Search Results (1,359)

Background: CLTC-related neurodevelopmental disorder is a rare condition primarily characterized by global developmental delay (GDD) and intellectual disability (ID). To date, approximately 41 cases involving CLTC gene alterations have been reported. We present the first individual with a complete deletion of the CLTC gene. Methods: The proband is a male from a non-consanguineous family, presenting with congenital nystagmus, hypotonia, GDD, and autism spectrum disorder (ASD). Chromosomal microarray analysis and trio exome sequencing were performed. A systematic review of previously reported CLTC variant cases was conducted to delineate the phenotypic spectrum. Results: A de novo 363-kb heterozygous deletion at 17q23.1 spanning the entire CLTC gene was identified. The systematic review confirmed GDD/ID as core features and revealed various ocular abnormalities in a subset of cases. These findings indicate that the clinical phenotype extends beyond neurodevelopment, with multi-system involvement. Conclusions: The phenotypic heterogeneity of CLTC-related disorders underscores the need for comprehensive physical examination to identify extra-neurological manifestations. Accurate diagnosis relies on integrating detailed clinical phenotyping with comprehensive genomic testing. Early, precise diagnosis facilitates multidisciplinary management, informed genetic counseling, and the establishment of long-term surveillance protocols. Full article

Background/Objectives: Duloxetine is a serotonin–norepinephrine reuptake inhibitor used for psychiatric and chronic pain conditions. It enhances serotonergic and noradrenergic neurotransmission by inhibiting the reuptake of serotonin and norepinephrine. Acute poisoning, most commonly resulting from intentional oral ingestion, may frequently present with neurological and cardiovascular manifestations. Although duloxetine is widely prescribed, evidence regarding acute overdose remains limited, and no validated toxic duloxetine concentration threshold reliably predicts the severity of duloxetine toxicity. This systematic review aimed to synthesize published cases of duloxetine poisoning and characterize clinical manifestations, management strategies, and outcomes. Methods: We searched PubMed and Google Scholar for case reports and case series describing cases of duloxetine poisoning. We included cases of acute duloxetine poisoning with a clearly toxic ingested dose and/or analytically confirmed toxic duloxetine concentrations. Results: A total of 18 publications describing 23 patients were included in this systematic review. Duloxetine intoxication was classified as suicidal in 17 cases (73.9%), accidental in 5 cases (21.7%), and not specified in one case (4.3%). In most cases (78.3%), duloxetine overdoses involved co-ingestion of other central nervous system depressants. The most common clinical manifestation was altered mental status, ranging from somnolence, confusion, disorientation, and drowsiness to impaired consciousness, coma, or unresponsiveness in severe cases. Nearly half of the included duloxetine poisoning cases (47.8%) were fatal. Conclusions: In conclusion, acute duloxetine intoxication is most frequently associated with the co-ingestion of other central nervous system depressants, and early recognition with prompt supportive management is essential to minimize the risk of fatal outcomes. Full article

Background and Clinical Significance: Encephalitis is a rare neurological complication associated with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection. In rare cases, focal neuroinflammation can manifest as a mass-like parenchymal lesion, creating profound diagnostic and treatment dilemmas by mimicking primary central nervous system neoplasms. Case Presentation: A 34-year-old female presented with cephalalgia, nausea, confusion, facial palsy, and a new onset of focal impaired awareness seizures (FIAS). Brain magnetic resonance imaging (MRI) revealed a prominent hyperintense lesion within the left temporal lobe with associated vasogenic edema and focal leptomeningeal enhancement highly suspicious of a low-grade glial neoplasm. Although nasopharyngeal RT-PCT was negative, the presence of serum anti-SARS-CoV-2 IgM and IgG suggested recent subclinical SARS-CoV-2 infection. To resolve diagnostic ambiguity and avoid empiric oncological overtreatment, a stereotactic brain biopsy was performed. Histopathology revealed acute neuroinflammation characterized by reactive gliosis, microglial hyperplasia, and perivascular lymphatic cuffing, with no evidence of neoplastic presence. Quantitative tissue RT-PCR confirmed the presence of SARS-CoV-2 (Ct33). Follow-up imaging demonstrated complete resolution of the abnormalities following conservative treatment with corticosteroids and antiepileptics, though mild clinical symptoms persisted for 12 months thereafter. Conclusions: Encephalitis presents a rare yet critical manifestation of SARS-CoV-2. Establishing definitive etiology remains challenging. Stereotactic biopsy is a valuable tool to guide appropriate treatment in cases of ambiguous imaging and clinical findings. Radiographic resolution may precede complete clinical recovery. Full article

