Diving deep: zebrafish models in motor neuron degeneration research.

In the dynamic landscape of biomedical science, the pursuit of effective treatments for motor neuron disorders like hereditary spastic paraplegia (HSP), amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy (SMA) remains a key priority. Central to this endeavor is the development of robust animal models, with the zebrafish emerging as a prime candidate. Exhibiting embryonic transparency, a swift life cycle, and significant genetic and neuroanatomical congruencies with humans, zebrafish offer substantial potential for research. Despite the difference in locomotion-zebrafish undulate while humans use limbs, the zebrafish presents relevant phenotypic parallels to human motor control disorders, providing valuable insights into neurodegenerative diseases. This review explores the zebrafish's inherent traits and how they facilitate profound insights into the complex behavioral and cellular phenotypes associated with these disorders. Furthermore, we examine recent advancements in high-throughput drug screening using the zebrafish model, a promising avenue for identifying therapeutically potent compounds.

Understanding public perceptions and discussions on diseases involving chronic pain through social media: cross-sectional infodemiology study.

BACKGROUND: Chronic pain is a highly prevalent medical condition that negatively impacts quality of life and is associated with considerable functional disability. Certain diseases, such as fibromyalgia, headache, paraplegia, neuropathy, and multiple sclerosis, manifest with chronic pain. OBJECTIVE: The aim of this study is to examine the number and type of tweets (original or retweet) related to chronic pain, as well as to analyze the emotions and compare the societal impact of the diseases under study. METHODS: We investigated tweets posted between January 1, 2018, and December 31, 2022, by Twitter users in English and Spanish, as well as the generated retweets. Additionally, emotions were extracted from these tweets and their diffusion was analyzed. Furthermore, the topics most frequently discussed by users were collected. RESULTS: A total of 72,874 tweets were analyzed, including 44,467 in English and 28,407 in Spanish. Paraplegia represented 23.3% with 16,461 of the classified tweets, followed by headache and fibromyalgia with 15,337 (21.7%) and 15,179 (21.5%) tweets, respectively. Multiple sclerosis generated 14,781 tweets (21%), and the fewest tweets were related to neuropathy with 8,830 tweets (12.5%). The results showed that the primary emotions extracted were "fear" and "sadness." Additionally, the reach and impact of these tweets were investigated through the generated retweets, with those related to headaches showing the highest interest and interaction among users. CONCLUSION: Our results underscore the potential of leveraging social media for a better understanding of patients suffering from chronic pain and its impact on society. Among the most frequently encountered topics are those related to treatment, symptoms, or causes of the disease. Therefore, it is relevant to inform the patient to prevent misconceptions regarding their illness.

Paraplegic Patient with Metastatic Papillary Thyroid Cancer: A Multidisciplinary Approach to Radioactive Iodine Therapy Safety and Efficacy Strategy.

High-activity radioactive iodine (RAI) therapy for metastatic thyroid cancer (TC) requires isolation to minimize radiation exposure to third parties, thus posing challenges for patients needing hands-on care. There are limited data on the approach to high-activity RAI treatment in paraplegic patients. We report a state-of-the-art multidisciplinary approach to the management of bedbound patients, covering necessary radiation safety measures that lead to radiation exposure levels as low as reasonably achievable. Given the limited literature resources on standardized approaches, we provide a practical example of the safe and successful treatment of a woman with BRAFV600E-mutant tall-cell-variant papillary TC and pulmonary metastases, who underwent dabrafenib redifferentiation before RAI therapy. The patient was 69 y old and had become paraplegic because of a motor-vehicle accident. Since caring for a paraplegic patient with neurogenic bowel and bladder dysfunction poses radiation safety challenges, a multidisciplinary team comprising endocrinologists, nuclear medicine physicians, radiation safety specialists, and the nursing department developed a radiation mitigation strategy to ensure patient and staff safety during RAI therapy. The proposed standardized approach includes thorough monitoring of radiation levels in the workplace, providing additional protective equipment for workers who handle radioactive materials or are in direct patient contact, and implementing strict guidelines for safely disposing of radioactive waste such as urine collected in lead-lined containers. This approach requires enhanced training, role preparation, and practice; use of physical therapy equipment to increase the exposure distance; and estimation of the safe exposure time for caregivers based on dosimetry. The effective and safe treatment of metastatic TC in paraplegic patients can be successfully implemented with a comprehensive radiation mitigation strategy and thorough surveying of personnel for contamination.

