Clinical and genetic factors affecting diagnostic timeline of amyotrophic lateral sclerosis: a 15-year retrospective study.

OBJECTIVES: Amyotrophic Lateral Sclerosis (ALS) diagnosis can take 10-16 months from symptom onset, leading to delays in treatment and patient counselling. We studied the impact of clinical and genetic risk factors on the diagnostic timeline of ALS. METHODS: Baseline characteristics, family history, gene testing, onset location, time from symptom onset to diagnosis, and time from first doctor visit to suspected ALS was collected. We used multiple regression to assess the interaction of these factors on ALS diagnostic timeline. We analysed a subgroup of patients with genetic testing and compared positive or negative tests, sporadic or familial and ALS-related genes to time for diagnosis. RESULTS: Four hundred and forty-eight patients diagnosed with ALS at the University of Massachusetts Chan Medical Center between January 2007 and December 2021 were analysed. The median time to ALS diagnosis was 12 months and remained unchanged from 2007 to 2021 (p = 0.20). Diagnosis was delayed in patients with sporadic compared with familial ALS (mean months [standard deviation], 16.5[13.5] and 11.2[8.5], p < 0.001); cognitive onset (41[21.26]) had longer time to diagnosis than bulbar (11.9[8.2]), limb (15.9[13.2]), respiratory (19.7[13.9]) and ALS with multiple onset locations (20.77[15.71], p < 0.001). One hundred and thirty-four patients had gene testing and 32 tested positive (23.8%). Gene testing (p = 0.23), a positive genetic test (p = 0.16), different ALS genes (p = 0.25) and sporadic (p = 0.92) or familial (p = 0.85) ALS testing positive for ALS genes did not influence time to diagnosis. DISCUSSION: Time for ALS diagnosis remained unchanged from 2007 to 2021, bulbar-onset and familial ALS made for faster diagnosis.

Miller-Fisher Syndrome With Initial Manifestation of Rhinolalia Aperta: A Case Report and Literature Review.

Rhinolalia aperta (hypernasal speech) is rarely reported in patients with Miller-Fisher syndrome (MFS). Here, we report a patient with MFS who presented with rhinolalia aperta. A 35-year-old man with a history of alcohol abuse and hepatic cirrhosis presented with a three-day acute hypernasal voice change and numbness of both hands/thighs. After admission, the exam also revealed palatal hypomobility, decreased bilateral hand/thigh sensation, ataxic gait, dysmetria, areflexia, and bilateral abducens palsy. Serum immunoglobulin G (IgG) anti-GQ1b antibody titer was elevated (1:6400). A five-day intravenous IgG was administered with a robust clinical response. Oropharyngeal involvement in MFS can initially manifest with isolated hypernasal speech.

A single-center retrospective study of hospitalized COVID-19 patients: demographics, laboratory markers, neurological complications, ICU admission, and mortality.

The coronavirus disease 2019 (COVID-19) pandemic has unveiled a wide array of clinical biomarkers, and neurological manifestations in affected patients, necessitating further exploration. Methods: This single-center retrospective study evaluated clinical and neurological sequelae, demographics, as well as laboratory markers, in hospitalized COVID-19 patients from January to September 2020. Results: Among 1248 inpatients (median age: 68 years; 651 women), 387 (31%) were admitted to the ICU. Central nervous system (CNS) manifestations were present in 521 (41.74%) patients, while peripheral nervous system manifestations were observed in 84 (6.73%). COVID-19-related mortality occurred in 314 (25.16%) cases. ICU-admitted patients were predominantly male (P<0.0001), older (age≥60; P=0.037) and had more comorbidities such as diabetes (P=0.001), hyperlipidemia (P=0.043), and coronary artery disease (P=0.015). ICU patients exhibited more CNS manifestations (P=0.001), including impaired consciousness (P<0.0001) and acute cerebrovascular disease (P=0.023). Biomarkers linked to admission to the ICU included elevated white blood cell count, ferritin, lactate dehydrogenase, creatine kinase, blood urea nitrogen, creatinine, and acute phase reactants (e.g. erythrocyte sedimentation rate and C-reactive protein). ICU patients demonstrated lower lymphocyte and platelet counts compared to non-ICU patients. Those with CNS involvement in the ICU often exhibited elevated blood urea nitrogen, creatinine, and creatine kinase levels. Higher mortality from COVID-19 was observed in ICU patients (P<0.0001). Conclusions: Multiple serum biomarkers, comorbidities, and neurological manifestations in COVID-19 patients have been consistently documented and may be linked to increased morbidity, ICU admission, and mortality. Recognizing and addressing these clinical and laboratory markers is essential for effective COVID-19 management.

COVID-19 in the intensive care unit: Unmasking the critical factors impacting patient survival.

