Judith Spies

Prospective evaluation of somatic and autonomic small fibers in selected autonomic neuropathies

Background: There are a number of distal and generalized small-fiber neuropathies. The neuropathologic basis is poorly understood as somatic and autonomic C fibers are not usually studied in the same region of the body. Objective: To evaluate prospective somatic and autonomic C-fiber function in 11 healthy control subjects and 38 patients with different clinical patterns of neuropathy. Methods: Distal small-fiber neuropathy (DSFN), peripheral neuropathy (PN), diabetic neuropathy (DN), neuropathic postural tachycardia syndrome (POTS), and idiopathic autonomic neuropathy (IAN) were evaluated. Intraepidermal nerve fiber density was used to evaluate distal somatic C fibers. Both quantitative sudomotor axon reflex test and skin norepinephrine content were measured for the biopsy site to assess distal autonomic C-fiber function. Postganglionic sudomotor, adrenergic, and cardiovagal functions were evaluated by autonomic reflex testing and quantified using a Composite Autonomic Severity Scale. Results: Skin norepinephrine concentration was significantly related to CASS. DN was associated with somatic and autonomic C-fiber impairment with good agreement. POTS was associated with selective distal autonomic deficit. DSFN had combined distal somatic and C-fiber impairment. IAN showed combined and selective distal and generalized autonomic C-fiber impairment. The somatic neuropathies had C-fiber impairment affecting both populations to varying degrees. Conclusion: Although a general agreement exists between the loss of somatic C fibers and autonomic deficits, selective involvement occurs for specific autonomic neuropathies.

Synergy between antibody and P2-reactive T cells in experimental allergic neuritis

Studies were conducted in experimental allergic neuritis (EAN) to evaluate the possible interaction of cellular and humoral immune mechanisms in the demyelinating process. EAN was induced in Lewis rats by passive transfer of T cells reactive to P2 myelin protein or by active immunisation with whole myelin. Animals were then given systemic antimyelin antibody or control serum and assessed clinically, electrophysiologically and with semiquantitative histological studies. Animals given intraperitoneal (i.p.) P2-reactive T cells and systemic antimyelin antibody developed much more severe disease than those given i.p. T cells alone (P < 0.001). In actively immunised animals, the addition of systemic antimyelin antibody did not significantly alter disease severity. We believe the more severe disease in animals receiving T cells and antimyelin antibody reflects synergy between cellular and humoral immune mechanisms whereby neural antigen-specific T cells breach the blood-nerve barrier, allowing demyelinating antibody access to the endoneurium. In EAN induced by active immunisation with whole myelin it is likely that both B and T cell activation occurs and that the more severe demyelination characteristic of this disease reflects the involvement of both humoral and cellular immunity.

Gain and Loss of Gastrointestinal Symptoms in Diabetes Mellitus: Associations With Psychiatric Disease, Glycemic Control, and Autonomic Neuropathy over 2 Years of Follow-up

OBJECTIVE:To prospectively determine the turnover (gain or loss) of gastrointestinal (GI) symptoms in diabetic subjects in relation to glycemic control, autonomic neuropathy and psychiatric disease over a 2-year follow-up.METHODS:Type 1 and type 2 diabetic subjects were recruited from the community, as were community controls. Individual GI symptoms were examined by a validated questionnaire and classified as diarrhea, irritable bowel syndrome, upper GI symptoms, and any GI symptoms at baseline, 12 and 24 months. Glycemic control (glycated hemoglobin), autonomic function (using standardized tests), and psychiatric disease (using the Composite International Diagnostic Interview) were also assessed at these time points.RESULTS:Baseline and 2-year follow-up data were available for 139 diabetic subjects and 55 controls. Glycated hemoglobin at baseline was 7.7% (±1.36) in the diabetic group; 5% had severe autonomic dysfunction. There was a significantly higher prevalence of diarrhea in the diabetic subjects. GI symptom turnover varied between 15% and 25% in the diabetic group and was not significantly different from the controls. There was no clear association between turnover of GI symptoms and either glycemic control or autonomic neuropathy. The appearance of depression was associated with gaining of most symptoms apart from irritable bowel syndrome, although the associations did not always reach significance. The univariate results were confirmed after adjusting for age, gender, body mass index, and metformin use.CONCLUSION:The turnover of GI symptoms in diabetic subjects was not associated with glycemic control but there was a positive association with change in depression.

Effect of leflunomide on the peripheral nerves in rheumatoid arthritis

Background: The objective of this study was to determine the neurophysiological effects of leflunomide on peripheral nerves in rheumatoid arthritis.

Myasthenia gravis: options and timing of immunomodulatory treatment.

