Acute neutrophilic vasculitis (leukocytoclasia) in 36 COVID-19 autopsy brains.

BACKGROUND: Hypercytokinemia, the renin-angiotensin system, hypoxia, immune dysregulation, and vasculopathy with evidence of immune-related damage are implicated in brain morbidity in COVID-19 along with a wide variety of genomic and environmental influences. There is relatively little evidence of direct SARS-CoV-2 brain infection in COVID-19 patients. METHODS: Brain histopathology of 36 consecutive autopsies of patients who were RT-PCR positive for SARS-CoV-2 was studied along with findings from contemporary and pre-pandemic historical control groups. Immunostaining for serum and blood cell proteins and for complement components was employed. Microcirculatory wall complement deposition in the COVID-19 cohort was compared to historical control cases. Comparisons also included other relevant clinicopathological and microcirculatory findings in the COVID-19 cohort and control groups. RESULTS: The COVID-19 cohort and both the contemporary and historical control groups had the same rate of hypertension, diabetes mellitus, and obesity. The COVID-19 cohort had varying amounts of acute neutrophilic vasculitis with leukocytoclasia in the microcirculation of the brain in all cases. Prominent vascular neutrophilic transmural migration was found in several cases and 25 cases had acute perivasculitis. Paravascular microhemorrhages and petechial hemorrhages (small brain parenchymal hemorrhages) had a slight tendency to be more numerous in cohort cases that displayed less acute neutrophilic vasculitis. Tissue burden of acute neutrophilic vasculitis with leukocytoclasia was the same in control cases as a group, while it was significantly higher in COVID-19 cases. Both the tissue burden of acute neutrophilic vasculitis and the activation of complement components, including membrane attack complex, were significantly higher in microcirculatory channels in COVID-19 cohort brains than in historical controls. CONCLUSIONS: Acute neutrophilic vasculitis with leukocytoclasia, acute perivasculitis, and associated paravascular blood extravasation into brain parenchyma constitute the first phase of an immune-related, acute small-vessel inflammatory condition often termed type 3 hypersensitivity vasculitis or leukocytoclastic vasculitis. There is a higher tissue burden of acute neutrophilic vasculitis and an increased level of activated complement components in microcirculatory walls in COVID-19 cases than in pre-pandemic control cases. These findings are consistent with a more extensive small-vessel immune-related vasculitis in COVID-19 cases than in control cases. The pathway(s) and mechanism for these findings are speculative.

Congenital Spinal Lipomatous Malformations. Part 2. Differentiation from Selected Closed Spinal Malformations.

BACKGROUND: Congenital spinal lipomatous malformations (spinal lipomas, lipomyeloceles, and lipomyelomeningoceles) are closed neural tube defects over the lower back. Differentiation from some other closed neural tube defects in this region can be problematic for pathologists. MATERIALS AND METHODS: This review is based on PubMed searches of the embryology, gross and histopathologic findings, and laboratory reporting requisites for retained medullary spinal cords, coccygeal medullary vestiges and cysts, myelocystoceles, true human vestigial tails, and pseudotails for comparison with congenital spinal lipomatous malformations. RESULTS: Embryology, imaging, gross and histopathology of these closed neural tube lesions have different but overlapping features compared to congenital spinal lipomatous malformations, requiring context for diagnosis. CONCLUSION: The lipomyelocele spectrum and to some degree all of the malformations discussed, even though they may not share gross appearance, anatomic site, surgical approach, or prognosis, require clinical and histopathologic correlation for final diagnosis.

Congenital Spinal Lipomatous Malformations. Part 1. Spinal Lipomas, Lipomyeloceles, and Lipomyelomeningoceles.

Background: Lumbosacral spinal lipomas and lipomyeloceles are usually identified in early childhood. Terminology, histopathology, and diagnosis for these malformations can be confusing. Materials and Methods: This is a PubMed review with comparison of embryology, gross, and histopathology, and reporting requisites for these and related closed spinal malformations. Results: The spinal lipoma group (congenital spinal lipomatous malformations) includes subcutaneous, transdural, intradural, and noncontiguous malformations stretching through the entire lower spinal region. This lipomyelocele trajectory overlaps the embryonic tail's caudal eminence. Histopathologically, the lipomyelocele spectrum is a heterogeneous, stereotypical set of findings encountered from dermis to spinal cord. Diagnosis requires detailed correlation of images, intraoperative inspection, and histopathology. Conclusions: Appropriate terminology and clinicopathologic correlation to arrive at a diagnosis is a critical activity shared by pathologist and clinician. Prognostic and management differences depend on specific diagnoses. Familial and genetic influences play little if any role in patient management in closed spinal malformations.

Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy.

