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Wilson's disease (WD) with extensive cortico-subcortical lesions represents a rare neuropathological subgroup, the pathogenesis of which is not clearly determined. We report two new cases with identical lesions. In the families of each of the patient, there were mutations in the ATPase7B gene, especially in the family of proband 1, and in the first cousin of proband 2. These cases included massive destruction of the white matter in superior gyri, mostly frontal, extending to the deep cortex with neuronal loss and capillary proliferation. Astrocytes were of Alzheimer type 1 and 2; and type 1 were labeled by anti-metallothionein. Opalski cells were abundant and their macrophagic lineage was confirmed by immunostaining. Among the possible mechanisms proposed, the role of vascular factors and penicillamine treatment could be excluded. Cerebral copper content in white matter and putamen of case 1 was at the same level as in common WD but accumulation of unbound copper in the white matter was a distinctive feature, which suggested a pathological neurotoxic effect.

A 73-year-old man was investigated for a peripheral neuropathy which occurred in the course of a Waldenstrom's macroglobulinemia. Serum immuno-fixation electrophoresis demonstrated two IgM monoclonal gammopathies of the kappa and lambda chain isotypes, and one had the physical characteristics of cryoglobulin. Immunoblot studies on the patient's serum revealed antibodies which reacted with peripheral nervous system proteins of different molecular weights including the myelin-associated glycoprotein (MAG). An immunofluorescence study of a superficial peroneal nerve biopsy revealed not only a binding of IgM and kappa light chain on several myelin sheaths but also the presence of IgM and kappa light chain deposits in the endoneurium. On electron microscopic examination, numerous fibres presented a widely spaced myelin and the endoneurial deposits had the ultrastructure of cryoglobulin. This is the first case presenting features of widely spaced myelin related to serum anti-MAG activity associated with monoclonal cryoglobulin deposits in the endoneurium.

A peripheral nerve biopsy was performed in 15 patients with human immunodeficiency virus (HIV) infection and polyneuropathy. Two cases [1 asymptomatic, 1 AIDS-related complex (ARC)] presented with chronic inflammatory demyelinating polyneuropathy; there was 1 case (asymptomatic) of mononeuropathy multiplex and 12 cases (1 asymptomatic, 1 ARC, 10 AIDS) with distal symmetrical polyneuropathy. Epi- or endoneurial microvasculitis was observed in 6 cases. Electron microscopy showed that nerve fiber lesions were mainly axonal. Severe segmental demyelination was also present in both cases of chronic inflammatory demyelinating polyneuropathy, with characteristic features of active demyelination in one. Numerous plasmacytoid cells were found in the endoneurium in 4 patients. Tubuloreticular inclusions were present in endothelial cells in the 10 cases with AIDS but absent in the other patients. Direct immunopathological examination with anti-immunoglobulin sera was negative in all cases. HIV was evidenced by in situ hybridization in 2 AIDS patients; no Epstein-Barr virus or cytomegalovirus was detected.

The possible occurrence of chronic inflammatory demyelinating polyneuropathy (CIDP) in association with an identified dysglobulinemic status is recognized and a causal relationship between the two has been suggested. We had the opportunity to study 18 patients presenting with CIDP and dysglobulinemia. This was an IgG monoclonal gammopathy (IgG MG) in 8 cases, an IgM monoclonal gammopathy (IgM MG) in 8, an IgG-IgM biclonal gammopathy in 1 case and an IgM monoclonal cryoglobulinemia in another. A peripheral nerve biopsy specimen was available for all patients and the morphological findings in these specimens in the cases of CIDP with IgG MG or cryoglobulin did not differ from those without, whereas characteristic features were observed in the cases of CIDP with IgM MG and anti-myelin associated glycoprotein activity.

Unlike cytomegalovirus (CMV) ventriculoencephalitis, herpes simplex virus type 1 necrotizing encephalitis has only rarely been observed in AIDS patients. A 40-year-old bisexual man was followed for an HIV1 infection from 1987 onwards. In June 1993 he was referred for sudden confusion, left hemiparesia and fever. The blood contained less than 10 CD4 lymphocytes/mm3. The patient remained comatose and febrile, and died 4 weeks later. In coronal sections of the brain there was necrosis of the internal parts of the left temporal lobe, necrosis of certain areas of the ventricular walls and a small tumor at the top of the right frontal lobe, which proved to be a polymorphic high-grade lymphoma. CMV ventriculoencephalitis lesions were prominent in the ventricular walls of the oecipital lobes and there was a strong nuclear signal for CMV using in situ hybridization. Herpes simplex virus type 1 was shown in the nuclei and cytoplasm of certain neurons and astrocytes in the borders of the necrotized temporal lobe areas by immunohistochemistry, in situ hybridization and electron microscopy, whereas in situ hybridization and immunohistochemistry for CMV were negative in such areas. Necrotizing type 1 encephalitis must not be overlooked in immunodeficient patients.

