Cortical Lesions Research Articles

Clinical characteristics, course and prognosis of Multiple Sclerosis patients with epilepsy. A case control study: MS and epilepsy

Background and purposeAlthough more common than in the general population, seizures are an atypical manifestation of multiple sclerosis (MS) and their pathophysiology is not well understood. This study aims to examine the prevalence, clinical characteristics, brain imaging findings and course of epilepsy, presenting in patients with MS. MethodsObservational retrospective study of MS patients evaluated at a single MS reference center in Buenos Aires, Argentina, between 2011 and 2022, focusing on those who developed epilepsy (EMS). Clinical, demographic, and prognostic factors were evaluated and compared to a control group of non-epileptic MS patients (NEMS). To analyze specific epilepsy characteristics, a second control group of patients with non-lesional focal epilepsy (FNLE) was also included. ResultsTwenty-five patients (18 women), were diagnosed with epilepsy, corresponding to a prevalence of 1.95%. Comparison of brain imaging characteristics between EMS and NEMS patients showed brain atrophy (32% vs 6.1%, p<0.01), as well as cortical (26% vs 4%, p=0.03) and juxtacortical lesions (84% vs 55%, p=0.05), were more frequent in EMS patients. However, after multivariate analysis, cortical atrophy was the only variable linked to a significant increase in risk of epilepsy (OR 24, 95%CI=2.3-200, p<0.01). No significant differences in clinical characteristics, disease activity, disability levels, response to disease modified treatment (DMT) or lack of DMT efficacy were observed between MS patients with or without epilepsy. Most patients received anti-seizure medication (ASM), and seizure control was better in EMS than in FNLE patients (92% vs 58%, p=0.022) with no differences found in drug resistance. We did not find predictors of seizure recurrence in the population studied. ConclusionWe observed a lower prevalence of epilepsy in this group of MS patients, compared to other reported cohorts. Although epilepsy seems to have a benign course in MS patients, cortical atrophy appears to be an important contributor to the development of secondary epilepsy in MS patients. Further investigations will be necessary to identify risk factors or biomarkers predicting increased epilepsy risk in MS.

A taxonomy for superficial cerebral cavernous malformations: subtypes of cortical and subcortical lesions.

A taxonomy for superficial cerebral cavernous malformations (CMs), those based cortically in gyral gray matter or subcortically in underlying white matter, is proposed to build on the comprehensive, systematic characterization of CMs in the entire brain. Patients with superficial cerebral CMs were retrospectively analyzed from a consecutive surgical series between November 2008 and June 2021 at the authors' center. Superficial cerebral CMs were categorized into 4 subtypes based on their cortical location or, if subcortical, proximity to the nearest cerebral surface: convexity, medial, basal, and sylvian. Lobar location was also included for subtyping: frontal, temporal, parietal, and occipital. A total of 362 CMs were resected in 346 patients. CM subtypes were as follows: 132 (36.5%) convexity, 78 (21.5%) medial, 72 (19.9%) basal, and 80 (22.1%) sylvian. Frontal CMs were most common (155 [42.8%]), followed by parietal (89 [24.6%]), temporal (87 [24.0%]), and occipital (31 [8.6%]). Of all CMs, 302 (83.4%) were cortical and 60 (16.6%) were subcortical. The mean subcortical depth of deep lesions was 2.97 cm, and the mean lesion volume was 4.68 cm3. Overall, 228 lesions (63.0%) were resected through a transgyral approach, and 134 (37.0%) were resected through a transsulcal approach. Good outcomes (modified Rankin Scale [mRS] score ≤ 2) were observed in 314 patients (86.7%) and poor outcomes (mRS score > 2) in 25 patients (6.9%), and 23 patients (6.4%) were lost to late follow-up (mean follow-up duration 11.5 months). Relative outcomes were good (unchanged or improved mRS score) in 327 patients (90.3%) and poor (worse or died) in 35 patients (9.7%). Superficial cerebral CMs were resected through a gyrus or sulcus to open the subarachnoid dissection corridors, traversing the full extent of sulci to deepen the approach and minimize tissue transgression. Transgyral dissection avoids associated arteries but is inherently transgressive, whereas transsulcal dissection preserves cortical tissue and may reduce morbidity. Superficial cerebral CMs occupy the largest territory of the 7 types, and the size and surface complexity of the cerebrum make taxonomic subtyping valuable for clear anatomical description.

