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A 50-year-old white woman with an 8-month history of Parkinson's syndrome which did not respond to levodopa therapy was found on pathological examination to have the topographical lesions of striato-nigral degeneration. In addition to those characteristic lesions, an associated degeneration of the optic pathways, from the level of the optic nerve to the geniculo-collicular fibers, of the corticospinal tract and of the olivo-dentate axis, were found. While offering further evidence for the concept of “multiple system degeneration”, no pathogenetic relationship either to previous cases of striato-nigral degeneration or to other multiple system degenerations is implied.

GM2 Gangliosidosis is an inherited dysmetabolic disease, characterized by accumulation of GM2 and GA2 gangliosides in neuronal as well as in non-neuronal tissues. Biochemically the disorder can be due either to a deficiency of hexosaminidase isoenzyme A (Tay-Sachs form) or isoenzymes A and B (Sandhoff variant) or to absence of the activator protein of the enzyme (Sandhoff and Christomanov, 1979). Infantile, juvenile and adult phenotypes are known. Recently patients with late-onset disease with amyotrophic lateral sclerosis-like or Kugebelg-Welander phenotypes or spinocerebellar ataxia have been described, and a large heterogeneity is increasingly being discovered (Johnson, 1981; Federico, in press).

An autopsied case of arteriovenous aneurysm of the vein of Galen in a 31/2-month-old female is reported. Arteriovenous aneurysm of the vein of Galen is a rare vascular malformation of the central nervous system consisting of a saccular dilatation of the vein which receives blood shunted through enlarged arteries. These peculiar structural and hemodynamic characteristics differentiate this particular malformation from the other AVMs of the central nervous system. In infants the arteriovenous aneurysm of the vein of Galen is characterized clinically by hydrocephalus and cardiomegaly. In the present paper the clinical features and diagnostic indications are discussed and, in particular, the role of computerized cranial tomography (CT) is emphasized as a rapid and noninvasive procedure for detection of intracranial disorders.

A case of stiff-man syndrome associated with primary generalised epilepsy is reported. In addition, nocturnal polygraphic recording revealed a nocturnal myoclonus. Detailed examination of the central nervous system did not show specific changes. There is no direct proof as to a spinal or supraspinal origin of the stiff-man syndrome. The absence of specific anatomical lesions may indicate a functional rather than a structural disturbance in its physiopathogenesis.

This case of subacute encephalomyelitis with a hyperekplexia type syndrome was characterized histologically by marked lymphomonocytic infiltrates, nodules of microglia, evidence of neuronophagia. These findings suggested a viral infection. The clinical peculiarities of this encephalomyelitis are explained by the elective site of the lesions in the grey substance of the spinal cord, of the tegmentum of the medulla oblongata and pons and of some nuclei of the extrapyramidal system.

The effect on central myelin of Actinomycin D, an RNA--and, secondarily, a protein-synthesis inhibitor, has been studied by light and electron microscopy. The intracranial injection of this drug produced an extensive status spongiosus of the white matter in the cerebrum, cerebellum, brain stem and optic nerve within 48 h. The status spongiosus was due to vacuole formation within the myelin sheath and to enlargement of the extracellular space. Three types of vacuoles were observed: (a) the most common varieties formed between the inner tongue and the remainder of the myelin sheath; (b) a second variety formed by enlargement of the periaxonal space with separation of the axon from its myelin sheath, and (c) a less common type of vacuolization was due to splitting of the myelin lamellae at the interperiod line to form large intramyelinic vacuoles. Myelinic vacuoles were preceded by nuclear and cytoplasmic changes in oligodendrocytes, which included nucleolar segregation, disaggregation, and diminution in number of ribosomes. These changes were similar to those previously reported in a variety of cells exposed to Actinomycin D. It is suggested that myelin vacuoles result secondarily from the Actinomycin D inhibitory effect on oligodendroglial RNA--and protein-synthesis, rather than from a direct effect of this drug on the myelin sheath.

The clinico-pathologic findings in two patients with chronic relapsing polyneuritis are reported. The patients had several attacks of diffuse polyneuritis followed by partial recovery. The tendency to persisting disability increased following relapses and in the late stages there was a progressive motor deterioration suggesting a continuing activity of nerve damage. The biopsies of peripheral nerves, obtained in the advanced stages of the disease, showed severe loss of myelinated fibers and aspects of repeated demyelination and remyelination, with formation of onion bulb complexes. Completely demyelinated axons together with remyelinating fibers as well as remyelinated fibers invested by macrophages were seen at the same time. The clinical and pathological evidences suggest that in chronic relapsing polyneuritis, at least in the late stages of the disease, besides clinical relapses, there is a continuing activity of nerve damage. Thus, due to this ongoing activity of demyelination and remyelination, the elimination of the supernumerary Schwann cells does not take place satisfactorily and hypertrophic changes of the nerve fascicles are produced.

