Background: Early treatment of autoimmune encephalitis (AE) can improve outcomes. Despite expert recommendation, it remains unclear if suspected AE patients consistently receive empiric treatments prior to availability of antibody results. Methods: Retrospective chart review of patients referred for AE testing in Manitoba. Primary outcomes were the proportion of patients treated empirically prior to the availability of antibody results. Incidence, clinical presentation, investigations, complications, mortality rates, and hospital course were secondary outcome measures. Results: We identified 151 patients from 2012-2018. 43 patients met inclusion criteria. The annual incidence of AE in Manitoba was 0.37/100,000. 28/43 (65%) patients were treated prior to availability of antibody results (“Early group”). 15/43 (35%) patients did not receive treatment (“Late group”). Significantly more Early group patients had repeat immunotherapy (p=0.001), abnormal MRI (p=0.027), and investigations for malignancy (p=0.015). Durations of hospital and intensive care admission, complication rates, and mortality rates were not different between the two groups. Conclusions: This is the first-ever AE incidence, timing, and management study of a comprehensive Canadian geopolitical and medical catchment area. Just over 1/3 of suspected AE over seven years were not treated prior to antibody results becoming available. Patients treated earlier did not experience greater complication rates.

Background: Surgical instruments used in patients with prion disease must be decontaminated or decommissioned to prevent iatrogenic transmission. This is only done when the diagnosis of prion disease is known. To assess the potential for iatrogenic transmission, we determined the prevalence of surgeries and use of precautions in patients with prion disease at two academic medical centers. Methods: Clinical details, results of investigations, and surgical interventions (performed within one-year of symptom onset) were extracted for patients with probable/definite prion disease at Mayo Clinic (n=107; 1-2014 to 12-2020) and Washington University School of Medicine (n=14; 2-2015 to 12-2019). Results: Twenty-six patients (21.5%) underwent 32 procedures, including 2 high-risk procedures involving the brain. Most procedures (17/32, 53%) occurred in the 1-year period preceding the onset of symptoms attributed to CJD. History of arthritis (OR: 7.4, 95%CI: 1.05-51.8), lack of behavioral symptoms (OR: 3.0, 95%CI 0.97-9.1), and greater time (months) from symptom onset to first MRI (OR: 1.1, 95%CI 1.03-1.2) were independently associated with odds of undergoing an invasive procedure. Prion disease precautions were observed in one case (diagnostic brain biopsy). Conclusions: Procedures were common in patients with diagnosis of prion disease; precautions were not. Coordinated approaches to screening and reporting are needed to prevent iatrogenic transmission.

Background: Assays capable of detecting prions in CSF (e.g., RT-QuIC) have greatly improved the antemortem diagnosis of Creutzfeldt-Jakob disease (CJD) yet take time to conduct and are not widely accessible. There is a need to identify clinical features and common tests that identify mimics at presentation. Methods: Mimics were identified within longitudinal studies of rapidly progressive dementia at study sites. Mimics met clinical criteria for probable CJD but did not have CJD. Clinical features were compared between mimics and patients with CJD assessed at Mayo Clinic Enterprise (n=79) and Washington University in St. Louis (n=10; Jan-2014 to Oct-2020). Results: Mimics (10/155; 6.5%) were diagnosed with autoimmune encephalitis (n=7), neurosarcoidosis, frontotemporal lobar degeneration with motor neuron disease, and unknown dementia. Age-at-symptom onset, gender, presenting symptoms, and EEG and MRI findings were similar between mimics and CJD patients. Focal motor abnormalities (49/93, 10/10), elevations in CSF leukocytosis (4/92, 5/10) and protein (39/92, 9/10) were more common in mimics (p<0.01). Neural-specific autoantibodies associated with autoimmune encephalitis were detected within the serum (4/9) and CSF (5/10) of mimics, but not CJD cases. Conclusions: Autoimmune encephalitis, neurosarcoidosis and neurodegenerative diseases may mimic CJD at presentation and should be considered in patients with early motor dysfunction and abnormal CSF studies.

