Background: Post-craniotomy pain can be severe and is often undermanaged. Opioids can interfere with neurological monitoring and are associated with adverse effects. This systematic review aimed to identify measures of opioid-free analgesia and compare their effectiveness with opioid analgesia for post-craniotomy pain in patients with supratentorial tumors. Methods: EMBASE, MEDLINE, and Cochrane databases were searched from their inception to February 14, 2017, for randomized controlled trials (RCTs) evaluating opioid versus non-opioid analgesia post-supratentorial craniotomy. Two reviewers independently carried out study selection and data extraction. Risk of bias assessment was performed using the Cochrane Collaboration’s tool. Outcomes were pain control (changes to pain scores or use of rescue analgesia) and adverse effects. Considering the number of studies and heterogeneity, a narrative synthesis was done without pooling and results were summarized using tables. Non-opioids were assessed for the potential to be equivalent to opioid-based analgesics for pain relief and adverse effects. Results: Of 467 RCTs, 4 met our inclusion criteria (n = 186 patients). Patients with scalp blocks (2 RCTs) had less post-operative nausea and vomiting (PONV), but scalp block was not superior to morphine for analgesia. Acetaminophen (1 RCT) was less likely to induce PONV but provided inadequate pain relief compared to morphine and sufentanil. Dexmedetomidine (1 RCT) was not superior to remifentanil for analgesia although it delayed time to rescue analgesia. Conclusions: Limited evidence suggests that scalp blocks and dexmedetomidine have the potential to eliminate the need for opioid analgesia. Multimodal analgesia should be considered as significant opioid-sparing effects have been shown.

The increased use and mastery of ceasarian section for deliveries and the refinement of technologies for assisted delivery in the setting of dfficult second stage of labour have made intrapartum deaths more rare and modern obstetrical pracices are rarely accompanied by the classic forceps related intracranial injuries. We document a novel pattern of intracranial injury in three cases of neonatal death following prolonged labor, of which two out of three required vacuum and forceps.

All three showed similar bilateral parasagittal intraparenchymal haemorrhages and cerebral edema, in a pattern reminiscent of “gliding contusion, as well as subgaleal haemorrhage of varying amout. Two out of the three cases showed parietal bone fractures and one demonstrated extensive craniolcuniae. We briefly discuss the significance of these findings and implications for future cases.

Background: Essential tremor (ET) is reported to have a bimodal distribution of age at onset (AAO) with phenotypic variability based on the AAO. This study aims to explore the distribution of AAO based on mathematical modeling and ascertain the differences, if any, in the clinical features of groups. Methods: A chart review was conducted for 252 patients with ET diagnosed based on the Consensus statement of the Movement Disorder Society on Tremor. Finite mixture modeling was performed to identify groups of the cohort based on the AAO. Results: Three groups were defined: early onset (EO): AAO ≤ 22 years, n = 63, intermediate onset (IO): 23 ≤ AAO ≤ 35 years, n = 43, and late onset (LO): AAO ≥ 36 years, n = 146. There were no significant differences related to family history or responsiveness to alcohol. The EO group had significantly higher prevalence of upper limb and lower limb tremor. Head tremor and voice tremor was more prevalent in the IO and LO groups. Cerebellar signs showed a significant increase with an increase in AAO. Conclusions: ET shows significant phenotypic variability based on the AAO. Patients with an early AAO are more likely to develop an appendicular tremor, whereas the probability of axial tremor and cerebellar signs increases with increasing AAO.

Objective: To systematically evaluate how different deep brain stimulation of the subthalamic nucleus (STN-DBS) amplitude, frequency, and pulse-width electrical parameter settings impact speech intensity, voice quality, and prosody of speech in Parkinson’s disease (PD). Methods: Ten individuals with PD receiving bilateral STN-DBS treatments were seen for three baseline and five treatment visits. The five treatment visits involved an examination of the standard clinical settings as well as manipulation of different combinations of frequency (low, mid, and high), pulse width (low, mid, and high), and voltage (low, mid, and high) of stimulation. Measures of speech intensity, jitter, shimmer, harmonics–noise ratio, semitone standard deviation, and listener ratings of voice quality and prosody were obtained for each STN-DBS manipulation. Results: The combinations of lower frequency, lower pulse width, and higher voltage settings were associated with improved speech outcomes compared to the current standard clinical settings. In addition, decreased total electrical energy delivered to the STN appears to be associated with speech improvements. Conclusions: This study provides preliminary evidence that STN-DBS may be optimized for Parkinson-related problems with voice quality, speech intensity, and prosody of speech.