The clinicopathological findings in a child with extraskeletal Ewing sarcoma are described. The patient complained of pain in the lower back and difficulty walking. An extraskeletal, epidural, friable tumor, 2-3 cm long was removed from the epidural space. It had no relationship with the bone structures. Light and electron microscopic examination of the tumor led to the diagnosis of Ewing sarcoma. The morphological aspects of this neoplasia and the problem of the differential diagnosis with other small cell tumors of the epidural space are discussed.

The epidemiological, clinical, electrophysiological and nerve biopsy findings of 3 cases of n-hexane neuropathy in shoe industry are reported. The disease affects more than 1 person working in the sam

BAEPs were recorded in a 70-year-old man who had developed symptoms indicative of Wallenberg syndrome. He died, of extracerebral causes, shortly after hospitalization and an autopsy study was done on the brainstem lesions. Right ear stimulation disclosed BAEP abnormalities, but gave no indication of the level of the ischemic disorder. Histopathological examination showed a typical right dorsolateral medullary infarct. A detailed study of the acoustic pathways demonstrated their anatomical integrity. These findings confirm the uncertainty that still exists as to the exact location and type of generators of BAEP components. They suggest, moreover, that BAEPs can give objective evidence of functional impairment of brainstem acoustic structures even in the absence of persistent anatomical damage.

The case of a 22 year old woman presenting progressive peroneal muscular atrophy (PMA) is described. Electrophysiological and pathological studies demonstrated features of hereditary motor and sensory neuropathy -HMSN- type I. Laboratory findings showed two erythrocytic defects: beta-thalassemia trait and a glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Unlike the past, these inherited disorders are associated with PMA.

n-Hexane is a solvent causing peripheral neuropathies. On several occasions it has been postulated that it may act via metabolic products. Therefore, the neurotoxicity of hexanol-1 and hexanol-2, hexane's principal metabolites, was studied. The compounds were given to rats ip for 8 months. Hexanol-1 produced equivocal signs of neurotoxicity in the peripheral nervous system. Hexanol-2 caused a peripheral neuropathy verified both neurophysiologically and histologically. This neuropathy was similar to those observed in experimental polyneuritis due to n-hexane, methyl n-butyl ketone, and 2,5-hexanedione. Hexanol-2 may therefore be considered as a neurotoxic product connecting the metabolic pathways of n-hexane and methyl n-butyl ketone.

The clinico-pathologic findings in an additional case of gliomatosis cerebri are reported: a 60-year-old woman died 8 months after the onset of a progressive deterioration of both the neurologic and mental conditions. Neuropathologic examination disclosed wide demyelination of both hemispheres, communicating through the corpus callosum, extending downward along the internal capsule to the brainstem structures. Cellular stains showed the presence of elongated astrocytes, multinucleated cells, mitotic and anaplastic figures, involving the demyelinated areas and the neighboring regions, and allowed the diagnosis of gliomatosis cerebri diffusa. The nosologic and pathogenetic aspects of this rare entity are discussed.

We describe the case of a patient with a history of resistant asthma who presented with subacute neuropathy, hypereosiniphilia and central nervous system involvement; these findings were consistent with allergic granulomatous angiitis (Churg-Strauss syndrome). Although cutaneous biopsy prompted the diagnosis, the cases reported suggests that clinical, biological and histological data are all essential for the diagnosis. We emphasize that an early recognition of this syndrome may be important, since appropriate therapy may lead to recovery or influence favorably at least long term survival.

A case of congenital toxoplasmosis is reported in which the patient died at 32 days following seizures, coma and respiratory disturbances. Neuropathological examination showed numerous foci of softening throughout the brain. Histological examination disclosed widespread areas of inflammatory necrosis. Circumscribed areas of granulomatous inflammation were also found. Cysts containing a variable number of microorganisms and toxoplasmas free in the damaged areas were frequently observed. Small calcifications were scattered in the cerebral cortex and basal ganglia. Electron microscopy of postmortem brain specimens demonstrated toxoplasmas at various stages of development. The microorganism is enveloped by a two-layered membrane, the pellicle. Replication occurs in a vacuole inside the host cell. Following replication the newly formed parasites, the trophozoites, are released. Several replications without release may also occur with consequent cyst formation. The motile form of the toxoplasma, the tachyzoite, is fusiform with truncated cone shape of the anterior ending which is the presenting surface modified for host cell penetration. The modality of transplacental transmission and the clinical syndromes associated with toxoplasma infection are discussed. EM even of post mortem material contributes to knowledge of the structure of the parasite and of its life cycles.

