Brainstem Lesions Research Articles

Frame-based stereotactic biopsies of brainstem lesions – Monocentric comparison of the transfrontal and the suboccipital-transcerebellar approach over a 16-year period

Both the transfrontal and the suboccipital-transcerebellar approach are frequently used trajectories for frame-based stereotactic biopsies of brainstem lesions. Nevertheless, it remains unclear which approach is more favorable in terms of complications, diagnostic success and outcome, especially considering the location of the lesion within the brainstem. This study compared the safety and diagnostic yield of these two approaches. Furthermore, a brainstem zone model was created to answer the question, whether there is a favorable approach depending on the location of the lesion in the brainstem. A retrospective analysis of 84 consecutive cases of frame-based stereotactic biopsies for brainstem lesions via either transfrontal or suboccipital-transcerebellar approaches over a 16-year period was performed. Clinical and surgical data regarding trajectories, histopathology, complications and outcome was collected. The brainstem was divided in anatomical zones to compare the use of the two approaches depending on the location of the lesions. A total of n = 84 cases of stereotactic biopsies for brainstem lesions were performed. In 36 cases the suboccipital-transcerebellar approach was used, while in 48 cases surgery was performed via the transfrontal approach. The patient’s demographic data were comparable between the two approaches. Overall diagnostic yield was 90.5% (93.8% transfrontal vs. 86.1% suboccipital, p = 0.21, Risk Difference (RD) 0.077, CI [-0.0550, 0.2090]). Complications occurred in 11 cases (total complication rate: 13.1%; 12.5% transfrontal vs. 13.9% suboccipital, p = 0.55, RD 0.014, CI [-0.1607, 0.1327]). The brainstem model showed a more frequent use of the suboccipital approach in lesions of the dorsal pons. The transfrontal approach was used more frequently in mesencephalic targets. No significant differences in terms of complications and diagnostic yield were observed, even though complications in medullary lesions appeared higher using the transfrontal approach. This study showed, that if the approaches are used for their intended target locations there are no significant differences between the transfrontal and the suboccipital-transcerebellar approach for frame-based stereotactic biopsies of brainstem lesions in terms of diagnostic yield and safety. Therefore, our data suggests that both approaches should be considered for stereotactic biopsy of brainstem lesions.

Subcortical plaques and inflammation reflect cortical and meningeal pathologies in progressive multiple sclerosis.

It remains elusive whether lesions and inflammation in the sub/juxtacortical white matter reflect cortical and/or meningeal pathologies. Elucidating this could have implications for MRI monitoring as sub/juxtacortical lesions are detectable by routine MRI, while cortical lesions and meningeal inflammation are not. By large-area microscopy, we quantified total and mixed active plaque loads along with densities and sizes of perivascular mononuclear infiltrates (infiltrates) in the sub/juxtacortical white matter ≤2 mm from the cortex, intra-cortically and in the meninges. Data were related to ante-mortem clinical parameters in a false discovery rate-corrected analysis. We compared 12 patients with primary progressive multiple sclerosis (PPMS) and 15 with secondary progressive MS to 22 controls. Fifteen patients and 11 controls contributed with hemispheric sections. Sections were stained with haematoxylin-eosin, for myelin and for microglia/macrophages. B cells and T cells were confirmed in a subset. Immunoglobulin G depositions in selected cortical plaques resembled depositions described before in "slowly expanding" plaques in the white matter. We quantified plaque activity by measuring microglia-dominated and macrophage-dominated areas. Sub/juxtacortical plaques (load and activity) reflected plaque activity in the cerebral cortex. Plaque activity and infiltrates were more pronounced in the sub/juxtacortical white matter than in the cerebral cortex while conversely, the total plaque load was highest in the cortex. Infiltrates correlated trans-cortically and sub/juxtacortical plaque activity reflected cortical and meningeal infiltrates. Sub/juxtacortical infiltrate sizes correlated with shorter survival after progression onset. Two patients with PPMS and putatively fatal brain stem lesions argue against incidental findings. Trans-cortical inflammatory flares and plaque activity may be pathogenic in progressive MS. We suggest emphasis on sub/juxtacortical MRI lesions as plausible surrogates for cortical and meningeal pathologies and, when present, as indicators for cognitive testing.

