Microglial Characterization in Transient Human Neurodevelopmental Structures.

Human neurodevelopment is characterized by the appearance, development, and disappearance or transformation of various transient structures that underlie the establishment of connectivity within and between future cortical and subcortical areas. Examples of transient structures in the forebrain (among many others) include the subpial granular layer and the subplate zone. We have previously characterized the precise spatiotemporal dynamics of microglia in the human telencephalon. Here, we describe the diversity of microglial morphologies in the subpial granular layer and the subplate zone. Where possible, we couple the predominant morphological phenotype with functional characterizations to infer tentative roles for microglia in a changing neurodevelopmental landscape. We interpret these findings within the context of relevant morphogenetic and neurogenetic events in humans. Due to the unique genetic, molecular, and anatomical features of the human brain and because many human neurological and psychiatric diseases have their origins during development, these structures deserve special attention.

Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain.

Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) that persisted for a minimum of 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (e.g., sedation, motor weakness, loss of normal sensation) were seen between 2 and 13 months post-treatment in naive adult mice, pigs, and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord or peripheral nerve injury-induced neuropathic pain.

Anatomical landmarks during high-magnification microsurgery for a safe and effective resection of high-grade gliomas: how I do it.

BACKGROUND: Gross total resection, when possible, is the first crucial treatment for high-grade gliomas, as it has been demonstrated to be associated with longer survival. Different intraoperative tools, such as neuronavigation, fluorescent agents, and intra-operative ultrasound, have been developed to help neurosurgeons to extend the resection. METHODS: We describe the high-magnification microsurgery technique used during the first surgical removal for high-grade gliomas. We illustrate the key anatomical "markers" of normal brain parenchyma, which guide the surgery. CONCLUSION: High-magnification microsurgery is an anatomically based approach that allows the identification of key anatomical "markers" of normal brain parenchyma in order to resect high-grade gliomas safely and effectively.

Subpial Hemorrhage in Neonates: What Radiologists Need to Know.

OBJECTIVE. Subpial hemorrhages, typically seen in neonates, are rare but can harm the adjacent brain parenchyma. The purpose of this review is to summarize the anatomy and pathophysiology of subpial hemorrhage and highlight its characteristic neuro-imaging pattern. CONCLUSION. The distinctive neuroimaging pattern of subpial hemorrhage is best appreciated on brain MRI, which shows the morphology over the cortex and injury to adjacent cortex and subcortical white matter. These findings do not occur in subarachnoid and subdural hemorrhages. Recognizing the pattern of subpial hemorrhages should guide prognostic precision, prognostication, and counseling.

Glial-Neuronal Interactions in Pathogenesis and Treatment of Spinal Cord Injury.

Traumatic spinal cord injury (SCI) elicits an acute inflammatory response which comprises numerous cell populations. It is driven by the immediate response of macrophages and microglia, which triggers activation of genes responsible for the dysregulated microenvironment within the lesion site and in the spinal cord parenchyma immediately adjacent to the lesion. Recently published data indicate that microglia induces astrocyte activation and determines the fate of astrocytes. Conversely, astrocytes have the potency to trigger microglial activation and control their cellular functions. Here we review current information about the release of diverse signaling molecules (pro-inflammatory vs. anti-inflammatory) in individual cell phenotypes (microglia, astrocytes, blood inflammatory cells) in acute and subacute SCI stages, and how they contribute to delayed neuronal death in the surrounding spinal cord tissue which is spared and functional but reactive. In addition, temporal correlation in progressive degeneration of neurons and astrocytes and their functional interactions after SCI are discussed. Finally, the review highlights the time-dependent transformation of reactive microglia and astrocytes into their neuroprotective phenotypes (M2a, M2c and A2) which are crucial for spontaneous post-SCI locomotor recovery. We also provide suggestions on how to modulate the inflammation and discuss key therapeutic approaches leading to better functional outcome after SCI.

Microsurgical subpial resections for diffuse gliomas-old wine in a new bottle.

BACKGROUND: Maximizing resection is an oft-sought-after albeit challenging goal in diffuse gliomas. Microsurgical technique remains the mainstay. METHOD: By virtue of their pattern of growth and spread, gliomas respect anatomical boundaries like the pia. Using subpial dissection, en bloc resections provide the most optimal surgical technique. This paper revisits this technique and describes the rationale and basic principles integrating it in the modern multimodal glioma surgery workflow. CONCLUSION: Subpial resection is a very useful and "anatomical" technique for en bloc resection of diffuse gliomas which is easy to master and execute and optimizes the extent of resection and minimizes complications effectively.

