White Matter Signal Abnormalities Research Articles

Clinical and genetic spectrum of 6 cases with asparagine synthetase deficiency

Objective: To explore the clinical and genetic characteristics of asparagine synthase deficiency. Methods: Case series studies. Retrospective analysis and summary of the clinical data of 6 cases with asparagine synthase deficiency who were diagnosed by genetic testing and admitted to the Third Affiliated Hospital of Zhengzhou University from May 2017 to April 2023 were analyzed retrospectively. The main clinical features, laboratory and imaging examination characteristics of the 6 cases were summarized, and the gene variation sites of them were analyzed. Results: All of the 6 cases were male, with onset ages ranging from 1 month to 1 year and 4 months. All of the 6 cases had cognitive and motor developmental delay, with 3 cases starting with developmental delay, 3 cases starting with convulsions and later experiencing developmental arrest or even regression. All of 6 cases had epilepsy, in whom 2 cases with severe microcephaly developed epileptic encephalopathy in the early stages of infancy with spasms as the main form of convulsions, 4 cases with mild or no microcephaly gradually evolved into convulsions with no fever after multiple febrile convulsions with focal seizures, tonic clonic seizures and tonic seizure as the main forms of convulsions. Three cases of 4 gradually developed into stagnation or even regression of development and ataxia after multiple convulsions with no fever. There were normal cranial imaging in 2 cases, dysplasia of the brains in 1 cases, frontal lobe apex accompanied by abnormal white matter signal in the frontal lobe and thin corpus callosum in 1 case, thin corpus callosum and abnormal lateral ventricular morphology in 1 case, and normal in early stage, but gradually developing into cerebellar atrophy at the age of 5 years and 9 months in 1 case. Two cases underwent visual evoked potential tests, the results of which were both abnormal. Three cases underwent auditory evoked potential examination, with 1 being normal and 2 being abnormal. All of 6 cases had variations in the asparagine synthase gene, with 2 deletion variations and 7 missense variations. The variations of 2 cases had not been reported so far, including c.1341_1343del and c.1283A>G, c.1165_1167del and c.1075G>A. The follow-up time ranged from 3 months to 53 months. Two cases who had severe microcephaly died in infancy, while the other 4 cases with mild or no microcephaly were in survival states until the follow-up days but the control of epilepsy was poor. Conclusions: Asparagine synthase deficiency has a certain degree of heterogeneity in clinical phenotype. Children with obvious microcephaly often present as severe cases, while children with mild or no microcephaly have relatively mild clinical manifestations. The variation of asparagine synthetase gene is mainly missense variation.

In vivo microstructural heterogeneity of white matter and cognitive correlates in aging using tissue compositional analysis of diffusion magnetic resonance imaging.

Age-related cognitive decline is linked to changes in the brain, particularly the deterioration of white matter (WM) microstructure that accelerates after the age of 60. WM deterioration is associated with mild cognitive impairment and dementia, but the origin and role of white matter signal abnormalities (WMSA) seen in standard MRI remain debated due to their heterogeneity. This study explores the potential of single-shell 3-tissue constrained spherical deconvolution (SS3T-CSD), a novel technique that models diffusion data in terms of gray matter (TG ), white matter (Tw ), and cerebrospinal fluid (TC ), to differentiate WMSA from normal-appearing white matter and better understand the interplay between changes in WM microstructure and decline in cognition. A total of 189 individuals from the GENIC cohort were included. MRI data, including T1-weighted and diffusion images, were obtained. Preprocessing steps were performed on the diffusion MRI data, followed by the SS3T-CSD. WMSA were segmented using FreeSurfer. Statistical analyses were conducted to assess the association between age, WMSA volume, 3-tissue signal fractions (Tw , TG , and TC ), and neuropsychological variables. Participants above 60 years old showed worse cognitive performance and processing speed compared to those below 60 (p < .001). Age was negatively associated with Tw in normal-appearing white matter (p < .001) and positively associated with TG in both WMSA (p < .01) and normal-appearing white matter (p < .001). Age was also significantly associated with WMSA volume (p < .001). Higher processing speed was associated with lower Tw and higher TG , in normal-appearing white matter (p < .01 and p < .001, respectively), as well as increased WMSA volume (p < .001). Similarly, lower MMSE scores correlated with lower Tw and higher TG in normal-appearing white matter (p < .05). High cholesterol and hypertension were associated with higher WMSA volume (p < .05). The microstructural heterogeneity within normal-appearing white matter and WMSA is associated with increasing age and cognitive variation, in cognitively unimpaired individuals. Furthermore, the 3-tissue signal fractions are more specific to potential white matter alterations than conventional MRI measures such as WMSA volume. These findings also support the view that the WMSA volumes may be more influenced by vascular risk factors than the 3-tissue metrics. Finally, the 3-tissue metrics were able to capture associations with cognitive tests and therefore capable of capturing subtle pathological changes in the brain in individuals who are still within the normal range of cognitive performance.