Clinical Efficacy Analysis of Acupuncture Treatment in the Acute Phase of Peripheral Facial Paralysis

Peripheral facial paralysis, caused by damage to the lower motor neurons of the facial nerve, is a neurological disorder characterized by partial or complete loss of facial expression. It typically manifests suddenly with symptoms such as post-auricular pain, diminished taste, excessive tearing, difficulty speaking, and facial muscle twitching. Depending on the underlying cause, this condition can be categorized into spontaneous facial nerve palsy, peripheral facial paralysis induced by Guillain-Barré syndrome, and peripheral facial paralysis caused by brainstem lesions. Among these, the most common type is Bell’s palsy, which usually presents as sudden unilateral facial muscle paralysis. The incidence rate is approximately 20 to 40 cases per 100,000 people annually, with patients ranging in age from young to old, although it is most prevalent in those aged 20 to 40, and it tends to occur more frequently in men than in women. Conventional treatments for peripheral facial nerve paralysis include hormone therapy, antiviral medication, and surgical intervention. However, hormone therapy may not be effective for some patients due to its side effects, the efficacy of antiviral therapy remains controversial, and surgery is costly and may lead to postoperative complications. Traditional Chinese Medicine (TCM) acupuncture therapy, with a long-standing history, has been widely used to treat such facial nerve disorders as documented in the "Huangdi Neijing · Suwen."

HGGL-03 DIFFUSE MIDLINE GLIOMA IN GHANA-AN ILL-FATED DIAGNOSIS

Abstract PURPOSE Diffuse midline gliomas (DMG) based on the updated WHO classification are pediatric-type diffuse high-grade gliomas common in children and young adults. They are highly aggressive with dismal outcomes. Unfortunately, not much is known about these tumours in Ghana. This study seeks to provide initial data on the subject. METHODS A 2-year retrospective review of cases seen at the Pediatric Multidisciplinary Team and Radiotherapy Department yielded 9 cases. Their demographics, clinical presentation, radiologic features, and therapeutic outcomes were documented. RESULTS A total of nine cases, 55.6% males (n = 5), and 44.4% females (n = 4) were documented with a median age of 7 years. They presented with symptoms of vomiting in 44.4% of cases, multiple cranial nerve palsies (CN III, CN VI) in 55.6% of cases, and ataxia in 33.3 cases. None presented with paralysis. Imaging showed brainstem lesions in all 9 cases and thalamic involvement in 11.1%. Acute hydrocephalus was a feature in 44% of cases requiring CSF diversion. Up to 6 cases were lost to follow-up with 3 mortalities. CONCLUSION With DMG imaging is key for diagnosis due to the pathognomonic features, surgery plays a minimal role due to limited access to the lesion and related complications. In our series, the majority of lesions were localized within the brainstem with nearly half the number presenting with acute hydrocephalus. Overall, the outcomes were poor. Understanding the local picture is vital to addressing this devastating pathology.

How i do it: Robot-assisted transcerebellar stereotactic approach for brainstem lesion.

Stereotactic approaches to diffuse intrinsic pontine gliomas (DIPGs) remain essential due to advances in molecular biology and management, necessitating tissue sampling. Here we present an effective technique with a biopsy by robot-assisted transcerebellar approach. Our procedure was performed using the ROSA robotic system and the OARM CT scan, which provided stereotactic conditions for this transcerebellar approach to brainstem lesions. The robot-assisted transcerebellar stereotactic approach remains essential to provide complications for biopsy of brainstem lesions.

Clinical Acute Bulbar Syndrome in a 6-Month-Old Child with Cortical Brain Dysplasia

The article presents a rare clinical case of Autoimmune brain stem encephalitis of unknown etiology in a 6-month-old girl. The manifestation of the disease began with a subacute growing bulbar syndrome, however, in the clinical picture noted hemiparesis, which was not typical for the brain stem lesions. In the series of examinations, we revealed a concomitant congenital pathology of the cerebral cortex, which was the cause of child hemiparesis. The clinical case shows the importance of differential diagnosis in limited conditions and medical alertness for the correct diagnosis and further treatment.

