Psychophysiological correlates of coping and quality of life in patients with ALS.

OBJECTIVE: Self-regulation models of coping suggest that patients with chronic diseases reporting low quality of life (QoL), an indicator of failed coping efforts, should show facilitated access to disease related words. Here we investigated whether a reduced N400 amplitude within an incongruent, i.e. unpredictable disease-related context would be a correlate of this facilitated access. METHODS: ERPs were recorded in N=18 patients with amyotrophic lateral sclerosis (ALS) and N=20 age-matched healthy controls during reading of sentences, ending either with congruent or incongruent words. Incongruent and congruent words were disease related or disease unrelated. Mean N400 amplitudes were analyzed with mixed models. RESULTS: Generally, incongruent words elicited a more negative N400 amplitude than congruent words in all groups and conditions, i.e. an N400 effect. In patients with high QoL this N400 effect did not differ between disease related and unrelated words. In patients with low QoL, however, the N400 effect was significantly smaller for disease related than for disease unrelated words. In healthy controls N400 amplitudes showed no such interaction between congruence, disease relatedness and QoL. Results remained stable when controlling for disease severity, duration and depression. CONCLUSION: The N400 indicates increased accessibility to disease related information in ALS patients with low QoL. The increased access may imply a constantly activated disease related context which is linked to low QoL. SIGNIFICANCE: N400 modulation by disease related information may serve as a psychophysiological correlate of coping and the patient's QoL.

[Lesions of the peripheral nerves: MR neurography as an innovative supplement to electrodiagnostics]. / Läsionen peripherer Nerven: MR-Neurografie als innovative Ergänzung zur Elektrodiagnostik.

The diagnostic work-up of peripheral neuropathies largely depends on neurophysiological investigations. Recently, progress in magnetic resonance imaging (MRI) has lead to new perspectives in the diagnostics of disorders of the peripheral nervous system (PNS). Experimental data show how MR neurography visualises axonal and demyelinating lesions of the PNS. In clinical use, difficult cases of focal nerve compression, traumatic or inflammatory lesions can be solved by the combination of MR neurography and neurophysiology. In particular, the localisation of nerve lesions can be improved by MR techniques. Furthermore, MR neurography enables new insights in the pathophysiology of neuropathies which will be shown for diabetic polyneuropathy.

In vivo imaging of inflammation in the peripheral nervous system by (19)F MRI.

Visualization of neuroinflammation is still a major task in neuroscience and neurology since inflammatory processes play a central pathophysiological role in many disorders of the nervous system but are not yet covered by conventional imaging techniques. Recently, (19)F magnetic resonance imaging (MRI) was introduced as a new cellular imaging technology. In the present study, we established (19)F high field MRI for cell tracking in the peripheral nervous system (PNS) of rats using dedicated MR coils. To mimic focal neuroinflammation, lysolecithin was locally injected into the left sciatic nerve inducing demyelination followed by severe infiltration of monocytes/macrophages from the circulation. Systemic administration of perfluorocarbons (PFC) led to a fluorine signal along the proximal stretch of the affected sciatic nerves in in vivo(19)F MRI which was not seen on the right healthy side. The preferential in vivo uptake of PFC by circulating mononuclear cells was confirmed by density gradient centrifugation of the blood. Removal of nerves with consecutive ex vivo(19)F MRI and additional (19)F spectroscopy for quantification corroborated the localization of the (19)F marker within the injured nerves (1.07×10(18)±1.00×10(18) mean detectable fluorine spins) while contralateral naive nerves did not exhibit any detectable fluorine signal. Histological assessment confirmed the presence of numerous ED1-positive macrophages within the nerve lesions. Control experiments showed that intraneural application of saline led to an inflammatory reaction restricted to the perineurium which could also be detected by (19)F MRI. In conclusion, we show that (19)F MRI is a promising new technology to visualize hematogenous macrophage responses in the nervous system.

[Amyotrophic lateral sclerosis: management of bulbar symptoms]. / Amyotrophe Lateralsklerose: Symptomatische Therapie bulbärer Symptome.