The added value of double inversion recovery (DIR) sequence compared to fluid attenuation inversion recovery (FLAIR) in identifying multiple sclerosis lesions and different cortical subtypes

Background. Diabetic here is a rising concern about multiple sclerosis (MS) lesions that occur in the cortical gray matter (GM), owing to its direct relationship with the disability and cognition dysfunction that occur during the MS course. Two magnetic resonance imaging (MRI) sequences that aid in the precise identification of these lesions are the Double Inversion Recovery (DIR) and Fluid Attenuation Inversion Recovery (FLAIR) sequences. Objective. To study the importance of the DIR for brain lesion detection and the various cortical subtypes distinction in MS-diagnosed patients and its correlations to the level of patient disability by comparing it to FLAIR. Patients and Methods: Thirty MS patients participated in this retrospective cross-sectional study, who had been previously diagnosed with MS and were routinely followed up at the Radiology Department at Ain-Shams University. Results. Comparing the DIR sequence to FLAIR, the overall MS lesion detection enhanced by 8% (p&lt;0.001). Regarding the detection of cortical lesion subtypes (I–IV), it was discovered that the DIR sequence revealed significantly more lesions than FLAIR (p&lt;0.001). The cortical lesions detected by DIR or FLAIR were found to have positive, highly significant correlations with both patients’ disability and the MS duration. Conclusion. For lesion identification, DIR is more effective than FLAIR, particularly for cortical and juxtacortical lesions in MS patients.

The Role of Transcranial Doppler in Patients with Cryptogenic Stroke

Identifying the stroke mechanism is crucial for secondary prevention of ischemic stroke. However, approximately 20% to 30% of patients with ischemic stroke do not display a discernible cause after standard diagnostic evaluation and are classified as having cryptogenic stroke. Most cryptogenic strokes are believed to be of embolic origin, referred to as embolic stroke of undetermined source. Several potential causes, including occult atrial fibrillation, aortic arch atheroma, non-stenotic atherosclerosis, coagulopathy, and patent foramen ovale (PFO), are significant contributors to cryptogenic stroke. Among these, PFO-associated strokes often manifest as small cortical lesions in the posterior circulation and are associated with fewer traditional risk factors. Ischemic stroke is considered a high risk if there is a large PFO with significant shunting or the presence of an atrial septal aneurysm. Although transesophageal echocardiography is regarded as the gold standard for diagnosing PFO, its invasiveness, high cost, and challenges in certain stroke patients necessitate alternative approaches. Recently, transcranial Doppler (TCD) has emerged as a valuable screening tool for detecting high-risk PFOs, as supported by recent research. Accurate determination of the culprit PFO responsible for ischemic stroke remains crucial for guiding appropriate treatment decisions. This article provides a comprehensive review of the different modalities used to diagnose PFO, strategies for assessing the risk of PFO causing paradoxical embolism, and the role of TCD in patients with cryptogenic stroke caused by other etiologies.

Associations between cortical lesions, optic nerve damage, and disability at the onset of multiple sclerosis: insights into neurodegenerative processes.