Marfan syndrome (MFS) is a connective tissue disorder classically associated with cardiovascular, musculoskeletal, and ocular manifestations. Neurological involvement is increasingly recognized and is most commonly related to spontaneous intracranial hypotension secondary to dural ectasia and cerebrospinal fluid (CSF) leakage. By contrast, idiopathic intracranial hypertension (IIH) is exceptionally rare in pediatric patients with MFS. We report the case of an 8-year-old girl with Marfan syndrome presenting with neck pain, diplopia, bilateral papilledema, and bilateral sixth cranial nerve palsy. Brain MRI demonstrated optic nerve tortuosity, distension of the perioptic subarachnoid spaces, and partial empty sella, while venous sinus thrombosis and spinal CSF leakage were excluded. Lumbar puncture confirmed markedly elevated CSF opening pressure (48 cmH₂O), consistent with IIH. CSF and plasma neurofilament light chain levels were elevated, whereas anti-MOG antibodies and autoimmune investigations were negative. The patient showed rapid clinical improvement following therapeutic CSF drainage and acetazolamide treatment. To the best of our knowledge, this represents only the second report of pediatric IIH associated with Marfan syndrome. Our patient developed idiopathic intracranial hypertension, an uncommon neurological manifestation in this condition. Through this case, we aim to highlight the diagnostic challenges, discuss the possible pathophysiological mechanisms underlying this rare association and emphasize the importance of considering intracranial hypertension in the differential diagnosis of children with Marfan syndrome presenting with neuro-ophthalmological symptoms. Full article

Background/Objectives: Danon disease is a rare X-linked lysosomal disorder caused by pathogenic variants in LAMP2. In women, cardiac involvement may occur later in life and may resemble sarcomeric hypertrophic cardiomyopathy (HCM), particularly when extracardiac manifestations are absent or subtle. A 42-year-old woman presented with chest discomfort in 2017 and was initially diagnosed with hypertrophic cardiomyopathy (HCM). She underwent serial 3.0-T cardiovascular magnetic resonance (CMR) over an 8-year period. Initial CMR showed left-ventricular hypertrophy, preserved left-ventricular ejection fraction (65.0%), increased native T1 and T2 relaxation times, extracellular volume (ECV) of 24.9%, and patchy apical late gadolinium enhancement (LGE extent, 12.35%). Five years later, worsening dyspnea was accompanied by increased left-ventricular mass index, higher native T1 and ECV, greater LGE extent (15.18%), and slow atrial fibrillation with ventricular ectopy on Holter monitoring. Genetic testing identified a likely pathogenic LAMP2 variant, c.928G>A (p.Val310Ile), supporting the diagnosis of Danon disease in the clinical context. During a subsequent readmission three years later with acute amaurosis and dyspnea, no definite neurologic cause was identified in the available record. Repeat CMR showed the highest recorded native T1 and ECV values and diffuse LGE with relatively less interventricular-septal involvement, particularly in the basal septum (LGE extent, 24.59%); repeat Holter monitoring showed frequent long R-R intervals and ventricular escape beats. Because of progressive imaging and electrical deterioration, implantable cardioverter-defibrillator therapy and heart-transplantation assessment were recommended, and the patient ultimately chose to proceed with pre-transplant assessment in December 2025. Conclusions: Female LAMP2-related Danon disease may initially resemble HCM, but differs from it with diffusely abnormal T1/ECV measurements. Follow up in our case revealed progressive storage cardiomyopathy with diffuse myocardial injury and clinically relevant bradyarrhythmia. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes an immune-mediated neurological syndrome, which persists long after infection. Mechanisms for SARS-CoV-2-associated neurological complications are multifactorial, with an increased risk of drug abuse such as methamphetamine (meth). SARS-CoV-2 infection and its viral proteins play pivotal roles in coronavirus disease 2019 (COVID-19)-associated neuroinflammation, which can lead to long COVID. We hypothesize that meth augments activation of the microglial NOD-, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome by the SARS-CoV-2 nucleocapsid (N) protein, resulting in neuroinflammation. To test this hypothesis, we investigated the effect of N-protein and meth on NLRP3 inflammasome activation in primary rat microglial cultures using enzyme-linked immunosorbent assay (ELISA), Reverse Transcription quantitative Polymerase Chain reaction (RT-qPCR), western blot (WB), and immunofluorescence assay (IFA). Our results showed that meth augmented N-protein-induced microglial activation, as evidenced by increased ionized calcium-binding adapter 1 (Iba-1) expression. The addition of meth to the microglial cultures treated with N-protein increased proinflammatory cytokine production. Meth augmentation of N-protein-induced neuroinflammation was further supported by increased inducible nitric oxide synthase (iNOS)-mediated nitric oxide (NO) production. The effects of meth on N-protein-associated inflammatory responses were significantly attenuated by MCC950, a specific NLRP3 inhibitor. Moreover, meth-associated NLRP3 activation was either blocked by the opioid sigma1-receptor (σ1_-R) inhibitor BD1047 or by σ1R siRNA knockdown. Taken together, these results demonstrated that meth augmented SARS-CoV-2 N-protein-induced neuroinflammation via microglial σ1_-R and the NLRP3 inflammasome, which may underlie the pathogenesis of neurological manifestations in COVID-19, such as long COVID with meth abuse. These results may also underscore the impact of drug abuse on long COVID and provide targets for the development of therapeutic strategies to control the neurological outcomes of long COVID. Full article

