The p75 neurotrophin receptor attenuates secondary thalamic damage after cortical infarction by promoting angiogenesis.

BACKGROUND: Angiogenesis is crucial in neuroprotection of secondary thalamic injury after cortical infarction. The p75 neurotrophin receptor (p75NTR) plays a key role in activating angiogenesis. However, the effects of p75NTR on angiogenesis in the thalamus after cortical infarction are largely unknown. Herein we investigate whether p75NTR facilitates angiogenesis to attenuate secondary thalamic damage via activating hypoxia-inducible factor 1α (HIF-1α)/vascular endothelial growth factor (VEGF) pathway mediated by Von Hippel-Lindau (VHL) after distal middle cerebral artery occlusion (dMCAO). METHODS: The male rat model of dMCAO was established. The effects of p75NTR on the angiogenesis was evaluated using RNA-sequencing, immunohistochemistry, western blot, quantitative real-time polymerase chain reaction, magnetic resonance imaging, behavior tests, viral and pharmacological interventions. RESULTS: We found that the p75NTR and vessel density were decreased in ipsilateral thalamus after dMCAO. The p75NTR-VHL interaction was reduced, which promoted the ubiquitination degradation of HIF-1α and reduced VEGF expression after dMCAO. Notably, p75NTR overexpression restrained the ubiquitination degradation of HIF-1α by inhibiting VHL-HIF-1α interaction, further promoted angiogenesis, increased cerebral blood flow of ipsilateral thalamus and improved neurological function after dMCAO. CONCLUSION: For the first time, we highlighted that the enhancement of p75NTR-VHL interaction promoted angiogenesis in attenuating secondary thalamic damage after dMCAO.

Thalamic H3K27M altered diffuse midline gliomas: Clinicopathological and outcome analysis.

INTRODUCTION: Diffuse 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. METHODOLOGY: This 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. RESULTS: There 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). CONCLUSION: Thalamic 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.

Autistic-like behaviour and changes in thalamic cell numbers a rat model of valproic acid-induced autism; A behavioural and stereological study.

The contribution of the thalamus to the development and behavioural changes in autism spectrum disorders (ASD), a neurodevelopmental syndrome, remains unclear. The aim of this study was to determine the changes in thalamic volume and cell number in the valproic acid (VPA)-induced ASD model using stereological methods and to clarify the relationship between thalamus and ASD-like behaviour. Ten pregnant rats were administered a single dose (600 mg/kg) of VPA intraperitoneally on G12.5 (VPA group), while five pregnant rats were injected with 5 ml saline (control group). Behavioural tests were performed to determine appropriate subjects and ASD-like behaviours. At P55, the brains of the subjects were removed. The sagittal sections were stained with cresyl violet and toluidine blue. The thalamic and hemispheric volumes with their ratios, the total number of thalamic cells, neurons and non-neuronal cells were calculated using stereological methods. Data were compared using a t-test and a Pearson correlation analysis was performed to examine the relationship between behaviour and stereological outcomes. VPA-treated rats had lower sociability and sociability indexes. There was no difference in social novelty preference and anxiety. The VPA group had larger hemispheric volume, lower thalamic volume, and fewer neurons. The highest percentage decrease was in non-neuronal cells. There was a moderate positive correlation between the number of non-neuronal cells and sociability, thalamic volume and the number of neurons as well as the time spent in the light box. The correlation between behaviour and stereological data suggests that the thalamus is associated with ASD-like behaviour.

Concurrent brain structural and functional alterations in the thalamus of adult survivors of childhood brain tumors: a multimodal MRI study.

Adult survivors of childhood brain tumors often present with cognitive deficits that affect their quality of life. Studying brain structure and function in brain tumor survivors can help understand the underlying mechanisms of their cognitive deficits to improve long-term prognosis of these patients. This study analyzed voxel-based morphometry (VBM) derived from T1-weighted MRI and the amplitude of low-frequency fluctuation (ALFF) from resting-state functional magnetic resonance imaging (rs-fMRI) to examine the structural and functional alterations in 35 brain tumor survivors using 35 matching healthy individuals as controls. Compared with healthy controls, brain tumor survivors had decreased gray matter volumes (GMV) in the thalamus and increased GMV in the superior frontal gyrus. Functionally, brain tumor survivors had lower ALFF values in the inferior temporal gyrus and medial prefrontal area and higher ALFF values in the thalamus. Importantly, we found concurrent but negatively correlated structural and functional alterations in the thalamus based on observed significant differences in GMV and ALFF values. These findings on concurrent brain structural and functional alterations provide new insights towards a better understanding of the cognitive deficits in brain tumor survivors.

