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.     

The spectrum of changes on 20 nerve biopsies in patients with HIV infection

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.     

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.     

Involvement of the peripheral nervous system in HIV infection: electromyographic study and nerve conduction velocity]

Disorders of the peripheral nervous system occur at all stages of HIV1 infection. Acute and subacute inflammatory demyelinating polyneuropathies are mainly observed in otherwise asymptomatic HIV+ patients and in patients with ARC (AIDS-related complex): clinical and electrophysiological features are similar to those observed in Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP), but CSF examination usually shows pleocytosis, and an infiltration of the endoneurium and/or the epineurium is commonly seen in nerve biopsies. Mononeuropathy multiplex is a rare complication occurring in ARC-patients: electrophysiological studies are consistent with an axonopathy and nerve biopsies may show vasculitis. Distal predominantly sensory polyneuropathies are the most frequent peripheral neuropathies in HIV1 infection and are usually reported in patients with AIDS and severe immunosuppression: electrophysiological features are of an axonopathy with signs of acute denervation. Meningoradiculitis is observed at the late stages of the disease and is mainly due to a cytomegalovirus infection. On the other hand, systematic electrophysiological studies in HIV+ cases reveal a high percentage of abnormalities concerning sensory and less frequently motor nerve conduction velocities. The severity of this asymptomatic involvement of the peripheral nervous system seems to be related to the degree of the immunodeficiency. The mechanism of these peripheral neuropathies remains hypothetical in most cases.     

Chronic inflammatory demyelinating polyneuropathy caused by HIV infection in a patient with asymptomatic CMT 1A

It is well known that patients with Charcot-Marie-Tooth (CMT) disease are liable to present with episodes of cortisone-responsive demyelination, and a superimposed inflammatory component has been suggested. We report a patient who presented with a chronic inflammatory demyelinating polyneuropathy due to a recent HIV infection, which revealed a previously asymptomatic CMT 1A disease documented by identification of the characteristic duplication on the p11.2 region of chromosome 17. The inflammatory process was characterized by pathologic findings on a superficial peroneal nerve biopsy, and the patient improved significantly after corticotherapy. This report gives support to the hypothesis of a genetic susceptibility to inflammatory demyelinating processes in certain CMT kindreds.     

Charcot-Marie-Tooth disease type 1A: clinicopathological correlations in 24 patients

We examined nerve biopsies from 24 patients with Charcot-Marie-Tooth disease type 1A (CMT1A) and proven 17p11.2-12 duplication. There were seven males and 17 females with a mean age of 27.85 +/- 18.95 years at the time of nerve biopsy. A family history consistent with dominant inheritance was present in 17 patients. Clinical features were classical in 16 patients and were atypical in the other eight: one had calf hypertrophy; two had Roussy-Levy syndrome; one had had a subacute inflammatory demyelinating polyneuropathy 11 years earlier and presented a relapse on the form of a chronic inflammatory demyelinating polyneuropathy; one had carpal tunnel syndrome; one had a recent painful neuropathy in both legs; and two had chronic inflammatory demyelinating polyneuropathy. Onion bulb formations (OMFs) were present in every case and most of them were characteristic, whereas burnt-out or cluster-associated OMFs were less common. Depletion of myelinated fibers was severe in 20 cases (169-2927/mm2) and varied from 5187 to 3725/mm2 in three children (4-9 years old). In addition, features of macrophage-associated demyelination were observed in the last four atypical cases. Known for more than 20 years, inflammatory demyelination superimposed in the course of CMT1A has been reported in a few cases in the past few years, mainly concerning asymptomatic or atypical patients. Such an association deserves to be better known because corticotherapy improves weakness in most of these patients.     

"Chronic sensory demyelinating neuropathy": chronic inflammatory demyelinating polyneuropathy presenting as a pure sensory neuropathy.

The clinical electrophysiological and histological features of 10 cases of "chronic sensory demyelinating neuropathy" (CSDN) are reported. This entity is characterised by: 1) subacute or chronic progression; 2) pure sensory neuropathy; 3) high spinal fluid protein in the majority of cases; 4) electrophysiological evidence of demyelination affecting motor as well as sensory nerve fibres; 5) demyelination on sural nerve biopsy and 6) good response to immunotherapy in progressive phase. It is believed that this entity represents chronic inflammatory demyelinating polyneuropathy (CIDP) presenting as pure sensory neuropathy.     

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.     