Background: Neurofibromatosis type 1 (NF1) is a multisystem genetic disorder characterized by marked phenotypic heterogeneity. This study aimed to describe the clinical spectrum and multisystem burden of NF1 in a regional retrospective cohort. Methods: We retrospectively analyzed 77 unique patients with NF1 after removal of duplicate records. Demographic characteristics, cutaneous manifestations, extracutaneous involvement, therapeutic interventions, and disease evolution were evaluated. An exploratory multisystem burden score was calculated using six extracutaneous clinical domains. Results: Café-au-lait macules were present in all patients, axillary/inguinal freckling in 93.5%, cutaneous neurofibromas in 63.6%, and plexiform tumors in 28.6%. Psychiatric/behavioral (67.5%), skeletal (57.1%), ophthalmological (51.9%), and neurological (45.5%) involvement were common. More than half of the cohort had involvement of at least three extracutaneous domains. Plexiform tumors were more common in patients with progressive or unfavorable disease compared to those with stationary disease. Progressive or unfavorable evolution was associated with a higher frequency of plexiform tumors. Therapeutic interventions were reported descriptively. Conclusions: NF1 showed substantial multisystem involvement beyond its characteristic cutaneous manifestations. Plexiform tumors were associated with a more complex clinical course. The proposed exploratory multisystem burden score may facilitate descriptive assessment of disease breadth but requires prospective validation. Full article