Abstract TP38: Cognitive Decline After Stroke Correlates With Small Vessel Disease and Race

Introduction: An Asian study found 30% of patients showed a cognitive decline measured by Montreal Cognitive Assessment (MoCA) score one year after stroke. There is limited US data on this subject. We investigated 1) decline rate in MoCA one year post-stroke 2) racial differences in baseline MoCA post-stroke and 3) if racial differences in small vessel disease (SVD) correlated with the decline in MoCA. Methods: MoCA was assessed in the PREMIERS trial (NCT#02541032) at baseline and one year after index stroke. Sub-scores for each MoCA domain were combined into a total score. The Fazekas scale was used to rate white matter signal abnormalities on patient MRI FLAIR images at baseline. Patients were categorized by total, deep white matter (DWM), and periventricular white matter scores. They were then sub-categorized into none/mild or moderate/severe groups. A one year cognitive decline was defined as a decline in MoCA scores by ≥2 points. Results: Of 280 patients, 30.4% had a ≥2 decline in MoCA score, with no significant difference between AA and white (29.4% vs. 32.9%, p=0.57). However, AA patients had lower baseline total MoCA scores (20.4±4.6 vs. 22.6±3.9, p&lt;0.001), visuospatial/executive (3.1±1.5 vs. 3.7±1.3, p&lt;0.001), naming (2.5±0.7 vs. 2.8±0.4, p=0.001), and attention (4.2±2.1 vs. 4.9±1.9, p&lt;0.001) sub-scores. Overall, baseline MoCA was lower in patients with moderate/severe total Fazekas scores (20.1±5.0 vs. 21.6±4.2, p=0.015) and DWM sub-scores (20.1±5.2 vs. 21.4±4.2, p=0.048). In AA, baseline MoCA remained lower in patients with moderate/severe total Fazekas scores (19.6±5.1 vs. 21.0±4.2, p=0.039) and DWM sub-scores (19.4±5.5 vs. 21.0±4.1, p=0.055). This was contrary to White patients with moderate/severe total Fazekas scores (22.3. ±4.4 vs. 23.0±3.9, p=0.50) and DWM sub-scores (23.1±2.3 vs. 22.7±4.4, p=0.73). Conclusion: We report that 30.4% of patients in this US-based study showed a decline in MoCA score one year post-stroke, which aligns with a similar study conducted in Asia. A significant association was found between the AA race and lower baseline total MoCA score compared to white patients. Moderate/severe total and DWM Fazekas scores are also significantly associated with lower baseline MoCA scores, a finding specific to AA patients.

Synergistic role of white matter changes and CSF biomarkers in amnestic and non‐amnestic AD phenotypes

AbstractBackgroundAlzheimer’s disease (AD) is pathologically diagnosed based on abnormal amyloid and tau pathology but is also related to additional pathologic processes. (1) The cognitive symptoms are not directly associated with AD pathology but are the consequence of a complex mechanism, showing discordance between clinical symptoms and CSF biomarkers. (2) Previous evidence suggests a range from the synergistic role of white matter signal abnormality (WMSA) and CSF biomarkers on AD to no relationship between the two. (1) We aimed to analyze the CSF biomarker profiles, and brain MRI changes in AD patients with different phenotypes.MethodCSF was collected by lumbar puncture from 40 individuals with AD. We analyzed CSF levels (Aβ‐42, Aβ‐40, t‐tau, p‐tau, tau / Aβ‐42, and Aβ‐42/40) in two different samples. The clinical characteristics included: AD phenotype (amnestic or non‐amnestic), age, gender, education, and age‐onset. We used the brain MRI scales: MTA (mesial temporal lobe atrophy), and Fazekas, for white matter signal abnormality (WMSA), considering pathological changes (≥ 2).ResultPreliminary results in 16 patients showed that most of the patients with CSF typical AD pattern presented an amnestic phenotype, revealing WMSA changes. The patients with no CSF changes showed little or no WMSA changes in both clinical presentations. The amnestic phenotype showed more MTA changes in patients with typical AD CSF pattern, and no difference was found between the phenotypes in patients with no CSF changes.ConclusionIt can be a positive relation between cerebrovascular diseases, WMSA changes, and CSF pathological changes in AD, regardless of the phenotype, supporting that Aβ pathology may lead to secondary vascular damage including white matter lesions.

