Clinical characteristics, Risk factors, and outcomes of Posterior circulation stroke: A retrospective study between younger and older adults in Saudi Arabia.

INTRODUCTION: Posterior circulation stroke (PCS) may be less prevalent than its anterior counterpart but contributes to substantial morbidity and mortality. The aim was to characterize PCS's demographics, clinical presentation, management, and outcomes between younger and older adults in Saudi Arabia. METHODS: This retrospective cohort study was conducted at two tertiary medical centers in Saudi Arabia between March 2016 and December 2020. All patients who presented with symptoms of posterior circulation stroke and had positive brain imaging were included. RESULTS: The study involved 160 posterior circulation stroke patients, stratified into two age groups: 71 patients aged 18-59 years and 89 patients aged 60 years and above. The mean age of the entire cohort was 60.9 years, and 77 % were males. Hypertension was more prevalent in the older age group (88 % vs. 69 %, p=0.005), and smoking was significantly higher among younger patients (38 % vs. 15 %; p=0.0009). Only 22.4 % received thrombolysis and/or thrombectomy. Most strokes involved the posterior cerebral artery (45.6 %). Large artery atherosclerosis was the most common subtype. At discharge, younger patients had higher NIHSS compared to older patients. CONCLUSION: Our investigation of 160 PCS patients in Saudi Arabia uncovers notable trends: a mere 22.4 % received thrombolysis and/or thrombectomy and a significant prevalence of posterior cerebral artery involvement due to large artery atherosclerosis. The study further reveals younger patients disproportionately had severe outcomes. Highlighting the need for improved stroke care and heightened awareness, this research contributes vital data to an underexplored domain, urging further study to optimize care and understand PCS dynamics in Saudi Arabia.

Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.

PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.

Clinical characterization and further confirmation of the autosomal recessive SLC12A2 disease.

Heterozygous pathogenic variants in SLC12A2 are reported in patients with nonsyndromic hearing loss. Recently, homozygous loss-of-function variants have been reported in two patients with syndromic intellectual disability, with or without hearing loss. However, the clinical and molecular spectrum of SLC12A2 disease has yet to be characterized and confirmed. Using whole-exome sequencing, we detected a homozygous splicing variant in four patients from two independent families with severe developmental delay, microcephaly, respiratory abnormalities, and subtle dysmorphic features, with or without congenital hearing loss. We also reviewed the reported cases with pathogenic variants associated with autosomal dominant and recessive forms of the SLC12A2 disease. About 50% of the cases have syndromic and nonsyndromic congenital hearing loss. All patients harboring the recessive forms of the disease presented with severe global developmental delay. Interestingly, all reported variants are located in the c-terminal domain, suggesting a critical role of this domain for the proper function of the encoded co-transporter protein. In conclusion, our study provides an additional confirmation of the autosomal recessive SLC12A2 disease.

Biallelic loss of function variant in the unfolded protein response gene PDIA6 is associated with asphyxiating thoracic dystrophy and neonatal-onset diabetes.

Protein disulfide isomerase A6 (PDIA6) is an unfolded protein response (UPR)-regulating protein. PDIA6 regulates the UPR sensing proteins, Inositol requiring enzyme 1, and EIF2AK3. Biallelic inactivation of the two genes in mice and humans resulted in embryonic lethality, diabetes, skeletal defects, and renal insufficiency. We recently showed that PDIA6 inactivation in mice caused embryonic and early lethality, diabetes and immunodeficiency. Here, we present a case with asphyxiating thoracic dystrophy (ATD) syndrome and infantile-onset diabetes. Whole exome sequencing revealed a homozygous frameshift variant in the PDIA6 gene. RNA expression was reduced in a gene dosage-dependent manner, supporting a loss-of-function effect of this variant. Phenotypic correlation with the mouse model recapitulated the growth defect and delay, early lethality, coagulation, diabetes, immunological, and polycystic kidney disease phenotypes. In general, the phenotype of the current patient is consistent with phenotypes associated with the disruption of PDIA6 and the sensors of UPR in mice and humans. This is the first study to associate ATD to the UPR gene, PDIA6. We recommend screening ATD cases with or without insulin-dependent diabetes for variants in PDIA6.

Clinical, molecular, and biochemical delineation of asparagine synthetase deficiency in Saudi cohort.

