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Background and purpose In a recent trial in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), the ICE study, grip strength measurement captured significantly more improvement in patients receiving immune globulin (IGIV-C) intravenously than in those receiving placebo. Methods We conducted a systematic analysis to determine the sensitivity of grip strength as an indicator of meaningful clinical changes in CIDP. Results A randomized double-blind trial was undertaken in 117 CIDP patients who received IGIV-C or placebo every 3 weeks for up to 24 weeks. Grip strength and inflammatory neuropathy cause and treatment (INCAT) disability scores were assessed at each visit, and the responsiveness of each scale was compared. A minimum clinically important difference cut-off value for grip strength (>8 kPa) and INCAT score (>1 point) was applied to assess the proportion of responders to IGIV-C versus placebo. This analysis showed that grip strength demonstrated significant improvement earlier (as early as day 16) than the INCAT disability scale in patients receiving IGIV-C compared with placebo. A significantly higher proportion of improvers were seen in the IGIV-C group (37.5%–50.9%) than in the placebo group (21.1%–25.9%) for grip strength at day 16, week 3, week 6 and the end of the first period. Also, grip strength showed within the first 6 weeks in the placebo group significantly more patients with a clinically meaningful deterioration (>8 kPa), compared with the INCAT (>1-point deterioration) findings. Conclusions Grip strength can be considered a sensitive tool for assessing clinically relevant changes in patients with CIDP. Its use in daily practice is suggested.

Matrix metalloproteinases (MMPs) and the cytokine tumour necrosis factor (TNF)-alpha are implicated in the pathology of inflammatory demyelinating diseases of the CNS, and may also be involved in peripheral demyelinating diseases such as acute inflammatory demyelinating polyradiculoneuropathy. We have tested an inhibitor of MMP activity and TNF-alpha processing, BB-1101, in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome. Treatment with BB-1101 from the time of immunization prevented the development of EAN, and when given from the onset of symptoms, it significantly reduced disease severity. These results indicate that MMPs and/or TNF-alpha are involved in the pathogenesis of EAN, and that drugs of this type may have potential as novel therapeutic agents in the therapy of peripheral nervous system demyelinating diseases.

Human immunoglobulin is an effective treatment for Guillain-Barré syndrome, although the mechanism of action is not understood. We have investigated the effect of human immunoglobulin in an animal model of Guillain-Barré syndrome, namely experimental autoimmune neuritis (EAN), induced in Lewis rats by immunization with bovine spinal root myelin. Human immunoglobulin administered intraperitoneally at the time of onset of disease accelerated the rate of recovery from EAN. This improvement was associated with a reduction in the titre of anti-rat myelin antibodies and may be due to earlier remyelination of demyelinated nerve fibres. This model may facilitate further investigation of the mechanism of therapeutic action of immunoglobulin in inflammatory neuropathy.

A man with subacute sensory ncuronopathy (SSN) had a stage 1 seminoma. His serum and cerebrospinal fluid (CSF) contained anti-Hu antibodies (type 1 anti-neuronal nuclear antibodies, ANNA-1). Following orchidectomy, radiotherapy, prednisolone, plasma exchange and intravenous immunoglobulin the antineuronal antibody titre fell and the neuropathy improved.

We discovered many reports of other immunosuppressive drugs being used in adults with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but none of methotrexate. As weekly low dose oral methotrexate is safe, effective, and well tolerated in other diseases, we treated 10 patients with otherwise treatment resistant CIDP. Seven showed improvement in strength by at least two points on the MRC sum score and three worsened. Only two showed an improvement in disability and both were also receiving corticosteroids. We discuss the difficulty of detecting an improvement in treatment resistant CIDP and propose methotrexate as a suitable agent for testing in a randomised trial.

