Intravenous thrombolysis for acute ischaemic stroke in the elderly: data from the Baden-Wuerttemberg stroke registry.

BACKGROUND AND PURPOSE: In Europe intravenous thrombolysis (IVT) for ischaemic stroke is still not approved for patients aged >80 years. However, elderly patients are frequently treated based on individual decision making. In a retrospective observational study a consecutive and prospective stroke registry in southwest Germany was analysed. METHODS: The data registry collected 101,349 patients with ischaemic stroke hospitalized from January 2008 to December 2012. Of these, 38,575 (38%) were aged 80 years and older and 10 286 (10.1%) underwent IVT. Favourable outcome at discharge was defined as modified Rankin Scale (mRS) ≤1 or not worse than prior to stroke. Multiple logistic regression models stratified by 10-year age groups were used to assess the relationship between IVT and mRS at discharge, adjusted for patient characteristics, admitting facility and length of hospital stay. RESULTS: The highest IVT rate was 15% in patients aged <50 years, with a continuous decline down to 8% in patients aged ≥90 years. Adjusted odds ratios and 95% confidence intervals for patients 80-89 years of age were 2.20 (1.95-2.47) (P < 0.0001) and 1.25 (0.88-1.78) (P = 0.21) for patients >90 years of age, compared to patients of the same age decade not treated with IVT. CONCLUSIONS: The evidence from routine hospital care in southwest Germany indicates that IVT is an effective treatment also for aged patients with ischaemic stroke in an age range between 80 and 89 years. Although no clear evidence for the effectiveness of IVT beyond 90 years was found, treatment should also be carefully considered in these patients. High age should not discourage from treatment.

A consecutive and prospective stroke database covers the state of Baden-Wuerttemberg with 10.8 million inhabitants in Germany.

BACKGROUND: In 1998 Baden-Wuerttemberg (BW), a federal state in southwest Germany with 10.8 million inhabitants, implemented a structured medical concept for the treatment of acute stroke. METHODS: Since 2004 participation in the BW stroke database is mandatory for all hospitals in BW involved in acute stroke care. The stroke database includes all inpatients ≥18 years of age who have suffered an ischemic or hemorrhagic stroke within 7 days before hospitalization. This article presents methodological aspects and first results of the BW stroke database in the time period from 2007 to 2011. RESULTS: Annual inclusion numbers increased continuously (29,422 vs. 35,724, p < 0.001). Median age of stroke onset was stable over time. The proportion of stroke patients ≥80 years increased from 36.9 to 38.8% (p < 0.001). Rates of patients treated in neurology departments rose from 50.7 to 60.9% (p < 0.001) and numbers of patients treated in stroke units rose from 59.1 to 68.4% (p < 0.001). Admission via emergency medical systems increased from 42.8 to 49.7% (p < 0.001) and arrival within 3 h increased from 29.8 to 34.4% (p < 0.001). CONCLUSION: We present results from a large, prospective and consecutive stroke patient database. This first analysis demonstrates a continuous increase of absolute and relative numbers of stroke patients who arrive within 3 h after onset, are hospitalized in neurology departments and treated in stroke units, and are aged ≥80 years.

Analysis of immunoregulatory T-helper cell subsets in patients with multiple sclerosis: relapsing-progressive course correlates with enhanced T H1, relapsing-remitting course with enhanced T H0 reactivity.

In this study, we analysed the recall antigen-induced cytokine production by peripheral blood mononuclear cells (PBMC) from 31 patients with multiple sclerosis (MS) with a relapsing-remitting (rr) and a relapsing-progressive (rp) course and from 40 healthy controls. Cells were stimulated with purified protein derivative (PPD; type 1 response) and tetanus toxoid (TT; type 2 response). Cytokines were determined in the supernatants by ELISA. One of the interesting findings was that healthy controls showed more frequently an IL-5 production after incubation with TT than MS-patients (68% vs.37%; p<0.01), while the type 1 reactivity was only slightly enhanced in MS patients as compared to the controls. However, within the MS patients, there was a significant difference in the incidence of the type 1 reactivity comparing patients with an rp and an rr course (60% vs. 24%; p<0.05). Furthermore, the frequency of a type 0 profile (simultaneous PPD-induced IFN-gamma and TT-induced IL-5 production) was fourfold higher in rr than in the rp patients (43% vs. 10%, p<0.05). In vitro analysis of cytokine profiles in MS could therefore be an interesting approach to evaluate the prognosis of MS (rr vs. rp) already at the beginning of the disease. Thus, it seems that the presence of a type 0 profile is a valid indicator for a favorable course, while a type 1 profile is rather associated with rp MS.