Ultrastructural examination of white blood cells of 8 patients with neuronal ceroid lipofuscinosis showed the characteristic cytosomes, i.e. curvilinear bodies, fingerprint profiles, osmiophilic bodies, as seen in nerve cells. The reliability of this simple technique in the diagnostic work-up of this progressive neurodegenerative disorder is emphasized.

A clinical, genetic, electrophysiological and ultrastructural study of a large kinship with peroneal muscular atrophy is reported. There was a noteworthy homogeneity in the phenotype as well as in the electrophysiological characteristics encountered in 15 affected members aged between 7 and 72 years. The symptoms appeared first in the second decade of life and stabilized by the fourth decade. There was no evidence of linkage of the neuropathy gene to the Duffy blood group locus on chromosome 1. The electrophysiological data in this family as well as the ultrastructural findings confirm that there is heterogeneity in hereditary motor and sensory neuropathy type I, and support the concept of an intermediate form of Charcot-Marie-Tooth disease.

The clinicopathological findings are reported in a child with congenital oculofacial diplegia, paresis of pharyngeal and laryngeal muscles, and concomitant tetraparesis. The constellation of signs and symptoms correlates with a complex picture of maldevelopment, including absence of olfactory bulbs, hippocampal abnormalities, hypoplasia of the corpus callosum and of the cerebellum, and severe hypoplysia of the descending pathways. We stress the role played by the hypoplasia of the descending fibres, with consequent denervation of the cranial nerve nuclei, in producing the Mobius-like picture.

Light-, electron microscopic and immunopathological findings in a nerve biopsy of a patient with peripheral neuropathy associated with monoclonal gammopathy are reported. Loss of fibers, Wallerian-like degeneration and segmental demyelination were the most important features observed in light microscopy. In E.M. widening of the peripheral lamellae of myelin sheaths and occasional aspects of hypermyelination were seen. Immunoperoxidase study showed binding of IgM (k light chain) on the myelin sheath. The possible pathogenetic implications of these findings are discussed.

Dorsal root ganglion cells, obtained from 8–10-week human foetuses, were isolated by enzymatic procedure and grown on poly-l-lysine-coated coverslips. Most of the cultured cells showed the ultrastructural and immunological features of normal peripheral neurons. By immunocytochemistry neurons reacted with IgM antibodies with specificity for myelin-associated glycoprotein (MAG) from patients affected with IgM k gammopathy and peripheral neuropathy. The antigen was located on the plasmalemma of both perikarion and axon. We suggest that anti-MAG antibodies do not recognize neuronal MAG, but rather an epitope shared with different glycoproteins.

A 20-year-old woman was admitted to the Hospital because of tetraparesis and respiratory failure, requiring mechanical ventilation. No disturbances of consciousness were associated. She had a residual left lower limb paresis from the age of 14, lasting unchanged until this final episode of bulbar paralysis. She did not recover: death occurred 3 months later. Neuropathological examination revealed Rosenthal fibers in the gray and white matter with typical perivascular and subpial distribution. Areas of mild demyelination were found in the periventricular white matter of the centrum ovale and in the hilum of the nucleus dentatus. In the brain stem the highest density of Rosenthal fibers was found in the medulla where the deposits extended deeply into parenchyma. The relationship of this case with Alexander's disease is discussed.

The pattern of recovery of myelinated axons in the posterior tibial nerve after crushing was studied in rats chronically intoxicated with 2,5-hexanedione. It was given for 2 weeks before crushing (200 mg/kg i.p. 5 times a week) or additionally for two further weeks after the nerve crush. Two animals were examined from each group at approximately 1,2,3,4 and 8 weeks later. Return of function in poisoned animals was slower than in the controls. The numbers of regenerating myelinated fibres was severely reduced in poisoned animals up to 4 weeks later, but by 8 weeks the numbers equalled those in the control nerves. Marked impairment of initiation of neurite outgrowth was found, but once begun, axonal growth was comparable to controls and myelination occurred normally. Above the crush for 10 mm, filament-filled axonal swellings were found in poisoned animals accompanied by varying amounts of retrograde axonal degeneration. These findings are discussed in relation to the role of normal neurofilaments in axonal growth and the effects of probably cross-linking of these by 2,5-hexanedione on regenerating neurites.

A case of meningeal gliomatosis following a primary spinal cord tumor is reported. The clinico-pathological features of this unusual extension of a spinal glioma are described. The rare incidence of this malignancy and its occurrence in young patients only are stressed. The possible pathophysiological events leading to the diffuse dissemination of the neoplastic cells are discussed.

