Targeting pain in the long-term treatment of cervical dystonia with botulinum toxin A.

AIMS: Cervical pain is one of the most common non-motor symptoms of cervical dystonia (CD) and affects from 54.6% to 88.9% of patients. To date, minority of studies investigated the relevance of pain in a long-term botulinum toxin (BoNT) therapy of CD. The aim of the study was to define an impact of cervical pain on the disease severity and disability, as well as to assess antinociceptive BoNT efficacy in a long-term treatment of CD. MATERIALS AND METHODS: In this case-control study, CD patients who received stable doses of BoNT for at least 3 years were assessed with the use of validated scales. Participants were divided into two groups depending on the occurrence of CD-related pain. RESULTS: We examined 50 participants who received a mean of 24 injection cycles (6-51) of BoNT during a mean treatment period of 10.3 years (3.0-23.5). Participants with cervical pain (68.0%) were characterized by higher scores in all scales used in this study: TWSTRS severity (p = 0.030), disability (p < 0.001), total (p < 0.001) and TSUI score (p = 0.046). Pain reduction following BoNT injection lasted longer than muscle relaxation in 85.3% of patients. Pain improvement between first and last BoNT injection cycle was reported by 76.5% of patients with CD-related pain. CONCLUSIONS: The presence of cervical pain in CD may increase the severity of muscular symptoms and disease-related disability. BoNT has a noticeable antinociceptive effect in the long-term treatment of CD.

Cervical dystonia: factors deteriorating patient satisfaction of long-term treatment with botulinum toxin.

OBJECTIVES: Botulinum toxin (BoNT) is an effective first-line treatment for cervical dystonia (CD). Despite generally good therapeutic efficacy, approximately 20-40% of CD patients do not achieve acceptable relief of the dystonic symptoms. The aim of this study was to identify factors of low patient satisfaction of long-term BoNT therapy for CD. METHODS: In this case-control study CD patients treated with BoNT intramuscular injections for up to 24 years were assessed by two independent assessors in three validated scales: TWSTRS, Tsui and VAS for pain measurement. Data on received BoNT doses and treatment duration were obtained from medical history. All of participants rated their long-term treatment satisfaction compared to the therapy onset on a 0-3 scale. RESULTS: Study was completed by 58 participants who were treated with BoNT for 9.0 ± 6.3 years and received a median of 19 injection cycles. None/low therapy satisfaction was reported by 20.7% of participants. Compared to moderate/good treatment satisfaction, CD patients with none/low BoNT efficacy had increased incidence of cervical pain (p =.018), enhanced mean VAS score for pain (p =.037) and had higher coexistence of oromandibular dystonia (p =.018). In addition, worse treatment satisfaction correlated with shorter time intervals between treatment cycles, enhanced scores of Tsui total, TWSTRS total, as well as TWSTRS subscales: severity, disability and pain. CONCLUSION: Cervical pain and coexistence of oromandibular dystonia deteriorated long-term treatment satisfaction in CD patients. Higher scores of Tsui and TWSTRS subscales were correlated with worse subjective BoNT treatment response.

Clinical and biochemical predictors of late-outcome in patients after ischemic stroke.

OBJECTIVE: The aim of this study is to evaluate neurological scales, as well as biochemical and radiological parameters measured on day 10 after ischemic stroke (IS), according to their value as predictors of the long-term outcome. MATERIAL AND METHODS: 45 patients were assessed according to the Barthel Index (BI) and National Institute of Health Stroke Scale (NIHSS) on day 10, and according to Modified Rankin Scale (mRS) 3 months after the onset of IS. On day 10 of IS, the serum level of C-reactive protein (CRP), albumin, D-dimers (DD), S100BB and Tau proteins was measured and the volume of ischemic focus assessed with the use of Computed Tomography (CT). The patients were divided into groups with good outcome (GO) and mRS 0-2, and with bad outcome (BO) and mRS 3-6. RESULTS: NIHSS and BI scores (p<0.001), the volume of ischemic focus (p<0.01), CRP (p<0.01) and albumin level (p<0.05), but not DD, S100BB and Tau protein levels evaluated on day 10, correlated with mRS after 3 months since IS onset. Patients from the BO group were observed to have lower BI (p=0.001), higher NIHSS (p<0.01) and CRP levels (p<0.05), and bigger volume of ischemic focus (p<0.05) measured on day 10 of IS. In the GO group, there were more patients with atherosclerotic etiology (p=0.02 x2=7.856). Regression analysis showed that only the BI score assessed on day 10 of IS can predict the outcome after 3 months assessed by mRS (OR=1.102, 95%, CI:1.01-1.203; p=0.001). CONCLUSIONS: BI assessed on day 10 has a predictive value for the outcome evaluated by mRS 3 months after the onset of IS.

