Detection of High-Risk Paraneoplastic Antibodies against TRIM9 and TRIM67 Proteins.

OBJECTIVE: Co-occurring anti-tripartite motif-containing protein 9 and 67 autoantibodies (TRIM9/67-IgG) have been reported in only a very few cases of paraneoplastic cerebellar syndrome. The value of these biomarkers and the most sensitive methods of TRIM9/67-IgG detection are not known. METHODS: We performed a retrospective, multicenter study to evaluate the cerebrospinal fluid and serum of candidate TRIM9/67-IgG cases by tissue-based immunofluorescence, peptide phage display immunoprecipitation sequencing, overexpression cell-based assay (CBA), and immunoblot. Cases in which TRIM9/67-IgG was detected by at least 2 assays were considered TRIM9/67-IgG positive. RESULTS: Among these cases (n = 13), CBA was the most sensitive (100%) and revealed that all cases had TRIM9 and TRIM67 autoantibodies. Of TRIM9/67-IgG cases with available clinical history, a subacute cerebellar syndrome was the most common presentation (n = 7/10), followed by encephalitis (n = 3/10). Of these 10 patients, 70% had comorbid cancer (7/10), 85% of whom (n = 6/7) had confirmed metastatic disease. All evaluable cancer biopsies expressed TRIM9 protein (n = 5/5), whose expression was elevated in the cancerous regions of the tissue in 4 of 5 cases. INTERPRETATION: TRIM9/67-IgG is a rare but likely high-risk paraneoplastic biomarker for which CBA appears to be the most sensitive diagnostic assay. ANN NEUROL 2023;94:1086-1101.

Needs assessment for direct ophthalmoscopy training in neurology residency.

BACKGROUND: Assessment of the ocular fundus, traditionally by direct ophthalmoscopy (DO), is essential to evaluate many neurologic diseases. However, the status of DO training in neurology residencies is unknown. We conducted a needs assessment to determine current attitudes, curricula, and gaps in DO training. METHODS: A survey was developed and administered to residents and program directors (PDs) at ACGME accredited neurology residencies in the United States. The survey assessed factors such as current DO curricula, perceived importance of DO, confidence of skills, and need for improvement. Data analysis was performed using the Mann Whitney U test and Fisher Exact Test. RESULTS: Nineteen PDs (11.6%) and 74 (41.1%) residents responded to the survey. 97.1% of residents and 100.0% of PDs believe DO is an important skill to learn. 29.4% of PDs expected graduating residents to have completed > 10 supervised DO exams, while 0.0% of graduating fourth year residents reported doing so (p = 0.03). 35.7% of graduating residents had never correctly identified an abnormal finding on DO. The number of times residents practiced DO unsupervised correlated with increasing confidence in all components of the DO exam (p < 0.05). Residents who felt their program emphasized DO were more likely to perform DO at least once a week compared to residents who did not perceive program emphasis (61.9% vs. 35.0%, p = 0.02) and were more confident in DO (p < 0.05). 66.7% of residents and 42.1% of PDs were not satisfied with current levels of DO training. 96.7% of residents and 78.9% of PDs felt it was important to improve curriculum for DO training. Supervised practice and practice skills sessions were identified as the most helpful interventions to improve DO training. CONCLUSIONS: The vast majority of neurology PDs and residents believe DO is an important skill to learn, are unsatisfied with the current level of DO training, and advocate for improvement in DO curricula. Current DO curricula have limited formal didactic training and supervised practice. The bulk of DO learning occurs through unsupervised practice, which is influenced by motivational factors such as perceived residency emphasis on DO learning.

ALSUntangled #65: glucocorticoid corticosteroids.

ALSUntangled reviews alternative and off-label treatments for people with amyotrophic lateral sclerosis (PALS). Here we review glucocorticoids. Neuroinflammation plays a prominent role in amyotrophic lateral sclerosis (ALS) pathogenesis, so some hypothesize that glucocorticoids might be an effective ALS therapy through their immunosuppressive effects. In this paper, we review the available evidence for glucocorticoids in ALS, including one pre-clinical study with a genetic mouse model of ALS, nine case reports (ranging from 1 to 26 patients each), and four clinical trials. We also review the possible side effects (including steroid myopathy) and the costs of therapy. We graded the level of evidence as follows: Mechanism, D; Pre-Clinical, F; Cases, B; Trials, F; Risks, C. Our review of the current evidence concludes that glucocorticoids do not offer clinical benefit in ALS and confer serious risks. Thus, ALSUntangled does not recommend glucocorticoids as a treatment for ALS.

ALSUntangled #63: ketogenic diets.

ALSUntangled reviews alternative and off label treatments with a goal of helping patients make more informed decisions about them. Here we review ketogenic diets. We shows that these have plausible mechanisms, including augmenting cellular energy balance and reducing excitotoxicity, neuroinflammation and oxidative stress. We review a mouse model study, anecdotal reports and trials in ALS and other diseases. We conclude that there is yet not enough data to recommend ketogenic diets for patients with ALS, especially in light of the many side effects these can have.

Common Focal Neuropathies in the Hospitalized Patient.

Neuropathies are a common problem encountered by neurologist in the hospitalized setting. Nerve injury may occur secondary to compression, stretch, and direct trauma, among other causes. Common focal neuropathies include the ulnar, median, and radial nerve in the upper extremities and sciatic, peroneal, and femoral nerve in the lower extremities. Surgical and obstetric risk factors are especially important considerations in evaluation of patients with focal neuropathies. Treatment is either conservative therapy or surgery depending on the mechanism of injury and extent of recovery.

