Meenakshi Bidwai Bhattacharjee

Objectives: Use of off-label tissue graft materials, such as acellular dermal matrix (ADM), for in utero repair of severe spina bifida (SB), where primary skin layer closure is not possible, is associated with poor neurological outcomes. The cryopreserved human umbilical cord (HUC) patch has regenerative, anti-inflammatory, and anti-scarring properties, and provides watertight SB repair. We tested the hypothesis that the HUC is a superior skin patch to ADM for reducing inflammation at the repair site and preserving spinal cord function. Methods: In timed-pregnant ewes with twins, on gestational day (GD) 75, spina bifida was created without a myelotomy (functional model). On GD 95, repair was performed using HUC vs. ADM patches (randomly assigned) by suturing them to the skin edges. Additionally, full thickness skin closure as a primary skin closure (PSC) served as a positive control. Delivery was performed on GD 140, followed by blinded to treatment neurological assessments of the lambs using the Texas Spinal Cord Injury Scale (TSCIS) for gait, proprioception, and nociception. Lambs without spina bifida were used as controls (CTL). Ex vivo magnetic resonance imaging of spines at the repair site were performed, followed by quantitative pathological assessments. Histological assessments (blinded) included Masson’s trichrome, and immunofluorescence for myeloperoxidase (MPO; neutrophils) and for reactive astrocytes (inflammation) by co-staining vimentin and GFAP. Results: The combined hind limbs’ TSCIS was significantly higher in the HUC group than in ADM and PSC groups, p = 0.007. Both ADM and PSC groups exhibited loss of proprioception and mild to moderate ataxia compared to controls. MRI showed increased pathological findings in the PSC group when compared to the HUC group, p = 0.045. Histologically, the meningeal layer was thickened (inflammation) by 2–3 fold in ADM and PSC groups when compared to HUC and CTL groups, p = 0.01. There was lower MPO positive cells in the HUC group than in the ADM group, p = 0.018. Posterior column astrocyte activation was increased in ADM and PSC lambs compared to HUC lambs, p = 0.03. Conclusion: The HUC as a skin patch for in utero spina bifida repair preserves spinal cord function by reducing underlying inflammation when compared to ADM.

Objective Pathogenic variants in TNNT3, the gene encoding fast skeletal muscle troponin T, were first described in autosomal dominant distal arthrogryposis type 2B2. Recently, a homozygous splice site variant, c.681+1G>A, was identified in a patient with nemaline myopathy and distal arthrogryposis. Here, we describe the second individual with congenital myopathy associated with biallelic TNNT3 variants. Methods Clinical exome sequencing data from a patient with molecularly undiagnosed congenital myopathy underwent research reanalysis. Clinical and histopathologic data were collected and compared with the single reported patient with TNNT3-related congenital myopathy. Results A homozygous TNNT3 variant, c.481-1G>A, was identified. This variant alters a consensus splice acceptor and is predicted to affect splicing by multiple in silico prediction tools. Both the patient reported here and the previously published patient exhibited limb, bulbar, and respiratory muscle weakness from birth, which improved over time. Other shared features include history of polyhydramnios, hypotonia, scoliosis, and high-arched palate. Distal arthrogryposis and nemaline rods, findings reported in the first patient with TNNT3-related congenital myopathy, were not observed in the patient reported here. Conclusions This report provides further evidence for the association of biallelic TNNT3 variants with severe recessive congenital myopathy with or without nemaline rods and distal arthrogryposis. TNNT3 sequencing and copy number analysis should be incorporated into the workup of congenital myopathies.

Giant cell tumor of bone is a benign but locally aggressive osteolytic neoplasm that represents 3% to 5% of all primary bone tumors, primarily found at the epiphyses of long bones. Less than 1% are of calvarial origin. Herein, we report a rare case of a nine-year-old girl with a hemorrhagic giant cell tumor of the left occipital skull base.

Although rare, hyaline cytoplasmic inclusions isolated to astrocytes of the cerebral cortex have been identified in a spectrum of diseases ranging from intractable epilepsy in pediatric patients with only mild to moderate developmental delays to Aicardi syndrome. These inclusions classically stain positive for filamin A, giving rise to the term "filaminopathies." The authors report on 2 pediatric patients with intractable epilepsy and developmental delay who uniquely displayed filamin A-negative hyaline astrocytic inclusions in resected brain tissues. Additionally, these inclusions stained positive for S100 and negative for glial fibrillary acidic protein, chromogranin, neurofilament, CD34, vimentin, periodic acid-Schiff (PAS), and Alcian blue. These are the first reported cases of filamin A-negative hyaline astrocytic inclusions, providing a novel variation on a previously reported entity and justification to further investigate the pathogenesis of these inclusions. The authors compare their findings with previously reported cases and review the literature on hyaline astrocytic inclusions in intractable pediatric epilepsy.