Peripheral neuropathies in human immunodeficiency virus infection. A prospective study of 56 patients

Neurologic disorders are common in patients infected with HIV1. Judging from reported cases, the central nervous system would be more frequently involved than the peripheral nervous system (PNS). The purpose of the present prospective study was to ascertain the incidence and the nature of PNS disorders in patients infected with HIV1. Fifty-six patients [asymptomatic carriers: 5; persistent generalized lymphadenopathy (PGL): 13; AIDS related complex (ARC): 9 and acquired immunodeficiency syndrome (AIDS): 29] were submitted to clinical and laboratory investigations and 52 underwent electromyogram and nerve conduction velocity tests. CSF was examined in 29 and nerve biopsies in 28. Our findings showed that a PNS impairment was present in 50/56 patients i.e. 89 p. 100. It was mainly a moderate sensory polyneuropathy, more often at the subclinical (29/50: 58 p. 100) than at the clinical (21/50: 42 p. 100) level. It concerned asymptomatic carriers (2/5) as well as PGL (11/13), ARC (8/9) and AIDS (29/29) patients. These data show that peripheral nerves are a target for HIV1.     

Evoked potentials in chronic inflammatory demyelinating polyneuropathy

Eighteen patients with chronic inflammatory demyelinating polyneuropathy were studied with evoked potentials to assess for evidence of central nervous system demyelination. Both visual and brain-stem auditory evoked responses were obtained, and the results were compared with magnetic resonance imaging (MRI). An evoked potential was abnormal in nine of 18 patients, five of whom had central nervous system evidence of demyelination by MRI. Evoked potentials identified four patients with probable anterior optic pathway involvement that was not demonstrable by MRI. These findings continue to support that chronic inflammatory demyelinating polyneuropathy is associated with a central demyelinating disorder and more importantly emphasize the possibility of a common pathogenic mechanism in central and peripheral nerve demyelination.     

Up-regulation of cyclooxygenase-2 in inflammatory demyelinating neuropathy

To clarify the role of prostaglandins in peripheral nerve demyelination, we examined the expression of cyclooxygenase-2 (COX-2) using selected nerve specimens from patients with chronic inflammatory demyelinating polyneuropathy. COX-2 protein was up-regulated in macrophages causing active demyelination. In situ hybridization revealed that COX-2 mRNA signals were strongly expressed on macrophages adhering to the demyelinating nerve fibers at the endoneurium. This observation may provide a rationale for application of neuroprotective strategies employing COX-2 inhibitors in inflammatory demyelinating neuropathies.     

Can antiglycolipid antibodies present in HIV‐infected individuals induce immune demyelination?

Of the eight clinically defined neuropathies associated with HIV infection, there is compelling evidence that acute and chronic inflammatory demyelinating polyneuropathy (IDPN) have an autoimmune pathogenesis. Many non‐HIV infected individuals who suffer from sensorymotor nerve dysfunction have autoimmune indicators. The immunopathogenesis of demyelination must involve neuritogenic components in myelin. The various antigens suspected to play a role in HIV‐seronegative IDPN include (i) P₂ protein; (ii) sulfatide (GalS); (iii) various gangliosides (especially GM₁); (iv) galactocerebroside (GalC); and (v) glycoproteins or glycolipids with the carbohydrate epitope glucuronyl‐3‐sulfate. These glycoproteins or glycolipids may be individually targeted, or an immune attack may be raised against a combination of any of these epitopes. The glycolipids, however, especially GalS, have recently evoked much interest as mediators of immune events underlying both non‐HIV and HIV‐associated demyelinating neuropathies. The present review outlines the recent research findings of antiglycolipid antibodies present in HIV‐infected patients with and without peripheral nerve dysfunction, in an attempt to arrive at some consensus as to whether these antibodies may play a role in the immunopathogenesis of HIV‐associated inflammatory demyelinating polyneuropathy.     

Immune-mediated components of hereditary demyelinating neuropathies: lessons from animal models and patients

Most demyelinating forms of Charcot-Marie-Tooth type 1 (CMT1) neuropathy are slowly progressive and do not respond to anti-inflammatory treatment. In nerve biopsy samples, overt lymphocytic infiltration is absent, but pathological features typical of macrophage-related demyelination have been reported. In mouse models of CMT1, demyelination was substantially reduced when the mutants were backcrossed into an immunodeficient genetic background. A few individual patients with CMT1 respond to anti-inflammatory treatment; however, unlike most patients with CMT1, these patients show accelerated worsening of symptoms, inflammatory infiltrates in nerve biopsies, and clinical features resembling chronic inflammatory demyelinating polyneuropathy as well as CMT1. We conclude that in patients with typical CMT1 and in animal models, a cryptic and mild inflammatory process not responsive to standard anti-inflammatory treatment fosters genetically mediated demyelination.     