Background: Microglia and macrophages (MMs) are the largest component of the inflammatory infiltrate in glioblastoma (GBM). However, whether there are immunophenotypic differences in isocitrate dehydrogenase (IDH)-mutated and -wildtype GBMs is unknown. Studies on specimens of untreated IDH-mutant GBMs are rare given they comprise 10% of all GBMs and often receive treatment at lower grades that can drastically alter MM phenotypes. Methods: We obtained large samples of untreated IDH-mutant and -wildtype GBMs. Using immunofluorescence techniques with single-cell automated segmentation, and comparison between single-cell RNA-sequencing (scRNA-seq) databases of human GBM, we discerned dissimilarities between GBM-associated MMs (GAMMs). Results: There are significantly fewer but more pro-inflammatory GAMMs in IDH-mutant GBMs, suggesting this contributes to the better prognosis of these tumors. Our pro-inflammatory score which combines the expression of inflammatory markers (CD68/HLA-A, -B, -C/TNF/CD163/IL10/TGFB2), Iba1 intensity, and GAMM surface area also indicates more pro-inflammatory GAMMs are associated with longer overall survival independent of IDH status. scRNA-seq analysis demonstrates microglia in IDH-mutants are mainly pro-inflammatory, while anti-inflammatory macrophages that upregulate genes such as FCER1G and TYROBP predominate in IDH-wildtype GBM. Conclusions: Taken together, these observations are the first head-to-head comparison of GAMMs in treatment-naïve IDH-mutant versus -wildtype GBMs that highlight biological disparities that can be exploited for therapeutic purposes.

In recent decades, clinical trials in Alzheimer’s disease (AD) have failed at an unprecedented rate. The etiology of AD has since come under renewed scrutiny, both to elucidate the underlying pathologies and to identify novel therapeutic strategies. Here, diet has emerged as a potential causative/protective agent. A variety of nutrients, including lipids, minerals, vitamins, antioxidants and sugars as well as broader dietary patterns and microbiotal interactions have demonstrated associations with AD. Although clinical trials have yet to definitively implicate any singular dietary element as therapeutic or causative, it is apparent that dietary preferences, likely in complex synergies, may influence the risk, onset and course of AD. This review catalogs the impact of major dietary elements on AD. It further examines an unexplored reciprocal association where AD may modulate diet, as well as how potential therapeutics may complicate these interactions. In doing so, we observe diet may have profound effects on the outcome of a clinical trial, either as a confounder of a drug/disease interaction or as a generally disruptive covariate. We therefore conclude that future clinical trials in AD should endeavor to control for diet, either in study design or subsequent analyses.

10 cases of pneumonia causing cardiac arrest and non-perfused brain occurred at ages 40 days-30 months, in a medico-legal setting. In each deceased child, both the pneumonia and non-perfused brain were verified histologically. Upper respiratory infection and mouth-breathing accompanied the pneumonia, with ongoing choking on formula or food in three cases, and vomiting in an additional five cases. In eight of the 10 cases, the pre-terminal event was a quiet respiratory arrest while sleeping, or being carried in the arms. Adrenaline was given up to 7 times during CPR lasting 44±32 minutes, with up to 2 hours CPR and fall in body temp to <32°C. Mean survival was 1.9±1.5 days and heparin was given for organ donation in 3 cases. The lungs showed chronic interstitial pneumonia as described by Katzenstein, with superadded acute bronchiolo-alveolar infiltrates in two cases of aspiration. The court permitted recuts and cellular characterization of the interstitial cells in one case, revealing the infiltrate was ~40% histiocytes, 5% T or B cells, and ~50% vimentin+ mesenchymal cells. All brains showed features of non-perfused brain and retino-dural hemorrhage. The observed features of non-perfused brain were blurring of the gray-white junction, edema, gross friability, histologic pallor, closure of the microcirculation, patchy acidophilic neurons and recent demarcated pan-necrosis, and pituitary infarction in one patient where hypophysis was sampled. Normally, from birth to 30 months, cerebral blood flow increases to 55% of cardiac output, accompanying physical brain growth. Restoration of high cardiac output using adrenaline-CPR means that on resuscitation, re-routing of blood that can no longer go through the non-perfused brain detours through dura, face, scalp, eyes and optic nerve sheaths. The diversion of blood around non-perfused brain results in facial bruising and retino-dural hemorrhage that can be misinterpreted as head trauma, and a common inference of child abuse in the courts. In the present series from Australia, Canada and the USA, outcomes ranged from acquittal to life imprisonment.

