Faculty Bibliography

Judicious multiple sclerosis (MS) diagnosis and early start of disease modifying therapy significantly improves long-term disability outcomes in persons with MS (pwMS). Retrospective analysis based on 25-year New York State MS Consortium (NYSMSC) data determined the effect of changes in the respective diagnostic criteria in shortening the time between symptom onset to MS diagnosis. Based on 9378 current and historical MS cases, there was a significant decrease in time to diagnosis in pwMS from 1982-2001 to >2017 periods (average 4.2 vs. 1.1 years, p < 0.001). Additional improvements and better implementation of the MS diagnostic criteria can further decrease the diagnosis lag.

This manuscript explores the international variability in the diagnosis and management of disorders of consciousness (DoC). The identification, evaluation, intervention, exploration, prognostication and limitation of therapy for patients with DoC is reviewed through an international lens. The myriad factors that impact the diagnosis and management of DoC including 1) financial, 2) legal and regulatory, 3) cultural, 4) religious and 5) psychosocial considerations are discussed. As data comparing patients with DoC internationally are limited, findings from the general critical care or neurocritical care literature are described when information specific to patients with DoC is unavailable. There is a need for improvements in clinical care, education, advocacy and research related to patients with DoC worldwide. It is imperative to standardize methodology to evaluate consciousness and prognosticate outcome. Further, education is needed to 1) generate awareness of the impact of the aforementioned considerations on patients with DoC and 2) develop techniques to optimize communication about DoC with families. It is necessary to promote equity in access to expertise and resources for patients with DoC to enhance the care of patients with DoC worldwide. Improving understanding and management of patients with DoC requires harmonization of existing datasets, development of registries where none exist and establishment of international clinical trial networks that include patients in all phases along the spectrum of care. The work of international organizations like the Curing Coma Campaign can hopefully minimize international variability in the diagnosis and management of DoC and optimize care.

Background: We performed a focused review to determine the "non-inferiority", potential superiority, and relative safety/efficacy for performing cervical disc arthroplasty (CDA)/total disc replacement (TDR) in carefully selected patients vs. anterior cervical diskectomy/fusion (ACDF). Notably, CDA/TDR were devised to preserve adjacent level range of motion (ROM), reduce the incidence of adjacent segment degeneration (ASD), and the need for secondary ASD surgery. Methods: We compared the incidence of ASD, reoperations for ASD, safety/efficacy, and outcomes for cervical CDA/TDR vs. ACDF. Indications, based upon the North American Spine Society (NASS) Coverage Policy Recommendations (Cervical Artificial Disc Replacement Revised 11/2015 and other studies) included the presence of radiculopathy or myelopathy/myeloradiculopathy at 1-2 levels between C3-C7 with/without neck pain. Contraindications for CDA/TDR procedures as quoted from the NASS Recommendations (i.e. cited above) included the presence of; "Infection ", "Osteoporosis and Osteopenia", "Instability ", "Sensitivity or Allergy to Implant Materials", "Severe Spondylosis ", "Severe Facet Joint Arthropathy ", "Ankylosing Spondylitis"(AS), "Rheumatoid Arthritis (RA), Previous Fracture ", "Ossification of the Posterior Longitudinal Ligament (OPLL)", and "Malignancy ". Other sources also included spinal stenosis and scoliosis. Results: Cervical CDA/TDR studies in the appropriately selected patient population showed no inferiority/ occasionally superiority, reduced the incidence of ASD/need for secondary ASD surgery, and demonstrated comparable safety/efficacy vs. ACDF. Conclusion: Cervical CDA/TDR studies performed in appropriately selected patients showed a "lack of inferiority", occasional superiority, a reduction in the incidence of ASD, and ASD reoperation rates, plus comparable safety/efficacy vs. ACDF.

