M. De Baets

Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor

The binding of affinity-purified anticardiolipin antibodies (ACA) to liposomes that contained cardiolipin or phosphatidylserine was investigated. ACA bound to these liposomes only in the presence of plasma or serum, which indicated a requirement for a plasma component. This component--referred to as aca-cofactor--was purified; its activity to support ACA binding to liposomes that contained cardiolipin was not destroyed by heat (10 min at 90 degrees C), but was greatly diminished on incubation with trypsin. aca-cofactor bound liposomes that contained negatively charged phospholipid but had no affinity for liposomes that contained neutral phospholipid (eg, phosphatidylcholine); this binding was independent of calcium ions. aca-cofactor was essential for ACA to bind to liposomes that contained cardiolipin or phosphatidylserine and, when coated on a microtitre plate in the absence of any phospholipid, aca-cofactor was an apparent antigen for ACA in an enzyme-linked immunosorbent assay. aca-cofactor is a single chain polypeptide with an apparent molecular weight of 50 kD (non-reduced), which increases to 70 kD upon reduction, and its properties closely resemble those of beta 2-glycoprotein I (apolipoprotein H).

An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis

Background: This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with myasthenia gravis (MG). Methods: Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America [MGFA] criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety. Results: A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%). Conclusions: Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.

Small fiber neuropathy: a common and important clinical disorder

Small fiber neuropathy (SFN) is a neuropathy selectively involving small diameter myelinated and unmyelinated nerve fibers. Interest in this disorder has considerably increased during the past few years. It is often idiopathic and typically presents with peripheral pain and/or symptoms of autonomic dysfunction. Diagnosis is made on the basis of the clinical features, normal nerve conduction studies (NCS) and abnormal specialized tests of small nerve fibers. Among others, these tests include assessment of epidermal nerve fiber density, temperature sensation tests for sensory fibers and sudomotor and cardiovagal testing (QSART) for autonomic fibers. Unless an underlying disease is identified, treatment is usually symptomatic and directed towards alleviation of neuropathic pain.

Small fibre neuropathy in sarcoidosis.

Some patients with sarcoidosis have unexplained pain and dysaesthesia. We did quantitative sensory testing in 31 sarcoidosis patients with pain or autonomic dysfunction. 25 patients had reduced warmth sensitivity, cold sensitivity, or both. Intraepidermal nerve fibre density (IENFD) was measured in punch biopsy skin samples in seven consecutive patients. All seven patients had reduced IENFD compared with controls, which confirmed the presence of small fibre neuropathy in these patients. Some patients with sarcoidosis may have small fibre neuropathy with autonomic involvement.

Intraepidermal nerve fiber density and its application in sarcoidosis

Background: Intraepidermal nerve fiber density (IENFD) is considered a good diagnostic tool for small fiber neuropathy (SFN). Objectives: To assess stratified normative values for IENFD and determine the reliability and validity of IENFD in sarcoidosis. Methods: IENFD was assessed in 188 healthy volunteers and 72 patients with sarcoidosis (n = 58 with SFN symptoms, n = 14 without SFN symptoms). Healthy controls were stratified (for age and sex), resulting in 6 age groups (20–29, 30–39, … up to ≥70 years) containing at least 15 men and 15 women. A skin biopsy was taken in each participant 10 cm above the lateral malleolus and analyzed in accordance with the international guidelines using bright-field microscopy. Interobserver/intraobserver reliability of IENFD was examined. In the patients, a symptoms inventory questionnaire (SIQ; assessing SFN symptoms) and the Vickrey Peripheral Neuropathy Quality-of-Life Instrument-97 (PNQoL-97) were assessed to examine the discriminative ability of normative IENFD values. Results: There was a significant age-dependent decrease of IENFD values in healthy controls, with lower densities in men compared with women. Good interobserver/intraobserver reliability scores were obtained (κ values ≥0.90). A total of 21 patients with sarcoidosis had a reduced IENFD score (<5th percentile; 19 [32.8%] in patients with SFN symptoms, 2 [14.3%] in patients without SFN symptoms). The validity of the normative IENFD values was demonstrated by distinguishing between the SIQ scores and various PNQoL-97 values for the different patient groups. Conclusion: This study provides clinically applicable distal intraepidermal nerve fiber density normative values, showing age- and sex-related differences.