Erdheim-Chester Disease Masquerading as CLIPPERS.

To present 4 patients with Erdheim-Chester disease (ECD) based on clinical, radiologic, histopathologic, and molecular genetic findings who had enhancing brainstem lesions and were initially believed to have chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Case series. Although patients with ECD can demonstrate clinical and imaging features similar to CLIPPERS, refractoriness to corticosteroids, lack of fulfillment of specific MRI criteria (i.e., enhancing lesions >3 mm, T2 abnormalities that exceed areas of T1 postgadolinium enhancement), and systemic findings such as "hairy kidney" appearance and metadiaphyseal osteosclerosis on 18F-fluorodeoxyglucose PET-CT help discriminate it from CLIPPERS. ECD is a histiocytic neoplasm characterized by multiorgan infiltration of clonal histiocytes carrying activating variants of the MAPK-ERK pathway. Neurologic involvement occurs in up to 40% of ECD with frequent brainstem lesions that can mimic acquired neuroinflammatory disorders, such as CLIPPERS. ECD is an important CLIPPERS mimic with distinct pathophysiology and targeted treatments. We highlight the need to consider histiocytic disorders among other alternate diagnoses when findings are not classic for CLIPPERS.

Multifraction stereotactic radiotherapy utilizing inhomogeneous dose distribution for brainstem metastases: a single-center retrospective analysis.

Brainstem metastases are challenging to manage owing to the critical neurological structures involved. Although stereotactic radiotherapy (SRT) offers targeted high doses while minimizing damage to adjacent normal tissues, the optimal dose fractionation remains undefined. This study evaluated the efficacy and safety of multifraction SRT with an inhomogeneous dose distribution. This retrospective study included 31 patients who underwent 33 treatments for 35 brainstem lesions using linear accelerator-based multifraction SRT (30Gy in five fractions, 35Gy in five fractions or 42Gy in 10 fractions) with an inhomogeneous dose distribution (median isodose, 51.9%). The outcomes of interest were local failure, toxicity and symptomatic failure. The median follow-up time after brainstem SRT for a lesion was 18.6months (interquartile range, 10.0-24.3months; range, 1.8-39.0months). Grade 2 toxicities were observed in two lesions, and local failure occurred in three lesions. No grade 3 or higher toxicities were observed. The 1-year local and symptomatic failure rates were 8.8 and 16.7%, respectively. Toxicity was observed in two of seven treatments with a gross tumor volume (GTV) greater than 1cc, whereas no toxicity was observed in treatments with a GTV less than 1cc. No clear association was observed between the biologically effective dose of the maximum brainstem dose and the occurrence of toxicity. Our findings indicate that multifraction SRT with an inhomogeneous dose distribution offers a favorable balance between local control and toxicity in brainstem metastases. Larger multicenter studies are needed to validate these results and determine the optimal dose fractionation.

Differential Analysis of Venous Sinus Diameters: Unveiling Vascular Alterations in Patients with Multiple Sclerosis.

Alterations in the cerebral venous system have been increasingly recognized as a significant component of the pathophysiology of multiple sclerosis (MS). This study aimed to explore the relationship between venous sinus diameter and MS to understand potential vascular alterations in MS patients compared with controls. We sought to determine whether these alterations were correlated with disease characteristics such as duration, lesion type, and disability score. This study included 79 MS patients diagnosed according to the 2017 McDonald criteria and 67 healthy individuals. Magnetic resonance imaging (MRI) scans via a 1.5 Tesla system provided measurements of the superior sagittal sinus, right and left transverse sinus, sinus rectus, and venous structures. Statistical analysis was conducted via SPSS, employing independent sample t tests, ANOVA, chi-square tests, and Pearson correlation analysis, with the significance level set at p < 0.05. This study revealed significant differences in venous sinus diameter between MS patients and controls, with MS patients exhibiting larger diameters. Specifically, patients with brainstem and spinal lesions had larger diameters in certain sinus regions. No significant correlations were found between venous sinus diameter and demographic factors, expanded disability status scale scores, or lesion counts. However, a significant increase in perivenular lesions was noted in patients with longer disease durations. The findings indicate notable vascular alterations in MS patients, particularly in venous sinus diameters, suggesting a potential vascular component in MS pathology. The lack of correlation with conventional clinical and MRI metrics highlights the complexity of MS pathology. These insights underscore the need for further research, particularly longitudinal studies, to elucidate the role of venous changes in MS progression and their potential as therapeutic targets.

