Aicardi-Goutières Syndrome due to a SAMHD1 Mutation Presenting with Deep White Matter Cysts

We report on the first Polish patient diagnosed with the Aicardi-Goutières syndrome 5 (AGS5). AGS is caused by mutations in one of 9 genes (<i>TREX1</i>, <i>RNASEH2A</i>, <i>RNASEH2B</i>, <i>RNASEH2C</i>, <i>SAMHD1</i>, <i>ADAR</i>, <i>IFIH</i>, <i>LSM11</i>, <i>RNU7-1</i>) which stimulate the type I interferon response. The diagnosis was confirmed by identifying a compound heterozygous mutation p.(Phe165Ser)/p.(Gln235*) in the <i>SAMHD1</i> gene using whole-exome sequencing. The cystic lesions in the temporal lobes are an uncommon finding in the presented patient carrying a <i>SAMHD1</i> mutation. Reporting new cases expands the range of phenotypes and plays the crucial role in understanding the AGS pathogenesis and creates new therapy approaches.

New-Onset Right-Sided Numbness and Double Vision

A 40-year-old right-handed man sought care for right hand numbness, right-sided facial numbness, and diplopia progressing to maximal severity over 10 days. At his worst he was unable to write. His symptoms remained maximal for 4 weeks. He was hospitalized and treated with 5 days of intravenous methylprednisolone. He improved to approximately 95% of normal over 4 weeks. He had residual mild right-sided facial and right leg numbness. Antibodies to JC polyoma virus and varicella-zoster virus were positive, which indicated prior exposure to these viruses. Total 25-hydroxyvitamin D level was low at 8.2 ng/mL. Optical coherence tomography findings were normal. Magnetic resonance imaging of the brain performed 3 months after the onset of symptoms demonstrated a T2-hyperintense lesion in the left midbrain peduncle extending into the upper pons, without gadolinium enhancement. A small area of T2 hyperintensity was seen in the right frontal deep white matter. Follow-up brain magnetic resonance imaging showed almost complete resolution of the left midbrain peduncle lesion with persistence of the right frontal deep white matter lesion. Spinal fluid analysis showed 1 white blood cell/µL with 95% lymphocytes, protein 35 mg/dL, 0 unique oligoclonal bands, and normal immunoglobulin G index (0.54). A diagnosis of clinically isolated syndrome-first episode of multiple sclerosis was made. After detailed discussion with the patient, he elected to commence disease-modifying therapy with fingolimod. He underwent routine monitoring with magnetic resonance imaging of the brain and cervical and thoracic spine on an annual basis, without any further relapses at 5-year follow-up. Patients with typical demyelinating syndromes may not always fulfill the diagnostic criteria for multiple sclerosis. After careful exclusion of other mimicking conditions, most notably aquaporin-4-immunoglobulin G– and myelin oligodendrocyte glycoprotein-immunoglobulin G–associated disease, a diagnosis of clinically isolated syndrome may be made.

Abstract 1122‐000153: Larger Functional Shunts are Associated with Greater Cerebrovascular Disease Burden

Introduction : The relationship between embolic stroke and patent foramen ovale (PFO) is well‐established. Our objective was to evaluate the association between high intensity transient signals (HITS) in contrast‐enhanced transcranial doppler ultrasonography (ceTCD), baseline MRI brain small vessel ischemic changes, and rates of acute ischemic stroke in the setting of focal neurological deficits. Methods : Electronic medical records of subjects with acute onset neurological symptoms who had ceTCD and MRI brain were evaluated. Subjects without a reported Spencer grade and/or MRI brain without available DWI and FLAIR sequences were excluded. Acute stroke rates and baseline Fazekas score in low‐grade (Spencer grade 1–2) and high‐grade (Spender grade 3–5) shunts were analyzed using Z score for 2 population proportions and Mann‐Whitney U test, respectively. Social Science Statistics was used for data analysis. Results : From June 2016 to August 2021, of 7,498 consecutive ischemic stroke patients, 132 patients were identified as possible strokes related to PFO and were hospitalized with focal neurological deficit, underwent ceTCD and MRI brain. Acute stroke was confirmed on DWI in 60% of Spencer grade 1 (n = 73), 72.2% of grade 2 (n = 19), 72.7% of grade 3 (n = 29), and 80% of grades 4 and 5 shunts (n = 11). Acute stroke rates between low grade (grades 1–2) and high grade shunts (grades 3–5), did not reach statistical significance (z = ‐0.9181; p = 0.17879). There was no significant difference in periventricular white matter disease (z = 0.85697; p = 0.19489). Fazekas scores assessing deep white matter disease were statistically significant between low‐ and high‐grade shunts (z = 1.92818; p = 0.0268 Conclusions : A trend towards statistical significance was observed in high‐grade shunt association with higher rate of acute stroke. Deep white matter disease burden may be significantly higher in high‐grade shunts. Further prospective studies are needed to corroborate our findings.

