Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature.

BACKGROUND: Neuromyelitis optica (NMO, Devic syndrome) and myasthenia gravis (MG) are rare antibody-mediated autoimmune disorders. Concurrent incidence has been reported in only few patients, mostly non-Caucasians. OBJECTIVE: To report on ten Caucasian patients with NMO spectrum disorders (NMOSD) and MG and to provide a comprehensive review of the literature. METHOD: Retrospective study. RESULTS: In total, 26 patients (m:f = 1:12; Caucasian in 12) with MG (generalized in 17) and NMOSD (NMO in 21, longitudinally extensive transverse myelitis in five) were identified from the authors' own files (n = 10) and the previous literature (n = 16). MG preceded NMOSD in 24/25 cases (96%). AQP4-Ab were tested in 20 patients and were positive in 17 (85%). Twenty out of 25 patients (80%) had been treated with thymectomy or thymic irradiation, which preceded NMOSD in all cases (median latency, 12 years; range, 0.3-32). At last follow-up, complete remission of MG was reported in 15/22 (68%), and MG was well controlled with pyridostigmine in three. Co-existing autoimmune disorders or autoimmune antibodies were reported in 17 patients. CONCLUSION: Our study demonstrates that i) AQP4-Ab-positive NMOSD are more commonly associated with MG in Caucasians than previously thought; ii) MG precedes NMOSD in most cases, often by more than a decade; iii) NMOSD almost exclusively occur in females with juvenile or early-onset MG; and iv) MG frequently takes an unusually mild course in patients with NMOSD. A history of thymectomy could be a possible risk factor for the later development of NMOSD. We recommend testing for AQP4-Ab in MG patients presenting with atypical motor or optic symptoms.

Decision-making for and impact of early immunomodulatory treatment: the Austrian Clinically Isolated Syndrome Study (ACISS).

BACKGROUND AND PURPOSE: When to start disease-modifying treatment (DMT) in patients with a clinically isolated syndrome (CIS) requires individual weighing of benefits versus possible burden of side effects and costs. How this occurs in a routine setting is barely known. The aim of the study was to investigate the decision-making process regarding immediate or later DMT and the ensuing impact on CIS patients in Austria. METHODS: Demographic and (para) clinical characteristics of 296 CIS patients were recorded in 29 multiple sclerosis (MS) centres, and the patients' overall condition was rated on a visual analogue scale (VAS). Clinical follow-up and VAS ratings were repeated at 6-month intervals over 2 years. The decision for initiation of DMT was at the physician's and patient's discretion. RESULTS: In 29% of patients, DMT was started within 3 months and this decision was independently associated with a T2-lesion number >or=9 on MRI and a worse VAS rating by the physician. DMT initiation in the subsequent 6 months was additionally associated with the presence of oligoclonal bands and rarely occurred thereafter. Adapted to the clinical course, later treatment was associated with the highest rate of conversion to clinically definite MS and greatest disability after 2 years whilst never treated patients fared best. Patient VAS ratings significantly improved during follow-up independently of treatment decisions. CONCLUSION: The management of Austrian CIS patients relies strongly on MRI findings and the physicians' interpretation of the patients' overall situation which, after 2 years, depends primarily on the course of the disease.

Antibody to aquaporin-4 in the long-term course of neuromyelitis optica.

Neuromyelitis optica (NMO) is a severe inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the spinal cord and optic nerves. Recently, a highly specific serum reactivity to CNS microvessels, subpia and Virchow-Robin spaces was described in patients with NMO [called NMO-IgG (NMO-immunoglobulin G)]. Subsequently, aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Strong support for a pathogenic role of the antibody would come from studies demonstrating a correlation between AQP4-Ab (AQP4-antibody) titres and the clinical course of disease. In this study, we determined AQP4-Ab serum levels in 96 samples from eight NMO-IgG positive patients (median follow-up 62 months) in a newly developed fluorescence-based immunoprecipitation assay employing recombinant human AQP4. We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates. Our results demonstrate a strong relationship between AQP4-Abs and clinical state, and support the hypothesis that these antibodies are involved in the pathogenesis of NMO.

To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis: a position paper of ESGBOR, the ESCMID study group for Lyme borreliosis.