Clinical and radiological features, treatment responses and prognosis in pediatric patients with co-existing anti-N-methyl-D-aspartate receptor and myelin oligodendrocyte glycoprotein antibody-associated encephalitis: A single center study

To characterize the clinical and radiological features, treatment responses and outcomes of children with co-existing anti-N-methyl-D-aspartate receptor(NMDAR) and myelin oligodendrocyte glycoprotein(MOG) antibody-associated encephalitis. Clinical manifestations, imaging features, effectiveness of treatment and outcomes of patients who were cerebral spinal fluid(CSF)-positive for NMDAR-antibody(NMDAR-ab) and seropositive for MOG-antibody(MOG-ab) were analyzed. Twelve patients including 8 females and 4 males were enrolled. The median onset age was 9 years, ranging from 2.2 to 12.8 years. Behavioral changes and/or psychiatric symptoms (n=8/12), seizures (n=8/12), encephalopathy (n=7/12) were 3 of the most common symptoms. Brain magnetic resonance imaging(MRI) of all the patients showed T2/fluid attenuation inversion recovery(FLAIR) abnormal signal in the cerebral white matter at least once in the courses of disease, 2 of whom developed new brain lesions which were asymptomatic. All of the patients had supratentorial lesions. Spinal cord MRI was performed in 7 patients. Only 1 patient showed related abnormalities with increased T2 signal in the spinal cord C1-5. Nine patients underwent optic nerve MRI; 5 patients demonstrated abnormal results, among whom 4 exhibited T2 abnormal signal (2 were symptom-free) and 1 showed a little effusion in bilateral optic nerve sheats. Intravenous immunoglobulin (IVIG) and intravenous methylprednisolone (IVMP) were the most common used therapies in those patients. Nine patients were treated with second-line therapy to prevent relapses. For total 29 clinical attacks, the median modified Rankin Scale (mRS) before treatment and after therapy of acute stage was 1 and 0, respectively. Seven of 12 patients(58.3%) experienced clinical relapses. In terms of outcome, all of the patients' mRS of last follow-up (≥6 months) was ≤2. Behavioral changes and/or psychiatric symptoms, seizures and encephalopathy were common in children with co-existing anti-NMDAR and MOG antibody-associated encephalitis. A minority of subjects may develop asymptomatic lesions on brain and optic nerve MRI. The relapse rate of this disease is relatively high. The majority of patients responded well to the immunotherapies and had a good outcome(mRS of last follow-up≤2).

Development of neonatal-specific sequences for portable ultralow field magnetic resonance brain imaging: a prospective, single-centre, cohort study

Magnetic Resonance (MR) imaging is key for investigation of suspected newborn brain abnormalities. Access is limited in low-resource settings and challenging in infants needing intensive care. Portable ultralow field (ULF) MRI is showing promise in bedside adult brain imaging. Use in infants and children has been limited as brain-tissue composition differences necessitate sequence modification. The aim of this study was to develop neonatal-specific ULF structural sequences and test these across a range of gestational maturities and pathologies to inform future validation studies. Prospective cohort study within a UK neonatal specialist referral centre. Infants undergoing 3T MRI were recruited for paired ULF (64mT) portable MRI by convenience sampling from the neonatal unit and post-natal ward. Key inclusion criteria: 1) Infants with risk or suspicion of brain abnormality, or 2) preterm and term infants without suspicion of major genetic, chromosomal or neurological abnormality. Exclusions: presence of contra-indication for MR scanning. ULF sequence parameters were optimised for neonatal brain-tissues by iterative and explorative design. Neuroanatomic and pathologic features were compared by unblinded review, informing optimisation of subsequent sequence generations in a step-wise manner. Main outcome: visual identification of healthy and abnormal brain tissues/structures. ULF MR spectroscopy, diffusion, susceptibility weighted imaging, arteriography, and venography require pre-clinical technical development and have not been tested. Between September 23, 2021 and October 25, 2022, 102 paired scans were acquired in 87 infants; 1.17 paired scans per infant. Median age 9 days, median postmenstrual age 40+2 weeks (range: 31+3-53+4). Infants had a range of intensive care requirements. No adverse events observed. Optimised ULF sequences can visualise key neuroanatomy and brain abnormalities. In finalised neonatal sequences: T2w imaging distinguished grey and white matter (7/7 infants), ventricles (7/7), pituitary tissue (5/7), corpus callosum (7/7) and optic nerves (7/7). Signal congruence was seen within the posterior limb of the internal capsule in 10/11 infants on finalised T1w scans. In addition, brain abnormalities visualised on ULF optimised sequences have similar MR signal patterns to 3T imaging, including injury secondary to infarction (6/6 infants on T2w scans), hypoxia-ischaemia (abnormal signal in basal ganglia, thalami and white matter 2/2 infants on T2w scans, cortical highlighting 1/1 infant on T1w scan), and congenital malformations: polymicrogyria 3/3, absent corpus callosum 2/2, and vermian hypoplasia 3/3 infants on T2w scans. Sequences are susceptible to motion corruption, noise, and ULF artefact. Non-identified pathologies were small or subtle. On unblinded review, optimised portable MR can provide sufficient contrast, signal, and resolution for neuroanatomical identification and detection of a range of clinically important abnormalities. Blinded validation studies are now warranted. The Bill and Melinda Gates Foundation, the MRC, the Wellcome/EPSRC Centre for Medical Engineering, the MRC Centre for Neurodevelopmental Disorders, and the National Institute for Health Research (NIHR) Biomedical Research Centres based at Guy's and St Thomas' and South London & Maudsley NHS Foundation Trusts and King's College London.

