Lack of mitochondrial complex I assembly factor NDUFAF2 results in a distinctive infantile-onset brainstem neurodegenerative disease with early lethality.

BACKGROUND: Congenital disorders of the mitochondrial respiratory chain are a heterogeneous group of inborn errors of metabolism. Among them, NADH:ubiquinone oxidoreductase (complex I, CI) deficiency is the most common. Biallelic pathogenic variants in NDUFAF2, encoding the nuclear assembly CI factor NDUFAF2, were initially reported to cause progressive encephalopathy beginning in infancy. Since the initial report in 2005, less than a dozen patients with NDUFAF2-related disease have been reported. METHODS: Clinical, biochemical, and neuroradiological features of four new patients residing in Northern Israel were collected during 2016-2022 at Emek Medical Center. Enzymatic activities of the five respiratory-chain complexes were determined in isolated fibroblast mitochondria by spectrophotometric methods. Western blot analyses were conducted with anti-human NDUFAF2 antibody; antibody against the mitochondrial marker VDAC1 was used as a loading control. Genetic studies were performed by chromosome microarray analysis using Affymetrix CytoScan 750 K arrays. RESULTS: All four patients presented with infantile-onset growth retardation, ophthalmological impairments with nystagmus, strabismus (starting between 5 and 9 months), and further progressed to life-threatening episodes of apnea usually triggered by trivial febrile illnesses (between 10 and 18 months) with gradual loss of acquired developmental milestones (3 of 4 patients). Serial magnetic-resonance imaging studies in two of the four patients showed a progressive pattern of abnormal T2-weighted hyperintense signals involving primarily the brainstem, the upper cervical cord, and later, the basal ganglia and thalami. Magnetic-resonance spectroscopy in one patient showed an increased lactate peak. Disease progression was marked by ventilatory dependency and early lethality. 3 of the 4 patients tested, harbored a homozygous 142-kb partial interstitial deletion that omits exons 2-4 of NDUFAF2. Mitochondrial CI activity was significantly decreased in the only patient tested. Western blot analysis disclosed the absence of NDUFAF2 protein compared to normal controls. In addition, we reviewed all 10 previously reported NDUFAF2-deficient cases to better characterize the disease. CONCLUSIONS: Biallelic loss-of-function mutations in NDUFAF2 result in a distinctive phenotype in the spectrum of Leigh syndrome with clinical and neuroradiological features that are primarily attributed to progressive brainstem damage.

Inflammatory lesions of the brainstem: Keys for the diagnosis by MRI.

OBJECTIVE: To describe the magnetic resonance imaging (MRI) findings for the most common inflammatory and immune-mediated diseases that involve the brainstem. CONCLUSION: Inflammatory lesions involving the brainstem are associated with a wide range of autoimmune, infectious, and paraneoplastic syndromes, making the differential diagnosis complex. Being familiar with these entities, their clinical characteristics, and their manifestations on MRI, especially the number of lesions, their shape and extension, and their appearance in different sequences, is useful for orienting the radiological diagnosis.

Multiomic Analysis of Neuroinflammation and Occult Infection in Sudden Infant Death Syndrome.

Importance: Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)-the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed. Objective: To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection. Design, Setting, and Participants: In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type-specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes. Exposures: There were no interventions or exposures. Main Outcomes and Measures: CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue. Results: A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5 (11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5 (17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels. Conclusions and Relevance: Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.

Postoperative disappearance of leptomeningeal enhancement around the brainstem in glioblastoma.