PURPOSE: Asparagine synthetase deficiency (ASNSD) is a rare neurometabolic disease. Patients may not demonstrate low asparagine levels, which highlights the advantage of molecular over biochemical testing in the initial work-up of ASNSD. We aimed to further delineate the ASNSD variant and phenotypic spectrum and determine the value of biochemical testing as a frontline investigation in ASNSD. METHODS: We retrospectively collected the clinical and molecular information on 13 families with ASNSD from the major metabolic clinics in Saudi Arabia. RESULTS: The major phenotypes included congenital microcephaly (100%), facial dysmorphism (100%), global developmental delay (100%), brain abnormalities (100%), spasticity (86%), and infantile-onset seizures (93%). Additional unreported phenotypes included umbilical hernia, osteopenia, eczema, lung hypoplasia, and hearing loss. Overall, seven homozygous variants accounted for ASNSD. The p.Tyr398Cys and p.Asn75Ile variants accounted for 54% of the cases. The clinical sensitivity and specificity of the proposed biochemical analysis of cerebrospinal fluid (CSF) for the detection of patients with ASNSD were 83% and 98%, respectively. CONCLUSION: Our study describes the largest reported ASNSD cohort with clinical, molecular, and biochemical characterization. Taking into consideration the suboptimal sensitivity of biochemical screening, the delineation of the phenotype variant spectrum is of diagnostic utility for accurate diagnosis, prognosis, counseling, and carrier screening.

ISCA2 mutation causes infantile neurodegenerative mitochondrial disorder.

BACKGROUND: There are numerous nuclear genes that cause mitochondrial disorders and clinically and genetically heterogeneous disorders whose aetiology often remains unsolved. In this study, we aim to investigate an autosomal recessive syndrome causing leukodystrophy and neuroregression. We studied six patients from five unrelated consanguineous families. METHODS: Patients underwent full neurological, radiological, genetic, metabolic and dysmorphological examinations. Exome sequencing coupled with autozygosity mapping, Sanger sequencing, microsatellite haplotyping, standard and molecular karyotyping and whole mitochondrial DNA sequencing were used to identify the genetic cause of the syndrome. Immunohistochemistry, transmission electron microscopy, confocal microscopy, dipstick assays, quantitative PCR, reverse transcription PCR and quantitative reverse transcription PCR were performed on different tissue samples from the patients. RESULTS: We identified a homoallelic missense founder mutation in ISCA2 leading to mitochondrial depletion and reduced complex I activity as well as decreased ISCA2, ISCA1 and IBA57 expression in fibroblasts. MRI indicated similar white matter abnormalities in the patients. Histological examination of the skeletal muscle showed mild to moderate variation in myofibre size and the presence of many randomly distributed atrophic fibres. CONCLUSIONS: Our data demonstrate that ISCA2 deficiency leads to a hereditary mitochondrial neurodegenerative white matter disease in infancy.

A case of fatal acute bacterial meningoencephalitis with extremely high cerebrospinal fluid white blood cell count.

Acute bacterial meningoencephalitis is still prevalent despite the widespread vaccination and still fatal despite the advances in antimicrobial therapy. Identifying patients at risk, lowering the threshold of clinical diagnosis and early treatment of such a curable disease will save patients' lives.

Traumatic superficial temporal artery pseudoaneurysm: Successful management using endovascular embolization.

Superficial temporal artery pseudoaneurysms are uncommon but can be potentially life-threatening. Considering their rarity, the present article outlines the clinical presentation, radiological findings, intervention, and outcome of traumatic pseudoaneurysm of the superficial temporal artery. An 83-year-old female sustained a traumatic injury to the temple, resulting in right-sided swelling of the forehead. Brain computed tomography and cerebral angiogram revealed a right-sided homogenously-enhancing pseudoaneurysm in the frontal region. Successful occlusion of the lesion was achieved utilizing endovascular embolization. Three months after discharge, the patient reported no complaints or recurrence. Subsequent management included reassurance and observation with periodic clinical assessments. The unusual presentation of superficial temporal artery pseudoaneurysms requires clinicians to have thorough knowledge on the clinical presentation, proper steps in diagnosis, and the approach of choice in management. Endovascular embolization of superficial temporal artery pseudoaneurysms remains a valid approach to achieve successful occlusion of the lesion.

Hypothalamic Lipoma: Outcome of an Intracranial Developmental Lesion.

BACKGROUND: Hypothalamic lipomas are benign developmental lesions that tend to be discovered incidentally. This article describes the radiological features, outcome, and the postulated theories behind hypothalamic lipomas development. METHODS: The electronic archive of neurosurgery was retrospectively reviewed. All patients with a neuroradiological diagnosis of hypothalamic lipoma, between 2005 and 2020, were included. RESULTS: Out of 246 patients with intracranial lipomas, a total of six patients with hypothalamic lipomas have been identified. On computed tomography images, one of the hypothalamic lipomas demonstrated calcification. On magnetic resonance imaging, peripheral enhancement after contrast administration was noted in one of the lesions. Considering the benign nature of the lesions, neurosurgical intervention was not indicated. CONCLUSION: The majority of patients with hypothalamic lipomas are asymptomatic and undergo brain imaging for other indications. Although uncommon, such developmental lesions can be identified in the general population, especially with the advancement of neuroimaging techniques.