Longitudinal volumetric analysis of gray matter atrophy in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross-sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment.

Bilateral thalamic high-grade astrocytomas in an early-adolescent child: A case report.

An early-adolescent girl presented with incoordination, headache, vomiting and dysphonia. MRI brain demonstrated diffuse increased T2 and FLAIR signal in bilateral thalami, consistent with anaplastic astrocytomas. A stereotactic burr-hole biopsy provided frozen tissues sections demonstrating an IDH-1 wildtype astrocytoma (anaplastic grade III according to prior WHO classification 2016-21). Chemoradiotherapy was commenced. Bilateral thalamic high-grade astrocytomas are very rare in the paediatric population and require timely diagnosis and interdisciplinary management. CT and MR imaging help point towards this diagnosis in the correct clinical context.

Thalamic connectivity topography in newborns with spina bifida: association with neurological functional level but not developmental outcome at 2 years.

Spina bifida affects spinal cord and cerebral development, leading to motor and cognitive delay. We investigated whether there are associations between thalamocortical connectivity topography, neurological function, and developmental outcomes in open spina bifida. Diffusion tensor MRI was used to assess thalamocortical connectivity in 44 newborns with open spina bifida who underwent prenatal surgical repair. We quantified the volume of clusters formed based on the strongest probabilistic connectivity to the frontal, parietal, and temporal cortex. Developmental outcomes were assessed using the Bayley III Scales, while the functional level of the lesion was assessed by neurological examination at 2 years of age. Higher functional level was associated with smaller thalamo-parietal, while lower functional level was associated with smaller thalamo-temporal connectivity clusters (Bonferroni-corrected P < 0.05). Lower functional levels were associated with weaker thalamic temporal connectivity, particularly in the ventrolateral and ventral anterior nuclei. No associations were found between thalamocortical connectivity and developmental outcomes. Our findings suggest that altered thalamocortical circuitry development in open spina bifida may contribute to impaired lower extremity function, impacting motor function and independent ambulation. We hypothesize that the neurologic function might not merely be caused by the spinal cord lesion, but further impacted by the disruption of cerebral neuronal circuitry.

Asymmetry of thalamic hypometabolism on FDG-PET/CT in neurofibromatosis type 1: Association with peripheral tumor burden.

BACKGROUND AND PURPOSE: Thalamic hypometabolism is a consistent finding in brain PET with F-18 fluorodeoxyglucose (FDG) in patients with neurofibromatosis type 1 (NF1). However, the pathophysiology of this metabolic alteration is unknown. We hypothesized that it might be secondary to disturbance of peripheral input to the thalamus by NF1-characteristic peripheral nerve sheath tumors (PNSTs). To test this hypothesis, we investigated the relationship between thalamic FDG uptake and the number, volume, and localization of PNSTs. METHODS: This retrospective study included 22 adult NF1 patients (41% women, 36.2 ± 13.0 years) referred to whole-body FDG-PET/contrast-enhanced CT for suspected malignant transformation of PNSTs and 22 sex- and age-matched controls. Brain FDG uptake was scaled voxelwise to the individual median uptake in cerebellar gray matter. Bilateral mean and left-right asymmetry of thalamic FDG uptake were determined using a left-right symmetric anatomical thalamus mask. PNSTs were manually segmented in contrast-enhanced CT. RESULTS: Thalamic FDG uptake was reduced in NF1 patients by 2.0 standard deviations (p < .0005) compared to controls. Left-right asymmetry was increased by 1.3 standard deviations (p = .013). Thalamic hypometabolism was higher in NF1 patients with ≥3 PNSTs than in patients with ≤2 PNSTs (2.6 vs. 1.6 standard deviations, p = .032). The impact of the occurrence of paraspinal/paravertebral PNSTs and of the mean PNST volume on thalamic FDG uptake did not reach statistical significance (p = .098 and p = .189). Left-right asymmetry of thalamic FDG uptake was not associated with left-right asymmetry of PNST burden (p = .658). CONCLUSIONS: This study provides first evidence of left-right asymmetry of thalamic hypometabolism in NF1 and that it might be mediated by NF1-associated peripheral tumors.