Does Higher Temperature during Moderate Hypothermic Circulatory Arrest Increase the Risk of Paraplegia in Acute DeBakey I Aortic Dissection Patients?

BACKGROUND: To assess the safety of high-moderate (24.1-28.0°C) and low-moderate (20.1-24.0°C) systemic hypothermia (MHCA) during circulatory arrest in patients with acute DeBakey I aortic dissection (DeBakey I AAD), particularly concerning spinal cord protection. METHODS: Between 2009 and 2020, 1759 patients with DeBakey I AAD who underwent frozen elephant trunk and total arch replacement surgery at a tertiary center were divided into preoperative malperfusion (viscera, spinal cord, or lower extremities) and non-malperfusion subgroups. The baseline differences were balanced using propensity score matching. Prognoses were compared between those who were subjected to high-MHCA (nasopharyngeal temperature, 24.1-28.0°C) and low-MHCA (20.1-24.0°C). RESULTS: In the non-malperfusion subgroup (n=1389), 469 pairs of matched patients showed lower in-hospital mortality and incidence of acute kidney injury in the high-MHCA group than in the low-MHCA group (in-hospital mortality, 7.0% vs. 10.2%, P=0.01; acute kidney injury, 57.1% vs. 64.6%, P<0.01). The duration of mechanical ventilation was shorter in the high-MHCA group than that in the low-MHCA group (P=0.03). No significant difference in the incidence of paraplegia was observed between the two groups. In the malperfusion subgroup (n=370), 112 pairs of matched patients showed a higher incidence of paraplegia in the high-MHCA group than in the low-MHCA group (15.9% vs. 6.5%, P=0.04). CONCLUSIONS: The safety of high-MHCA, a commonly used temperature management strategy during aortic arch surgery, was recognized in most patients with DeBakey I AAD. However, among patients with preoperative distal organ malperfusion, low-MHCA may be more appropriate because of an increased risk of postoperative paraplegia associated with high-MHCA.

An exploratory analysis of the metabolic syndrome and cardiovascular disease risk calculations in veterans with spinal cord injury and disorders.

OBJECTIVES: (1) To describe and compare cardiovascular and cardiometabolic disease risk scores using three existing risk calculators: Framingham Risk Score (FRS), American Heart Association (AHA) and Metabolic Syndrome Severity Score (MSSS) in Veterans with spinal cord injury and disorders (SCI/D); (2) To examine level of agreement between risk scores derived from three different risk scoring systems; and (3) To investigate whether the agreement among these methods is different for Veterans with Tetraplegia versus Paraplegia. DESIGN: Retrospective chart review. METHODS: Electronic medical records of 194 Veterans with SCI/D who were seen at the VAPAHCS SCI/D Center between August 2004 and June 2022 were reviewed. Cardiovascular disease (CVD) risk scores (FRS and AHA) along with a Metabolic Syndrome Severity Score (MSSS) were computed using web-based calculators. RESULTS: Moderate agreement between CVD risk scores (FRS and AHA) was observed; however, the agreement was poor between MSSS and both AHA and FRS. No differences were observed between the paraplegia and tetraplegia cohorts. From the AHA risk score, more than half the study population was found to be at high risk while less than half was considered high risk from the FRS and MSSS scores. CONCLUSIONS: Given the moderate association between AHA and FRS scores along with considerable variation in risk predictors, CVD risk prediction assessment tools should be interpreted cautiously in the SCI population. SCI-related clinical biomarkers and other clinically relevant risk factors should be taken into consideration to optimize risk estimation in persons with SCI/D.

