[Characterization of inflammatory cell infiltrates of peripheral neuropathies in human immunodeficiency virus infection].
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Publications and source records attributed to M P Chaunu.
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A 51 year old woman presented with cerebellar ataxia and paralysis of conjugate lateral movement of the eyes. She had xerophtalmia and xerostomia. Biopsy of minor salivary glands showed mononuclear infiltrates typical of Sjögren's syndrome. Peripheral neuropathy was of the axonal type, and nerve biopsy showed a vasculitis made of a mononuclear infiltrate with only a few polymorphonuclears. The patient deteriorated despite corticosteroid therapy, plasma exchange and cyclophosphamide. Ciclosporin seemed to be transitorily beneficial. Epileptic seizures (auditory hallucinations) occurred. MRI showed hypersignal in the right temporal lobe. At post-mortem examination, a small ischaemic lesion with a large lymphocytic infiltrate was present in the left putamen. Neuronal loss and gliosis with some rod cells and glial stars were found in the brainstem, dentate nucleus and internal part of the right temporal lobe. Inflammatory changes were limited. The posterior columns of the spinal cord were pale, and some residual nodules of Nageotte were present in the spinal ganglia. These lesions were similar to those seen in encephalomyelitic syndromes associated with carcinoma. Lesions of the peripheral nerves were associated with vasculitis but changes in the central nervous system were morphologically similar to those observed as remote effects of carcinoma.
Nerve and muscle biopsies were performed on 20 patients with HIV infection and peripheral neuropathy. Nine patients had distal symmetrical peripheral neuropathy (DSPN) (six ARC and three AIDS), six had inflammatory demyelinating polyneuropathy (IDP) (three ARC, one AIDS, and two otherwise asymptomatic patients), one had mononeuropathy multiplex (MM) (AIDS), 1 had mononeuropathy (ARC), one had meningoradiculitis (AIDS), and two had areflexia-associated lymphocytic meningitides (ARC), DSPN exhibited axonal degeneration in four of nine cases and was associated with segmental demyelination in five of nine cases. IDP exhibited segmental demyelination associated with axonal degeneration in four of six cases. Demyelination was more frequent in asymptomatic patients (2 of 2 cases) and in ARC (7 of 12 cases), whereas axonal degeneration was predominant in AIDS (6 of 6 cases). Mononuclear cell infiltration was seen in 1 of 2 asymptomatic patients and in 11 of 12 ARC patients but was exceptionally found in AIDS (1 of 6 cases). Involvement of the walls of small vessels, mostly venules ("subacute microvasculitis"), was found in 1 of 2 asymptomatic patients, in 8 of 12 ARC patients, and never in AIDS. The polyclonal mononuclear cell population was composed mainly of Leu 2 (T8) positive cells in seven cases of ARC. No virions were seen in electron microscopy. HIV was isolated in two cases from the CSF or the nerve biopsy.
Almitrine bismesylate is thought to cause sensory peripheral neuropathy. Forty-six patients are reported who received almitrine bismesylate alone for chronic respiratory failure or in combination with raubasine for various cerebrovascular diseases. Polyneuropathy appeared between 9 and 25 months after the onset of treatment. Sensory signs and symptoms were confined to the distal parts of the lower limbs and involved large and small fibres. Histological and electrophysiological findings indicated axonal degeneration. Respiratory failure could have caused the polyneuropathy in some cases but many had no chest disease. Patients began to improve between 3 and 6 months after withdrawal of the drug. Recovery was usually complete after 12 months.
Twenty five patients with peripheral neuropathy at different stages of human immunodeficiency virus (HIV) infection are reported. Cerebrospinal fluid (CSF) findings were available in 17 cases, electrophysiology in all and a neuromuscular biopsy in 11. Of six otherwise asymptomatic HIV+ patients, five had chronic inflammatory demyelinating polyneuropathy (CIDP) and one acute inflammatory demyelinating polyneuropathy (AIDP). CSF showed pleocytosis in all cases. Infiltration of the endoneurium and/or the epineurium by mononuclear cells was seen in biopsies from three cases. These six patients recovered either spontaneously, or with corticosteroids or plasmaphereses. Of five patients with AIDS related complex (ARC), three had distal predominantly sensory peripheral neuropathy (DSPN), one CIDP and one mixed neuropathy. Of 14 patients with AIDS, one had mononeuropathy multiplex and 13 painful DSPN. Electrophysiological studies were consistent with an axonopathy. Nerve biopsies in six cases showed axonal changes but surprisingly associated with marked segmental demyelination in two cases. Cell infiltration was present in nerve samples in two cases. Five patients died within six months after the onset of the neuropathy.