Background: Discussions around driving cessation between clinicians and dementia patients are challenging. Patients view giving up their license as losing their independence. We sought to develop a tool that enables standardized and consistent driving messaging across clinicians working in a specialist memory clinic, across the span of cognitive disorders Methods: We developed a driving recommendations generator that allows clinicians to produce information handouts personalized to individual patient capabilities and needs. Clinicians select from a list of established recommendations that were developed with neurologist and geriatrician input, and consistent with provincial requirements. Recommendations cover patients’ current driving ability, road safety examinations, alternate transportation, and license revocation. Early driving retirement is emphasized and encouraged, to proactively support patients’ choices, safety and independence. Recommendation and handouts are printed for the patients. Results: Patients reported that the recommendations were easy to read and understand, and helped them to implement physician suggestions. All surveyed clients recommended continuing to provide such recommendations to future patients and families. Clinicians agreed that the tool helped them to save time, and simplified the process of finding accurate information to provide patients. Conclusions: Clinicians have found the system timesaving and useful for simplifying the process of providing helpful, informative resources for patients.

Background: With the advance of technology, our capacity to assess patients with dementia is also developing. It is possible to administer cognitive examinations using technology, such as the iPad-based Toronto Cognitive Assessment, but hitherto difficult to autonomously administer them. Many of the ’inputs’ from patients could be easily scored with software, but highly variable inputs such as the clock drawing are extremely difficult to score, precluding automated administration and scoring. This work focuses on the development of a neural network designed to assess cube drawings, infinity drawings, and clock drawings. Methods: 3200 drawings, evenly split between clocks, cubes and infinities were generated, with half being correct and half incorrect. A SqueezeNet was trained on 2000 images, validated on 800 drawings, and then tested on 400 drawings. Results: The SqueezeNet was able to achieve 97% accuracy on 400 images it had never seen before in categorizing images as “Cube”, “Clock”,

“Infinity”, or “Other” (incorrectly drawn). Conclusions: This neural network can successfully determine the difference between correctly and incorrectly drawn images commonly used in cognitive examinations, overcoming the final barrier to autonomously administering and scoring cognitive examinations. Next steps are to clinically validate an autonomous examination program which has been modeled after the Addenbrooke Cognitive Examination-3.

Background: Machine learning (ML) methods hold promise in allowing early detection of dementia. We performed a systematic review to assess the quality of published evidence for using ML methods applied to drawing tests of cognition, and to describe the accuracy of the methods. Methods: Embase, Medline, and Cochrane Central Library databases were searched for potential studies up to December 8, 2018 by four independent reviewers. Included articles satisfied the following criteria: 1) use of ML on 2) a drawing test in order to 3) assess cognition. The quality of evidence was then assessed using GRADE methodology. Results: The initial search yielded 4620 citations. Of these, 64 were eligible for full text review. 18 articles then met inclusion criteria. Median AUC across all models was 0.765, with certain ML algorithms performing better in terms of AUC or diagnostic accuracy. However, based on GRADE, the quality of evidence was deemed very low. Conclusions: ML has been applied by several groups to drawing tests of cognition. The quality of evidence is currently too low to make recommendations on their use. Future work must focus on improving reporting, and using standard algorithms and larger, more diverse datasets to improve comparability and generalizability.

Background: The IVS10+14 mutation in the microtubule-associated protein tau gene, MAPT, is a rare point mutation that dysregulates tau splicing resulting in pathological aggregation. This mutation has been identified in three families with severe neurodegenerative disease. We characterized the clinicopathological features of a fourth, Canadian family with the IVS10+14 MAPT mutation and compared them to previously reported families. Methods: Clinical and neuropathological records from three family members with the IVS10+14 MAPT mutation were reviewed. Neuropathological section from one available case were analyzed. Results: Considerable interfamilial phenotypic heterogeneity is reported in all cohorts that express the IVS10+14 MAPT mutation, with prominent motor, cognitive, behavioural, and respiratory symptoms. The Canadian cohort also expressed profound sensory and sleep abnormalities, not reported previously. In the two siblings with available neuropathological records, neuropathological changes ranged from mild to severe. Conclusions: All families expressing the IVS10+14 MAPT mutation display striking inter- and intrafamilial clinical and neuropathologic phenotypic variability. Our cohort adds sensory and sleep abnormalities as potential symptoms and illustrates a lack of clear clinicopathological correlates for these heterogenous symptoms.