Risk factors for pressure injuries in individuals with spinal cord injuries who have sarcopenic obesity: A comparison of time-dependent changes in sacral region pressure between individuals with and without sarcopenic obesity.

OBJECTIVE: To identify the risk factors for pressure injuries in individuals with spinal cord injuries (SCIs) who have sarcopenic obesity, comparing time-dependent changes in sacral region pressure in individuals with and without sarcopenic obesity. DESIGN: An experimental time series study. SETTING: Single-center hospital. PARTICIPANTS: Twenty-five adult participants with subacute and chronic paraplegia who visited our rehabilitation center, Republic of Korea, between May 2021 and June 2022. INTERVENTIONS: Whole-body dual-energy X-ray absorptiometry was performed to diagnose sarcopenic obesity. After the participants were placed in the supine position for 1 hour, the average pressure (mmHg), peak pressure (mmHg), and total contact area (cm2) of the sacral region were measured using the pressure-mapping system. RESULTS: Compared with the non-sarcopenic obesity group, the sarcopenic obesity group showed significant before-and-after differences in peak pressure. Furthermore, the risk factors that were significantly associated with peak pressure in the sarcopenic obesity group were the American Spinal Injury Association Impairment Scale score and the fat mass index. CONCLUSION: Among participants with SCIs, the risk of pressure injuries is higher in the sarcopenic obesity group than in the non-sarcopenic obesity group. Notably, the risk of pressure injuries increases in participants who have complete injury and an increased fat mass index, indicating the importance of close monitoring and more active management to prevent pressure injuries in this subpopulation.

Refining the phenotype of SINO syndrome: A comprehensive cohort report of 14 novel cases.

BACKGROUND: SINO syndrome (Spastic paraplegia, Intellectual disability, Nystagmus and Obesity) is a rare autosomal dominant condition caused by heterozygous variants in KIDINS220. A total of 12 individuals are reported, comprising eight with SINO and four with an autosomal recessive condition attributed to bi-allelic KIDINS220 variants. METHODS: In our international cohort, we have comprised 14 individuals, carrying 13 novel pathogenic KIDINS220 variants in heterozygous form. We assessed clinical and molecular data of our cohort and previously reported individuals and based on functional experiments reached a better understanding of the pathogenesis behind KIDINS220-related disease. RESULTS: Using fetal tissue and in vitro assays, we demonstrate that the variants generate KIDINS220 truncated forms that mislocalize in punctate intracellular structures, with decreased levels of the full-length protein, suggesting a trans-dominant negative effect. 92% had their diagnosis within three years, with symptoms of developmental delay, spasticity, hypotonia, lack of eye contact and nystagmus. We identified a KIDINS220 variant associated with fetal hydrocephalus and show that 58% of examined individuals present brain ventricular dilatation. We extend the phenotypic spectrum of SINO syndrome to behavioral manifestations not previously highlighted. CONCLUSION: Our study provides further insights into the clinical spectrum, etiology and predicted functional impact of KIDINS220 variants.

A challenging diagnosis of spinal epidural lipomatosis: A case report and review of the literature.

INTRODUCTION: Spinal Epidural Lipomatosis (SEL) is a rare disorder of pathological overgrowth of the spinal epidural fat in the extradural space. The pathogenesis of SEL usually involves exogenous steroid use or endogenous steroids overproduction. However, idiopathic cases have been reported. Magnetic resonance imaging (MRI) is the gold standard for diagnosis. Both conservative and surgical approaches are employed in management of these patients. CASE PRESENTATION: A 17-year-old male presented to our hospital complaining of progressive lower limb weakness, loss of sensation with urinary incontinence which ended up with paraplegia. He underwent extensive investigations and received multiple inaccurate diagnoses. MRI of the thoracic spine showed spinal epidural lipomatosis with dorsal kyphosis. Hemi-laminectomy for spinal cord decompression and trans-pedicular fixation for correction of kyphosis were performed showing excellent outcomes. CLINICAL DISCUSSION: Diagnosing SEL can be challenging due to its symptom overlap with other neurological conditions. Thus, higher levels of clinical suspicions and utilization of numerous diagnostic modalities including MRI are required. Treatment is largely determined by the clinical presentation and the severity of symptoms. Given the severity of neurological symptoms in our case, surgical intervention was performed resulting in fully regained functionality of previously paralyzed muscles. CONCLUSION: This case highlights the rare presentation and the diagnostic challenges of spinal epidural lipomatosis SEL in a young patient who was misdiagnosed for 9 consecutive months before receiving the correct diagnosis, emphasizing the importance of considering SEL in the differential diagnosis for progressive neurological deficits and the importance of MRI, especially in atypical cases.

