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.

IgG4-Related Disease of the Craniovertebral Junction.

BACKGROUND: The majority of the abnormalities and diseases that affect the craniovertebral junction (CVJ) have already been reported, and therefore it is exceedingly rare to identify new pathology that affects the CVJ. Immunoglobulin G4-related disease (IgG4-RD) is an immune mediated process treated with immunosuppressive medications. To our knowledge, this is the first reported case of IgG4-RD affecting the CVJ. CASE DESCRIPTION: The authors report the case of a woman aged 71 years with IgG4-RD of the CVJ. She presented with intractable left occipital pain and limited flexion, extension, and rotation of the neck. Computed tomography and magnetic resonance imaging revealed a lytic enhancing lesion of the left occipital condyle, left C1 lateral mass, and left C1 anterior arch resulting in cranial settling, basilar invagination, and CVJ instability. An open biopsy, subtotal resection, and occiput to C2 fusion was performed. Pathology revealed IgG4-RD. The patient was subsequently placed on rituximab immunotherapy with complete resolution of enhancement on magnetic resonance imaging and bone growth at the previous site of the lytic IgG4-RD lesion. CONCLUSIONS: To our knowledge, this case describes the first case of IgG4-RD affecting the CVJ, which mimicked a tumor-like process. When IgG4-RD affects the CVJ, stability must be accounted for, especially in the cases of osteolytic destruction. The combination of medical therapy to target the underlying inflammatory process and surgery to provide structural stability was successful.

Acute Hydrocephalus Resulting from Neuromyelitis Optica: A Case Report and Review of the Literature.

BACKGROUND: Neuromyelitis optica is an autoimmune disorder of the central nervous system that predominantly affects the optic nerves and spinal cord. The neuropathologic hallmark of the disease is deposits of antibodies and complement, loss of astrocytes, secondary degeneration of oligodendrocytes and neurons, and necrotic lesions with infiltration of neutrophilic and eosinophilic granulocytes. It can rarely be associated with hydrocephalus, but the cause and mechanisms that result in hydrocephalus are not clear. CASE DESCRIPTION: A 35-year-old woman with a history of neuromyelitis optica presented with a 5-day history of progressively worsening lethargy, fatigue, somnolence, and headaches. Imaging demonstrated new hydrocephalus without evidence of obstruction, and extensive periventricular enhancement concerning for active demyelination. She underwent placement of a ventriculostomy, and subsequently underwent endoscopic biopsy and ventriculoperitoneal shunt placement. Pathology confirmed demyelination secondary to neuromyelitis optica. CONCLUSIONS: This case provides evidence of the rapid development of hydrocephalus in association with periventricular inflammation, without aqueductal stenosis. In a state of aquaporin-4 dysfunction such as in neuromyelitis optica, altered cerebrospinal fluid resorption could lead to acute hydrocephalus by a nonobstructive mechanism.

Amygdala enlargement in mesial temporal lobe epilepsy: an alternative imaging presentation of limbic epilepsy.

PURPOSE: To assess imaging, clinical, and pathological features of mesial temporal lobe epilepsy (mTLE) patients with amygdala enlargement (AE) in comparison with those with mesial temporal sclerosis (MTS). METHODS: Clinical, imaging, and pathologic features were retrospectively reviewed in 40 mTLE patients with postoperative follow-up (10 with AE and 30 with MTS). The volumes and signal intensity of the amygdala and hippocampus were assessed in 10 AE, 10 age- and sex-matched MTS patients, and 12 controls (HC). RESULTS: AE patients had a lower rate of concordant FDG PET (p < 0.05) and required more frequently intracerebral electrodes compared to MTS patients (p < 0.05). AE had larger ipsilateral amygdala (p < 0.0001) and hippocampus volumes (p < 0.0001) compared to MTS and to HC, with no significant differences for other brain structures. Normalized FLAIR signal was higher in the ipsilateral than contralateral amygdala in both AE and MTS (p < 0.001 and p < 0.05, respectively) and higher in the ipsilateral amygdala compared to HC (p < 0.05). In MTS, ADC in the ipsilateral amygdala (867 mm2/s) was higher compared to the contralateral one (804.8 × 10-6 mm2/s, p < 0.01), compared to HC (773 × 10-6 mm2/s, p < 0.01) and compared to the ipsilateral amygdala in AE (813.7 × 10-6 mm2/s, p < 0.05). AE patients had dysplasia (50%) or astrocytic gliosis (50%) of the amygdala extending to the hippocampus and temporal isocortex, and only 2/10 cases had pathologic findings of MTS. CONCLUSION: AE patients have distinct imaging and pathologic features compared to MTS, and require more extensive preoperative workup. Recognition of AE may improve preoperative assessment in TLE surgical candidates.