[The stiff-man syndrome with diabetes mellitus type 1 and autoimmune thyroiditis]. / Stiff-man-Syndrom mit Diabetes mellitus Typ 1 und Autoimmunthyreoditis.

HISTORY AND ADMISSION FINDINGS: A 54-year-old woman with type 1 diabetes of about 2 years' duration developed painful cramps in the muscles of the abdominal wall, the back and the thighs. On admission physical examination confirmed markedly increased tone of the muscles of the trunk and those proximal to it. INVESTIGATIONS: Markedly increased amounts of anti-GAD (glutamic acid decarboxylase) antibodies were present in both serum and cerebrospinal fluid (CSF). Electroneurography and -myography revealed mild polyneuropathy but no other neurological abnormality. DIAGNOSIS, TREATMENT AND COURSE: Suspected stiff-man syndrome (SMS) was confirmed by the increased anti-GAD antibodies and the marked improvement on gradually increasing doses of clonazepam. The autoimmune syndrome affected several organ systems: central nervous system (SMS), pancreas (diabetes), thyroid (immuno-thyroiditis). Immunosuppressive treatment with azathioprine was begun. The patient remains in good general condition 22 months after the initial diagnosis, and there have been no new organ involvement. CONCLUSION: It is important to include SMS in the differential diagnosis, even though the symptoms are not those of the full-blown picture of this rare disease. Absence of muscle cramps and myoclonus but presence of depressive symptoms can easily result in misdiagnosis, preventing early initiation of effective symptomatic treatment.

[Continuing medical education (CME) in neurology. Concept of the German Society of Neurology (DGN) and the Neurology Section of the Professional League of German Neurologic Medicine (BVDN)]. / Kontinuierliche medizinische Fortbildung (CME) in der Neurologie. Konzept der Deutschen Gesellschaft für Neurologie (DGN) und der Sektion Neurologie im Berufsverband Deutscher Nervenärzte (BVDN).

Continuous medical education in Neurology (CME-Neurology) has been promoted in a concept organized by both the German society of neurology, German association for occupational interests of neurologists and psychiatrists). CME-Neurology has been started in January 1999 and is closely adapted to the CME guidelines of neurology section of UEMS and EFNS. The program shall serve to the maintenance and upgrading of knowledge skills and competence of postgraduate training in neurology.

The antibody repertoire in experimental allergic neuritis: evidence for PMP-22 as a novel neuritogen.

Experimental allergic neuritis (EAN) is an autoimmune disease that serves as an animal model for the Guillain-Barré syndrome (GBS). In both disorders there is still great uncertainty as to the significance and diversity of autoantibodies involved. We focused on the characterization of serum antibody production in response to various peripheral nervous system (PNS) myelin proteins during the course of actively induced EAN in Lewis rats. These data were compared with EAN induced by adoptive transfer of P2-specific CD4+ T cells (AT-EAN) and with inoculation with complete Freund's adjuvant (CFA) alone. Semiquantitative Western blotting was applied to measure serum IgM and IgG titers against specific myelin proteins, including P2, P0, myelin basic protein (MBP), myelin-associated glycoprotein (MAG) and PMP-22. Considerable differences in the dynamics of antibody titers against individual myelin proteins were observed in active EAN and after inoculation with CFA alone. Our data suggest a pathogenic role of IgM antibodies against HNK adhesion carbohydrate epitope expressing PNS proteins P0, MAG and PMP-22. Among these, PMP-22, a novel candidate neuritogen may be of particular relevance. Thus, we provide evidence for the involvement of antibody-mediated immune response in actively induced EAN and a basis for similar studies on related human disorders such as GBS or other demyelinating neuropathies.

Critical time of exposure of the rabbit inferior alveolar nerve to Carnoy's solution.

To reduce the recurrence of keratocysts, tanning of the epithelial lining with modified Carnoy's solution has been advocated as an ancillary procedure. This agent has occasionally been reported to induce long-lasting local neurotoxicity, when the inferior alveolar nerve (IAN) was located within the bony cavity of larger cysts. As the severity of the neurologic damage depends on the tissue penetration of the solution, a critical exposure time must be assumed. To substantiate this hypothesis, rabbit IANs were decorticated over an approximate length of 1 cm and soaked with modified Carnoy's solution for periods from 30 seconds to 10 minutes. Sensory nerve function was monitored using somatosensory evoked potentials. Exposures up to 2 minutes did not result in any electrophysiologic abnormality. Exposure for 3 minutes led to either normal or rudimentary evoked potentials. After exposure of 5 minutes, and invariably after 10 minutes, the evoked potentials from the IAN were absent. Nerve segments were removed for histologic examination and the penetration depth of the Carnoy's solution was identified by staining with the Berlin-blue reaction. The involved areas were morphometrically evaluated and they reflected the electrophysiological findings. Transmission electron microscopy showed morphologic changes confined to the outer nerve sheaths (epineurium and perineurium) after exposure of 3 minutes. Exposure of 5 minutes and longer resulted in involvement of both the nerve sheaths and their axonal contents, with disruption and disintegration of the neural tissue. This study clearly supports the hypothesis that contact of a peripheral nerve (ie, IAN) with Carnoy's solution carries a time-related risk to produce acute sensory impairment.(ABSTRACT TRUNCATED AT 250 WORDS)

