudden infant death syndrome (SIDS), but perinatal risk factors such as those identified for SIDS have not been assessed previously for SUDEP. We conducted a population-based case-control study of 58 SUDEP individuals and 384 living epilepsy controls born after 1982, utilizing the Swedish Medical Birth Register together with other national health registers and individual medical records to examine if prenatal and perinatal factors are associated with SUDEP risk. We observed a 3-fold SUDEP risk increase for infants who were small for gestational age (SGA) (odds ratio [OR] 3.13; 95% confidence interval [CI] 1.05-9.30) and for those with an Apgar score of 0-6 compared to 9-10 at 10 min (OR 3.22; 95% CI 1.05-9.87). After adjusting for a number of known SUDEP risk factors, we observed that the Apgar score between 0 and 6 after 10 min had a 10-fold increased risk for SUDEP OR 10.37 (95% CI 1.49-72.01) and over a 2-fold risk for those born after the 40th gestational week (OR 2.42; 95% CI 1.03-5.65). The potential mechanisms linking low Apgar score, gestational age, and SGA to SUDEP risk remain to be explored.

A genome-wide meta-analysis identifies 50 genetic loci associated with carpal tunnel syndrome.

Carpal tunnel syndrome (CTS) is the most common entrapment neuropathy and has a largely unknown underlying biology. In a genome-wide association study of CTS (48,843 cases and 1,190,837 controls), we found 53 sequence variants at 50 loci associated with the syndrome. The most significant association is with a missense variant (p.Glu366Lys) in SERPINA1 that protects against CTS (P = 2.9 × 10-24, OR = 0.76). Through various functional analyses, we conclude that at least 22 genes mediate CTS risk and highlight the role of 19 CTS variants in the biology of the extracellular matrix. We show that the genetic component to the risk is higher in bilateral/recurrent/persistent cases than nonrecurrent/nonpersistent cases. Anthropometric traits including height and BMI are genetically correlated with CTS, in addition to early hormonal-replacement therapy, osteoarthritis, and restlessness. Our findings suggest that the components of the extracellular matrix play a key role in the pathogenesis of CTS.

[The incidence of sinus thrombosis in Iceland 2008-202].

BACKGROUND: Cerebral venous sinus thrombosis (CSVT) is the cause of 0.5%-1% of all strokes. CSVT can cause haemorrhage, cerebral infarction and increased intracranial pressure. Due to a variety of symptoms, CSVT can be difficult to diagnose. The purpose of this study was to examine the incidence of CSVT in Iceland 2008-2020, risk factors, symptoms, treatment and outcome. METHODS: A retrospective reviewing of medical records of those diagnosed with CSVT from 1. January 2008 to 31. December 2020, was performed. Sex, age at diagnosis, symptoms, known risk factors, imaging results, treatment and outcome were studied. Statistical processing was performed with Excel and Rstudio. RESULTS: Overall, 31 patients were diagnosed with CSVT (22 women). The mean incidence was 0.72/100.00 per year. The mean age was 34.3 years (14-63 years). The most common symptom was headache (87%), other symptoms included focal symptoms and seizures. The most common risk factor was the use of oral contraceptives (73%). Four patients had no risk factor. The most commonly affected sinus was the transverse-sinus (74%). All patients were treated with anticoagulants. Most received heparin or low-molecular-weight heparin then succeeded by warfarin or NOACs. Three months after diagnosis, 87% of the patients scored 0-2 on the modified Rankin Scale. One patient died as a result of CSVT. DISCUSSION: The incidence of CSVT in Iceland is in accordance with other studies. Headache was the most common symptom and oral contraceptives the most common risk factor among women. Most patients made a good recovery, which suggests a timely diagnosis and appropriate treatment for CSVT in Iceland.

Genome-wide analysis of 102,084 migraine cases identifies 123 risk loci and subtype-specific risk alleles.

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology.

ALS patients with concurrent neuroinflammatory disorders; a nationwide clinical records study.

Objective:To determine if inflammation in proximity of the motor unit may contribute to neurodegeneration in amyotrophic lateral sclerosis (ALS). Methods: We identified all patients diagnosed in Sweden with concurrent ALS and multiple sclerosis (MS), myasthenia gravis (MG), inflammatory polyneuropathies (IP), or dermatopolymyositis (DMPM) during 1991-2014 according to the Swedish Patient Register (N = 263). We validated medical records for 92% of these patients (18 records were not retrieved and three did not contain enough information) and compared patients with a confirmed overlap (N = 28) with an independent sample of patients with solely ALS (N = 271). Results: Ninety-one patients were deemed as not having ALS (34.6%). Among the remaining 151 with validated ALS, 12 had also a confirmed MS diagnosis, nine a confirmed MG diagnosis, four a confirmed IP diagnosis, and three a confirmed DMPM diagnosis. Seventeen of the patients were women and 11 were men. Seventy-nine percent of the patients with a confirmed overlap had MS, MG, IP, or DMPM diagnosed prior to ALS. Compared to patients with only ALS, the concurrent patients were significantly older at symptoms onset, had higher prevalence of bulbar onset, but used Riluzole and noninvasive ventilation less frequently. Conclusions: We found that a high concurrence of ALS and MS/MG/IP/DMPM diagnoses is largely due to diagnostic uncertainty. A minority of patients had a true concurrence, where MS, MG, IP, and DMPM preceded the ALS diagnosis, which might be due to chance alone. Four patients were diagnosed with MG shortly after onset of ALS, suggesting that neurodegeneration might trigger autoimmunity.

