Search

We describe the evolution of neuropathology in Canada, beginning with William Osler who began working in Montréal in 1874 and finishing with the major period of expansion in the 1970s. Organized services began in the 1930s, in Montréal with the neurosurgeons Wilder Penfield and William Cone, and in Toronto with Eric Linell and Mary Tom, who both began their careers as neuroanatomists. Jerzy Olszewski and Gordon Mathieson, who trained in Montréal and Toronto, drove the creation of the Canadian Association of Neuropathologists in 1960. Training guided by the Royal College of Physicians and Surgeons of Canada was formalized in 1965, with the first certifying examination in 1968 and the subsequent creation of formal structured training programs. The number of neuropathologists in Canada increased rapidly through the 1960s and 1970s, with individuals coming from both clinical neuroscience and anatomic pathology backgrounds, a pattern that persists to the present day.

Purpose: Human reovirus type 3 has been proposed to kill cancer cells with an activated Ras signaling pathway. The purpose of this study was to investigate the efficacy of reovirus in immunocompetent glioma animal models and safety/toxicity in immunocompetent animals, including nonhuman primates., Experimental Design: Racine glioma cells 9L and RG2 were implanted s.c. or intracranially in Fisher 344 rats with or without reovirus antibodies, followed by treatment of reovirus. To study whether reovirus kills contralateral tumors in the brain and to determine viral distribution, we established an in situ dual tumor model followed by reovirus intratumoral inoculation only into the ipsilateral tumor. To evaluate neurotoxicity/safety of reovirus, Cynomolgus monkeys and immunocompetent rats were given intracranially with reovirus, and pathological examination and/or behavioral studies were done. Viral shedding and clinical biochemistry were systematically studied in monkeys., Results: Intratumorally given reovirus significantly suppressed the growth of both s.c. and intracranially tumors and significantly prolonged survival. The presence of reovirus-neutralizing antibodies did not abort the reovirus' antitumor effect. Reovirus inhibited glioma growth intracranially in the ipsilateral but not the contralateral tumors; viral load in ipsilateral tumors was 15 to 330-fold higher than the contralateral tumors. No encephalitis or behavioral abnormalities were found in monkeys and rats given reovirus intracranially. No treatment-related clinical biochemistry changes or diffuse histopathological abnormality were found in monkeys inoculated intracranially with Good Manufacturing Practice prepared reovirus. Microscopic changes were confined to the region of viral inoculation and were dose related, suggesting reovirus intracranially was well tolerated in nonhuman primates., Conclusions: These data show the efficacy and safety of reovirus when it is used in the treatment of gliomas in immunocompetent hosts. Inoculation of reovirus into the brain of nonhuman primates did not produce significant toxicities.

Medulloblastoma (MB), the most common pediatric brain tumor, is a highly malignant disease with a 5-year survival rate of only 60%. Tumor cells invade surrounding tissue and disseminate through cerebral spinal fluid, making treatment difficult. Human reovirus type 3 exploits an activated Ras pathway in tumor cells to support productive infection as an oncolytic virus. Here, we examined the ability of human reovirus to kill MB cells lines and surgical specimens in vitro and inhibit tumor growth/metastases in vivo. Most human MB cell lines tested (five of seven = 71.4%), two MB cell lines derived from spontaneously arising tumors in Patched-1(+/-) mice (two of two = 100%) and three MB primary cultures derived from surgical specimens, were susceptible to reovirus infection. Reovirus was internalized and transcribed in both susceptible and resistant cell lines. However, viral protein synthesis was restricted to cell lines with higher levels of activated Ras, suggesting that Ras plays a critical role in reovirus oncolysis in MB. Using an in vivo Daoy orthotopic animal model, we found that a single i.t. injection of reovirus dramatically prolonged survival compared with controls (160 versus 70 days, respectively; P = 0.0003). Repeating this experiment with GFP-labeled Daoy cells and multiple i.t. administrations of reovirus, we again found prolonged survival and a dramatic reduction in spinal and leptomeningeal metastases (66.7% in control injections versus 0.0% in the live virus group). These data suggest that this oncolytic virus may be a potentially effective novel therapy against human MB. Its ability to reduce metastases to the spinal cord could allow a reduction in the dose/field of total neuroaxis cerebral-spinal radiotherapy currently used to treat/prevent cerebral spinal fluid dissemination.

