Diabetes Mellitus Is a Possible Risk Factor for Nodo-paranodopathy With Antiparanodal Autoantibodies.

BACKGROUND AND OBJECTIVES: Nodo-paranodopathies are peripheral neuropathies with dysfunction of the node of Ranvier. Affected patients who are seropositive for antibodies against adhesion molecules like contactin-1 and neurofascin show distinct clinical features and a disruption of the paranodal complex. An axoglial dysjunction is also a characteristic finding of diabetic neuropathy. Here, we aim to investigate a possible association of antibody-mediated nodo-paranodopathy and diabetes mellitus (DM). METHODS: We retrospectively analyzed clinical data of 227 patients with chronic inflammatory demyelinating polyradiculoneuropathy and Guillain-Barré syndrome from multiple centers in Germany who had undergone diagnostic testing for antiparanodal antibodies targeting neurofascin-155, pan-neurofascin, contactin-1-associated protein 1, and contactin-1. To study possible direct pathogenic effects of antiparanodal antibodies, we performed immunofluorescence binding assays on human pancreatic tissue sections. RESULTS: The frequency of DM was 33.3% in seropositive patients and thus higher compared with seronegative patients (14.1%, OR = 3.04, 95% CI = 1.31-6.80). The relative risk of DM in seropositive patients was 3.4-fold higher compared with the general German population. Seropositive patients with DM most frequently harbored anti-contactin-1 antibodies and had higher antibody titers than seropositive patients without DM. The diagnosis of DM preceded the onset of neuropathy in seropositive patients. No immunoreactivity of antiparanodal antibodies against pancreatic tissue was detected. DISCUSSION: We report an association of nodo-paranodopathy and DM. Our results suggest that DM may be a potential risk factor for predisposing to developing nodo-paranodopathy and argue against DM being induced by the autoantibodies. Our findings set the basis for further research investigating underlying immunopathogenetic connections.

Effects of poor bone window on the assessment of cerebral autoregulation with transcranial Doppler sonography - a source of systematic bias and strategies to avoid it.

BACKGROUND: The consequences of poor insonation conditions on autoregulation parameters assessed with transcranial Doppler (TCD) are unclear. METHODS: We present two new complementary methods to assess the quality of a TCD signal. Inserting a thin aluminium foil between TCD probe and skin makes a simple model to artificially worsen a good insonation window. Validation studies are presented. We assessed insonation quality and cerebral autoregulation parameters with transfer function analysis and cross correlation in 46 healthy volunteers with and without the aluminium foil model. The same studies were operated on 45 patients with good insonation windows, naïve, after worsening the bone window and during constant infusion of an ultrasound contrast agent. For studying reproducibility, we assessed autoregulation twice in 30 patients with poor bone windows, with and without constant contrast infusion. RESULTS: Both methods to measure insonation quality are valid and reproducible. The aluminium foil model realistically simulates a natural poor bone window, reducing the signal quality (e.g. energy of the signal spectrum from 33.4+/-3.5 to 26.2+/-2.5 dB, p<0.001). Thereby, the autoregulation parameters are systematically biased (e.g. phase difference from 37.3+/-10.1 degrees to 25.9+/-15.1 degrees , p<0.001); while with the use of an ultrasound contrast agent this can be largely compensated (phase difference 35.7+/-10.7 degrees , p<0.001). The reproducibility is significantly improved (ICC from 0.76 to 0.90, p<0.05). CONCLUSIONS: Poor bone windows can cause considerable bias in TCD autoregulation parameters. This bias might be avoided by the use of ultrasound contrast agents, which may greatly improve the credibility of TCD autoregulation assessment in elderly patients.

Characterisation of the diagnostic window of serum glial fibrillary acidic protein for the differentiation of intracerebral haemorrhage and ischaemic stroke.

BACKGROUND: The rapid differentiation between intracerebral haemorrhage (ICH) and ischaemic stroke (IS) using biomarker testing would allow the prehospital, cause-specific management of stroke patients. Based on single measurements made during the acute phase of stroke, the value of serum glial fibrillary acidic protein (GFAP) was reported to be higher in ICH patients than in IS patients. The aim of the present study was to characterise the diagnostic window of serum GFAP for differentiating between ICH and IS. METHODS: 63 stroke patients admitted within 6 h of symptom onset were prospectively included. ICH (n = 18) and IS (n = 45) were diagnosed using brain imaging. Blood sampling was scheduled for 1, 2, 3, 4, 6, 12, 24 and 48 h after stroke onset (if applicable), and serum GFAP was measured using an ELISA test. RESULTS: For the first 24 h after stroke, median GFAP values in IS patients remained below the detection limit. Between 2 and 6 h of stroke onset, serum GFAP was significantly higher in ICH patients than in IS patients (p < 0.001 for all 4 time points). According to a receiver operating characteristic curve analysis, the overall diagnostic accuracy of GFAP in differentiating between ICH and IS was >0.80 within the 2- to 6-hour time window. Two hours after stroke onset, serum GFAP values were significantly correlated with ICH volume (r = 0.755, p = 0.007). CONCLUSIONS: The time window between 2 and 6 h after stroke onset is best for using GFAP to differentiate between ICH and IS. In the very early phase (i.e. <2 h), sensitivity for detecting ICH is low, thus hampering the application of GFAP as a near-patient test in the prehospital phase.

