Murad Alturkustani

Intracranial segmental arterial mediolysis: report of 2 cases and review of the literature.

Extensive nontraumatic subarachnoid hemorrhage is an important cause of unexpected death in young adults. Segmental arterial mediolysis (SAM) represents an uncommon pathologic finding in the intracranial blood vessels associated with this type of hemorrhage. Segmental arterial mediolysis is a pathologic entity with putative vasospastic etiology, which recently has been reported to be associated with Ehlers-Danlos syndrome type 4. We describe 2 additional cases of ruptured intracranial vertebral artery with features of SAM that resulted in fatal subarachnoid hemorrhage. We also review the literature on vessels with features of SAM that are either intracranial or affecting the internal carotid artery with major direct effects (ie, stroke or transient ischemic attack) on the central nervous system.

Adult-Onset Leukodystrophy: Review of 3 Clinicopathologic Phenotypes and a Proposed Classification

Adult-onset leukodystrophies are clinically and pathologically heterogeneous diseases, and the overlapping morphologic features among these disorders can lead to confusion in pathologic classification. We report 3 recent autopsy cases that illustrate the clinicopathologic distinction between the 3 entities. The first, autosomal dominant leukodystrophy, is characterized clinically by early autonomic dysfunction and genetically by LMNB1 (lamin B1 gene) duplication. Recently, another clinical subtype emerged without the early autonomic dysfunction but with a similar genetic abnormality documented in 1 family. We reviewed the reported autopsy cases and show that both clinical subtypes share distinctive pathologic features. Other forms of adult-onset leukodystrophy can be classified based on the histologic evidence of the primary pathologic processes. A case of axonopathy with secondary demyelination serves as a prototype for adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids; the genetic mutation of CSF1R (colony stimulating factor 1R) was recently discovered in patients with this disorder. A case of a primary demyelinating disease with no other distinctive pathologic features is designated as orthochromatic leukodystrophy. Pigmented glia can be present in both of the latter two categories and should not be used as a differentiating diagnostic feature. Based on the observations of our cases and literature review, we propose an algorithm for a practical diagnostic approach to adult-onset leukodystrophies.

Pathologic staging of white matter lesions in adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids.

Abstract The pathologic features of adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids (ALAS) are variable, and this has led to different hypotheses as to whether primarily demyelination or axonopathy may underlie this disorder. Typical ALAS pathology is rarely accompanied by focal multiple sclerosis (MS)–like plaques. In ALAS pathology accompanied by focal multiple sclerosis (MS)-like plaques cases, the pathologic features cannot be distinguished from those of progressive MS with diffusely abnormal white matter. To clarify these issues, we examined neuropathologic features in 159 representative samples from 5 ALAS cases (3 men and 2 women aged 39–61 years) and in 95 representative samples from 3 chronic MS cases (1 man and 2 women aged 50–73 years). The white matter abnormalities in ALAS cases were characterized by 3 evolving stages: 1) white matter with numerous spheroids in a background of well-myelinated fibers; 2) moderate loss of myelinated fibers with sparse to moderate number of spheroids; and 3) leukodystrophy-like pattern of confluent axonal and myelin loss. The application of this staging system suggests that myelin loss in ALAS is preceded by axonopathy. In progressive MS cases, the diffusely abnormal white matter pathology could be attributed to both primary demyelination and axonopathy. Some cases with predominant axonopathy are difficult to distinguish from cases with ALAS.

[(18)F]-NaF PET/CT Identifies Active Calcification in Carotid Plaque.

Although macroscopic calcium deposits in atherosclerotic plaques impart stability, microcalcific deposits can amplify mechanical stress in the fibrous cap by 600 kPa [(1)][1]. Blood flow, stress, and tension between calcified and noncalcified tissue can increase the risk of plaque rupture. It is