Biomarkers of Alzheimer's Disease and Cerebrovascular Disease in Relation to Depressive Symptomatology in Individuals With Subjective Cognitive Decline.

Subjective cognitive decline (SCD) has gained recent interest as a potential harbinger of neurodegenerative diseases such as Alzheimer's disease (AD) and cerebrovascular disease (CVD). In addition, SCD can be related to depressive symptomatology. However, the association between AD and CVD biomarkers, depressive symptomatology, and SCD is still unclear. We investigated the association of AD and CVD biomarkers and depressive symptomatology with SCD in individuals with subjective memory complaints (SCD-memory group) and individuals with subjective concentration complaints (SCD-concentration group). We recruited a population-based cohort of 217 individuals (all aged 70 years, 53% female participants, 119 SCD-memory individuals, 23 SCD-concentration individuals, and 89 controls). AD and CVD were assessed through cerebrospinal fluid levels of the Aβ42/40 ratio and phosphorylated tau, and white matter signal abnormalities on magnetic resonance imaging, respectively. Associations between biomarkers, depressive symptomatology, and SCD were tested via logistic regression and correlation analyses. We found a significant association between depressive symptomatology with SCD-memory and SCD-concentration. Depressive symptomatology was not associated with AD and CVD biomarkers. Both the phosphorylated tau biomarker and depressive symptomatology predicted SCD-memory, and the Aβ42/40 ratio and depressive symptomatology predicted SCD-concentration. The role of depressive symptomatology in SCD may differ depending on the stage within the spectrum of preclinical AD (as determined by amyloid-beta and tau positivity), and does not seem to reflect AD pathology. Our findings contribute to the emerging field of subclinical depressive symptomatology in SCD and clarify the association of different types of subjective complaints with distinct syndromic and biomarker profiles.

Role of Imaging in Diagnosis of Neurological Complications of COVID-19

Background The COVID-19 pandemic has become a challenging world issue after its emergence in December 2019. Despite its most characteristic symptom of respiratory distress, patients with COVID-19 have also shown neurologic manifestations. Aim of the Work To investigate the yield of neuroimaging in patients with COVID-19 undergoing CT or MR imaging of the brain and to describe associated imaging findings. Patients and Methods A descriptive cross–sectional study conducted at Ain Shams University Hospitals over a course of eight months from December 2020 to July 2021. All patients with confirmed COVID-19 infection who presented with neurological symptoms and underwent neuroimaging were included. Results 39 patients were included in the study, with both adults (84.6%) and children (15.4%). Acute ischemic stroke is found to be the most common complication among adult group (48.5%) followed by Post-covid invasive fungal sinusitis (45.5%). Among the children, the neurological complications are rare but severe including vasculitis (50%), infarctions (33.3 %), cerebritis (16.7 %), venous sinus thrombosis (16.7 %), PRES (16.7 %) and non-specific white matter signal abnormality (16.7 %). Conclusion COVID-19 primarily affects the respiratory system. However, neurological involvement is not uncommon and can result in serious complications if not detected and managed early. These complications in some cases can even precede the respiratory symptoms or may be the only symptoms in COVID-19 patients. Therefore, a high index of suspicion is required while dealing with such cases for proper treatment and prevention.

Neurodevelopmental Correlates of Brain Magnetic Resonance Imaging Abnormalities in Extremely Low-birth-weight Infants

To evaluate the relationship between impaired brain growth and structural brain abnormalities at term-equivalent age (TEA) and neurodevelopment in extremely low-birth-weight (ELBW) infants over the first 2years. ELBW infants born from 2009 through 2018 and undergoing brain magnetic resonance imaging (MRI) at TEA were enrolled in this retrospective cohort study. MRI scans were reviewed using a validated quali-quantitative score, including several white and gray matter items. Neurodevelopment was assessed at 6, 12, 18, and 24months using the Griffiths scales. The independent associations between MRI subscores and the trajectories of general and specific neurodevelopmental functions were analyzed by generalized estimating equations. One hundred-nine ELBW infants were included. White matter volume reduction and delayed myelination were associated with worse general development (b = -2.33, P=.040; b = -6.88, P=.049 respectively), social skills (b = -3.13, P=.019; b = -4.79, P=.049), and eye-hand coordination (b = -3.48, P=.009; b = -7.21, P=.045). Cystic white matter lesions were associated with poorer motor outcomes (b = -4.99, P=.027), while white matter signal abnormalities and corpus callosum thinning were associated with worse nonverbal cognitive performances (b = -6.42, P=.010; b = -6.72, P=.021, respectively). Deep gray matter volume reduction correlated with worse developmental trajectories. Distinctive MRI abnormalities correlate with specific later developmental skills. This finding may suggest that TEA brain MRI may assist with neurodevelopmental prediction, counseling of families, and development of targeted supportive interventions to improve neurodevelopment in ELBW neonates.