BackgroundMultiple sclerosis cortical lesions are areas of demyelination and neuroaxonal loss. Retinal layer thickness, measured with optical coherence tomography (OCT), is an emerging biomarker of neuroaxonal loss. Studies have reported correlations between cortical lesions and retinal layer thinning in established multiple sclerosis, suggesting a shared pathophysiological process. Here, we assessed the correlation between cortical lesions and OCT metrics at the onset of multiple sclerosis, examining, for the first time, associations with physical or cognitive disability. ObjectiveTo examine the relationship between cortical lesions, optic nerve and retinal layer thicknesses, and physical and cognitive disability at the first demyelinating event. MethodsThirty-nine patients and 22 controls underwent 3T-MRI, optical coherence tomography, and clinical tests. We identified cortical lesions on phase-sensitive inversion recovery sequences, including occipital cortex lesions. We measured the estimated total intracranial volume and the white matter lesion volume. OCT metrics included peripapillary retinal nerve fibre layer (pRNFL), ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL) thicknesses. ResultsHigher total cortical and leukocortical lesion volumes correlated with thinner pRNFL (B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01; B = -0.0005, 95 % CI -0.0008 to -0.0001, p = 0.01, respectively). Leukocortical lesion number correlated with colour vision deficits (B = 0.58, 95 %CI 0.039 to 1,11, p = 0.036). Thinner GCIPL correlated with a higher Expanded Disability Status Scale (B = -0.06, 95 % CI -1.1 to -0.008, p = 0.026). MS diagnosis (n = 18) correlated with higher cortical and leukocortical lesion numbers (p = 0.004 and p = 0.003), thinner GCIPL (p = 0.029) and INL (p = 0.041). ConclusionThe association between cortical lesions and axonal damage in the optic nerve reinforces the role of neurodegenerative processes in MS pathogenesis at onset.

Pushing MP2RAGE boundaries: Ultimate time-efficient parameterization combined with exhaustive T1 synthetic contrasts.

MP2RAGE parameter optimization is redefined to allow more time-efficient MR acquisitions, whereas the T1 -based synthetic imaging framework is used to obtain on-demand T1 -weighted contrasts. Our aim was to validate this concept on healthy volunteers and patients with multiple sclerosis, using plug-and-play parallel-transmission brain imaging at 7 T. A "time-efficient" MP2RAGE sequence was designed with optimized parameters including TI and TR set as small as possible. Extended phase graph formalism was used to set flip-angle values to maximize the gray-to-white-matter contrast-to-noise ratio (CNR). Several synthetic contrasts (UNI, EDGE, FGATIR, FLAWSMIN , FLAWSHCO ) were generated online based on the acquired T1 maps. Experimental validation was performed on 4 healthy volunteers at various spatial resolutions. Clinical applicability was evaluated on 6 patients with multiple sclerosis, scanned with both time-efficient and conventional MP2RAGE parameterizations. The proposed time-efficient MP2RAGE protocols reduced acquisition time by 40%, 30%, and 19% for brain imaging at (1 mm)3 , (0.80 mm)3 and (0.65 mm)3 , respectively, when compared with conventional parameterizations. They also provided all synthetic contrasts and comparable contrast-to-noise ratio on UNI images. The flexibility in parameter selection allowed us to obtain a whole-brain (0.45 mm)3 acquisition in 19 min 56 s. On patients with multiple sclerosis, a (0.67 mm)3 time-efficient acquisition enhanced cortical lesion visualization compared with a conventional (0.80 mm)3 protocol, while decreasing the scan time by 15%. The proposed optimization, associated with T1 -based synthetic contrasts, enabled substantial decrease of the acquisition time or higher spatial resolution scans for a given time budget, while generating all typical brain contrasts derived from MP2RAGE.

Diagnostic Performance of Cortical Lesions and the Central Vein Sign in Multiple Sclerosis

Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). MS/CIS vs non-MS conditions. Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

A bridge to recovery: Acute amantadine prior to environmental enrichment after brain trauma augments cognitive benefit