Oculomotor nerve palsy following coronary artery bypass graft surgery: can pituitary apoplexy complicate the post-operative course of cardiac surgery?

Oculomotor nerve palsy, due to pituitary apoplexy, has been previously reported in the literature. However, the association with coronary artery bypass graft surgery (CABG) is rarely investigated. This article reports a case of pituitary apoplexy presenting with oculomotor nerve palsy following CABG. A 65-year-old male, known to have ischemic heart disease, diabetes mellitus and hypertension, presented with ptosis, diplopia and anisocoria that developed after 1 day of CABG. Radiological imaging demonstrated a pituitary adenoma with acute/subacute hemorrhage causing mild mass effect on the cavernous sinus. Considering the acute state of bypass surgery and pre-existing cardiac co-morbidities, expectant management was considered. The visual acuity and palsy gradually improved. Pituitary apoplexy, following CABG, is a rare phenomenon in the post-operative period. High index of suspicious is required to promptly identify high-risk patients to avoid further neurological sequelae.

Progressive Ataxia and Neurologic Regression in RFXANK-Associated Bare Lymphocyte Syndrome.

OBJECTIVE: To identify the genetic cause of a late-onset immunodeficiency and subacute progressive neurodegenerative disease affecting cognition, motor, visual, and cerebellar systems in a patient with a family history of 2 younger siblings with an early-onset immunodeficiency disease. METHODS: Physical examinations, immunologic, brain MRI, whole-exome sequencing, and segregation studies were used to identify the genetic and neuroimmunologic etiology of disease in this family. RESULTS: We identified a homozygous loss-of-function (LOF) mutation (c.271+1G>C) in the RFXANK gene in the index patient and one of his younger affected siblings. Biallelic mutations in the RFXANK gene are known to cause bare lymphocyte syndrome (BLS) type II, complementation group B. The clinical and immunologic investigations were consistent with a clinical diagnosis of BLS type II. MRI demonstrated global cerebral and cerebellar atrophy with white matter signal changes in the index case. CONCLUSIONS: In addition to BLS type II, our study has expanded and further characterized the phenotype associated with the LOF of RFXANK to include progressive neurodegenerative disease. Our study also provides evidence for the impact of LOF on brain development and function. Thus, early bone marrow transplantation, as a standard of care for BLS, could prove to be protective against the neurologic phenotypes in this group of patients.

Endoscopic versus Open Microsurgical Excision of Colloid Cysts: A Comparative Analysis and State-of-the-Art Review of Neurosurgical Techniques.

BACKGROUND: The surgical approaches of colloid cysts commonly include endoscopy or open microsurgery. Each approach carries its own challenges, feasibility, and complications. The aim of the current study is to compare endoscopic versus open microsurgical excision of third ventricular colloid cysts. METHODS: A retrospective cohort study was conducted to compare the surgical outcomes of endoscopic versus open microsurgical (transcortical-transventricular and transcallosal approaches) excision of colloid cyst of the third ventricle at a tertiary-care medical institute. All patients with a neuroradiologic diagnosis of colloid cyst who subsequently underwent surgical management between January 2003 and June 2020 were included. The neurologic outcome was assessed at the last follow-up visit. RESULTS: A total of 32 patients with colloid cysts were included in the study. The mean age was 35.8 ± 18.3 years (range, 4-75 years). Female patients slightly outnumbered male patients (n = 17; 53.1%). A total of 21 patients (65.6%) underwent endoscopic resection of the colloid cyst. Complications were encountered in 7 patients (endoscopic, n = 3; microsurgery, n = 4; P = 0.151). Recurrence was identified in 4 patients (endoscopic, n = 3; microsurgery, n = 1; P = 0.673). Most patients improved neurologically on follow-up visits to the clinic (endoscopic, n = 19; microsurgery, n = 9; P = 0.482). CONCLUSIONS: Both endoscopic and microsurgical approaches provide favorable surgical outcomes in colloid cyst resection. The complication rates between both approaches is statistically insignificant. The optimal surgical approach for colloid cyst resection remains controversial.

Bilateral petrous apex cephaloceles: Is surgical intervention indicated?