PURPOSE: Leptomeningeal enhancement (LME) suggests leptomeningeal dissemination (LMD) of tumor cells, which is a complication of end-stage glioblastoma, and is associated with a poor prognosis. However, magnetic resonance imaging (MRI) occasionally indicates the disappearance of peri-brainstem LME after surgical resection of glioblastoma. Since preoperative LMD may affect treatment indications, we aimed to analyze the clinical significance of preoperative LME of the brainstem in glioblastoma. METHODS: We retrospectively collected clinical and radiological data from consecutive patients with glioblastoma and preoperative LME of the brainstem, who were treated at our hospital between 2017 and 2020. RESULTS: Among 112 patients with glioblastoma, nine (8%) showed preoperative LME of the brainstem. In comparison with tumors without LME, tumor size was significantly associated with the preoperative LME of the brainstem (p = 0.016). In addition, there was a trend toward significance for a relationship between deep tumor location and preoperative LME of the brainstem (p = 0.058). Notably, among six patients who underwent surgical resection for glioblastoma with LME of the brainstem, four showed significant radiological disappearance of the LME on postoperative MRI. This suggests that the LME did not result from LMD in these cases. Moreover, these four patients lived longer than would be expected from the presence of LMD. However, this LME disappearance was not observed after biopsy or chemoradiotherapy. CONCLUSIONS: These findings suggest that preoperative LME does not necessarily indicate the presence of untreatable LMD; moreover, LME may disappear after surgical tumor resection. Thus, transient preoperative LME could be attributed to other mechanisms, including impaired venous flow due to intratumoral arteriovenous shunts, which can be resolved by reducing the tumor burden.

Progressive white matter degeneration in patients with spinocerebellar ataxia type 2.

PURPOSE: Spinocerebellar ataxia type 2 (SCA2) is a progressive neurodegenerative disorder characterized by cerebellar atrophy. However, studies to elucidate the longitudinal progression of the neuropathology are limited. We sought to identify brain macrostructural and microstructural alterations in patients with SCA2 using fixel-based analysis (FBA) to better understand its distribution patterns and progression. METHODS: We enrolled 9 patients with SCA2 and 16 age- and gender-matched controls. Longitudinal clinical and imaging data were collected at baseline, and 3.5 years later. Fiber density (FD), fiber-bundle cross-section (FC), and a combination of FD and FC (FDC) were calculated. The paired t-test was used to examine longitudinal differences. The associations between fixel-based metrics and clinical variables were explored in SCA2 patients. RESULTS: At baseline, patients with SCA2 displayed multiple white matter tracts with significantly decreased FD, FC, and FDC in the corticospinal tract, cerebellar peduncles, brainstem, corpus callosum, thalamus, striatum, and prefrontal cortex, compared to controls. Over time, many of these macrostructural and microstructural alterations progressed, manifesting lower FD, FC, and FDC in corticospinal tract, middle cerebellar peduncle, brainstem, striatum, fornix, and cingulum. No significant brain white matter alterations were found in the healthy controls over time. There was no association between the FBA-derived metrics and clinical variables in SCA2. CONCLUSION: This study provides evidence of brain macrostructural and microstructural alterations and of progression over time in SCA2. The FBA-derived metrics may serve as potential biomarkers of SCA2 progression.

TAF15 amyloid filaments in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

Stereotactic Radiosurgery for Vestibular Schwannoma With Radiographic Brainstem Compression.

OBJECTIVE: The safety of single-treatment stereotactic radiosurgery (SRS) for vestibular schwannoma (VS) with radiographic evidence of brainstem compression but without motor deficit is controversial. Data on linear accelerator (linac)-based SRS in this setting are scarce. We address this with an outcomes report from an unselected series of patients with VS with radiographic brainstem compression treated with linac SRS. METHODS: We included 139 patients with unilateral VS (any size) with radiographic brainstem compression (all without serious brainstem neurological deficits). The SRS prescription dose was 12.5 Gy (single fraction) using 6MV linac-produced photon beams, delivered with a multiple arc technique. Inclusion criteria required at least 1 year of radiographic follow-up with magnetic resonance imaging. The primary endpoint was freedom from serious brainstem toxicity (≥grade 3 Common Terminology Criteria for Adverse Events v5); the secondary was freedom from enlargement (tumor progression or any requiring intervention). We assessed serious cranial nerve complications, excluding hearing loss, defined as Common Terminology Criteria for Adverse Events v5 grade 3 toxicity. RESULTS: Median magnetic resonance imaging follow-up time was 5 years, and median tumor size was 2.5 cm in greatest axial dimension and 5 ml in volume. The median brainstem D0.03 ml=12.6 Gy and median brainstem V10 Gy=0.4 ml. At 5 years, the actuarial freedom from serious brainstem toxicity was 100%, and freedom from tumor enlargement (requiring surgery and/or due to progression) was 90%. Severe facial nerve damage in patients without tumor enlargement was 0.9%. CONCLUSION: Linac-based SRS, as delivered in our series for VS with radiographic brainstem compression, is safe and effective.