Rosette-Forming Glioneuronal Tumour of the 4th Ventricle in a NF1 Patient

of the 4th ventricle in a 41 year-old man with neurofibromatosis type 1 (NF1). This patient had a family history of NF1 and presented with café-au-lait spots and multiple neurofibromata. At the age of 16 years (1983), he presented with severe headache and the head computed tomogram (CT) scan showed a 4th ventricular mass. The mass was partially resected and the histology was initially reported as a low grade astrocytoma. The patient died at age 41 years. The smear cytology from the original biopsy 25 years ago, showed a biphasic lesion composed of piloid cells with elongated fibrillary processes accompanied by Rosenthal fibers, and small round cells with finely granular nuclear chromatin forming rare neurocytic rosette (Figure 1a, b). The paraffin sections revealed a tumour with small round nuclei and scanty cytoplasm forming perivascular pseudorosettes surrounded by a low cellular glial component with piloid cells, microcystic areas and Rosenthal fibers. The perivascular cells were immunoreactive to synaptophysin, microtubule-associated protein 2 (MAP2) and neuron specific enolase (NSE) (Figure 1c-f) and immuno-negative for glial fibrillary acidic protein (GFAP). The glial areas were GFAP immuno-positive. There was no mitotic activity, vascular endothelial proliferation or tumour necrosis. At the follow-up after 23 years (2006), the patient had spastic gait and the MRI showed a 7 to 8 mm focus of increased signal in the fourth ventricular region within the periaqueductal grey matter of the right rostral pons (Figure 2a). It had no mass effect or enhancement. He suffered from schizophrenia and depression and two years later (2008), committed suicide. The general autopsy demonstrated findings of NF1 (multiple café-aulait spots and neurofibromata) and the brain was referred for neuropathological examination. Neuropathological examination revealed the residual tumour at the rostral pons around the fourth ventricle. The glial component was predominant with numerous microcystic areas. A few microcysts contained clusters of cells with small round nuclei and visible nucleoli. Morphologically, these cells resembled the neurocytic component of the original biopsy, but the neuronal markers were immuno-negative. Although relatively well circumscribed, there were atypical glial cells in the pontine tegmentum (Figure 2b-d). In the frontal cortex and

Intracallosal longitudinal fiber bundle: an unexpected finding mimicking demyelination in a patient with Turner syndrome.

We describe the first case of an intracallosal longitudinal fiber bundle in a patient with Turner syndrome (TS). Macroscopically, it mimicked a demyelinating lesion. A 45-year-old woman with TS (karyotype 45X) had a complex medical history including hemodialysis-dependent chronic renal failure, hypertension and chronic pancreatitis. She had a recent history of seizures. Episodes lasted 1 min, and were temporally related to hemodialysis. A cranial MRI showed a previous right cerebellar hemorrhage and high-signal cerebral white matter changes suggestive of chronic ischemia. No white matter abnormalities were identified in the corpus callosum. An electroencephalogram demonstrated triphasic waves with an absence of epileptiform spikes, consistent with a metabolic encephalopathy. She subsequently died of severe multi-lobar pneumonia that was confirmed on postmortem examination. Autopsy also identified multiple abnormalities associated with TS including short stature (height 1.44 m), a bicuspid aortic valve, absent ovaries and no identifiable thyroid gland. The kidneys showed changes of end-stage renal disease. Neuropathological examination of the brain was requested because of the history of seizures. The fresh brain weight was 1,376 g. The external surface of the brain was unremarkable. Coronal slices through the cerebral hemispheres revealed a gray midline lesion extending from the genu to the splenium of the corpus callosum (Fig. 1a). The lesion was intracallosal and measured 1.0 9 0.2 cm in maximal cross-section. At the time of autopsy, a demyelinating lesion, such as in Marchiafava–Bignami disease was considered. No other white matter lesions were identified macroscopically. The whole of the corpus callosum was submitted for histological examination. Microscopic sections of the lesion showed a large longitudinal fiber bundle that was predominantly intracallosal. The aberrant bundle could be traced throughout the corpus callosum, and appeared to merge with subcortical white matter at its anterior and posterior extents. Luxol fast blue and Bielschowsky staining highlighted the aberrant fiber bundle, as did neurofilament immunostaining (Fig. 1b–e). There was no evidence of demyelination, and the fornix and indusium griseum appeared normal. There was mild gliosis in the CA4 region of the hippocampus and the amygdala. Other findings included moderate arteriosclerosis, with two microscopic white matter infarcts and a hemorrhagic right cerebellar infarct. All infarcts were subacute to chronic in nature. There was no evidence of other structural malformations or previous perinatal brain injury. Several central nervous syndrome abnormalities have been reported in TS, including cortical dysplasia, pachygyria and polymicrogyria and Dandy–Walker abnormalities [5, 6]. Callosal abnormalities have also been reported in TS, including cases of partial and complete callosal agenesis [1, 3]. The exact mechanism behind callosal abnormalities in this group of patients is still unknown. However, callosal anomalies have been well recognized in other chromosomal syndromes (trisomy 8, 13, 18, 21) [3]. Two theories have been proposed for the anatomical basis of aberrant longitudinal callosal bundles. Reinhold et al. [4] described a case with bilateral parasagittal longitudinal bundles on the dorsal corpus callosum which anteriorly merged into neocortical white matter and posteriorly passed over to the hippocampal formation. The J. Sy (&) M. Alturkustani L.-C. Ang Department of Pathology (Neuropathology), University of Western Ontario, University Hospital, 339 Windermere Rd, London, ON N6A5A5, Canada e-mail: drjoannesy@gmail.com

[18F]-Fluorodeoxyglucose PET/CT imaging as a marker of carotid plaque inflammation: Comparison to immunohistology and relationship to acuity of events

