Biomedical subjects
Publications and source records attributed to R Nemni.
We report a 74-year-old woman with a slowly progressive sensory motor axonal neuropathy and a monoclonal IgG-kappa that bound to a 68-kd axonal protein identified as the low molecular weight neurofilament protein. The sera of control subjects and disease controls did not bind to neurofilament protein.
We used an indirect immunoperoxidase technique (Avidin-Biotin system) to study the sera of patients with "clinically probable" Alzheimer's disease (AD) and with Down's Syndrome (DS), compared with age-matched controls. Diluted sera were incubated with paraffin sections of hippocampus, frontal, temporal, and parieto-occipital lobes from normal human brains. Biotinylated anti-human goat gamma-globulins were used as secondary antisera. A significantly greater percentage of neurons were immunostained in all the brain regions (frontal, temporal, and parieto-occipital lobes and hippocampus) incubated with sera of AD patients than with sera of DS patients or of controls. This indicates that AD patients have an excess of circulating neuron-binding antibodies (NBAs), mainly reacting with cytoplasmic structures. NBAs could be either the cause or the result of the cerebral lesion found in AD. This study is not able to answer this question, but some previous data from our own and other laboratories suggest that NBAs have a role in the pathogenesis of AD lesions. Since we found no increase of NBAs in DS patients, the brain lesions in DS appear to have a different pathogenesis.
A 56 year old man with acute sensory-motor polyneuropathy associated with mycosis fungoides is described. EMG studies showed diffuse signs of muscle denervation. A skin biopsy specimen showed a lymphocyte infiltration in the dermis, composed of mycosis cells characterised by deep invaginations of the nuclear membrane, and small Pautrier's microabscesses in the epidermis. Sural nerve biopsy revealed endoneurial fibrosis, a decreased number of myelinated fibres and acute axonal degeneration.
We report the case of a 51-year-old man affected by mainly motor polyneuropathy with subacute onset and tendency to chronicization. Several possible etiological factors were present, but nerve biopsy, showing ischemic and inflammatory neuropathy, led us to consider cryoglobulinemia as the most important.
Clinical, pathological and immunocytochemical studies are described for 8 patients with cryoglobulinaemia and peripheral neuropathy: 5 had essential cryoglobulinaemia and 3 secondary cryoglobulinaemia. The cryoglobulins in 2 cases were type II (mixed cryoglobulins with a monoclonal component), type III (mixed polyclonal cryoglobulins) in 2 others, and were not characterized in 4. In all patients the neuropathy had an acute or subacute onset and in 7 it was initially asymmetric but, during the illness, in 3 it gradually progressed to a symmetric sensorimotor polyneuropathy. All patients had sural nerve biopsies. In 4 there was widespread vasculitis with necrosis of vessel walls and perivascular inflammatory cells. In another 2, thickening of vessel walls and luminal narrowing without inflammatory cell infiltration, together with loss of myelinated fibres from single fascicles or focally within fascicles, suggested that the neuropathy was of vascular origin. In all patients the main pathological damage was axonal degeneration. Signs of axonal regeneration were rare. The total number of myelinated fibres was reduced in all cases, from 24 to 95% below the lower limit of normal control values. Large diameter fibres were lost preferentially in 7 patients, being below 16.5% of the total number. Several possible pathogenetic mechanisms have been suggested for cryoglobulinaemic neuropathy, including immunologically mediated demyelination and ischaemic injury due to intravascular deposits of cryoglobulins or vasculitis. Our observations therefore confirm a major role for ischaemic factors, secondary to inflammatory vascular destruction, in the pathogenesis of peripheral neuropathy in most cases of types II and III cryoglobulinaemia.
In order to investigate the role of paraproteins in the production of neuropathy we experimentally induced monoclonal immunoglobulin-producing tumours into 32 BALB/c mice by injecting mineral oil or pristane intraperitoneally. In 11 mice morphologic and histometric studies of the sciatic nerve revealed the presence of neuropathy. Immunohistochemical studies did not demonstrate a significant amount of immunoglobulins and light chains in the endoneurium. The advantages and limits of this experimental model are discussed.
Clinical, neurophysiological and morphological studies of four patients with polyneuropathy and secondary hypothyroidism are reported. Neurophysiological studies revealed signs of muscle denervation and reduction of conduction velocity in all the patients. Sural nerve biopsies showed axonal degeneration in all cases but one. All the patients were treated with replacement therapy and clinical symptomatology and neurophysiological parameters improved in all patients.
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Peripheral neuropathy in Crohn's disease has been described, to date, only with vitamin B12 deficiency or as due to oral metronidazole treatment. We report the association of Crohn's disease and peripheral neuropathy in two patients in whom neither of these pathogenetic factors of nerve damage apply. The CSF of both was normal. Patient 1 has had Crohn's disease for 12 years with predominantly sensory distal neuropathy and recurrent course related to worsening and improvement of the enteritis. Patient 2 had Crohn's disease some years before symptoms of recurrent sensory loss in the feet. Axonal degeneration was the mechanism of nerve damage in both patients.
Two females mother and daughter, were affected by a neuromuscular disorder, characterized by slow progression, humeroperoneal weakness and wasting, limited neck flexion, elbow and ankle joint contractures, cardiopathy and myopathic pattern on EMG. Muscle histology and histochemistry showed type I fiber atrophy and predominance in both. Cardiac abnormalities, in the first case, were suggestive of a hypertrophic cardiomyopathy while in the second hypotension and chronic bradycardia were present. Neurological signs, EMG and morphology seemed to point to a genetic variant of the form of dystrophy named Emery-Dreifuss disease. The mode of transmission and cardiac abnormalities, however, raise the problem of variability even in this well-defined, usually X-linked, disorder.