Safety and efficacy of the endoscopic transsphenoidal transclival approach performed using direct cortical stimulation for pontine cavernous malformations.

OBJECTIVE: Surgical treatment of brainstem cavernous malformations (CMs) is challenging. Surgery using the endoscopic transsphenoidal transclival approach (eTSTCA) is reported as a useful alternative for ventral brainstem CMs. However, CMs located in the ventral midline of the brainstem are rare, and only a small number of case reports on these CMs treated with the eTSTCA exist. The efficacy and safety of the eTSTCA have not yet been fully examined. METHODS: A retrospective analysis was performed for 5 consecutive patients who underwent surgery via the eTSTCA for treating ventral pontine CMs. RESULTS: The average maximum CM diameter was 26.0 mm (18-38 mm). All patients underwent MR-diffusion tensor imaging, which confirmed that the corticospinal tract (CST) deviated posteriorly or laterally to the CM. Direct brainstem cortical stimulation was performed to localize the CST before making the cortical incision. After the excision of the CM, the cavity was filled with artificial CSF to make an aqueous surgical field (wet-field technique) for observing the tumor cavity and confirming complete hemostasis and resection. Total removal was achieved in all patients. The preoperative modified Rankin Scale score was 3 in 3 patients and 4 in 2 patients, whereas it was 1 in 2 patients and 0 in 3 patients 3 months after surgery. Postoperative CSF leakage was observed in 1 patient, and transient abducens nerve palsy was observed in 1 patient. No other intra- or postoperative complications were observed. CONCLUSIONS: MR-diffusion tensor imaging and direct brainstem cortical stimulation were useful to ascertain the proximity of the CST to the CM. The endoscope provides a clear view even underwater, and it was safe and effective to observe the entire CM cavity and confirm complete hemostasis without additional retraction of the brainstem parenchyma, including the CST. The eTSTCA provides a direct access point to the lesion and may be a safer alternative treatment for patients whose CST deviates laterally or posteriorly to the CM.

Coexistence of longitudinally extensive transverse myelitis and diffuse midline glioma in the brainstem in an adolescent boy with acute flaccid paralysis.

We present the case of a previously healthy 13-year-old boy who was admitted to the emergency department with acute flaccid paralysis. Magnetic resonance imaging revealed radiological evidence of longitudinally extensive transverse myelitis. Additionally, homogeneous T2 signal increase was observed in the pons and medulla oblongata, initially indicating brainstem encephalitis. Subsequent evaluations confirmed a coexistence of diffuse midline glioma (DMG) in the brain stem alongside acute transverse myelitis (ATM). Children with ATM generally have a more favorable prognosis than adults. However, despite the implementation of advanced treatment methods, the patient's quadriplegia did not improve and resulted in spinal cord sequela atrophy. DMG exhibits an aggressive growth pattern and lacks a known curative treatment. This case represents an exceedingly rare synchronous occurrence of aggressive conditions, underscoring the importance of raising awareness among physicians. Furthermore, we aim to discuss the radiologic differential diagnosis, as this is the first documented instance in the literature.

Volumetric alteration of brainstem in female migraineurs with and without aura.