A genome-wide meta-analysis uncovers six sequence variants conferring risk of vertigo.

Vertigo is the leading symptom of vestibular disorders and a major risk factor for falls. In a genome-wide association study of vertigo (Ncases = 48,072, Ncontrols = 894,541), we uncovered an association with six common sequence variants in individuals of European ancestry, including missense variants in ZNF91, OTOG, OTOGL, and TECTA, and a cis-eQTL for ARMC9. The association of variants in ZNF91, OTOGL, and OTOP1 was driven by an association with benign paroxysmal positional vertigo. Using previous reports of sequence variants associating with age-related hearing impairment and motion sickness, we found eight additional variants that associate with vertigo. Although disorders of the auditory and the vestibular system may co-occur, none of the six genome-wide significant vertigo variants were associated with hearing loss and only one was associated with age-related hearing impairment. Our results uncovered sequence variants associating with vertigo in a genome-wide association study and implicated genes with known roles in inner ear development, maintenance, and disease.

X-linked serotonin 2C receptor is associated with a non-canonical pathway for sudden unexpected death in epilepsy.

Sudden Unexpected Death in Epilepsy is a leading cause of epilepsy-related mortality, and the analysis of mouse Sudden Unexpected Death in Epilepsy models is steadily revealing a spectrum of inherited risk phenotypes based on distinct genetic mechanisms. Serotonin (5-HT) signalling enhances post-ictal cardiorespiratory drive and, when elevated in the brain, reduces death following evoked audiogenic brainstem seizures in inbred mouse models. However, no gene in this pathway has yet been linked to a spontaneous epilepsy phenotype, the defining criterion of Sudden Unexpected Death in Epilepsy. Most monogenic models of Sudden Unexpected Death in Epilepsy invoke a failure of inhibitory synaptic drive as a critical pathogenic step. Accordingly, the G protein-coupled, membrane serotonin receptor 5-HT2C inhibits forebrain and brainstem networks by exciting GABAergic interneurons, and deletion of this gene lowers the threshold for lethal evoked audiogenic seizures. Here, we characterize epileptogenesis throughout the lifespan of mice lacking X-linked, 5-HT2C receptors (loxTB Htr2c). We find that loss of Htr2c generates a complex, adult-onset spontaneous epileptic phenotype with a novel progressive hyperexcitability pattern of absences, non-convulsive, and convulsive behavioural seizures culminating in late onset sudden mortality predominantly in male mice. RNAscope localized Htr2c mRNA in subsets of Gad2+ GABAergic neurons in forebrain and brainstem regions. To evaluate the contribution of 5-HT2C receptor-mediated inhibitory drive, we selectively spared their deletion in GAD2+ GABAergic neurons of pan-deleted loxTB Htr2c mice, yet unexpectedly found no amelioration of survival or epileptic phenotype, indicating that expression of 5-HT2C receptors in GAD2+ inhibitory neurons was not sufficient to prevent hyperexcitability and lethal seizures. Analysis of human Sudden Unexpected Death in Epilepsy and epilepsy genetic databases identified an enrichment of HTR2C non-synonymous variants in Sudden Unexpected Death in Epilepsy cases. Interestingly, while early lethality is not reflected in the mouse model, we also identified variants mainly among male Sudden Infant Death Syndrome patients. Our findings validate HTR2C as a novel, sex-linked candidate gene modifying Sudden Unexpected Death in Epilepsy risk, and demonstrate that the complex epilepsy phenotype does not arise solely from 5-HT2C-mediated synaptic disinhibition. These results strengthen the evidence for the serotonin hypothesis of Sudden Unexpected Death in Epilepsy risk in humans, and advance current efforts to develop gene-guided interventions to mitigate premature mortality in epilepsy.

[Sudden loss of consciousness due to artery of Percheron infarction].

Acute cerebral infarction due to occlusion of the artery of Percheron (AOP) is rare and poses a diagnostic challenge due to unspecific clinical symptoms. A prompt diagnosis and treatment is vital due to a potentially very serious outcome. Here we represent a healthy young woman who developed sudden headache and loss of consciousness. At admission she was unconscious with GCS of 4, pupils were unevenly dilated and poorly reactive and the plantar reflex was upward bilaterally. She had seizure like movements in all limbs. CT of brain and CT angiography were normal but acute MRI showed bilateral paramedian thalamic diffusion restriction. The patient was treated with i.v. thrombolysis (tPA) 70 minutes after hospital arrival and recovered fully.