The presence of contrast enhancement in a brain tumor is often regarded as a sign of malignancy. The authors identified 314 patients with malignant and low-grade supratentorial glial neoplasms in an unselected population, 58 of which lacked contrast enhancement on preoperative neuroimaging. Nonenhancing gliomas were malignant in approximately one third of cases, especially in older patients. Histologic confirmation of the diagnosis is therefore important in all patients suspected of harboring a primary glial neoplasm.

Studies have suggested that an imbalance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may contribute to the malignant phenotype of gliomas. In this study, we have undertaken a detailed analysis of expression of the TIMP family in normal human brain and malignant gliomas at both the mRNA and protein level. Reverse transcription-PCR (RT-PCR) analyses of total RNA from surgical tumour specimens revealed unique expression patterns for the 4 members of the TIMP family, with TIMP-1 and -4 showing positive and negative correlations, respectively, with glioma malignancy. By RT-PCR, TIMP-2 and TIMP-3 expression did not change with tumour grade. In situ hybridization localized TIMP-1 to glial tumour cells and also to the surrounding tumour vasculature. TIMP-4 transcripts were predominantly localized to tumour cells, though minor expression was found in vessels. Recombinant TIMP-4 reduced invasion of U251 glioma cells through Matrigel, and U87 clones overexpressing TIMP-4 showed reduced invasive capacity in vitro. TIMP-4, but not TIMP-1, blocked Membrane Type-1-MMP-mediated progelatinase-A (MMP-2) activation in human umbilical vein endothelial cells. The differential expression and localization of individual TIMPs may contribute to the pathophysiology of human malignant gliomas, particularly with regard to tumour vascularization., (Copyright 2001 Cancer Research Campaign.)

Background: Reovirus is a naturally occurring oncolytic virus that usurps activated Ras-signaling pathways of tumor cells for its replication. Ras pathways are activated in most malignant gliomas via upstream signaling by receptor tyrosine kinases. The purpose of this study was to determine the effectiveness of reovirus as an experimental treatment for malignant gliomas., Methods: We investigated whether reovirus would infect and lyse human glioma cell lines in vitro. We also tested the effect of injecting live reovirus in vivo on human gliomas grown subcutaneously or orthotopically (i.e., intracerebrally) in mice. Finally, reovirus was tested ex vivo against low-passage cell lines derived from human glioma specimens. All P values were two-sided., Results: Reovirus killed 20 (83%) of 24 established malignant glioma cell lines tested. It caused a dramatic and often complete tumor regression in vivo in two subcutaneous (P =.0002 for both U251N and U87) and in two intracerebral (P =.0004 for U251N and P =.0009 for U87) human malignant glioma mouse models. As expected, serious toxic effects were found in these severely immunocompromised hosts. In a less immunocompromised mouse model, a single intratumoral inoculation of live reovirus led to a dramatic prolongation of survival (compared with control mice treated with dead virus; log-rank test, P<.0001 for both U251N and U87 cell lines). The animals treated with live virus also appeared to be healthier and gained body weight (P =.0001). We then tested the ability of reovirus to infect and kill primary cultures of brain tumors removed from patients and found that it killed nine (100%) of nine glioma specimens but none of the cultured meningiomas., Conclusions: Reovirus has potent activity against human malignant gliomas in vitro, in vivo, and ex vivo. Oncolysis with reovirus may be a potentially useful treatment for a broad range of human cancers.

Malignant gliomas maintain a poor prognosis and survival rate due to their marked local invasive growth and neovascularization. Matrix metalloproteinases (MMPs) have been implicated in glioma invasion and angiogenesis, but it is unknown whether they are produced by the tumor cells or surrounding stroma. Using in situ hybridization and immunohistochemistry, we found expression of mRNA for both gelatinase-A (MMP2) and gelatinase-B (MMP9) localized to tumor cells and vascular structures in glioma sections. Gelatinase-A protein expression was detected most prominently in tumor cells, with very little signal seen in vasculature. Gelatinase-B protein expression was prominent in vascular structures but was also expressed in tumor cells. Our data show that these proteases are produced by glioma cells and vascular structures and suggest that synthetic MMP inhibitors might be useful in this disease.