Background: To assess the prevalence of three nociceptive primitive reflexes (nPR), i.e., glabellar tap, snout reflex, and palmomental reflex, in neurologically and cognitively healthy (NCH) aging subjects. Objective: To investigate whether nPR are cross-sectionally associated with white matter hyperintensities (WMH), lacunes, atrophy of the caudate nuclei, and global brain atrophy. Methods: A total of 1246 NCH subjects aged 45–91 years were included in the study and underwent standard brain MRI. Atrophy of the caudate nuclei and global brain atrophy were assessed through the bicaudate ratio (BCr) and lateral ventricles to brain ratio (LVBr), respectively. WMH were assessed through visual rating scales. Lacunes were also rated. Association of nPR with vascular risk factors/diseases and imaging findings was evaluated using logistic regression analysis. Results: nPR were exhibited by 33.1% of subjects and increased with age. Subjects with nPR performed less than subjects without nPR in tests evaluating global cognition, executive functions, attention, and language. Snout reflex was the most common nPR, followed by glabellar tap and palmomental reflex. Glabellar tap was associated with parieto-temporal WMH, BCr, and LVBr; snout reflex was associated with frontal lacunes, temporal WMH, BCr, and LVBr; palmomental reflex was associated with parieto-occipital WMH, basal ganglia lacunes, BCr, and LVBr. Conclusions: This study demonstrates that in NCH aging individuals, nPR are associated with WMH, lacunes, BCr, and LVBr and are probably a warning sign of incipient cognitive decline. Therefore, NCH subjects presenting nPR should manage their vascular risk factors/vascular diseases rigorously in order to prevent or delay progression of small vessel disease, and future neurological and cognitive disabilities.

Introduction: Controversy exists in antiepileptic drug (AED) prophylaxis prescribing in patients with aneurysmal subarachnoid hemorrhage (SAH). We undertook the Use of Antiepileptic Drugs in Aneurysmal Subarachnoid Hemorrhage (ALIBI) study to identify factors associated with prescribing practices. Methods: A retrospective chart review of all consecutive patients requiring Level 1 care with aneurysmal SAH admitted between 2012 and 2014 to the intensive care unit at Toronto Western Hospital, Ontario, Canada, was conducted. Data were collected on clinical and imaging characteristics. Primary and secondary outcomes were AED prophylaxis and clinical seizure activity during hospitalization. Data were compared using chi-square or Mann–Whitney U-tests. Those variables found to be significant, or trending toward significance, on univariate analysis were fitted to multivariate regression. Results: Sixty-eight patients were included. Mean age was 62 ± 12.2, and 42.6% of patients were male. Of these, 21 patients (30.9%) received AED prophylactically, while 18 (26.5%) had reported seizures at some point during hospitalization. Female gender and presence of midline shift (MLS) were significantly associated or approached significance with AED prophylaxis in univariate analysis (p = 0.036 and p = 0.062, respectively). In multivariate analysis, only MLS was an independent predictor (odds ratio 5.09, p = 0.04). Conclusion: The presence of MLS was an independent predictor of seizure activity in patients with aneurysmal SAH. AED prophylaxis prescribing patterns seemed arbitrary and was not informed by identifiable clinical factors or true risk factors for seizure. A current lack of evidence guiding AED prescribing practice highlights the need for larger studies in this patient population.

Background: Patients with anti-acetylcholine receptor antibody-positive (AChR+) generalized myasthenia gravis (MG) unresponsive to conventional treatment experience greater disease burden than responsive patients. This is partly due to exacerbations, which may result in significant healthcare resource utilization. Eculizumab is well tolerated and gives clinically meaningful benefits in these patients. We evaluated the effect of long-term eculizumab treatment on exacerbations, hospitalizations and rescue therapy in the REGAIN study and its open-label extension. Methods: Exacerbations were defined as clinical worsening/deterioration, MG crises or rescue therapy usage; pre-study exacerbations/hospitalizations were defined from patient records. Event rates adjusted for patient-years were calculated for all patients in the pre-study year, patients receiving placebo during REGAIN, and patients receiving eculizumab during REGAIN and its open-label extension (median exposure, 27.5 months [range, 22 days–42.8 months]); rates were compared using a Poisson regression model. Results: Eculizumab treatment reduced exacerbations by 65% (p=0.0057), hospitalizations by 71% (p=0.0316) and rescue therapy use by 66% (p=0.0072) versus placebo. Eculizumab treatment reduced exacerbations by 74% and hospitalizations by 83% (both p<0.0001) versus the pre-study year. Conclusions: Long-term eculizumab treatment reduces disease burden and healthcare resource utilization, demonstrating continuing improvements in clinical endpoints that lead to additional meaningful outcomes for patients with AChR+ generalized MG. (NCT01997229, NCT02301624).