Biomarkers in Multiple Sclerosis: a review of diagnostic and prognostic factors.

INTRODUCTION: Multiple Sclerosis (MS) is a chronic, demyelinating disease of the central nervous system which affects mostly young people. Because it leads to disability and cognitive impairment, it is crucial to recognise MS at an early stage. STATE OF THE ART: Magnetic resonance imaging is the golden standard in MS diagnosis. However, it is not an infallible diagnostic tool, especially at the stage of clinically isolated syndrome. The incorporation of oligoclonal bands in the diagnostic process of MS is a step towards the extension of diagnostic methods. Recently, a lot of research has been carried out on potential biomarkers in blood serum and cerebrospinal fluid that may be useful in the diagnosis of MS. CLINICAL IMPLICATIONS: This article summarises current knowledge on the use of new prognostic factors such as neurofilament light chain, chitinase 3-like 1 and 2, heat shock proteins, and tubulins in MS. FUTURE DIRECTIONS: Despite numerous studies on the use of biomarkers in the diagnosis of MS, more extensive research is needed to determine the clinical usefulness of these molecules and to develop diagnostic tests applicable in everyday practice. This in turn may result in earlier MS detection, faster implementation of treatment, and better therapeutic effects.

Real-world effectiveness of abobotulinumtoxinA (Dysport®) in adults with upper limb spasticity in routine clinical practice: an observational study.

AbobotulinumtoxinA (aboBoNT-A, Dysport®) is used in clinical practice as a well-tolerated and effective therapy for muscle spasticity. AboBoNT-A has been shown to reduce upper and lower limb spastic paresis in clinical trials, demonstrating improvements in muscle tone and limb function. This open-label, multicentre, observational, non-interventional study was the first to investigate aboBoNT-A's efficacy in adult patients with upper limb spasticity (ULS) in routine clinical practice in Poland. All enrolled patients received ≥1 aboBoNT-A injection cycles, per routine clinical practice (full analysis set, FAS), and ≥1 rehabilitation session. Patients attended a baseline visit (V1) and two follow-up visits (V2, V3) for retreatment, depending on the investigator's assessment of individual patient needs, with a mean interval (SD) between injections of 4.4 (1.4) and 4.5 (1.2) months. The primary effectiveness endpoint was patient- and physician-based evaluation using the Clinical Global Impression-Improvement Scale (CGII), a validated 7-point scale (1 = very much improved to 7 = very much worse) relative to baseline. CGI-I has not previously been used as a primary endpoint in studies evaluating ULS. Secondary endpoints included muscle tone in shoulder, elbow, carpal joint, and finger muscles, measured by the Modified Ashworth Scale (MAS), and muscle strength according to the Medical Research Council scale (MRC). Of 108 enrolled patients (FAS), 92 (85.2%) completed the study and 57 (52.8%) were included in the per protocol (PP) population. AboBoNT-A improved patient conditions in 96.4% and 98.6% at V2 and V3 (investigator assessment) and 92.8% and 98.6% (as reported by patient) of patients, respectively. Significant reductions in muscle tone from baseline were observed at both visits (p < 0.0001-0.0077) across muscle groups. Increased muscle strength by cumulative MRC was observed at V2 (p = 0.0566) and V3 (p = 0.0282) versus baseline. Safety was consistent with the known profile of aboBoNT-A. In conclusion, aboBoNT-A treatment is beneficial in patients with post-stroke ULS in routine clinical practice, assessed by patients and investigators.

