The spectrum of polyneuropathies in patients infected with HIV.

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.     

Morphological findings on peripheral nerve biopsies in 15 patients with human immunodeficiency virus infection

Summary 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.     

Peripheral neuropathy in the acquired immunodeficiency syndrome

The histopathological and immunopathological features of peripheral neuropathy were investigated in 21 patients with the acquired immunopathological syndrome (AIDS) or AIDS-related complex (ARC). Clinical syndromes observed in the 11 (52%) symptomatic patients included distal symmetrical polyneuropathy (DSPN) and chronic inflammatory demyelinative polyneuropathy (CIDP). Specimens from 19 of 20 patients (95%), both symptomatic and asymptomatic, had histopathological evidence of moderate or severe demyelination (79%), axonal degeneration (36%), and mononuclear cell inflammation (37%). Nerves from patients with CIDP and DSPN showed similar degrees of demyelination and axonal degeneration, but inflammation was more intense in CIDP. Immunohistochemical staining identified the majority of inflammatory cells as T lymphocytes or macrophages, with a predominance of CD8+ cytotoxic/suppressor cells. Diffuse immunostaining for human leukocyte antigen (HLA)-DR was present on endothelial cells, mononuclear inflammatory cells, and Schwann cells, and variable patchy immunostaining for HLA-DR was present on nerve fibers. Control nerve specimens showed staining for HLA-DR limited to endothelial, and a few mononuclear cells. The patterns of immunostaining were similar for AIDS and ARC patients. Human immunodeficiency virus (HIV) was cultured from peripheral nerve in 3 patients, but HIV antigen was not detected by immunohistochemical staining of 8 specimens. The findings implicate HIV infection in nerve, with T cell- and macrophage-mediated tissue destruction as the pathogenetic mechanism of the AIDS/ARC neuropathy.     

The peripheral nervous system and HIV infection. 13 cases

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.     

Morphometric analysis of the peripheral neuropathy of AIDS

A morphometric study of the peripheral nervous system at autopsy was undertaken in 11 AIDS patients and 10 controls. The left L4, L5, and S1 dorsal root ganglia (DRG) and samples of the sciatic nerve at the buttock, tibial nerve at the knee, and sural nerve at the ankle were collected. Indices of neuronal/axonal degeneration and of segmental demyelination/remyelination were measured at each level. The small number of cases and evidence of neuropathy in a number of the control cases resulted in statistical significance for only a limited number of comparisons. Nodules of Nageotte in the DRG were increased fivefold in AIDS cases compared with controls, and axonal degeneration in single-teased nerve fibers was increased 9-fold in the sciatic nerve, 28-fold in the tibial nerve, and 12-fold in the sural nerve. The ratios of AIDS to controls for the density of remaining DRG neurons and large myelinated axons were reduced to 0.71 in the DRG, 0.84 in the sciatic nerve, 0.84 in the tibial nerve, and 0.66 in the sural nerve. Axonal regeneration in single-teased nerve fibers was increased threefold at the sciatic nerve level in AIDS, but was markedly reduced at distal levels. Acute segmental demyelination in single-teased nerve fibers was present to a greater extent than in controls at all levels of the peripheral nerves in the AIDS cases. Remyelinating fibers were increased compared with controls only in the proximal sciatic nerve. No case showed the changes of cytomegalovirus infection. In a parallel immunohistochemical study of these AIDS peripheral nerves, T-cell and macrophage infiltration, with cytokine expression, was demonstrated. The pathological process in the neuropathy of terminal AIDS appears to be a multifocal immunologically mediated inflammatory disease, with increased density of macrophages and T cells at all levels of the peripheral nervous system, producing segmental demyelination and axonal degeneration. Reparative processes (axonal regeneration and remyelination) occurred only at the most proximal levels of the nerves. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1188–1195, 1998.     

Subclinical peripheral nerve involvement in AIDS: an electrophysiological and pathological study.

