Neuropathology of Congenital Heart Disease in an Inpatient Autopsy Cohort 2000-2017.

Background As a result of medical and surgical advancements in the management of congenital heart disease (CHD), survival rates have improved substantially, which has allowed the focus of CHD management to shift toward neurodevelopmental outcomes. Previous studies of the neuropathology occurring in CHD focused on cases preceding 1995 and reported high rates of white matter injury and intracranial hemorrhage, but do not reflect improvements in management of CHD in the past 2 decades. The purpose of this study is therefore to characterize the neuropathological lesions identified in subjects dying from CHD in a more-recent cohort from 2 institutions. Methods and Results We searched the autopsy archives at 2 major children's hospitals for patients with cyanotic congenital cardiac malformations who underwent autopsy. We identified 50 cases ranging in age from 20 gestational weeks to 46 years. Acquired neuropathological lesions were identified in 60% (30 of 50) of subjects upon postmortem examination. The most common lesions were intracranial hemorrhage, most commonly subarachnoid (12 of 50; 24%) or germinal matrix (10 of 50; 20%), hippocampal injuries (10 of 50; 20%), and diffuse white matter gliosis (8 of 50; 16%). Periventricular leukomalacia was rare (3 of 50). Twenty-six subjects underwent repair or palliation of their lesions. Of the 50 subjects, 60% (30 of 50) had isolated CHD, whereas 24% (12 of 50) were diagnosed with chromosomal abnormalities (trisomy 13, 18, chromosomal deletions, and duplications) and 16% (8/50) had multiple congenital anomalies. Conclusions In the modern era of pediatric cardiology and cardiac surgery, intracranial hemorrhage and microscopic gray matter hypoxic-ischemic lesions are the dominant neuropathological lesions identified in patients coming to autopsy. Rates of more severe focal lesions, particularly periventricular leukomalacia, have decreased compared with historical controls.

Brain death: Radiologic signs of a non-radiologic diagnosis.

Brain death is a clinical diagnosis characterized by the irreversible loss of neurologic function caused by global injury to the brain, including the brain stem. This is often caused by trauma and subarachnoid hemorrhage amongst other etiologies. This injury results in extensive cerebral edema, a rise in intracranial pressure, and eventual cessation of cerebral blood flow. Although brain death is a clinical diagnosis, ancillary and confirmatory tests are widely used. These are categorized into imaging that demonstrates absence of cerebral blood flow and electroencephalography that demonstrates absence of cortical electrical activity. Cerebral angiography, transcranial Doppler, and cerebral scintigraphy are the only imaging studies to have been validated by the American Academy of Neurology for diagnosis of brain death. However, characteristic findings on computed tomography, computed tomography perfusion, computed tomography angiography, magnetic resonance imaging, and magnetic resonance angiography may suggest the diagnosis. In this article, the clinical criteria, pathophysiology, pathology, and variations in current practice of brain death diagnosis are discussed, and the imaging findings of brain death are reviewed.

Unexpected Death of a Child with Complex Febrile Seizures-Pathophysiology Similar to Sudden Unexpected Death in Epilepsy?

Febrile seizures are usually considered relatively benign. Although some cases of sudden unexplained death in childhood have a history of febrile seizures, no documented case of febrile seizure-induced death has been reported. Here, we describe a child with complex febrile seizures who died suddenly and unexpectedly after a suspected seizure while in bed at night during the beginning phases of sleep. She was resuscitated and pronounced brain dead 2 days later at our regional medical center. Autopsy revealed multiorgan effects of hypoperfusion and did not reveal an underlying (precipitating) disease, injury, or toxicological cause of death. Although a seizure was not witnessed, it was suspected as the underlying cause of death based on the medical examiner and forensic pathologist (author Marcus Nashelsky) investigation, the post-resuscitation clinical findings, and multiple aspects of the clinical history. The child had a history of complex febrile seizures that had previously caused apnea and oxygen desaturation. She had two febrile seizures earlier on the same day of the fatal event. Interestingly, her mother also experienced a febrile seizure as a child, which led to respiratory arrest requiring cardiorespiratory resuscitation. This case suggests that in a child with complex febrile seizures, a seizure can induce death in a manner that is consistent with the majority of cases of sudden unexpected death in epilepsy (SUDEP). Further work is needed to better understand how and why certain individuals, with a history of epilepsy or not, die suddenly and unexpectedly from seizures. This will only occur through better understanding of the pathophysiologic mechanisms underlying epileptic and febrile seizures and death from seizures including SUDEP.