Reference: Maxwell et al. 2021. Clinical and Neuropathological Variability in the Rare IVS10+14 Tau Mutation. Neurobiology of Aging. In Press. DOI: 10.1016/j.neurobiolaging.2021.01.004.

Background: Concern around perceived neurocognitive decline is increasing, leading to increased number of referrals and anxiety for patients. We aimed to explore the likelihood of the “worried well” experiencing neurocognitive decline. Methods: 166 “worried well” patients who attended the Rural and Remote Memory Clinic between 2004 and 2019 were included. Mini Mental Status Examination, Center for Epidemiologic Studies Depression Scale, and Functional Assessment Questionnaire scores were measured and compared at initial assessment and at 1-year follow-up. MMSE scores over time were assessed with a mean follow-up of 2.95 years (SD 2.87). Results: There was no statistically significant difference in MMSE, CESD, or FAQ scores between clinic day and one-year follow-up, and no consistent pattern of MMSE score over time. Of the 166 patients with SCI on initial assessment, nine were eventually given a neurological diagnosis. Conclusions: There is no pattern of neurologic decline observed in the “worried well”. Though the likelihood of a patient with SCI developing a neurological diagnosis is reassuringly low, (9/166), it is not irrelevant. This, along with the benefits of early diagnosis and treatment for dementia, leads us to believe that patients with SCI should still be seen in follow-up at least at the one-year mark.

Background: We aimed to evaluate the association between hypertensive disorders in pregnancy (HDP) and future risk of cognitive impairment and dementia. Methods: Systematic searches were performed in MEDLINE and EMBASE up to April 27th, 2020. Exposure of interest included the different types of HDP. Outcomes of interest included dementia incidence, dementia subtype, and cognitive testing. Results: On qualitative review, 4/9 studies showed impaired memory, visual motor processing speed, executive function, and verbal testing in previously preeclamptic women. 2/4 studies showed impaired visual motor processing and subjective cognitive complaints in previously eclamptic women. Six cohort studies involving >2.6 million women were included in the meta-analysis. Pooled hazard ratios (aHR) with 95% confidence intervals were generally adjusted for age at delivery ethnicity, and vascular risk factors. Women with a history of gestational hypertension were more likely to develop vascular dementia (aHR 2.02 [1.45-2.83],I2:0%), but not Alzheimer disease (1.24 [0.93-1.66],single-study). Women with a history of preeclampsia were also more likely to develop vascular dementia (2.17 [1.20-3.91],I2:61.1%), but not Alzheimer dementia (1.19 [0.83-1.69],I2:69.9%). Conclusions: Whereas studies of neuropsychological testing in previously preeclamptic and eclamptic women have been heterogeneous, a history of HDP is associated with developing vascular dementia in later life.

Background: As a neuroactive steroid, vitamin D is essential for optimal neuronal functioning1. Its immunomodulatory and neuroprotective effects aid in reduction of proconvulsant cytokines, membrane excitability and seizure prevention2-3. Deficiency plays an important role in neurological and psychiatric illnesses, though clinical manifestation with seizures and psychosis have not been described. Methods: A 61-year-old female presented with 3-day history of confusion, insomnia and new onset seizure. She was noted to have poor dentition, deformed nail bed and multiple ecchymosis. Neurologically, there were brisk reflexes with some spread. She worsened with frequent seizures and psychosis. Results: Laboratory investigation showed serum Vitamin D level of 19nmol/L, hemoglobin of 70g/L. MRI head revealed T2 hyperintensities in bilateral anterolateral temporal lobes and EEG consistent with bitemporal lobe epilepsy. Autoimmune and infectious work up were negative. Treatment with antipsychotics, several antiepileptics, high dose Vitamin-D and iron supplements were initiated. Initially, she remained unresponsive to neuro/psych medications. Improvement in clinical symptoms was noticed in 4th week of admission, with complete resolution of MRI, EEG findings. Conclusions: Evidence surrounding hypovitaminosis D and risk on the central nervous system continues to grow. This case highlights the significance of vitamin-D on brain processes and its neurological manifestations in state of deficiency.