Interthalamic Adhesion: Can it be used to Diagnose Idiopathic Intracranial Hypertension?

OBJECTIVE: This retrospective study aimed at determining the dimension of the interthalamic adhesion (ITA) in patients with the idiopathic intracranial hypertension (IIH) for assisting in preoperative radiologic diagnosis. METHODS: The study universe consisted of magnetic resonance images of 20 patients with IIH (age: 22.70 ± 4.04 years, sex: 14 females and 6 males) and 20 normal subjects (age 22.30± 2.94 years, sex: 14 females and 6 males). To determine the morphology of ITA, its height (vertical diameter) and width (horizontal diameter) were measured on the coronal and axial planes, respectively. RESULTS: The height and width of ITA in IIH were measured as 2.58 ± 0.71 mm (range: 1.40-4.20 mm) and 2.73 ± 0.77 mm (range: 1.70-4.40 mm), respectively. Its height and width in controls were measured as 4.99 ± 1.04 mm (range: 2.70-6.30 mm) and 4.92 ± 1.11 mm (range: 2.60-6.50 mm), respectively. ITA height and width in IIH was significantly smaller compared with controls (P < 0.001). For an arbitrary cutoff of 3.85 mm, the sensitivity of the height of ITA was 85% with 95% specificity. For an arbitrary cutoff of 4.45 mm, the sensitivity of the width of ITA was 75% with 100% specificity. CONCLUSIONS: The height and width of ITA are approximately 50% smaller in IIH than controls; therefore alterations in the dimension of ITA may be a valuable radiologic sign for the diagnosis of IIH.

Use of Thalamus L-Sign to Differentiate Periventricular Leukomalacia From Neurometabolic Disorders.

PURPOSE: To assess the diagnostic value of the thalamus L-sign on magnetic resonance imaging (MRI) in distinguishing between periventricular leukomalacia and neurometabolic disorders in pediatric patients. METHODS: In this retrospective study, clinical and imaging information was collected from 50 children with periventricular leukomalacia and 52 children with neurometabolic disorders. MRI was used to evaluate the L-sign of the thalamus (ie, injury to the posterolateral thalamus) and the lobar distribution of signal intensity changes. Age, sex, gestational age, and level of Gross Motor Function Classification System (only for periventricular leukomalacia) constituted the clinical parameters. Statistical evaluation of group differences for imaging and clinical variables were conducted using univariable statistical methods. The intra- and inter-observer agreement was evaluated using Cohen's kappa. Univariable or multivariable logistic regression was employed for selection of variables, determining independent predictors, and modeling. RESULTS: The thalamus L-sign was observed in 70% (35/50) of patients in the periventricular leukomalacia group, but in none of the patients with neurometabolic disorder (P < .001). The gestational age between groups varied significantly (P < .001). Involvement of frontal, parietal, and occipital lobes differed significantly between groups (P < .001). In the logistic regression, the best model included negative thalamus L-sign and gestational age, yielding an area under the curve, accuracy, sensitivity, specificity, and precision values of 0.995, 96.1%, 96%, 96.2%, and 96%, respectively. Both the lack of thalamus L-sign and gestational age were independent predictors (P < .001). CONCLUSIONS: The thalamus L-sign and gestational age may be useful in distinguishing between periventricular leukomalacia and neurometabolic disorders.

Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model.

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

Gamma Knife Thalamotomy for Essential Tremor: A Retrospective Analysis.

BACKGROUND: Gamma knife (GK) thalamotomy has been used as a treatment option for essential tremor (ET). Numerous studies on GK use in ET treatment have reported more varied responses and complication rates. METHODS: Data from 27 patients with ET who underwent GK thalamotomy were retrospectively analyzed. The Fahn-Tolosa-Marin Clinical Rating Scale for Tremor, handwriting, and spiral drawing were evaluated. Postoperative adverse events and magnetic resonance imaging findings were also evaluated. RESULTS: The mean age at GK thalamotomy was 78.1 ± 4.2 years. The mean follow-up period was 32.5 ± 19.4 months. The preoperative postural tremor, handwriting, and spiral drawing scores were 3.4 ± 0.6, 3.3 ± 1.0, and 3.2 ± 0.8, respectively, all of which showed significant improvements to 1.5 ± 1.2 (55.9% improvement, P < 0.001), 1.4 ± 1.1 (57.6% improvement, P < 0.001), and 1.6 ± 1.3 (50% improvement, P < 0.001), respectively, at the available final follow-up evaluations. Three patients presented with no improvement in tremor. Six patients presented with adverse effects, including complete hemiparesis, foot weakness, dysarthria, dysphagia, lip numbness, and finger numbness, at the final follow-up period. Two patients presented with serious complications, including complete hemiparesis due to massive widespread edema and chronic encapsulated expanding hematoma. One patient died of aspiration pneumonia following severe dysphagia secondary to chronic encapsulated expanding hematoma. CONCLUSIONS: GK thalamotomy is an efficient procedure for treating ET. Careful treatment planning is necessary to reduce complication rates. The prediction of radiation complications will increase the safety and effectiveness of GK treatment.