MRI and Clinical Variables for Prediction of Outcomes After Pediatric Severe Traumatic Brain Injury

Traumatic brain injury (TBI) is a leading cause of death and disability in children, and predicting functional outcome after TBI is challenging. Magnetic resonance imaging (MRI) is frequently conducted after severe TBI; however, the predictive value of MRI remains uncertain. To identify early MRI measures that predict long-term outcome after severe TBI in children and to assess the added predictive value of MRI measures over well-validated clinical predictors. This preplanned prognostic study used data from the Approaches and Decisions in Acute Pediatric TBI (ADAPT) prospective observational comparative effectiveness study. The ADAPT study enrolled 1000 consecutive children (aged <18 years) with severe TBI between February 1, 2014, and September 30, 2017. Participants had a Glasgow Coma Scale (GCS) score of 8 or less and received intracranial pressure monitoring. Magnetic resonance imaging scans performed as part of standard clinical care within 30 days of injury were collected at 24 participating sites in the US, UK, and Australia. Summary imaging measures were correlated with the Glasgow Outcome Scale-Extended for Pediatrics (GOSE-Peds), and the predictive value of MRI measures was compared with the International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) core clinical predictors. Data collection, image analysis, and data analyses were completed in July 2023. Pediatric severe TBI with an MRI scan performed as part of clinical care. All measures were selected a priori. Magnetic resonance imaging measures included contusion, ischemia, diffuse axonal injury, intracerebral hemorrhage, and brainstem injury. Clinical predictors included the IMPACT core measures (GCS motor score and pupil reactivity). All models adjusted for age and sex. Outcome measures included the GOSE-Peds score obtained at 3, 6, and 12 months after injury. This study included 233 children with severe TBI who were enrolled at participating sites and had an MRI scan and preselected clinical predictors available. Their median age was 6.9 (IQR, 3.0-13.3) years, and more than half of participants (134 [57.5%]) were male. In a multivariable model including MRI measures and IMPACT core clinical variables, contusion volume (odds ratio [OR], 1.13; 95% CI, 1.02-1.26), brain ischemia (OR, 2.11; 95% CI, 1.58-2.81), brainstem lesions (OR, 5.40; 95% CI, 1.90-15.35), and pupil reactivity were each independently associated with GOSE-Peds score. Adding MRI measures to the IMPACT clinical predictors significantly improved model fit and discrimination between favorable and unfavorable outcomes compared with IMPACT predictors alone (area under the receiver operating characteristic curve, 0.77; 95% CI, 0.72-0.85 vs 0.67; 95% CI, 0.61-0.76 for GOSE-Peds score >3 at 6 months after injury). In this prognostic study of children with severe TBI, the addition of MRI measures significantly improved outcome prediction over well-established and validated clinical predictors. Magnetic resonance imaging should be considered in children with severe TBI to inform prognosis and may also promote stratification of patients in future clinical trials.

Clinical pattern, neuroimaging findings and outcome of Acute Disseminated Encephalomyelitis in children: A retrospective study.

To determine the clinical spectrum, neuroimaging findings, and outcome of Acute Disseminated Encephalomyelitis (ADEM) in children. We conducted a descriptive cross sectional study of all children aged 6 months to 18 years, diagnosed with ADEM at Aga Khan University Hospital, Karachi from January 2018 till December 2022. This retrospective study enrolled 30 cases of ADEM, with a mean age of 6.43 ± 4.079, including 13 males and 17 females. The average hospital stay was 7.29 ± 4.379 days. The most common clinical features were fever, headache, and altered consciousness, while motor deficit was observed in 15 (53.5%) patients. Abnormal cerebrospinal fluid was found in 14 (46.6%) patients. Brain MRI identified bilateral and multifocal lesions in 22 (78.6%) patients, with brainstem lesions detected in 7 (25%) patients. Treatment included IV methylprednisolone (22; 73%), IVIG (9; 30%), or both (6; 20%). Clinical improvement was observed in 25 (89.3%) patients, with residual weakness present in eight (26%) patients at discharge. There was one reported death. Long-term complications included motor deficits, seizures, poor scholastic performance, and behavioral issues. The clinical presentation of ADEM is variable, but the most common symptoms are fever, headache, and altered consciousness. Despite generally favorable outcome, long-term monitoring revealed that patients may experience motor deficits, seizures, cognitive impairment, and academic difficulties.