Thirty patients with AIDS without symptoms or signs of peripheral neuropathy were compared electrophysiologically with 23 age and sex matched healthy controls. The patients had a mean reduction in the amplitude of common peroneal compound muscle action potentials of 37% (95% CI 11-70%) and of sural sensory action potentials of 34% (CI 18-49%). Mean conduction velocity of both motor and sensory nerves was reduced by between 1 and 7 m/s, with a prolongation of F waves corrected for height of 5% in the arms and 13% in the legs. The distal motor latencies were unchanged. These changes did not correlate with the duration of AIDS, degree of immunosuppression (CD4 count), Body Mass Index, albumin or vitamin B12 level. Four patients had subclinical mononeuropathies. Sural nerve taken at necropsy from five asymptomatic AIDS patients had evidence of axonal degeneration without inflammation or demyelination. There was a mean reduction in myelinated fibre density of 30.5% (CI 10-51%) compared with eight age matched sudden death controls (p = 0.01). This loss principally affected the larger fibres. The pathological and electrophysiological changes indicate axonal degeneration and are similar to those seen in other chronic disorders and in normal ageing. It is concluded that this axonal degeneration is not specific to HIV.     

Predominantly sensory neuropathy in patients with AIDS and AIDS-related complex

The most common type of peripheral neuropathy associated with human immunodeficiency virus (HIV) infection, predominantly sensory neuropathy, affects 10-30% of patients with acquired immunodeficiency syndrome (AIDS). From 40 individuals with peripheral neuropathy and HIV infection, we have identified 26 patients with this syndrome. All had constitutional symptoms when neuropathic symptoms developed; 20 had AIDS and six had AIDS-related complex. The most common complaint was pain on the soles. Paresthesias were frequent and usually involved the entire foot. Signs of peripheral neuropathy were present in all; the most frequent finding was absent or reduced ankle reflexes. Electrophysiologic studies revealed abnormal sensory and motor conduction, studies suggesting a dying-back axonopathy. Over time, the neuropathy progressed in all except one patient with ARC, who had spontaneous subjective improvement. Tricyclic antidepressants provided partial symptomatic relief. In three patients, the neuropathy did not change during azidothymidine treatment. Predominantly sensory neuropathy in HIV infection appears to be a distal axonal degeneration primarily involving sensory neurons. The mechanism is unknown, but the neuropathy is associated with the late manifestations of HIV infection.     

Inflammatory neuropathy in homosexual men with lymphadenopathy

Twelve homosexual men had peripheral neuropathy with fever, night sweats, and lymphadenopathy. Sensory symptoms predominated, but there was also weakness and cranial nerve dysfunction. Manifestations were multifocal in nine and distal and symmetric in three. CSF was abnormal in all eight patients examined. Sural nerve in five patients showed axonal degeneration, accompanied in two by segmental demyelination. Four patients had epineurial and endoneurial perivascular chronic inflammatory cells without evidence of vasculitis. Neuropathy remitted spontaneously in six patients. Four patients received steroids without clinical response, although one later responded to plasmapheresis-lymphocytapheresis. Four patients later progressed to AIDS.     

Sensory testing in human immunodeficiency virus type 1-infected men. HIV Neurobehavioral Research Center Group.

Patients with acquired immunodeficiency syndrome frequently suffer peripheral neuropathy. We investigated its prevalence and relationship to clinical stage of human immunodeficiency virus (HIV) infection using quantitative sensory testing and nerve conduction testing. Vibratory threshold was determined in the right great toe and index finger of 179 men seropositive for HIV (28 with acquired immunodeficiency syndrome [AIDS] or AIDS-related complex [ARC], 151 asymptomatic) and 32 HIV-seronegative controls. None had clinical peripheral neuropathy. Abnormal threshold was control mean plus 2.5 SDs. In the toe, 10 (36%) of 28 subjects with AIDS or ARC had abnormal vibratory thresholds, compared with seven (5%) of 151 asymptomatic seropositive subjects and none of 32 controls. A subgroup of 168 seropositive subjects underwent nerve conduction testing. Abnormality rates were similar, but abnormalities of nerve conduction coincided with quantitative sensory testing abnormalities in only half the cases. Mean (+/-SD) vibratory threshold was significantly greater in subjects with AIDS or ARC (3.00 +/- 0.51 vibratory units) than in asymptomatic subjects (1.56 +/- 0.27 vibratory units) and controls (1.63 +/- 0.54 vibratory units). Finger abnormality rates did not differ, although subjects with AIDS or ARC had greater mean vibratory threshold. Subclinical peripheral neuropathy is thus related to stage of HIV infection and is present by quantitative sensory testing in 36% of patients with AIDS or ARC.     