Acute coronary syndrome (ACS) remains a leading cause of cardiovascular morbidity and mortality worldwide. Although traditional cardiovascular risk factors remain central to ACS development, recreational drug use is increasingly recognized as a clinically relevant trigger, particularly in younger patients with fewer conventional risk factors. This narrative review synthesized evidence identified through searches of PubMed/MEDLINE and Scopus up to June 2026, including clinical guidelines, systematic reviews, observational studies, mechanistic investigations, and clinically informative case-based evidence. Cannabis, cocaine, amphetamines, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), opioids, lysergic acid diethylamide (LSD), synthetic cannabinoids, and polysubstance use may promote myocardial ischemia and infarction through overlapping mechanisms, including sympathetic activation, coronary vasospasm, endothelial dysfunction, oxidative stress, inflammation, platelet activation, thrombosis, arrhythmogenesis, and myocardial oxygen supply–demand mismatch. Clinical presentation may be typical or atypical and may overlap with intoxication, withdrawal, anxiety, neurological symptoms, or non-cardiac chest pain, making diagnosis challenging. Underreporting of recreational drug use is common, and targeted toxicology screening may improve diagnostic accuracy and risk stratification, particularly in patients younger than 50 years, those with few traditional cardiovascular risk factors, or those presenting with otherwise unexplained ST-segment elevation myocardial infarction (STEMI), non-ST-segment elevation myocardial infarction (NSTEMI), coronary vasospasm, arrhythmias, or cardiac arrest. Acute management should generally follow standard ACS guidelines, while considering drug-specific issues such as stimulant-induced vasospasm, sympathetic excess, cautious use of beta-blockers during acute intoxication, and preference for primary percutaneous coronary intervention when fibrinolysis carries increased risk. Long-term care should combine evidence-based secondary prevention with substance-use counseling, addiction medicine referral, cardiac rehabilitation, and behavioural interventions. This review summarizes the pathophysiology, clinical manifestations, epidemiology, treatment considerations, preventive strategies, and knowledge gaps related to recreational drug-associated ACS. Full article

Background/Objectives: Wolfram syndrome is an ultra-rare, progressive multisystem disorder in which endocrine and sensory manifestations coexist with neurological involvement. Quantitative magnetic resonance imaging (MRI) may help characterize central nervous system involvement in this condition; however, evidence derived from small imaging cohorts requires cautious interpretation. This study aimed to examine the relationships between different MRI-derived attributes and neurological symptoms in Wolfram syndrome, with the goal of identifying exploratory imaging patterns that may suggest the involvement of specific neural systems. Methods: We analyzed a Spanish cohort of 45 genetically confirmed patients with Wolfram syndrome. A homogeneous subset of 15 patients with standardized 3-Tesla multimodal MRI and adequate image quality was included in the quantitative imaging analysis. T1-weighted MRI, T2-weighted/fluid-attenuated inversion recovery (FLAIR) imaging, and diffusion tensor imaging (DTI) were processed using a standardized workflow for brain extraction, anatomical segmentation, cortical reconstruction, and quantitative feature extraction. A total of 172 MRI-derived features were examined in relation to neurological phenotypes, including dysphagia, ataxia, gait instability, and cognitive impairment. Analyses included principal component analysis, exploratory factor analysis, correlation analyses, and symptom-specific group comparisons. Given the small MRI sample size and the high feature-to-subject ratio, all analyses were considered exploratory and hypothesis-generating, and the findings should be interpreted cautiously pending validation in larger, independent cohorts. Results: Multimodal MRI-derived features showed distributed associations with neurological manifestations. The most recurrent exploratory imaging correlates involved the thalamus, lateral geniculate nucleus, cerebellum, brainstem, ventricular system, corpus callosum, posterior cortical regions, and white-matter pathways. FLAIR-derived signal heterogeneity in the thalamus and lateral geniculate nucleus appeared repeatedly across several clinical manifestations. Dysphagia was associated with a distributed pattern involving cortical thinning, thalamic and brainstem volume reduction, reduced cerebellar white-matter integrity, increased FLAIR heterogeneity, and ventricular enlargement. Ataxia and gait instability showed overlapping but partially distinct imaging profiles, whereas cognitive impairment was associated with broader cortical, subcortical, callosal, cerebellar, and ventricular alterations. Conclusions: In this exploratory pilot study, multimodal MRI-derived features showed clinically plausible associations with neurological manifestations in Wolfram syndrome. The findings support a distributed model of neurological involvement affecting cerebello-thalamo-cortical circuits, visual relay structures, brainstem pathways, and long-range white-matter connections. These results should be interpreted as exploratory MRI-derived attributes rather than as validated biomarkers, prognostic indicators, or clinically applicable imaging signatures. Confirmation in future longitudinal, multicenter studies with harmonized imaging protocols and external validation will be required. Full article