Background: Multiple anterior cervical diskectomy/fusion (ACDF) techniques now use a variety of Polyehteretherketone (PEEK) cages; stand-alone (SA) and zero-profile (ZP) with/without screws, cages filled with demineralized bone matrix/autograft, and cages coated with hydroxyapatite or titanium. We compared the safety/ efficacy between different PEEK ACDF cage constructs in 17 studies, and in some cases, additionally contrasted results with "routine"ACDF (i.e. series/historical data performed with combinations of iliac autograft/allograft and plates). Methods: We focused on the clinical outcomes, fusion rates, postoperative radiographic changes/lordosis/ subsidence, and/or reoperation rates for various PEEK ACDF constructs vs. "routine"ACDF. Results: One to 3 and 4-level PEEK ACDF cages demonstrated high fusion rates, few cage failures, and low reoperation rates. Subsidence for PEEK ACDF cages did not reduce fusion rates or diminish the quality of postoperative outcomes. Further, titanium-coated (T-C) PEEK cages lowered fusion rates in one study (i.e. 44.1% fusions vs. 88.2% for routine PEEK ACDF) while ACDF PEEK cages coated with hydroxyapatite (HA) showed only a "trend"toward enhanced arthrodesis. Conclusion: One to 3-4 multilevel ACDF PEEK cage constructs demonstrated comparable safety/efficacy when compared with each other, or in select cases, with "routine"ACDF (i.e. using autograft/allograft and plates).

B-cell depleting therapies such as rituximab and ocrelizumab are widely used for the treatment of Multiple Sclerosis but have increased risks of adverse reactions compared to earlier MS therapies. One rarely reported reaction is pyoderma gangrenosum (PG), an inflammatory, ulcerative, skin disease of unclear etiology. Here we describe a male and female patient, each with Relapsing-Remitting Multiple Sclerosis, and both of whom developed PG while on rituximab. Both PG diagnoses were supported by persistent fever, biopsy reports of sterile neutrophilia, and leukocytosis in the absence of an identifiable infectious agent. The diagnoses were further confirmed by dramatic clinical improvement following initiation of high dose steroids and intravenous immunoglobulins, and discontinuation of rituximab.

BACKGROUND:Late-Onset Tay-Sachs (LOTS) disease is a rare, progressive neurological condition that can dramatically affect the life of these patients. The diagnosis of LOTS is easily missed because of the multifaced presentation of these patients, who can initially be assessed by neuromuscular or movement disorder specialists, or psychiatrists. Clinical trials are now becoming available for LOTS. Therefore, early diagnosis can be detrimental for these patients and for insuring informative research outcomes. METHODS:We characterized a cohort of nine patients with LOTS through a detailed clinical and video description. We then reviewed the available literature regarding the clinical description of patients with LOTS. Our findings were summarized based on the predominant phenotype of presentation to highlight diagnostic clues to guide the diagnosis of LOTS for different neurology specialists (neuromuscular, movement disorders) and psychiatrist. RESULTS:We described a cohort of 9 new patients with LOTS seen at our clinic. Our literature review identified 76 patients mainly presenting with a neuromuscular, cerebellar, psychiatric, stuttering, or movement disorder phenotype. Diagnostic tips, such as the triceps sign, distinct speech patterns, early psychiatric presentation and impulsivity, as well as neurological symptoms (cerebellar or neuromuscular) in patients with a prominent psychiatric presentation, are described. DISCUSSION:Specific diagnostics clues can help neurologists and psychiatrists in the early diagnosis of LOTS disease. Our work also represent the first video presentation of a cohort of patients with LOTS that can help different specialists to familiarize with these features and improve diagnostic outcomes. HIGHLIGHTS:Late-Onset Tay-Sachs (LOTS) disease, a severe progressive neurological condition, has multifaced presentations causing diagnostic delays that can significantly affect research outcomes now that clinical trials are available. We highlight useful diagnostic clues from our cohort (including the first video representation of a LOTS cohort) and comprehensive literature review.