Background: Quadriplegic myopathy (QM) and its variants generally are described in critically ill patients who are exposed to steroids and nondepolarizing muscle blocking agents (NDMBAs)., Methods: A patient with sepsis who was not exposed to steroids or an NDMBA infusion developed QM and was studied using serial quantitative electromyography., Results: Clinical and electrophysiological studies identified evidence of a severe myopathy and muscle biopsy showed necrosis, calcifications and selective loss of myosin filaments in non-necrotic fibers. Her clinical recovery paralleled rises in motor unit action potential (MUAP) amplitudes studied by serial automatic decomposition electromyography (ADEMG)., Conclusions: QM can develop with sepsis and without significant exposure to steroids and NDMBAs. ADEMG can be a useful tool in electrophysiological evaluation of critically ill patients with weakness.

In this clinical and histopathological study, the frequency of long-term glioblastoma multiforme (GBM) survivors (LTGBMSs) was determined in a population-based study. The Alberta Cancer Registry was used to identify all patients diagnosed with GBM in Alberta between January 1, 1975, and December 31, 1991. Patient charts were reviewed and histology reexamined. LTGBMSs were defined as GBM patients surviving 3 years after diagnosis. Each LTGBMS was compared with 3 age-, sex-, and year of diagnosis-matched controls, and patient/treatment or tumor characteristics that predicted long-term survival were determined. There were 689 GBMs diagnosed in the study period; 15 (2.2%) of these patients survived 3 years. LTGBMSs (average age, 43.5 +/- 3.3 years) were significantly younger when compared with all GBM patients (average age, 53.0 +/- 0.56 years). LTGBMSs had a higher Karnofsky Performance Status score at diagnosis compared with controls. LTGBMSs were much more likely to have had a gross total resection and adjuvant chemotherapy than control GBM patients. Tumors from LTGBMSs tended to have fewer mitoses and a significantly lower Ki-67 cellular proliferation index compared with controls. Radiation-induced dementia was common and disabling in LTG-BMSs. In conclusion, conventionally treated GBM patients in an unselected population have a very small chance of long-term survival. The use of aggressive surgical resection and adjuvant chemotherapy may make long-term survival more likely in GBM patients if their performance status is high at diagnosis.

Matrix metalloproteinases (MMPs) have been implicated as important factors in gliomas since they may both facilitate invasion into the surrounding brain and participate in neovascularization. We have tested the hypothesis that deregulated expression of gelatinase-A or B, or an activator of gelatinase-A, MT1-MMP, may contribute directly to human gliomas by quantifying the expression of these MMPs in 46 brain tumour specimens and seven control tissues. Quantitative RT-PCR and gelatin zymography showed that gelatinase-A in glioma specimens was higher than in normal tissue; these were significantly elevated in low grade gliomas and remained elevated in GBMs. Gelatinase-B transcript and activity levels were also higher than in normal brain and more strongly correlated with tumour grade. We did not see a close relationship between the levels of expression of MT1-MMP mRNA and amounts of activated gelatinase-A. In situ hybridization localized gelatinase-A and MT1-MMP transcripts to normal neuronal and glia, malignant glioma cells and blood vessels. In contrast, gelatinase-B showed a more restricted pattern of expression; it was strongly expressed in blood vessels at proliferating margins, as well as tumour cells in some cases. These data suggest that gelatinase-A, -B and MT1-MMP are important in the pathophysiology of human gliomas. The primary role of gelatinase-B may lie in remodelling associated with neovascularization, whereas gelatinase-A and MT1-MMP may be involved in both glial invasion and angiogenesis.