Rheumatoid neuropathy: a histological and electrophysiological study

Peripheral nerves in five patients with rheumatoid neuropathy were examined electrophysiologically and by sural nerve biopsy. There was close correlation between the clinical severity of the disease and the degree of nerve damage found histologically and by EMG. Group 1 patients with a mild distal sensory neuropathy showed varying degrees of axonal degeneration in the large myelinated fibres and some segmental demyelination. Group 2 patients with a severe, rapidly progressive sensori-motor neuropathy had extensive loss of myelinated fibres. In one case all the large fibres had degenerated. The second case had lost both large and small myelinated fibres together with many of the non-myelinated axons. The major nerve damage in both groups appeared to be axonal degeneration but some segmental demyelination was detected. Occlusive vascular disease in the vasa nervorum was considered to be the major cause of the nerve damage.     

Electrophysiological findings in immune checkpoint inhibitor-related peripheral neuropathy

ObjectiveTo report the electrodiagnostic features of immune checkpoint inhibitor (ICI)-related neuropathy.MethodsWe retrospectively reviewed clinical presentations and electrodiagnostic features of 23 patients studied after receiving immune checkpoint inhibitors (ICIs). The presentations for electrodiagnostic evaluation included an acute neuropathy or neuromuscular junction disorder. We applied established electrodiagnostic criteria for polyneuropathy and acute demyelinating neuropathy.ResultsWe identified acute demyelinating neuropathy (13 cases), axonal sensory motor neuropathy (5), pure sensory neuropathy (4) and mononeuropathy (1). 13 patients had acute demyelinating neuropathy confirmed by demonstrating demyelination in 2 or more nerves; 3 additional patients had demyelination in only one nerve. Analysis of motor nerve conduction parameters revealed demyelination involving median and ulnar nerve distal motor latencies as well as median, ulnar and peroneal nerve conduction velocities. Conduction block was found in median, ulnar and peroneal nerves. The remaining one-third patients without demyelination had acute painful axonal neuropathy. Coexisting myopathic changes (6) and neuromuscular junction dysfunction (4) were also identified.ConclusionsOur findings suggest that, while immune-mediated motor nerve demyelination is the primary underlying mechanism of ICI-related neuropathy, axonal painful neuropathy can also be an important presentation. Early recognition and effective intervention may reduce morbidity and permanent disability.SignificanceElectrophysiological studies might be useful in the evaluation of ICI-related neuropathy.     

Peripheral neuropathy in individuals with HIV infection in Zimbabwe

Peripheral neuropathy is associated with HIV infection. The prevalence and types of peripheral neuropathy encountered in a randomly-selected HIV infected African population at different stages of disease were investigated. HIV positive individuals were categorized into 1 of 3 groups: asymptomatic, symptomatic and AIDS. HIV negative individuals formed the control group. Nerve conduction data were obtained using standard electrophysiological procedures and CD4⁺ levels were measured. The type of neuropathy was determined from the history, clinical presentation and electrophysiological abnormalities. The prevalence of peripheral neuropathy was 44%: subclinical neuropathy (SCN) accounted for 56%, acute inflammatory demyelinating polyneuropathy (AIDP) for 15% and distal symmetrical polyneuropathy (DSPN) for 22% of cases of neuropathy. SCN was found in all categories whereas AIDP predominated in the symptomatic category and DSPN in individuals with AIDS. The pattern and frequency of neuropathies seen in our African population is similar to that reported from other continents.     