Symptomatic treatment of amyotrophic lateral sclerosis (ALS) is relevant in preventing complications and improving quality of life as long as curative therapies are still out of sight. About one third of ALS patients show disabling problems associated with dysarthria, dysphagia, sialorrhea, and a pseudobulbar affective disorder already in the early stages of ALS. A multidisciplinary approach is the cornerstone of symptomatic treatment of bulbar and pseudobulbar ALS features. Except for riluzole randomized controlled trials are lacking. Here, we review the current views with regard to epidemiology, pathophysiology, diagnosis, and practical aspects of treating bulbar and pseudobulbar symptoms.

Enzyme replacement therapy with alglucosidase alfa in 44 patients with late-onset glycogen storage disease type 2: 12-month results of an observational clinical trial.

Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.

[Reversible loss of vision in severe preeclampsia: case report and review of the literature]. / Reversibler Visusverlust bei schwerer Präeklampsie - Fallbericht und Literaturübersicht.

Visual disturbances occur in up to 25 % of the patients with preeclampsia. However, blindness remains a rare phenomenon. A 39 year old primigravida was admitted for observation at 30 weeks gestation with signs of preeclampsia. After 11 days she suffered a complete loss of vision. The blindness reversed completely after cesarean section and antihypertensive treatment. Blindness in preeclamptic patients is mostly caused by hypertensive encephalopathy. We discuss pathophysiological aspects as well as diagnostic approaches and therapeutic options with respect to the available literature.

Neuropathology and binding studies in anti-amphiphysin-associated stiff-person syndrome.

The authors report a 71-year-old woman with amphiphysin-associated paraneoplastic stiff-person syndrome, opsoclonus, and encephalopathy. The patient's symptoms temporarily responded to plasmapheresis in parallel with a decline of serum anti-amphiphysin antibody titers. Later, the encephalopathy progressed rapidly and the patient died. Binding studies and the detection of autoantibodies in the patient's CNS as well as the treatment response suggest a pathogenic role of the anti-amphiphysin antibodies.

Preserved myelin integrity and reduced axonopathy in connexin32-deficient mice lacking the recombination activating gene-1.

Mice heterozygously deficient for myelin protein zero (P0) mimicking human Charcot-Marie-Tooth (CMT) disease 1B show T-lymphocyte and macrophage upregulation in peripheral nerves, which aggravates and modulates the genetically mediated demyelinating neuropathy. In connexin32 (cx32)-deficient (cx32(def)) mice, which mimic the X-linked dominant form of CMT (CMTX), T-lymphocyte and macrophage numbers are also significantly elevated in peripheral nerves. To test the hypothesis that immune cells are indeed pathogenic in this model, we cross-bred cx32(def) mice with recombination activating gene-1 (RAG-1)-deficient mice, which lack mature T- and B-lymphocytes. In these immunoincompetent double mutants, the number of endoneurial macrophages was reduced. Furthermore, features indicative of myelin degeneration and axonopathic changes were mitigated in the RAG-1-deficient double mutants, whereas enlarged periaxonal Schwann cell collars, a hallmark specific for cx32-mutants, were not reduced. Since both cx32- and P0 deficiency lead to similar immunopathogenic processes, we conclude that immune-mediated demyelination may be a feature common to many CMT-like neuropathies independent of the genetic origin.

Creatine monohydrate in DM2/PROMM: a double-blind placebo-controlled clinical study. Proximal myotonic myopathy.

The efficacy and safety of creatine monohydrate (Cr) in patients with myotonic dystrophy type 2/proximal myotonic myopathy were studied in a small placebo-controlled double-blind trial. Twenty patients received either Cr or placebo for 3 months. After 3 months, there were no significant differences of muscle strength as assessed by hand-held dynamometry, testing of maximum grip strength, Medical Research Council scoring, and the Neuromuscular Symptom Score between the two groups. Some measures indicated trends toward mild improvement with Cr. Myalgia improved in two patients.

Proximal myotonic myopathy and proximal myotonic dystrophy: two different entities? The phenotypic variability of proximal myotonic syndromes.