Objective: To determine the relationship between intraoperative flash visual evoked potential (FVEP) monitoring and visual function. Methods: Intraoperative FVEPs were recorded from electrodes placed in the scalp overlying the visual cortex (Oz) after flashing red light stimulation delivered by Cadwell LED stimulating goggles in 89 patients. Restrictive filtering (typically 10–100 Hz), optimal reject window settings, mastoid reference site, total intravenous anesthetic (TIVA), and stable retinal stimulation (ensured by concomitant electroretinogram [ERG] recording) were used to enhance FVEP reproducibility. Results: The relationship between FVEP amplitude change and visual outcome was determined from 179 eyes. One eye had a permanent intraoperative FVEP loss despite stable ERG, and this eye had new, severe postoperative visual dysfunction. Seven eyes had transient significant FVEP change (>50% amplitude decrease that recovered by the end of surgery), but only one of those had a decrease in postoperative visual acuity. FVEP changes in all eight eyes (one permanent FVEP loss plus seven transient FVEP changes) were related to surgical manipulation. In each case the surgeon was promptly informed of the FVEP deterioration and took remedial action. The other eyes did not have FVEP changes, and none of those eyes had new postoperative visual deficits. Conclusions: Our FVEP findings relate to visual outcome with a sensitivity and specificity of 1.0. New methods for rapidly acquiring reproducible FVEP waveforms allowed for timely reporting of significant FVEP change resulting in prompt surgical action. This may have accounted for the low postoperative visual deficit rate (1%) in this series.

Background: There is an unmet need for blood-based biomarkers that can reliably detect MS disease activity. Serum Biomarkers of interest includ Neurofilament-light-chain (NfL), Glial-fibrillary-strocyte-protein(GFAP) and Tau. Bone Marrow Transplantation (BMT) is reserved for aggressive forms of MS and has been shown to halt detectable CNS inflammatory activity for prolonged periods. Significant pre-treatment tissue damage at followed by inflammatory disease abeyance should be reflected longitudinal sera collected from these patients. Methods: Sera were collected from 23 MS patients pre-treatment, and following BMT at 3, 6, 9 and 12-months in addition from 33 non-inflammatory neurological controls. Biomarker quantification was performed with SiMoA. Results: Pre-AHSCT levels of serum NfL and GFAP but not Tau were elevated compared to controls (p=0.0001), and NfL correlated with lesion-based disease activity (6-month-relapse, MRI-T2 and Gadolinium-enhancement). 3-months post-treatment, while NfL levels remained elevated, Tau/GFAP paradoxically increased (p=0.0023/0.0017). These increases at 3m correlated with MRI ‘pseudoatrophy’ at 6-months. NfL/Tau levels dropped to that of controls by 6-months (p=0.0036/0.0159). GFAP levels dropped progressively after 6-months although even at 12-months remained higher than controls (p=0.004). Conclusions: NfL was the closest correlate of MS disease activity and treatment response. Chemotherapy-related toxicity may account for transient increases in NfL, Tau and MRI brain atrophy post-BMT.

Premature mortality among epilepsy patients is well recognized. Except a few identifiable causes of unnatural death, more than half of the epilepsy related death remains unexplained after extensive workup. These cases are classified as sudden unexpected death in epilepsy (SUDEP). SUDEP incidence varies significantly depending on the population, the methods documenting cause of death and the availability of Neuropathological examination. An accurate diagnosis of the cause of death is needed for epilepsy related death. The goal of this study is to present the relevant clinical data, the general autopsy and Neuropathology findings of epilepsy related death investigated in London Health Sciences Center during the period of 2000 to 2011. We identified 71 cases with known history of chronic epilepsy. In the 29 cases of epilepsy associated death, the causes of death have been classified as cardiac, pulmonary, accidental (e.g. drowning), toxic (e.g. drug overdose) and non-related causes. Forty two cases are considered to be SUDEP, and were categorized according to the recently proposed SUDEP Definition and Classification. Half of the SUDEP cases have no specific Neuropathological findings. The most common identifiable lesions in SUDEP cases are perinatal/neonatal destructive lesions (29%), hippocampal sclerosis (24%), and focal cortical dysplasia (20%). These are followed by neuronal heterotopia (9%), previous head trauma (9%), and cavernoma (5%).

Background: We reviewed numerous variables for ischemic stroke patients admitted to a rehabilitation unit to determine those that were statistically associated with discharge destination. Methods: A retrospective chart review of patients with ischemic stroke discharged from the rehabilitation unit between January 1, 2005 and December 31, 2015. Variables were examined for their association with discharge destination (home versus long-term care (LTC)). Univariable relationships with discharge destination were assessed, and a multivariable logistic regression model was built. Results: Univariate predictors of discharge to LTC: advanced age, decreasing admission and discharge functional independence measure (FIM) scores, increasing change in FIM score from admission to discharge, dependency, residence outside of home before the stroke, absence of a caregiver, urinary and bowel incontinence, low Berg balance score at admission and discharge, low Montreal Cognitive Assessment scores, smoking, chronic heart failure, and an inability to transfer. Multivariable logistic regression: five factors remained significant predictors with LTC disposition: advanced age, bowel incontinence, residence outside of the home prior to stroke, right hemisphere site of the stroke, and absence of a caregiver. Conclusions: Several easily measured variables were significantly associated with discharge to LTC versus home following stroke rehabilitation.