Thalamic H3K27M altered diffuse midline gliomas: Clinicopathological and outcome analysis

IntroductionDiffuse midline glioma (DMG) is a relatively new entity which was introduced in the fourth edition of the WHO classification of CNS tumours in 2016 and later underwent revision in 2021. It is an infiltrative glioma arising from midline structures, viz., thalamus, spine, and brainstem. Current literature on DMG is based majorly on brainstem lesions, and DMGs arising elsewhere remain unexplored. In our study, we have discussed our experience with thalamic DMGs. MethodologyThis is a retrospective observational study of all patients with histopathologically proven DMG H3K27M altered, arising in the thalamus from 2018 to 2022. Clinical, neuroimaging, and pathology were re-reviewed, and prognostic factors for 3 months, 6 months, and overall survival (OS) were analyzed for all patients. ResultsThere were 89 patients- 64 adults and 25 pediatric patients with thalamic DMG. The median age at presentation was 24 years. Raised ICP followed by limb weakness were the most common presenting complaints. Stereotactic biopsy was performed in 64 (71.9 %) patients and surgical decompression in 25 (28.1 %) patients. CSF diversion was required in 53 (59.6 %) patients. Median survival was 8 months in adults and 7 months in pediatric (p-value: 0.51). Raised ICP and TP53 mutation were prognostic factors in pediatric population. Radiotherapy with or without chemotherapy improved survival (p-value- <0.01). ConclusionThalamic DMGs have a poor prognosis which is comparable to brainstem DMGs. Radiotherapy improves survival in these patients. However, the disease remains an enigma and further work delving into its molecular characterization should be encouraged.

Emotional Incontinence in a Patient with Neuromyelitis Optica Spectrum Disorder

The pathologic laughing is involuntary and associated with brain damage seen in a variety of disorders, which occurs as a result of lesions in various locations and is often seen associated with prefrontal or brainstem lesions. Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system characterized by severe attacks of optic neuritis and myelitis, and also develops brain lesions involving the bilateral diencephalic regions adjacent to the third ventricles, the brainstem and cerebellum surrounding the fourth ventricles, and the periventricular white matter adjacent to the lateral ventricles. Emotional incontinence refers to episodic laughing or crying, and occurs as a result of brain damage in various locations and is often seen associated with prefrontal or brainstem lesions. Emotional incontinence has been well described in multiple sclerosis, however the emotional incontinence in NMO has not been systemically documented. My report a characteristic patient with NMO showing the pathologic laughing as an initial manifestation, and the plasmapheresis therapy showed remarkable improvement in severity and occurrence of the pathologic laughing.

Emotional Incontinence in a Patient with Neuromyelitis Optica Spectrum Disorder

The pathologic laughing is involuntary and associated with brain damage seen in a variety of disorders, which occurs as a result of lesions in various locations and is often seen associated with prefrontal or brainstem lesions. Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system characterized by severe attacks of optic neuritis and myelitis, and also develops brain lesions involving the bilateral diencephalic regions adjacent to the third ventricles, the brainstem and cerebellum surrounding the fourth ventricles, and the periventricular white matter adjacent to the lateral ventricles. Emotional incontinence refers to episodic laughing or crying, and occurs as a result of brain damage in various locations and is often seen associated with prefrontal or brainstem lesions. Emotional incontinence has been well described in multiple sclerosis, however the emotional incontinence in NMO has not been systemically documented. My report a characteristic patient with NMO showing the pathologic laughing as an initial manifestation, and the plasmapheresis therapy showed remarkable improvement in severity and occurrence of the pathologic laughing.

