Faculty Bibliography

CONTEXT/BACKGROUND:X-linked acrogigantism (X-LAG), a condition of infant-onset acrogigantism marked by elevated GH, IGF-1, and prolactin (PRL), is extremely rare. Thirty-three cases, including three kindreds, have been reported. These patients have pituitary adenomas that are thought to be mixed lactotrophs and somatotrophs. CASE DESCRIPTION/METHODS:The patient's mother, diagnosed with acrogigantism at 21 months, underwent pituitary tumor excision at 24 months. For over 30 years, stable PRL, GH, and IGF-1 concentrations and serial imaging studies indicated no tumor recurrence. During pre-conception planning, X-LAG was diagnosed: single-nucleotide polymorphism (SNP) microarray showed chromosome Xq26.3 microduplication. After conception, SNP microarray on a chorionic villus sample showed the same microduplication in the fetus, confirming familial X-LAG. The infant grew rapidly with rising PRL, GH, and IGF-1 concentrations and an enlarging suprasellar pituitary mass, despite treatment with bromocriptine. At 15 months, he underwent tumor resection. The pituitary adenoma resembled the mother's pituitary adenoma, with tumor cells arranged in trabeculae and glandular structures. In both cases, many tumor cells expressed PRL, GH, and PIT1. Furthermore, the tumor expressed other lineage-specific transcription factors, as well as SOX2 and OCT4, demonstrating the multipotentiality of X-LAG tumors. Both showed an elevated Ki-67 proliferation index-5.6% (mother) and 8.5% (infant)-the highest reported in X-LAG. CONCLUSIONS:This is the first prenatally diagnosed case of X-LAG. Clinical follow-up and biochemical evaluation have provided insight into the natural history of this disease. Expression of stem cell markers and several cell lineage-specific transcription factors suggests that these tumors are multipotential.

PURPOSE OF REVIEW/OBJECTIVE:This article provides an overview of nystagmus and saccadic intrusions with the goal of facilitating recognition and differentiation of abnormal eye movements to assist with accurate diagnosis of neurologic disease and evidence-based specific treatment of oscillopsia. Myriad advances have been made in the understanding of several types of nystagmus and saccadic intrusions, even in the past 5 to 10 years, especially regarding underlying pathophysiology, leading to pharmacologic advances rooted in physiologic principles. RECENT FINDINGS/RESULTS:Specific recent advances in the study of nystagmus and saccadic intrusions include (1) improved understanding of the underlying etiologies and mechanisms of nystagmus enhanced or unmasked by provocative maneuvers such as supine position or head shaking; (2) recognition of the differences in behavior and treatment responsivity of acquired pendular nystagmus in demyelinating disease versus oculopalatal myoclonus; (3) recognition that oculopalatal myoclonus results from a dual mechanism of abnormal inferior olivary gap junction connection formation and maladaptive cerebellar learning; and (4) well-controlled clinical trials to evaluate the efficacy of pharmacologic interventions, such as memantine for acquired pendular nystagmus and 4-aminopyridine for downbeat nystagmus. SUMMARY/CONCLUSIONS:Accurate recognition of nystagmus and saccadic intrusions, including familiarity with the subtleties of examination techniques that allow such eye movements to be unmasked, is critical to proper diagnosis and ultimate alleviation of the visual impairment these patients experience.

Aneurysm size correlates with rupture risk and is important for treatment planning. User annotation of aneurysm size is slow and tedious, particularly for large data sets. Geometric shortcuts to compute size have been shown to be inaccurate, particularly for nonstandard aneurysm geometries. To develop and train a convolutional neural network (CNN) to detect and measure cerebral aneurysms from magnetic resonance angiography (MRA) automatically and without geometric shortcuts. In step 1, a CNN based on the U-net architecture was trained on 250 MRA maximum intensity projection (MIP) images, then applied to a testing set. In step 2, the trained CNN was applied to a separate set of 14 basilar tip aneurysms for size prediction. Step 1-the CNN successfully identified aneurysms in 85/86 (98.8% of) testing set cases, with a receiver operating characteristic (ROC) area-under-the-curve of 0.87. Step 2-automated basilar tip aneurysm linear size differed from radiologist-traced aneurysm size on average by 2.01 mm, or 30%. The CNN aneurysm area differed from radiologist-derived area on average by 8.1 mm² or 27%. CNN correctly predicted the area trend for the set of aneurysms. This approach is to our knowledge the first using CNNs to derive aneurysm size. In particular, we demonstrate the clinically pertinent application of computing maximal aneurysm one-dimensional size and two-dimensional area. We propose that future work can apply this to facilitate pre-treatment planning and possibly identify previously missed aneurysms in retrospective assessment.

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.

INTRODUCTION: Familial dysautonomia (FD) is a progressive neurogenetic disease with carrier rate as high as 1 in 18 persons in European Jews of Polish origin. Clinical hallmarks include cardiovascular instability, spinal deformities, renal dysfunction, alacrima, ataxia, and impaired nociception. Physical or emotional stress may elicit autonomic crises characterized by hypertension and vomiting. Despite profound sensory deficits, GI perturbations are frequently reported by FD patients. While the incidence of inflammatory bowel disease (IBD) and FD is unknown, concurrence is underreported given increased frequency of both diseases in Ashkenazi Jews. CASE DESCRIPTION/METHODS: We report a 33-year-old female with FD and ulcerative colitis who presented with one week of abdominal pain and bloody diarrhea. She had been maintained on balsalazide. Colonoscopy one year prior revealed endoscopic and histologic remission. On physical examination, her abdomen was tender in the lower quadrants. A CT scan revealed pancolitis. Stool studies resulted negative. Her CRP was 58.4 mg/L and albumin was 2.4 g/dL. A flexible sigmoidoscopy noted Mayo endoscopic score 3 in the rectum and CMV staining was negative. The patient was started on IV steroids. Her hospital course was complicated by ileus, parainfluenza infection, and MSSA bacteremia with a pacemaker lead vegetation, requiring extraction. Lack of optimal clinical response to treatment on hospital day five led to consideration of alternative treatments with careful attention to her underlying FD. A subtotal colectomy with end ileostomy was unfavorable due to concern for volume loss. Infliximab and cyclosporine were opposed due to infection risk and later exhibiting possible nephrotoxicity. During this discussion the patient improved enough to be transitioned to oral steroids with a plan to initiate vedolizumab as an outpatient. On recent colonoscopy she had achieved mucosal healing. DISCUSSION: This is the first case of UC in a FD patient reported. Given myriad GI symptoms in the later diagnosis it can be hard to distinguish disease-related from treatment-related events. Due to the gut-specificity of vedolizumab, infection risk is considerably reduced compared to that of other biologics and is the most favorable option in the setting of underlying FD. This case highlights the difficulty encountered when treating IBD in the setting of systemic illness and underscores the need to carefully consider management options to enhance patient outcomes. (Figure Presented)

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: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.

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.