Two myelin proteins, P2 basic protein and P0 glycoprotein, can induce experimental autoimmune neuritis (EAN), a model of human inflammatory neuropathy. We investigated whether peripheral nerve myelin protein-22 (PMP22), the gene for which is duplicated in hereditary motor sensory neuropathy type la, can also induce EAN. PMP22 cDNA produced by the reverse transcriptase-polymerase chain reaction from rat sciatic nerve was expressed in Escherichia coli as a fusion protein with glutathione-S-transferase (GST). Ten Lewis rats were immunized with purified PMP22 fusion protein (50-100 microg) and eight controls with the same amount of GST. Two additional animals were immunized with each of two peptides (250 microg) of the human PMP22 extracellular sequences. Animals were examined daily until 20 days following immunization, when they underwent neurophysiological examination. A serum sample was then taken, prior to perfusion with glutaraldehyde and removal of the sciatic nerves and cauda equina. PMP22-immunized animals developed antibodies to the fusion protein and five out of 10 developed limp tails. No changes were observed in controls immunized with GST or in animals immunized with peptide. The mean compound motor action potentials elicited in the foot muscles by stimulation of the sciatic nerve at the sciatic notch and of the tibial nerve at the ankle were significantly reduced in the PMP22-immunized group (P < 0.05). Spinal roots from the group of animals immunized with PMP22 showed sparse infiltration of mononuclear cells, oedema and demyelination. PMP22 now deserves consideration as an autoantigen in human acute inflammatory demyelinating polyradiculoneuropathy.

Human sensory neuropathies having an inflammatory component or presumed immune pathogenesis are reviewed. Sensory forms of acute (Miller Fisher syndrome) and chronic idiopathic demyelinating polyradiculoneuropathy are probably due to autoimmune responses against antigens relatively restricted to the myelin of sensory nerves. Subacute sensory neuronopathy associated with small cell carcinoma of the lung is caused by dorsal root ganglionitis: an antibody against a neuronal nuclear antigen is characteristically present in this syndrome and may be important in pathogenesis. Similar mechanisms might explain the dorsal root ganglionitis associated with Sjogren’s syndrome and the inflammation of the trigeminal ganglion which is thought to underlie benign trigeminal neuropathy. Nonspecific inflammatory disorders, including amyloid deposition, granulomas associated with leprosy or sarcoidosis, and vasculitis, also produce sensory neuropathy. The leakiness of the blood-nerve barrier and the presence of satellite cells expressing MHC class II antigen in the dorsal root ganglion may contribute to the susceptibility of sensory nerves to autoimmune damage.

It is remarkable that we should have discovered a useful treatment for neurological disorders which we do not fully understand. There is evidence from controlled trials that plasma exchange (PE) helps each of the conditions in bold type in Table 1 and 2, and anecdotal evidence that it helps the others.

Same short term benefit as plasma exchange but easier to administer The commonest misdiagnosis of Guillain-Barre syndrome by the doctor of first contact is hysteria. This is understandable when most doctors have not seen a case since medical school. However, the syndrome is neither rare nor trivial. With an incidence of one or two cases per 100 000 population per year, new cases are about half as common as new cases of multiple sclerosis—a disease confined to the central nervous system as closely as Guillain-Barre syndrome is restricted to the peripheral nervous system. A quarter of adult patients require artificial ventilation, 10% die as a result of complications of the disease, and 10% are left with such severe disability that they cannot walk unaided a year later.1 The pathological process underlying Guillain-Barre syndrome is heterogeneous. Most patients have an acute multifocal lymphocytic infiltration in their peripheral nerves and spinal roots causing primary demyelination, which will recover quickly. Severely affected patients usually have additional axonal degeneration, which causes delayed and often incomplete recovery. About 10% of patients have an acute motor, or motor and sensory, axonal neuropathy in which macrophages invade the axons, especially in the spinal roots.2 3 Both types of Guillain-Barre syndrome are thought to be due to an autoimmune response triggered …