Non-traumatic cervical artery dissection and ischemic stroke: A narrative review of recent research.

Cervical artery dissection (CAD) is a leading cause of ischaemic stroke (IS) in young and middle-aged adults. Despite well characterized clinical presentation, the diagnosis of CAD can be quite challenging due to a wide variety of symptoms ranging from minor neck pain to severe neurological symptoms. Invasive diagnostic procedures such as DSA are nowadays being replaced by the sensitive and CAD-specific sequences of MR. The most recent studies confirmed the overall efficacy of antiplatelet and anticoagulant therapies for CAD patients is equivalent, although patients should be qualified for concrete treatment on the basis of recently characterized clinical features. The use of NOAC in CAD-related IS prevention cannot yet be recommended due to the lack of evidences from randomized controlled trials. Endovascular therapies should be considered as the treatment of CAD, especially in the cases of large occlusion or antithrombotic treatment failure. Further research is needed to evaluate the efficacy of new imaging modalities and treatment options. This review summarize the last 5-year development of the diagnosis and treatment for CAD as a causative factor for IS.

Pain in cervical dystonia and the antinociceptive effects of botulinum toxin: what is currently known?

Pain is the most common and disabling non-motor symptom in cervical dystonia (CD). Up to 88.9% of patients report pain at some point in the course of the disease. It is still a matter of debate whether CD-related pain originates only from prolonged muscle contraction. Recent data suggest that the alterations of transmission and processing of nociceptive stimuli play a crucial role in pain development. Botulinum toxin (BT) is the first-line therapy for CD. Despite fully elucidated muscle relaxant action, the antinociceptive effect of BT remains unclear and probably exceeds a simple decompression of the nerve fibers due to the reduction in muscle tone. The proposed mechanisms of the antinociceptive action of BT include inhibition of pain mediator release, inhibition of membrane sodium channels, retrograde axonal transport and impact on the other pain pathways. This article summarizes the current knowledge about the antinociceptive properties of BT and the clinical analgesic efficacy in the treatment of CD patients.

Wernicke-Korsakoff syndrome as a rare phenotype of sporadic Creutzfeldt-Jakob disease.

We reported the case of a patient with Wernicke-Korsakoff syndrome (WKs) as an early clinical manifestation of sporadic Creutzfeld-Jakob disease (sCJD). The 66-year-old female complained of dizziness and imbalance which mostly occurred while walking. A neurological examination revealed a triad of symptoms characteristic for WKs such as gaze paresis, ataxia of limbs and trunk as well as memory disturbances with confabulations. The disturbances increased during the course of the disease, which led to the death of the patient four months after the appearance of the signs. The patient was finally diagnosed with sCJD disease. The most useful ancillary examination results supporting sCJD diagnosis were brain diffusion DWI MRI (diffusion weighted magnetic resonance imaging) and the presence of 14-3-3 protein in CSF (cerebrospinal fluid). Since that manifestation of sCJD is very unique other causes should be taken into consideration while making a final diagnosis.

Correlation between CH2DS2-VASc Score and Serum Leptin Levels in Cardioembolic Stroke Patients: The Impact of Metabolic Syndrome.

OBJECTIVE: To determine adipokines levels in patients with different etiologic subtypes of acute ischemic stroke (AIS) and metabolic syndrome (MetS) status. METHODS: Serum adiponectin, leptin, and resistin levels were determined by ELISA in 99 AIS patients and 59 stroke-free control group subjects. Stroke patients were grouped based on MetS, modified TOAST classification, and CHA2DS2-VASc scale in case of cardioembolic stroke following atrial fibrillation. RESULTS: No differences were found in all adipokine serum levels between AIS patients and appropriately matched control group. MetS-AIS patients had significantly higher leptin levels (22.71 ± 19.01 ng/ml versus 8.95 ± 9.22 ng/ml, p < 0.001) and lower adiponectin levels (10.71 ± 8.59 ng/ml versus 14.93 ± 10.95 ng/ml, p < 0.05) than non-MetS-AIS patients. In patients with cardioembolic stroke, leptin levels were significantly higher than in remaining stroke cases (19.57 ± 20.53 ng/ml versus 13.17 ± 12.36 ng/ml, p < 0.05) and CHA2DS2-VASc score positively correlated with leptin levels only (p < 0.001). Analysis of individual components of CHA2DS2-VASc score showed that hypertension, female gender, and diabetes had greatest impact on elevated serum leptin level. CONCLUSION: This pilot study revealed that leptin could be a potential biomarker for risk stratification of cardioembolic stroke in MetS patients and that heterogeneity of stroke subtypes should be considered for more refined and precise clinical stroke studies.