Longitudinal imaging in Kleefstra syndrome—Brief report and literature review

AbstractBackgroundKleefstra syndrome (KS) is a rare genetic condition affecting the euchromatic histone methyltransferase 1 (EHMT1) gene, typically presenting with developmental delay, generalized hypotonia, distinctive facial dysmorphisms, and neuropsychiatric anomalies.MethodsWe collected longitudinal magnetic resonance imaging (MRI) data of a child with KS and cerebrospinal fluid (CSF) dissection over 16 years and reviewed the literature focusing on articles reporting MRI findings in KS based on a PubMed search.ResultsAn 18‐year‐old female with KS presented with developmental delay at age 18 months and seizures at age 10 years. At age 23 months, MRI showed ventriculomegaly. Follow‐up MRI nine years later showed CSF dissection from the right lateral ventricle, which progressed similarly in the contralateral side 3 years later and stabilized over time. To date, only 20 articles report MRI findings from 49 patients with KS. The brain imaging findings range from normal (about 25%) to various abnormalities, including ventriculomegaly, white matter signal abnormalities, and dysmorphic corpus callosum and brainstem structures. CSF dissection was not found in any cases with white matter or other abnormalities.ConclusionsCSF dissection may be a rare neuroimaging finding of KS. Its etiology is unclear, but we speculate that epigenetic mutations could indirectly affect the development and integrity of ependymal cell lining along the ventricles. Alternatively, the long‐standing hydrocephalus may have caused the development of pseudodiverticula and subsequent CSF dissection.

Double inversion recovery MRI of subcortical band heterotopia and its variations.

Subcortical band heterotopia (SBH) is a malformation of cortical development diagnosed via MRI. Currently, patients with SBH are classified according to Di Donato's classification. We aimed to show a variation of SBH and the usefulness of double inversion recovery (DIR) images. We retrospectively reviewed the MRI findings of 28 patients with SBH. The patients were classified according to Donato's classification by using conventional MR images, and their DIR findings were reviewed. Of 28 patients, 20 were grade 1 and 8 were grade 2 according to Di Donato's classification. In 15 of 28 patients, the following four types of atypical MRI findings were detected: asymmetry distribution (four cases), coexistence of thin and thick SBH (five cases), and DIR faint abnormal signal intensity in subcortical white matter (five cases) and in deep white matter (five cases). The latter two types were detected on DIR alone and have not been reported. Additionally, these were identified only in the mild group (Di Donato's classification 1-1 or 1-2). DIR is a useful MRI sequence for detecting faint white matter signal abnormalities, and it can aid in the accurate classification of SBH and identification of its variations, which may reflect the pathology of SBH.

Clinical analysis in patients with SPG11 hereditary spastic paraplegia.

To analyze the clinical phenotype of hereditary spastic paraplegia (HSP) caused by SPG11 mutations (SPG11-HSP). Among the 17 patients with sporadic HSP who performed whole exome sequencing analysis, six were diagnosed with SPG11-HSP. The clinical and radiologic findings and the results of the electrodiagnostic and neuropsychologic tests were reviewed retrospectively. The median age at onset was 16.5 years (range, 13-38 years). Progressive spastic paraparesis was a core feature, and the median spastic paraplegia rating scale score was 24/52 (range, 16-31 points). Additional major symptoms were pseudobulbar dysarthria, intellectual disability, bladder dysfunction, and being overweight. Minor symptoms included upper limbs rigidity and sensory axonopathy. The median body mass index was 26.2 kg/m2 (range, 25.2-32.3 kg/m2). The thin corpus callosum (TCC) was predominant at the rostral body or anterior midbody, and the ears of the lynx sign was seen in all. The follow-up MRI showed the worsening of periventricular white matter (PVWM) signal abnormalities with ventricular widening or the extension of the TCC. Motor evoked potentials (MEP) to the lower limbs showed an absent central motor conduction time (CMCT) in all subjects. The upper limb CMCT was initially absent in three subjects, although it became abnormal in all at the follow-up. The mini-mental state examination median score was 27/30 (range, 26-28) with selective impairment of the attention/calculation domain. The median score of the full-scale intelligence quotient was 48 (range, 42-72) on the Wechsler Adult Intelligence Scale test. Attention/calculation deficits and being overweight as well as pseudobulbar dysarthria were common additional symptoms in patients with SPG11-HSP. The rostral body and anterior midbody of the corpus callosum were preferentially thinned, especially in the early stage of the disease. The TCC, PVWM signal changes, and MEP abnormality worsened as the disease progressed.