Environmental enrichment (EE) facilitates motor and cognitive recovery after traumatic brain injury (TBI). Historically, EE has been provided immediately and continuously after TBI, but this paradigm does not model the clinic where rehabilitation is typically not initiated until after critical care. Yet, treating TBI early may facilitate recovery. Hence, we sought to provide amantadine (AMT) as a bridge therapy before commencing EE. It was hypothesized that bridging EE with AMT would augment motor and cognitive benefits. Anesthetized adult male rats received a cortical impact (2.8 mm deformation at 4 m/s) or sham surgery and then were housed in standard (STD) conditions where they received intraperitoneal AMT (10 mg/kg or 20 mg/kg) or saline vehicle (VEH; 1 mL/kg) beginning 24 h after surgery and once daily during the 6-day bridge phase or once daily for 19 days for the non-bridge groups (i.e., continuously STD-housed) to compare the effects of acute AMT plus EE vs. chronic AMT alone. Abbreviated EE, which was presented to closer emulate clinical rehabilitation (e.g., 6 h/day), began on day 7 for the AMT bridge and chronic EE groups. Motor (beam-walking) and cognition (acquisition of spatial learning and memory) were assessed on days 7–11 and 14–19, respectively. Cortical lesion volume and hippocampal cell survival were quantified on day 21. EE, whether provided in combination with VEH or AMT, and AMT (20 mg/kg) + STD, benefitted motor and cognition vs. the STD-housed VEH and AMT (10 mg/kg) groups (p < 0.05). The AMT (20 mg/kg) + EE group performed better than the VEH + EE, AMT (10 mg/kg) + EE, and AMT (20 mg/kg) + STD groups in the acquisition of spatial learning (p < 0.05) but did not differ in motor function (p > 0.05). All groups receiving EE exhibited decreased cortical lesion volumes and increased CA3 neuron survival relative to the STD-housed groups (p < 0.05) but did not differ from one another (p > 0.05). The added cognitive benefit achieved by bridging EE with AMT (20 mg/kg) supports the hypothesis that the temporal separation of combinational therapies is more effective after TBI.

Cortical Lesions in a Sample of Egyptian MS Patients

Cortical Lesions in a Sample of Egyptian MS Patients

Association between cortical lesions and white matter lesions in clinical symptoms of Alzheimer's disease

Association between cortical lesions and white matter lesions in clinical symptoms of Alzheimer's disease

Plasma neurofilament light and brain volumetric outcomes among middle‐aged urban adults

AbstractBackgroundElevated plasma neurofilament light chain (NfL) is associated with dementia, but the specific underlying mechanisms are largely unknown. We examined cross‐sectional and longitudinal relationships of plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia, namely global and cortical brain, hippocampal and white matter lesion volumes (WMLV).MethodData were extracted from three prospective visits within the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v1 (2004‐2009) and v2 (2009‐2013) plasma NfL exposure and ancillary sMRI data at vscan (2011‐2015, n = 179, mean v1 to vscan time: 5.4y). Multivariable‐adjusted linear regression models were conducted, overall, by sex, and by race, correcting for multiple testing with q‐values.ResultNfL(v1) (Loge transformed) had a moderately strong association with larger WMLV at follow‐up vscan visit, after a period of 5‐6 years of follow‐up, overall (β = +2.131±0.660, b = +0.29, p = 0.001, q = 0.0029). Moreover, a 1 unit increase in NfLv2 was linked to a left hippocampal volume that was lower by 125 mm3 (p = 0.004, q = 0.015), using minimally adjusted models and mainly among males. Associations were largely unaltered by further adjustment for downstream health‐related factors.ConclusionIn summary, plasma NfL may be an independent medium‐term (within 5 years) marker for increase in WMLV, and a short term (within 1 year) marker for smaller hippocampal volumes normalized to the intracranial volume, independently of other confounding factors. Therefore, plasma NfL holds promise as a blood‐based marker to predict future subclinical brain pathologies in middle‐aged adults.

Post-stroke seizures, epilepsy, and mortality in a prospective hospital-based study.

Post-stroke epilepsy (PSE) is a significant concern in the elderly population, with stroke being a leading cause of epilepsy in this demographic. Several factors have shown consistent associations with the risk of developing PSE, including cortical lesions, initial stroke severity, younger age, and the occurrence of early seizures. The primary objectives of this study were two-fold: (1) to determine the incidence of PSE and (2) to identify the risk factors associated with PSE in a prospective cohort of post-stroke patients. A prospective single-hospital study was conducted, involving patients diagnosed with acute ischemic and hemorrhagic stroke. The patients were followed up for 2 years (or until death) from the time of admission. Data about seizure occurrence and recurrent stroke were collected. Kaplan-Meyer curves were used for the assessment of PSE incidence and mortality. Possible predictors of PSE and mortality were selected from between-group analysis and tested in multivariable regressions. Our study enrolled a total of 424 patients diagnosed with acute stroke. Among them, 97 cases (23%) experienced early post-stroke seizures, and 28 patients (6.6%) developed PSE. The cumulative risks of developing PSE were found to be 15.4% after hemorrhagic stroke and 8.7% after ischemic stroke. In multivariable fine and gray regression with competitive risk of death, significant predictors for developing PSE in the ischemic cohort were watershed infarction (HR 6.01, 95% CI 2.29-15.77, p < 0.001) and low Barthel index at discharge (HR 0.98, CI 0.96-0.99, p = 0.04). Furthermore, patients who eventually developed PSE showed slower recovery and presented a worse neurologic status at the time of discharge. The in-hospital dynamics of the National Institutes of Health Stroke Scale (NIHSS) were significantly worse in the PSE group compared to the non-PSE group (p = 0.01). A higher proportion of cases experienced early seizures compared to what has been commonly reported in similar studies. Watershed stroke and low Barthel index at discharge were both identified as independent risk factors of PSE in ischemic strokes, which sheds light on the underlying mechanisms that may predispose individuals to post-stroke epilepsy after experiencing an ischemic stroke.