Increased cortical grey matter lesion detection in multiple sclerosis with 7 T MRI: a post-mortem verification study.

The relevance of cortical grey matter pathology in multiple sclerosis has become increasingly recognized over the past decade. Unfortunately, a large part of cortical lesions remain undetected on magnetic resonance imaging using standard field strength. In vivo studies have shown improved detection by using higher magnetic field strengths up to 7 T. So far, a systematic histopathological verification of ultra-high field magnetic resonance imaging pulse sequences has been lacking. The aim of this study was to determine the sensitivity of 7 T versus 3 T magnetic resonance imaging pulse sequences for the detection of cortical multiple sclerosis lesions by directly comparing them to histopathology. We obtained hemispheric coronally cut brain sections of 19 patients with multiple sclerosis and four control subjects after rapid autopsy and formalin fixation, and scanned them using 3 T and 7 T magnetic resonance imaging systems. Pulse sequences included T1-weighted, T2-weighted, fluid attenuated inversion recovery, double inversion recovery and T2*. Cortical lesions (type I-IV) were scored on all sequences by an experienced rater blinded to histopathology and clinical data. Staining was performed with antibodies against proteolipid protein and scored by a second reader blinded to magnetic resonance imaging and clinical data. Subsequently, magnetic resonance imaging images were matched to histopathology and sensitivity of pulse sequences was calculated. Additionally, a second unblinded (retrospective) scoring of magnetic resonance images was performed. Regardless of pulse sequence, 7 T magnetic resonance imaging detected more cortical lesions than 3 T. Fluid attenuated inversion recovery (7 T) detected 225% more cortical lesions than 3 T fluid attenuated inversion recovery (Z = 2.22, P < 0.05) and 7 T T2* detected 200% more cortical lesions than 3 T T2* (Z = 2.05, P < 0.05). Sensitivity of 7 T magnetic resonance imaging was influenced by cortical lesion type: 100% for type I (T2), 11% for type II (FLAIR/T2), 32% for type III (T2*), and 68% for type IV (T2). We conclude that ultra-high field 7 T magnetic resonance imaging more than doubles detection of cortical multiple sclerosis lesions, compared to 3 T magnetic resonance imaging. Unfortunately, (subpial) cortical pathology remains more extensive than 7 T magnetic resonance imaging can reveal.

A gradient in cortical pathology in multiple sclerosis by in vivo quantitative 7 T imaging.

We used a surface-based analysis of T2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2* throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤ 3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (≥ 4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2* maps were registered to anatomical cortical surfaces for sampling T2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2* was compared with patients' normal-appearing cortical grey matter T2* (paired t-test) and with mean cortical T2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2*, consistent with cortical myelin and iron loss. In early disease, T2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10(-10) and P < 10(-7)), and mean cortical T2* in controls (P < 10(-5) and P < 10(-6)). In secondary progressive multiple sclerosis, T2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface.

Accumulation of phosphorylated α-synuclein in subpial and periventricular astrocytes in multiple system atrophy of long duration.

The histological hallmark of multiple system atrophy (MSA) is accumulation of phosphorylated α-synuclein in oligodendrocytes. However, it is uncertain whether phosphorylated α-synuclein accumulates in astrocytes of MSA patients. We immunohistochemically examined the frontal and temporal lobes, basal ganglia, cerebellum, brainstem and spinal cord of patients with MSA (n = 15) and Lewy body disease (n = 20), and also in control subjects (n = 20). Accumulation of abnormally phosphorylated and aggregated α-synuclein was found in subpial and periventricular astrocytes in six of the 15 patients with MSA (40%). The structures were confined to the subpial surface of the ventro-lateral part of the spinal cord and brainstem, as well as the subependymal region of the lateral ventricles. They were not visualized by Gallyas-Braak staining, and were immunonegative for ubiquitin and p62. Immunoelectron microscopy revealed that the phosphorylated α-synuclein-immunoreactive structures in astrocytes were non-fibrillar and associated with granular and vesicular structures. The extent of phosphorylated α-synuclein-immunoreactive astrocytes was correlated with disease duration. No such structures were found in Lewy body disease or controls. Accumulation of phosphorylated α-synuclein can occur in subpial and periventricular astrocytes in patients with MSA, especially in those with a long disease duration.

Minimally invasive subpial tonsillectomy for Chiari I decompression.