Assessment of cerebral autoregulation with transcranial Doppler sonography in poor bone windows using constant infusion of an ultrasound contrast agent.

Cerebral autoregulation is an important pathophysiological and prognostic parameter for a variety of neurologic conditions. It can be assessed quickly and safely using transcranial Doppler sonography (TCD). In elderly patients, poor insonation conditions decrease the number of examinable patients and can cause a systematic bias in autoregulation parameters. The aim of this study was to investigate whether a constant infusion of an ultrasound contrast agent (Levovist((R))) can counteract these effects. We examined two cohorts of unselected neurologic patients. In 45 patients with good insonation windows (cohort 1), we used a thin aluminium foil between the skin and the TCD probe to artificially decrease the insonation quality. We determined two parameters of cerebral autoregulation (phase difference [PD] and a cross-correlation coefficient [Mx]) in native patients, with aluminium foil and with aluminium foil and a constant infusion of Levovist. In 30 patients with poor insonation windows (cohort 2), we measured the autoregulation twice, with and without an infusion of Levovist, to assess the reproducibility of the autoregulation parameters. In cohort 1, the foil model significantly decreased the Doppler signal quality, i.e., the mean spectrum energy decreased from 33.9 +/- 2.7 dB to 26.3 +/- 2.4 dB (p < 0.001). This introduced a significant bias to all autoregulation parameters (PD: decreased from 38.2 +/- 10.0 degrees to 27.9 +/- 12.5 degrees (p < 0.001); Mx: decreased from 0.308 +/- 0.170 to 0.254 +/- 0.162 (p < 0.01)). Both effects were compensated largely by a constant infusion of Levovist (300 mg/min). In cohort 2, infusion of the contrast agent at the same rate increased insonation quality, too, but to a lesser degree (27.4 +/- 2.4 dB to 32.0 +/- 3.7 dB, p < 0.001). This smaller increase did not cause a significant change in the autoregulation parameters, but the reproducibility of the PD was significantly improved (intraclass coefficient coefficient [ICC] 0.76, 95% confidence interval [0.59-0.87] in native poor bone window compared with ICC 0.90, 95% confidence interval [0.81-0.95] with infusion of the contrast agent). Our data show that constant infusion of an ultrasound contrast agent during the assessment of cerebral autoregulation can avoid potential bias introduced by poor insonation conditions. Furthermore, infusion of the contrast agent can improve reproducibility and contribute to the credibility of autoregulation assessment in the elderly. (E-mail: matthias.lorenz@em.uni-frankfurt.de).

Elevated serum S100B levels indicate a higher risk of hemorrhagic transformation after thrombolytic therapy in acute stroke.

BACKGROUND AND PURPOSE: Intracerebral hemorrhage constitutes an often fatal sequela of thrombolytic therapy in patients with ischemic stroke. Early blood-brain barrier disruption may play an important role, and the astroglial protein S100B is known to indicate blood-brain barrier dysfunction. We investigated whether elevated pretreatment serum S100B levels predict hemorrhagic transformation (HT) in thrombolyzed patients with stroke. METHODS: We retrospectively included 275 patients with ischemic stroke (mean age of 69+/-13 years; 46% female) who had received thrombolytic therapy within 6 hours of symptom onset. S100B levels were determined from pretreatment blood samples. Follow-up brain scans were obtained 24 hours after admission, and HT was classified as either hemorrhagic infarction (1, 2) or parenchymal hemorrhage (1, 2). RESULTS: HT occurred in 80 patients (29%; 45 hemorrhagic infarction, 35 parenchymal hemorrhage). Median S100B values were significantly higher in patients with HT (0.14 versus 0.11 mug/L; P=0.017). An S100B value in the highest quintile corresponded to an OR for any HT of 2.87 (95% CI: 1.55 to 5.32; P=0.001) in univariate analysis and of 2.80 (1.40 to 5.62; P=0.004) after adjustment for age, sex, symptom severity, timespan from symptom onset to hospital admission, vascular risk factors, and storage time of serum probes. A pretreatment S100B value above 0.23 mug/L had only a moderate sensitivity (0.46) and specificity (0.82) for predicting severe parenchymal bleeding (parenchymal hemorrhage 2). CONCLUSIONS: Elevated S100B serum levels before thrombolytic therapy constitute an independent risk factor for HT in patients with acute stroke. Unfortunately, the diagnostic accuracy of S100B is too low for it to function in this context as a reliable biomarker in clinical practice.