Optineurin regulates osteoblast function in an age-dependent fashion in a mouse model of Paget's disease of bone.

Paget's disease of bone (PDB) is a degenerative disorder affecting the skull and bones. Hyperactive osteoclasts (OCs) initiate bone degradation in the early stage, followed by increased bone formation by osteoblasts (OBs) in trabecular bones during the advanced stage. This OB-OC uncoupling results in bone deformations and irregular trabecular bone patterns. Current mouse models poorly replicate the advanced-stage characteristics of PDB. Optineurin (Gene: OPTN in humans, Optn in mice, protein: OPTN) has been implicated in PDB by genetic analyses. We identified PDB-like cortical lesions associated with OC hyperactivation in an Optn knockout (Optn-/-) mouse model. However, the effects of OPTN dysfunction on OBs and trabecular bone in advanced PDB remain unclear. In this study, we used the Optn-/- mouse model to investigate trabecular bone abnormalities and OB activity in PDB. Micro-computed tomography analysis revealed severe pagetic alterations in craniofacial bones and femurs of aged Optn-/- mice, resembling clinical manifestations of PDB. Altered OB activity was observed in aged Optn-/- mice, implicating compensatory OB response in trabecular bone anomalies. To elucidate the role of OC-OB interactions in PDB, we conducted in vitro experiments using OC conditioned media (CM) to examine the effects on OB osteogenic potential. We found OC CM restored compromised osteogenic induction of Optn-/- bone marrow stromal cells (BMSCs) from young mice, suggesting OCs maintain OB activity through secreted factors. Strikingly, OC CM from aged Optn-/- mice significantly enhanced osteogenic capability of Optn-/- BMSCs, providing evidence for increased OB activity in advanced stages of PDB. We further identified TGF-β/BMP signaling pathway in mediating the effects of OC CM on OBs. Our findings provide insights into Optn's role in trabecular bone abnormalities and OB activity in PDB. This enhances understanding of PDB pathogenesis and may contribute to potential therapeutic strategies for PDB and related skeletal disorders.

POEMS-associated Multicentric Castleman Disease: A diagnostic and Therapeutic Conundrum

Abstract Introduction/Objective A rare multisystemic, paraneoplastic hematologic disorder, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is associated with an overproduction of pro-inflammatory cytokines caused by a plasma cell proliferative disorder. Castleman disease is a rare clinical entity described as a polyclonal lymphoid proliferation, that leads to generalized lymphadenopathy. It is rarely presented in association with POEMS Syndrome. Methods/Case Report A 55-year-old hispanic male, when being evaluated for liver mass, revealed bile duct thickening and a pancreatic head mass. Endoscopic fine needle aspiration biopsies were negative; however, the cross sectional imaging identified enlarged left axillary lymph nodes. His excisional lymph node biopsy showed human herpese virus-8 (HHV-8) negative multicentric Castleman disease (MCD). Several features of POEMS syndrome were noted. The axillary lymph node biopsy demonstrated florid follicular hyperplasia, scattered regressed germinal centers and concentric rings of mantle zone lymphocytes. CD138, kappa-ISH, and lambda-ISH highlight scattered polytypic plasma cells. Our case fulfills the mandatory criteria of POEMS syndrome with the presence of neuropathy and a constellation of other major and minor criterion including, axillary Castleman, splenomegaly, hepatomegaly, skin changes, ascites and bilateral renal cortical lesions. Furthermore the patient also has a history of cerebrovascular accident and chronic cough favoring POEMS syndrome. Results (if a Case Study enter NA) NA Conclusion The complexity and multi-organ involvement, leads to frequent misdiagnosis of POEMS disease. In addition significant overlap of symptoms of POEMS syndrome makes it difficult to differentiate from other plasma cell disorders associated with MCD. Our study includes a brief review of the literature delineating the characteristics and overlap between POEMS syndrome and other diseases.