A case of HTLV-I associated myelopathy in a 51 year-old Haitian woman is reported. MRI showed high signals in the cerebral white matter on T2-weighted images. There also was clinical and electrophysiological evidence of myositis, and a biopsy of the quadriceps muscle showed dense inflammatory infiltrates surrounding several small perimysial blood vessels. The virus was not demonstrated in the muscle. The presence of several systemic abnormalities (polyclonal gammapathy, circulating immune complexes, Sjögren's syndrome) and the vasculitis suggest an immunopathological mechanism for this HTLV-I associated myositis.
A device using a Macintosh microcomputer and a light microscope equipped with a drawing tube is described. The mirror of the drawing tube is turned to the screen of the microcomputer. An example of its use in morphometry of peripheral nerves is given. At a 1000X magnification, the resolution of the system is 10 pixels per 2.6-microns. The coefficient of variation between 20 measurements of diameter of thin (3 microns in diameter) and large (12 microns in diameter) myelinated fibers was 8% and 2% respectively. This precise and inexpensive system could be easily run in laboratories of morphology.
Lesions of vasculitis of nerve were found in 33 of 140 patients hospitalized for peripheral neuropathy over a little less than 2 years, and in 113 specimens from neuromuscular biopsies. A first group of 7 patients had histological lesions suggestive of systemic necrotizing vasculitis (periarteritis nodosa in 4 cases and Churg and Strauss disease in 2 cases); the 7th patient was treated for myeloproliferative syndrome. The clinical and electromyographic signs were those of an axonal polyneuropathy which was improved by various treatments in 6 cases. A second group of 26 patients had histological lesions of vasculitis of nerve. Ten of these patients presented with single or multiple neuritis (of unknown origin in 5 cases), 11 with distal polyneuropathy (of unknown origin in 5 cases) and 3 with chronic polyradiculoneuritis; in 2 cases, clinical and electromyographic findings were in favour of an anterior horn lesion. The duration of the disease varied from 6 months to 10 years. The principal causes identified were connective tissue diseases, solid cancer or lymphoma and isolated gammapathy. Two patients with multiple neuritis recovered spontaneously. The finding of vasculitis of nerve at biopsy therefore is of unequivocal significance outside the better known but smaller group of systemic necrotizing vasculitis.
An immunological mechanism may be responsible for the peripheral neuropathies related to IgM monoclonal gammopathies. Myelin-associated glycoprotein (MAG) has been found to be one the main target antigens for these paraproteinemias. Glycosphingolipids of peripheral nerve have been also found to be targets for these antibodies, especially a sulfated glycosphingolipid containing glucuronic acid (GLSG) specific for peripheral nerve. Crossed reactivity has been found between MAG and GLSG. Anti-glycolipid antibodies were determined in 14 patients with IgM gammopathy and polyneuropathy. Glycosphingolipids from human peripheral nerve were purified and chromatographed by thin-layer chromatography for immunodetection of the antibodies. The 12 patients who had GLSG antibody activity had a clinical status identical to the reported cases of dysglobulinemic neuropathies with anti-MAG antibodies.