BACKGROUND: Lyme borreliosis (LB) is a tick-borne infection caused by Borrelia burgdorferi sensu lato. The most frequent clinical manifestations are erythema migrans and Lyme neuroborreliosis. Currently, a large volume of diagnostic testing for LB is reported, whereas the incidence of clinically relevant disease manifestations is low. This indicates overuse of diagnostic testing for LB with implications for patient care and cost-effective health management. AIM: The recommendations provided in this review are intended to support both the clinical diagnosis and initiatives for a more rational use of laboratory testing in patients with clinically suspected LB. SOURCES: This is a narrative review combining various aspects of the clinical and laboratory diagnosis with an educational purpose. The literature search was based on existing systematic reviews, national and international guidelines and supplemented with specific citations. IMPLICATIONS: The main recommendations according to current European case definitions for LB are as follows. Typical erythema migrans should be diagnosed clinically and does not require laboratory testing. The diagnosis of Lyme neuroborreliosis requires laboratory investigation of the spinal fluid including intrathecal antibody production, and the remaining disease manifestations require testing for serum antibodies to B. burgdorferi. Testing individuals with non-specific subjective symptoms is not recommended, because of a low positive predictive value.

Ganglionitis in paraneoplastic subacute sensory neuronopathy: a morphologic study.

A 69-year-old woman presented with subacute sensory neuropathy and autonomic dysfunction of 9 months' duration, associated with high serum titers of anti-Hu antibodies. A small cell carcinoma of the lung was diagnosed by biopsy. She died after cardiorespiratory arrest. At autopsy, spinal and autonomic ganglia showed subacute inflammation with diffuse endoneurial T-cell, B-cell, and plasma cell infiltration. The cytoplasm and nuclei of some ganglion neurons displayed IgG immunocytochemical positivity. CD8+ T cells were tightly attached to, and indented the cell surface of, IgG-positive and IgG-negative neurons. This observation suggests that both cytotoxic T-cell-mediated attack against neurons and humoral mechanisms play a role in paraneoplastic subacute sensory neuronopathy.

Apolipoprotein E epsilon 4 is associated with rapid progression of multiple sclerosis.

OBJECTIVE: The apolipoprotein E (APOE) polymorphism is known to impact on various neurologic disorders and has differential effects on the immune system and on CNS repair. Previous findings concerning a possible modulation of the clinical course of MS have been inconsistent, however. METHODS: In a cross-sectional study, the authors investigated 374 patients with clinically definite MS and a disease duration of at least 3 years and related their clinical and demographic findings to the allelic polymorphism of the APOE gene. The genotype distribution of patients with MS was compared with a cohort of 389 asymptomatic, randomly selected elderly volunteers. RESULTS: The authors found no significant differences in the distribution of genotypes between patients with MS and controls. However, patients with MS with the epsilon4 allele (n = 85) had a significantly higher progression index of disability (0.46 +/- 0.4 versus 0.33 +/- 0.26; p < 0.004) and a worse ranked MS severity score (5.1 +/- 1.9 versus 5.7 +/- 1.7; p = 0.05) than their non-epsilon4 counterparts, despite significantly more frequent long-term immunotherapy in epsilon4 carriers (74% versus 58%; p < 0.007). The annual relapse rate in epsilon4 carriers (0.87 +/- 0.56) was significantly higher than in patients with MS without an epsilon4 allele (0.71 +/- 0.47; p = 0.03). CONCLUSIONS: These results suggest no effect of the APOE genotype on susceptibility to MS, but indicate an association of the APOE epsilon4 allele with a more severe course of the disease.

Lyme borreliosis in Europe. Neurologic disorders.

In Europe the tick-transmitted neurologic disorders MPN-GBB or Bannwarth's syndrome and ACA-associated neuropathy have been identified as clinical entities long before their causative agent was discovered. When Lyme disease and its neurologic manifestations were recognized in the United States, differences in the clinical pattern between North American and European cases with Lyme borreliosis were described in the initial reports. In the same way with the availability of serodiagnostic tests as the clinical spectrum of Lyme borreliosis was enlarging in Europe and in North America, these clinical differences became less prominent.

Cyclic adenosine 3',5' monophosphate in cerebrospinal fluid of multiple sclerosis patients.

Cyclic adenosine 3',5' monophosphate (cAMP) was assayed in CSF and plasma obtained from patients with multiple sclerosis. Decreased CSF cAMP levels were found in more than half of the patients while plasma cAMP was normal. The decrease is correlated significantly with the disability of the patient and with the progression of the disease. A low CSF cAMP level can be considered as prognostically unfavorable, particularly in the early stage of the disease. There was no correlation between the cAMP levels and the duration of the disease or with bouts and remissions. ACTH therapy did not normalize the decreased values. Obviously the decrease of CSF cAMP is related to the demyelination and not to the intensity of the pathological immunoreactions.