BACKGROUND: The identification of the molecular basis of mitochondrial disorders continues to be challenging and expensive. The increasing usage of next-generation sequencing is facilitating the discovery of the genetic aetiology of heterogeneous phenotypes associated with these conditions. Coenzyme Q(10) (CoQ(10)) is an essential cofactor for mitochondrial respiratory chain complexes and other biochemical pathways. Mutations in genes involved in CoQ(10) biosynthesis cause primary CoQ(10) deficiency syndromes that can be treated with oral supplementation of ubiquinone. METHODS: We used whole exome sequencing to evaluate six probands from four unrelated families with clinical findings suggestive of a mitochondrial disorder. Clinical data were obtained by chart review, parental interviews, direct patient assessment and biochemical and pathological evaluation. RESULTS: We identified five recessive missense mutations in COQ4 segregating with disease in all four families. One mutation was found in a homozygous state in two unrelated Ashkenazi Jewish probands. All patients were female, and presented on the first day of life, and died in the neonatal period or early infancy. Clinical findings included hypotonia (6/6), encephalopathy with EEG abnormalities (4/4), neonatal seizures (3/6), cerebellar atrophy (4/5), cardiomyopathy (5/6) and lactic acidosis (4/6). Autopsy findings in two patients revealed neuron loss and reactive astrocytosis or cerebellar and brainstem hypoplasia and microdysgenesis. CONCLUSIONS: Mutations in COQ4 cause an autosomal recessive lethal neonatal mitochondrial encephalomyopathy associated with a founder mutation in the Ashkenazi Jewish population. The early mortality in our cohort suggests that COQ4 is an essential component of the multisubunit complex required for CoQ(10) biosynthesis.

Identification of a novel polyomavirus in a pancreatic transplant recipient with retinal blindness and vasculitic myopathy.

BACKGROUND: A 33 year-old pancreatic transplant recipient developed weakness, retinal blindness, and necrotic plaques on her face, scalp, and hands. METHODS: A muscle biopsy was analyzed by light and electron microscopy and high-throughput nucleic acid sequencing. RESULTS: The biopsy revealed microthrombosis and viral particles in swollen endothelial cell nuclei. High-throughput sequencing of nucleic acid revealed a novel polyomavirus. In situ hybridization confirmed the presence of the polyomavirus in endothelial cells at sites of myositis and cutaneous necrosis. CONCLUSIONS: New Jersey polyomavirus (NJPyV-2013) is a novel polyomavirus that may have tropism for vascular endothelial cells.

Next generation sequencing as an aid to diagnosis and treatment of an unusual pediatric brain cancer.

Classification of pediatric brain tumors with unusual histologic and clinical features may be a diagnostic challenge to the pathologist. We present a case of a 12-year-old girl with a primary intracranial tumor. The tumor classification was not certain initially, and the site of origin and clinical behavior were unusual. Genomic characterization of the tumor using a Clinical Laboratory Improvement Amendment (CLIA)-certified next-generation sequencing assay assisted in the diagnosis and translated into patient benefit, albeit transient. Our case argues that next generation sequencing may play a role in the pathological classification of pediatric brain cancers and guiding targeted therapy, supporting additional studies of genetically targeted therapeutics.

Mycoplasmal cerebral vasculopathy in a lymphoma patient: presumptive evidence of Mycoplasma pneumoniae microvascular endothelial cell invasion in a brain biopsy.

A 73-year-old man had episodic encephalopathy, ataxia and neuropathy. Symptoms largely resolved but adenopathy later lead to the diagnosis of a low-grade follicular lymphoma. The neurological symptoms soon recurred with new pontine calcifications identified by computed tomography. Brain biopsy revealed microvascular endothelial cell nuclear changes. Electron microscopy identified small polymorphic bacteria without a cell wall and with terminal and attachment organelles within endothelial cells and clustered in some microvascular lumina. Immunostaining was positive for Mycoplasma pneumoniae and convalescent serum enzyme immunoassay was positive for M. pneumoniae IgG. The patient again recovered and he was neurologically stable 33 months after the initial episode. The ultrastructural findings of the bacterial cells are distinctive of some mycoplasmal species when compared to other small bacteria. Mycoplasma-like organisms are reported in four autopsied patients who had chronic encephalopathy, movement disorders, and some of the same light- and electron-microscopic findings in the brain as our patient. Direct neuroinvasion by Mycoplasma species has been suggested, while anatomic observations in our patient and in the four autopsy cases show microvascular invasion but not parenchymal invasion. Most mycoplasmal encephalitis may be immune-mediated. The frequency of neurovascular invasion is not known. It may be rare and it may persist.

I-Z-I complexes in congenital myopathy.

