Faculty Bibliography

BACKGROUND:Deep brain stimulation (DBS) can be an effective therapy for tics and comorbidities in select cases of severe, treatment-refractory Tourette syndrome (TS). Clinical responses remain variable across patients, which may be attributed to differences in the location of the neuroanatomical regions being stimulated. We evaluated active contact locations and regions of stimulation across a large cohort of patients with TS in an effort to guide future targeting. METHODS:We collected retrospective clinical data and imaging from 13 international sites on 123 patients. We assessed the effects of DBS over time in 110 patients who were implanted in the centromedial (CM) thalamus (n=51), globus pallidus internus (GPi) (n=47), nucleus accumbens/anterior limb of the internal capsule (n=4) or a combination of targets (n=8). Contact locations (n=70 patients) and volumes of tissue activated (n=63 patients) were coregistered to create probabilistic stimulation atlases. RESULTS:Tics and obsessive-compulsive behaviour (OCB) significantly improved over time (p<0.01), and there were no significant differences across brain targets (p>0.05). The median time was 13 months to reach a 40% improvement in tics, and there were no significant differences across targets (p=0.84), presence of OCB (p=0.09) or age at implantation (p=0.08). Active contacts were generally clustered near the target nuclei, with some variability that may reflect differences in targeting protocols, lead models and contact configurations. There were regions within and surrounding GPi and CM thalamus that improved tics for some patients but were ineffective for others. Regions within, superior or medial to GPi were associated with a greater improvement in OCB than regions inferior to GPi. CONCLUSION/CONCLUSIONS:The results collectively indicate that DBS may improve tics and OCB, the effects may develop over several months, and stimulation locations relative to structural anatomy alone may not predict response. This study was the first to visualise and evaluate the regions of stimulation across a large cohort of patients with TS to generate new hypotheses about potential targets for improving tics and comorbidities.

BACKGROUND:H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS:Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS/RESULTS:Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION/CONCLUSIONS:The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

The role of Varicella zoster virus (VZV) in neurological illness, particularly cerebrovascular disease, has been increasingly recognized. Primary infection by VZV causes varicella (chickenpox), after which the virus remains latent in neuronal ganglia. Later, during aging or immunosuppression, the virus can reactivate causing zoster (shingles). Virus reactivation can also spread to cerebral arteries causing vasculitis and stroke. Zoster is a recognized risk factor for stroke, but stroke can occur without preceding zoster rash. The diagnosis of VZV cerebral vasculitis is established by abnormal brain imaging and confirmed by presence of viral DNA or anti-VZV antibodies in cerebrospinal fluid. Treatment with acyclovir with or without prednisone is usually recommended. VZV vasculitis is a unique and uncommon stroke mechanism that has been under recognized. Careful diagnostic investigation may be warranted in a subgroup of patients with ischemic stroke to detect VZV vasculitis and initiate appropriate therapy. In the following review, we detail the clinical presentation of VZV vasculitis, diagnostic challenges in VZV detection, and suggest the ways to enhance recognition and treatment of this uncommon disease.

The current planned secondary analysis of a randomized clinical trial aimed to evaluate whether the efficacy of Mindfulness-Based Cognitive Therapy for Migraine (MBCTM) to reduce headache-related disability differs among people with episodic migraine (EM) and chronic migraine (CM). After a 30-day monitoring period, participants were stratified by EM (6-14 days/month) and CM (15-30 days/month) and randomized to receive MBCT-M (8 weekly individual sessions) or 8 weeks of wait list/treatment as usual (WL/TAU). Surveys were completed at Months 0, 1, 2, and 4; daily diary was also completed during the 30-day post-treatment evaluation period. Primary outcomes were the Headache Disability Inventory (HDI; Range 0-100) and the Migraine Disability Assessment (MIDAS >= 21 indicating Severe Disability); secondary outcomes (headache days/30 days, average headache attack pain intensity) were derived from daily headache diary. Intent-to-treat mixed models for repeated measures tested formal moderation (time*treatment*CM) in the full sample. Planned subgroup analyses evaluated treatment*time effects EM and CM separately. Sixty participants were randomized to receive MBCT-M (n = 31) or WL/TAU (n = 29). Participants (M age = 40.1, SD = 11.7) were predominantly White (n = 49/60; 81.7%), Non-Hispanic (N = 50/60; 83.3%) women (n = 55/60; 91.7%). At baseline, 29 participants (48.3%) met criteria for EM and 31 (51.7%) met criteria for CM. At baseline, people with CM reporter higher HDI [M(SD) = 57.6 (16.7) vs. 45.5 (19.4), p = .015] and greater headache days/30 days [M(SD) = 20.5 (3.0) vs 11.2 (4.2), p < .001]; no other variable differed by CM status (ps > .30). For the MIDAS, CM status moderated the effect of MBCTM on the MIDAS; MBCT-M reduced the proportion of people reporting severe disability in EM only, p = .013. For the HDI, subgroup analysis revealed that MBCT-M (vs WL/TAU) significantly reduced HDI for EM (p = .011) but not for CM (p = .268). Subgroup analysis found no significant effect of MBCT-M on headache days/30 days or average headache attack pain intensity in either EM or CM. MBCT-M is a promising treatment for reducing disability. Surprisingly, MBCT-M produced larger changes on both primary outcomes in the EM, rather than CM, subgroup