Anterior Spinal Artery Syndrome in a Patient With Multilevel Cervical Disc Disease: A Case Report.

Anterior spinal artery syndrome (ASAS) is a rare form of spinal cord infarction, making its incidence and prevalence difficult to determine. We present the case of a 60-year-old woman with multiple vascular risk factors who experienced a sudden onset of severe lower limb weakness, raising immediate concerns about spinal cord ischemia. Diagnostic evaluations confirmed ASAS, although the exact cause and mechanism of her spinal cord infarction remained undetermined. The potential presence of significant cervical disc disease suggests fibrocartilaginous embolism (FCE) as a possible underlying mechanism, despite the lack of direct evidence. This case underscores the importance of clinical awareness and timely intervention in patients with similar symptoms and vascular risk factors. Early recognition, cause identification, and appropriate management are crucial for improving outcomes in spinal cord ischemia, guiding specific treatment strategies, and potentially preventing recurrence.

ITPR1 variant-induced autosomal dominant hereditary spastic paraplegia in a Chinese family.

Hereditary spastic paraplegia (HSP) is a rare neurodegenerative disease prominently characterized by slowly progressive lower limb weakness and spasticity. The significant genotypic and phenotypic heterogeneity of this disease makes its accurate diagnosis challenging. In this study, we identified the NM_001168272: c.2714A > G (chr3.hg19: g.4716912A > G, N905S) variant in the ITPR1 gene in a three-generation Chinese family with multiple individuals affected by HSP, which we believed to be associated with HSP pathogenesis. To confirm, we performed whole exome sequencing, copy number variant assays, dynamic mutation analysis of the entire family, and protein structure prediction. The variant identified in this study was in the coupling domain, and this is the first corroborated report assigning ITPR1 variants to HSP. These findings expand the clinical and genetic spectrum of HSP and provide important data for its genetic analysis and diagnosis.

Patients with complex and very-early-onset ATL1-related spastic paraplegia offer insights on genotype/phenotype correlations and support for autosomal recessive forms of SPG3A.

Spastic paraplegia type 3A (SPG3A) is the second most common form of hereditary spastic paraplegia (HSP). This autosomal-dominant-inherited motor disorder is caused by heterozygous variants in the ATL1 gene which usually presents as a pure childhood-onset spastic paraplegia. Affected individuals present muscle weakness and spasticity in the lower limbs, with symptom onset in the first decade of life. Individuals with SPG3A typically present a slow progression and remain ambulatory throughout their life. Here we report three unrelated individuals presenting with very-early-onset (before 7 months) complex, and severe HSP phenotypes (axial hypotonia, spastic quadriplegia, dystonia, seizures and intellectual disability). For 2 of the 3 patients, these phenotypes led to the initial diagnosis of cerebral palsy (CP). These individuals carried novel ATL1 pathogenic variants (a de novo ATL1 missense p.(Lys406Glu), a homozygous frameshift p.(Arg403Glufs*3) and a homozygous missense variant (p.Tyr367His)). The parents carrying the heterozygous frameshift and missense variants were asymptomatic. Through these observations, we increase the knowledge on genotype-phenotype correlations in SPG3A and offer additional proof for possible autosomal recessive forms of SPG3A, while raising awareness on these exceptional phenotypes. Their ability to mimic CP also implies that genetic testing should be considered for patients with atypical forms of CP, given the implications for genetic counseling.