Cerebellar Atrophy and Language Processing in Chronic Left-Hemisphere Stroke.

Chronic stroke results in significant downstream changes at connected cortical sites. However, less is known about the impact of cortical stroke on cerebellar structure. Here, we examined the relationship between chronic stroke, cerebellar volume, cerebellar symmetry, language impairment, and treatment trajectories in a large cohort (N = 249) of chronic left hemisphere (LH) stroke patients with aphasia, using a healthy aging cohort (N = 244) as control data. Cerebellar gray matter volume was significantly reduced in chronic LH stroke relative to healthy control brains. Within the chronic LH stroke group, we observed a robust relationship between cerebellar volume, lesion size, and days post-stroke. Notably, the extent of cerebellar atrophy in chronic LH patients, particularly in the contralesional (right) cerebellar gray matter, explained significant variability in post-stroke aphasia severity, as measured by the Western Aphasia Battery-Revised, above and beyond traditional considerations such as cortical lesion size, days post-stroke, and demographic measures (age, race, sex). In a subset of participants that took part in language treatment studies, greater cerebellar gray matter volume was associated with greater treatment gains. These data support the importance of considering both cerebellar volume and symmetry in models of post-stroke aphasia severity and recovery.

Morphological and Functional Principles Governing the Plasticity Reserve in the Cerebellum: The Cortico-Deep Cerebellar Nuclei Loop Model.

Cerebellar reserve compensates for and restores functions lost through cerebellar damage. This is a fundamental property of cerebellar circuitry. Clinical studies suggest (1) the involvement of synaptic plasticity in the cerebellar cortex for functional compensation and restoration, and (2) that the integrity of the cerebellar reserve requires the survival and functioning of cerebellar nuclei. On the other hand, recent physiological studies have shown that the internal forward model, embedded within the cerebellum, controls motor accuracy in a predictive fashion, and that maintaining predictive control to achieve accurate motion ultimately promotes learning and compensatory processes. Furthermore, within the proposed framework of the Kalman filter, the current status is transformed into a predictive state in the cerebellar cortex (prediction step), whereas the predictive state and sensory feedback from the periphery are integrated into a filtered state at the cerebellar nuclei (filtering step). Based on the abovementioned clinical and physiological studies, we propose that the cerebellar reserve consists of two elementary mechanisms which are critical for cerebellar functions: the first is involved in updating predictions in the residual or affected cerebellar cortex, while the second acts by adjusting its updated forecasts with the current status in the cerebellar nuclei. Cerebellar cortical lesions would impair predictive behavior, whereas cerebellar nuclear lesions would impact on adjustments of neuronal commands. We postulate that the multiple forms of distributed plasticity at the cerebellar cortex and cerebellar nuclei are the neuronal events which allow the cerebellar reserve to operate in vivo. This cortico-deep cerebellar nuclei loop model attributes two complementary functions as the underpinnings behind cerebellar reserve.