BACKGROUND: A number of different surgical techniques have been used through the years to address Chiari I malformation (CMI). METHODS: This article describes how we surgically manage CMI at two high-volume centers. We call the technique the minimally invasive subpial tonsillectomy (MIST). The technique consists of a minimalistic dissection and craniectomy with a short, linear durotomy for the subpial tonsillar resection. The dura is closed without the use of a duraplasty. CONCLUSIONS: We describe our current methods of surgery for CMI.

Outcome following multiple subpial transection in Landau-Kleffner syndrome and related regression.

OBJECTIVE: To determine whether multiple subpial transection in the posterior temporal lobe has an impact on long-term outcome in children who have drug-resistant Landau-Kleffner syndrome (LKS) or other "electrical status epilepticus during sleep" (ESES)-related regression. Given the wide variability in outcomes reported in the literature, a secondary aim was to explore predictors of outcome. METHODS: The current study includes a surgery group (n = 14) comprising patients who underwent multiple subpial transection of the posterior temporal lobe and a nonsurgery comparison group (n = 21) comprising patients who underwent presurgical investigations for the procedure, but who did not undergo surgery. Outcomes were assessed utilizing clinical note review as well as direct assessment and questionnaires. RESULTS: The distribution of nonclassical cases was comparable between groups. There were some differences between the surgery and nonsurgery groups at presurgical investigation including laterality of discharges, level of language impairment, and age; therefore, follow-up analyses focused on change over time and predictors of outcome. There were no statistically significant differences between the groups in language, nonverbal ability, adaptive behavior, or quality of life at follow-up. There was no difference in the proportion of patients showing improvement or deterioration in language category over time for either group. Continuing seizures and an earlier age of onset were most predictive of poorer quality of life at long-term follow-up (F2,23 = 26.2, p = <0.001, R(2) = 0.714). SIGNIFICANCE: Both surgery and nonsurgery groups had similar proportions of classic LKS and ESES-related regression. Because no significant differences were found in the changes observed from baseline to follow-up between the two groups, it is argued that there is insufficient evidence to suggest that multiple subpial transection provides additional benefits over and above the mixed recovery often seen in LKS and related regressive epilepsies.

Surface-based analysis reveals regions of reduced cortical magnetization transfer ratio in patients with multiple sclerosis: a proposed method for imaging subpial demyelination.

The in vivo detection of subpial cortical gray matter lesions in multiple sclerosis is challenging. We quantified the spatial extent of subpial decreases in the magnetization transfer ratio (MTR) of cortical gray matter in subjects with multiple sclerosis, as such reductions may indicate regions of cortical demyelination. We exploited the unique geometry of cortical lesions by using two-dimensional parametric surface models of the cortex instead of traditional three-dimensional voxel-wise analyses. MTR images were mapped onto intermediate surfaces between the pial and white matter surfaces and were used to compute differences between secondary-progressive MS (n = 12), relapsing-remitting MS (n = 12), and normal control (n = 12) groups as well as between each individual patient and the normal controls. We identified large regions of significantly reduced cortical MTR in secondary-progressive patients when compared with normal controls. We also identified large regions of reduced cortical MTR in 11 individual patients (8 secondary-progressive, 3 relapsing-remitting). The secondary-progressive patients showed larger areas of abnormally low MTR compared with relapsing-remitting patients both at the group level and on an individual basis. The spatial distributions of abnormal MTR preferentially involved cingulate cortex, insula, and the depths of sulci, in agreement with pathological descriptions of subpial gray matter lesion distribution. These findings suggest that our method is a plausible in vivo imaging technique for quantifying subpial cortical demyelinating lesions in patients with multiple sclerosis and, furthermore, can be applied at the typical clinical field strength of 1.5 T.

Subpial resection of epileptogenic tubers: operative nuances and lessons learned.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder. Tubers of the central nervous system are a hallmark of the disorder and often cause epilepsy. Many TSC patients fail to achieve seizure control with medication alone. Several case series have demonstrated high seizure freedom rates after resective surgery. However, the technique for the resection of epileptogenic tubers has largely been unreported. Here the authors present 2 cases to illustrate their multistage approach for localizing and resecting the seizure onset zone in patients with TSC. At their institution, they have excellent seizure outcomes and a low complication rate with this technique. The video can be found here: https://stream.cadmore.media/r10.3171/2024.4.FOCVID2411.

Subpial transplantation of adipose-derived stem cells alleviates paraplegia in a rat model of aortic occlusion/reperfusion-induced spinal cord infarction.

