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Byline: J. Wissel (1), P. Kanovsky (2), E. Ruzicka (3), M. Bares (2), H. Hortova (2), H. Streitova (2), R. Jech (3), J. Roth (3), C. Brenneis (1), J. Muller (1), P. Schnider (4), E. Auff (4), A. Richardson (5), W. Poewe (1) Keywords: Key words Botulinum toxin A; Cervical dystonia; Dose recommendation Abstract: Results from a dose-ranging study in a selected group of de novo patients with rotational cervical dystonia (CD) suggest that 500 units of Dysport (Clostridium botulinum toxin type A haemaglutinin complex) is the optimal starting dose. The present study aimed to confirm the efficacy and safety profile of this dose in a population of CD patients more representative of those seen in a typical dystonia clinic. A total of 68 patients with moderate to severe CD (Tsui score aY= 9) were randomly assigned to receive placebo or Dysport 500 units. Treatment was administered according to the clinical pattern of head deviation, using a standardised injection protocol. A total of 21 patients (11 Dysport, 10 placebo) had not previously received botulinum toxin type A (BtxA) injections, and 47 patients (24 Dysport, 23 placebo) had received BtxA more than 12 weeks previously. Assessments were performed at baseline and weeks 4, 8 and 16. Patients defined as non-responders at week 4 were re-treated in an open phase with 500 units of Dysport at week 6, and were followed up at week 10. Significant between-group differences in Tsui scores were present at weeks 4 (p=0.001) and 8 (p=0.002). Similarly, there were significant between-group differences (p &lt 0.001) in patient and investigator assessments of response in favour of Dysport at weeks 4 and 8. Also, more Dysport (49 %) than placebo (33 %) patients were pain-free at week 4 (p=0.02). Overall, 30/35 (86 %) Dysport patients and 14/33 (42 %) placebo patients were classified as responders at week 4. Adverse events were reported by 15/35 Dysport patients and 9/33 placebo patients. Open phase treatment produced improvements in Tsui (p &lt 0.001) and pain scores (p=0.011), and 23/24 patients were classified as responders. Although individual dose titration and muscle selection is desirable, this study demonstrated that a dose of 500 units of Dysport injected into clinically identified neck muscles without electromyographic guidance is safe and effective in the treatment of patients with the major clinical types of cervical dystonia. Author Affiliation: (1) Universitatsklinik fur Neurologie, Anichstr. 35, 6020 Innsbruck, Austria, Tel.: +43-5 12/5 04-38 50, Fax: +43-5 12/5 04-38 52, E-Mail: werner.poewe@uibk.ac.at, AT (2) Department of Neurology, Masaryk University, St. Anne's Hospital, Brno,Czech Republic, CZ (3) Department of Neurology, Charles University, Prague, Czech Republic, CZ (4) Universitatsklinik fur Neurologie, Vienna, Austria, AT (5) Ipsen Limited, Maidenhead, UK, GB Article note: Received: 3 October 2000, Received in revised form: 20 March 2001, Accepted: 2 May 2001

Byline: M. Naumann (1), B. Eberhardt (2), R. Laskawi (3), M. Porta (4), P. Schnider (5), P. Sostak (6), M. Lutze (7) Author Affiliation: (1) Department of Neurology, University of Wurzburg, Josef-Schneider-Str. 11, 97080, Wurzburg, Germany (2) Frankfurt, Germany (3) Gottingen, Germany (4) Zingonia-Bergamo, Italy (5) Hochegg, Austria (6) Munchen, Germany (7) Berlin, Germany Article History: Registration Date: 01/01/2004 Article note: This revised version was published online in December 2004. On the preceding contents--page the sequence of the authors had been initially given wrong. The publisher apologizes for the confusion.