Objectives: Fifty three patients were studied to investigate whether autoimmune or inflammatory mechanisms could explain the phenotypic heterogeneity of patients with hereditary motor and sensory neuropathy type 1a (HMSN1a). Methods: Serum samples were examined for antibodies to peripheral nerve myelin protein 22 (PMP22), ganglioside GM1 and cauda equina homogenate, and interleukin-6 (IL-6) and soluble tumour necrosis factor receptor 1 (sTNF R1) concentrations. Serological results were compared with those from patients with other neuropathies (ONPs, n = 30) and with normal subjects (n = 51). Results: In the group as a whole, no relation emerged between clinical severity and any immune parameters. Immunohistochemical examination of four sural nerve biopsies did not show significant inflammatory infiltration. In a subset of 12 patients who experienced stepwise progression of disease, there was a trend towards a higher proportion having anti-PMP22 antibodies (33% v 15% of those with gradual disease progression, 3% ONPs, and no normal controls) and complement fixing antibodies to human cauda equina (25% v 5% with gradual progression, 8.6% ONPs, 3.9% normal controls, p = 0.07). Conclusions: Patients with HMSN1a and a stepwise disease progression may have an inflammatory, autoimmune component superimposed on the genetic condition.

A 62-year-old man with scleredema of Buschke was referred to the cardiology clinic because of an abnormal ECG. He had no cardiac symptoms, and the cardiovascular examination was unremarkable. The echocardiogram showed a dilated, nonhypertrophied left ventricle with no regional wall …

A randomized controlled trial of exchange versus no exchange was conducted to find out whether plasma exchange would be useful in acute inflammatory polyradiculoneuropathy. It was calculated that 15 patients would be required in each group to demonstrate a worthwhile improvement in functional ability one month after completion of treatment. Treatment comprised five exchanges in 10 days (55 ml plasma/kg body weight/exchange). Both groups received normal supportive care and were followed up periodically for a year. Overall the treated group showed a slight but not significant benefit (p>0.05); at two weeks' follow-up of patients admitted to the trial within 14 days of onset of neuropathic symptoms, p=0.07. These results do not provide grounds for recommending plasma exchange for the treatment of severe AIP.

The clinical and electrophysiological findings in 22 patients with chronic trigeminal sensory neuropathy are described. The main clinical feature was slowly evolving unilateral or bilateral facial numbness sometimes associated with pain and paraesthesiae and commonly with disturbed taste. Nine patients had either systemic sclerosis or mixed connective tissue disease. Of the 13 other patients, 9 had either organ or nonorgan specific serum autoantibodies. Blink reflex latencies were recorded in 17 patients, the commonest abnormality being an 'afferent' defect with modest prolongation of latency. Trigeminal sensory evoked responses were recorded in 14 cases, 6 showing mild prolongation of latencies. It is suggested that the lesion in this type of trigeminal neuropathy is in the trigeminal ganglion or in the proximal part of the main trigeminal divisions. This conclusion is supported by limited pathological data.

Three patients with peripheral neuropathy and mixed or immune complex cryoglobulinaemia are reported. The significance of mixed cryoglobulinaemia and the pathogenesis of the peripheral neuropathy are discussed.

Experimental allergic neuritis was induced in male inbred Lewis rats immunized with myelin, P2 alone, P2 mixed with galactocerebroside and P2 mixed with glucocerebroside. Neurological deficit started significantly earlier in myelin-immunized rats than in P2-immunized rats. Although myelin-immunized rats appeared most severely affected, differences between of groups in maximum neurological deficit were not significant. The course of the disease of P2-galactocerebroside-immunized animals did not differ from that of P2-glucocerebroside-immunized group. Histologically, cellular infiltration and demyelination were more conspicuous 12 days after immunization in the group immunized with myelin than in the other rats. After 21 days, primary demyelination was prominent in all groups: its frequency and severity were similar in the myelin-immunized and P2-immunized animals. The P2-galactocerebroside-immunized group had significantly more frequent demyelination than of P2-immunized rats, but did not differ in this or any other respect from of P2-glucocerebroside-immunized group. Wallerian degeneration was prominent in all groups at this stage. We conclude that P2 alone does induce demyelination and that galactocerebroside added to the immunizing emulsion enhances of response but no more than the non-myelin lipid glucocerebroside