Resection of a Pediatric Intramedullary Spinal Cord Tumor: 2-Dimensional Operative Video.

This video is a case presentation and demonstration of surgical approach to a pediatric intramedullary spinal cord tumor (IMSCT). IMSCT can be associated with significant morbidity and aggressive resection is associated with more favorable long-term outcome. A 13-yr-old male presented to clinic for evaluation of rapidly progressive scoliosis to the left. A contrasted MRI revealed expansion of the spinal cord with edema from approximately T3 to T9 and an enhancing lesion at T6-7 associated with a small cyst. On neurological exam, the patient had good strength throughout, but decreased sensation in the T7-12 dermatomes and decreased deep tendon reflexes in his lower extremities. The procedure included T5 to T8 osteoplastic laminectomies and IMSCT resection followed by spinal reconstruction. Intraoperative ultrasound was used to verify the tumor's location and somatosensory and motor evoked potentials were monitored throughout the procedure. Intraoperative consultation with neuropathology suggested the mass was likely pilocytic astrocytoma; therefore, it was aggressively debulked using microsurgical techniques including an ultrasonic aspirator. There was a plane between the tumor and spinal cord white matter allowing for a gross total resection. Postoperatively the patient had good strength throughout and sensation was intact except for continued numbness of the anterior thigh bilaterally. Immediate postoperative MRI demonstrated complete resection of the tumor without residual enhancement and the patient was ultimately discharged home on postoperative day 8. Follow-up imaging remained stable at 2 mo and the patient continued to do well neurologically. All patient identifiers were removed from the presented material, thus, patient consent was not obtained.

Snyder-Robinson syndrome

Snyder-Robinson syndrome, also known as spermine synthase deficiency, is an X-linked intellectual disability syndrome (OMIM #390583). First described by Drs. Snyder and Robinson in 1969, this syndrome is characterized by an asthenic body habitus, facial dysmorphism, broad-based gait, and osteoporosis with frequent fractures. We report here a pediatric autopsy of a 4 year old male with a history of intellectual disability, gait abnormalities, multiple fractures, and seizures previously diagnosed with Snyder-Robinson syndrome with an SMS gene mutation (c.831G>T:p.L277F). The cause of death was hypoxic-ischemic encephalopathy secondary to prolonged seizure activity. Although Snyder-Robinson syndrome is rare, the need to recognize clinical findings in order to trigger genetic testing has likely resulted in under diagnosis.

Persistent Oxidative Stress in Vestibular Schwannomas After Stereotactic Radiation Therapy.

OBJECTIVE: Stereotactic radiation therapy is increasingly used to treat vestibular schwannomas (VSs) primarily and to treat tumor remnants following microsurgery. Little data are available regarding the effects of radiation on VS cells. Tyrosine nitrosylation is a marker of oxidative stress following radiation in malignant tumors. It is not known how long irradiated tissue remains under oxidative stress, and if such modifications occur in benign neoplasms such as VSs treated with significantly lower doses of radiation. We immunostained sections from previously radiated VSs with an antibody that recognizes nitrosylated tyrosine residues to assess for ongoing oxidative stress. STUDY DESIGN: Immunohistochemical analysis. METHODS: Four VSs, which recurred after excision, were treated with stereotactic radiation therapy. Ultimately each tumor required salvage reresection for regrowth. Histologic sections of each tumor before and after radiation were immunolabeled with a monoclonal antibody specific to nitrotyrosine and compared. Two VSs that underwent reresection of a growing tumor remnant without previous radiation therapy served as additional controls. RESULTS: Irradiated tumors enlarged in volume by 3.16 to 8.62 mL following radiation. Preradiation sections demonstrated little to no nitrotyrosine immunostaining. Three of four of irradiated VSs demonstrated increased nitrotyrosine immunostaining in the postradiation sections compared with preradiation tumor sections. Nonirradiated VSs did not label with the antinitrotyrosine antibody. CONCLUSIONS: VSs exhibit oxidative stress up to 7 years after radiotherapy, yet these VSs continued to enlarge. Thus, VSs that grow following radiation appear to possess mechanisms for cell survival and proliferation despite radiation-induced oxidative stress.

Roles of the apparent diffusion coefficient and tumor volume in predicting tumor grade in patients with choroid plexus tumors.