1. Kalueff.A.,2006. 2. Garcion. E, 2003. 3. Eyles, D., 2013.

Background: Epilepsy is the most common chronic neurological illness worldwide, affecting more than 330, 000 people in Canada, 10, 000 of which reside in the Ottawa area. Despite facing higher mortality, stigma and social barriers, PLE (people living with epilepsy) incur treatment gaps even in high income countries like ours. Our goal was to address this burden locally with the creation of novel, community-integrated, care delivery for PLE in our area; we describe its inception. Methods: A transition program bridging pediatric and adult institutions was created to address the care continuity gap in 2017. Following a meeting of key stakeholders in the region in 2019, the community group was integrated into the model of care and the city-wide program was created incorporating adult, pediatric, transition and community pillars. A patient friendly website was launched in 2020 (ottawaepilepsyprogram.ca). Results: 170 patients were followed in the transition program since 2017. Adult and pediatric pillars have referred 70 patients to the community program between 2019-2020, 48 between 2020-2021. Through this, PLE are able to access the Clinic to community (C2C) and UPLIFT programs for social support services and mental health, respectively. Conclusions: An interconnected region-wide program can support PLE and foster innovative care integration across disciplines.

Background: Treatment of refractory status epilepticus (RSE) is often titrated to achieve EEG burst suppression. However, optimal burst suppression characteristics are largely unknown. We used an unsupervised machine learning algorithm to predict RSE outcome based on the quantitative burst suppression ratio (QBSR). Methods: We conducted principal component analysis (PCA) as a linear combination of 22 QBSR features from non-anoxic adult RSE patients at the Winnipeg Health Sciences Centre. We also determined the most predictive components that significantly differed between survivors and non-survivors. Results: Using 135,765 QBSRs from 7 survivors and 10 non-survivors, PCA identified a predominantly non-survivor cluster of 8 patients (75% non-survivors). The first 2 PCA components comprised 75% data variance. The most important first component feature was skewness of QBSR distribution in the right or left hemisphere (0.52 each). The most important second component feature was third QBSR quantile of the left hemisphere (0.49). Only right hemispheric QBSR features significantly differed between groups: QBSR skewness for the first component (Benjamini-Hochberg adjusted p=0.038) and average QBSR for the second component (0.32, Benjamini-Hochberg adjusted p=0.046). Conclusions: Our pilot study shows that RSE patient survival may be impacted by QBSR, with differential hemispheric EEG burst suppression characteristics predicting poor RSE outcome.

Background: This study aims to provide data on the care of pregnant women with epilepsy (pWWE) that is directly applicable to the Canadian context. Methods: Between 1997 and 2019, pWWE from Canada and the USA who enrolled into the North American AED Pregnancy Registry (NAARP) completed a questionnaire on their AED (anti-epileptic drug) usage. Enrollment rates to NAARP were compared between the two countries, and between the different Canadian provinces using population-based enrollment rate ratios (PERR). The AED prescription pattern among Canadian pWWE was analysed and compared with the USA. Results: During the study period, 10,215 women enrolled into NAARP : 4.1% (n=419) were Canadian, below the expected population-based contribution (PERR=0.42; p<0.01). Within Canada, the three northern territories (PERR=0; p<0.01), Prince-Edward Island (PERR=0; p<0.01), and Quebec (PERR=0.41; p<0.01) had the lowest enrollment rate ratios. Lamotrigine was the most commonly prescribed AED among canadian pWWE; they were, however, more likely to be on polytherapy (25%; p=0.13), on Carbamazepine (24%; p<0.01) or valproic acid (21%; p<0.01) than their American counterparts. Conclusions: Greater enrollment of Canadian women to NAARP, through enhanced clinician referrals, in particular from underrepresented provinces/territories, could lead to more accurate population-specific data and help identify gaps in the care of this vulnerable patient population.