Recovery of the hypothalamic-pituitary-adrenal axis from suppression by short-term, high-dose intravenous prednisolone therapy in patients with MS.

We have studied the recovery of the hypothalamic-pituitary-adrenal (HPA) axis from inhibition by short-term, intravenous high-dose, corticosteroid therapy (IVHDCT) without subsequent oral replacement therapy in 10 patients with relapsing-remitting or progressive multiple sclerosis (MS) using the human corticotrophin-releasing hormone (hCRH) test. There was significant HPA suppression with profoundly decreased basal and peak plasma ACTH and cortisol levels 24 h after cessation of therapy. However, at 48 h the pituitary response was greatly enhanced with peak ACTH concentrations rising by more than 100% over baseline values in 7 of 10 patients. Basal and stimulated ACTH concentrations returned to pre-treatment levels at 120 h. Basal and stimulated plasma cortisol levels remained subnormal in 6 patients 120 h after IVHDCT. We conclude that IVHDCT without oral replacement therapy in MS patients is endocrinologically safe.

Photochemically induced experimental ischemic neuropathy: a clinical, electrophysiological and immunohistochemical study.

A new experimental model of focal peripheral nerve infarction is presented. Ischemia was produced in 12 rats by intravascular thrombosis induced by the photochemical reaction of systemically injected rose bengal to the local application of light from a cold light source. Clinical, electrophysiological and immunohistochemical techniques were used to monitor the pathology and the time course of experimental ischemic neuropathy (EIN) of the sciatic nerve. Primary axonal neurofilament disintegration was detectable 4-24 h after illumination and was followed by wallerian degeneration within the first week. At 7 days, there was a secondary disruption of myelin sheaths accompanied by massive infiltration of macrophages and phagocytosis of the necrotic debris. The majority of detected macrophages were derived from circulating blood monocytes which had invaded the nerve. Two weeks after the initial lesions, degeneration had advanced without any signs of regeneration or remyelination. Electrophysiological recordings corroborate the findings of primary axonal degeneration and failure of regeneration up to 2 weeks after the lesion.

A characteristic ganglioside antibody pattern in the CSF of patients with amyotrophic lateral sclerosis.

Paired cerebrospinal fluid and serum samples of patients with amyotrophic lateral sclerosis (n = 35) revealed no consistent abnormalities of CSF cell count, CSF albumin, CSF IgG, CSF IgM, IgG or IgM index, or oligoclonal immunoglobulin band formation in the CSF. Determination of IgG and IgM CSF and serum antibodies to gangliosides GM1, GM2, GM3, AGM1, GD1a, GD1b, and GT1b showed a characteristic pattern which allowed the differentiation of amyotrophic lateral sclerosis from controls and from patients with other neurological disorders including multiple sclerosis. Specifically, patients with the disease had elevated CSF IgM antibodies to all gangliosides except AGM1. The lack of correlation between the CSF findings and corresponding serum antibodies suggests a chronic, compartmental, intrathecal immune response of low activity in amyotrophic lateral sclerosis. Whether this immune response is primary and of pathogenetic significance, or an epiphenomenon of neuronal degeneration, remains to be investigated.

Intrathecal IgM response in disseminated cerebrospinal metastasis from malignant melanoma.

Neurological complications are a major cause of morbidity and mortality in patients with disseminated malignant melanoma. We have studied and correlated clinical and cerebrospinal fluid (CSF) findings in 20 patients with central nervous system metastases from malignant melanoma including 8 patients with metastatic meningeal melanomatosis (MMM) and 12 patients with solid cerebral metastases (SCM). The putative CSF tumor markers, fibronectin and beta 2-microglobulin, were elevated significantly in MMM but not in SCM patients. A prominent increase in the IgM index, which reflects intrathecal B-cell stimulation, and a rise of IgG index, interleukin-6, and tumor necrosis factor-alpha in MMM patients provide preliminary evidence for a local intrathecal immune response triggered by melanoma cell invasion of the subarachnoid space.

Thymectomy and azathioprine have no effect on the phenotype of CD4 T lymphocyte subsets in myasthenia gravis.