Intra- and Early Post-Operative Factors Affecting Spinal Cord Ischemia in Patients Undergoing Fenestrated and Branched Endovascular Aortic Repair.

Background: Spinal cord ischemia (SCI) is a severe complication after fenestrated/branched endovascular repair (f/bEVAR). The underlying causes of SCI are still under investigation. This study aimed to evaluate intra- and early post-operative parameters that may affect SCI evolution. Methods: A single-center retrospective analysis was conducted including SCI patients with complete anesthesiologic records (1 January 2011 to 31 December 2023). Values of intra-operative glucose, hemoglobin, lactate, activated clotting time (ACT), and the need for transfusion were collected. The cohort was compared to a matched cohort of non-SCI patients. Results: Fifty-one patients with SCI and complete anesthesiologic records were included (mean age: 69.8 ± 6.2 years; 39.2% male). Intra-operative glucose value < 110 mg/dL (AUC: 0.73; sensitivity 91%, specificity of 83%) and hemoglobin value > 8.5 mg/dL (AUC: 0.61; sensitivity 83%, specificity 78%) were protective for Grade 3 SCI. Twenty-three patients with SCI were matched to 23 patients without SCI. SCI patients presented significantly higher glucose levels intra-operatively (glucose mean value: SCI 150 ± 46 mg/dL vs. non-SCI: 122 ± 30 mg/dL, p = 0.005). ACT (SCI 259 ± 31 svs. non-SCI 288 ± 28 s, p = 0.001), volume input (SCI 4030 ± 1430 mL vs. non-SCI 3020 ± 113 mL, p = 0.009), and need for transfusion (SCI: 52.5% vs. 4.3%, p < 0.001) were related to SCI. Higher glucose levels were detected among patients with SCI, at 24 (SCI: 142 ± 30 mg/dL vs. non-SCI: 118 ± 26 mg/dL, p=0.004) and 48 h (SCI: 140 ± 29 mg/dL vs. non-SCI: 112 ± 20 mg/dL, p < 0.001) post-operatively. Conclusions: SCI is a multifactorial complication after f/bEVAR. Intra-operative and early post-operative glucose levels may be related to SCI evolution. Targeted glucose < 110 mg/dL may be protective for Grade 3 SCI.

Point-of-care ultrasound (POCUS) in the surgery of a paraplegic pregnant female: A case of "do no harm".

We present here a case of multidisciplinary management of a 20-year-old pregnant woman who presented with sudden paraplegia attributed to a large paraspinal tumor. Magnetic resonance imaging (MRI) revealed compressive dorsal myelopathy due to an extramedullary tumor. Given the urgency of her symptoms and pregnancy status, a multidisciplinary team decided to proceed with surgery while avoiding radiation exposure (eg, O/C-arm). Intraoperative point-of-care ultrasound (POCUS) was utilized for tumor localization and surgical guidance, facilitating successful gross total excision with minimal risk to the fetus. Postoperative recovery was uneventful, with improvement in muscle strength and preservation of the pregnancy. Beyond tumor localization, POCUS offers additional benefits in assessing maternal hemodynamics and detecting potential complications. This case highlights the utility of POCUS as a radiation-free theranostic imaging modality in pregnant patients with spinal tumors, enhancing safety in surgery and optimizing outcomes for both mother and fetus.

Autosomal Recessive Spastic Paraplegia and Psychomotor Retardation With or Without Seizures: A Case Report From Saudi Arabia.

Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) is a rare neurodevelopmental disorder associated with autosomal recessive mutations in the HACE1 gene. This case report presents the clinical features and genetic analysis of an 11-month-old girl and her sister with SPPRS, making it the third reported case in the Middle East and the second in Saudi Arabia. The patient exhibited hypotonia, global developmental delay, speech delay, swallowing difficulties, and recurrent respiratory infections. A homozygous pathogenic variant in the HACE1 gene (p.R664*) was identified through genetic analysis, confirming the diagnosis of SPPRS. This case report emphasizes the importance of considering variations in clinical presentation, especially in rare disorders where only a few cases are reported. Further research and case studies are needed to better understand the complete phenotypic spectrum of SPPRS and its complications.

