Martin Hecht

EUROPEAN CONSENSUS TABLE ON THE USE OF BOTULINUM TOXIN TYPE A IN ADULT SPASTICITY

A group of clinicians from across Europe experienced in the use of botulinum toxin type A for the treatment of spasticity following acquired brain injury gathered to develop a consensus statement on best practice in managing adults with spasticity. This consensus table summarizes the current published data, which was collated following extensive literature searches, their assessment for level of evidence and discussion among the whole group. Published information is supplemented by expert opinion based on clinical experience from 16 European countries, involving 28 clinicians, who treat an average of approximately 200 patients annually, representing many thousand spasticity treatments with botulinum toxin per year.

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.

Summary.Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. Methods. 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP’s were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an “intent-to-treat” (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. Results. Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. Conclusion. Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

MRI-FLAIR images of the head show corticospinal tract alterations in ALS patients more frequently than T2-, T1- and proton-density-weighted images

In some patients with amyotrophic lateral sclerosis (ALS), T2-weighted and proton-density-weighted magnetic resonance imaging (MRI) shows hyperintense or hypointense signals at the corticospinal tract. Fluid-attenuated inversion recovery (FLAIR) sequences increase the sensitivity of MRI to detect cortical and subcortical tissue changes. In 31 ALS patients and 33 controls, we studied the frequency and the extent of signal abnormalities in FLAIR images compared to T2-, T1- and proton-density-weighted images. Hyperintense signals at the corticospinal tract were significantly more frequent in FLAIR images than in all other tested sequences. In FLAIR images of ALS patients only, distinct hyperintense signals at the subcortical precentral gyrus (five patients), the centrum semiovale (eight patients), the crus cerebri (nine patients) and the pons (four patients) as well as mild hyperintense signals in the medulla oblongata (three patients) were seen. More frequently, but not exclusively in ALS patients, FLAIR images showed mild hyperintense signals at the subcortical precentral gyrus (15 patients vs. 1 control). Quantitative analysis confirmed the significant difference between ALS patients and controls at the subcortical precentral gyrus in FLAIR images. In T1-weighted images, the corticospinal tract at the capsula interna was hypointense in significantly more controls than ALS patients. Also this difference was confirmed in the quantitative analysis. Similar to previous results, MR image alterations did correlate poorly to clinical data of upper motor neuron affliction.MR images of the head, including FLAIR images, provide additional information regarding corticospinal tract involvement in ALS patients. Because of an overlap with physiological findings, they have to be interpreted cautiously, with the exception of hyperintense signals at the subcortical precentral gyrus.

Hyperintense and hypointense MRI signals of the precentral gyrus and corticospinal tract in ALS: A follow-up examination including FLAIR images

In amyotrophic lateral sclerosis (ALS) patients, hyperintense signals at the subcortical precentral gyrus in brain fluid attenuated inversion recovery (FLAIR) MR images have been found more frequently than in controls. Quantitative analysis has revealed a significant increase of the FLAIR-magnetic resonance imaging (MRI) signal at the subcortical precentral gyrus of ALS patients compared to healthy controls. In addition, hypointense signals at the rim of the precentral gyrus in FLAIR and T2-weighted images have been shown in ALS patients. In 17 ALS patients, we evaluated hyperintense signals in T2-, T1-, proton density-weighted and FLAIR MR images, and hypointense signals in T2-weighted and FLAIR images 15.7+/-3.0 months after the initial examination by visual scoring. In FLAIR images, a quantitative analysis was added. The visual scores of hyperintense signals along the corticospinal tract did not change significantly in all sequences. However, the quantitative evaluation of FLAIR images revealed a significant increase of the signal intensity at the subcortical precentral gyrus (p<0.005). In addition, the frequency of the visually evaluated hypointense signals at the precentral gyrus increased significantly (p<0.05). The change of MR results did not correlate with the change of clinical parameters. In ALS patients, the increase of the quantified MRI signal at the subcortical precentral gyrus in FLAIR images and the increase of hypointense signals at the rim of the precentral gyrus corroborate the hypothesis that these signals are related to the upper motor neuron degeneration in ALS. Their specificity and clinical relevance have to be clarified further.

