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.

Immunological analysis of human microglia: lack of monocytic and lymphoid membrane differentiation antigens.

While it is certain that reactive microglia (phagocytes in damaged brain tissue) originate from monocytes, the derivation of resting microglia (argentophilic cells in undamaged brain tissue) is not clear. In order to examine a possible lymphocytic and/or monocytic origin for resting microglia, cryostat sections of presumably normal human brain tissue were treated with anti-lymphocyte, anti-monocyte and anti-beta 2-microglobulin sera and then stained with the immunoperoxidase technique. No positive reaction was obtained. It must be concluded that resting microglia are not derived from mononuclear blood cells.

Cerebrospinal fluid interleukins, immunoglobulins, and fibronectin in neuroborreliosis.

Intrathecal synthesis of IgM and IgG, oligoclonal immunoglobulin bands, and the levels of fibronectin, soluble interleukin 2 receptor, interleukin 6, and tumor necrosis factor alpha were investigated with the use of enzyme-linked immunosorbent assay in 46 paired cerebrospinal fluid and serum samples from 32 patients with meningopolyradiculoneuritis due to Borrelia burgdorferi (Lyme borreliosis stage 2). Cerebrospinal fluid and serum interleukin 6, although not specific for neuroborreliosis, were good indicators of disease activity, while the serum soluble interleukin 2 receptor level was only mildly elevated. Tumor necrosis factor alpha was never detected in cerebrospinal fluid or serum specimens, and cerebrospinal fluid IgM, IgM index, and cerebrospinal fluid IgM/cerebrospinal fluid IgG ratios were significantly higher than in all other neuroimmunologic disorders evaluated and may be valuable diagnostic indicators for neuroborreliosis. The estimation of intrathecally synthesized IgG and IgM fractions for the differential diagnosis of neuroimmunologic disorders did not add to IgG and IgM index calculations.

Cytochemical marking of T lymphocytes in human cerebrospinal fluid.

Demonstration of nonspecific acid alpha-naphthyl acetate esterase activity is a simple and practical method for classifying mononuclear cells in the cerebrospinal fluid. In addition to mononuclear phagocytes, T lymphocytes may also be characterized.

Prednisolone therapy of experimental allergic neuritis in Lewis rats does not induce relapsing or chronic disease.

The effects of therapeutic prednisolone treatment on experimental allergic neuritis (EAN) in Lewis rats were evaluated in a controlled clinical and electrophysiological study. Since steroid therapy has been suspected to cause relapsing or chronic disease, monitoring was extended over 200 days. Short-term steroid treatment (5 days of 15 mg/kg prednisolone, n = 8) with sudden steroid withdrawal was compared with long-term application (30 days, beginning at 7.5 mg/kg) in descending dosage (n = 8). The experiment included saline-injected controls (n = 8) and controls for stress possibly exerted by the handling of the animals. Treatment was begun at the onset of clinical signs. The clinical and electrophysiological data indicated that deterioration, recovery and mild (insignificant) relapse (after day 30 and day 108) occurred in all groups at the same time. Both steroid application schemes significantly (p less than 0.03) attenuated the severity and shortened the duration of EAN. Relapse was not aggravated after steroid treatment. The clinical course and electrophysiological findings were unaltered by the experimental procedures and by mild experimental stress.

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.

Demyelination of sciatic nerve in acute experimental allergic neuritis of the rat. A gel electrophoresis investigation.

Acute experimental allergic neuritis (EAN) of Lewis rats was monitored by clinical and electrophysiological tests for 60 days. Sciatic nerve myelin proteins were analyzed by quantitative microgel electrophoresis and electroimmunoblotting at different clinical stages of the disease. The clinical severity of EAN and the demyelination as measured by electrophysiological tests and myelin protein concentrations in sciatic nerve did not correspond during the course of the disease. Demyelination reached its peak after partial clinical recovery and was still present on day 60. The major peripheral nervous system (PNS) myelin proteins P0, P1 and P2 decreased at different rates during the course of the disease, indicating possible differences in their proteolytic degradation. Treatment with Freund's complete adjuvant (CFA) alone resulted in alterations of membrane and myelin protein patterns challenging the widely held belief that pure CFA is inert with regard to demyelination.