BACKGROUND AND AIM: Brainstem descending modulatory circuits have been postulated to be involved in migraine. Differences in brainstem volume between migraineurs and healthy controls have been demonstrated in previous research, nevertheless, the effect of migraine aura on brainstem volume is still uncertain. The aim of this study was to investigate the brainstem volume in migraineurs and examine the effect of migraine aura on brainstem volume. METHODS: Our study included 90 female migraine patients without white matter lesions. (29 migraine patients with aura (MwA) and 61 migraine patients without aura (MwoA) and 32 age-matched female healthy controls (HC). Using the FreeSurfer image analysis suite, the volumes of the entire brainstem and its subfields (medulla, pons, and midbrain) were measured and compared between migraine subgroups (MwA vs. MwoA) and the healthy control group. The possible effects of migraine characteristics (i.e., disease duration and migraine attack frequency) on brainstem volume were also investigated. RESULTS: Migraineurs had greater medulla volume (MwoA 3552 ± 459 mm3, MwA 3424 ± 448 mm3) than healthy controls (3236 ± 411 mm3). Statistically, MwA vs. HC p = 0.040, MwoA vs. HC p = 0.002, MwA vs. MwoA p = 0.555. A significant positive correlation was found between disease duration and the volume of medulla in the whole migraine group (r = 0.334, p = 0.001). Neither the whole brainstem nor its subfields were significantly different in volume between migraine subgroups. CONCLUSION: Brainstem volume changes in migraine are mainly localized to the medulla and not specific to the presence of aura.

Surgical Management of Adult Brainstem Gliomas: A Systematic Review and Meta-Analysis.

The present review aims to investigate the survival and functional outcomes in adult high-grade brainstem gliomas (BGSs) by comparing data from resective surgery and biopsy. MEDLINE, EMBASE and Cochrane Library were screened to conduct a systematic review of the literature, according to the PRISMA statement. Analysis was limited to articles including patients older than 18 years of age and those published from 1990 to September 2022. Case reports, review articles, meta-analyses, abstracts, reports of aggregated data, and reports on multimodal therapy where surgery was not the primary treatment were excluded. The ROBINS-I tool was applied to evaluate the risk of bias. Six studies were ultimately considered for the meta-analysis. The resective group was composed of 213 subjects and the bioptic group comprised 125. The analysis demonstrated a survival benefit in those patients in which an extensive resection was possible (STR HR 0.59 (95% CI 0.42, 0.82)) (GTR HR 0.63 (95% CI 0.43, 0.92)). Although surgical resection is associated with increased survival, the significantly higher complication rate makes it difficult to recommend surgery instead of biopsy for BSGs. Future investigations combining volumetric data and molecular profiles could add important data to better define the proper indication between resection and biopsy.

Delayed onset Bickerstaff brainstem encephalitis overlapping Miller-Fisher Syndrome during SARS-CoV-2 infection.

Bickerstaff brainstem encephalitis (BBE) is a neuroimmunologic disease characterized by the acute onset of external ophthalmoplegia, ataxia, and consciousness disturbance, mostly subsequent to an infection. BBE is considered to be a variant of Miller-Fisher syndrome (MFS), which also exhibits external ophthalmoplegia and ataxia but not presenting consciousness alterations. Therefore, these two medical conditions are included in the clinical spectrum of the "Fisher-Bickerstaff syndrome" ( Shahrizaila and Yuki in J Neurol Neurosurg Psychiatry 84(5):576-583) [1]. With regard to the etiopathogenesis, increasing evidence worldwide suggests that SARS-CoV-2 infection-enhanced immune response is involved in a wide range of neurological complications such as Guillain-Barré syndrome (GBS), MFS, acute necrotizing encephalitis (ANE), myelitis, acute disseminated encephalomyelitis (ADEM), and, although very rarely, BBE either (Hosseini et al. in Rev Neurosci 32:671-691) [2]. We report a case of a patient affected by delayed onset BBE overlapping MFS during a mild SARS-CoV-2 infection. To the best of our knowledge, similar cases have never been reported.

X-linked cerebral adrenoleukodystrophy.