Background: The term myofibrillar myopathy refers to a rare and clinically heterogeneous group of muscle disorders. The pathogenesis of this myopathy is not well understood. The morphologic hallmark is myofibrillar destruction with abnormal expression of numerous proteins, most consistently of desmin. Methods: The authors investigated eight patients with myofibrillar myopathy belonging to four families. They studied the role of different protein kinase C isoforms and of interleukin-1β, a cytokine that might activate protein kinase C and, in addition, mediate myofibrillar proteolysis. Results: Immunohistochemical analysis showed the expression of α, η, and ζ isoforms of protein kinase C and of interleukin-1β in abnormal muscle fibers. Immunoblots confirmed the immunohistochemical data and revealed the absence of protein kinase C δ and e in muscle fibers from patients and controls. Conclusions: These data suggest that protein kinase C and interleukin-1β may play a role in the pathogenesis of myofibrillar myopathy.

Neuropathic complication often occurs in critically ill patients, and changes in the microcirculation of the peripheral nerve have been suggested to play a role in the pathogenesis of the nerve lesion. We report the results of a pathological and immunohistochemical study of superficial peroneal nerve biopsy specimens in a series of 22 critically ill patients with sepsis and neuromuscular disorders. Eight patients had histopathological features of axonal neuropathy compatible with critical illness polyneuropathy (CIP). The nerve lesions ranged in severity from mildly reduced myelin-fiber density with sporadic axonal degeneration to marked fiber loss with abundant degenerative changes. In no patient did we detect evidence of primary demyelinization or inflammatory infiltrates. We analyzed the immunohistochemical expression of E-selectin, vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF-alpha) in nerve microvessels. Expression of E-selectin was significantly increased in endothelium of epineurial and endoneurial vessels, suggesting endothelial cell activation. These findings again confirm axonal degeneration as the major pathological feature of CIP. Our immunohistochemical data provide first evidence that activation of the endothelial cells of the microvessels in the endoneurium of human peripheral nerve does occur during sepsis. This specific activation might have implications with the mechanisms responsible for the axonopathy in critically ill patients.

M. G. Passarin, S. Monaco, S. Ferrari, C. Giannini, N. Rizzuto and G. Moretto (1996) Neuropathology and Applied Neurobiology 22, 60-67 Cytoskeletal changes in cultured human f ibroblasts following exposure to 2,5-hexanedione In the present study, the effects of the 2,5-hexanedione (HD) on the various cytoskeletal components of human eukaryotic cells were investigated. Primary cultures of human fibroblasts from three healthy donors were exposed to 2.8 mM HD for 14 days; unexposed cultures were used as controls. At different time intervals, cells were counted and the growth curves compared. After 14 days of treatment, the cultures were processed for immu-noblotting, immunocytochemistry and ultrastructural studies. As compared to controls, morphological abnormalities induced by HD consisted of modification of the cell shape, formation of tangles composed by 10 nm filaments and cytoplasmic segregation of microtubules and membrane-bound organelles. By immunocytochemistry, the tangles of cytoplasmic filaments were stained by an antibody specific for vimentin. By immunoblotting, the anti-vimentin antibody recognized only bands of 50-60 kDa. Comparison of growth curves between treated and control fibroblasts clearly revealed an interference of HD with the cell cycle. The present results demonstrate that the cytotoxicity of HD is not restricted to intermediate filaments, but affects other cytoskeletal components, such as microtubules, as suggested by the impairment of cell division cycle

The study describes the mutations causing adrenoleukodystrophy in seven Italian families. Four missense mutations leading to amino acid substitutions, two frameshift mutations leading to a premature termination signal, and a splicing mutation were identified. Mutations 2014C>T (P543L), 2053A>G (Q556A), 673-674insCC, and 1874+1G>A are described for the first time in this report. Mutations 1638C>T (R418W), 1588G>A(R401Q), and 1801-1802delAG are already known to be link to ALD.

“Locked-in” syndrome was observed in a 42-year-old woman with multiple sclerosis. Autopsy revealed extensive demyelination in both cerebral peduncles, the periaqueductal region, and the internal capsule, but the ventral portion of the pons was spared.

We investigated two patients with the idiopathic hypereosinophilic syndrome and peripheral neuropathy. Clinical, EMG, and pathological findings were consistent with axonal polyneuropathy. Morphologic changes of the nerve biopsies suggested axonal damage secondary to increased endoneurial pressure from leakage of capillaries. We postulate that endothelial cell damage, followed by nerve edema, is the first step in the pathogenesis of peripheral neuropathy in these patients.