Synthetic matrix metalloproteinase (MMP) inhibitors have activity against a variety of tumors in preclinical models but have not been studied in gliomas. We determined the effect of AG3340, a novel synthetic MMP inhibitor with Ki values against gelatinases in the low picomolar range, on the growth of a human malignant glioma cell line (U87) in SCID-NOD mice. Mice were injected s.c. with U87 cells. Tumors were allowed to grow to a size of approximately 0.5 x 0.5 cm (after about 3 weeks), and the mice were randomized to receive either: (a) 100 mg/kg AG3340 in vehicle; or (b) vehicle control (0.5% carboxymethyl cellulose, 0.1% pluronic F68), both given daily i.p. Tumor area was measured twice weekly, and animals were sacrificed when moribund, or earlier if premorbid histology was examined. In vivo inhibition of tumor growth was profound, with AG3340 decreasing tumor size by 78% compared with controls after 31 days (when controls were sacrificed; P < 0.01, Wilcoxon test). Control animals survived 31 days after the i.p. injections began, and AG3340 mice survived 71 days, representing a >2-fold increase in survival associated with tumor growth delay. Histological examination found that AG3340-treated tumors were smaller, had lower rates of proliferation, and significantly less invasion than control-treated tumors. Hepatic or pulmonary metastases were not seen in either group. In a separate experiment, the tumors were smaller and sampled after a shorter duration of treatment; the changes in proliferation were more marked and occurred earlier than differences in tumor invasion between the two groups. Furthermore, in vitro cell growth was not inhibited at AG3340 concentrations of <1 mM. AG3340 plasma concentrations in vivo, 1 h after administration, ranged from 67 to 365 nM. Thus, AG3340 produced a profound inhibition of glioma tumor growth and invasion. AG3340 markedly increased survival in this in vivo glioma model. Treatment with AG3340 may be potentially useful in patients with malignant gliomas.

Background: Long-term glioblastoma multiforme survivors (LTGBMS) are uncommon. The frequency which these occur in an unselected population and factors which produce these unusually long survivors are unknown., Objectives: To determine in a population-based study 1) the frequency of LTGBMS in a population and 2) identify which patient, treatment or tumor characteristics would predict which glioblastoma (GBM) patient would become a LTGBMS., Methods: The Alberta Cancer Registry was used to identify all patients diagnosed with GBM in southern Alberta between 1/1/75-12/31/91. Patient charts were reviewed and histology re-examined by a blinded neuropathologist. LTGBMS were defined as GBM patients surviving > or = 3 years after diagnosis. Each LTGBMS was compared to three age-, gender-, and year of diagnosis-matched controls to compare patient, treatment, and tumor factors to GBM patients without long-term survival., Results: There were 279 GBMs diagnosed in the study period. Five (1.8%) survived > or = three years (range, 3.2-15.8 years). Seven additional long-term survivors, who carried a diagnosis of GBM, were excluded after neuropathologic review; the most common revised diagnosis was malignant oligodendroglioma. LTGBMS (avg. age = 45 years) were significantly younger when compared to all GBM patients (avg. age = 59 years, p = 0.0001) diagnosed in the study period. LTGBMS had a higher KPS at diagnosis (p = 0.001) compared to controls. Tumors from LTGBMS tended to have fewer mitoses and a lower Ki-67 cellular proliferative index compared to controls. Radiation-induced dementia was common and disabling in LTGBMS., Conclusions: These data highlight the dismal prognosis for GBM patients who have both a short median survival and very small chance (1.8%) of long-term survival. The LTGBMS were younger, had a higher performance status, and their tumors tended to proliferate less rapidly than control GBM patients. When long-term survival does occur it is often accompanied by severe treatment-induced dementia.

Purpose: Extra-neural metastases from glioblastoma multiforme (GBM) are rare. Because gelatinases-A and -B have been implicated in tumor invasion/metastasis in non-neural tumors, we compared the expression of gelatinase-A and -B in 2 patients (both had a prior craniotomy performed) with extraneural metastases from GBM to expression levels in 24 other gliomas; 15 non-metastatic GBMs, 9 other lower grade gliomas, and 7 normal brain tissues., Methods: The intracerebral tumor from both patients, patient # 1's extraneural metastases, 24 other gliomas, 1 sample of reactive astrocytes and 7 normal brain tissues were studied using gelatin zymography. The active form of gelatinases was confirmed by co-migration after activation with APMA., Results: Expression of the latent form of gelatinase-A correlated with glioma grade (r = 0.486; p = 0.0053). Active gelatinase-A was found only in the 2 GBMs with extraneural metastases and patient # 1's cervical metastases. In contrast, latent gelatinase-B levels correlated more strongly with histologic grade (r = 0.577; p = 0.0009) (higher levels with higher grades). Very high levels of gelatinase-B were seen in both GBMs with extraneural metastases, a cervical extraneural metastases, and 2 GBMs without metastases., Conclusions: We observed that gelatinases-A and -B are present in most gliomas but we found active gelatinase-A only in the GBMs with extraneural metastases suggesting that the active form of this enzyme may determine the metastatic potential of GBMs. We propose that high levels of gelatinolytic activities are associated with intracerebral invasion and rarely, metastases of GBMs.