Mechanical thrombectomy in acute stroke - Five years of experience in Poland.

OBJECTIVES: Mechanical thrombectomy (MT) is not reimbursed by the Polish public health system. We present a description of 5 years of experience with MT in acute stroke in Comprehensive Stroke Centers (CSCs) in Poland. METHODS AND RESULTS: We retrospectively analyzed the results of a structured questionnaire from 23 out of 25 identified CSCs and 22 data sets that include 61 clinical, radiological and outcome measures. RESULTS: Most of the CSCs (74%) were founded at University Hospitals and most (65.2%) work round the clock. In 78.3% of them, the working teams are composed of neurologists and neuro-radiologists. All CSCs perform CT and angio-CT before MT. In total 586 patients were subjected to MT and data from 531 of them were analyzed. Mean time laps from stroke onset to groin puncture was 250±99min. 90.3% of the studied patients had MT within 6h from stroke onset; 59.3% of them were treated with IV rt-PA prior to MT; 15.1% had IA rt-PA during MT and 4.7% - emergent stenting of a large vessel. M1 of MCA was occluded in 47.8% of cases. The Solitaire device was used in 53% of cases. Successful recanalization (TICI2b-TICI3) was achieved in 64.6% of cases and 53.4% of patients did not experience hemorrhagic transformation. Clinical improvement on discharge was noticed in 53.7% of cases, futile recanalization - in 30.7%, mRS of 0-2 - in 31.4% and mRS of 6 in 22% of cases. CONCLUSION: Our results can help harmonize standards for MT in Poland according to international guidelines.

Effectiveness and safety of tapentadol prolonged release for severe, chronic low back pain with or without a neuropathic pain component: results of an open-label, phase 3b study.

OBJECTIVE: This open-label, phase 3b study evaluated the effectiveness and tolerability of tapentadol prolonged release and tapentadol immediate release (for acute pain episodes) for severe, chronic low back pain with or without a neuropathic pain component that was inadequately managed in patients taking World Health Organization (WHO) Step I or II analgesics or who were not regularly treated with analgesics. RESEARCH DESIGN AND METHODS: Average baseline pain intensity was greater than 5 (11-point numerical rating scale-3 [NRS-3; 3-day average pain intensity]) with WHO Step I or II analgesics and greater than 6 with no regular analgesic regimen. WHO Step II analgesics were discontinued before starting study treatment; WHO Step I analgesics or co-analgesics were continued at the same dose. Patients received tapentadol prolonged release (50-250 mg bid) during a 5-week titration and 7-week maintenance period. Tapentadol immediate release was permitted for acute pain episodes (tapentadol prolonged release and immediate release maximum combined dose, ≤500 mg/day). The painDETECT questionnaire was used to define subsets of patients based on the probability of a neuropathic pain component to their low back pain as 'negative', 'unclear', or 'positive'. CLINICAL TRIAL REGISTRATION: NCT00983385. MAIN OUTCOME MEASURE: The primary endpoint was the change from baseline to week 6 in average pain intensity (NRS-3), using the last observation carried forward to impute missing scores. RESULTS: In the painDETECT negative (n = 49) and unclear/positive (n = 126) subsets, respectively, mean (SD) changes in pain intensity from baseline to week 6 were -2.4 (2.18) and -3.0 (2.07; both p < 0.0001). Among patients who had not received prior WHO Step II treatment, lower doses of tapentadol prolonged release were generally required with increasing likelihood of a neuropathic pain component. Based on the painDETECT questionnaire and the Neuropathic Pain Symptom Inventory (NPSI), tapentadol prolonged release treatment was also associated with significant improvements in neuropathic pain symptoms, with decreases in the number of pain attacks and the duration of spontaneous pain in the last 24 hours in patients with low back pain with a neuropathic pain component (painDETECT unclear or positive score at baseline or screening). The most common treatment-emergent adverse events (incidence ≥10%, n = 176) were nausea, dizziness, headache, dry mouth, fatigue, constipation, diarrhea, nasopharyngitis, and somnolence. CONCLUSIONS: Tapentadol prolonged release was well tolerated and effective for managing severe, chronic low back pain with or without a neuropathic pain component.