SURG-13. PEDIATRIC PRIMARY CENTRAL NERVOUS SYSTEM NEOPLASMS: RELATIVE UTILITY OF OPEN, MULTI-STAGE CRANIAL SURGERY

Abstract OBJECTIVE Staged surgery for skull base lesions has been utilized to facilitate maximal safe resection and optimize outcomes in pediatric patients. Despite its extensive applications, there is a paucity of information regarding open multi-stage resection of intrinsic, intra-axial neoplasms. We reviewed the literature in order to shed light on relevant considerations including the timing between surgeries, indications for staged approaches, and clinical outcomes following staged resection of pediatric intra-axial neoplasms. METHODS We conducted a literature search using PubMed, Web of Science, and Cochrane databases according to PRISMA recommendations. RESULTS Of 115 results, 7 articles were included for final analysis and consisted of 17 pediatric patients, including 6 (35%) male, 5 (29%) female, and 6 (35%) unspecified sex patients. Age ranged from 18 months to 17 years (mean 9 years). Tumor pathologies consisted of 5 (29%) astrocytomas, 2 (12%) ependymomas, 2 (12%) teratoid rhabdoid tumors, 2 (12%) oligodendromas, 1 (6%) glioma, 1 (6%) dysembryoplastic neuroepithelial tumor, 1 (6%) meningioangiomatosis, 1 (6%) pleomorphic xanthoastrocytoma, 1 (6%) ganglioglioma, and 1 (6%) germ cell tumor. Primary sites of the tumor included 4 (24%) temporal lobe, 3 (18%) thalamic, 3 (18%) thalamopeduncular, 3 (18%) frontal lobe, 2 (12%) posterior fossa, 1 (6%) cerebral hemisphere, and 1 (6%) frontoparietal lobe. Three studies reported complications, which included subtle hemiparesis, hydrocephalus, cranial nerve (CN) VI and VII palsies, truncal ataxia, and cerebellar mutism. Timing between surgeries varied from 5 days to several weeks CONCLUSION Indications for performing multi-stage resections included large tumor volume requiring multiple long stages of debulking, significant tumor vascularity, multicompartmental lesions, and planned staging due to presence of large tumors requiring resection around eloquent speech and motor cortical and white matter tract lesions that enabled use of awake functional mapping after a primary debulking performed in proximity to less eloquent regions.

PATH-56. SUPRATENTORIAL NEUROEPITHELIAL TUMORS WITH NOVEL PLAGL1 FUSIONS: 2 CASE REPORTS

Abstract Neuroepithelial tumors with pleomorphic adenoma gene-like (PLAGL1) fusions represent a distinct subgroup of neoplasms that have been recently identified. These fusions are quite rare and most commonly associated with fusions in the EWSR1 or FOXO1 genes. Limited reports in literature have indicated a median age of diagnosis of 6.2 years and poor progression-free survival at 35 months. Here we present two cases of patients with neuroepithelial tumors with PLAGL1 fusions. Case 1 was a 49 year old male who underwent resection of a left frontal lobe mass at 2 year old that was reported as a low grade ependymoma. He did not receive radiation or chemotherapy and subsequently developed seizures in childhood. At age 47, he presented with worsening seizures and MRI brain revealed a 4.5 cm mass in the left frontal lobe with serpiginous enhancement. He underwent surgical resection and molecular profiling demonstrated PLAGL1-FOXO1 fusion. Case 2 was an 18 year old female presenting with generalized tonic-clonic seizures. MRI brain demonstrated a 1.4 x 1.2 cm cortical and subcortical lesion in the right parietal lobe. Following surgical resection, pathology reported a low grade neuroepithelial neoplasm with ependymal-like features. Molecular profiling showed PLAGL1-EWSR1 fusion. As PLAGL1 fusions are not yet characterized in the WHO classification system, these cases aid in tumor characterization and highlight the importance of molecular and methylation analysis for accurate tumor classification. Case 2 presents a notable variation from reported age of presentation of 6.2 years with diagnosis at 18 years of age, indicating these tumors may also present in young adulthood. Additionally, Case 1 demonstrated 45 years progression-free survival compared to previously reported median of 35 months, suggesting outcomes may be heterogeneous with potential for prolonged survival. Further research is needed to better elucidate the imaging, clinical course, and prognosis for tumors with this novel fusion.

Expression profiles of α-synuclein in cortical lesions of patients with FCD IIb and TSC, and FCD rats.