Electrophysiological findings in 10 patients with polyneuropathy and nonmalignant IgMk plasma cell dyscrasia are reported. The amplitude of sensory action potentials and maximum conduction velocity along the sural and median nerves are related to the structural changes found at the biopsy and to the immunologic results. Quantitative analysis of the sural nerve showed a loss of large myelinated fibers in all 8 patients, in whom the nerve could be examined. The sural action potential as well as conduction velocity were undetectable in 4 cases, diminished in 5 and normal in 1. The primary mechanism underlying nerve damage in these neuropathies is discussed. It is suggested that the IgM paraprotein may act heterogeneously on the peripheral nerve's component.
The diagnostic value of nerve and muscle biopsy in detecting several neurological diseases is discussed. A bioptic technique for current surgical practice is proposed.
Immunofluorescence histochemistry was used to study the pathogenesis of polyneuropathy in patients with an IgM M protein. Seventeen patients had an M protein that reacted with myelin-associated glycoprotein (MAG), and their serum immunostained myelin sheaths of normal peripheral nerve of humans and certain other species. The staining was specific for the M protein idiotype and was abolished by prior absorption of serum with MAG. The sural nerve biopsy specimens from these 17 patients had pathological features of primary demyelination and deposits of IgM on the myelin sheaths. Sural nerve specimens of 2 patients with an M protein reactive with chondroitin sulfate showed axonal degeneration and diffuse deposits of IgM in the endoneurium. Serum of one of these patients immunostained connective tissue; the staining was specific for the M protein idiotype and was blocked by absorption of the serum with chondroitin sulfate. The antigenic specificity of the IgM M protein in another 9 patients with neuropathy is not known; however, sural nerve specimens obtained from some of the patients showed axonal degeneration and endoneurial deposits of IgM, and the serum IgM immunostained axons in some instances. The findings suggest that IgM M proteins may cause the neuropathy and that more than one autoantigen is involved.
A case of HMN, distal type transmitted as autosomal dominant is described. Clinical findings appear to be consistent with a peroneal muscular atrophy, indistinguishable from HMSN types I and II. The electrophysiological data reveal a pathological involvement of the anterior horns, whereas sensory and motor conduction are normal. A muscle biopsy showed neurogenic atrophy, while the morphology of the sural nerve was normal.
Two cases of sarcoid polyneuropathy were diagnosed by histological examination of the nerve biopsy. The electrophysiological findings in both patients suggested a neuropathy of axonal type, confirmed by a morphological study of a sural nerve biopsy by light microscopy and on teased-fiber preparations. The sarcoid granulomas were multiple, especially in case 2; they were sparse in the epineurial and perineurial spaces and absent in the endoneurium, whose interstitial component contained cellular infiltrations of scattered macrophages. Blood vessel changes were a constant morphological feature. The mechanisms that possibly contribute to the pathogenesis of the sarcoid neuropathy are discussed in relation to previous reports.
Six patients had peripheral neuropathy and nonmalignant IgM plasma cell dyscrasia. In two of them, immunological studies indicated that the monoclonal immunoglobulin reacted with myelin-associated glycoprotein, a constituent of peripheral nerve myelin. Sural nerve biopsy specimens from both patients showed morphological signs of primary damage to the myelin sheath. In the other four patients, two of whom had a monoclonal IgMK reactive with chondroitin sulfate C, the axon rather than the myelin sheath was considered the chief site of nerve injury. The morphological findings suggest that the pathogenesis of peripheral neuropathies in IgM plasma cell dyscrasia is heterogeneous. Moreover, the observations are consistent with a pathogenic interaction of the IgM paraprotein with autoantigens in peripheral nerve in some instances.
The development of amyloid neuropathy is an uncommon complication of multiple myeloma. The clinical, electrophysiological and pathological features of 3 such patients are described. The small fiber neuropathy in these 3 cases was similar to that in patients with primary amyloidosis and with the Andrade-type of familial neuropathy, and differed from the large fiber neuropathy which more commonly develops in patients with multiple myeloma. We advance the hypothesis that the absence of the blood-nerve barrier in the dorsal root and sympathetic ganglia allows the access of amyloidogenic proteins to these ganglia, and that these ganglia are the primary site of damage to the peripheral nervous system in the amyloid neuropathies.
We studied two patients with an axonal type of polyneuropathy, epidermolysis, and IgM kappa plasma cell dyscrasia. The IgM kappa was deposited in the dermis, was absorbed from the serum by axonal micelle preparations, and was precipitated with chondroitin sulfate in highly purified agarose in 0.15 M NaCl with 0.01 M phosphate buffer, pH 7.8. In contrast, we found none of these abnormalities in three patients with IgM plasma cell dyscrasia and demyelinating neuropathy. Of 78 other macroglobulinemic serum samples from patients without neuropathy, 7 precipitated with a sulfated polysaccharide. This reaction occurred at low ionic strength, 0.05 M barbital buffer, pH 8.1, but did not occur in the higher ionic strength of 0.01 M phosphate with 0.15 M NaCl (PBS). The interaction of the IgM with chondroitin sulfate at relatively high ionic strength could cause both the axonal polyneuropathy and the epidermolysis.