The features of myasthenia gravis with autoantibodies to MuSK.

Objectives: To determine if myasthenia gravis (MG) with antibodies to MuSK is a distinct subgroup of seronegative MG. Methods: We assayed antibodies to muscle specific tyrosine kinase (MuSK) in 55 MG patients who had no antibodies to acetylcholine receptors and looked for the specific phenotype, comparing clinical features of anti-MuSK positive and anti-MuSK negative MG patients. Results: MG with anti-MuSK antibodies was characterised by a striking prevalence of female patients (15 women, two men). Age at onset ranged from 22 to 52 years, with 70.6% of patients presenting at <40 years of age. The majority of patients (82.4%) had prevalent involvement of facial and bulbar muscles. One third of them did not respond well to anticholinesterase drugs. Steroid immunosuppression was effective in eight patients (44.4%). Nine patients underwent thymectomy; six of these had no thymus pathology, while three had a hyperplastic thymus. At the end of the observation period, six (35.3%) patients were in remission, five (29.4%) improved, four (23.6%) did not change, and two (11.7%) had died. Conclusions: MG patients with antibodies to MuSK have characteristic clinical features that are different from features of the remaining seronegative MG patients. This emphasises the predictive value of anti-MuSK antibody analysis in seronegative MG patients.

Immunologic, clinical, and radiologic status 14 months after cessation of natalizumab therapy

Objective: Natalizumab is a humanized recombinant monoclonal antibody against very late activation antigen-4 approved for the treatment of patients with multiple sclerosis (MS). A phase II study failed to demonstrate a difference between natalizumab treatment groups and the placebo group with regard to gadolinium enhancing lesions on MRI 3 months after discontinuation of therapy. The objective of this study was to assess clinical MS disease activity, surrogate disease markers on MRI, immunologic parameters in peripheral blood and CSF, as well as safety in patients with MS after discontinuation of natalizumab therapy. Methods: This study is a longitudinal and serial cross-sectional assessment, in which 23 patients who were treated with natalizumab in the context of two phase III clinical trials were originally enrolled. A subgroup of patients was followed over 14 months. The annual relapse rate, neurologic disease progression assessed by the Expanded Disability Status Scale, disease surrogate markers on MRI, cellular and humoral immune markers in peripheral blood and CSF, and adverse events of the drug were monitored. Results: With regard to clinical disease activity, neuroimaging, and immune responses, the majority of patients in our cohort were stable. Decreased lymphocyte cell numbers and altered cell ratios returned to normal 14 months after cessation of natalizumab. No infectious complications were observed. Conclusion: This is the first long-term follow-up of patients who discontinued natalizumab. We did not observe a clinical, radiographic, or immunologic rebound phenomenon after discontinuation of natalizumab therapy.

Strong association of MuSK antibody–positive myasthenia gravis and HLA-DR14-DQ5

The authors studied the HLA profile of 23 white Dutch patients with muscle-specific kinase antibody–positive myasthenia gravis (MuSK Ab+ MG) and found an association with HLA-DR14-DQ5 (odds ratio 8.5; 95% CI 3.9 to 18.7; p = 4.9 × 10−5). Fifty-two percent of the patients carried the DR14 allele compared with 5% of the controls (p = 1.0 × 10−8). This association between MuSK Ab+ MG and a relatively rare HLA haplotype differs from the previously described association of early-onset acetylcholine receptor Ab+ MG with HLA-B8-DR3.