Amyloid plaques in Alzheimer’s disease (AD) are associated with inflammation. Recent studies demonstrated the involvement of the gut in cerebral amyloid-beta (Aβ) pathogenesis; however, the mechanisms are still not well understood. We hypothesize that the gut bears the Aβ burden prior to brain, highlighting gut–brain axis (GBA) interaction in neurodegenerative disorders. We used pre-symptomatic (6-months) and symptomatic (15-months) Tg2576 mouse model of AD compared to their age-matched littermate WT control. We identified that dysfunction of intestinal epithelial barrier (IEB), dysregulation of absorption, and vascular Aβ deposition in the IEB occur before cerebral Aβ aggregation is detectible. These changes in the GBA were associated with elevated inflammatory plasma cytokines including IL-9, VEGF and IP-10. In association with reduced cerebral myelin tight junction proteins, we identified reduced levels of systemic vitamin B12 and decrease cubilin, an intestinal B12 transporter, after the development of cerebral Aβ pathology. Lastly, we report Aβ deposition in the intestinal autopsy from AD patients with confirmed cerebral Aβ pathology that is not present in intestine from non-AD controls. Our data provide evidence that gut dysfunction occurs in AD and may contribute to its etiology. Future therapeutic strategies to reverse AD pathology may involve the early manipulation of gut physiology and its microbiota.

We report a case of alveolar soft part sarcoma (ASPS) presenting as an isolated frontal lobe metastasis. The tumor demonstrated little or no immunoreactivity for a broad panel of antibodies yet strong, diffuse immunoreactivity with CD68. On electron microscopy, the characteristic rectangular to rhomboid crystalline inclusions of ASPS were not present. Electron-dense granules resembling peroxisomes were present, sometimes in association with elongated granular structures having a periodic, lattice-like arrangement. Metastatic ASPS was confirmed by demonstration of an ASPSCR1–TFE3 fusion and imaging studies that excluded metastatic Xp11.2 translocation renal cell carcinoma. The primary site was subsequently identified in the lower extremity.

Dermoid tumors are benign congenital cystic lesions that usually present with local mass effect. Very rarely, they present as spontaneous ruptures. Traumatic rupture of these dermoid cysts is an extremely rare event and only a handful of such cases have been ever reported. A 47-year-old female presented to our hospital with a ruptured intracranial dermoid cyst following a mild head injury. The ruptured cyst contents were disseminated into the subarachnoid and intraventricular compartments, resulting in an obstructive hydrocephalus. After medical stabilization, she underwent gross total resection of the cyst using combined transsylvian, transcortical-transventricular, and sub-frontal approaches. A ventriculo-peritoneal shunt was eventually also needed. Traumatic rupture of an intracranial dermoid cyst is an extremely rare event and this is only the fourth such case reported in the literature. We presume that this rupture occurs due to sudden shifts in the cyst sac, which is adherent to some partially mobile intracranial contents. Although computed tomography (CT) is often adequate in making a diagnosis of this entity, magnetic resonance imaging (MRI) provides complete characterization of the extent of lipid dissemination, and is essential for operative planning. Intravenous steroids at presentation are helpful in managing the aseptic meningitis associated with rupture. Complete surgical resection is the goal, but must be weighed against the risk for injury to nearby vital structures. Hydrocephalus should be managed promptly, and patients should be monitored for it closely in the perioperative period. Even though the recurrence rate with subtotal resection is extremely rare, follow up should be done routinely.

Immunohistochemistry (IHC) has become an important tool in the diagnosis of brain tumors. To review the latest advances in IHC in the diagnostic neuro-oncologic pathology. Original research and review articles and the authors' personal experiences. We review the features of new, useful or potentially applicable marker antibodies as well as the new uses of already established antibodies in the area of diagnostic neuro-oncologic pathology, focusing on the use of IHC for differential diagnosis and prognosis. We discuss (1) placental alkaline phosphatase, c-Kit, and OCT4 for germinoma, (2) alpha-inhibin and D2-40 for capillary hemangioblastoma, (3) phosphohistone-H3 (PHH3), MIB-1/Ki-67, and claudin-1 for meningioma, (4) PHH3, MIB-1/Ki-67, and p53 for astrocytoma, (5) synaptophysin, microtubule-associated protein 2, neurofilament protein, and neuronal nuclei for medulloblastoma, (6) INI1 for atypical teratoid/rhabdoid tumor, and (7) epithelial membrane antigen for ependymoma. All the markers presented here are used mainly for supporting or confirming the diagnosis, with the exception of the proliferation markers (MIB-1/Ki-67 and PHH3), which are primarily used to support grading and are reportedly associated with prognosis in certain categories of brain tumors. Although conventional hematoxylin-eosin staining is the mainstay for pathologic diagnosis, IHC has played a major role in differential diagnosis and in improving diagnostic accuracy not only in general surgical pathology but also in neuro-oncologic pathology. The judicious use of a panel of selected immunostains is unquestionably helpful in diagnostically challenging cases. In addition, IHC is also of great help in predicting the prognosis for certain brain tumors.