Disorders of the peripheral nervous system occur at all stages of HIV infection. From 13 patients referred for a peripheral neuropathy, 9 were known to be HIV seropositive and 4 were found to be seropositive. All were Caucasian males aged 27 to 58. Ten were homosexual, 2 were drug-addicts. Patients fell into several groups: the first group was made of 5 patients, 4 asymptomatic and 1 AIDS-related-complex (ARC), with an inflammatory demyelinating polyneuropathy, acute in 1 case and subacute in 4; the CSF showed pleiocytosis in all cases. Motor conduction nerve velocities were markedly reduced and motor distal latencies prolonged. Three patients recovered spontaneously, 1 responded to corticosteroids, 1 to plasmapheresis. In the second group, 4 patients, 1 asymptomatic and 3 ARC, had a distal symmetrical polyneuropathy; CSF was normal in 2 cases. Electrophysiological studies and nerve biopsies indicated a mixed axonal-demyelinating polyneuropathy. Three patients recovered spontaneously, 1 is unchanged. Among both groups, an infiltration of mononuclear cells was found on nerve biopsies in 4 cases. The third group was made of 3 patients with AIDS who presented with a painful sensory polyneuropathy involving the distal lower limbs. Electrophysiological and pathological study of the nerve indicated axonal degeneration. No cell infiltration was found. The last patient with AIDS had a progressive meningoradiculopathy. These 4 patients died within 6 months after the onset of the neuropathy. These findings are close to those previously reported, and confirm the wide spectrum of disorders of the peripheral nervous system associated to HIV infection.
Sixteen cases of anoxic encephalopathy in adult patients admitted to the intensive Care Department of Raymond Poincaré Hospital (Garches) have been selected on the following criteria: resuscitation by external cardiac massage for cardio-respiratory failure, without any previous history of anoxia and with detailed data on the subsequent evolution of neurological signs and symptoms. Main clinical features were compared to the results of the neuropathological examination. The pattern and the distribution of changes are detailed. The cerebral cortex was always involved by diffuse ischemic cell changes or by laminar necrosis. The Sommer's sector of Ammon's horn was affected in 15 cases, the basal ganglia in 14, the cerebellum in 11, the brain stem in 6. The very rarely mentionned necrotic brain stem changes, which involved inferior colliculi, periaqueductal gray matter and substantia nigra were sometimes associated with lesions of the floor of the IVth Ventricle and of the mamillary bodies. They were different from Wernicke's encephalopathy with could be dismissed on clinical and pathological grounds. No clinical signs or symptoms specific for this distribution of changes could be found by the retrospective study of the clinical files.
Recent data favor the hypothesis of a genetically-induced overproduction of amyloid protein as the cause of Alzheimer's disease. This could be responsible for the occurrence of senile changes (senile plaques and neurofibrillary tangles) which are both characteristic of so-called normal aging of the brain and of Alzheimer's disease and lead to neuronal death. However, as shown by studies of twins, epigenetic factors must be very important in the triggering and/or acceleration of this process since the concordance between monozygotes does not reach higher levels than 41. It is argued that brain microglia, and/or astrocytes are the most likely candidates to the regulatory function of amyloid deposit in the brain. These cells could act by modulation of either the hydrolysis of the precursor protein during amyloidogenesis or the resorption of amyloid fibrils, which could occur in Alzheimer's disease as suggested by recent data. Further research on this topic could have therapeutical repercussions.
Lymphocytic visceral infiltration has recently been noted in association with lymphadenopathy-associated virus infection. A homosexual man, who had clinical and immunologic features of the acquired immune deficiency syndrome (AIDS)-related complex, is described. The patient presented not only with peripheral blood lymphocytosis but also with extensive lymphocytic infiltration involving lungs, lymph nodes, nerves, muscles, and esophagus. Lymphocyte subset immunostaining analysis showed that the lymphocytes were T8-positive. Thirty months after the clinical onset of the disease, no evidence of progression to AIDS was seen. Moreover, clinical improvement was observed, even though the patient did not receive long-term treatment. The clinical history of this patient suggests that lung T8-positive lymphocytic infiltration is associated with an increased risk of infectious episodes such as pneumonia and bronchitis.