Background: Thoracoabdominal periprocedural occlusion/reperfusion injury of the spinal cord (SCII/R) can lead to devastating paraplegia, underscoring the critical need for effective interventions. However, our knowledge of optimal medical strategies and their efficacy remains limited. Preclinical investigations have shown promise in harnessing adult stem cells, including pluripotent and multipotent stem cells such as mesenchymal stem cells (MSCs), to address SCII/R by enhancing neuro-inflammation, axonal growth, and myelination. Particularly, growth factors derived from adipose tissue-derived MSCs (ADSCs) have been proposed to facilitate recovery. Despite advancements, achieving complete recovery remains a formidable challenge. Therefore, gaining a more profound insight into the role of ADSCs in alleviating SCII/R-induced paraplegia, including optimizing the delivery systems for therapies, is imperative. Materials and methods: In this study, we assessed the impact of subpial allogeneic rat adipose tissue-derived MSCs (rADSCs) transplantation on paraplegia using a rat SCII/R model induced by ephemeral aortic occlusion, known as the Taira-Marsala model. rADSCs were isolated from adipose tissue of male Sprague-Dawley rats, cultured, characterized, and cryopreserved. One week following the induction of paraplegia, rADSCs (n = 6) or physiological saline (n = 6) were transplanted. Hind limb motor function was evaluated before treatment and at 3-, 7-, and 14-days post-treatment using the Basso-Beattie-Bresnahan scoring system. Results: The rADSC-treated group demonstrated a significant improvement in hind limb motor function compared to the saline-treated group (p < 0.05), with 5 out of 6 rats exhibiting enhanced motor function following treatment. Conclusions: Our findings suggest that subpial rADSC engraftment may enhance SCII/R-induced paraplegia recovery. These initial results drive further research to validate this potential, understand the molecular mechanisms, and optimize therapies.

Ultrasound findings of subpial hemorrhage in neonates.

PURPOSE: Subpial hemorrhage (SPH) is a subtype of intracranial hemorrhage characterized by damage to the adjacent brain parenchyma. The aim of this study was to describe the sonographic features of SPH in neonates. METHODS: The cranial ultrasound (US) findings of neonates with SPH confirmed by brain magnetic resonance imaging (MRI) were analyzed retrospectively. Initial and follow-up US and MRI scans were reviewed by two pediatric radiologists who were blinded to both clinical history and outcomes. The US features were compared with the MRI findings. RESULTS: Sixteen patients were included (median gestational age, 38 weeks; range, 26 to 40 weeks; 69% term). SPH was detected most often in the temporal lobe (63%), and multiple SPHs were found in seven of 16 neonates, based on MRI. Acute SPH with an underlying venous infarct (UVI) was detected on US in 15 of 16 patients: small or large fan-shaped hyperechoic lesions (n=7 and 4, respectively) and gyriform hyperechoic lesions (n=4). The sonographic yin-yang sign was observed in three of the four large fan-shaped SPH cases. The accompanying findings on US were intraventricular hemorrhage (four out of six MRI-confirmed cases), and concurrent periventricular venous infarcts (five out of nine MRI-confirmed cases). In five patients, subpial cysts were observed on follow-up US or MRI (n=4 and n=4, respectively). CONCLUSION: Acute SPH with UVI can appear as a peripheral fan-shaped or gyriform hyperechoic lesion on cranial US. SPH can be detected and suspected based on the US features of SPH with the accompanying findings.

Non-dysraphic intramedullary spinal cord lipoma of the child: Report of 3 cases.

BACKGROUND AND PURPOSE: Non-dysraphic intramedullary spinal cord lipomas (NDSCL) represent 1% of spinal cord tumors. They are less frequent than dysraphic spinal cord lipomas and clinical presentation is unspecific. There are no guidelines on surgical management. MATERIAL AND METHODS: We report three observations of NDSCL in children, focusing on the clinical presentation, surgical management and postoperative outcome. RESULTS: The patients, one female and two males, aged from 5 months to 10 years presented with neurological deterioration, pain, spinal rigidity and in two cases, a subcutaneous mass. Spinal MRI found intradural lipomas without spina bifida, located in the cervico-thoracic area in all cases. The lipoma extended to the medulla oblongata in two cases and was in the lumbar region in the third. These lipomas were massive, requiring decompression surgery. Surgery confirmed the lipoma to be subpial. We performed debulking of the lipoma without attempting total resection, and with or without dural plasty and laminoplasty, followed by minerva cast in two cases, and avoidance of standing in the youngest. Satisfactory recovery occurred in all three cases. After a follow-up between 4 months and 9 years, the outcome was favorable in all cases, and no patient presented with secondary spinal deformation or lipoma progression. CONCLUSION: NDSCL is a rare entity, which often manifests with progressive pain and neurological deficits. In our experience, partial resection with or without dural plasty and laminoplasty has been associated with satisfactory postoperative outcomes and no recurrence of symptoms. We should be attentive to the risk of postoperative spinal deformity in these young patients.