A 3-month-old boy with hypotonia at birth succumbed to a congenital myopathy. The major finding in his muscle biopsy corresponded to I-Z-I complexes described previously in embryonic skeletal muscle. A few previous myopathy cases have described findings suggestive of I-Z-I-like complexes. A mutation affecting mononuclear myoblasts or early myotubes was suspected, although an acquired lesion could not be ruled out. The findings may also have been altered by secondary events in this unusual case.

Focal chronic inflammatory epileptic encephalopathy in a patient with malformations of cortical development, with a review of the spectrum of chronic inflammatory epileptic encephalopathy.

PURPOSE: Chronic cellular inflammation closely associated with epilepsy without an active infection is a hallmark of Rasmussen encephalitis (RE). RE has typical and defining features lacking in other rare epilepsy patients who also have neocortical lymphocytes without an identifiable cause. A patient with malformations of cortical development had an abrupt change in frequency and epileptic focus after 22 years of a stable seizure disorder. Functional neurosurgery yielded a specimen showing a mixed cellular meningoencephalitis in the absence of a demonstrable infection. METHODS: Historical, neurologic, electroencephalographic, pathologic, and literature data were correlated. RESULTS: There was a subarachnoid mixed infiltrate including evidence of dendritic cells in our patient and also cytotoxic T lymphocytes adjacent to karyolytic neurons that corresponded to cells previously demonstrated to damage neurons in RE. Literature review disclosed 42 other cases similar to RE but with heterogeneous findings. The course was more protracted and often more benign than in RE. The inflammation that would have markedly decreased or disappeared in RE over that period was generally still well represented. CONCLUSIONS: Our patient has heterogeneous features similar to, yet with differences from, RE. Literature review of chronic cellular inflammatory epileptic encephalopathy cases also similar to RE discloses important differences that may reflect idiosyncratic reactions and pace of the disease rather than a different disease. Comorbidity factors, genetic population traits, and secondary effects of the seizure disorder may lead to an expansion of the initial site of damage by an autoimmune reaction. These cases might best be grouped, probably along with RE, as secondary autoimmune diseases.

Peripheral primitive neuroectodermal tumor of the cavernous sinus: case report.

OBJECTIVE: Ewing sarcoma/peripheral primitive neuroectodermal tumors (pPNET family) are small, round, blue cell tumors that have a decided predilection for young patients and commonly arise in bone and soft tissue. We are reporting a rare case of cavernous sinus pPNET in a 48-year-old woman. CLINICAL PRESENTATION: A 48-year-old woman presented with headache, ipsilateral maxillary, and ophthalmic and oculomotor nerve palsies. Neuroimaging revealed a cavernous sinus lesion. INTERVENTION: The patient underwent debulking of the tumor, and the diagnosis of a pPNET was made based on histological, immunohistochemical, and molecular genetics (EWS-FLI1 fusion gene) findings. Bone scans, bone marrow aspiration, and biopsy and chest computed tomographic scans showed no evidence of systemic involvement. The patient had adjuvant treatment with radiotherapy and chemotherapy. After 14 months, the patient had no neurological deficits, and neuroimaging showed stable disease, although some chemotherapy complications occurred. CONCLUSION: This is a case of cavernous sinus pPNET in a 48-year-old woman, in whom the diagnosis is supported by the presence of EWS-FLI1 fusion gene. This seems to be the first reported case of a cavernous sinus pPNET confirmed by molecular genetic analysis.

Age-related differences in 1p and 19q deletions in oligodendrogliomas.

BACKGROUND: Recent reports indicate that anaplastic oligodendrogliomas frequently show allelic losses on chromosome arms 1p and 19q, and that these deletions are associated with better chemotherapeutic response and overall patient survival. Because of the diversified genetic makeup of the population and the centralized provincial referral system for brain tumor patients in Manitoba, the epidemiological features of such tumors sometimes differ from the published data acquired from non-community based settings. In this study, we assessed the prevalence of allelic deletions for chromosome arms 1p and 19q in anaplastic and in low-grade oligodendrogliomas in the Manitoba population. METHODS: Loss of heterozygosity (LOH) analysis of brain tumors was carried out using 4 microsatellite markers (D1S508, D1S2734, D19S219 and D19S412) and a PCR based assay. The tumors were consecutively acquired during the period September 1999-March 2001 and a total of 63 tumors were assessed. RESULTS: We found that allelic loss of chromosome 1p and 19q was higher in oligodendrogliomas than in other diffuse gliomas and that for anaplastic oligodendrogliomas, younger patients exhibited significantly more deletions than older patients (>60 years of age). CONCLUSIONS: These studies suggest that age may be a factor in the genetic alterations of oligodendrogliomas. In addition, these studies demonstrate that this assay can easily be carried out in a cost-effective manner in a small tertiary center.