Jeffrey T. Joseph

Wolfram syndrome: a clinicopathologic correlation.

Wolfram syndrome or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy and deafness) is a neurodegenerative disorder characterized by diabetes mellitus and optic atrophy as well as diabetes insipidus and deafness in many cases. We report the post-mortem neuropathologic findings of a patient with Wolfram syndrome and correlate them with his clinical presentation. In the hypothalamus, neurons in the paraventricular and supraoptic nuclei were markedly decreased and minimal neurohypophyseal tissue remained in the pituitary. The pontine base and inferior olivary nucleus showed gross shrinkage and neuron loss, while the cerebellum was relatively unaffected. The visual system had moderate to marked loss of retinal ganglion neurons, commensurate loss of myelinated axons in the optic nerve, chiasm and tract, and neuron loss in the lateral geniculate nucleus but preservation of the primary visual cortex. The patient’s inner ear showed loss of the organ of Corti in the basal turn of the cochleae and mild focal atrophy of the stria vascularis. These findings correlated well with the patient’s high-frequency hearing loss. The pathologic findings correlated closely with the patient’s clinical symptoms and further support the concept of Wolfram syndrome as a neurodegenerative disorder. Our findings extend prior neuropathologic reports of Wolfram syndrome by providing contributions to our understanding of eye, inner ear and olivopontine pathology in this disease.

Neuroinflammation and demyelination in multiple sclerosis after allogeneic hematopoietic stem cell transplantation.

OBJECTIVE To evaluate the effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the brains of persons with and without multiple sclerosis (MS) by means of postmortem histopathological examination. DESIGN Postmortem histopathology, case studies, and case-control studies. Patients Four patients with MS who died at a median of 4.5 months (range, 3-9 months) after allo-HSCT for a concomitant hematologic malignant neoplasm; 5 patients without MS who died at a median of 10.0 months (1-29 months) after allo-HSCT; and 5 control subjects without MS who did not undergo allo-HSCT. SETTING Referral centers. Intervention Allogeneic hematopoietic stem cell transplantation. MAIN OUTCOME MEASURES Morphological features and immunohistochemical features, including the quantitative measures of chronic inflammatory cells. RESULTS Demyelinating and inflammatory activities of MS persisted after allo-HSCT in all of the patients with MS. Active and chronic active MS lesions exhibited significantly higher numbers of CD3+ T cells and CD8+ cytotoxic T cells and significantly higher scores of CD68+ microglia/macrophages than did chronic inactive lesions or normal-appearing white matter. The normal-appearing brains of allo-HSCT recipients who did not have MS were found to have significantly higher numbers of CD3+ T cells and CD8+ cytotoxic T cells and higher scores of CD68+ microglia/macrophages compared with the controls; however, no demyelination was identified in these non-MS samples. CONCLUSION Allo-HSCT fails to halt the demyelination and inflammation of MS.

Continued Disease Activity in a Patient With Multiple Sclerosis After Allogeneic Hematopoietic Cell Transplantation

OBJECTIVE To examine the effect of allogeneic hematopoietic cell transplantation (HCT) on disease activity in a patient with multiple sclerosis (MS). DESIGN Case report, prospective study, and autopsy. SETTING Departments of Clinical Neurosciences, Internal Medicine, and Pathology at the University of Calgary, Alberta, Canada. PATIENT A 39-year-old woman with chronic myelogenous leukemia and concurrent mild MS. INTERVENTIONS Hematopoietic cell transplantation from a healthy unrelated donor. RESULTS After HCT the patient developed graft-vs-host disease and experienced worsening, but not new, neurological symptoms. Her circulating leukocytes were 100% of donor origin. Magnetic resonance imaging showed increased lesion burden. She died of adenovirus hepatitis 20 weeks after HCT. An autopsy revealed demyelinating-inflammatory activity in active lesions and chronic active lesions. CONCLUSION Despite high-dose, cytotoxic, immunosuppressive therapy and exchange of a presumed autoreactive immune system with a healthy immune system, MS in this patient continued to be active.

Shaken Infants Die of Neck Trauma, Not of Brain Trauma

Objective review of the vital statistics of sudden unexplained infant death indicates a failure of what was, initially, a public health success. Early categorization of sudden unexplained infant deaths as SIDS was a tremendously productive stimulus for wide-ranging, high profile research. It provided a very important proverbial flag around which to rally. Over time, however, many death investigators recognized the major shortcomings of the use of SIDS: 1) its inconsistent use among forensic pathologists wreaks havoc with vital statistics and 2) it masks the fundamental truth for any consumer of death certificate information (in-

Pathologic Evaluation of the Cervical Spine Following Surgical and Chiropractic Interventions

Abstract:  When patients die after chiropractic or surgical interventions of the cervical spine, pathologists tasked with the autopsy are frequently overwhelmed by the complicated anatomy, laborious dissections, complex operative procedures and surgical hardware, and the necessity to differentiate artifacts from trauma and disease. However, abundant data can be obtained from careful evaluation of the cervical spine in situ; extensive postmortem diagnostic imaging procedures; detailed dissections of the removed, formalin‐fixed and decalcified spine; and histology. This study presents a regimented, stepwise approach to the evaluation of the cervical spine in these difficult cases, promotes uniform assessment, facilitates diagnoses, and supports the accumulation of otherwise hard‐to‐come‐by reference material that can be of value in future cases. The resultant detailed autopsy findings may prove useful in the medico‐legal death investigation process. Autopsy findings may also be of great value to health care providers involved in quality assurance processes.