Neonatal subpial hemorrhage along the medial side of the temporal lobe: Two case reports.

Neonatal subpial hemorrhage has been underrecognized until recently and its pathophysiology remains unclear. Advances in magnetic resonance imaging have facilitated the identification of hemorrhage within the subpial space and cohort studies recently reported its imaging and clinical features. We encountered two cases of neonatal subpial hemorrhage along the medial side of the temporal lobe. Case 1: A 1-day-old boy had repeated apneic attacks with cyanosis from 2 hours after birth at 39 weeks of gestation by vacuum extraction delivery. Computed tomography and magnetic resonance imaging showed subpial hemorrhage from the medial to caudal side of the right temporal lobe with T2 prolongation in the underlying cerebral parenchyma. Case 2: A 0-day-old boy had repeated apneic attacks with cyanosis from 3 hours after birth at 39 weeks of gestation by vaginal delivery. Subpial hemorrhage was observed from the anterior to medial side of the left temporal lobe on computed tomography and magnetic resonance imaging. On magnetic resonance imaging, the adjacent brain parenchyma showed a hyperintense signal on T2-weighted imaging. No abnormalities or signs of fetal distress were noted in the course of delivery. A mildly prolonged activated partial thromboplastin clotting time, an elevated D-dimer level, and low fibrinogen level were detected in a blood examination after birth in both cases. Both cases had subpial hemorrhage along the medial side of the temporal lobe, which suggested that an external mechanical force with fetal head molding during delivery caused subpial hemorrhage; however, other factors, including coagulopathy, may be involved in its pathophysiology.

Subpial Schwannoma of the Cervical Spinal Cord: A Case Report and Its Intraoperative Finding Supporting a Theory of the Pathogenesis of an Intramedullary Schwannoma.

Because of its tumor origin from nerve sheath cells (the Schwann cells), the pathogenesis of an extraordinary rare intramedullary schwannoma, which should not have any Schwann's cells in nature, is controversial and still in debate. We report a case of a 63-year-old man diagnosed with a cervical cord intramedullary schwannoma with an interesting intraoperative finding that could support one of the theories on its genesis.

Subpial en bloc resection improves extent of resection in infiltrating gliomas - A propensity matched comparative cohort analysis.

BACKGROUND: Surgery remains the mainstay of glioma therapy and extent of resection is an important prognostic factor. Optimization of surgical outcomes is essential and to this end the technique of resection can potentially play an important role. Based on patterns of glioma growth and extrapolating from other solid cancer surgical principles, a subpial dissection combined with an en-bloc resection (SPER) technique appears to have advantages METHODS: We performed a propensity matched analysis comparing gliomas that were resected using SPER versus a standard piecemeal debulking technique at our centre. Potentially confounding factors (including eloquent location, use of intraoperative imaging, surgeon experience) were adjusted for in the matching of the two cohorts. Outcomes included postoperative morbidity and blinded radiological review documented postoperative ischemia (on diffusion weighted MR imaging - DWI) as well as extent of resection. RESULTS: In 57 gliomas (23 SPER and 34 standard), the gross total resection (GTR) rates were significantly higher with SPER (91 vs 65%). Postoperative DWI revealed significant ischemia in almost 50% of cases in either group, though many did not have postoperative deficits. Arterial ischemia was higher in the standard surgery group and this was associated with a significantly higher risk (seven times) of resulting in prolonged neurological deficits. CONCLUSIONS: SPER is a useful technique which increases the GTR rates in gliomas undergoing resection. It is associated with lower incidence of arterial ischemia in the postoperative period and this can result in improved long term functional outcomes.

Factor XIII deficiency in a neonate presenting as subpial haemorrhage.

Subpial haemorrhage is a rare cause of seizures in term neonates. A 3-day-old male infant, born at term with no history of perinatal hypoxia, presented with seizures and unremarkable physical examination in the interictal state. Imaging demonstrated left temporal subpial haemorrhage with the classic 'yin-yang sign' on MRI. The patient was subsequently diagnosed with factor XIII deficiency. Follow-up at 6 months and 12 months revealed encephalomalacia in the previous haemorrhagic areas with normal developmental milestones.