A meta-analysis uncovers the first sequence variant conferring risk of Bell's palsy.

Bell's palsy is the most common cause of unilateral facial paralysis and is defined as an idiopathic and acute inability to control movements of the facial muscles on the affected side. While the pathogenesis remains unknown, previous studies have implicated post-viral inflammation and resulting compression of the facial nerve. Reported heritability estimates of 4-14% suggest a genetic component in the etiology and an autosomal dominant inheritance has been proposed. Here, we report findings from a meta-analysis of genome-wide association studies uncovering the first unequivocal association with Bell's palsy (rs9357446-A; P = 6.79 × 10-23, OR = 1.23; Ncases = 4714, Ncontrols = 1,011,520). The variant also confers risk of intervertebral disc disorders (P = 2.99 × 10-11, OR = 1.04) suggesting a common pathogenesis in part or a true pleiotropy.

[Spinal cord infarction - a rare condition and a diagnostic challenge]. / Ryggmärgsinfarkt ­ ett ovanligt och svårdiagnostiserat tillstånd.

Spinal cord infarction (SCI) causes acute spinal cord dysfunction with high morbidity. Without an inciting event such as a surgical procedure, a definitive diagnosis may be challenging. Thus, patients with a spontaneous (i e, non-traumatic, non-surgical) SCI are often misdiagnosed and the radiological distinction between SCI and other conditions with similar symptoms is more difficult than in cerebral infarction. Compared to cerebral infarction, SCI is rare and only accounts for approximately 1.2% of all strokes. SCI is usually localized to the anterior spinal artery area, causing the anterior spinal artery syndrome. Misdiagnosis may lead to unnecessary and possibly deleterious treatments as well as missed secondary stroke prevention. In this review, a typical case, an overview of the disease and newly proposed diagnostic criteria are presented.

[Syndrome of transient headache and neurologic deficits with cerebrospinal fluid lymphocytosis ­ two cases and review]

Here we describe two cases of HaNDL (Headache with Neurological Deficits and cerebrospinal fluid Lymphocytosis). A thirty year old man with episodes of headache with lateralizing symptoms and confusion and a 41 year old man with headache, aphasia and right hemiparesis. Symptoms resolved completely in both patients. Considerable cerebrospinal fluid lymphocytosis was present but no signs of CNS infection and MRIs of the brain were normal. Although the cause of HaNDL is unknown, it is thought to be triggered by a viral infection by some. The prognosis is excellent and symptoms normally resolve within 1-3 weeks. It is important to rule out more serious etiologies like stroke, subarachnoid hemorrhage or central nervous system infections.

Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review.

OBJECTIVE: Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies. METHODS: PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group-specific incidence or prevalence. RESULTS: We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45-1.01] and 10/100 000 persons [95% CI: 6.8-13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036-0.038] and 0.7/100,000 persons [95% CI: 0.66-0.74]). There was prominent female predominance in adults and the AQP4-Ab-seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time. CONCLUSION: NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.

Pharmacologic treatment and SUDEP risk: A nationwide, population-based, case-control study.

OBJECTIVE: We conducted a nationwide case-control study in Sweden to test the hypothesis that antiepileptic drugs (AEDs) mono- or polytherapy, adherence, antidepressants, neuroleptics, ß-blockers, and statins are associated with sudden unexpected death in epilepsy (SUDEP) risk. METHODS: Included were 255 SUDEP cases and 1,148 matched controls. Information on clinical factors and medications came from medical records and the National Patient and Prescription Registers. The association between SUDEP and medications was assessed by odds ratios (ORs) with 95% confidence intervals (CIs) adjusted for potential risk factors including type of epilepsy, living conditions, comorbidity, and frequency of generalized tonic-clonic seizures (GTCS). RESULTS: Polytherapy, especially taking 3 or more AEDs, was associated with a substantially reduced risk of SUDEP (OR 0.31, 95% CI 0.14-0.67). Combinations including lamotrigine (OR 0.55, 95% CI 0.31-0.97), valproic acid (OR 0.53, 95% CI 0.29-0.98), and levetiracetam (OR 0.49, 95% CI 0.27-0.90) were associated with reduced risk. No specific AED was associated with increased risk. Regarding monotherapy, although numbers were limited, the lowest SUDEP risk was seen in users of levetiracetam (0.10, 95% CI 0.02-0.61). Having nonadherence mentioned in the medical record was associated with an OR of 2.75 (95% CI 1.58-4.78). Statin use was associated with a reduced SUDEP risk (OR 0.34, 95% CI 0.11-0.99) but selective serotonin reuptake inhibitor use was not. CONCLUSION: These results provide support for the importance of medication adherence and intensified AED treatment for patients with poorly controlled GTCS in the effort to reduce SUDEP risk and suggest that comedication with statins may reduce risk.