Alveolar Soft Part Sarcoma.

Alveolar soft part sarcoma is a rare neoplasm usually arising in the soft tissues of the lower limbs in adults and in the head and neck region in children. It presents primarily as a slowly growing mass or as metastatic disease. It is characterized by a specific chromosomal alteration, der(17)t(X:17)(p11:q25), resulting in fusion of the transcription factor E3 (TFE3) with alveolar soft part sarcoma critical region 1 (ASPSCR1) at 17q25. This translocation is diagnostically useful because the tumor nuclei are positive for TFE3 by immunohistochemistry. Real-time polymerase chain reaction to detect the ASPSCR1-TFE3 fusion transcript on paraffin-embedded tissue blocks has been shown to be more sensitive and specific than detection of TFE3 by immunohistochemical stain. Cathepsin K is a relatively recent immunohistochemical stain that can aid in the diagnosis. The recent discovery of the role of the ASPSCR1-TFE3 fusion protein in the MET proto-oncogene signaling pathway promoting angiogenesis and cell proliferation offers a promising targeted molecular therapy.

Metastatic involvement of the pituitary gland: a systematic review with pooled individual patient data analysis.

PURPOSE: To report a rare case of pituitary metastasis (PM) from hepatocellular carcinoma (HCC) and help better understand the incidence of PM and its most common presenting symptoms through a pooled individual patient data analysis. METHODS: Literature regarding PM was systematically reviewed with a pooled individual patient data analysis conducted. Pooled individual data analysis result is also compared with the result in a most recent systematic review. RESULTS: Our results demonstrate that the incidence of PM among all intracranial metastases is 0.87% (95% CI 0.56, 1.18); it is 1.9% (95% CI 1.46, 2.34) among all autopsied cancer cases; it is 11.56% (95% CI 7.08, 16.04) among all breast cancer patients who had hypophysectomies and 12.83% (95% CI 10.5, 15.16) among all autopsied breast cancer patients. The fixed effect model showed that the incidence of PM in breast cancer patients group is significantly higher (p < 0.001) with an odds ratio of 6.71 (95% CI 4.24, 10.61). Breast and lung cancer are the most common primary cancer of PM with a percentage of 37.2 and 24.2 respectively. The next most common primary sites are prostate and kidney respectively, although the percentages for each are only about 5. Diabetes insipidus (DI) remains the most common symptom among all reported PM cases with a pooled incidence of 42.34% (95% CI 36.15, 48.53). Although not significant (χ(2) = 2.846, df = 1, p = 0.061), it is less common in the most recent reported cases which has a pooled incidence of 32.76% (95% CI 20.31, 45.21). DI is extremely rare in the reported PM cases from HCC (none of the eight cases presented with DI). The symptoms of anterior hypopituitarism (23.68 vs 39.66%, p = 0.015), visual deterioration (27.89 vs 41.38%, p = 0.039), cranial nerve palsies (21.58 vs 41.38%, p = 0.003) and headaches (15.79 vs 32.76%, p = 0.005) were reported significantly higher than previously described in the literature. CONCLUSIONS: Pituitary metastasis is rare in patients with cancer, and the pituitary gland is an uncommonly involved location in patients with intracranial metastases. With advanced diagnostic imaging techniques and increased awareness about the manifestation of sellar lesions, the incidence of cranial nerve palsies and anterior pituitarism are higher than reported. This information may allow earlier diagnosis of PM.

FSH receptor (FSHR) expression in human extragonadal reproductive tissues and the developing placenta, and the impact of its deletion on pregnancy in mice.