KIBRA, MTNR1B, and FKBP5 genotypes are associated with decreased odds of incident delirium in elderly post-surgical patients.

Despite the association between cognitive impairment and delirium, little is known about whether genetic differences that confer cognitive resilience also confer resistance to delirium. To investigate whether older adults without postoperative delirium, compared with those with postoperative delirium, are more likely to have specific single nucleotide polymorphisms (SNPs) in the FKBP5, KIBRA, KLOTHO, MTNR1B, and SIRT1 genes known to be associated with cognition or delirium. This prospective nested matched exploratory case-control study included 94 older adults who underwent orthopedic surgery and screened for postoperative delirium. Forty-seven subjects had incident delirium, and 47 age-matched controls were not delirious. The primary study outcome was genotype frequency for the five SNPs. Compared with participants with delirium, those without delirium had higher adjusted odds of KIBRA SNP rs17070145 CT/TT [vs. CC; adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.03, 7.54; p = 0.04] and MTNR1B SNP rs10830963 CG/GG (vs. CC; aOR 4.14, 95% CI 1.36, 12.59; p = 0.01). FKBP5 SNP rs1360780 CT/TT (vs. CC) demonstrated borderline increased adjusted odds of not developing delirium (aOR 2.51, 95% CI 1.00, 7.34; p = 0.05). Our results highlight the relevance of KIBRA, MTNR1B, and FKBP5 in understanding the complex relationship between delirium, cognition, and sleep, which warrant further study in larger, more diverse populations.

Outcomes Following Implementation of a Hospital-Wide, Multicomponent Delirium Care Pathway.

BACKGROUND: Delirium is associated with poor clinical outcomes that could be improved with targeted interventions. OBJECTIVE: To determine whether a multicomponent delirium care pathway implemented across seven specialty nonintensive care units is associated with reduced hospital length of stay (LOS). Secondary objectives were reductions in total direct cost, odds of 30-day hospital readmission, and rates of safety attendant and restraint use. METHODS: This retrospective cohort study included 22,708 hospitalized patients (11,018 preintervention) aged ≥50 years encompassing seven nonintensive care units: neurosciences, medicine, cardiology, general and specialty surgery, hematology-oncology, and transplant. The multicomponent delirium care pathway included a nurse-administered delirium risk assessment at admission, nurse-administered delirium screening scale every shift, and a multicomponent delirium intervention. The primary study outcome was LOS for all units combined and the medicine unit separately. Secondary outcomes included total direct cost, odds of 30-day hospital readmission, and rates of safety attendant and restraint use. RESULTS: Adjusted mean LOS for all units combined decreased by 2% post intervention (proportional change, 0.98; 95% CI, 0.96-0.99; P = .0087). Medicine unit adjusted LOS decreased by 9% (proportional change, 0.91; 95% CI, 0.83-0.99; P = .028). For all units combined, adjusted odds of 30-day readmission decreased by 14% (odds ratio [OR], 0.86; 95% CI, 0.80-0.93; P = .0002). Medicine unit adjusted cost decreased by 7% (proportional change, 0.93; 95% CI, 0.89-0.96; P = .0002). CONCLUSION: This multicomponent hospital-wide delirium care pathway intervention is associated with reduced hospital LOS, especially for patients on the medicine unit. Odds of 30-day readmission decreased throughout the entire cohort.

CSF ß-Amyloid 1-42 Predicts Progression to Cognitive Impairment in Newly Diagnosed Parkinson Disease.

Low CSF ß-amyloid 1-42 has been associated with cognitive decline in advanced Parkinson's disease; data from a single cohort suggest ß-amyloid 1-42 may be an early marker of cognitive impairment. Newly diagnosed Parkinson's participants (mean duration, 6.9 months) in the Parkinson's Progression Markers Initiative (n = 341) were assessed at baseline (untreated state) and followed for 2 years. CSF ß-amyloid 1-42, α-synuclein, total tau, and tau phosphorylated at threonine 181 were collected at baseline. Participants were classified as having cognitive impairment (CI) if scores on two of six cognitive tests were 1.5 standard deviations below the standardized mean based on published norms in healthy controls. Multivariable regression analyses were used to determine the association between baseline CSF markers with cognitive impairment, defined by neuropsychological testing performance at 2-year follow-up. Fifty-five participants (16.1 %) had CI at baseline and were not included in further analyses. Thirty-seven of the 286 participants without CI at baseline (12.9 %) developed CI at 2 years. Participants with CI at 2 years had significantly lower mean baseline CSF ß-amyloid 1-42 levels than non-CI participants (343.8 vs. 380.4 pg/mL, p < 0.01); no significant difference was seen for α-synuclein, T-tau, or P-tau 181. In a regression model of 286 participants without baseline CI adjusted for age, gender, disease duration, education, motor severity, and depression status, lower baseline ß-amyloid 1-42 levels were associated with higher odds of CI at 2 years. (OR(10pg/mL) = 1.04, 95 % CI 1.01-1.08, p < 0.05). CSF ß-amyloid 1-42 level at disease onset is an independent predictor of cognitive impairment in early Parkinson's disease.