DIPG-25. RELATIONSHIP BETWEEN MOLECULAR CLASSIFICATION, ORIGIN AND PROGNOSIS IN DIFFUSE MALIGNANT GLIOMA IN CHILDREN

Abstract INTRODUCTION Diffuse malignant gliomas that occurs in childhood is recognized as a biologically different disease from that in adults. Furthermore, with the recent development of molecular diagnostics, diffuse midline glioma (DMG), which occurs mainly in the thalamus and brainstem, frequently occurs in childhood and have poor prognosis. We report the relationship between imaging findings, origin, and prognosis of diffuse malignant glioma in children or young adult based on our case series. PATIENTS AND METHODS 43 cases of malignant glioma that occurred from childhood to young adult (below 30 years old) and were treated at our hospital since 2004 were registered in the analysis. Of the 42 cases, 24 cases were in brain stem, 11 cases in cerebral hemisphere, 6 cases in thalamus, and 1 case in cerebellar hemisphere. Histological diagnosis was possible in 31 cases, but without histological verification in 11 brain stem lesions. Histological diagnosis included 13 high-grade glioma (GBM, including NOS and G34R mutations), 11 DMG, and 7 anaplastic astrocytoma. RESULTS Of 13 cases of hemispheric high-grade gliomas, 2 cases had long-term survival (both cases received WT1 peptide vaccination), and 1 case survived for more than 5 years (total resection, MGMT methylation). Among the DMGs, 7 cases were found in brain stem (5 pons, 2 pontomedullary junction, 1 cerebellar peduncle, and 1 midbrain), 3 cases in the thalamus. Two cases of onset at the pontomedullary junction were found incidentally, and the symptoms gradually increased during follow-up, and multidisciplinary treatment was performed. Bilateral thalamus DMG with HIST1H3B mutation showed slowly growing and invasion. SUMMARY There were cases of pediatric hemisphere glioblastoma with long-term survival. In addition, the origin and imaging findings of DMG were various, and tumors that originate at the pontomedullary junction may be relatively favorable.

DIPG-53. AN EXCEPTIONALLY RARE CASE OF A DIFFUSE MIDLINE GLIOMA WITH CONCOMITANT H3.1 K27M AND G34R MUTATIONS IN THEHIST1H3C (H3C3) GENE

Abstract BACKGROUND Histone mutations (H3 K27M, H3 G34R/V) define subtypes of paediatric-type diffuse high-grade gliomas (HGG) (diffuse midline glioma (DMG), H3 K27-altered, diffuse hemispheric glioma (DHG), H3 G34-mutant). The WHO classification recognises exceptional cases where these mutations co-occur. We report one such case of a 2-year-old female presenting with neurological symptoms and lethargy. METHODS MRI imaging identified a brainstem lesion; a stereotactic needle biopsy was undertaken, followed by standard diagnostic neuropathology workflows including histology review, panel immunohistochemistry, DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNP v12.5 R package)) and WES/WGS. Patient-derived in vitro cell cultures were established allowing further characterisation using RNAseq and chromatin immunoprecipitation assays with sequencing (ChIP-seq). RESULTS Histology showed diffusely infiltrating pleomorphic astrocytes, multinucleated cells, and conspicuous mitotic activity; the diagnosis was DMG, H3 K27-altered (immunohistochemistry: H3K27me3 loss, H3K27M positivity). DNA methylation profiling classified the tumour as ‘DMG, H3 K27-altered’ (calibrated score=0.99). WES/WGS revealed concurrent H3.1 K27M and G34R mutations (clonal, in the same reads) of HIST1H3C (H3C3), somatic variants in FGF11 and PIK3CA, and a pathogenic germline NBN variant. The RNAseq profile of the primary tumour and cell cultures clustered with H3 K27M-mutant tumours. Unbiased in vitro drug screening showed no selective sensitivities. ChIP-seq (H3K27ac, H3K27me3, H3K36me3, RNApol2 marks) showed features in keeping with DMG H3 K27M-mutant tumours (H3K27ac loci including OLIG2, IRX1/2, PKDCC). The patient was treated with adjuvant radiotherapy and everolimus, but progressed and passed away 13 months post-diagnosis. CONCLUSION This case is an exceptionally rare, complex variant of histone-mutant paediatric HGG, and the first reported occurrence in HIST1H3C (H3C3). It illustrates that in cis, the H3.1 K27M mutation demonstrates a dominance over molecular and clinical profiles compared to G34R, and highlights the importance of broad molecular profiling to identify such examples for further study.