Expression and function of the follicle-stimulating hormone receptor (FSHR) in females were long thought to be limited to the ovary. Here, however, we identify extragonadal FSHR in both the human female reproductive tract and the placenta, and test its physiological relevance in mice. We show that in nonpregnant women FSHR is present on: endothelial cells of blood vessels in the endometrium, myometrium, and cervix; endometrial glands of the proliferative and secretory endometrium; cervical glands and the cervical stroma; and (at low levels) stromal cells and muscle fibers of the myometrium. In pregnant women, placental FSHR was detected as early as 8-10 wk of gestation and continued through term. It was expressed on: endothelial cells in fetal portions of the placenta and the umbilical cord; epithelial cells of the amnion; decidualized cells surrounding the maternal arteries in the maternal decidua; and the stromal cells and muscle fibers of the myometrium, with particularly strong expression at term. These findings suggest that FSHR expression is upregulated during decidualization and upregulated in myometrium as a function of pregnancy. The presence of FSHR in the placental vasculature suggests a role in placental angiogenesis. Analysis of genetically modified mice in which Fshr is lacking in fetal portions of the placenta revealed adverse effects on fetoplacental development. Our data further demonstrate FSHB and CGA mRNAs in placenta and uterus, consistent with potential local sources of FSH. Collectively, our data suggest heretofore unappreciated roles of extragonadal FSHR in female reproductive physiology.

Cordectomy for intramedullary spinal cord glioblastoma with a 12-year survival.

BACKGROUND: Prognosis of patients with spinal cord glioblastoma is poor, with an average survival of 18 months. There are reports in the literature describing cordectomy as a treatment option for patients with spinal cord tumors. CASE DESCRIPTION: This is a case report of a patient with spinal cord glioblastoma who, in addition to radiation and chemotherapy, was treated with cordectomy. Outcome of treatment resulted in 12-year survival. CONCLUSION: Cordectomy in spinal cord glioblastoma can result in prolonged and meaningful survival.

Autograft-derived spinal cord mass following olfactory mucosal cell transplantation in a spinal cord injury patient: Case report.

Over the last decade, human cell transplantation and neural stem cell trials have examined the feasibility and safety of these potential therapies for treatment of a variety of neurological disorders. However, significant safety concerns have surrounded these trials due to the possibility of ectopic, uncontrolled cellular growth and tumor formation. The authors present the case of an 18-year-old woman who sustained a complete spinal cord injury at T10-11. Three years after injury, she remained paraplegic and underwent olfactory mucosal cell implantation at the site of injury. She developed back pain 8 years later, and imaging revealed an intramedullary spinal cord mass at the site of cell implantation, which required resection. Intraoperative findings revealed an expanded spinal cord with a multicystic mass containing large amounts of thick mucus-like material. Histological examination and immunohistochemical staining revealed that the mass was composed mostly of cysts lined by respiratory epithelium, submucosal glands with goblet cells, and intervening nerve twigs. This is the first report of a human spinal cord mass complicating spinal cord cell transplantation and neural stem cell therapy. Given the prolonged time to presentation, safety monitoring of all patients with cell transplantation and neural stem cell implantation should be maintained for many years.

Limited Wegener's Granulomatosis Presenting with an Isolated Abduction Deficit.

Wegener's granulomatosis often affects the orbit, typically presenting with painful proptosis. The authors describe a 14 year-old girl, with limited Wegener's granulomatosis, who initially presented with an isolated painless abduction deficit that spontaneously resolved over several weeks. She subsequently developed painful proptosis and diplopia, followed by facial and oral nodules. This case demonstrates that limited Wegener's granulomatosis can rarely present with an isolated painless abduction deficit.

G-protein coupled receptor expression patterns delineate medulloblastoma subgroups.