A man in his 30s presented with a 6-month history of progressive left face, arm and leg weakness. Medical history included epilepsy and vitamin B12 deficiency. Three maternal second degree relatives died before the age of 7 from various neurological disorders. Examination revealed a mild left facial droop and weakness of the left shoulder, hip and ankle. Reflexes were symmetrical and tone was normal. Differential diagnosis included glioma, subacute infarction, lymphoma and demyelination. MRI brain showed an extensive right sided subcortical white matter lesion, with extension into the brainstem. The patient's weakness progressed over 3 months. Brain biopsy showed evidence of demyelination and gliosis. A pathological diagnosis of tumefactive multiple sclerosis was made, but also rare metabolic disorders such as X-linked adrenoleukodystrophy (X-ALD) were proposed. Serum very long-chain fatty acids were significantly elevated. Genetic testing showed a mutation in the ABCD1 gene, confirming a diagnosis of X-ALD.

Bickerstaff's brainstem encephalitis: a rare case of neurologic complication in Ulcerative Colitis.

Bickerstaff's brainstem encephalitis is a rare autoimmune disorder that presents with ataxia, ophthalmoplegia, disturbance of consciousness and quadriplegia. A 45-year-old man with a history of ulcerative colitis (UC) taking mesalazine (5-aminosalicylic acid) visited the emergency room presenting with ataxia, ophthalmoplegia and a progressively worsening cognitive impairment. Cerebrospinal fluid analysis showed mild elevation in protein and white blood cell count and increased intracranial pressure. Anti-GQ1b autoantibodies were found positive in the patient's serum and contrast-enhanced brain magnetic resonance imaging showed diffuse leptomeningeal enhancement and pontine lesions. Based on these findings and the patient's clinical course and history, he was diagnosed with Bickerstaff's brainstem encephalitis. Mesalazine was discontinued and high-dose steroid pulse therapy was started, followed by intravenous immunoglobulin, which resulted in gradual improvement of the neurologic symptoms. When an ulcerative colitis patient presents with progressive cognitive impairment, quadriplegia and disturbance of consciousness and gait, Bickerstaff brainstem encephalitis should be considered in the differential diagnosis and prompt immunotherapy may lead to favorable prognosis.

Intrinsic epidermoid cyst of the brainstem in children-review and case report.

PURPOSE: The study aimed to summarize all published cases of intrinsic brainstem epidermoid cysts in a timeline to highlight the specific characteristics and individualize the disease, in addition to discussing the best treatment used. METHODS: The scientific literature on pediatric cases of intrinsic epidermoid cysts of the brainstem was analyzed. We present the case of a 1.5-year-old male with incidental presentation, who was treated with gross total resection. We summarize all previously published cases to individualize the disease. RESULTS: We identified 21 patients, including 10 boys and 11 girls, with a mean age of 4.85 (1-15) years at the time of surgery. The most frequent symptoms were cranial nerve palsy (71.4%), pyramidal tract deficit (57.14%), and headache (52.38%). Among the affected cranial nerves, VII was the most frequently reported in 10 patients. CONCLUSION: Brainstem epidermoid cysts are extremely rare pathologies with relevant age involvement in young children. The treatment objective should be the maximum resection of the lesion through a careful approach and with the appropriate tools for the functional preservation of the patient.

The Effect of Posterior Fossa Decompression Surgery on Brainstem and Cervical Spinal Cord Dimensions in Adults with Chiari Malformation Type 1.