This paper aims to highlight how to reduce medication errors through the implementation of human factors science to the design features of medication containers. Despite efforts to employ automation for increased safety and decreased workload, medication administration in hospital wards is still heavily dependent on human operators (pharmacists, nurses, physicians, etc.). Improving this multi-step process requires its being studied and designed as an interface in a complex socio-technical system. Human factors engineering, also known as ergonomics, involves designing socio-technical systems to improve overall system performance, and reduces the risk of system, and in particular, operator, failures. The incorporation of human factors principles into the design of the work environment and tools that are in use during medication administration could improve this process. During periods of high workload, the cognitive effort necessary to work through a very demanding process may overwhelm even expert operators. In such conditions, the entire system should facilitate the human operator's high level of performance. Regarding medications, clinicians should be provided with as many perceptual cues as possible to facilitate medication identification. Neglecting the shape of the container as one of the features that differentiates between classes of medications is a lost opportunity to use a helpful characteristic, and medication administration failures that happen in the absence of such intentional design arise from "designer error" rather than "user error". Guidelines that define a container's shape for each class of medication would compel pharmaceutical manufacturers to be compatible and would eliminate the confusion that arises when a hospital changes the supplier of a given medication.

OBJECTIVE:Genetic factors have long been debated as a cause of failure of surgery for mesial temporal lobe epilepsy (MTLE). We investigated whether rare genetic variation influences seizure outcomes of MTLE surgery. METHODS:We performed an international, multicenter, whole exome sequencing study of patients who underwent surgery for drug-resistant, unilateral MTLE with normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis and ≥2-year postsurgical follow-up. Patients with either sustained seizure freedom (favorable outcome) or ongoing uncontrolled seizures since surgery (unfavorable outcome) were included. Exomes of controls without epilepsy were also included. Gene set burden analyses were carried out to identify genes with significant enrichment of rare deleterious variants in patients compared to controls. RESULTS:Nine centers from 3 continents contributed 206 patients operated for drug-resistant unilateral MTLE, of whom 196 (149 with favorable outcome and 47 with unfavorable outcome) were included after stringent quality control. Compared to 8,718 controls, MTLE cases carried a higher burden of ultrarare missense variants in constrained genes that are intolerant to loss-of-function (LoF) variants (odds ratio [OR] = 2.6, 95% confidence interval [CI] = 1.9-3.5, p = 1.3E-09) and in genes encoding voltage-gated cation channels (OR = 2.4, 95% CI = 1.4-3.8, p = 2.7E-04). Proportions of subjects with such variants were comparable between patients with favorable outcome and those with unfavorable outcome, with no significant between-group differences. INTERPRETATION/CONCLUSIONS:Rare variation contributes to the genetic architecture of MTLE, but does not appear to have a major role in failure of MTLE surgery. These findings can be incorporated into presurgical decision-making and counseling. ANN NEUROL 2022.

Non-human primates have an important translational value given their close phylogenetic relationship to humans. Studies in these animals remain essential for evaluating efficacy and safety of new therapeutic approaches, particularly in aging primates that display Alzheimer's disease (AD) -like pathology. With the objective to improve amyloid-β (Aβ) targeting immunotherapy, we investigated the safety and efficacy of an active immunisation with an Aβ derivative, K6Aβ1-30-NH₂, in old non-human primates. Thirty-two aged (4-10 year-old) mouse lemurs were enrolled in the study, and received up to four subcutaneous injections of the vaccine in alum adjuvant or adjuvant alone. Even though antibody titres to Aβ were not high, pathological examination of the mouse lemur brains showed a significant reduction in intraneuronal Aβ that was associated with reduced microgliosis, and the vaccination did not lead to microhemorrhages. Moreover, a subtle cognitive improvement was observed in the vaccinated primates, which was probably linked to Aβ clearance. This Aβ derivative vaccine appeared to be safe as a prophylactic measure based on the brain analyses and because it did not appear to have detrimental effects on the general health of these old animals.