Spontaneous chemiluminescence activity of peripheral blood cells during experimental allergic neuritis (EAN).

In 30 Lewis rats the time course of spontaneous monocyte and granulocyte chemiluminescence activity (CLA) during myelin-induced experimental allergic neuritis (EAN) was studied. CLA of blood and peritoneal cells, and clinical, histopathological and electrophysiological findings were compared with data from 14 animals immunized with complete Freund's adjuvant and ten normal Lewis rats. About 12 days post-immunization there was a significant (p less than 0.003) rise in monocyte, but not in granulocyte CLA in EAN animals. CLA correlated significantly (p less than 0.02) with infiltrate formation in nerve roots, preceding clinical or electrophysiological signs of disease by 1-2 days. There was no increase in peritoneal monocyte CLA, which was consistently higher than blood monocyte CLA (p less than 0.002).

The use of protease inhibitors in experimental allergic neuritis.

In experimental allergic neuritis (EAN) break-down of myelin is attributed to macrophages, which among other factors contain and secrete proteases. In vitro studies have shown that cathepsin D, an acidic aspartyl endopeptidase, and plasmin can degrade myelin proteins. In order to elucidate a potential therapeutic effect of protease inhibitors we treated Lewis rats, immunized with bovine peripheral nervous system myelin, with epsilon-amino-caproic acid (EACA) or pepstatin. EACA or pepstatin was administered twice daily by intraperitoneal injection beginning on day 6 postimmunization or from the onset of disease (on day 12) through day 24. Compared to saline-treated controls, animals treated with either of the inhibitors showed delayed development of clinical signs and electrophysiological abnormalities. Maximal severity and the further course of disease, however, were not different in control and treated groups. Immunohistological evaluation of sciatic nerve specimens on day 24 postimmunization showed equal numbers of cells positive for ED1 (macrophages) and cathepsin D in all animal groups. There was also no difference in the spontaneous proteolytic activity of the sciatic nerve homogenates at pH 2.8, 5.0, and 7.4. Incubation of the homogenates with pepstatin, however, significantly reduced proteolytic activity at pH 2.8 and 5.0, while EACA had no effect at any pH tested. These results imply that treatment to limit the infiltration of cathepsin D-positive cells or to reduce the induction or activity of cathepsin D may provide a therapeutic avenue for treating inflammatory demyelination of the peripheral nervous system.

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.

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.

Measurement of atactic and paretic gait in neuropathies of rats based on analysis of walking tracks.

In 23 Lewis rats 2 forms of neuropathy both with atactic gait were studied by morphometric analysis of walking tracks. In one group of animals experimental allergic neuritis (EAN) was induced which leads to both sensory and motor dysfunction. Clinical symptoms are atactic gait and hindlimb paresis. In another group pyridoxine (vitamin B6) neuropathy was induced which is a purely sensory neuropathy clinically presenting with gait ataxia, too. Track analysis is a simple method that requires no visualisation process and produces significant and reproducible data. The findings were compared with the clinical scores and electrophysiological data. In EAN, toe spreading was impaired early, and at a later stage stride width, print length and outward rotation of the hind feet changed. Pyridoxine-induced neuropathy produced only an increase in stride width. Track analysis correlated well with clinical grading and electrophysiological recordings. We propose track analysis as a reliable and accurate indicator of neuropathy symptoms in rats.

Origin, proliferation, and fate of cerebrospinal fluid cells. A review on cerebrospinal fluid cell kinetics.

Four aspects of cytokinetic investigations of cerebrospinal fluid cells were reviewed: the origin of these cells, their ability to divide, their fate, and the alterations occurring under pathologic conditions. Animal experiments and in vitro reactions of human cerebrospinal fluid cells indicated that, under normal and pathologic conditions, blood lymphocytes and blood monocytes are capable of leaving the vascular system inside the subarachnoid space. When these cells are located extravascularily, they seldom divide in the subarachnoid space under normal conditions. Migration via lymphatic pathways is possible, at lest under pathologic conditions. Cell turnover, as a whole, is extremely low under normal conditions. It is markedly altered by meningeal inflammation and meningeal tumor cell dissemination. Diagnostic significance other than morphology cannot yet result from cytokinetic investigations of cerebrospinal fluid cytology; prognostic significance may be possible.