An unexplained peripheral neuropathy was observed in five patients with positive serology for LAV/HTLV III. Three of them presented with polyneuropathy, one with chronic meningitis and oculomotor palsies, and one with a mononeuropathy. CSF was abnormal in 5/5, with elevated protein content (0.4-4 g/l) and abnormal cell count (29-65/mm3). Intrathecal production of LAV-specific IgG was demonstrated in 3/4 cases. Electromyographic examination showed reduced nerve conduction velocity in 4/5. Neuromuscular biopsy revealed microvasculitis with mononuclear cell infiltrates in 3/4 cases; characterization of these cells showed that they were predominantly non monoclonal T8 lymphocytes. Other symptoms of "AIDS-related complex" were present in all five patients. None had other causes of peripheral neuropathy. Thus, peripheral neuropathy can be the initial manifestation of LAV/HTLV III infection. Isolation of the virus from the nerve in one published case, and arguments for intrathecal synthesis of LAV-specific IgG suggest the direct role of this agent; however, the lymphocytic infiltration seen in three of our cases favours an indirect immune mechanism, as in other organs, such as lungs and lymph nodes.
Post-mortem study of every patient who died from AIDS in Pitié-Salpêtrire Hospital from June 1984 to November 1985 was performed without regard to the presence of neurological signs and symptoms. Autopsy were performed in 31/48 cases. Patients had been hospitalized in the Departments of Parasitology-Infectious Disease (24 cases) Internal Medicine (4 cases) and Neurology (3 cases). In every case, formalin-fixed material from the brain and the spinal cord were embedded in paraffin (20 samples), stained with hematoxylin-eosin, PAS, Alcian blue, Giemsa, Grocott and Ziehl techniques and Bodian's silver impregnation along with Luxol fast blue, and, in celloïdin (8 samples), stained with hematoxylin-eosin and Loyez' impregnation. There were 30 men (27 caucasian, 1 egyptian, 1 haïtian, 1 senegalese) and one woman (congolese). Twenty eight (28) patients were homosexuals. AIDS was transfusion-associated in two cases. Neurologic complications revealed the disease in 2 cases. Eighteen (18) patients had neurological signs or symptoms before death. Age range at death was 22-58 (mean 38). Brain weight in AIDS (from 1150 gms to 1750 gms-mean 1428 gms) was not statistically different from the mean weight of 100 male patients in the same age range autopsied in the same laboratory during the identical period (mean 1427 gms, standard deviation: 23). Microscopic abnormalities were present in every brain examined. These included non-Hodgkin lymphoma (3 cases), opportunistic infections (21 cases: 13 toxoplasmosis, 4 cytomegalovirus encephalitis, 3 cryptococcal meningitis, 1 infection by mycobacterium avium-intracellulare), and subacute encephalitis (17 cases, 9 isolated, 8 associated with other disorders). The characteristic changes consisted of lympho-monocytic focal infiltrates (so-called microglial nodules) and mild lympho-monocytic perivascular cuffs in 10 cases. Typical giant cells were seen only in one case. Mild demyelinating changes were also seen in only one case. No spinal cord spongiosis, nor Progressive Multifocal Leukoencephalopathy was found. HIV localization was performed on frozen sections utilizing in situ hybridization techniques (2 cases) and immunohistologic techniques (5 cases). HIV, RNA and proteins, was detected in 2 cases with subacute encephalitis. Infected cells were labeled with macrophage markers, and rarely with T4 lymphocyte markers. Infected astrocytes (identified by anti-GFAP serum) or neurons (identified by anti-NSE serum) were never observed. No giant cells were seen in these two cases.
To determine cognitive disturbances in recent demyelinating disease, we studied 21 patients with definite or probable multiple sclerosis (MS) of less than two years' duration and nine patients with recently isolated optic neuritis. None had any clinical or social evidence of cognitive impairment. Mild to moderate cognitive impairment. Mild to moderate cognitive impairment was present in 18 (60%) of 30 cases, affecting visual and/or verbal efficiency. These abnormalities were statistically significant when compared with the results of a control group of 29 patients. There was no correlation with a depressive status, between the presence of cognitive impairment and either the degree of handicap or the activity of the disease. The frequency of cognitive dysfunction (60%) appears to be comparable to that reported in other series in which MS evolution is over ten years. The natural history of cognitive functions in MS has to be identified. Neuropsychologic tests could be useful in the diagnosis of monosymptomatic or paucisymptomatic forms of MS (ie, visual or medullary).
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A 65 year-old man with an oesophageal carcinoma had an acute polymyositis with an extensive oedema of shoulders and arms which improved spontaneously. The significance of these disorders is discussed.