Abstract #1411492: Loss-of-Function EGFR Mutation in Bartter Syndrome with Neonatal Epithelial Autoinflammation

Bartter syndrome (BS) manifests as hypokalemic and hypochloremic metabolic alkalosis and hyperreninemic hyperaldosteronism. Loss-of-function (LoF) mutations in any of seven genes cause different subtypes of BS. We sought the genetic cause of BS in a 17-year-old patient who presented with progressive nephrocalcinosis, hypercalciuria, polyuria, metabolic alkalosis, hypokalemia, significantly high urine chloride, failure-to-thrive, hypergammaglobulinemia, abnormal cerebral white matter signal changes, autoinflammation, and moderate intellectual disability. No mutations were identified in previously BS-associated genes in this patient with consanguineous parents, and all seven genes resided outside of genomic regions of homozygosity (ROH). Instead, whole-exome sequencing and homozygosity mapping identified a homozygous intronic mutation, c.2702-2A >G, in the epidermal growth factor receptor (EGFR) gene within an ROH of ∼28 Mb in chromosome 7p. Examination of the patient's RNA by RNA-Seq and RT-PCR confirmed the pathogenicity of this variant, causing aberrant splicing resulting in an in-frame retention of 27 nucleotides of intron 22 of EGFR. Immunofluorescence of proband's skin, with a monoclonal antibody, revealed reduced protein level of EGFR, instead of complete protein absence, presumably justifying the life compatibility of this mutation. Previously, three loss-of-function EGFR mutations have been reported in patients with neonatal lethal inflammatory skin lesions and bowel disease. Thus, these observations provide an association of an autosomal recessive BS with hypomorphic EGFR mutation, expanding the phenotypic spectrum of the EGFR-associated disorders.

Dramatic Improvement of MRI Abnormalities of HIV Dementia after Suppressive Antiretroviral Therapy (S25.002)

<h3>Objective:</h3> Not applicable. <h3>Background:</h3> A 59-year-old man diagnosed with HIV 26 years prior and a long history of antiretroviral therapy (ART) non-adherence presented with subacute cognitive decline. A neurologic workup including cerebrospinal fluid testing showed no evidence of opportunistic infections. He was admitted to an assisted care facility where he restarted ART. However, he remained viremic and was referred to the National Institutes of Health (NIH). On admission to the NIH, he had an HIV plasma viral load of 28,056 copies/mL and CD4 T-cell count of 5 cells/μL. He was started on a new ART regimen with increased central nervous system penetration (etravirine, dolutegravir, darunavir/cobicistat, tenofovir/emtricitabine). MRI revealed extensive leukoencephalopathy and volume loss, consistent with HIV encephalopathy. Comprehensive neuropsychological testing revealed significant deficits in all cognitive domains, including learning, memory, attention, executive function, and psychomotor speed. The patient was followed for two years, during which time he achieved and sustained viral suppression (&lt;40 copies/mL) and reached a CD4 T-cell count of 197 with ART. A repeat MRI showed profound improvement in the white matter signal abnormality. Repeat neuropsychological testing demonstrated notable improvements in several tests of attention, information processing, and psychomotor speed, but continued difficulty in most other cognitive domains. <h3>Design/Methods:</h3> Not applicable. <h3>Results:</h3> Not applicable. <h3>Conclusions:</h3> While current ART regimens are highly effective in reducing the incidence of HIV-associated neurologic complications, their role in reversing the MRI abnormalities seen in HIV encephalopathy remains unclear. In this case, we tracked HIV encephalopathy in the current era of effective ART with serial MRI evaluations. Our results provide a rare example of dramatic reduction of periventricular white matter hyperintensities and improved performance in a subset of cognitive domains. Providers encountering white matter abnormalities in patients with treated HIV should consider this legacy effect in evaluating whether disease is progressive, or as in this case, improved. <b>Disclosure:</b> Ms. Dietrich has nothing to disclose. Miss Laidlaw has nothing to disclose. Dr. Hammoud has nothing to disclose. Dr. Pau has nothing to disclose. Dr. Smith has nothing to disclose.

Non-Iatrogenic Cerebral Air Embolism: A Case Report of an Extremely Rare Cause of Ischemic Stroke (P6-5.031)

<h3>Objective:</h3> NA <h3>Background:</h3> Air embolism is an uncommon but potentially catastrophic event due to air entry into the vasculature resulting in ischemic strokes. Cerebral air embolism (CAE) can be a complication of medical procedures, although non-iatrogenic sources have rarely been reported. Nonetheless, it is a life-threatening emergency with high mortality and disability. We present a patient with an acute infarct due to a CAE during air travel. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case Report:</h3> A 67-year-old woman presents with two episodes of impaired consciousness during flights while in Europe. Both happened shortly after ascent. Her symptoms quickly resolved after an emergent landing on her first trip. During the second trip, however, symptoms recurred, and she remained unconscious. She was evaluated at a local hospital where a head computed tomography (CT) showed multiple cortical air locules, predominantly in the right hemisphere, consistent with cerebral air embolism. CT chest revealed a large left bulla with surrounding neovascularization, likely the cause of the embolism. A magnetic resonance imaging (MRI) brain confirmed numerous subacute infarcts across multiple vascular territories and diffuse white matter signal abnormality, consistent with the sequela of cerebral air embolism. She was transported to the US by sea for further management at a tertiary hospital, where she had successful resection of left lung bulla. She was subsequently discharged home with very mild left ataxia. <h3>Conclusions:</h3> Non-iatrogenic CAE is an extremely rare cause of ischemic stroke. Previously described cases relate to barometric pressure changes: during diving and ascent. We describe a patient presenting with CAE secondary to pulmonary shunt from a large lung bulla under barometric pressure changes during aircraft ascent. While literature suggests CAE as a life-threatening emergency with poor prognosis, this patient had an excellent outcome after surgical resection of the lung bulla, indicating possibly different outcomes between non-iatrogenic vs. iatrogenic CAE. <b>Disclosure:</b> Dr. Su has nothing to disclose. Dr. Pandya has nothing to disclose. Dr. Reyes has nothing to disclose. Dr. Shastry has nothing to disclose. Dr. Varade has nothing to disclose.