The purpose of this study was to evaluate the in vivo characteristics of coronary atherosclerosis by using high frequency epicardial echocardiography. High frequency epicardial echocardiography was used to evaluate residual lumen and wall morphology at the sites of maximal coronary atherosclerosis in 26 patients undergoing coronary artery bypass grafting. The maximal/minimal wall thickness ratio was 3.1 +/- 0.2 (mean +/- SEM) with a large range (1.3 to 7.5). Portions of the wall were normal in 16 of 31 lesions; the percent normal circumference ranged from 9% to 85%. Maximal/minimal lumen diameter ratio was 1.5 +/- 0.1 (range 1.1 to 2.9). The shape of the residual coronary lumen was noncircular in 16 lesions: oval in 13 and complex in 3. The residual coronary lumen was eccentrically placed within six arteries. These data emphasize the variability of residual lumen and wall geometry in atherosclerosis.

False-positive and false-negative interpretations of sellar tomography were found in about one-fifth of cases in a recent autopsy study correlating the presence of pituitary microadenomas with abnormal sellar tomograms. An analysis of minor variations in the bony configuration of the sella disclosed variations due to posterior lobe asymmetry, intercavernous venous channels, bony asymmetry, and an empty sella in 27 of the 120 sellas examined. In some instances, the asymmetry resulted from a combination of these causes. A further study of 50 pituitary glands in situ showed posterior lobe asymmetry to be a common anomaly (76%) that can produce an obvious disparity between the two halves of the sella. Thus, the minor radiologic criteria of local thinning of the anterior wall or floor, slant of the floor, or asymmetry of the two halves of the sella must be interpreted with caution as being indicative of the presence of pituitary microadenoma. In the absence of clinical or biochemical dysfunction, the changes more likely result from explainable anatomic causes.

Acridine orange fluorochrome of nucleic acids was applied to sections of cerebral tissue from 20 patients showing acute or chronic reactive gliosis. The results were compared with the findings in 39 well differentiated and malignant astrocytomas. The orange cytoplasmic fluorescence of ribonucleic acid is lacking in reactive astrocytes of all ages including gemistocytes, but is uniformly present in astrocytoma cells. Acridine orange is a useful supplementary stain for distinguishing between astrocytosis and astrocytoma, particularly for small cerebral biopsies showing scattered or diffusely infiltrating pleomorphic glial cells.

The histopathologic effects of methanol on the optic nerve were studied in four patients. Circumscribed myelin damage occurred behind the lamina cribrosa in each nerve. Axons were preserved. Demyelination also occurred in cerebral hemispheric white matter in one patient. This selective myelinoclastic effect of methanol metabolism is probably caused by histotoxic anoxia in watershed areas of the cerebral and distal optic nerve circulations. Juxtabulbar demyelination may cause optic disk edema in methanol poisoning by compressive obstruction of orthograde axoplasmic flow. Visual loss may be due to disruption of saltatory conduction. Retrolaminar demyelinating optic neuropathy is an early morphologic correlate of visual loss in methanol intoxication.