Limb Preference Changes after Focused-Ultrasound Thalamotomy for Tremor.

BACKGROUND: Magnetic resonance-guided focused-ultrasound (MRgFUS) thalamotomy is an effective treatment for essential and other tremors. It targets the ventrointermedius (Vim) nucleus, which is the thalamic relay in a proprioceptive pathway, and contains kinesthetic cells. Although MRgFUS thalamotomy reduces some risks associated with more invasive surgeries, it still has side effects, such as balance and gait disturbances; these may be caused by the lesion impacting proprioception. OBJECTIVES: Our aim was to quantitatively measure the effects of MRgFUS on proprioception and limb use in essential tremor patients. We hypothesized that this thalamotomy alters proprioception, because the sensorimotor Vim thalamus is lesioned. METHODS: Proprioception was measured using the Kinarm exoskeleton robot in 18 patients. Data were collected pre-operatively, and then 1 day, 3 months, and 1 year after surgery. Patients completed four tasks, assessing motor coordination and postural control, goal-directed movement and bimanual planning, position sense, and kinesthesia. RESULTS: Immediately after surgery there were changes in posture speed (indicating tremor improvement), and in bimanual hand use, with the untreated limb being preferred. However, these measures returned to pre-operative baseline over time. There were no changes in parameters related to proprioception. None of these measures correlated with lesion size or lesion-overlap with the dentato-rubro-thalamic tract. CONCLUSIONS: This is the first quantitative assessment of proprioception and limb preference following MRgFUS thalamotomy. Our results suggest that focused-ultrasound lesioning of the Vim thalamus does not degrade proprioception but alters limb preference. This change may indicate a required "relearning" in the treated limb, because the effect is transient. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

High incidence of early thalamic lesions in the Continuous Spike-Wave related with slow Sleep (CSWS).

OBJECTIVE: Continuous Spike-Wave during slow Sleep (CSWS) syndrome associates a clinically important neurocognitive regression with strong activation of non-REM sleep spikes. Its mechanisms remain unknown, but a contribution of rare perinatal thalamic injuries has been highlighted. We determine the incidence of such lesions in a cohort of CSWS patients. METHODS: N = 65 patients with CSWS and a control group (N = 51) were studied. Spikes were quantified in long-term ambulatory EEGs, brain Magnetic Ressonance Imaging (MRI) structural lesions were assessed and thalamic volumetry was performed. A neurocognitive scale was used to assess dysfunction. RESULTS: The most common etiologies in the control patients were not represented in the CSWS group. Structural lesions were detected in a minority of CSWS patients (25/53) but included a thalamic injury in the large majority (24/25). This ratio was 4/40 in controls. Lesions belonged to one of five types: 1. Circumscribed to the thalamus (N = 11); 2. Extending beyond the thalamus (N = 3); 3. Hypothalamic-Hamartomas (N = 4); 4. Periventricular-Leukomalacia (N = 4); 5. Hypoplasia-Polymicrogyria (N = 1). Most lesions were lateralized to one hemisphere, which in all cases corresponded to the lateralization of the CSWS. SIGNIFICANCE: Thalamic lesions are present in most CSWS patients with abnormal MRIs, supporting an important role in its genesis.

Hemidystonia secondary to pediatric thalamic glioblastoma: a case report.