Introduction: Stiff-Person Syndrome (SPS) is a rare autoimmune neurological disorder characterized by progressive muscle rigidity and painful spasms, primarily affecting axial and proximal musculature. Its diagnosis can be challenging due to clinical overlap with other neurological conditions such as spasticity, dystonia, or functional movement disorders. The detection of antibodies against glutamic acid decarboxylase (anti-GAD) is a key biomarker that supports diagnosis. Methods: Two clinical cases of patients with manifestations consistent with classic SPS are described, and were evaluated in a specialized neurology service. Both patients underwent detailed clinical assessment, complementary studies, and serum testing for anti-GAD antibodies. Results: Both patients presented with progressive rigidity and fluctuating muscle spasms, predominantly involving axial musculature. After an extensive diagnostic workup, elevated anti-GAD antibody titers were documented in both cases, confirming the diagnosis of classic SPS. Treatment with medications enhancing GABAergic neurotransmission was associated with significant clinical improvement, evidenced by reduced rigidity and the decreased frequency of spasms. Conclusions: These cases highlight the importance of considering SPS in the differential diagnosis of progressive rigidity syndromes. Identification of anti-GAD antibodies is essential for diagnostic confirmation, and treatment that aims to enhance GABAergic neurotransmission can significantly improve symptoms and patient functionality. Full article

Hepatic encephalopathy (HE) is a complex of pathological processes in the brain caused by liver failure or portosystemic shunting. Even though ammonia (In this review, the term “ammonia” refers to total ammonia (ammonia gas and ammonium ion)) is widely recognized as the primary neurotoxin responsible for triggering the cerebral energy crisis and subsequent neurological manifestations of HE, its broader systemic effects are often overlooked. Meanwhile, the brain, which features the highest level of oxidative metabolism and extremely low energy reserves requires a constant supply of highly oxygenated and glucose-rich blood. Therefore, ammonia-induced disruptions in interorgan metabolic communication, leading to a restriction of vital energy substrates reaching the brain, are highly likely involved in this pathology. Currently, ammonia-related impairment of the metabolic relationship between the brain and extracerebral tissues is underestimated. This review summarizes generally accepted concepts and focuses on recent advances detailing how ammonia pathologically disrupts the highly integrated metabolic pathways in the liver and erythrocytes, thereby impairing the delivery of vital energy substrates to the brain. Additionally, the role of glutamate NMDA receptors in these metabolic disorders is discussed. The gathered information provides a deeper understanding of the indirect mechanisms by which ammonia compromises brain energy homeostasis, thereby ultimately leading to encephalopathy. Simultaneous measurement of plasma and erythrocyte ammonia is required to avoid measurement artifacts. Full article

A 40-year-old man presented with thunderclap headache (TCH) and vomiting post-masturbatory ejaculation. He reported a similar episode with posterior neck pain five days earlier after ejaculation. Unlike his migraine history, these headaches were unusually severe. Upon arrival, physical and neurological examinations were unremarkable except for an elevated blood pressure (154/110 mmHg). Brain MRI/MRA systematically ruled out intracerebral/subarachnoid hemorrhages, aneurysms, cerebral venous thrombosis, and cervical artery dissection, with preserved flow voids on B-PASS, T2, and T2-FLAIR. Notably, MRA demonstrated multiple segmental vasoconstrictions compared to a baseline MRA from five years prior. With an RCVS₂ score of 8, he was diagnosed with reversible cerebral vasoconstriction syndrome (RCVS). Symptoms resolved within 10 days of starting oral verapamil (120 mg/day), and follow-up MRA at one month showed partial improvement. This case highlights RCVS manifesting as a secondary cause sharing features with the proposed headaches associated with sexual activity (HSA) spectrum. RCVS is the predominant secondary cause of HSA (67–90%), often indistinguishable from primary HSA at onset due to the shared presentation of sudden TCH. Its pathophysiology likely involves an orgasm-induced sympathetic surge causing transient dysregulation of cerebral vascular tone. This case emphasizes that thorough neurovascular imaging is important in HSA to differentiate RCVS from primary headaches, ensuring the prompt initiation of calcium channel blockers and the avoidance of triptans. Full article