A simple 3-item stroke scale: comparison with the National Institutes of Health Stroke Scale and prediction of middle cerebral artery occlusion.

BACKGROUND AND PURPOSE: The purpose of the study was to design a simple stroke scale that requires minimal training but reflects initial stroke severity and is predictive of middle cerebral artery (MCA) occlusion. METHODS: The new stroke scale assessed 3 parameters: (1) level of consciousness, (2) gaze, and (3) motor function. Each item was graded 0 to 2, where 0 indicated normal findings and 2 severe abnormalities (ie, profound drowsiness or worse, forced gaze deviation, and severe hemiparesis, respectively). During a study period of 11 months, patients presenting with acute stroke symptoms (onset < or =6 hours) were examined by a stroke neurologist assessing the new scale as well as the National Institutes of Health Stroke Scale (NIHSS). In addition, 83 patients received acute magnetic resonance angiography (MRA; as part of an acute stroke protocol). RESULTS: The new stroke scale was strongly associated with the NIHSS. Interobserver reliability of the new scale was high (intraclass correlation coefficient 0.947). Using post hoc analysis, a score of > or =4 predicted proximal vessel occlusion (T-segment or M1-segment occlusion of the MCA on MRA) almost as accurately (overall accuracy 0.86) as an NIHSS score of >or =14 (overall accuracy 0.93). CONCLUSIONS: The new stroke scale reflects acute stroke severity well and predicts proximal MCA occlusion with reasonable accuracy. However, the clinical scale needs further evaluation before it can be recommended as a tool for the triage of acute stroke patients.

Acute and long-term alteration of chemokine mRNA expression after anti-viral and anti-inflammatory treatment in herpes simplex virus encephalitis.

Mortality and morbidity rates remain high among patients with herpes simplex virus encephalitis (HSVE). Chemokine-mediated recruitment and activation of leukocytes to focal areas of viral CNS infection are crucial steps in antiviral response and clearance. However, the inflammatory reaction and cellular antiviral response may enhance collateral damage to neurons and account for chronic progressive brain damage. We identified a specific mRNA expression of the interferon-gamma-inducible chemokines (CXCL9, CXCL10 and CXCL11), and RANTES (CCL5) in the acute course and long-term of experimental HSVE. This pattern was substantially altered by anti-viral and anti-inflammatory treatment. Our findings indicate a pivotal role of these chemokines in the immunopathogenesis of HSVE.

Experimental herpes simplex virus encephalitis: a long-term study of interleukin-6 expression in mouse brain tissue.

This study aimed to investigate the expression of interleukin-6 (IL-6) in acute and chronic herpes simplex virus encephalitis. In the brain of 15 SJL mice infected with herpes simplex virus type 1, strain F, and 14 control animals we performed a sequential quantitative analysis of expression of IL-6 mRNA with reverse transcription real-time polymerase chain reaction. The viral burden peaked in the acute disease, and then returned to a low baseline value. At day 7 following infection, IL-6 expression was significantly (2.05-fold) increased as compared with the baseline expression in uninfected animals. Twenty-one days after infection the mRNA expression still was significantly (1.78-fold) upregulated. No significant differences of IL-6 mRNA expression between infected and control mice were found after 2 and 6 months. We observed a 2.5-fold increase of IL-6 mRNA expression in control mice with increasing age of animals. We have additionally studied the clinical evolution of HSVE in IL-6 deficient mice. In experimental herpes simplex virus encephalitis IL-6, as a potent mediator of neuronal injury, is upregulated in the acute but not in the chronic disease. IL-6 deficient mice presented early and severe clinical signs of HSVE as compared to the wild-type C57/bl6 mice.

Experimental herpes simplex virus encephalitis: inhibition of the expression of inducible nitric oxide synthase in mouse brain tissue.

In the brain tissue of 36 mice infected with herpes simplex virus type 1, strain F, we determined the expression of inducible nitric oxide synthase (iNOS) with semiquantitative reverse transcription polymerase chain reaction. The viral burden was quantitated by polymerase chain reaction. Nitric oxide, induced by iNOS, may contribute to neuronal cell damage following virus infection. As the experimental therapeutic strategy in herpes simplex virus encephalitis (HSVE), we used: N-nitro-L-arginin (L-NA), a selective inhibitor of iNOS; and combination therapies of either methylprednisolone/acyclovir or L-NA/acyclovir. The viral burden peaked in acute disease, and then returned to a low baseline value, except in untreated controls. The expression of iNOS mRNA was suppressed by L-NA and by acyclovir/corticosteroids. INOS inhibition may provide an additional therapeutic strategy targeted specifically to suppress iNOS expression as a potential secondary mechanism of tissue damage in acute and chronic HSVE.