Mechanisms of peripheral neuropathies in polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome are poorly understood. A peripheral nerve biopsy was performed in 22 patients. Of these 9 had histological features of Castleman's disease on lymph node biopsies, and 19 had a monoclonal lambda light chain in their serum. Certain nerve fragments were paraffin embedded, others were frozen and studied by direct immuno-fluorescence, and others were fixed for ultrastructural examination. Paraffin-embedded fragments did not show any amyloid deposits, and at direct immunofluorescence there was no immunoglobulin fixation. At ultrastructural examination, features of uncompacted myelin lamellae (UML) were present in 19 patients, and their frequency varied from 1% to 16% of myelinated fibres. Up to now UML have been reported only in 7 patients with POEMS syndrome in the literature. UML have also been noticed in a few cases of inflammatory demyelinating polyradiculoneuritis and inherited tendency to pressure palsy.

In a large series of 116 cortical resections for treatment of medically intractable epilepsy, 10 glial hamartomas and 11 neuronoglial malformative lesions were found. Glial hamartomas were astrocytic in 3 cases, oligodendrocytic in 6 and mixed oligoastrocytic in 1. Neuronoglial lesions corresponded to “focal cortical dysplasia” in 6 patients and to “microdysgenesis” in 5 others. This study focuses on the various neuropathological presentations of these malformative epileptogenic lesions, and on correlations with neuro-imaging data.

Three cases of primary cerebral lymphoma in acquired immunodeficiency syndrome were studied. Tumoral fragments taken at autopsy were frozen and studied by the Southern blot technique (SBT). Other tumoral fragments were fixed in formalin, embedded in paraffin and used for in situ hybridization (ISH) with biotinylated probes for DNA of Epstein-Barr virus (EBV). ISH was positive in each case with a spotty nuclear labelling of certain tumoral cells. SBT evidenced a clonal rearrangement of the immunoglobulin heavy chain gene in each case. In addition, EBV DNA was detected in each frozen fragment with only one restriction pattern, indicating that the EBV- infected cell population was a clonal expansion of a progenitor cell.

In three children with dominant hereditary motor and sensory neuropathy type I, peripheral nerve biopsy showed the classical lesions of segmental demyelination with remyelination and onion bulb formations. In two cases, ultrastructural examination also demonstrated numerous characteristic features of active demyelination. The presence of active demyelinating lesions suggests an autoimmune attack superimposed on the course of a chronic genetic disease.

The present communication described changes on nerve biopsies from 16 diabetics without neuropathy, except the fact that the ankle jerks were often decreased bilaterally, as it is often encountered in diabetes mellitus. 16 non-diabetic patients with various peripheral neuropathies were also studied; the glucose tolerance tests were always normal in this group and none had any vascular or collagen disease. The three series included patients between 45 to 75 years old. Obervations made on nerve biopsies from these three groups have been compared. The basement membranes of endoneurial capillaries were measured. These measurements have been made on the thinnest part of the basement membranes and pericyte processes were not included. At least 5 capillaries per 1 patient have been studied. Averaging with a computer has permitted demonstration of significant thickenings of basement membranes in diabetic patients without neuropathy; such an observation was not made in non-diabetic patients with various peripheral neuropathies, while the thickenings were the most important in patients with diabetic neuropathy. It must be said that individual variations were encountered in each group. Nerve parenchyma has been carefully studied. In diabetic patients without neuropathy, 14 cases displayed a typical but usually moderate proliferation of Schwann cells. Axon lesions were mild and unfrequent. The exact relationships between thickening of basement membranes of vasa nervorum and lesions of nerve parenchyma need some further informations.

Quantitative, immunopathological, light and electron microscopic studies of superficial peroneal nerve biopsies from 31 patients with IgM monoclonal gammopathy were carried out. Six patients had Waldenström's macroglobulinemia and 25 had IgM monoclonal gammopathy of undetermined significance. Serum samples from 28 of these patients were assayed for anti-myelin-associated glycoprotein (anti-MAG) activity. Anti-MAG activity was found in 25 of the samples. There was a relationship between the widening of some myelin lamellae observed on ultrastructural examination and the serum anti-MAG activity (23 cases). Immunopathological examination showed IgM binding to myelin sheaths in 17 cases.

Inflammatory demyelinating polyradiculoneuropathies exhibit well-known ultrastructural lesions of the peripheral nerve, both in acute cases, i.e., Guillain-Barré syndrome, and in relapsing, sub-acute and chronic cases. We present a case of relapsing inflammatory demyelinating polyradiculoneuropathy in a diabetic patient with a biopsy exhibiting these lesions, as well as a widening of the outermost myelin lamellae in some fibers. Such associated lesions are classic in experimental inflammatory demyelinating polyradiculoneuropathies, but have not been reported in human pathology.