Acquired neuromyotonia: superiority of plasma exchange over high-dose intravenous human immunoglobulin

Sirs: Acquired neuromyotonia (or Isaacs’ syndrome) is characterized by hyperexcitability of (sudo)motor nerves that results in continuous muscle fiber activity (myokymia), muscle cramps, weakness, and excessive sweating [1]. It has been considered a paraneoplastic syndrome with a probable autoimmune response to ion channels [1]. About 20% of cases have an associated small cell lung carcinoma or thymoma [1], and antibodies to voltagegated potassium channels (VGKCs) have been described [2, 3]. We present a patient with two paraneoplastic syndromes, acquired neuromyotonia and a nephrotic syndrome in association with a thymoma. The neuromyotonia did not react to treatment with intravenous human immunoglobulin (IVIg), but plasmapheresis resulted in clinical improvement. Subsequent immunosuppressive treatment (prednisone and azathioprine) was associated with disappearance of all clinical signs and symptoms. A 47-year-old man was referred for painful paresthesias of the legs, excessive sweating, urine retention, and muscle twitching. Four years earlier an invasive thymoma of the “mixed type” (invasive thymoma mixed type stage IV-A) had been diagnosed which had been treated with chemotherapy (cyclophosphamide, vincristine, doxorubicin, prednisolone) after explorative surgery. Initial examination revealed hyperhydrosis, widespread fasciculations, and myokymia in limb muscles. In the lower extremities reflexes were absent, and sensation was lost distally. Chest radiography showed a thymoma in the mediastinum with pleural metastases. (For clinical course, and response to various treatments, see Fig.1.) A nephrotic syndrome with renal failure and respiratory failure developed 1 week after admission, and the patient had to be transferred to the intensive care unit. The nephrotic syndrome did not respond to corticosteroid and cyclosporin treatment. A partial pleuropneumectomy was performed to remove the thymoma. A few weeks later the nephrotic syndrome disappeared without any specific treatment. However, the patient’s clinical condition again deteriorated with hyperhydrosis, hallucinations, myokymia, and respiratory insufficiency. Electromyography showed spontaneous repetitive compound muscle action potentials in the biceps, gastrocnemius, and anterior tibial muscles confirming the diagnosis of neuromyotonia. The frequency of spontaneous muscle activity was 2 Hz. A 5-day treatment with IVIg (0.4 g/kg per day) had no effect on the clinical manifestations. Three weeks later plasma exchange (5 times a week 2.4 l for 2 weeks) resulted in a dramatic improvement within 2 days. Myokymia and hyperhydrosis disappeared, and 3 weeks later the patient could be weaned from the artificial ventilation. The patient was treated with radiotherapy (40 Gy on the left thorax and a 10Gy booster on the cutting edges), and plasma exchange (twice a week 2.4 l) was performed for another 5 weeks to prevent a possible rebound effect. Clinical improvement continued, and the patient was transferred to the neurological ward. Prednisone (20 mg per day) and azathioprine (50 mg twice a day) were started, and the patient was discharged from hospital. Follow-up computed toLETTER TO THE EDITORS J Neurol (1999) 246 :623–625

The role of interleukin-1 in seizures and epilepsy: a critical review.

Interleukin-1 (IL-1) has a multitude of functions in the central nervous system. Some of them involve mechanisms that are related to epileptogenesis. The role of IL-1 in seizures and epilepsy has been investigated in both patients and animal models. This review aims to synthesize, based on the currently available literature, the consensus role of IL-1 in epilepsy. Three lines of evidence suggest a role for IL-1: brain tissue from epilepsy patients and brain tissue from animal models shows increased IL-1 expression after seizures, and IL-1 has proconvulsive properties when applied exogeneously. However, opposing results have been published as well. More research is needed to fully establish the role of IL-1 in seizure generation and epilepsy, and to explore possible new treatment strategies that are based on interference with intracellular signaling cascades that are initiated when IL-1 binds to its receptor.