Neurophysiological measures in amyotrophic lateral sclerosis: Markers of progression in clinical trials

In this review we evaluate clinical neurophysiological methods, originally described for use in diagnosis that can be applied to measurement of change during the progress of amyotrophic lateral sclerosis (ALS). Such measurements are potentially important in clinical trials, and also in clinical practice. We have assessed methods for lower and upper motor neuron function, including conventional EMG, nerve conduction and F‐wave studies, the derived Neurophysiological Index, motor unit counting methods (MUNE), and transcranial magnetic motor cortex stimulation. We have also addressed the validity of measurements of electromechanical coupling. Methods for measuring muscle strength are beyond the scope of this review. We conclude that MUNE, M‐wave amplitude and the Neurophysiological Index are sufficiently reliable, sensitive, and relevant to the clinical problem of ALS, to be used in clinical trials in the disease. Transcranial magnetic stimulation is of limited value, but a combination of the measurements made as part of this technique may also be useful. We conclude that clinical neurophysiological techniques should now be used in measuring change in clinical trials in ALS.

Assessment of cerebrovascular and cardiovascular responses to lower body negative pressure as a test of cerebral autoregulation.

The aim of this study was to determine whether lower body negative pressure (LBNP), combined with noninvasive methods of assessing changes in systemic and cerebral vascular resistance, is suitable as a method for assessing cerebral autoregulation. In 13 subjects we continuously assessed heart rate, blood pressure, cerebral blood flow velocity (CBFV) and cardiac output during graded levels of LBNP from 0 to -50 mm Hg. With increasing levels of LBNP, cardiac output declined significantly (to 55.8+/-4.5% of baseline value) but there was no overall change in mean arterial pressure. CBFV also fell at higher levels of LBNP (to 81.4+/-3.2% of baseline) but the percentage CBFV change was significantly less than that in cardiac output (P<0.01). The maximum increase in cerebrovascular resistance (pulsatility ratio) was significantly less than that in total peripheral resistance (17+/-6% vs. 105+/-16%, P<0.01). Spectral analysis showed that the power of low-frequency oscillations in mean arterial pressure, but not CBFV, increased significantly at the -50 mm Hg level of LBNP. These results show that, even during high levels of orthostatic stress, cerebral autoregulation is preserved and continues to protect the cerebral circulation from changes in the systemic circulation. Furthermore, assessment of cardiovascular and cerebrovascular parameters during LBNP may provide a useful clinical test of cerebral autoregulation.

Effects of age on the cardiac and vascular limbs of the arterial baroreflex

Background Healthy ageing has several effects on the autonomic control of the circulation. Several studies have shown that baroreflex‐mediated vagal control of the heart deteriorates with age, but so far there is little information regarding the effect of ageing on sympathetically mediated baroreflex responses. The aim of this study was to assess the effects of ageing on baroreflex control of the heart and blood vessels.

Activation of the RAGE pathway: a general mechanism in the pathogenesis of polyneuropathies?