BACKGROUND: Medulloblastoma is the most common malignant brain tumor in children. Genetic profiling has identified four principle tumor subgroups; each subgroup is characterized by different initiating mutations, genetic and clinical profiles, and prognoses. The two most well-defined subgroups are caused by overactive signaling in the WNT and SHH mitogenic pathways; less is understood about Groups 3 and 4 medulloblastoma. Identification of tumor subgroup using molecular classification is set to become an important component of medulloblastoma diagnosis and staging, and will likely guide therapeutic options. However, thus far, few druggable targets have emerged. G-protein coupled receptors (GPCRs) possess characteristics that make them ideal targets for molecular imaging and therapeutics; drugs targeting GPCRs account for 30-40% of all current pharmaceuticals. While expression patterns of many proteins in human medulloblastoma subgroups have been discerned, the expression pattern of GPCRs in medulloblastoma has not been investigated. We hypothesized that analysis of GPCR expression would identify clear subsets of medulloblastoma and suggest distinct GPCRs that might serve as molecular targets for both imaging and therapy. RESULTS: Our study found that medulloblastoma tumors fall into distinct clusters based solely on GPCR expression patterns. Normal cerebellum clustered separately from the tumor samples. Further, two of the tumor clusters correspond with high fidelity to the WNT and SHH subgroups of medulloblastoma. Distinct over-expressed GPCRs emerge; for example, LGR5 and GPR64 are significantly and uniquely over-expressed in the WNT subgroup of tumors, while PTGER4 is over-expressed in the SHH subgroup. Uniquely under-expressed GPCRs were also observed. Our key findings were independently validated using a large international dataset. CONCLUSIONS: Our results identify GPCRs with potential to act as imaging and therapeutic targets. Elucidating tumorigenic pathways is a secondary benefit to identifying differential GPCR expression patterns in medulloblastoma tumors.

Spinal cord schistosomiasis: unexpected postmortem finding.

OBJECTIVES: To report a case of a US resident, originally from Liberia, with chronic hepatitis C infection who developed acute neurologic symptoms of the lower limbs. METHODS: Our case is compared to previously reported similar cases, with emphasis on clinical symptoms, investigations, diagnosis, and prognosis. RESULTS: The patient was transferred to the University of Iowa Hospital and Clinics for further management of severe retroperitoneal bleeding and died 2 days after admission. The diagnosis of schistosomiasis was established on examination of the spinal cord at autopsy, where multiple Schistosoma mansoni eggs were seen in the vasculature of the spinal cord. CONCLUSIONS: The diagnosis of schistosomiasis may go undiagnosed in countries where the disease is not endemic but should be considered when investigating spinal cord disease in patients native to an endemic area or international travelers.

A 50-year-old man with back pain and a sellar mass. Metastatic hepatocellular carcinoma.

Hepatocellular carcinoma rarely metastasizes to the pituitary gland and this site is very rarely the initial site of disease presentation. When it does, it may mimic a far more common pituitary adenoma. Metastatic hepatocellular carcinoma should be suspected in any individual with known liver disease or significant risk factors. The most common clinical sign of metastatic HCC to the skull is a subcutaneous mass followed by neurological deficits including visual disturbances, headache and seizure. The diagnosis can be made based on the histopathologic and immunohistochemical findings. When metastatic HCC is present in the skull base, appropriate work up should be done to rule out other metastatic sites, most commonly present in the spine.

Coexistence of Huntington's disease and amyotrophic lateral sclerosis: a clinicopathologic study.

We report a retrospective case series of four patients with genetically confirmed Huntington's disease (HD) and sporadic amyotrophic lateral sclerosis (ALS), examining the brain and spinal cord in two cases. Neuropathological assessment included a polyglutamine recruitment method to detect sites of active polyglutamine aggregation, and biochemical and immunohistochemical assessment of TDP-43 pathology. The clinical sequence of HD and ALS varied, with the onset of ALS occurring after the mid-50's in all cases. Neuropathologic features of HD and ALS coexisted in both cases examined pathologically: neuronal loss and gliosis in the neostriatum and upper and lower motor neurons, with Bunina bodies and ubiquitin-immunoreactive skein-like inclusions in remaining lower motor neurons. One case showed relatively early HD pathology while the other was advanced. Expanded polyglutamine-immunoreactive inclusions and TDP-43-immunoreactive inclusions were widespread in many regions of the CNS, including the motor cortex and spinal anterior horn. Although these two different proteinaceous inclusions coexisted in a small number of neurons, the two proteins did not co-localize within inclusions. The regional distribution of TDP-43-immunoreactive inclusions in the cerebral cortex partly overlapped with that of expanded polyglutamine-immunoreactive inclusions. In the one case examined by TDP-43 immunoblotting, similar TDP-43 isoforms were observed as in ALS. Our findings suggest the possibility that a rare subset of older HD patients is prone to develop features of ALS with an atypical TDP-43 distribution that resembles that of aggregated mutant huntingtin. Age-dependent neuronal dysfunction induced by mutant polyglutamine protein expression may contribute to later-life development of TDP-43 associated motor neuron disease in a small subset of patients with HD.

