Therapeutic Biomarkers in Friedreich's Ataxia: a Systematic Review and Meta-analysis.

Although a large array of biomarkers have been investigated in Friedreich's ataxia (FRDA) trials, the optimal biomarker for assessing disease progression or therapeutic benefit has yet to be identified. We searched PubMed, MEDLINE, and EMBASE databases up to June 2023 for any original study (with ≥ 5 participants and ≥ 2 months' follow-up) reporting the effect of therapeutic interventions on any clinical, cardiac, biochemical, patient-reported outcome measures, imaging, or neurophysiologic biomarker. We also explored the biomarkers' ability to detect subtle disease progression in untreated patients. The pooled standardized mean difference (SMD) was calculated using a random-effects model. The study's protocol was registered in PROSPERO (CRD42022319196). In total, 43 studies with 1409 FRDA patients were included in the qualitative synthesis. A statistically significant improvement was observed in Friedreich Ataxia Rating Scale scores [combining Friedreich Ataxia Rating Scale (FARS) and modified FARS (mFARS): SMD = - 0.32 (- 0.62 to - 0.02)] following drugs that augment mitochondrial function in a sensitivity analysis. Left ventricular mass index (LVMI) was improved significantly [SMD = - 0.34 (- 0.5 to - 0.18)] after 28.5 months of treatment with drugs that augment mitochondrial function. However, LVMI remained stable [SMD = 0.05 (- 0.3 to 0.41)] in untreated patients after 6-month follow-up. None of the remaining biomarkers changed significantly following any treatment intervention nor during the natural disease progression. Nevertheless, clinical implications of these results should be interpreted with caution because of low to very low quality of evidence. Further randomized controlled trials of at least 24 months' duration using a biomarker toolbox rather than a single biomarker are warranted.

Biomarkers of therapeutic efficacy in adolescents and adults with 5q spinal muscular atrophy: a systematic review.

BACKGROUND: The therapeutic landscape of spinal muscular atrophy (SMA) was dramatically transformed with the introduction of three disease-modifying therapies (DMTs). A systematic review was performed to assess available evidence regarding quantitative therapeutic biomarkers used in SMA patients older than 11 years under treatment with DMTs. METHODS: Latest literature search in MEDLINE, EMBASE, Cochrane databases and gray literature resources was performed in June 2021. Studies reporting only motor function or muscle strength scales or pulmonary function tests were excluded. Primary outcome was the change from baseline score of any serum, cerebrospinal fluid (CSF) or neurophysiologic biomarker examined. RESULTS: Database and gray literature search yielded a total of 8050 records. We identified 14 records published from 2019 until 2021 examining 18 putative serum, CSF or neurophysiologic biomarkers along with routine CSF parameters in 295 SMA nusinersen-treated type 2-4 patients older than 11 years of age. There is evidence based on real-world observational studies suggesting that serum creatinine, creatine kinase activity levels along with CSF Αß42, glial fibrillary acidic protein concentration as well as ulnar compound motor action potential amplitude and single motor unit potential amplitude changes may depict therapeutic response in this population. CONCLUSION: This systematic review explored for the first-time biomarkers used to monitor therapeutic efficacy in SMA adolescents and adults treated with DMTs. Research in this area is in its early stages, and our systematic review can facilitate selection of quantitative therapeutic biomarkers that may be used as surrogate measures of treatment efficacy in future trials. PROTOCOL REGISTRATION: PROSPERO CRD42021245516.

COVID-19 pandemic impact on neurologic emergencies: a single-center retrospective cohort study.

Introduction: COVID-19 pandemic caused a major disruption to healthcare system. A year after COVID-19 outbreak, the question remains to what extent the lockdowns changed the volume of non-infected patients who were admitted to the Neurologic Department (ND). To determine the impact of the pandemic´s first year on a tertiary ND. Methods: non-infected patients admitted to ND between March 2020 and February 2021 were examined. A control group was generated for the same time interval starting from March 2019. Primary outcomes were the number of patients presenting with neurologic complaint who were admitted to the hospital and the diagnosis type. Secondary outcomes were hospitalization length and patients´ outcome. Results: overall, 816 patients (49.4% females) were admitted during the predetermined periods. Median age was 55 years. Median length of hospitalization was six days. We observed a 47.2% reduction in our department´s admissions during pandemic (n=282). None of the examined variables (type of neurologic diagnosis, age, gender, hospitalization length and outcome) changed significantly during pandemic. However, the number of patients admitted during the pandemic with a diagnosis categorized as "other" was statistically significant lower compared to the year before COVID-19 (p=0.007). Hospitalization length was associated only with patients´ age. Conclusion: our study examined for the first-time the consequences of the first year of COVID-19 pandemic on ND admissions. COVID-19 outbreak resulted in decreased admissions. Delays in seeking medical consultation for urgent or undiagnosed neurologic conditions require rigorous long-term monitoring to fully understand the impact of COVID-19 pandemic on patients with neurologic diseases.