BACKGROUND [18F]-fluorodeoxyglucose (18FDG) uptake imaged with positron emission tomography (PET) and computed tomography (CT) may serve as a biomarker of plaque inflammation. This study evaluated the relationship between carotid plaque 18FDG uptake and a) intraplaque expression of macrophage and macrophage-like cellular CD68 immunohistology; b) intraplaque inflammatory burden using leukocyte-sensitive CD45 immunohistology; c) symptomatic patient presentation; d) time from last cerebrovascular event. METHODS 54 patients scheduled for carotid endarterectomy underwent 18FDG PET/CT imaging. Maximum 18FDG uptake (SUVmax) and tissue-to-blood ratio (TBRmax) was measured for carotid plaques. Quantitative immunohistological analysis of macrophage-like cell expression (CD68) and leukocyte content (CD45) was performed. RESULTS 18FDG uptake was related to CD68 macrophage expression (TBRmax: r = 0.51, p < 0.001), and total-plaque leukocyte CD45 expression (TBRmax: r = 0.632, p = 0.009, p < 0.001). 18FDG TBRmax uptake in carotid plaque associated with patient symptoms was greater than asymptomatic plaque (3.58 ± 1.01 vs. 3.13 ± 1.10, p = 0.008). 18FDG uptake differed between an acuity threshold of <90 days and >90 days (SUVmax:3.15 ± 0.87 vs. 2.52 ± 0.45, p = 0.015). CONCLUSIONS In this CAIN cohort, 18FDG uptake imaged with PET/CT serves a surrogate marker of intraplaque inflammatory macrophage, macrophage-like cell and leukocyte burden. 18FDG uptake is greater in plaque associated with patient symptoms and those with recent cerebrovascular events. Future studies are needed to relate 18FDG uptake and disease progression.

Pathology of toxic leucoencephalopathy in drug abuse supports hypoxic-ischemic pathophysiology/etiology

The histopathological features of leucoencephalopathy caused by illicit drugs (such as opioids and cocaine) are well documented in acute cases but not in long‐survival cases. There are several hypotheses about the pathogenesis of this disorder, including hypoperfusion, direct drug toxicity resulting from the neurotoxic effects of the drug itself or contaminants in the illicit drug vehicle. We reviewed the post mortem findings in five males (aged 24 to 56 years, with survival intervals ranging from 7 days to 5 months) with a history of illicit drug use and concomitant fatal white matter changes. The histological characteristics of leucoencephalopathy vary with survival period. Prominent axonal injury and axonal spheroids were observed with shorter survival and spongiform changes becoming apparent with longer survival (acute and chronic incomplete infarct pattern). Necrosis was present in all cases and its appearance changed with longer survival (acute and chronic complete infarct pattern). Significant primary demyelination was not observed. These observations suggest that the primary defect in this leucoencephalopathy is hypoxic‐ischemic injury, predominantly in the white matter. Spongiform leucoencephalopathy likely represents the longer‐survival incomplete infarct pattern and is observed with polydrug abuse.

Acute hypoxic-ischemia in cardiac arrest encephalopathy causes only minimal demyelination

The underlying pathological process of “ischemic leukoencephalopathy” is not well studied in humans and “demyelination” is thought to represent a major component. We selected brains from autopsy cases with definite histories of recent cardiac arrest, in which the autopsy findings demonstrated gray matter ischemic changes consistent with the survival time. We excluded cases with clinical or pathological evidence of other diseases that may affect the white matter, specifically those with moderate‐severe edema. The selected cases were then subjected to a review of the gross pathology (photographs) and microscopy. We used the normal white matter areas in the same brains as internal controls to exclude artefactual changes. Sixteen cases were selected. The pathological changes in acute ischemic leukoencephalopathy include: white matter pallor with separation of myelinated fibers and fine vacuoles, coarse vacuoles with or without attenuated axons, apoptotic nuclei, axonal abnormalities, focal scattered demyelinated axons and infarcts. The interpretation of these findings is controversial (i.e. ischemia, edema, artifact or combination) due to the postmortem nature of the specimens. However, these factors should not affect our interpretation of minimal demyelination in the pathological process. The major underlying pathological process in acute ischemic leukoencephalopathy is axonal degeneration, while demyelination represents only a minor component.

Simple partial seizures in a 70-year- old female.

History A 70 year-old female presented with a history of recurrent stereotyped “spells” over the past six years. She described involuntary horizontal saccadic eye movements as the initial event. This was followed by tonic deviation of her head to the left. There was intermittent jerking of her head to the left and quivering of her lower lip and jaw. There was no loss of awareness but it was difficult for her to speak during the spells which typically lasted three to four minutes. Her speech was slurred for a further five to ten minutes. The spells had recurred approximately twice a year until a recent increase in their frequency (four episodes in three months), prompting the patient to seek medical attention. She had a history of migraines, chronic obstructive lung disease, a 50 pack-year smoking history, and several remote minor surgeries including ureteral stenting, appendectomy, hemorrhoidectomy, and hysterectomy. She had been involved in two motor vehicle accidents, 28 years and 6 years earlier, with no recognized craniocerebral injury on either occasion. Her family history was not contributory.