Multisystemic myotonic myopathies are characterised by a variable pattern of symptoms and signs and a variable degree of disease severity. Proximal myotonic dystrophy has been described as an entity distinct from proximal myotonic myopathy because of severe proximal muscle weakness and dystrophic changes on magnetic reasonace imaging and on muscle histopathology. We describe two siblings, one of them presenting with a proximal myotonic myopathy phenotype, the other with a proximal myotonic dystrophy-like phenotype. The variability of disease expression in these two siblings suggests that a proximal myotonic dystrophy-like variant may occur in proximal myotonic myopathy.

Miller Fisher syndrome: immunofluorescence and immunoelectron microscopic localization of IgG at the mouse neuromuscular junction.

In vitro electrophysiological experiments have demonstrated that IgG antibodies from patients with Miller Fisher syndrome (MFS) impair neuromuscular transmission by a fast and completely reversible combined pre- and postsynaptic blockade. In this study we investigated the cellular and subcellular binding sites of IgG from four MFS patients at the mouse hemidiaphragm by immunofluorescence and immunoelectron microscopy. IgG from all patients produced significant immunostaining at the neuromuscular junction, whereas sera from healthy volunteers or from patients with other neurological diseases did not stain neuromuscular junction. Immunoelectron microscopy revealed that, when living hemidiaphragms were incubated with IgG from MFS patients, labeling was found on both pre- and postsynaptic membranes of the neuromuscular junction, whereas terminal Schwann cells and the basal lamina covering the synaptic membranes were not labeled. These findings demonstrate that IgG from MFS patients binds to synaptic membranes of the neuromuscular junction where it might interfere with the function of both the pre- and postsynaptic activities.

Role of various phospholipases A2 and inhibitors in the pathogenesis and prevention of pancreatic acinar cell necrosis: studies with isolated rat pancreatic acini.

BACKGROUND: Phospholipase A2 (PLA2) may play a central role in the pathogenesis of pancreatic acinar cell necrosis. Several questions, however, are unsolved: Is acinar cell necrosis caused by PLA2 derived from infiltrating leukocytes or from pancreatic PLA2 itself? Does PLA2 cause cellular lysis by the release of lysolecithin from lecithin or by generation of free radicals? The aims of this study were to determine which form of PLA2 is responsible for cellular damage and how to inhibit its action. METHODS: Isolated rat pancreatic acini were prepared by collagenase digestion. Newly synthesized proteins were labeled by 35S-methionine. Acini were incubated in buffer to which various factors, such as porcine pancreatic PLA2 or bee venom PLA2, homogenates of either leukocytes or pancreatic homogenates, all with or without lecithin and with or without potential inhibitors (aprotinin, 4-bromophenacylbromide, BM 16.2115, quinacrine, various analogs of arachidonic acid), or free radicals (hydrogen peroxide, xanthine/ xanthine oxidase) with or without allo-purinol or dismutase/catalase were added. Cellular destruction was measured by the release of radiolabeled proteins. RESULTS: PLA2 alone, free radicals, and granulocytes were not harmful to acini within 30 min of incubation. Free radicals caused significant release of radiolabeled proteins only after 3 h of incubation; this release could be inhibited by scavengers. Incubation of pancreatic acini with PLA2 in combination with lecithin caused rapid release of radiolabeled proteins. Addition of high concentrations of enterokinase activated pancreatic homogenates both alone and with lecithin caused release of cellular proteins, suggesting that pancreatic PLA2 uses lecithin from pancreatic membranes as substrate. Almost all tested potential inhibitors of PLA2 were unable to prevent the destruction caused by either pancreatic or bee venom PLA2 and lecithin. However, HK 42, a polyunsaturated fatty acid analog, was able to reduce dose dependently the release of acinar proteins caused by pancreatic PLA2 and lecithin. CONCLUSION: Pancreatic PLA2 and not PLA2 from infiltrating leukocytes may play a role in pancreatic acinar cell necrosis. Cellular lysis is caused upon the action of lysolecithin and probably not via the action of free radicals.