Simvastatin displays an antioxidative effect by inhibiting an increase in the serum 8-isoprostane level in patients with acute ischemic stroke: brief report.

OBJECTIVES: Oxidative stress plays an important role in ischemic stroke pathophysiology. Some drugs are known to have a substantial influence on oxidative stress. In this study, we examined the antioxidant effect of simvastatin through its influence on patients' serum 8-isoprostane levels. METHODS: We measured serum 8-isoprostane levels in 67 patients with acute ischemic stroke treated and not treated with simvastatin within 5 days after stroke onset, in comparison with 20 normal controls. RESULTS: Stroke patients from both groups had significantly higher initial serum 8-isoprostane levels than the controls. The median value of serum 8-isoprostane level was significantly lower in the simvastatin-treated group after 5 days of treatment. CONCLUSIONS: The results confirm the contribution of oxidative stress to brain ischemia and suggest antioxidative properties of statins in the acute phase of ischemic stroke patients.

B-type natriuretic peptide as a marker of subclinical heart injury during mitoxantrone therapy in MS patients--preliminary study.

The aim of this study was to evaluate the plasma level changes of B-type natriuretic peptide (BNP), biochemical marker of heart failure, and echocardiographic parameters during mitoxantrone treatment in 22 multiple sclerosis (MS) patients (8 males, 14 females, mean age 37.1+/-6.6). Mitoxantrone (after mean cumulative dose of 58.0+/-7.0 mg/m(2)) did not alter left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), posterior wall thickness (PWT) and left ventricular end-diastolic volume (LVEDV). However, mean plasma level of BNP raised from 14.53+/-3.29 pg/ml at the baseline to 16.79+/-3.05 pg/ml and 18.83+/-4.90 pg/ml (P<0.01) after mean mitoxantrone dose of 30.7+/-5.9 mg/m(2) and 58.0+/-7.0 mg/m(2), respectively. These results strongly suggest subclinical myocardial dysfunction in mitoxantrone-treated group. We assume, that low-cost, repeated BNP measurements may be a good alternative for detection of early subtle myocardial injury in MS patients during routine mitoxantrone therapy.

Simvastatin inhibits the increase in serum tau protein levels in the acute phase of ischemic stroke.

Our goal was to analyze the effects of treatment with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (simvastatin, 40 mg/day) on serum S100BB and tau protein levels during the acute ischemic stroke (IS). Twenty four patients with IS were divided into two equal groups; treated and untreated with simvastatin. Blood was obtained four times during acute IS. Tau protein was noticed in six patients from treated group and in five patients from untreated group. The serum tau protein levels significantly increased on the 10th day only in patients untreated with simvastatin (p < 0.05). Simvastatin did not exert an effect on serum S100BB protein levels.

Simvastatin-induced prevention of the increase in TNF-alpha level in the acute phase of ischemic stroke.

Like other proinflammatory cytokines, TNF-alpha may play an important role in the development of central nervous system injury following ischemic stroke. The aim of this study was to evaluate the influence of early treatment with simvastatin, an HMG-CoA reductase inhibitor, on serum TNF-alpha level in acute ischemic stroke (AIS). Patients with AIS (n = 36) were randomly assigned to the two groups: Group I (n = 18) treated with simvastatin 40 mg/day within 24 h after the onset of stroke and Group II (n = 18) not treated with the statin. Blood samples were obtained on days 1, 3 and 7 after stroke onset. Serum TNF-alpha level was significantly elevated on day 3 after the stroke onset in comparison to day 1 only in the simvastatin-treated group (increase in median values by 16.2% [p = 0.028] and 6.1% within 3 days in Group II and I, respectively). These findings indicate that simvastatin given within 24 h after the onset of stroke could prevent the increase in serum TNF-alpha level within 3 days.