A 72-year-old woman suffered a respiratory arrest following intoxication with barbiturates. Her examination 27 months after the anoxic incident revealed involuntary jerks of trunk and limb muscles triggered by willed movements. On a regimen of 1 g L-5-HTP and 100 mg l-alpha-methyldopa hydrazine (carbidopa), action myoclonus disappeared completely. This medication had to be discontinued because of a regressive hysterical reaction. Two months later, she was found unconscious; resuscitation efforts were unsuccessful. Autopsy showed death was caused by choking on food. Coronal slices of the cerebral hemispheres and transverse section of the brainstem and cerebellum revealed no lesion. No evidence of hypoxic damage could be demonstrated in the cerebral cortex, hippocampus, striatum, pallidum, subthalamus, thalamus, or other diencephalic structures. In the caudal half of the midbrain tegmentum, a marked astrocytic reaction of some duration was encountered in the lateral parts of the supratrochlearis nucleus, the lateral subnucleus of the mesencephalic gray, and the immediately adjacent cuneiform and subcuneiform nuclei. In the former nucleus, sites of presumed nerve cell disintegration were found, but the neuronal populations of this nucleus and of the other raphe nuclei were well maintained. The other brainstem structures and the cerebellum were normal. Our neuropathological findings suggest that hypoxic myoclonus (a) does not seem to be explained by demonstrable neuronal loss in motor structures, such as cerebellum, thalamus, or basal ganglia and (b) does not appear to be causally related to a detectable reduction in the serotonin-containing neurons of the brain but rather to a functional derangement of anatomically intact serotonergic pathways originating perhaps from other, as yet unidentified, damaged neuronal structures.

Acridine orange was used as a fluorochromic histochemical stain of nucleic acids, applied to 78 neoplasms of the central and peripheral nervous systems of 60 children. Some cases were compared with 5 adults and 4 other cases of chronic reactive gemistocytic gliosis. Opposite concentration gradients of cytoplasmic ribonucleic acid (RNA) was demonstrated in tumours of the neuronal/neuroectodermal series, and those of the glial/neuroepithelial series. Minimal AO-RNA fluorescence was seen in 8 cerebellar medulloblastomas and in a retinoblastoma; strong AO-RNA fluorescence occurred in one cerebellar medulloblastoma and in 3 primitive neuroectodemal tumours of the cerebral cortex. Intermediate intensity of fluorescence was found in neuroblastomas, and strong fluorescence was shown in well differentiated ganglioneuroma cells and in cells of chromaffin tumours. Among glial tumours, by contrast, the most anaplastic cells displayed the most RNA fluorescence, while better differentiated astrocytoma cells showed much less. Gradients also were found within some astrocytomas, corresponding to zones of relative anaplasia. Minimal or no fluorescence was detected in reactive gemistocytes or in oligodendroglioma cells. Ependymomas were weakly fluorescent and choroid plexus papillomas showed more fluorescence, similar to the findings in normal ependyma and choroid plexus. Several non-neuroepithelial tumours of the nervous system and Schwannomas also were studied. The acridine orange technique applied to either frozen or paraffin sections of nervous system tumours, has value as an adjunct in the diagnosis and grading of these neoplasms and perhaps in distinguishing reactive gliosis from benign astrocytoma.

A clinical, electrophysiological and pathological review of 14 patients having oculoskeletal myopathy with abnormal mitochondria was undertaken. These patients present with ophthalmoplegia, and mild skeletal muscle weakness. The clinical course is slowly progressive. Electromyographic examination shows myopathic changes. Serum enzymes are normal. The diagnosis is confirmed by skeletal muscle biopsy which shows abnormal mitochondria, including crystalloid inclusions on electron microscopy. These patients form a distinct clinical group in which the risk of sudden cardiac death is much less than it is in the Kearns-Sayre syndrome.

A 57-year-old woman, with long-standing hypogonadism secondary to irradiation of the ovaries, was found to have a pituitary tumor which was removed and investigated by histology, immunocytology and electron microscopy. Histologically, the tumor corresponded to a chromophobe, slightly PAS positive adenoma and the immunoperoxidase stain revealed the presence of both FSH and LH in the cytoplasm of the adenoma cells. The structural features of the adenoma cells resembled those of FSH cells in the nontumorous adenohypophysis. We thus believe that pituitary adenomas consisting of gonadotrophin-producing cells occur and that these may produce both FSH and LH. The relation between the gonadotrophin-producing adenoma and the preceding hypogonadism is uncertain.