Four cases of early infantile polyneuropathy with defective myelination are reported. The peripheral nerve was studied by light and electron microscopy; different morphological characteristics have been noticed in these patients. Case 1 presented aspects of defective myelination with atypical "onion bulb" formation composed of multiple layers of basement membrane. In case 2, defective myelination and atypical "onion bulb" formation were associated with aberrant hypermyelination. Cases 3 and 4 were brothers, who presented axonal damage and atypical "onion bulb" formation.

Peripheral nerve biopsies from two patients with chronic sensorimotor neuropathy were studied. The first case was a non-Hodgkin malignant lymphoma and did not show any dysglobulinemia. The second case had a benign monoclonal gammopathy IgG, Lambda type. Direct immunofluorescence showed no deposits in the first case and slight deposits of anti IgG sera on a few myelinated fibers in the second case. There were numerous fibers showing uncompacted myelin lamellae, 7% in the first case and 4% in the second case. Some of these fibers had axons containing more tubules than filaments. The very few cases reported on neuropathies showing that uncompacted myelin lamellae were frequently associated with dysglobulinemic neuropathy. However, this ultrastructural abnormality of the myelin sheath can be observed without any dysglobulinemia.

Essential mixed cryoglobulinemia, which can cause hypersensitivity vasculitis, was observed in five patients with peripheral neuropathy. Three cases presented with multifocal neuropathies and two cases with symmetrical polyneuropathy. One had cryoglobulinemia with IgM monoclonal gammopathy and IgG polyclonal gammopathy, and the other four had cryoglobulinemia with polyclonal gammopathy. Biopsies showed perivascular infiltration by mononuclaer cells around medium, and mainly small-sized blood vessels. This was observed in the epineurium (five cases) and muscular fragments (three cases). At ultrastructural examination two cases showed severe damage of most myelinated fibers, which presented acute stages of Wallerian-like degeneration, and the three other cases showed a less widespread destruction of myelinated fibers. Most endoneurial capillaries showed swollen endoneurial cells. Myelino-axonal degeneration of myelinated fibers is probably due mainly to the vasculitis always present in the epineurium. This damage was probably worsened by the modifications of endoneurial capillaries. These lesions and their mechanisms are quite different from those observed in cases of cryoglobulinemia with an isolated monoclonal gammopathy.

A 75 years old man had a chronic lymphoid leukemia for 5 years. Within a period of three months he developed a polyneuritis. The biopsy of a peripheral nerve showed a large cellular infiltration by lymphocytes. The ultrastructural study shows in some Schwann cells disruption of the myelin. Their cytoplasm is invaded by a lymphocyte process as in Guillain-Barre. But in this case some of these invading lymphocytes show polygonal structures in their cytoplasm; that is sometimes seen in the proliferating cells of the chronic lymphoid leukemia.

Angiotropic lymphoma can present as a vascular disease in the central nervous system. The patient described in this report had a sudden pain in the region of the right superficial peroneal nerve and a nerve biopsy showed tumoral cells in the lumen of most small blood vessels. This pathology, first described in the skin as malignant angioendotheliomatosis, can be compared with the occurrence of multiple emboli in the vasa nervorum. In recent cases, tumoral markers have evidenced a lymphomatous origin, generally of the B type.

A diabetic woman underwent an incision of the right big toe for an abscess and developed a typical Guillain-Barre syndrome 48 h later. A biopsy of a peripheral nerve, performed 10 days later, showed modifications usually seen in diabetic patients, as well as the characteristic ultrastructural modifications of the Guillain-Barre syndrome (GBS). Moreover, 22% of myelinated fibers exhibited vesicular disruption of the myelin sheaths. This lesion is rarely encountered on the biopsies of peripheral nerve in GBS and concerns only a few myelinated fibers. Such a prominence of myelinic vesicular disruption and its occurrence in a diabetic patient are discussed.

The peripheral nerve was taken from 25 diabetic patients with arteritis just before or after amputation of a leg. The ultrastructural study of myelinated fibers showed several alterations. Loss of fibers varied greatly from case to case. This was accompanied in some cases by hypertrophy of the Schwann cells around demyelinated fibers as has been observed in some ordinary diabetic neuropathies. Unusual abnormalities consisted of particular axonal degeneration and evidence of aberrant remyelination. This axonal injury was peculiar because of the accumulation of organelles which tended to transform some of the fibers into enlarged axons. Such a lesion might correspond to a hypoxic axonopathy.

Two cases of sarcoid neuropathy were diagnosed by histological examination of muscle and peripheral nerve biopsies. The epineurium of the first patient showed a few sarcoid granulomas surrounding and invading the wall of an arteriole, and in some arterioles there were sites of fibrinoid necrosis. Sarcoid granulomas encroached on the walls of arterioles in the epineurium of the second patient. Ultrastructural examination showed severe alteration of nerve fibres in the first case and only a few altered fibres in the second. Damage to nerve fibres in these cases depended mainly on the degree of arteriolar wall involvement.