INTRODCUTION: Petrous apex cephaloceles are characterized by herniation of Meckel's cave into the petrous apex. An extensive review of the literature reveals 20 cases of bilateral petrous apex cephaloceles. This article reports an additional case of bilateral petrous apex cephaloceles and reviews the pertinent literature. PRESENTATION OF CASE: A 64-year-old female was referred from a primary care clinic due to longstanding headache. A non-enhanced CT scan of the brain revealed osteolytic bony lesions at the petrous apices and an empty sella. A brain MRI with contrast showed CSF-containing lesions in the petrous apices, communicating with Meckel's cave bilaterally. The patient was managed conservatively and is currently followed up in the neurosurgery clinic. DISCUSSION: While the exact etiology remains uncertain, petrous apex cephaloceles are postulated to originate from sustained, chronic elevation of intracranial pressure. On MRI, petrous apex cephaloceles display signal intensities resembling CSF throughout all sequences. They demonstrate well-defined margins continuous with Meckel's cave. CT scans allow further characterization, i.e. invasive erosions, of the osseous structures in patients with petrous apex cephaloceles. CONCLUSION: A thorough understanding of the petrous apex anatomy and its pathological lesions is paramount. A brain MRI remains the diagnostic imaging of choice to characterize petrous apex cephaloceles.

Chondro-Osseous Metaplasia in Ependymoma: A Rare Histopathological Finding.

Ependymoma is a circumscribed glioma composed of uniform glial cells with bland nuclei in a fibrillary matrix. It is characterized by the presence of perivascular pseudorosettes. Unusual histopathological findings have rarely been reported in ependymomas, 0.5% of all diagnosed cases. Such unusual and exceedingly rare histological findings include osseous or chondroid metaplasia. To the best of our knowledge, only 15 cases of osseocartilaginous ependymomas have been reported in English literature. We report a 3-year-old boy who presented with ataxia, vomiting, and headache for three months. Radiological imaging revealed a posterior fossa lesion. Histopathological examination of the lesion confirmed a posterior fossa ependymoma with chondro-osseous metaplasia. The present case outlines the clinical presentation, histopathological findings, and outcome of chondro-osseous metaplasia in ependymomas. To date, the etiology of chondro-osseous metaplasia in ependymomas remains uncertain. Further research exploring such phenomenon is of paramount importance to explain how these tumors develop.

Atypical Location of Intracerebral Hemorrhage in Moyamoya Disease.

Moyamoya disease is a chronic, progressive bilateral occlusion or stenosis of terminal internal carotid arteries as well as the proximal anterior and middle cerebral arteries. Hemorrhage of the splenium of the corpus callosum rarely occurs with moyamoya disease. In this article, we report a case of a 53-year-old woman diagnosed with moyamoya disease by cerebral angiography. She presented to the emergency department complaining of unsteadiness and a tendency to fall forward for one week. The patient was investigated with head computed tomography (CT) scan upon presentation revealing atypical location of hemorrhage in the corpus callosum, mainly in the splenium.

Biotin-responsive basal ganglia disease should be renamed biotin-thiamine-responsive basal ganglia disease: a retrospective review of the clinical, radiological and molecular findings of 18 new cases.

BACKGROUND: Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive neurometabolic disorder. It is characterized by sub acute encephalopathy with confusion, seizure, dysarthria and dystonia following a history of febrile illness. If left untreated with biotin, the disease can progress to severe quadriparesis and even death. METHOD: A retrospective chart review of 18 patients with BBGD from two tertiary institutions describing their clinical, magnetic resonance imaging and molecular findings was conducted. RESULT: Eighteen children from 13 families seen over a period of nine years (2003-2012) were included. (Age range: 14month to 23 years, M: F: 1:1). The clinical features included sub acute encephalopathy, ataxia (n= 18), seizures (n= 13) dystonia (n=12) ,dysarthria (n= 9), quadriparesis and hyperreflexia (n=9). Magnetic resonance imaging demonstrated abnormal signal intensity with swelling in the basal ganglia during acute crises (n= 13/13) and atrophy of the basal ganglia and necrosis during follow up (n= 13/13). One-third of the present patients showed the recurrence of acute crises while on biotin therapy alone, but after the addition of thiamine, crises did not recur. All of the patients have a homozygous missense mutation in exon 5 of the SLC19A3 gene. The frequency of acute crises, delay in diagnosis and initiation of treatment significantly influenced the outcome. On follow up, four patients died, two had spastic quadriplegia, six had normal outcome and the rest had speech and motor dysfunctions. CONCLUSION: Clinicians should suspect BBGD in any child presenting with sub acute encephalopathy, abnormal movement and MRI findings as described above. Both biotin and thiamine are essential for disease management. Since biotin alone could not prevent the recurrence of crises in some patients, a more appropriate term to describe the disease would be biotin-thiamine-responsive basal ganglia disease (BTBGD).