Chronic inflammatory demyelinating polyneuropathy with tongue fasciculation: A case report

Chronic inflammatory demyelinating polyneuropathy is one of the immune-mediated polyneuropathies responsive to immunotherapy. Its usual clinical presentation is a chronic course of symmetric sensorimotor affectation of both proximal and distal extremities with signs of demyelination on electrophysiologic studies. Cranial nerve signs in this condition is not commonly encountered, particularly involvement of the hypoglossal nerve. To date, there are only three published cases of hypoglossal involvement in this condition. This case report presents a patient with tongue fasciculation, which is an uncommon finding in chronic inflammatory demyelinating polyneuropathy. This paper highlights the importance of considering chronic inflammatory demyelinating polyneuropathy in the differential diagnoses of a patient with tongue fasciculation as it has been found to be responsive to immunotherapy in comparison to other lower motor neuron syndromes.     

Advances in chronic inflammatory demyelinating polyneuropathy: disease variants and inflammatory response mediators and modifiers.

Available data on the immunopathogenesis of chronic inflammatory demyelinating polyneuropathy remain still fragmentary and insufficient for a unified hypothesis. Macrophage-mediated demyelination appears to play a fundamental role and cytokines, especially tumour necrosis factor-alpha, participate in this process. The nature of antigen presenting cells, T-cell receptors, adhesion molecules between inflammatory cells and myelinated fibers and the apparent predominance of T helper cell 1-related cytokines need to be explored to design more specific immunotherapies. In chronic cases of chronic inflammatory demyelinating polyneuropathy, a concomitant axonal loss secondary to primary demyelination is common and should be taken into consideration in the design of future therapeutic strategies.     

Neuropathies and HIV retrovirus infections

Neurologic complications are frequently observed during HIV-related infections and particularly in AIDS. According to the literature, these complications more often pertain to the central nervous system (CNS) than the peripheral nervous system (PNS). A prospective study was carried out in order to determine the frequency and type of PNS disorders during HIV infections, the neurotropism of which is now well established. Forty-one HIV-infected patients - 5 asymptomatic subjects, 14 ARC (AIDS-related complex) and 22 AIDS patients - were studied from a clinical and biological angle; 40 equally underwent an EMG and nervous conduction velocity tests, 26 a lumbar puncture and 25 a nervous biopsy (associated in three cases with a muscular biopsy). The study showed that a PNS-alteration is extremely frequent (36/41, or 88% of all cases), generally mild or even subclinical (17/36); most often, the aspect is that of a sensitive axonal polyneuropathy. More severe types (polyradiculoneuritis, sensorimotor polyneuropathy, etc.) are equally observed, but much rarer. Whatever their form may be, the PNS-lesions can be observed in so-called asymptomatic subjects (2/5) as well as ARC (12/14) and AIDS (22/22) patients. They are the manifestation either of a direct lesion of the nerve through HIV, or of immune mechanisms (of humoral or cellular mediation) or of both mechanisms combined.     

Lymphocytes in sural nerve biopsies from patients with plasma cell dyscrasia and polyneuropathy.

Sural nerve biopsies were examined in 36 patients with plasmacell dyscrasia and polyneuropathy. The M-component isotype was IgM in 19, IgG in 16 (one patient had both IgM and IgG) and IgA in 2 patients. Five of the IgM patients had Waldenstr?m's disease, one of the IgG cases a myeloma and two lymphoma. The remaining 28 patients had monoclonal gammopathy of uncertain significance (MGUS). Nerve conduction studies showed signs of mixed axonal/demyelinating polyneuropathy in most cases. The biopsies were evaluated with regard to nerve fibre loss, segmental demyelination and inflammatory cell infiltration. Inflammatory cells infiltrating the nerves were found in 7 of 19 IgM cases and in 6 of 16 IgG cases. Immunohistochemical staining with monoclonal antibodies to B-lymphocytes and to subsets of T-lymphocytes was performed in 33 cases. An equal distribution of CD4 and CD8 positive T cells, but no B cells, were found among the inflammatory cells. The findings indicate a possible role for cell mediated immunological mechanisms in some patients with plasma cell dyscrasia associated with polyneuropathy.     

Severe axonal polyneuropathy with onset in the postpartum period

We report two patients who presented severe polyneuropathy in the postpartum period. Electrophysiological studies evidenced an axonal process which was associated with proximal demyelination in the second patient. In both cases, a peripheral nerve biopsy showed severe axonal Wallerian-like degeneration and no feature of demyelination. The first patient had a dramatic loss of myelinated fibres, and severe disability persisted for several months. These two patients are different from cases of acute or chronic inflammatory demyelinating polyradiculoneuropathy previously reported in relation with pregnancy.     

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.