Diagnostic significance of nerve cells in human CSF with particular reference to CSF cytology in the brain death syndrome.

Cytological examination of the cerebrospinal fluid (CSF) in 5 cases of the brain death syndrome treated on a respirator revealed the presence of nerve cells (mostly Purkinje cells), massive pleocytosis with many polymorphonuclear leukocytes, and numerous macrophages containing erythrocytes, leukocytes, lipid droplets, and hemosiderin. Portions of connective tissue with well preserved capillaries, and debris which could not be more closely identified, were also found. Neuropathological examination in 4 cases revealed progressive autolysis of brain tissue and displacement of the autolyzed tissue into the subarachnoid space of the spinal canal, partly due to tonsillar herniation. All five patients exhibited clinical signs of brain death and had been placed on respirators for various periods of time. The cytological findings in the CSF, together with the clinical signs of brain death, constitute an intravital morphological indication of brain tissue autolysis.

Tonic pupil, areflexia, and segmental anhidrosis: two additional cases of Ross syndrome and review of the literature.

Two patients are described with the triad of tonic pupil, hyporeflexia and segmental anhidrosis (Ross syndrome). Only 18 cases of this syndrome have been reported in the literature so far. While tonic pupil and reduced sweating can be attributed to the affection of postganglionic cholinergic parasympathetic and sympathetic fibres projecting to the iris and sweat glands, respectively, the pathogenesis of diminished or lost tendon jerks remains obscure. To identify the characteristic clinical features, the previous cases of Ross syndrome are reviewed. Recent evidence of subclinical disturbances of sweating in most patients with Adie's syndrome, i.e. tonic pupil and areflexia, casts doubt on the nosological concept of Ross syndrome as a distinct clinical entity.

Additional biochemical criteria in the differential diagnosis of myositis.

Thirty-six biopsy specimens of human biceps and vastus lateralis muscles were examined by histometric analysis and determination of enzyme activities (phosphorylase, triosephosphate dehydrogenase, 3-hydroxacyl-CoA-dehydrogenase, lactate dehydrogenase, hexose isomerase, citrate synthetase, 6-phosphogluconate dehydrogenase). The series included 13 specimens from patients suffering from a benign form of muscular dystrophy (limb girdle and Becker type of muscular dystrophy) and 12 specimens from patients with an acute (n = 5) or chronic (n = 7) form of myositis. Muscle fibres were atrophic in myositis and hypertrophic (with an increased variation of fibre diameters) in muscular dystrophies, as has been shown previously. When myositis samples were compared with either normal or dystrophic muscles, a highly significant lowering of glycolytic enzyme activity was found in chronic myositis, while the activity of 6-phosphogluconate dehydrogenase was elevated to highly significant levels. Measurements of the latter enzyme's activity might be of additional value in differentiating chronic forms of myositis from benign muscular dystrophies.

Central pontine myelinolysis associated with low potassium levels in alcoholism.

Two patients with chronic alcohol abuse and central pontine myelinolysis are described. One developed a Korsakoff syndrome 2 days before admission to our hospital and the other showed signs of a incipient delirium without Korsakoff syndrome. Diagnosis of incipient central pontine myelinolysis was based on acute brain-stem dysfunction, serum electrolyte disturbances, malnutrition with vitamin B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin) deficiency in combination with typical neuroradiological findings. Hypokalaemia but no disturbance in serum sodium levels was found in both patients. After correction of hypokalaemia and vitamin deficiency the patients showed complete recovery of neurological and neuropsychological function. The findings are interpreted as suggesting that disturbances in serum potassium levels as well as rapid correction of hyponatraemia may be associated with pontine swelling and dysfunction which, if undetected, leads to central pontine myelinolysis.

Cerebellar dysfunction in patients with bronchogenic carcinoma: immunological investigations.

Sera from seven patients with bronchogenic carcinoma and cerebellar dysfunction were tested for anti-Purkinje cell antibodies (APCA) by indirect immunofluorescence and indirect immunoperoxidase reaction. Specific APCA as described in paraneoplastic cerebellar degeneration (PCD) were not detected in any of these patients or in control patients. The lack of APCA in patients with bronchogenic carcinoma and their presence in association with ovarian or breast cancer indicate that different pathogenetic mechanisms may play a role in PCD.