Experimental neuropathy, characterized by endoneurial edema and demyelination, was induced by inoculating rabbits with a combination of Freund's complete adjuvant (FCA), gangliosides, lecithin and cholesterol. A less severe demyelinating neuropathy could be induced by treatment with FCA alone but no significant change could be elicited by injection of swine influenza vaccine (SFV) alone. When FCA was combined with gangliosides, lecithins, cholesterol and SFV, neuropathy occurred, but the changes were less severe than if these agents were used without SFV. Sera were tested for myelin basic protein (MBP) and galactocerebroside (GC) antibodies in each experimental group. Neither SFV alone nor SFV combined with Freund's complete adjuvant, gangliosides, cholesterol and lecithin evoked significant antibody titers to MBP or GC. However, rabbits inoculated with FCA, gangliosides, lecithin and cholesterol had rising titers of antibody to both MBP and GC over the 3-month experimental period. One rabbit inoculated with FCA alone had significant antibody to MBP. The findings suggest that Freund's complete adjuvant alone can induce demyelination in the peripheral nerves of rabbits and that SFV may modulate the immune response acting either as an adjuvant or suppressant in the experimental demyelinating disease.

A case of fatal cardiomyopathy presenting in the puerperium is described. Despite extensive investigation and post-mortem examination no aetiological factor was found. The diagnosis of specific peri-partum cardiomyopathy is discussed.

Many arguments can be marshalled to support the use of immunosuppressive treatment in multiple sclerosis (MS)

Controlled trials are particularly important in evaluating treatment in a condition such as Guillain-Barre syndrome (GBS), which has a high incidence of spontaneous recovery. Nevertheless analysis of 904 cases published in the last 15 years indicates the need for improved treatment since only two-thirds of patients had recovered by the end of a year, while 7% had died [15].

Erythrocyte and plasma glutathione peroxidase levels were measured in 12 patients with multiple sclerosis, in 11 age- and sex-matched normal subjects, and in 12 similarly matched patients with other neurological diseases. No difference was found in the enzyme levels in the three groups, indicating that glutathione peroxidase deficiency is not a contributing factor in the aetiology of multiple sclerosis.

EXPERIMENTAL ALLERGIC NEURITIS (EAN) is a model of human acute inflammatory polyneuropathy, Guillain–Barre syndrome. It can be produced in several species of laboratory animal by immunisation with homologous or heterologous peripheral nerve emulsified in Freund's complete adjuvant1,2. After about two weeks the animals may develop signs varying from ataxia to paralysis and death. EAN has been produced using crude acid extracts of peripheral nerve3,4, but investigations into the neuritogenic properties of the component proteins of peripheral nerve myelin have yielded inconclusive results5–10. In experimental allergic encephalomyelitis (EAE), the central nervous system (CNS) counterpart of EAN, the encephalitogenic antigen has been shown to be a CNS myelin basic protein of molecular weight 18,000 (ref. 11). The three major proteins of peripheral nerve myelin, which together account for about 75% of the myelin protein, are usually referred to as P0, P1 and P2 (ref. 12). P0 is a glycoprotein of molecular weight 30,000 and P1 and P2 are both basic proteins with molecular weights of 18,000 and 12,000–14,000, respectively12–13. We describe here a reliable method for producing severe EAN in inbred Lewis rats with bovine intradural root material, and show that intact P2, the major basic protein of peripheral nerve myelin, is the responsible neuritogen.

Preliminary observations suggested that arterial and arteriolar necrosis in vasculitis of the peripheral nerve leads to local haemorrhage and subsequent deposition of haemosiderin. This pigment is more readily recognized in the nerve by the sensitive Perls' test for iron than by relying on recognizing its yellow colour. To support the use of iron staining as an index of vasculitis, in addition to necrosis and fibrin deposition, we obtained the following results from nerve biopsy and autopsy nerve specimens: vasculitis confined to PNS = 5/6 iron positive; polyarteritis nodosa and Wegener's granulomatosis = 4/5 iron positive; systemic lupus erythematosus 2/3 iron positive; rheumatoid disease 1/1 iron positive; acute Guillain–Barre syndrome and subacute or chronic demyelinating polyradiculoneuropathy = 12/12 iron negative; and other perivascular inflammation in the PNS (without evidence of vasculitis) = 2/2 iron negative. One case of Churg–Strauss syndrome showed no changes on nerve biopsy. Iron staining was also demonstrated in the kidneys of five or six patients with polyarteritis nodosa.