Two new cases with the UBQLN2 gene mutation in Han Chinese.

Variations in the UBQLN2 gene are associated with a group of diseases with X-linked dominant inheritance and clinical phenotypes of amyotrophic lateral sclerosis (ALS) and/or frontal temporal lobe dementia (FTD). Cases with UBQLN2 variations have been rarely reported worldwide. The reported cases exhibit strong clinical heterogeneity. Here, we report two adult-onset cases with UBQLN2 variations in Han Chinese. Whole exome sequencing revealed the hemizygous P506S (c.1516C > T) and the heterozygous P509S variation (c.1525C > T), both of which were located within the hotspot mutation region. The patient with the P506S variation was a 24-year-old male. The clinical feature was spastic paraplegia without lower motor neuron damage. The patient's mother was an asymptomatic heterozygote carrier with skewed X-chromosome inactivation. The patient with the P509S variation was a 63-year-old female. Clinical features included ALS and parkinsonism. 18F-fluorodopa PET-CT revealed presynaptic dopaminergic deficits in bilateral posterior putamen. These cases further highlight the clinical heterogeneity of UBQLN2 cases.

Unexpected complexity in the molecular diagnosis of spastic paraplegia 11.

BACKGROUND: Spastic paraplegia 11 (SPG11) is the most prevalent form of autosomal recessive hereditary spastic paraplegia, resulting from biallelic pathogenic variants in the SPG11 gene (MIM *610844). METHODS: The proband is a 36-year-old female referred for genetic evaluation due to cognitive dysfunction, gait impairment, and corpus callosum atrophy (brain MRI was normal at 25-years-old). Diagnostic approaches included CGH array, next-generation sequencing, and whole transcriptome sequencing. RESULTS: CGH array revealed a 180 kb deletion located upstream of SPG11. Sequencing of SPG11 uncovered two rare single nucleotide variants: the novel variant c.3143C>T in exon 17 (in cis with the deletion), and the previously reported pathogenic variant c.6409C>T in exon 34 (in trans). Whole transcriptome sequencing revealed that the variant c.3143C>T caused exon 17 skipping. CONCLUSION: We report a novel sequence variant in the SPG11 gene resulting in exon 17 skipping, which, along with a nonsense variant, causes Spastic Paraplegia 11 in our proband. In addition, a deletion upstream of SPG11 was identified in the patient, whose implication in the phenotype remains uncertain. Nonetheless, the deletion apparently affects cis-regulatory elements of the gene, suggesting a potential new pathogenic mechanism underlying the disease in a subset of undiagnosed patients. Our findings further support the hypothesis that the origin of thin corpus callosum in patients with SPG11 is of progressive nature.

Spinal cord ischemia following laryngotracheal reconstruction surgery: a case report.

We present a 20-year-old patient with subglottic and tracheal stenosis was taken for a tracheal resection and end-to-end anastomosis. The patient's neck was positioned in hyperflexion using chin stitches to minimize tension at the anastomosis. On post-operative period, the patient developed paresthesias in upper and lower extremities associated with motor weakness. Magnetic resonance imaging was performed showing lesions compromising ventral spinal cord at the level of C4-C5 and C6-C7. Chin stitches were removed and neck flexion was reduced. The patient remained in the intensive care unit with vasopressors, physical therapy and intravenous fluid-therapy to maintain mean arterial pressure above 90 mmHg. After 3 weeks, the patient was discharged with no neurologic deficit. There are few cases reported of acute ischemic spinal injury following tracheal reconstruction. If this complication arises, neck posture should be corrected, maintenance of MAP above 90 mmHg and implementation of early physical therapy is key to improve neurologic outcomes.