Background: Intracranial electroencephalography (iEEG) recordings are obtained from the sampling of sub-cortical structures and provide extraordinary insight into the spatiotemporal dynamics of the brain. As these recordings are increasingly obtained at higher channel counts and greater sampling frequencies, preprocessing through visual inspection is becoming untenable. Consequently, artificial neural networks (ANNs) are now being leveraged for this task. Methods: One-hour recordings from six patients diagnosed with drug-resistant epilepsy at Toronto Western Hospital were obtained alongside fiduciary ECG and EOG activity. R-wave peaks and local maxima were identified in the ECG and EOG recordings, respectively, and were time-mapped onto the iEEG recordings to delimit one-second epochs around 1.6 million cardiac and 600 thousand ocular artifacts. Epochs were then split into train-test-evaluation sets and fed into an ANN as one-second spectrograms (0 - 1,000 Hz) over 30-time steps. Results: The ANN model achieved formidable classification results on the evaluation set with an F1, positive predictive value, and sensitivity scores of 0.93. Furthermore, model architecture computed the classification probability at each time-step and enabled insight into the spatiotemporal features driving classification. Conclusions: We expect this research to promote the public sharing of new ANN from multiple institutions and enable novel automated algorithms for artifact detection in iEEG recordings.

Background: The quality of sleep is frequently impacted in patients with epilepsy. Vagus Nerve Stimulation is a relatively common treatment used in patients with medically resistant epilepsy. Some studies show an improvement in quality of life, however, there is limited data on the impact on sleep quality. Methods: A database analysis was conducted on Medline, Embase, and Cochrane to find studies that examined the VNS’s effect on quality of sleep in medically resistant epilepsy. These studies included randomized clinical trails, case studies or reports, cohort studies, and systematic reviews. Results: 75 papers were reviewed and 16 studies from eight countries were included in the analysis. A total of 93 patients with ages ranged from 10 – 49 were included. Analyzing the change in the quality of sleep after VNS was evaluated using Multiple Sleep Latency Test. The literature showed that at low stimulus intensities, VNS treatment improves daytime sleepiness in patients. However, VNS setting titration has a dose-dependent effect on obstructive sleep apnea where higher VNS frequencies are related to higher apnea events. Conclusions: Limited data is available on the impact of VNS on the quality of sleep. Further studies are required to evaluate the improvement of sleep in patients with VNS.

Background: Drug-resistant epilepsy (DRE) can affect up to one third of individuals with epilepsy. We conducted a systematic review and meta-analysis of vagus nerve stimulation (VNS), responsive neurostimulation (RNS), and deep brain stimulation (DBS) in patients with DRE to summarize the current evidence on efficacy and tolerability for these neuromodulation modalities. Methods: We searched three online databases with a pre-specified search strategy. We included published randomized controlled trials (RCT) and their open-label extension studies, as well as prospective case series, with samples greater than 20 participants, reporting efficacy and tolerability. Results: We identified 31 studies, six of which are RCTs and 25 prospective observational studies. At long term follow-up, five observational studies for VNS reported a pooled mean decrease in seizure frequency at last follow-up of 35%. In the extension studies for RNS, the median seizure reduction was 53%, 66% and 75.0% at two, five and nine years respectively. For DBS, the median reduction was then 56%, 69% and 75% at two, five and seven years respectively. Conclusions: Neurostimulation modalities are effective for the treatment of DRE, with improving outcomes over time and few major complications. Higher quality long-term data on DBS and RNS suggest larger seizure reduction rates than VNS.

Background: A female carrying the common MERRF mitochondrial DNA A8344G mutation had multiple symmetric lipomatosis (MSL) as the primary disease manifestation. Methods: Case report of a mitochondrial disease patient treating her severe lipomas by lifestyle modifications including a modified ketogenic diet. Results: The patient required lipoma reduction surgery after a rapid rate of lipoma progression. Following a difficult recovery, the patient independently researched an alternative therapy for her disease. The intervention was multi-faceted (dietary, physical activity, meditation) and progressive over two years. A carbohydrate reduced (5–10% of calories) modified ketogenic diet was a major part of the treatment owing to its incidental success in MSL management in her brother for management of glioblastoma multiforme. The outcome of her intervention was positive: weight loss, lipoma size reduction, improvement in physical activity/strength, laboratory markers of insulin resistance, and sense of well including a return to full time work. Conclusions: A potential non-surgical therapy for mitochondrial disease associated MSL appears feasible over the short term. The success of the lifestyle intervention in MSL therapy is unprecedented and, importantly, was fully patient initiated. This novel therapy provides potential insight into the mechanism of MSL exacerbation: suggesting insulin resistance or other lifestyle modifiable factors as mediators of disease progression.