Metachronous Type I pleuropulmonary blastoma and atypical choroid plexus papilloma in a young child.

Pleuropulmonary blastoma (PPB) is a rare childhood tumor, often associated with germline DICER1 mutations and a risk for development of other benign and malignant tumors, a constellation termed DICER1 syndrome. A 1‐year‐old male was diagnosed with Type I PPB and screened regularly thereafter for detection of intrathoracic and intraabdominal disease. Ten months after diagnosis of PPB, he presented with headaches and vomiting. He was diagnosed with atypical choroid plexus papilloma, a lesion not previously reported with PPB. The presence of central nervous system symptoms in patients with PPB or a phenotype suggestive of DICER1 syndrome should prompt early intracranial imaging.

Amyloid myoneuropathy mimicking inclusion body myositis.

myopathy affecting proximal and distal musculature with typical onset of symptoms after age 50 years. Inclusion body myositis more often affects males and results in a classical pattern of early asymmetric weakness and wasting of forearm flexors (wrist and long finger flexors), quadriceps and ankle dorsiflexors. Inclusion body myositis is more frequently associated with a monoclonal gammopathy than is seen in the general population but the implications of this association remain unclear1. Importantly, there is no available therapy to slow disease progression in IBM. Primary systemic amyloidosis (AL) typically results in light chain deposition in the tongue, kidneys, heart, liver, spleen and peripheral nerves with accompanying respective clinical sequelae. Rarely, light chain deposition can focally involve components of the nervous system. Peripheral nerve complications include carpal tunnel syndrome, dysautonomia and polyneuropathy2,3. Amyloid myopathy is rare and typically demonstrates proximal muscle involvement and electrophysiological findings indistinguishable from the inflammatory myopathies4. Prompt differentiation of amyloid myopathy from the inflammatory myopathies is essential as AL may respond to chemotherapy resulting in improved progression free survival5. We report a case of AL presenting with predominant myopathy clinically suggestive of IBM and with similar findings on initial muscle biopsy, an important distinction in light of recent treatment advances in AL.

Colloid Cyst of the Third Ventricle and Sudden Unexpected Death

Colloid cysts of the third ventricle are rare intracranial lesions; though developmental malformations, they typically present in the third to fifth decades of life. Classically they are described as presenting with episodic and position-dependent headaches due to intermittent obstruction of cerebrospinal fluid (CSF) flow at the foramina of Monro. However, most individuals present with non-specific symptoms of increased intracranial pressure (ICP), memory deficits, or neuropsychiatric deficits. A large proportion of cases are asymptomatic and are incidental findings on imaging studies or at autopsy (1).

A novel Gerstmann-Sträussler-Scheinker disease mutation defines a precursor for amyloidogenic 8 kDa PrP fragments and reveals N-terminal structural changes shared by other GSS alleles

To explore pathogenesis in a young Gerstmann-Sträussler-Scheinker Disease (GSS) patient, the corresponding mutation, an eight-residue duplication in the hydrophobic region (HR), was inserted into the wild type mouse PrP gene. Transgenic (Tg) mouse lines expressing this mutation (Tg.HRdup) developed spontaneous neurologic syndromes and brain extracts hastened disease in low-expressor Tg.HRdup mice, suggesting de novo formation of prions. While Tg.HRdup mice exhibited spongiform change, PrP aggregates and the anticipated GSS hallmark of a proteinase K (PK)-resistant 8 kDa fragment deriving from the center of PrP, the LGGLGGYV insertion also imparted alterations in PrPs unstructured N-terminus, resulting in a 16 kDa species following thermolysin exposure. This species comprises a plausible precursor to the 8 kDa PK-resistant fragment and its detection in adolescent Tg.HRdup mice suggests that an early start to accumulation could account for early disease of the index case. A 16 kDa thermolysin-resistant signature was also found in GSS patients with P102L, A117V, H187R and F198S alleles and has coordinates similar to GSS stop codon mutations. Our data suggest a novel shared pathway of GSS pathogenesis that is fundamentally distinct from that producing structural alterations in the C-terminus of PrP, as observed in other prion diseases such as Creutzfeldt-Jakob Disease and scrapie.