OBJECTIVE:(1) Determine the pervasiveness of the belief that brain death/death by neurologic criteria (BD/DNC) is not death among rabbis. (2) Examine rabbinic beliefs about management after BD/DNC. METHODS:An electronic anonymous survey about BD/DNC determination and management after BD/DNC was created and distributed to members of the Central Conference of American Rabbis (the Reform Rabbinic leadership organization), the Rabbinic Council of America (an Orthodox organization), the Rabbinic Assembly (a Conservative organization), and the Reconstructionist Rabbinic Association. RESULTS:Ninety-nine rabbis (40 Reform, 32 Orthodox, 22 Conservative, and 5 Reconstructionist) completed the survey. Awareness of the requirements for BD/DNC was poor (median of 33% of the requirements correctly identified [interquartile range of 22-66%]), but 81% of rabbis knew that absence of heartbeat is not required for BD/DNC. Although only 5% of all rabbis believed a person who is brain dead could recover, 22% did not believe BD/DNC is death, and 18% believed mechanical ventilation should be continued after BD/DNC. There was a significant relationship between denomination and belief that: (1) a person who is brain dead can recover (p = 0.04); (2) a person who is brain dead is dead (p < 0.001); (3) mechanical ventilation should be continued after BD/DNC (p < 0.001); (4) hydration should be continued after BD/DNC (p = 0.002); (5) nutrition should be continued after BD/DNC (p < 0.001); (6) medications to support blood pressure should be continued after BD/DNC (p < 0.001); and (7) cardiopulmonary resuscitation should be performed when a brain dead person's heart stops (p = 0.006). CONCLUSIONS:Rabbinic knowledge about the intricacies of BD determination is poor. Rabbinic perspectives on management after BD/DNC vary. These empirical data on rabbinic perspectives about BD/DNC may be helpful when considering accommodation of religious objections to BD/DNC.

Diabetes mellitus is becoming increasingly common worldwide. As this occurs, there will be an increase in the prevalence of known comorbidities from this disorder of glucose metabolism. One of the most disabling adverse comorbidities is diabetic neuropathy. The most common neuropathic manifestation is distal symmetric polyneuropathy, which can lead to sensory disturbances, including diminished protective sense, making patients prone to foot injuries. However, focal, multifocal, and autonomic neuropathies are also common. Diabetic nerve pain and Charcot osteoarthropathy are advanced neuropathic conditions that portend a severe deterioration in quality of life. To combat these symptoms, along with glycemic control and establishment of health care systems to educate and support patients with the complexities of diabetes, there are pharmacologic remedies to ameliorate the neurologic symptoms. Several guidelines and review boards generally recommend the use of tricyclic antidepressants, serotonin/norepinephrine-reuptake inhibitors, α-2-delta ligands, and anticonvulsants as medications to improve painful diabetic neuropathy and quality of life.

BACKGROUND:Fear of falling may be significantly associated with falls in Parkinson's disease (PD) and may have a negative impact on quality of life. Nevertheless, there are no valid and reliable tools to examine this condition in PD. The objective of this study was to design and determine the psychometric attributes of an instrument to assess fear of falling in PD. METHODS:A prospective 1-year, 2-phase study was conducted to validate the Fear of Falling Scale, a self-assessed instrument for assessing fear of falling in PD. During phase 1, we designed a scale to measure the severity of fear of falling and determine its baseline psychometric characteristics, whereas phase 2 was a 1-year follow-up study to assess the frequency of falls and other clinical factors linked to fear of falling. Convergent and discriminant validity were assessed against the Fear of Falling Measure and the Starkstein Apathy Scale, respectively. RESULTS:The Fear of Falling Scale showed high internal consistency, test-retest reliability, and strong convergent and discriminant validity. There was a significant association between fear of falling score and the presence of both generalized anxiety disorder and major depression, poor balance-related motor ability, increased nonmotor symptoms of PD, more severe impairments in activities of daily living, and increased motor fluctuations. Finally, generalized anxiety disorder was a significant predictor of number of falls during a 12-month follow-up period. CONCLUSIONS:The Fear of Falling Scale is a valid and reliable instrument to assess fear of falling in PD. Fear of falling in PD is associated with specific psychiatric and motor disorders and is significantly related to the performance of balance-related motor functions. © 2019 International Parkinson and Movement Disorder Society.