Focal cortical dysplasia (FCD) IIb and tuberous sclerosis complex (TSC) are common causes of drug-resistant epilepsy in children. However, the etiologies related to the development of FCD IIb and TSC are not fully understood. α-synuclein (α-syn) is a member of synucleins family that plays crucial roles in modulating synaptic transmission in central nervous system. Here, we explored the expression profiles and potential pathogenic functions of α-syn in cortical lesions of epileptic patients with FCD IIb and TSC. Surgical specimens from epileptic patients with FCD IIb and TSC, as well as FCD rats generated by in utero X-ray-radiation were adopted in this study and studied with immunohistochemistry, immunofluorescence, western blotting, and co-immunoprecipitation etc. molecular biological techniques. Our results showed that α-syn expression was reduced in FCD IIb and TSC lesions. Specifically, α-syn protein was intensely expressed in dysplastic neurons (DNs) and balloon cells (BCs) in FCD IIb lesions, whereas was barely detected in DNs and giant cells (GCs) of TSC lesions. Additionally, p-α-syn, the aggregated form of α-syn, was detected in DNs, BCs, GCs, and glia-like cells of FCD IIb and TSC lesions. We previous showed that the function of N-methyl-D-aspartate receptor (NMDAR) was enhanced in FCD rats generated by X-ray-radiation. Here, we found the interaction between α-syn and NMDAR subunits NMDAR2A, NMDAR2B were augmented in cortical lesions of FCD patients and FCD rats. These results suggested a potential role of α-syn in the pathogenesis of FCD IIb and TSC by interfering with NMDAR.

1 Predictors of Neurocognitive Outcome in Pediatric Ischemic and Hemorrhagic Stroke

Objective:Neurocognitive deficits commonly occur following pediatric stroke and can impact many neuropsychological domains. Despite awareness of these deleterious effects, neurocognitive outcome after pediatric stroke, especially hemorrhagic stroke, is understudied. This clinical study aimed to elucidate the impact of eight factors identified in the scientific literature as possible predictors of neurocognitive outcome following pediatric stroke: age at stroke, stroke type (i.e., ischemic vs. hemorrhagic), lesion size, lesion location (i.e., brain region, structures impacted, and laterality), time since stroke, neurologic severity, seizures post-stroke, and socioeconomic status.Participants and Methods:Ninety-two patients, ages six to 25 and with a history of pediatric stroke, chose to participate in the study and were administered standardized neuropsychological tests assessing verbal reasoning, abstract reasoning, working memory, processing speed, attention, learning ability, long-term memory, and visuomotor integration. A standardized parent questionnaire provided an estimate of executive functioning. Statistical analyses included spline regressions to examine the impact of age at stroke and lesion size, further divided by stroke type; a series of one-way analysis of variance to examine differences in variables with three levels; Welch’s t-tests to examine dichotomous variables; and simple linear regressions for continuous variables.Results:Lesion size, stroke type, age at stroke, and socioeconomic status were identified as predictors of neurocognitive outcome in our sample. Large lesions were associated with worse neurocognitive outcomes compared to small to medium lesions across neurocognitive domains. Exploratory spline regressions suggested that ischemic stroke was associated with worse neurocognitive outcomes than hemorrhagic stroke. Based on patterns shown in graphs, age at stroke appeared to have an impact on outcome depending on the neurocognitive domain and stroke type, with U-shaped trends suggesting worse outcome across most domains when stroke occurred at approximately 5 to 10 years of age. Socioeconomic status positively predicted outcomes across most neurocognitive domains. Participants with seizures had more severe executive functioning impairments than youth without seizures. Youth with combined cortical-subcortical lesions scored lower on abstract reasoning than youth with cortical and youth with subcortical lesions, and lower on attention than youth with cortical lesions. Neurologic severity predicted scores on abstract reasoning, attention, processing speed, and visuomotor integration, depending on stroke type. There was no evidence of differences on outcome measures based on time since stroke, lesion laterality, or lesion region defined as supra-versus infratentorial.Conclusions:The current study contributed to the scientific literature by identifying lesion size, stroke type, age at stroke, and socioeconomic status as predictors of neurocognitive outcome following pediatric stroke. Future research should examine other possible predictors of neurocognitive outcome that remain unexplored. Multisite collaborations would provide larger sample sizes and allow teams to build models with better statistical power and more predictors. Enhancing understanding of neurocognitive outcomes following pediatric stroke is a first step towards improving appraisals of prognosis.Findings are clinically applicable as they provide professionals with information that can help assess individual expected patterns of recovery and thus refer patients to appropriate support services.