INTRODUCTION: Thalamic tumors are rare and uncommonly manifest as movement disorders, including hemidystonia. Despite this association, little is known about the evolution of hemidystonia. CASE DESCRIPTION: We report on a 11-year-old boy who complained of hypaesthesia and fine motor problems in the left hand. A magnetic resonance imaging showed a large mass in the right thalamus. Stereotactic biopsy revealed a WHO grade 4 astrocytoma, and the patient underwent normofractioned radiochemotherapy with proton-beam radiation and temozolomide. Three months later, a spastic hemiparesis developed on the left side, which progressed over months. Over the following months, the hemiparesis slowly improved, but hemidystonia in the same side developed. This was accompanied with radiological evidence of tumor regression, showing a persistent lesion in the ventral posterolateral and the intralaminar thalamus. CONCLUSION: This case illustrates the unusual and complex temporal course of appearance and disappearance of hemidystonia along with the regression and growth in glioblastoma involving the thalamus.

Preventive treatment with sodium para-aminosalicylic acid inhibits manganese-induced apoptosis and inflammation via the MAPK pathway in rat thalamus.

Excessive exposure to manganese (Mn) may lead to neurotoxicity, referred to as manganism. In several studies, sodium para-aminosalicylic acid (PAS-Na) has shown efficacy against Mn-induced neurodegeneration by attenuating the neuroinflammatory response. The present study investigated the effect of Mn on inflammation and apoptosis in the rat thalamus, as well as the underlying mechanism of the PAS-Na protective effect. The study consisted of sub-acute (Mn treatment for 4 weeks) and sub-chronic (Mn and PAS-Na treatment for 8 weeks) experiments. In the sub-chronic experiments, pro-inflammatory cytokines, namely tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and cyclooxygenase 2 (COX-2) were significantly increased in the Mn-exposed group compared to the control II. PAS-Na treatment led to a significant reduction in the Mn-induced neuroinflammation by inhibiting IL-1ß and COX-2 mRNA expression and reducing IL-1ß secretion and JNK/p38 MAPK pathway activity. Furthermore, immunohistochemical analysis showed that the expression of caspase-3 was significantly increased in both the sub-acute and sub-chronic experimental paradigms concomitant with a significant decrease in B-cell lymphoma 2 (Bcl-2) in the thalamus of Mn-treated rats. PAS-Na also decreased the expression levels of several apoptotic markers downstream of the MAPK pathway, including Bcl-2/Bax and caspase-3, while up-regulating anti-apoptotic Bcl-2 proteins. In conclusion, Mn exposure led to inflammation in the rat thalamus concomitant with apoptosis, which was mediated via the MAPK signaling pathway. PAS-Na treatment antagonized effectively Mn-induced neurotoxicity by inhibiting the MAPK activity in the same brain region.

Neuronavigation-Guided Transcortical-Transventricular Endoport-Assisted Endoscopic Resection for Thalamic Lesions: Preliminary Experience.

BACKGROUND: Surgery for thalamic lesions is generally challenging because they are deep-seated lesions surrounded by vital neurovascular structures. Whether neuronavigation-guided transcortical-transventricular endoport-assisted endoscopic resection for thalamic lesions is feasible remains to be further evaluated. METHODS: A retrospective review of 8 who patients received neuronavigation-guided transcortical-transventricular endoport-assisted endoscopic resection for thalamic lesions was performed. Preoperative and tumor-related variables and postoperative outcomes were analyzed. RESULTS: All lesions were located in the medial part of the thalamus, and most of them expanded forward, downward, or backward. Median size of lesions was 31 mm (range, 16-52 mm). Final pathology results confirmed that 1 case was a cavernous malformation, 3 were pilocytic astrocytomas, and 4 were glioblastomas. None of the patients had postoperative seizures. Gross total resection and long-term postoperative survival were achieved in all patients with benign lesions, while near-total resection (>90%) was achieved in 3 of 4 patients (75%) with glioblastoma, and subtotal resection (<90%) was achieved in 1 patient (25%). Among patients with glioblastoma, 1 patient remained free of recurrence at 16 months of follow-up; the other 3 patients had worse Karnofsky performance scale scores after surgery and died within 6 months. CONCLUSIONS: Combining the advantages of neuronavigation, endoscopy, and endoport techniques via the middle frontal gyrus approach can safely and effectively remove benign lesions in the medial part of the thalamus. This procedure can also be performed in well-selected cases of glioblastoma and likely confers a survival advantage for this rapidly and universally fatal disease.

"Ependymal-in" Gradient of Thalamic Damage in Progressive Multiple Sclerosis.

Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage and disease progression in multiple sclerosis (MS). Whereas perivenular inflammation induces vasculocentric lesions, leptomeningeal involvement follows a subpial "surface-in" gradient. To determine whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and cerebrospinal fluid (CSF) samples from 41 postmortem secondary progressive MS cases compared with 5 non-neurological controls and 12 controls with other neurological diseases. CSF/ependyma-oriented gradient of reduction in NeuN+ neuron density was present in MS thalamic lesions compared to controls, greatest (26%) in subventricular locations at the ependyma/CSF boundary and least with increasing distance (12% at 10 mm). Concomitant graded reduction in SMI31+ axon density was observed, greatest (38%) at 2 mm from the ependyma/CSF boundary and least at 10 mm (13%). Conversely, gradient of major histocompatibility complex (MHC)-II+ microglia density increased by over 50% at 2 mm at the ependyma/CSF boundary and only by 15% at 10 mm and this gradient inversely correlated with the neuronal (R = -0.91, p < 0.0001) and axonal (R = -0.79, p < 0.0001) thalamic changes. Observed gradients were also detected in normal-appearing thalamus and were associated with rapid/severe disease progression; presence of leptomeningeal tertiary lymphoid-like structures; large subependymal infiltrates, enriched in CD20+ B cells and occasionally containing CXCL13+ CD35+ follicular dendritic cells; and high CSF protein expression of a complex pattern of soluble inflammatory/neurodegeneration factors, including chitinase-3-like-1, TNFR1, parvalbumin, neurofilament-light-chains and TNF. Substantial "ependymal-in" gradient of pathological cell alterations, accompanied by presence of intrathecal inflammation, compartmentalized either in subependymal lymphoid perivascular infiltrates or in CSF, may play a key role in MS progression. SUMMARY FOR SOCIAL MEDIA: Imaging and neuropathological evidences demonstrated the unique feature of "surface-in" gradient of damage in multiple sclerosis (MS) since early pediatric stages, often associated with more severe brain atrophy and disease progression. In particular, increased inflammation in the cerebral meninges has been shown to be strictly associated with an MS-specific gradient of neuronal, astrocyte, and oligodendrocyte loss accompanied by microglial activation in subpial cortical layers, which is not directly related to demyelination. To determine whether a similar gradient of damage occurs in deep grey matter nuclei, we examined the potential neuronal and microglia alterations in the dorsomedial thalamic nuclei from postmortem secondary progressive MS cases in combination with detailed neuropathological characterization of the inflammatory features and protein profiling of paired CSF samples. We observed a substantial "subependymal-in" gradient of neuro-axonal loss and microglia activation in active thalamic lesions of progressive MS cases, in particular in the presence of increased leptomeningeal and cerebrospinal fluid (CSF) inflammation. This altered graded pathology was found associated with more severe and rapid progressive MS and increased inflammatory degree either in large perivascular subependymal infiltrates, enriched in B cells, or within the paired CSF, in particular with elevated levels of a complex pattern of soluble inflammatory and neurodegeneration factors, including chitinase 3-like-1, TNFR1, parvalbumin, neurofilament light-chains and TNF. These data support a key role for chronic, intrathecally compartmentalized inflammation in specific disease endophenotypes. CSF biomarkers, together with advance imaging tools, may therefore help to improve not only the disease diagnosis but also the early identification of specific MS subgroups that would benefit of more personalized treatments. ANN NEUROL 2022;92:670-685.

Disseminated diffuse midline glioma associated with poorly differentiated orbital lesion and metastases in an 8-year-old girl: case report and literature review.

BACKGROUND: Disseminated diffuse midline glioma (DMG) is a devastating diagnosis. Molecular subtyping has increased our understanding of this tumor. CASE: Here, we report the case of an 8-year-old girl who presented with symptoms of brainstem dysfunction and was found to have disseminated DMG with lesions in the pons, thalamus and bilateral temporal lobes. Molecular subtyping of the temporal lobe tumor tissue was consistent with H3 K27me3 loss and EZHIP overexpression, falling under the newly designated "H3 K27-altered" AQ5WHO subtype of DMG. Pathology from biopsy of the orbital lesion showed poorly differentiated rhabdoid-like disseminated tumor cells. The patient went on to develop lesions in the peritoneum, infratemporal fossa, and along the lumbosacral nerve roots. CONCLUSION: This unique case illustrates the aggressive behavior of H3 K27-altered tumors and their potential to metastasize.