Acute haematomyelia, an unrecognized sequela of sudden intracranial hypertension is described in 3 patients with massive intracerebral and intraventricular haemorrhage. The presence of a persistent central canal of the spinal cord in communication with the 4th ventricle and acute functional obstruction of the latter allows CSF and blood to pass down into the spinal cord with subsequent rupture into the cord parenchyma.

Five patients studied by the authors and 28 mentioned in the literature indicate that recurrent stenosis occurs in no less than 0.6% of patients after carotid endarterectomy. The pathology of the recurrent stenosis was stated in only 10 cases indicating atherosclerotic disease in various stages of development in 7 and a fibrous intimal hyperplasia in 3. Correlation between risk factors for the development of atherosclerosis and the pathology of the recurrent disease was poor. Six patients developed recurrent disease despite postoperative prophylactic oral anticoagulation. Surgical technique appeared to have contributed to re-stenosis in 8 patients (1) by failure to remove the distal tongue of plaque or (2) narrowing of the lumen by the arteriotomy suture or (3) damage by a vascular clamp. In 18 symptomatic patients, 44% had symptoms by 3 years, 67% by 5 years, and 83% by 7 years after operation. The 8 patients with possible errors in surgical technique did not develop symptoms earlier than the other patients. Seventeen symptomatic patients had surgical correction of the re-stenosis (endarterectomy 9, vein patch 6, arterial homograft 1, not detailed 1). The incidence of recurrent stenosis after carotid endarterectomy is low and usually the operation provides a patent artery for life.

Nontraumatic intracranial dissecting aneurysms have rarely been reported as the cause of acute infantile and childhood hemiplegia. The present case is unique because dissecting aneurysms occurred bilaterally in two clinically distinct episodes. A recent dissecting aneurysm of the right intracranial internal carotid artery was present with a healed dissecting aneurysm of left internal carotid artery in an 8-year-old boy.

Isolated ipsilateral fifth, seventh, tenth and twelfth cranial nerve palsies in a 74-year-old woman were shown at autopsy to result from an inferior lateral pontine infarction. The clinical features and pathogenesis of this uncommon lesion are discussed.

The histologic, immunocytologic, and electron microscopic features of pituitary adenomas surgically removed from two men with elevated levels of blood follicle-stimulating hormone (FSH) are described. In both cases, the high blood FSH levels were reduced after surgery. By light microscopy, the tumors corresponded to chromophobic adenomas, and the immunoperoxidase technique revealed the presence of immunoreactive FSH (beta-subunit) in the cytoplasm of the adenoma cells. By electron microscopy, the adenoma cells differed considerably from nontumorous FSH cells. They were smaller and angular and contained numerous microtubules as well as spherical secretory granules measuring 100 to 250 nm in diameter and often lining up along the cell membranes. The present findings are consistent with the view that FSH-producing adenomas may originate in the human pituitary.

This paper describes a special form of mitochondria which has been observed using the electron microscope in certain astrocytes of the Syrian hamster brain. The interior structural pattern of these mitochondria is characterized by the presence of numerous equilateral prismatic tubules in a highly regular hexagonal arrangement, instead of the customary foliate cristae. Such mitochondria have been designated as "prismatic type," in contradistinction to the more usually encountered crista and tubular types. The findings are compared with the occasional similar findings reported in the literature, and their possible functional meaning is briefly discussed.

A blow to the head will impart rotational velocity to the brain and, depending on its magnitude, will produce effects ranging from concussion to profound neurological dysfunction. Resultant shear strains distort and rupture axons, blood vessels and major fibre tracts. Thirty-seven patients with head injury that was not complicated by significant hemorrhage or superficial laceration of the brain had coma or severe dementia, spastic quadriparesis, incontinence and autonomic dysfunction. These patients survived 24 hours to 243 days. Gross pathological examination revealed little, but there was microscopic evidence of axonal and small vessel injury in all; this was localized to the basal and midsagittal areas of the diencephalon and mesencephalon, particularly in those less severely injured. Such changes represent the basic pathology of all head injury. Data from this study suggest that concussion depends upon varying degrees of damage to the axon as well as the neuron. The current definition of concussion-immediate loss of consciousness with rapid and complete recovery of cerebral function-should not exclude the fact that a small number of neurons may have been permanently disconnected or have perished.