In the midst of the coronavirus disease 2019 (COVID-19) pandemic, intensive care units (ICUs) around the world have been pushed to their limits as they grapple with the effects of the severe acute respiratory syndrome coronavirus 2 virus. Identifying prognostic factors that influence mortality in COVID-19 patients admitted to the ICU could offer valuable insights for clinicians seeking to prevent disease progression. A retrospective analysis was conducted on COVID-19 patients admitted to the ICU between January and September 2020. The analysis considered patient demographics, comorbidities, neurological and non-neurological symptoms, as well as laboratory markers. The multivariate logistic regression analysis aims to uncover associations between these factors and patient outcomes. Of the 387 patients included in this study, nearly half (48.5%) of the ICU patients succumbed to COVID-19. Factors that contributed to increased mortality included being 60 years of age or older, impaired consciousness, lung disease, elevated international normalized ratio (INR), and elevated blood urea nitrogen (BUN) levels. Surprisingly, symptoms such as dizziness/lightheadedness, myalgia, and headache were associated with a higher likelihood of survival. In addition, elevated D-dimer and aspartate aminotransferase (AST) levels, as well as lymphopenia, were more commonly observed in deceased patients. The study concluded that those who died in the ICU tended to be older, white, and burdened with more comorbidities and impaired consciousness. With the intriguing link between specific symptoms and survival, further research is essential to uncover the underlying pathophysiological mechanisms that influence ICU patient outcomes in the context of COVID-19.

Gene Therapy in Amyotrophic Lateral Sclerosis.

Since the discovery of Cu/Zn superoxide dismutase (SOD1) gene mutation, in 1993, as the first genetic abnormality in amyotrophic lateral sclerosis (ALS), over 50 genes have been identified as either cause or modifier in ALS and ALS/frontotemporal dementia (FTD) spectrum disease. Mutations in C9orf72, SOD1, TAR DNA binding protein 43 (TARDBP), and fused in sarcoma (FUS) genes are the four most common ones. During the last three decades, tremendous effort has been made worldwide to reveal biological pathways underlying the pathogenesis of these gene mutations in ALS/FTD. Accordingly, targeting etiologic genes (i.e., gene therapies) to suppress their toxic effects have been investigated widely. It includes four major strategies: (i) removal or inhibition of abnormal transcribed RNA using microRNA or antisense oligonucleotides (ASOs), (ii) degradation of abnormal mRNA using RNA interference (RNAi), (iii) decrease or inhibition of mutant proteins (e.g., using antibodies against misfolded proteins), and (iv) DNA genome editing with methods such as clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas). The promising results of these studies have led to the application of some of these strategies into ALS clinical trials, especially for C9orf72 and SOD1. In this paper, we will overview advances in gene therapy in ALS/FTD, focusing on C9orf72, SOD1, TARDBP, and FUS genes.

Increased prevalence of celiac disease and its clinical picture among patients with diabetes mellitus type 1 - observations from a single pediatric center in Central Europe.

INTRODUCTION: The aim of our study was to analyze the incidence and the clinical characteristic of celiac disease (CD) in pediatric population with type 1 diabetes mellitus (T1DM). MATERIAL AND METHODS: The data of 880 patients with T1DM, 429 girls, mean age 12.14 ±4.0 years was retrospectively retrieved from medical records. Patients with T1DM and CD were selected and a detailed analysis of CD prevalence and its clinical characteristic at the time of CD diagnosis was performed. The data were compared with the previous data from our center published a decade ago. RESULTS: CD was suspected in 85/880 patients (9.65%) on the base of results of serological tests, but finally CD was diagnosed in 73/880 patients with T1DM (8.3%), in 53/429 girls (12.3%) and in 20/451 boys (4.4%). Most patients (71%) had CD diagnosed after T1DM onset. The majority of CD patients (72%) was asymptomatic. The CD diagnosis was not associated with inappropriate metabolic control of diabetes. The onset age of diabetes in children with CD was significantly lower than in those without CD (5.8 ±3.6 years vs. 7.56 ±4.0 years, p = 0.04). The prevalence of CD is significantly higher than a decade ago in our center (8.3% vs. 5.7%, p = 0.001). CONCLUSIONS: In light of increasing prevalence of mainly asymptomatic CD in patients with T1DM, CD screening is necessary. However positive serological tests, which are currently used in screening, and are the first step of diagnostics, in some patients allow only to suspect the CD and further diagnostic steps should be performed.

Extrathyroidal congenital defects in children with congenital hypothyroidism - observations from a single paediatric centre in Central Europe with a review of literature.

INTRODUCTION: Patients with congenital hypothyroidism (CH) can have an increased risk of occurrence of extrathyroidal defects compared to the general population, which could influence their development. The abnormalities occur mainly in organ systems whose development and function is dependent on genes that are also responsible for proper organogenesis of the thyroid gland and thyroid hormone synthesis. AIM OF THE STUDY: The aim of the study was to evaluate the frequency of extrathyroidal defects in CH patients, taking into consideration the cause of this co-occurrence and the role of genetic tests. MATERIAL AND METHODS: The study included 54 newborns with positive screening test for CH based on elevated TSH level, in the years 2010-2017, from South-Eastern Poland. The data was retrieved retrospectively from patients' medical records. RESULTS: Twenty of 54 newborns with CH (37%) had congenital defects of other organs. In 10 (18.5%) cardiac defects were found, in 5 (9.25%) abnormal symptoms of the respiratory system, 7 (12.96%) had abnormalities of the gastrointestinal system, five (9.25%) had genitouri-nary abnormalities, 3 (5.55%) had abnormalities of the nervous system, and 6 (11.1%) had musculoskeletal abnormalities. CONCLUSIONS: The analysis of our data and current literature suggests that genetic factors play the most important role in the development of extrathy-roidal abnormalities in newborns with CH. Identifying the mutation causing CH, the potential defects that can accompany newborns with CH, screening could be offered for these patients in order to obtain an earlier diagnosis and implement early and appropriate treat-ment.