DEI-02. DIRECT PATIENT OUTREACH IN PEDIATRIC NEURO-ONCOLOGY TO IMPROVE ACCESS TO GENOMIC PROFILING – THE MAKE-AN-IMPACT PROGRAM

Abstract BACKGROUND Genomic profiling and precision medicine have revolutionized cancer care but are not accessible to all due to high costs, insurance issues, limited access to testing facilities or qualified personnel. We established a program providing free clinical genomic testing worldwide (Make-An-IMPACT) and report findings from the pediatric CNS tumor cohort. METHODS Following a referral from: (1) a physician, (2) a disease-specific advocacy group, or (3) submission of contact information through program website, patients were enrolled on an IRB-approved protocol (NCT01775072). CSF cell free DNA (cfDNA) and matched normal samples were analyzed using MSK-IMPACTTM, a New York State Department of Health authorized hybridization capture-based next-generation panel DNA sequencing clinical assay. If a driver mutation wasn’t reported, raw genomic data was reviewed. OncoKBTM was used to determine the level of evidence supporting the clinical actionability of genomic aberrations. RESULTS 24 patients (median age 7.5; range 0.1-20 years) were enrolled; 9 (38%) from 5 non-US countries and 6 (25%) from non-NYC US sites. African American and Hispanics constituted 8% and 13% of the cohort. Potentially actionable alterations were identified in 4/24 (17%) cases; 2/24 (8%) subsequently received matched therapy. In unbiopsied or non-diagnostic cases, a disease defining alteration was identified in 8/15 (53.3%). BRAF-KIAA1549 fusions were identified in 2/3 DLGNT patients and 1p loss in all 3. Both patients with BRAF fused DLGNT started targeted therapy with Trametinib, one of whom achieved a durable treatment response for 2.5 years. 3/8 patients with unbiopsied brainstem lesions had a H3.3K27M mutation, while 2 had non-H3.3K27M mutations detected (1 SMARCB1 deletion, 1 IDHR172G mutation) leading to treatment regimen changes. CONCLUSIONS This study captured a broad range of pediatric CNS malignancies with a diverse patient representation across geographic regions. CSF cfDNA profiling provided important diagnostic and therapeutic information reported in real time to patients and local physicians.

A histopathological analysis of extrapulmonary lesions in fatal coronavirus disease (COVID-19)

IntroductionThe coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents diverse clinical manifestations and multi-organ involvement. This study aimed to evaluate the extra-pulmonary histopathological patterns underpinning COVID-19-induced lesions in cardiac, hepatic, renal, brainstem, and splenic tissues. Materials and methodsThe research involved conventional forensic autopsies conducted between April 2020 and April 2021 on individuals with confirmed SARS-CoV-2 infection in Cluj-Napoca, Romania. Tissues were processed and stained for histological examination. Differences in patients with and without diffuse alveolar damage (DAD) were evaluated. ResultsIn our study of 79 COVID-19 autopsies conducted on unvaccinated patients besides lung involvement, the patients had histological changes in at least two out of five (brain, heart, liver, kidney, and spleen) organs. Notable findings include hepatitis observed in 46.8 % of cases, 21.5 % with lobular hepatitis, and 41.8 % with liver steatosis. Additionally, 69.6 % exhibited acute tubular necrosis, and 55.7 % had varying degrees of splenic lymphocyte depletion. Almost 41 % of cases had pericardial effusion, 36.7 % myocarditis, 24.1 % myocardial infarction, and 12.7 % of cases had encephalitis. Acute tubular necrosis (78.6 %) was the most frequent histopathological finding observed in patients with DAD. Myocarditis was described in 45.9 % of the patients without DAD. DiscussionThe autopsy findings in our cohort of COVID-19 victims align with international scientific literature. Distinguishing viral-induced myocarditis, encephalitis, hepatitis, or systemic inflammatory syndrome remains challenging. ConclusionPost-mortem analysis identified lesions associated with SARS-CoV-2 in multiple organs, highlighting the systemic nature of the virus and emphasizing the need for continued research into organ-specific damage and long-term sequelae of COVID-19.