The influence of thymectomy and long term immunosuppression on the phenotype of CD4 T lymphocyte subsets, which were defined by the restricted expression of CD45RA and CD45RO markers, was studied by double immunofluorescence in 29 patients in different clinical stages of generalised myasthenia gravis. In the acute stage of myasthenia, before thymectomy and immunosuppression, no differences in CD4 subsets were observed in the peripheral blood from nine patients and 21 matched controls. Four to seven weeks after thymectomy, there was a slightly decreased proportion of CD4+CD45RO+ (UCHL1+) memory cells (p < 0.05, paired t test). Patients on steroids showed a more pronounced decrease of CD4+CD45RO+ cells suggesting, in addition, a drug-related effect. CD4 subsets (CD45RA, CD45RO, and CD29 positive) in the peripheral blood compartment remained largely stable over 18 to 24 months thereafter. In addition, CD4 subsets were examined in 20 patients with myasthenia gravis who had had a thymectomy between two and 17 years before. With the exception of patients on steroids, there were no differences in CD4 subsets in patients on or off azathioprine. These data did not show any relation of CD4 T cell subsets to the clinical course of myasthenia, or significant changes due to thymectomy, or immunosuppression with azathioprine. These results also complement the authors' clinical experience that thymectomy in adults does not leave a deficit in cell-mediated immunity. The slight change associated with steroid treatment might deserve further attention.

CSF and serum ganglioside antibody patterns in MS.

The authors determined CSF and serum IgG and IgM antibodies to seven gangliosides in 48 patients with multiple sclerosis. Differing ganglioside antibody patterns in CSF but not serum allowed to reclassify 93% of MS patients correctly when compared to patients with Guillain-Barré syndrome or neuroborreliosis. This suggest that the antibody patterns are neither random nor alike in inflammatory diseases of the nervous system. CSF ganglioside antibody titres were found to be different for patients with relapsing remitting (RRMS; n = 35) and chronic progressive (CPMS; n = 13) multiple sclerosis. Our study reveals characteristic ganglioside antibody patterns in MS and confirms previous evidence of disturbed immunoregulation in MS.

Ganglioside antibodies: a lack of diagnostic specificity and clinical utility?

Serum IgG and IgM antibodies to gangliosides GM1, GM2, GM3, AGM1, GD1a, GD1b and GT1b were determined in 210 patients with different degenerative and inflammatory disorders including motor neuron diseases, peripheral radiculopathies and neuropathies, multiple sclerosis and neuroborreliosis. No single disorder was associated specifically with ganglioside antibodies. No characteristic patterns of ganglioside antibodies were observed in any disease category. However, 32% of all patients had pathological antibody titres to at least one ganglioside. Four patients had pathological IgG and IgM titres for all gangliosides evaluated. They suffered from systemic lupus erythematosus [2], neuroborreliosis and schizophrenia, respectively. The results of this study indicate that the introduction of ganglioside antibody determination as a differential diagnostic test in clinical neurology is only helpful in a few patients with typical lower motor neuron syndromes.

Humoral CSF parameters in the differential diagnosis of hematologic CNS neoplasia.

Cerebrospinal fluid (CSF) and serum samples of 20 patients with central nervous system manifestations of hematological malignancies including primary cerebral lymphoma (n = 5) and disseminated non-Hodgkin lymphoma (n = 7) were examined for albumin, IgG, IgM, fibronectin, beta 2-microglobulin, interleukin-6, soluble interleukin-2 receptor, tumor necrosis factor alpha, and oligoclonal immunoglobulin bands. Although a broad range of abnormalities were detected, no reliable CSF parameter for the diagnosis of leptomeningeal spread from hematological neoplasias could be identified. An analysis of 61 repeat lumbar punctures added little to the findings of the first CSF examinations. Currently, immunochemical studies of CSF cell surface markers and early biopsy have probably more clinical value than the determination of the humoral CSF parameters included in this study. However, analysis of cytokine synthesis by single CSF cells using molecular biology techniques may improve the differential diagnosis of hematological neoplasia of the brain and spinal cord in the future.

Influence of gangliosides on experimental allergic neuritis.

The development of myelin-induced experimental allergic neuritis (EAN) in Lewis rats can be depressed and delayed by adding a ganglioside mixture (GM1, GD1a, GD1b, GT1b) to the immunization compound; however, gangliosides may enhance the induction of adjuvant arthritis. Antibodies against multiple gangliosides are produced in rats after immunization with gangliosides after addition of myelin, but only low titers can be detected in animals immunized with myelin and complete Freund's adjuvant alone. We conclude that this antibody production is not the result of peripheral nerve inflammation but depends rather from external applied gangliosides.