Nusinersen in Adults with 5q Spinal Muscular Atrophy: a Systematic Review and Meta-analysis.

Evidence for nusinersen administration in adult 5q spinal muscular atrophy (5q-SMA) patients is scarce and based on real-world observational data. The present systematic review and meta-analysis aimed to explore the efficacy and safety of nusinersen in patients older than 12 years of age with 5q-SMA. We searched MEDLINE, EMBASE, the Cochrane Library, and grey literature through April 2021. Cross-sectional studies, case reports, review articles, and studies with follow-up less than 6 months were excluded. We included 12 records (seven case-series, five cohorts) representing 11 population cohorts and enrolling 428 SMA patients. We observed statistically significant improvements on motor function Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM) scores at the longest follow-up assessments [SMD = 0.17(95% CI 0.01-0.33), SMD = 0.22(95% CI 0.06-0.38), respectively]. HFMSE and RULM significant improvements were also detected at the subgroup analysis during 10 and 14 months. HFMSE and RULM amelioration occurred earlier in patients with SMA type 3 or 4 during short-term analysis (≤ 6 months). 6-min walk tests (6MWT) and pulmonary function tests did not change. Minimal clinically important differences in HFMSE and RULM were observed in 43.3% (95% CI 34.5-52.3) and 38.9% (95% CI 27.7-50.7), respectively. Severe adverse events were reported in 2% (95% CI 0-5.8). Treatment withdrawal rate was 3% (95% CI 0.5-6.6). Despite the low quality of evidence and the unmet need for randomized data to establish the safety and efficacy of nusinersen in adults, our meta-analysis confirms that nusinersen is a valuable treatment option for older patients with longer-disease duration.Trial registration: PROSPERO database CRD42020223109.

Biomarkers of disease progression in adolescents and adults with 5q spinal muscular atrophy: a systematic review and meta-analysis.

Since the introduction of disease modifying treatments there is an unmet need to identify biomarkers of spinal muscular atrophy (SMA) natural history. We performed a systematic review and meta-analysis to summarize available evidence. We searched MEDLINE, Embase, Cochrane Library and gray literature until February 2021. The primary outcome was biomarkers longitudinal course in adolescents and adults. The secondary outcome was the discrimination of patients from controls. We included 42 records examining 606 patients from 19 population cohorts over a maximum follow-up of 17-years. Lung function and serum biomarkers could not depict disease progression. We identified potential biomarkers of disease activity [SMA functional rating scale, MoviPlate, pinch strength, compound muscle action potential (CMAP), motor unit number estimation (MUNE)] that require further investigation. Data regarding Hammersmith functional motor scale expanded, Revised upper limb module, 6-minute walk test were contradictory impeding any pooled estimate. The pooled analysis regarding our secondary outcome revealed that upper limb CMAP amplitudes and MUNE mean values differed significantly between SMA patients and controls [mean difference -3.63(-6.2, -1.06), -119.74(-153.93, -85.56) respectively]. Given the lack of natural history data on this population, our qualitative synthesis and meta-analysis could provide valuable evidence and identify promising predictive biomarkers requiring further longitudinal examination. PROSPERO Registration: CRD42021235605.

Intrathecal Administration of Nusinersen Using the Ommaya Reservoir in an Adult with 5q-Related Spinal Muscular Atrophy Type 1 and Severe Spinal Deformity.

Spinal muscular atrophy (SMA) is a hereditary neuromuscular disorder, typically caused by survival motor neuron 1 (SMN1) gene deletion in chromosome 5q resulting in loss of SMN protein. SMA type 1 progresses rapidly leading to increased mortality usually before the age of 2 years. Nusinersen, the first approved disease-modifying treatment for all 5q-SMA types and ages, is an antisense oligonucleotide administered intrathecally via repeated lumbar punctures. However, adult SMA patients typically present with severe scoliosis and spinal deformity. We present a 28-year-old patient with SMA type 1 and severe spinal deformity, who received nusinersen via a subcutaneously implanted Ommaya reservoir connected with an intrathecal catheter at the thoracic level. The repetitive administrations were completed uneventfully, obviating the need for repeated laborious lumbar punctures and eliminating radiation exposure. In adult SMA patients, performing recurrent lumbar punctures can be technically challenging raising the need for an alternative route of administration. The use of Ommaya reservoirs is a viable, practical for repeated infusions, and safe option for the intrathecal delivery of nusinersen for select cases such as an adult SMA type 1 survivor with severe spinal deformity.