WWOX developmental and epileptic encephalopathy: Understanding the epileptology and the mortality risk.

WWOX is an autosomal recessive cause of early infantile developmental and epileptic encephalopathy (WWOX-DEE), also known as WOREE (WWOX-related epileptic encephalopathy). We analyzed the epileptology and imaging features of WWOX-DEE, and investigated genotype-phenotype correlations, particularly with regard to survival. We studied 13 patients from 12 families with WWOX-DEE. Information regarding seizure semiology, comorbidities, facial dysmorphisms, and disease outcome were collected. Electroencephalographic (EEG) and brain magnetic resonance imaging (MRI) data were analyzed. Pathogenic WWOX variants from our cohort and the literature were coded as either null or missense, allowing individuals to be classified into one of three genotype classes: (1) null/null, (2) null/missense, (3) missense/missense. Differences in survival outcome were estimated using the Kaplan-Meier method. All patients experienced multiple seizure types (median onset=5 weeks, range=1day-10months), the most frequent being focal (85%), epileptic spasms (77%), and tonic seizures (69%). Ictal EEG recordings in six of 13 patients showed tonic (n= 5), myoclonic (n= 2), epileptic spasms (n= 2), focal (n= 1), and migrating focal (n= 1) seizures. Interictal EEGs demonstrated slow background activity with multifocal discharges, predominantly over frontal or temporo-occipital regions. Eleven of 13 patients had a movement disorder, most frequently dystonia. Brain MRIs revealed severe frontotemporal, hippocampal, and optic atrophy, thin corpus callosum, and white matter signal abnormalities. Pathogenic variants were located throughout WWOX and comprised both missense and null changes including five copy number variants (four deletions, one duplication). Survival analyses showed that patients with two null variants are at higher mortality risk (p-value=.0085, log-rank test). Biallelic WWOX pathogenic variants cause an early infantile developmental and epileptic encephalopathy syndrome. The most common seizure types are focal seizures and epileptic spasms. Mortality risk is associated with mutation type; patients with biallelic null WWOX pathogenic variants have significantly lower survival probability compared to those carrying at least one presumed hypomorphic missense pathogenic variant.

MRI as a one-stop destination for evaluation of CSF shunt malfunction

BackgroundDespite the high-frequency rate of cerebrospinal fluid shunt malfunction, radiological evaluation of CSF shunts has remained deficient, focusing mainly on demonstrating secondary signs of shunt failure rather than evaluating the shunt tube itself. We aimed to study the utility of different MR pulse sequences in evaluating the cranial and abdominal ends of CSF shunts in order to identify the potential cause of shunt failure and its impact on patient management.ResultsTwenty-five patients (18 males, 7 females, median age 2.5 years, IQR 0.75–15) were enrolled in the study, having 28 ventriculo-peritoneal shunts and single ventriculo-gallbladder shunt. The catheter lumen and fine intraventricular septae were only demonstrated in 3D-DRIVE sequences (p < 0.001). Except for three patients (having cranial end-related complications), all patients with cranial and/or abdominal end-related complications received surgery (p < 0.001, positive likelihood and negative likelihood ratios = 7.27, 0.3, respectively, sensitivity = 0.7 and specificity = 0.9). MRI findings (luminal occlusion, disconnection, CSF collection, or migration) were consistent with operative data. There is no significant difference between patients who underwent surgery and those with conservative management, or symptomatic and asymptomatic patients in terms of the prevalence of ventricular dilatation or white matter signal abnormality. The results of the abdomino-pelvic fat-suppressed T2-WI showed excellent agreement with ultrasound findings (Cohen’s Kappa 0.9). Quantitative PC could give insights into CSF dynamics, which depend on the site and cause of shunt malfunction.ConclusionsMRI could be a one-stop destination for evaluating patients with suspected non-acute shunt malfunction. It was found to have clinical relevance in terms of accurately locating the exact site and possible cause of shunt-related complications.

Characterization of MRI White Matter Signal Abnormalities in the Pediatric Population.