OBJECTIVE: Posterior fossa decompression (PFD) surgery creates more space at the skull base, reduces the resistance to the cerebrospinal fluid motion, and alters craniocervical biomechanics. In this paper, we retrospectively examined the changes in neural tissue dimensions following PFD surgery on Chiari malformation type 1 adults. METHODS: Measurements were performed on T2-weighted brain magnetic resonance images acquired before and 4 months after surgery. Measurements were conducted for neural tissue volume and spinal cord/brainstem width at 4 different locations; 2 width measurements were made on the brainstem and 2 on the spinal cord in the midsagittal plane. Cerebellar tonsillar position (CTP) was also measured before and after surgery. RESULTS: Twenty-five adult patients, with a mean age of 38.9 ± 8.8 years, were included in the study. The cervical cord volume increased by an average of 2.3 ± 3.3% (P = 0.002). The width at the pontomedullary junction increased by 2.2 ± 3.5% (P < 0.01), while the width 10 mm caudal to this junction increased by 4.2 ± 3.9% (P < 0.0001). The spinal cord width at the base of second cervical vertebra and third cervical vertebra did not significantly change after surgery. The CTP decreased by 60 ± 37% (P < 0.0001) after surgery, but no correlation was found between CTP change and dimension change. CONCLUSIONS: The brainstem width and cervical cord volume showed a modest increase after PFD surgery, although standard deviations were large. A reduction in compression after PFD surgery may allow for an increase in neural tissue dimension. However, clinical relevance is unclear and should be assessed in future studies with high-resolution imaging.

Amide proton transfer-weighted imaging of pediatric brainstem glioma and its predicted value for H3 K27 alteration.

BACKGROUND: Non-invasive determination of H3 K27 alteration of pediatric brainstem glioma (pedBSG) remains a clinical challenge. PURPOSE: To predict H3 K27-altered pedBSG using amide proton transfer-weighted (APTw) imaging. MATERIAL AND METHODS: This retrospective study included patients with pedBSG who underwent APTw imaging and had the H3 K27 alteration status determined by immunohistochemical staining. The presence or absence of foci of markedly increased APTw signal in the lesion was visually assessed. Quantitative APTw histogram parameters within the entire solid portion of tumors were extracted and compared between H3 K27-altered and wild-type groups using Student's t-test. The ability of APTw for differential diagnosis was evaluated using logistic regression. RESULTS: Sixty pedBSG patients included 48 patients with H3 K27-altered tumor (aged 2-48 years) and 12 patients with wild-type tumor (aged 3-53 years). Visual assessment showed that the foci of markedly increased APTw signal intensity were more common in the H3 K27-altered group than in wild-type group (60% vs. 16%, P = 0.007). Histogram parameters of APTw signal intensity in the H3 K27-altered group were significantly higher than those in the wild-type group (median, 2.74% vs. 2.22%, P = 0.02). The maximum (area under the receiver operating characteristic curve [AUC] = 0.72, P = 0.01) showed the highest diagnostic performance among histogram analysis. A combination of age, median and maximum APTw signal intensity could predict H3 K27 alteration with a sensitivity of 81%, specificity of 75% and AUC of 0.80. CONCLUSION: APTw imaging may serve as an imaging biomarker for H3 K27 alteration of pedBSGs.

Anti-amphiphysin antibody-associated paraneoplastic brainstem encephalitis with pruritus and dysphagia as the first symptoms: A case report.

RATIONALE: Anti-amphiphysin antibodies are uncommonly detected in paraneoplastic neurologic syndromes (PNS), especially in patients with small cell lung cancer. Here, we report the first case of anti-amphiphysin antibody-associated PNS with pruritus and dysphagia as the first complaints. PATIENT CONCERNS: The patient was a 58-year-old man who sought medical advice with a chief complaint of dysphagia and the lung occupancy. We found that he had developed progressive pruritus several months ago. DIAGNOSES: In the outer basal segment of the right lung lower lobe, PET-CT revealed small occupancies with hypermetabolism. Later, the pathology showed small cell lung cancer. And anti-amphiphysin antibodies were detected in serum. Above all, the patient's symptoms improved significantly after antitumor treatment. Even neither of the 2 cranial enhancement MRIs showed any meaningful imaging signs, the above evidence could confirm the diagnosis of PNS. INTERVENTIONS: The chemotherapy regimen was etoposide 0.1g d1-3+cisplatin 40 mg d1-3 (q3w). Paroxetine 20 mg/day was given to relieve the itching. OUTCOMES: After the treatment, the Watian water swallowing test dropped from grade 5 to grade 1, the intense itching also became tolerable. LESSONS: Clinicians should consider diagnoses other than anxiety states or esophageal cancer in a patient with pruritus and dysphagia, such as PNS.