Sensorimotor and autonomic neuropathy associated with systemic lupus erythematosus

In this article, one described 7 patients with systemic lupus erythematosus (SLE) and the pathological findings of their sural nerves. In 4 of the 7 cases the criteria for diagnosis of SLE were satisfied and in 3 cases there was serological evidence of an undifferentiated connective tissue disease, most likely to be SLE. The peripheral neuropathy was of a chronic sensorimotor type with predominantly sensory features and gradual onset. In 2 cases the presentation was asymmetrical. One patient had autonomic dysfunction. There was ischemic neuropathy in 2 cases, segmental demyelination in 2 cases, and axonal degeneration with demyelination in 3 cases. In 6 cases there was increased expression of Ia antigen within the nerve fascicle, perineurium and endothelial cells.     

Role of HIV in the pathogenesis of distal symmetrical peripheral neuropathy

We report the results of a clinical, electrophysiological and pathological study conducted in 18 AIDS patients presenting a distal symmetrical predominantly sensory polyneuropathy (DSPN) characterized by painful dysesthesias as main complaint. Onset of the neuropathy was at CDC (Center for Disease Control) stage II in 2 patients, at CDC stage III in 5 patients and at CDC stage IV in the remainder. Electrophysiological investigation confirmed the presence of an axonal alteration in the sensory nerves, but also revealed motor involvement in all cases. The neuropathological features of sensory nerves were fiber loss and axonal degeneration with macrophagic activation. The expression of monocyte-macrophage markers and of major histocompatibily complex class II antigens appeared up-regulated in endoneurial ramified cells, while expression of CR3, a complement receptor involved in the process of phagocytosis, was down-regulated. In six nerve biopsy samples and in two out of five DSPN dorsal root ganglia we found HIV-related mRNA and protein located in scattered cells of the endoneurium which we presume to be macrophages. These data suggest that: (a) DSPN may occur early in the course of the disease and is not limited to later stages; (b) DSPN is not a ganglionitis but is actually a sensory-motor neuropathy; (c) the virus enters the peripheral nervous system and induces changes in the immunocompetent cell population with activation of macrophages. Storage of the virus inside macrophages may act both as a reservoir for the virus and as a putative cause of nerve damage, probably through release of cytotoxins and/or interaction with trophic factors.     

Mixed carcinomatous neuropathy in patients with lung cancer and lymphoma

A clinical, electrophysiological and histological study of the peripheral nerve was performed on 62 patients with lung cancer and 30 patients with lymphoma. There was a mild peripheral neuropathy (MPN) in 17.7% of patients with lung cancer and in 10% of those with lymphoma. MPN was related to the degree of weight loss. Histological studies of 5 patients with MPN demonstrated a loss of large myelinated fibers in all patients, axonal degeneration in 2 and remyelination in 3 patients. Electromyographic and histological findings indicate a primary axonal neuropathy with remyelination, probably secondary to axonal damage. 2 patients with lymphoma developed a severe neuropathy that remitted in 1 patient. The main pathological abnormality was segmental demyelination in both cases. Immunofluorescence studies were negative in all cases with mild or severe neuropathy.     

The spectrum of peripheral neuropathy associated with ARC and AIDS

Peripheral neuropathy is increasingly recognized as a complication of the Acquired Immune Deficiency Syndrome (AIDS) and AIDS-related complex (ARC), but the varied clinical features have been incompletely described. Thirty homosexual men with peripheral neuropathy were evaluated in this study. Twenty-one had ARC and nine had AIDS. Four distinct clinical syndromes were recognized: distal sensorimotor polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), mononeuropathy multiplex, and progressive polyradiculopathy. Four patients with clinical, electrophysiologic, and histologic evidence of CIDP and severe progressive weakness improved with plasma exchange, three regaining normal function.     