Acid sphingomyelinase deficiency (ASMD) is an autosomal recessive lysosomal storage disorder caused by mutations in the SMPD1 gene, resulting in sphingomyelin accumulation. With a birth prevalence of 0.25–0.6 per 100,000, it is more prevalent in Ashkenazi Jewish and Middle Eastern populations. The disease features a clinical spectrum ranging from severe, early-onset neurodegeneration (infantile neurovisceral ASMD) to chronic, non-neurological visceral involvement (chronic visceral ASMD) and intermediate forms (chronic neurovisceral ASMD). The chronic visceral form is characterized by liver dysfunction, respiratory symptoms, and hepatosplenomegaly, which can lead to secondary thrombocytopenia. The majority of patients exhibit thrombocytopenia and/or mild bleeding manifestations, most commonly easy bruising and epistaxis, whereas clinically significant bleeding events, including gastrointestinal or variceal hemorrhage, occur less frequently. Systematic platelet-function studies in patients with ASMD are currently lacking. Evidence retrieved from biological models indicates that ASMD contributes to platelet dysfunction, including impaired secretion and thrombin generation, mediated by complex pathological mechanisms. These findings underscore the importance of hematological monitoring and further research in patients with this condition and could potentially offer new therapeutic possibilities. Full article

Traumatic subarachnoid hemorrhage (tSAH) is a common complication of traumatic brain injury (TBI) and represents an important predictor of poor functional outcome. One of the most serious secondary complications is cerebral vasospasm. The pathophysiology of vasospasm is complex, involving the effects of blood breakdown products, inflammatory mediators, and direct mechanical injury to the cerebral vessels. Compared to aneurysmal subarachnoid hemorrhage (aSAH), vasospasm in tSAH typically occurs earlier, lasts for a shorter duration, and presents mostly with a milder clinical course. Due to its atypical clinical presentation and the presence of concurrent injuries, vasospasm is often not recognized in time and may manifest as neurological deterioration or new ischemic lesions on CT imaging. Timely recognition and appropriate management can significantly improve neurological outcomes. This paper presents key characteristics and differences between tSAH and aSAH, available diagnostic approaches, and treatment options, including nimodipine, milrinone, and stellate ganglion block. Owing to the lack of specific clinical guidelines for tSAH, current management strategies often rely on recommendations and experiences from aSAH. Further research is needed to better define risk factors for vasospasm following tSAH, optimize diagnostic pathways, and evaluate targeted treatment strategies. Full article

Background: Spinal cord cavernous malformations (SCCMs) are vascular malformations characterized by blood-filled cavities, often leading to neurological deficits. Familial cerebral cavernous malformation (FCCM) is a hereditary condition that predisposes individuals to develop multiple cavernous angiomas. Understanding the incidence, clinical presentation, and management strategies for spinal cavernous angiomas in the context of FCCM is crucial for improving patient outcomes. Methods: This narrative review synthesizes existing literature on SCCMs in patients with FCCM. A comprehensive search was conducted across multiple databases, including PubMed, Scopus, and Web of Science, utilizing keywords such as “spinal cavernous angiomas” and “familial cerebral cavernomatosis”. In addition, a further search was performed among papers discussing FCCM and SCCM, respectively. Discussion: In the paucity of published data about the presence of SCCMs in FCCM, the review highlights the clinical manifestations of SCCMs in both sporadic disease and FCCM, including recurrent hemorrhagic episodes and progressive neurological deficits. Although mutations in the KRIT1, CCM2, and PDCD10 genes play a significant role in the pathogenesis of FCCM, no single gene mutation has been identified as predisposing to SCCMs. Diagnosis was usually reached in patients symptomatic for spinal cord bleeding. Surgical intervention remains the primary treatment modality; however, the decision-making process is complicated by the potential for new lesion development. Conclusions: SCCMs in FCCM present distinct challenges in diagnosis and management and their prevalence is probably underestimated. This review underscores the need for heightened awareness among clinicians regarding the hereditary nature of these lesions. Future research should focus on the molecular mechanisms underlying FCCM, aiming to develop targeted therapies and improve clinical outcomes for affected individuals. Full article