The autoimmune pathogenesis of myasthenia gravis is relatively well understood. The current options for treatment of this disease are acute and long term immunotherapies, acetylcholinesterase inhibitors and thymectomy. Many factors influence the timing of initiation of immunomodulatory therapy in myasthenia gravis and both disease factors, such as stage and severity, and patient factors, such as age, pregnancy and intercurrent illness, must be considered. Decisions regarding the choice of therapy can be difficult because of the limited number of randomised controlled trials that have been performed in myasthenic patients. In general, acetylcholinesterase inhibitors alone are used only in mild ocular disease, and in the majority of other patients immunomodulatory therapy is begun early. Corticosteroids are the most commonly used initial therapy, followed by azathioprine. In refractory cases, the available options include immunosuppressants such as cyclosporin, mycophenolate mofetil and cyclophosphamide. Plasmapheresis and intravenous immunoglobulin are important in the treatment of acute exacerbations and myasthenic crisis and in the perioperative setting. Despite many years of experience, the role of thymectomy in improving long term outcome in nonthymomatous myasthenia gravis remains controversial.

Tuberculous cranial pachymeningitis

We describe two immunocompetent patients with tuberculous cranial pachymeningitis. Both patients underwent biopsy after focal dural thickening was identified on MRI. Histopathologic examination of tissue revealed necrotizing granulomatous inflammation. PCR for Mycobacterium tuberculosis DNA was negative on CSF but positive on tissue. Both patients responded to antituberculous therapy. Although uncommon as a cause of cranial pachymeningitis, tuberculosis should be considered, since it responds well to treatment.

Effective treatment of experimental autoimmune neuritis with human immunoglobulin

High-dose intravenous immunoglobulin (IVIg) is an effective treatment for inflammatory demyelinating neuropathies, although the mechanism(s) of action remain incompletely understood. Experimental autoimmune neuritis (EAN) is an animal model of inflammatory demyelinating neuropathies; however, there have been conflicting reports regarding the efficacy of human IVIg in EAN. To obtain a model suitable for the study of the mechanism(s) of action of IVIg in Guillain-Barré syndrome, we investigated the effect of IVIg in EAN in the rat using clinical, electrophysiological and morphological measures. Human IVIg administered at the onset of signs of disease proved effective in preventing further progression of disease and shortening disease duration. This effectiveness was associated with significant differences in electrophysiological parameters including less prolongation of somatosensory evoked potential (S wave) latencies, better maintained S wave amplitudes, less reduction of distal motor nerve conduction velocity, and better maintained amplitudes of compound muscle action potentials of the dorsal foot muscles after stimulation at ankle and hip. Moreover, treatment with IVIg resulted in significantly lower histological grades in rat EAN. The current study provides evidence that human IVIg is effective in the treatment of EAN in the rat, indicating that this model may facilitate further investigation of the mechanism(s) of action of IVIg in inflammatory demyelinating neuropathies.

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 2 New and emerging therapies and their efficacy

In Part 2 of this three part review of multiple sclerosis (MS) treatment with a particular focus on the Australian and New Zealand perspective, we review the newer therapies that have recently become available and emerging therapies that have now completed phase III clinical trial programs. We go on to compare the relative efficacies of these newer and emerging therapies alongside the existing therapies. The effectiveness of β-interferon in the treatment of different stages and the different disease courses of MS is critically reviewed with the conclusion that the absolute level of response in term of annualised relapse rates (where relapses occur) and MRI activity are similar, but are disappointing in terms of sustained disability progression for progressive forms of the disease. Finally we review the controversial area of combination therapy for MS. Whilst it remains the case that we have no cure or means of preventing MS, we do have a range of effective therapies that when used appropriately and early in the disease course can have a significant impact on short term and longer term outcomes.

Posterior reversible encephalopathy syndrome following chemotherapy with oxaliplatin and a fluoropyrimidine: A case report and literature review

Posterior reversible encephalopathy syndrome (PRES) is a neuro‐radiological syndrome characterized by seizures, altered level of consciousness and visual disturbance. PRES is associated with hyperintense lesions on magnetic resonance imaging (MRI) most commonly seen in the posterior regions. In most cases symptoms and radiological lesions are reversible. The aims of this article are: (i) to review the literature for all cases involving oxaliplatin, fluoropyrimidine and bevacizumab and (ii) highlight the increasing number of cases attributed to anti‐neoplastic agents. An in‐depth literature review was conducted by utilizing Pubmeds MEDLINE and Google Scholar databases. We found that there have been nine cases of PRES associated with oxaliplatin or fluoropyrimidine therapy; five cases also involved therapy with bevacizumab. Eight of the nine patients made a full recovery with a complete resolution of MRI changes. This is the first Australian case of PRES following treatment with oxaliplatin and a fluoropyrimidine and only the second case reported in which the patient did not recover despite appropriate medical management. It appears that PRES maybe more commonly associated with multi‐agent therapies and although reversible in most cases, PRES may result in adverse outcomes despite rapid intervention.

Autoantibody responses to nodal and paranodal antigens in chronic inflammatory neuropathies

Autoantibodies to nodal/paranodal proteins have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). To determine the frequency of anti-paranodal antibodies in our cohort of CIDP patients and to validate the presence anti-nodal antibodies in MMN, sera were screened for IgG against human neurofascin 155, contactin-1, neurofascin 186 and gliomedin using ELISA. In CIDP patients, 7% were anti-NF155 IgG4 positive and 7% were anti-CNTN1 IgG4 positive. Positive results were confirmed using cell based assays and indirect immunofluorescence on teased nerve fibres. We did not detect IgG autoantibodies against these nodal/paranodal antigens in MMN patients.