PURPOSE: To explore the utility of the apparent diffusion coefficient (ADC) and tumor volume to predict histological grade and prognosis in patients with choroid plexus tumors. METHODS: ADC and tumor volumes were retrospectively evaluated in 25 patients with choroid plexus papilloma (CPP; WHO grade 1 [n = 13]), atypical CPP (aCPP; grade 2 [n = 8]), or choroid plexus carcinoma (grade 3 [n = 4]) The prognostic roles of ADC and tumor volume were assessed. RESULTS: There were significant differences in mean and minimum ADC values, and tumor volume among the WHO grades (p = 0.033, p = 0.044, and p = 0.014, respectively). Receiver-operating characteristic analysis revealed a mean cutoff ADC value ≤ 1.397 × 10-3 mm2/s for aCPP (sensitivity = 0.667, specificity = 0.923). Multiple linear regression analysis demonstrated that both mean ADC (ß = - 0.455, p = 0.005) and tumor volume (ß = 0.513, p = 0.002) were correlated with WHO grade (adjusted R2 = 0.520, p = 0.005). Kaplan-Meier curve analysis identified poorer survival in patients with WHO grade 2 and 3 tumors than in those with WHO grade 1 disease (p = 0.049 and p = 0.012, respectively). A mean ADC ≤ 1.397 × 10-3 mm2/s (p = 0.001) and tumor volume 21.05 ml (p = 0.031) predicted significantly poorer survival. CONCLUSION: Mean ADC and tumor volume were correlated with WHO grade of choroid plexus tumors. A lower ADC value and a larger tumor volume predicted a poorer prognosis.

Ectopic Thymic Cyst of the Subglottis: Considerations for Diagnosis and Management.

OBJECTIVES: To share the diagnostic and management challenges created by an extremely rare airway lesion-the subglottic ectopic thymic cyst. STUDY DESIGN: Case report and literature review. METHODS: We review the presentation, management, and clinical course of an infant who presented with a subglottic mass that was histologically confirmed as a thymic cyst. A brief literature review supplements the case presentation Results: We present the third described case of an ectopic thymic cyst presenting as a subglottic mass. The differential diagnosis of subglottic masses in neonates consists primarily of subglottic hemangioma and mucous retention cysts. Otolaryngologists must be prepared for unexpected findings when dealing with critical airways. We compare the presentation and management of our patient with the 2 previously described cases. We propose an embryologic theory for the origin of these rare lesions. CONCLUSIONS: An ectopic thymic cyst is a rare and unexpected cause of neonatal stridor. Management of pediatric airway lesions must allow for unexpected findings at the time of diagnostic and therapeutic endoscopy. The appropriate management of subglottic thymic cysts is poorly defined, but close surveillance for recurrence is mandatory.

Role of the temporal pole in temporal lobe epilepsy seizure networks: an intracranial electrode investigation.

OBJECTIVE A convergence of clinical research suggests that the temporal pole (TP) plays an important and potentially underappreciated role in the genesis and propagation of seizures in temporal lobe epilepsy (TLE). Understanding its role is becoming increasingly important because selective resections for medically intractable TLE spare temporopolar cortex (TPC). The purpose of this study was to characterize the role of the TPC in TLE after using dense electrocorticography (ECoG) recordings in patients undergoing invasive monitoring for medically intractable TLE. METHODS Chronic ECoG recordings were obtained in 10 consecutive patients by using an array customized to provide dense coverage of the TP as part of invasive monitoring to localize the epileptogenic zone. All patients would eventually undergo cortico-amygdalohippocampectomy. A retrospective review of the patient clinical records including ECoG recordings, neuroimaging studies, neuropathology reports, and clinical outcomes was performed. RESULTS In 7 patients (70%), the TP was involved at seizure onset; in 7 patients (70%), there were interictal discharges from the TP; and in 1 case, there was early spread to the TP. Seizure onset in the TP did not necessarily correlate with preoperative neuroimaging abnormalities of the TP. CONCLUSIONS These data demonstrate that TPC commonly plays a crucial role in temporal lobe seizure networks. Seizure onset from the TP would not have been predicted based on available neuroimaging data or interictal discharges. These findings illustrate the importance of thoroughly considering the role of the TP prior to resective surgery for TLE, particularly when selective mesial resection is being considered.

Rathke's cleft cyst: A case report of recurrence and spontaneous involution.

Rathke's cleft cysts (RCC) are sellar lesions that typically remain asymptomatic throughout life. Symptomatic patients present with headache, visual disturbance and/or pituitary dysfunction and are treated with resection. We present a 61-year-old woman diagnosed with RCC which was resected twice then recurred before undergoing spontaneous resolution. RCC are often managed without surgical intervention. Some of these lesions may spontaneously resolve without surgical intervention while others may become symptomatic. In patients with asymptomatic recurrent RCC conservative management is recommended. Spontaneous involution may occur following initial resection and recurrence of RCC.