Arteriovenous malformations in the cerebellopontine angle: assessment of the "backdoor resection" technique and microsurgical results in 38 patients.

Posterior fossa arteriovenous malformations (AVMs) represent 7% to 15% of all intracranial AVMs and are associated with an increased risk of hemorrhage, morbidity, and mortality compared with supratentorial AVMs, thus prompting urgent and definitive treatment. Cerebellopontine angle (CPA) AVMs are a unique group of posterior fossa AVMs incorporating characteristics of brainstem and cerebellar lesions, which are particularly amenable to microsurgical resection. This study reports the clinical, radiological, operative, and outcome features of patients with CPA AVMs in a large cohort. The authors conducted a single-surgeon, 2-institution retrospective cohort study of all consecutive patients with CPA AVMs treated with microsurgical resection during a 25-year period. CPA AVMs represented 22% (38 of 176) of all infratentorial AVMs resected by the senior author. Overall, 38 patients (22 [58%] male and 16 [42%] female) met the study inclusion criteria and were analyzed. Most patients presented with hemorrhage (n = 29, 76%). The median age at surgery was 56 (range 6-82) years. Subtypes included 22 (58%) petrosal cerebellar AVMs, 11 (29%) lateral pontine AVMs, and 5 (13%) AVMs involving both the brainstem and cerebellum. Most AVM niduses were small (< 3 cm; n = 35, 92%) and compact (n = 31, 82%). Fourteen (37%) patients harbored flow-related aneurysms. Twenty (53%) patients underwent preoperative embolization. Complete angiographic obliteration was achieved with microsurgery in 35 (92%) patients. Five (13%) patients with poor neurological conditions at presentation died before hospital discharge. Of the 7 (18%) patients with new postoperative neurological deficits, 5 had transient deficits. The median (interquartile range) follow-up was 1.7 (0.5-3.2) years; 32 (84%) patients were alive at last follow-up, and 30 (79%) had achieved a favorable neurological outcome (modified Rankin Scale [mRS] score 0-2). The only independent predictor of unfavorable postoperative outcome (mRS score 3-6) was the preoperative mRS score (p = 0.002). CPA AVMs are unique posterior fossa lesions, including petrosal cerebellar and lateral pontine AVMs. The "backdoor resection" technique provides a safe and efficient strategy with high obliteration rates and a low risk of treatment-related morbidity. Microsurgical resection should be considered the frontline treatment for most CPA AVMs, except for those with a significant diffuse brainstem component.

Vestibular Rehabilitation of Patient with Hypertrophic Olivary Degeneration: A Case Report.

Background Hypertrophic olivary degeneration (HOD) is a rare disorder that typically develops in the weeks to months following a structural brainstem or cerebellar lesion in the Guillain-Mollaret triangle (GMT). Clinically, patients with HOD present with palatal myoclonus and nystagmus, which are difficult to treat and rarely resolve. Purpose The purpose of this case is to present the results of vestibular and balance assessments of a patient with bilateral HOD before and after vestibular rehabilitation. Methods This case report describes a 43-year-old trucker who presented with dizziness, blurred vision, and balance problems for more than 10 months, accompanied by new-onset tremors and ataxia for more than 6 months. The patient's characteristic clinical manifestations were palatal myoclonus and nystagmus. Magnetic resonance imaging (MRI) revealed bilateral HOD after an acute pontine hemorrhage. Comprehensive vestibular and balance assessments were performed. Results Vestibular and balance assessments demonstrated nystagmus, impaired vestibulo-ocular reflex (VOR), optokinetic reflex (OKR), and balance function. Following 4 months of vestibular rehabilitation, the patient's eye symptoms and balance function were improved. Conclusions The case presented here highlights the rare clinical manifestations of HOD after pontine hemorrhage. Vestibular rehabilitation training may be beneficial for the recovery of patients with HOD.