Brainstem and subcortical regions volume loss in patients with degenerative cervical myelopathy and its association with spinal cord compression severity.

BACKGROUND: In recent years, structural and functional reorganization of the brain and changes in brainstem structural connectivity have been shown in patients with degenerative cervical myelopathy (DCM). We hypothesized that volume loss in the basal ganglia, thalami, and brainstem structures exists and is associated with spinal cord compression severity in patients with DCM. METHODS: Forty-seven patients with DCM and 25 patients with cervical radiculopathy were evaluated using cervical spinal cord and brain magnetic resonance imaging (MRI). Brainstem structures, basal ganglia, and thalami volumes were evaluated with FreeSurfer and compared between groups with correction for individual intracranial volume, as well as patient age and sex. Additionally, spinal cord MRI data were analysed with the Spinal Cord Toolbox, and cross-sectional area (CSA) and fractional anisotropy (FA) values were calculated. Correlations between MR-morphometry data and spinal cord structural changes, as well as disease duration, were also evaluated in patients with DCM. RESULTS: A statistically significant reduction in the volume of the whole brainstem was revealed in the DCM group compared to the radiculopathy group (p < 0.01, FDR-corrected). Additionally, reductions in medulla oblongata, pons and midbrain volumes were found in patients with DCM (p < 0.01, p < 0.01 and p < 0.05, respectively, FDR-corrected). Additionally, a trend in the loss of volume of the left putamen was found (p = 0.087, FDR-corrected). Furthermore, medulla oblongata volume was correlated with spinal cord compression severity (R = 0.54, adjusted p < 0.001) and white matter damage (R = 0.46, adjusted p < 0.05) in patients with DCM. Negative correlations between the duration of the disease and the severity of spinal cord compression (R = -0.42, adjusted p < 0.05) and white matter damage (R = -0.49, adjusted p < 0.05) were also revealed, as well as a trend toward a negative association between the duration of the disease and the volume of the medulla oblongata (R = -0.35; adjusted p < 0.1). CONCLUSIONS: We revealed a reduction in the volume of brainstem structures in patients with DCM compared to patients with radiculopathy. Moreover, we found that these changes are associated with cord compression severity.

Peripheral macrophages drive CNS disease in the Ndufs4(-/-) model of Leigh syndrome.

Subacute necrotizing encephalopathy, or Leigh syndrome (LS), is the most common pediatric presentation of genetic mitochondrial disease. LS is a multi-system disorder with severe neurologic, metabolic, and musculoskeletal symptoms. The presence of progressive, symmetric, and necrotizing lesions in the brainstem are a defining feature of the disease, and the major cause of morbidity and mortality, but the mechanisms underlying their pathogenesis have been elusive. Recently, we demonstrated that high-dose pexidartinib, a CSF1R inhibitor, prevents LS CNS lesions and systemic disease in the Ndufs4(-/-) mouse model of LS. While the dose-response in this study implicated peripheral immune cells, the immune populations involved have not yet been elucidated. Here, we used a targeted genetic tool, deletion of the colony-stimulating Factor 1 receptor (CSF1R) macrophage super-enhancer FIRE (Csf1rΔFIRE), to specifically deplete microglia and define the role of microglia in the pathogenesis of LS. Homozygosity for the Csf1rΔFIRE allele ablates microglia in both control and Ndufs4(-/-) animals, but onset of CNS lesions and sequalae in the Ndufs4(-/-), including mortality, are only marginally impacted by microglia depletion. The overall development of necrotizing CNS lesions is not altered, though microglia remain absent. Finally, histologic analysis of brainstem lesions provides direct evidence of a causal role for peripheral macrophages in the characteristic CNS lesions. These data demonstrate that peripheral macrophages play a key role in the pathogenesis of disease in the Ndufs4(-/-) model.