(1) Background and Purpose: The aim of this study was to retrospectively characterize WMSAs in an unselected patient cohort at a large pediatric neuroimaging facility, in order to learn more about the spectrum of the underlying disorders encountered in everyday clinical practice. (2) Materials and Methods: Radiology reports of 5166 consecutive patients with standard brain MRI (2006-2018) were searched for predefined keywords describing WMSAs. A neuroradiology specialist enrolled patients with WMSAs following a structured approach. Imaging characteristics, etiology (autoimmune disorders, non-genetic hypoxic and ischemic insults, traumatic white matter injuries, no final diagnosis due to insufficient clinical information, "non-specific" WMSAs, infectious white matter damage, leukodystrophies, toxic white matter injuries, inborn errors of metabolism, and white matter damage caused by tumor infiltration/cancer-like disease), and age/gender distribution were evaluated. (3) Results: Overall, WMSAs were found in 3.4% of pediatric patients scanned at our and referring hospitals within the ten-year study period. The majority were found in the supratentorial region only (87%) and were non-enhancing (78% of CE-MRI). WMSAs caused by autoimmune disorders formed the largest group (23%), followed by "non-specific" WMSAs (18%), as well as non-genetic hypoxic and ischemic insults (17%). The majority were therefore acquired as opposed to inherited. Etiology-based classification of WMSAs was affected by age but not by gender. In 17% of the study population, a definite diagnosis could not be established due to insufficient clinical information (mostly external radiology consults). (4) Conclusions: An "integrated diagnosis" that combines baseline demographics, including patient age as an important factor, clinical characteristics, and additional diagnostic workup with imaging patterns can be made in the majority of cases.

Evolution of the intracranial features of congenital cytomegalovirus on MRI

To describe the evolution of the intracranial features of congenital cytomegalovirus (cCMV) on magnetic resonance imaging (MRI). Sixteen infants with polymerase chain reaction (PCR)-confirmed cCMV who had undergone at least two MRI examinations of the brain were identified. Two paediatric neuroradiologists reviewed the baseline studies retrospectively for intracranial features of cCMV, including white matter signal abnormalities, subependymal cysts, malformations of cortical development, and intracranial calcification. The subsequent MRI studies were then reviewed and directly compared to the baseline examinations. White matter signal abnormalities were seen on all 16 baseline studies (100%); these persisted on all subsequent examinations but were patchier, more focal, and associated with an interval reduction in white matter volume. Subependymal cysts were present on 11 (69%) of the baseline scans; these almost universally regressed (in 10 of the 11 cases [91%]), with no new cysts appreciable on subsequent imaging. Malformations of cortical development, exclusively in the form of polymicrogyria, were seen in six (38%) patients and persisted, unchanged, on subsequent imaging. Intracranial calcification was seen in a minority of baseline studies (4 [25%]) and remained stable on subsequent scans. Children with cCMV who present later in life without an established or suspected underlying pathology can pose a challenge to the assessing radiologist. The radiological sequelae of cCMV can be non-specific; in some cases, white matter signal abnormalities and focal loss of white matter volume may be the only intracranial features. It is therefore important that radiologists are aware of cCMV as a potential differential for these findings.

Underlying cerebrovascular pathology in Subjective Cognitive Decline: A systematic review and meta‐analysis

AbstractBackgroundSubjective cognitive decline (SCD) implies self‐reported cognitive complaints in absence of objective cognitive impairment. SCD has been postulated as an early marker of Alzheimer’s Disease (AD). However, longitudinal studies have linked SCD to future vascular dementia. Thus, we conducted a systematic review and meta‐analysis aiming to synthesise and analyse the available data on the association between SCD and the presence of underlying cerebrovascular pathology measured by MRI.MethodOur study was performed following the PRISMA statement. The search strategy included terms for “subjective cognitive decline” and “white matter signal abnormalities”. It was conducted in 3 databases (PubMed, Scopus and Web of Science) from origin by December 8th, 2021. Two authors screened the studies in a 2‐stepwise approach. Primary studies including cognitively unimpaired adults with subjective cognitive complaints meeting the SCD‐I criteria for SCD that evaluated cerebrovascular pathology based on white matter signal abnormalities (WMSA) on MR images were selected. Study quality was assessed using the FLC 3.0 tool. Meta‐analysis comparing case‐control mean difference of WMSA was performed.ResultOf 240 articles identified, 16 research articles were selected. Of those, 8 case‐control studies were selected for the meta‐analysis. The sample size of the SCD group across the studies ranged from 8 to 906 participants, with age ranged from 40 to 84 years. All eight studies comprised a total of 2.637 SCD individuals. Study quality was deemed moderate (n=6) to high (n=10). The meta‐analysis showed a significant overall effect‐size between the mean WMSA burden of SCD and the controls, that was not significantly heterogeneous (Q(gl=7)=14.20; p=0,04; I2=42,5%). SCD was significantly associated with higher CVP burden based on neuroimaging measures.ConclusionThis is the first study to synthesise and analyse the current evidence on the association between SCD and WMSA. Our findings show the usefulness of SCD as a marker of underlying cerebrovascular pathology. Thus, the potential role of SCD as a preclinical stage of vascular cognitive impairment needs further investigation. Changes in lifestyle (e.g. exercise, diet, smoking cessation), cognitive stimulation or pharmacotherapy may be key to avoid an evolution towards cognitive deterioration in SCD.