Endoscopic resection of calcifying pseudoneoplasm of the neuraxis (CAPNON) of the anterior skull base with sinonasal extension.

We present a calcifying pseudoneoplasm of the neuraxis (CAPNON) of the anterior skull base that was resected endoscopically. The clinical details are reported with a review of the relevant literature. CAPNON, although rare, should be considered in the differential diagnosis of tumors presenting along the anterior skull base with radiographic characteristics consistent with a fibro-osseous lesion. Endoscopic resection of these lesions is feasible in select patients with sinonasal extension.

Unusual "double density" colloid cysts.

Third ventricular tumors vary in etiology. Treatment and surgical approach usually depends on preoperative diagnosis. Colloid cysts are the most common tumors of the third ventricle and the occurrence of two colloid cysts in the ventricular system is rare. Here we present a patient with paired colloid cysts of the third and lateral ventricles that had different radiographic characteristics, and both of which were resected through a purely endoscopic approach. This is the third reported patient with dual or paired colloid cysts. It is the second report of a lateral and third ventricular cyst, and to our knowledge the first to be successfully managed with purely endoscopic techniques obviating the need for a craniotomy. This report illustrates the importance of a wide differential when investigating intraventricular lesions and provides another example of a purely endoscopic transcortical approach for the resection of colloid cyst.

Large osteolytic skull tumor presenting as a small subcutaneous scalp lesion.

Subcutaneous nodules of the scalp are common and usually benign. We describe a case that presented as a probable inclusion cyst or lipoma of the scalp that was discovered to be a benign osteolytic fibrohistiocytic lesion of the frontoparietal skull. This ultimately was successfully treated by neurosurgery with a craniectomy, tumor excision, and reconstructive cranioplasty.

A "neurosurgical crisis" of sickle cell disease.

The occurrence of spontaneous acute epidural hematomas is rare in patients with sickle cell disease. The authors report the case of a patient with sickle cell anemia who presented with a sickle cell crisis that was complicated by the development of multiple acute epidural and subgaleal hematomas requiring surgical evacuation. Possible underlying mechanisms are discussed. Although rare, clinicians should be aware of this phenomenon as part of a spectrum of neurological complications in these patients.

Mice defective in Trpm6 show embryonic mortality and neural tube defects.

The syndrome of hypomagnesemia with secondary hypocalcemia is caused by defective TRPM6. This protein is an ion channel that also contains a kinase in its C-terminus. It is usually diagnosed in childhood and, without treatment with supplemental Mg, affected children suffer from mental retardation, seizures and retarded development. We developed a mouse lacking Trpm6 in order to understand in greater detail the function of this protein. In contrast to our expectations, Trpm6(-/-) mice almost never survived to weaning. Many mice died by embryonic day 12.5. Most that survived to term had neural tube defects consisting of both exencephaly and spina bifida occulta, an unusual combination. Feeding dams a high Mg diet marginally improved offspring survival to weaning. The few Trpm6(-/-) mice that survived were fertile but matings between Trpm6(-/-) mice produced no viable pregnancies. Trpm6(+/-) mice had normal electrolytes except for modestly low plasma [Mg]. In addition, some Trpm6(+/-) mice died prematurely. Absence of Trpm6 produces an apparently different phenotype in mice than in humans. The presence of neural tube defects identifies a previously unsuspected role of Trpm6 in effecting neural tube closure. This genetic defect produces one of very few mouse models of spina bifida occulta. These results point to a critical role of Trpm6 in development and suggest an important role in neural tube closure.

Papillary tumor of the pineal region: report of a rapidly progressive tumor with possible multicentric origin.

Papillary tumor of the pineal region (PTPR) is an uncommon tumor recently added to the WHO classification of CNS tumors. We report a case of PTPR in a young boy that was noteworthy for early CSF dissemination and relentless progression. In spite of intensive chemotherapy and comprehensive radiotherapy, the boy died. The neuroimaging appearance is unique with possible multicentric origin of the tumor and intense uptake of (111)In-DTPA-pentetreotide.