Progressive cerebellar syndrome in adult coeliac disease.

A case of slowly progressing cerebellar syndrome and pathologically confirmed adult coeliac disease is presented. Neurological symptoms progressed although the patient had no enteric complaints. This case seems to be identical with 18 previously reported cases of encephalopathy and adult coeliac disease. However, the aetiology and pathogenesis of the encephalopathy are still not known.

Cerebral granulomatous angiitis with atypical features.

A case of cerebral granulomatous angiitis of the left temporal lobe mimicking a brain tumour is presented. Following surgical removal of a glioma-imitating mass, histological examination disclosed a granulomatous vasculitis. Treatment consisted of dexamethasone given in tapering doses for 5 days after surgery. Clinical and morphological differences from other reported cases of granulomatous angiitis of the nervous system are described.

HLA-DR in meningopolyneuritis of Garin-Bujadoux-Bannwarth: contrast to Lyme disease?

Sixteen patients with meningopolyneuritis of Garin-Bujadoux-Bannwarth (MPN-GBB) were examined for HLA-DR antigens. In contrast to data in Lyme disease (LD), which is caused by an identical or closely related spirochete, no significant association was found between the neurological disease and HLA-DR. The reported association between neurological disease and HLA-DR2 in LD may be due to the inclusion of cases with neurological disease and arthritis, since chronic arthritis in LD seems to be well correlated with HLA-DR2.

Specificity of CSF antibodies against components of Borrelia burgdorferi in patients with meningopolyneuritis Garin-Bujadoux-Bannwarth.

The specificity of immunoglobulin (Ig) for components of Borrelia burgdorferi was investigated in cerebrospinal fluid (CSF), serum and in CSF oligoclonal bands from nine patients with meningopolyneuritis Garin-Bujadoux-Bannwarth (MPN-GBB). All patients showed specific IgG and IgM antibodies in serum and CSF when incubated with a lysate of B. burgdorferi strain B 31. Specific antibody was detected in CSF but not in paired serum samples, indicating intrathecal synthesis. Investigation of the specificity of oligoclonal Ig in the CSF revealed oligoclonal bands with specificity for B. burgdorferi in one of the nine patients.

Escalating immunotherapy of multiple sclerosis--new aspects and practical application.

Recent clinical studies in multiple sclerosis (MS) provide new data on the treatment of clinically isolated syndromes, on secondary progression, on direct comparison of immunomodulatory treatments and on dosing issues. All these studies have important implications for the optimized care of MS patients. The multiple sclerosis therapy consensus group (MSTCG) critically evaluated the available data and provides recommendations for the application of immunoprophylactic therapies. Initiation of treatment after the first relapse may be indicated if there is clear evidence on MRI for subclinical dissemination of disease. Recent trials show that the efficacy of interferon beta treatment is more likely if patients in the secondary progressive phase of the disease still have superimposed bouts or other indicators of inflammatory disease activity than without having them. There are now data available, which suggest a possible dose-effect relation for recombinant beta-interferons. These studies have to be interpreted with caution, as some potentially important issues in the design of these studies (e. g. maintenance of blinding in the clinical part of the study) were not adequately addressed. A meta-analysis of selected interferon trials has been published challenging the value of recombinant IFN beta in MS. The pitfalls of that report are discussed in the present review as are other issues relevant to treatment including the new definition of MS, the problem of treatment failure and the impact of cost-effectiveness analyses. The MSTCG panel recommends that the new diagnostic criteria proposed by McDonald et al. should be applied if immunoprophylactic treatment is being considered. The use of standardized clinical documentation is now generally proposed to facilitate the systematic evaluation of individual patients over time and to allow retrospective evaluations in different patient cohorts. This in turn may help in formulating recommendations for the application of innovative products to patients and to health care providers. Moreover, in long-term treated patients, secondary treatment failure should be identified by pre-planned follow-up examinations, and other treatment options should then be considered.

[Cerebral manifestation in a case of Sjögren's syndrome (author's transl)]. / Zerebrale Beteiligung bei einem Fall von Sjögren-Syndrom.