Carcinomatous neuropathy: clinical and pathologic findings of sural nerve biopsy in 7 cases

Sural nerve biopsy was done 7 cases of cancer patients associated with peripheral neuropathy. There were 3 cases of lung carcinoma and one each of pancreas adenoma, seminoma, sigmoid carcinoma and chondrosarcoma of the femur. The neurological features manifested themselves with sensory pattern of neuropathy associated with ataxia in one case, sensorimotor neuropathy in 3 cases, and idiopathic polyneuropathy, peripheral neuropathy with proximal myopathy and neuropathy with paraneoplastic cerebellar syndrome each in one case, 6 patients showed neuropathy before malignancy was discovered and only one patient had neuropathy after the onset of carcinoma. Sural nerve biopsy studied in all the 7 patients with light and electron microscope revealed no infiltration of carcinomatous cells in the sural nerve fascicles. There was severe loss of myelinated fibers and severely axonal degeneration in one patient. Another patient showed segmental demyelination (5.03 x 10(3)/mm2). There was evidence of both axonal degeneration and demyelination associated with moderate reduction in the number of the myelinated fiber density ranging from 1.02 to 4.35 x 10(3)/mm2. In 6 cases, mononuclear cells were seen in nerve fascicles under the electron microscope. The characteristic pathological findings, their relation with the duration and onset of the cancer and some ideas regarding the pathogenesis are discussed.     

Sensorimotor neuropathy in a patient with Marinesco-Sj?gren syndrome

A case of Marinesco-Sj?gren syndrome, displaying the characteristic signs (ataxia, congenital cataract and mental retardation) is presented. Electrophysiological examination pointed to the presence of a sensorimotor peripheral neuropathy with an underlying mixed process of segmental demyelination and axonal degeneration (probably secondary). The sural nerve and gastrocnemius biopsy confirmed these data, showing that in this case the segmental demyelination process was accompanied by axonal degeneration.     

A micro-electrode study of peripheral neuropathy in man. Part 2. Responses to conditioning stimuli.

Surface, needle and micro-electrode recordings were obtained from sensory nerves of patients with various types of peripheral neuropathy. Changes in amplitude and conduction velocity of nerve action potentials were measured after a single conditioning stimulus and after tetanic stimulation for 2 min. In patients with hereditary forms of axonal degeneration (AD), recovery processes of nerve fibres of all conduction velocities were normal; in acquired forms of AD fibres with conduction velocity less than 30 m/sec had greater and more prolonged post-tetanic depression than control nerves of similar conduction velocity. Where neuropathy was associated with segmental demyelination (SD), fibres of all conduction velocities had prolonged recovery processes after both single and tetanic stimulation. The changes were especially marked at higher skin temperature, and were greater than the changes seen in nerves with acquired forms of AD. Finally, 2 sural nerves were studied during the process of Wallerian degeneration after a biopsy had been obtained proximally, and recovery processes did not change during the period of degeneration. Perceptual abnormalities were similar in AD and SD. It is suggested that changes in recovery processes of nerve fibres with segmental demyelination or regeneration after injury contribute to the perceptual abnormalities which occur in clinically encountered peripheral neuropathies.     

Motor and sensory demyelinating mononeuropathy multiplex (multifocal motor and sensory demyelinating neuropathy): a separate entity or a variant of chronic inflammatory demyelinating polyneuropathy?

We report 16 patients with motor and sensory demyelinating mononeuropathy multiplex (MSDMM) or multifocal motor and sensory demyelinating neuropathy (MMSDN). These patients had the clinical pattern of motor and sensory mononeuropathy multiplex, electrophysiological evidence of demyelination including conduction block, and segmental demyelination in the sural nerve biopsy. Sixty per cent of patients had high CSF protein. Eighty per cent of patients showed good responsiveness to steroid treatment. Unlike multifocal motor neuropathy (MMN), MSDMM is characterized by a shorter course, sensory deficits and sensory nerve conduction abnormalities, absence of GM1 antibody in most patients tested, and a good response to steroid therapy. We believe that MSDMM represents a variant of chronic inflammatory demyelinating polyneuropathy (CIDP) and an intermediate link between CIDP and MMN.