Abstract Objectives: Binding of ligands to the receptor for advanced glycation end products (RAGE) results in activation of the transcription factor NF-κB and subsequent expression of NF-κB regulated cytokines and is a possible pathomechanism in diabetic and in vasculitic polyneuropathies (PNP). We wanted to investigate whether the newly discovered RAGE pathway also contributes to the pathogenesis of various other PNP. Methods: The presence of the RAGE ligand Nϵ-Carboxymethyllysine (CML), the receptor itself and NF-κBp65 was studied in sural nerve biopsies of patients with alcohol-associated PNP (n = 5), PNP owing to vitamin B12 deficiency (n = 5), chronic inflammatory demyelinating PNP (CIDP, n = 10), Charcot-Marie-Tooth disease (CMT) I or II (n = 10), PNP caused by monoclonal gammopathy of unknown significance (MGUS) (n = 5), idiopathic PNP (n = 10) and five normal controls by immunohistochemistry. Biopsies of either ten patients with diabetic and vasculitic PNP served as positive controls. Results: CML, RAGE and NF-κBp65 were found in co-localization in epineurial vessels in PNP owing to vitamin B12 deficiency, diabetes and vasculitis and in the perineurium in diabetic PNP, vasculitic PNP and in some cases in CIDP and vitamin B12 deficiency. Only diabetic subjects demonstrated co-expression of the three antigens in endoneurial vessels. Increased CML, RAGE and NF-κBp65 expression was detected in endoneurial and epineurial mononuclear cells in CIDP and in vasculitic PNP. Additionally, RAGE expression in Schwann cells was significantly increased in diabetic PNP. Discussion: These data suggest that activation of the RAGE pathway might contribute to the pathogenesis of CIDP, PNP owing to vitamin B12 deficiency, diabetes and vasculitis, whereas it does not seem to be involved in the pathogenesis of PNP owing to alcohol, MGUS, CMT I or II and idiopathic PNP.

Dynamic cerebral autoregulation is impaired in glaucoma.

OBJECTIVES Autonomic and endothelial dysfunction is likely to contribute to the pathophysiology of normal pressure glaucoma (NPG) and primary open angle glaucoma (POAG). Although there is evidence of vasomotor dysregulation with decreased peripheral and ocular blood flow, cerebral autoregulation (CA) has not yet been evaluated. The aim of our study was to assess dynamic CA in patients with NPG and POAG. MATERIALS AND METHODS In 10 NPG patients, 11 POAG patients and 11 controls, we assessed the response of cerebral blood flow velocity (CBFV) to oscillations in mean arterial pressure (MAP) induced by deep breathing at 0.1 Hz. CA was assessed from the autoregressive cross-spectral gain between 0.1 Hz oscillations in MAP and CBFV. RESULTS 0.1 Hz spectral powers of MAP did not differ between NPG, POAG and controls; 0.1 Hz CBFV power was higher in patients with NPG (5.68+/-1.2 cm(2) s(-2)) and POAG (6.79+/-2.1 cm(2) s(-2)) than in controls (2.40+/-0.4 cm(2) s(-2)). Furthermore, the MAP-CBFV gain was higher in NPG (2.44+/-0.5 arbitrary units [a.u.]) and POAG (1.99+/-0.2 a.u.) than in controls (1.21+/-0.1 a.u.). CONCLUSION Enhanced transmission of oscillations in MAP onto CBFV in NPG and POAG indicates impaired cerebral autoregulation and might contribute to an increased risk of cerebrovascular disorders in these diseases.

Depression and bulbar involvement in amyotrophic lateral sclerosis

OBJECTIVE: Patients with amyotrophic lateral sclerosis (ALS) often develop depressive symptoms. Little is known of the factors that predict or influence depression in ALS patients. PATIENTS AND METHODS: In 41 ALS patients we compared a self-rating depression scale with the ALS Functional Rating Scale (ALS-FRS), duration of disease, age, sex, education and participation in a self-help group. RESULTS: There was no significant relation between the total ALS-FRS score and the self-rating depression scale. In contrast, we found a significant correlation between the swallowing (r=−0.453; P=0.003) and breathing (r=−0.333; P=0.033) items of the ALS-FRS and the depressive scale. Depressive symptoms were negatively correlated with the duration of the disease (r=−0.377; P=0.016); there was no influence of age or sex. CONCLUSION: We found no evidence for a direct association between the loss of physical ability in general and depression, but for a decrease of depressive symptoms in relation to the length of time since diagnosis. Therefore, depressive symptoms in ALS patients seem to occur mainly as a depressive reaction following the communication of the diagnosis. In addition, patients with bulbar and respiratory symptoms should carefully be screened for depressive symptoms.