White matter injury but not germinal matrix hemorrhage induces elevated osteopontin expression in human preterm brains

Osteopontin (OPN) is a matricellular protein that mediates various physiological functions and is implicated in neuroinflammation, myelination, and perinatal brain injury. However, its expression in association with brain injury in preterm infants is unexplored. Here we examined the expression of OPN in postmortem brains of preterm infants and explored how this expression is affected in brain injury. We analyzed brain sections from cases with white matter injury (WMI) and cases with germinal matrix hemorrhage (GMH) and compared them to control cases having no brain injury. WMI cases displayed moderate to severe tissue injury in the periventricular and deep white matter that was accompanied by an increase of microglia with amoeboid morphology. Apart from visible hemorrhage in the germinal matrix, GMH cases displayed diffuse white matter injury in the periventricular and deep white matter. In non-injured preterm brains, OPN was expressed at low levels in microglia, astrocytes, and oligodendrocytes. OPN expression was significantly increased in regions with white matter injury in both WMI cases and GMH cases. The main cellular source of OPN in white matter injury areas was amoeboid microglia, although a significant increase was also observed in astrocytes in WMI cases. OPN was not expressed in the germinal matrix of any case, regardless of whether there was hemorrhage. In conclusion, preterm brain injury induces elevated OPN expression in microglia and astrocytes, and this increase is found in sites closely related to injury in the white matter regions but not with the hemorrhage site in the germinal matrix. Thus, it appears that OPN takes part in the inflammatory process in white matter injury in preterm infants, and these findings facilitate our understanding of OPN’s role under both physiological and pathological conditions in the human brain that may lead to greater elucidation of disease mechanisms and potentially better treatment strategies.

Increased interstitial fluid in periventricular and deep white matter hyperintensities in patients with suspected idiopathic normal pressure hydrocephalus

Periventricular white matter changes are common in patients with idiopathic normal pressure hydrocephalus (iNPH) and considered to represent focally elevated interstitial fluid. We compared diffusion measures in periventricular hyperintensities in patients with imaging features of iNPH to patients without. The hypothesis is that periventricular hyperintensities in patients with presumed iNPH show higher water content than in patients without imaging features of iNPH. 21 patients with iNPH Radscale 7–12 (“high probability of iNPH”) and 10 patients with iNPH Radscale 2–4 (“low probability of iNPH”) were examined with a neurodegeneration imaging protocol including a diffusion microstructure imaging sequence. Periventricular hyperintensities and deep white matter hyperintensities were segmented and diffusion measures were compared. In patients with imaging features of iNPH, the free water content in periventricular hyperintensities was significantly higher compared to the control group (p = 0.005). This effect was also detectable in deep white matter hyperintensities (p = 0.024). Total brain volumes and total gray or white matter volumes did not differ between the groups. Periventricular cap free water fraction was highly discriminative regarding patients with presumed iNPH and controls with an ROC AUC of 0.933. Quantitative diffusion microstructure imaging shows elevated water content in periventricular hyperintensities in patients with imaging features of iNPH, which could be the imaging correlate for pathologic fluid accumulation and may be used as an imaging biomarker in the future.

OTHR-11. Comprehensive Analysis of Driver Mutation Profile in a Cohort of Lung Cancer Patients Using Targeted Gene Panel Analysis with Focus on Brain Metastatic Disease

Purpose Approximately 228,820 people are diagnosed annually with lung cancer diagnosis and 135,720 die from their disease1. EGFR and KRAS targeted therapies have been shown to significantly improve treatment of non-small cell lung cancer (NSCLC), but they don’t apply to the majority of patients. There’s a critical need to characterize the molecular signature of patients with lung cancer and to define the proportion of patients eligible for novel targeted therapies. Methods IRB approval was obtained to retrospectively extract data from tertiary hospital tumor registry from 2011 to 2017. Data collected included patient demographics, targeted next generation sequencing results (50 and 150 gene panel), histology, and biopsy location in the final 2,203 patients, 715 of which were manually checked. Findings 83.8% of patients in the lung cancer cohort that had targeted next-generation gene panel analysis demonstrated presence of at least one mutation. 50.9% of the patients in our cohort had a targetable mutation. There were 9.5% with hypermutated phenotype characterized as at least 5 mutations per sample. 1.3% of patients had at least 10 mutations per sample. We also characterize the distribution of mutations within brain metastatic lesions and demonstrate that brain metastases with hypermutated phenotype demonstrate larger volumes of edema and greater involvement of deep white matter than non-hypermutated brain metastases. Conclusion We present a comprehensive analysis of the molecular signature of lung cancer from a tertiary referral institution with focused analysis of brain metastases. Lung cancer brain metastases with greater than 5 mutations correspond to greater volume of edema and involvement of deep white matter.