[Complement system--an effector of inflammatory reactions. Possibilities of complement regulation in ischaemic diseases]. / Uklad dopelniacza--efektor reakcji zapalnej. Mozliwosci regulacji aktywnosci dopelniacza w chorobach niedokrwiennych.

Activation of the complement system (C) is an important aspect of the immune reaction, and therefore also of inflammatory response. This review summarizes the known pathways for C activation, including the relatively recently described lectin pathway. We must remember that the complement, like the immune response itself, is a two-edge sword. One side is beneficial to the host, aiming to eliminate pathogens, either free or attached to cells. On the other side, overactivation of C may lead to the destruction of tissues, which is obviously harmful. Thus activation of C must be regulated at each stage of the cascade (early, intermittent, and final), and to this end, act specific inhibitors, which often exist as cellular receptors. A list of diseases in which the complement is over-activated was presented, together with a summary of the currently tested or in-use cascade inhibitors. The most dangerous conditions include ischaemias--heart infarct and brain ischaemia. The crucial point in inhibiting C is the possibility of reducing the area of infarct or ischaemia by fast and effective intervention, aiming to disrupt the cascade chain. It is known that excessive killing by C activation is amplified in ischemic tissue; but that the inhibitors may offer protection. One should be aware that many of these exciting studies are being carried out on animals. However, existing knowledge on the efficacy of C inhibitors should be considered jointly with the current use of statins in human therapy, which, among their pleiotropic actions, also lower the level of C activation.

[Does diabetes mellitus affect the course and prognosis of ischemic stroke?]. / Czy cukrzyca zmienia przebieg kliniczny i rokowanie w udarach niedokrwiennych mózgu?

Although diabetes is a well-known risk factor for ischemic stroke, its role in ischemic stroke outcome has not been clarified yet. Stroke subtypes according to the TOAST (Trial of Org 10172 in Acute Stroke Treatment) classification, history of hypertension, serum glucose levels, blood pressure and OCSP (Oxfordshire Community Stroke Project) clinical types of admission, the presence of infections and seizures in the acute phase of illness, duration of hospitalisation, early and in-hospital mortality in diabetics and non-diabetic stroke patients were studied. CT scans in both groups were analysed by the size, localisation and number of ischemic foci. Significant differences were found only as regards the history of hypertension, as well as glucose levels and blood pressure on admission. The incidence of arterial hypertension prior to ischemic stroke was higher in the diabetic group. These patients had significantly higher blood glucose, systolic and diastolic blood pressure level on admission than had the non-diabetic group. No differences were found between the two groups on any other analysed variables. Our observations suggest that diabetes has no effect on the course and outcome of ischemic stroke.

[Botulinum toxin A in the treatment of stiff man syndrome]. / Zastosowanie toksyny botulinowej typu A w leczeniu zespolu sztywnosci uogólnionej.

Stiff-Person Syndrome (SPS) is a very rare disorder characterised by progressive fluctuating muscle rigidity and episodic spasm. So far, only two reports have demonstrated a significant clinical improvement in the patients with SPS when muscle were injected with Botulinum Toxin A (BTA). We investigated the effectiveness of intramuscular injections of BTA in a patient with clinical, biochemical and electrophysiological evidence of SPS. A 41-year-old woman with coexisting epilepsy and insulin-dependent diabetes mellitus was hospitalised in our Department because of stiffness and paroxysmal spasm of trunk and proximal limbs muscles. Because of not sufficient results of the pharmacological treatment the injections of BTA into involved muscles were done. Clinical observations included measure of pain, frequency of spasm, well-being and selection's activities were performed at baseline and in 1, 2, 7, 11, 16, 20, weeks. Significant improvement started one week after injections and lasting about 4 months was observed. Using BTA injections into involved muscles for the treatment of SPS can be followed by marked functional improvement and reducing the need for systemic drugs.