A case of Sjögren's disease is described in which isolated cerebellar symptoms were prominent. Serological investigations gave no evidence of disseminated immune vasculitis, systemic lupus erythematosus or any other autoimmune disease. The cerebrospinal fluid protein changes, which were diagnostic of an autoimmune process in the CNS and suggestive of Sjögren's syndrome are discussed.

[Vascular dementia and livedo reticularis]. / Vaskuläre Demenz und Livedo racemosa generalisata.

A case of idiopathic livedo reticularis with dementia is described in a 37 year-old women. The symptoms of livedo reticularis preceded the onset of dementia by more than 16 years. Cerebral angiographic examinations gave evidence of cerebrovascular disease.

[Neurological and psychiatric manifestations in Mycoplasma pneumoniae infections in childhood (author's transl)]. / Neurologische und psychiatrische Manifestationen bei Mykoplasmeninfekten im Kindesalter.

The questions of a causal connection between Mycoplasma pneumoniae infection and neurological psychiatric diseases is discussed on the basis of the case reports of two patients and a review of the literature. Since a causal connection can be assumed in the reported cases it is suggested that infection by Mycoplasma pneumoniae infections should be included in the differential diagnosis of aetiologically unclarified meningoencephalitis, polyradiculitis, and organically-based psychoses.

[Oligoclonal immunoglobulin M in the cerebrospinal fluid of patients with Garin-Bujadoux-Bannwarth meningopolyneuritis]. / Oligoklonales Immunglobulin M im Liquor cerebrospinalis von Patienten mit Meningopolyneuritis Garin-Bujadoux-Bannwarth.

Paired cerebrospinal fluid (CSF) and serum samples from 15 patients with meningopolyneuritis Garin-Bujadoux-Bannwarth (MPN-GBB) were investigated by agarosegel electrophoresis (AE) and consecutive immunofixation (IF). Oligoclonal immunoglobulin (Ig) was detected in the CSF in 13 cases, 8 of which showed oligoclonal IgM; oligoclonal Ig was not found in the respective serum samples. Local CSF synthesis of IgM is a characteristic feature in patients with MPN-GBB. Further serological testing for borreliosis is mandatory in such cases.

[Rare pathomorphologic findings in complicated migraine]. / Seltene pathomorphologische Befunde bei komplizierter Migräne.

137 patients suffering from classical or complicated migraine were investigated in the Neurology Department of the University of Vienna between 1971 and 1984. 13 of these patients were found to have pathological alterations and their case histories are presented. Clinically, 11 patients suffered from migraine accompagnée (in 2 cases accompanied by epileptic seizures), 1 patient had ophthalmoplegic migraine and 1 had a subarachnoid haemorrhage imitating migraine. The underlying pathological findings were: 1 tumour, 4 arteriovenous malformations, 4 aneurysms, 1 arterio-venous shunt, 1 pathological vascular network, 1 Moya-Moya syndrome and 1 intracerebral haemorrhage without detectable source of bleeding. 8 of the patients underwent successful surgery and most of them showed subsequent clinical improvement. The family history was positive in only 2 patients. The time interval between the occurrence of the first symptoms and the establishment of the final diagnosis was up to 25 years. The neurologist should undertake extensive investigation of the patient, including cerebral angiography, if the following criteria apply: hemicrania consistently on the same side; change in type of headache after a number of years; uniform complicating neurological symptoms; additional occurrence of epileptic seizures; manifestation of neurological symptoms after the prodromal phase; persistent neurological signs without remission; negative family history; persisting diffuse or locally accentuated EEG changes; pathological CAT results.

European Union Concerted Action on Risk Assessment in Lyme Borreliosis: clinical case definitions for Lyme borreliosis.

The EU Concerted Action on Risk Assessment in Lyme Borreliosis (EUCALB) has consulted other clinicians and scientists in Europe to produce case definitions of the principal manifestations of European Lyme borreliosis. These case definitions will not only be helpful in supporting its own research interests, but are also intended to assist other clinicians in appropriate management and to support further studies aimed at determining the full clinical spectrum of the disease. The case definitions were achieved after a series of meetings organised by EUCALB with other expert clinicians and scientists from twelve European countries. The definitions and the diagnostic criteria presented thus represent the consensus reached at these meetings. The proposed case definitions consider skin, nervous system, cardiac and musculoskeletal presentations and the role of laboratory investigation in supporting diagnosis.