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.

Malignant peripheral nerve sheath tumor arising in the setting of cervical nerve root schwannomas.

We present a 23-year-old woman who was diagnosed with a malignant peripheral nerve sheath tumor (MPNST), 17 months following the resection of a schwannoma. MPNST is rare and is usually associated with neurofibromatosis. The typical treatment of resection and radiation is difficult to achieve in the spine.

Intraventricular foramen of Monro cavernous malformation.

We present a 64-year-old woman who was evaluated after being found unresponsive. Imaging revealed a foramen of Monro cavernoma resulting in hydrocephalus. Supratentorial cavernomas are most frequently found in the cerebral cortex, and although ventricular cavernomas do occur, they are rarely located in the foramen of Monro. Foramen of Monro cavernomas are extremely dangerous, requiring aggressive management when identified.

Shedding light on inflammatory pseudotumor in children: spotlight on inflammatory myofibroblastic tumor.

Inflammatory pseudotumor is a generic term used to designate a heterogeneous group of inflammatory mass-forming lesions histologically characterized by myofibroblastic proliferation with chronic inflammatory infiltrate. Inflammatory pseudotumor is multifactorial in etiology and generally benign, but it is often mistaken for malignancy given its aggressive appearance. It can occur throughout the body and is seen in all age groups. Inflammatory pseudotumor has been described in the literature by many organ-specific names, resulting in confusion. Recently within this generic category of inflammatory pseudotumor, inflammatory myofibroblastic tumor has emerged as a distinct entity and is now recognized as a fibroblastic/myofibroblastic neoplasm with intermediate biological potential and occurring mostly in children. We present interesting pediatric cases of inflammatory myofibroblastic tumors given this entity's tendency to occur in children. Familiarity and knowledge of the imaging features of inflammatory pseudotumor can help in making an accurate diagnosis, thereby avoiding unnecessary radical surgery.

Low-cost workflow improvement reduces gastrointestinal block use 17% by altering classic histotechnology testing.

OBJECTIVES: Gastrointestinal (GI) biopsy specimens were previously limited to four per cassette to facilitate established internal technical work practices and histotechnology best practice guidelines. We evaluated the workflow of these biopsy specimens. METHODS: We implemented three specific changes: (1) up to 10 GI biopsy specimens could be placed in each cassette, (2) histotechnologists would no longer orient GI biopsy specimens, and (3) embedding would be in a straight line rather than diagonal. We evaluated the effects of these changes on total block numbers, quality of slides, and perceptions of staff. RESULTS: The mean number of cassettes used was reduced 17% for GI biopsy cases, or an overall decrease of 3% of total blocks processed by our histopathology laboratory. Slide quality was unchanged. Staff reported increased job satisfaction. CONCLUSIONS: This simple, low-cost, low-effort process change yielded immediate and significant time savings for grossing and histology staff, increased job satisfaction, and challenges conventional histotechnology teaching.

Fibro-osseous lesion of the cranium in an adolescent patient.

BACKGROUND: Fibrous dysplasia, ossifying fibroma, and desmoplastic fibroma are rare benign calvarial lesions, which can have local aggressive behavior. These tumors can present with similar clinical and radiologic characteristics making diagnosis difficult at times. CASE DESCRIPTION: A 16-year-old male presents after noting an indentation of his skull. Comparison with current and previous imaging revealed progressive erosion of the skull underlying the indentation. CONCLUSION: Fibrous dysplasia, ossifying fibroma, and desmoplastic fibroma are rare fibro-osseous tumors with similar characteristics radiographically. Accurate diagnosis of these tumors can be difficult even with the combination of clinical presentation, imaging, and pathology. The treatment of choice is resection and cranial reconstruction, if necessary, with close follow-up as recurrence can occur.

Isolated Supratentorial Intraventricular Recurrence of Medulloblastoma.

Medulloblastoma is a common pediatric tumor typically diagnosed before the age of fifteen. Initial therapy includes surgical resection and radiation of the entire neuro-axis. Recurrence is common and typically occurs within 2 years of initial diagnosis. Those fitting Collin's Law is considered tumor-free. We report a case of single supratentorial recurrence 13 years after initial diagnosis. Here we present a 22 year old male presenting 13 years after initial diagnosis with isolated septum pellucidum recurrence. He underwent complete resection of the tumor. Medulloblastoma is a common in the pediatric population. Late recurrence to the ventricular system is uncommon. Long term follow-up is recommended in these patients.

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.