Switching from fingolimod to alemtuzumab in patients with highly active relapsing-remitting multiple sclerosis: Α case series.

BACKGROUND: The management of "aggressive" and "highly-active" relapsing-remitting multiple sclerosis remains problematic. Although a number of highly efficacious agents are currently available, the optimal timing of their use and the balancing between efficacy and immediate and long-term consequences are still a matter of conjecture. METHODS: We describe the clinical, radiological and immunological profile of three multiple sclerosis patients with persistent clinical and radiological disease activity under fingolimod treatment. After fingolimod cessation patients demonstrated severe disease exacerbation and were successfully treated with alemtuzumab. RESULTS: All patients experienced significant improvement after the administration of alemtuzumab and achieved no evidence of disease activity status that persisted after a median of 19 months of follow-up (range: 17-25 months). Confirmed disability improvement was achieved in all cases. Quantitative MRI data demonstrated a reduction of the T2 lesion load in 2 out of 3 patients and complete abrogation of inflammatory activity in all patients after the administration of alemtuzumab. Α patient presented a previously unreported, persistent lymphocytosis after alemtuzumab administration, that was not associated with infectious, lymphoproliferative or autoimmune diseases and had no apparent clinical implications. CONCLUSIONS: Alemtuzumab appears to be an effective and safe short-term therapeutic option both as a rescue therapy for the disease flare-up associated with fingolimod withdrawal, as well as for the reversal of the deteriorating course observed in patients who fail treatment with fingolimod.

Splenic injury complicating ERCP.

Endoscopic retrograde cholangiopancreatography (ERCP) is an invasive procedure which carries a complication rate of 5-10%. Splenic injury is a very rare and potentially lethal complication following ERCP. We report a case of a 64-year-old man with a mass at the pancreatic head and obstructive jaundice, who sustained a splenic injury following ERCP. Six hours after the procedure, the patient presented with epigastric pain and hypotension. The abdominal CT scan revealed splenic hematoma. He was offered surgical treatment. Splenectomy was performed with enterogastrostomy.

Modified S-pouch neobladder vs ileal conduit and a matched control population: a quality-of-life survey.

OBJECTIVES: To measure the quality-of-life (QoL) outcome and urinary and sexual function and bother after radical cystectomy and different types of urinary tract reconstruction (Bricker vs modified S-pouch neobladder), also assessing differences between them and a normal population. PATIENTS, SUBJECTS AND METHODS: Two groups of patients with bladder cancer were assessed; group 1 comprised 58 (mean age 65 years, mean follow-up 28 months) with an ileal conduit diversion, and group 2, 50 (mean age 61 years, mean follow-up 26 months) with a modified S-pouch neobladder. All were disease-free. Group 3 comprised 54 healthy subjects (a control population) of similar age, gender and comorbidities other than bladder cancer. A QoL questionnaire was used to study changes in QoL, and a specific questionnaire for urinary and sexual function and bother was also constructed. RESULTS: There were no differences in the QoL scores among the three groups; group 3 (control) tended to have a better QoL for all domains except emotional functioning. Urinary function was seriously affected in group 1, with more daytime leakage than in groups 2 and 3 (37.8% vs 10%, P = 0.005, and 9.3%, P = 0.01), night loss of urine (39.5% vs 28%, P = 0.07, and 3.7%, P = 0.002) and urine odour (58.6% vs 4%, and 5.5%, both P = 0.001). Patients in group 2 differed from healthy individuals only in night loss of urine. Consequently urinary bother was more pronounced in group 1, as fewer were satisfied (68.9% vs 86% and 83.2%, both P = 0.03). Sexual function was seriously and similarly affected in groups 1 and 2; the erection rate was 28.9% for group 1, 35.5% for group 2 (P = 0.1) and 83.3% in group 3 (P = 0.003), while firm erections were present at 17.7%, 22.2% (P = 0.2) and 83.3% (P = 0.002). Women reported equivalent dysfunction in all three groups (15.4%, 20% and 16.6%, P = 0.3). Sexual desire was also equal in all groups (48.2%, 50% and 48.1). Patients in group 1 expressed more bother, while those in group 2 seemed more satisfied by their sexual life (84.4%, 68% and 68.5%, P = 0.04). CONCLUSIONS: Radical cystectomy does not affect QoL whichever urinary reconstruction is used, and this implies a determination by the patients to live and adjust to their new conditions. On the contrary, urinary and sexual function are affected and related to the method used to reconstruct the urinary system.