Byline: T. Sycha (2), G. Kranz (2), E. Auff (2), P. Schnider (1) Keywords: evidence-based medicine; botulinum toxins; pain; cervical dystonia; chronic neck pain; cervicogenic headache; cluster headache; chronic paroxysmal hemicrania; temporomandibular disorder; trigeminal neuralgia Abstract: Abstract. Background: Botulinum neurotoxin (BoNT) is used to treat various neurological disorders associated with pathologically increased muscle tone. Botulinum toxin inhibits the release of the neurotransmitter acetylcholine at the neuromuscular junction thereby inhibiting striatal muscle contractions. Besides the reduction in muscle tone BoNT tends to reduce pain in pain syndromes associated with muscle spasm. In addition, BoNT has been proposed as an analgesic, suggesting alternative non-cholinergic mechanisms of action. Surprisingly, BoNT was reported as a potential treatment for tensiontype headache and migraine--both primary headache syndromes without an apparent muscular component--however, varying responses to BoNT have been found, overall without sufficient evidence for a general treatment. In this systematic review we set out to clarify the efficacy and safety of BoNT in the treatment of rare head and neck pain syndromes (e. g. cervicogenic headache, chronic paroxysmal hemicrania, cluster headache, trigeminal neuralgia, temporomandibular disorders, cervical dystonia and whiplash injuries). Objectives: To assess the analgesic efficacy and safety of botulinum toxins versus other medicines, placebo or no treatment in rare head and neck pain syndromes. Search strategy: We searched the bibliographic databases MEDLINE, EMBASE and PASCAL Biomed to May 2003. We also reviewed the reference lists from identified articles including reviews and meta-analyses of treatment studies. Furthermore we searched booklets of scientific congresses in the field of neurology for potentially relevant studies. Additional reports were identified from the reference list of the retrieved papers, and by contacting experts in the field. Selection criteria: Randomized controlled trials (RCTs) with any dose of BoNT for rare head and neck pain syndromes, describing subjective pain assessment as either the primary or a secondary outcome, were included in this review. Data collection and analysis: All trials were quality scored and two independent reviewers extracted data. Results were compared for differences, and discrepancies were resolved by discussion. Main results: Fourteen RCTs of BoNT in cervical dystonia were included in this review. All except one showed significant pain relief following BoNT treatment compared to placebo. Studies providing dichotomous outcome data were pooled using the Peto method. The overall effect was found to be highly significant (OR 4.795 [95% CI 5.551--6.473]). For cervicogenic headache, two RCTs--one positive study and one negative study--were included. Two studies addressing chronic neck pain were included in this review. Both studies did not reveal significant effects. Furthermore, one small trial (N = 15 patients) focussing BoNT in temporomandibular disorders was included,without demonstrating significant effectiveness but a high proportion of patients lost to follow-up and a high rate of adverse effects. For the use of BoNT in cluster headache, chronic paroxysmal hemicrania and trigeminal neuralgia no RCTs were identified. Adverse effects (AEs) were found to be mild to moderate and dose-dependent. They were summarized where possible, irrespective of the formulation used and condition treated (OR = 5.066 [95% CI 2.770--9.265], number-needed-to-harm (NNH) = 5.5 [range 4.4--17]). Reviewers' conclusions: There is convincing evidence for the effectiveness of BoNT in the treatment of pain associated with cervical dystonia. Due to the frequent adverse effects predominantly observed with higher doses, the trade off in risk and benefit should be carefully considered in each case. For all other rare head and neck pain syndromes we found no RCTs (cluster headache, chronic paroxysmal hemicrania, trigeminal neuralgia) and only a few small sized trials (cervicogenic headache, chronic neck pain, temporomandibular disorders). We were therefore unable to draw any definite conclusions. Author Affiliation: (1) Department of Neurology, Landeskrankenhaus Grimmenstein-Hochegg, Hocheggerstrasse 88, 2840, Grimmenstein-Hochegg, Austria (2) Department of Neurology, Division of Neurological Rehabilitation, University of Vienna, Austria Article History: Registration Date: 01/01/2004

Spastic drop foot can be managed by physical measures, local pharmacological agents, oral anti-spastic drugs and surgical procedures. Recent studies have documented the clear effect of botulinum toxin type A (BTX-A) in the treatment of the spastic drop foot, particularly by reducing the resistance against passive movement and increasing the range of motion. Functional benefit and pain reduction have also been observed. The use of BTX-A is safe and free of serious side effects. Individual realistic treatment goals must be defined by the rehabilitation team before the treatment. Possible purposes of the treatment are the achievement of a straight foot to allow weight bearing or application of an orthosis and to reduce the premature activation of the calf muscles during gait. Other treatment goals are the facilitation of nursing care, as well as physical and occupational therapy. BTX-A injections can reduce pain, and prevent pressure ulcers or surgical interventions. Early physiotherapy or occupational therapy may increase the treatment effect of BTX-A. Close cooperation between the neurologist, physiotherapist, occupational therapist, nursing staff and other multidisciplinary rehabilitation team members is essential to maximize the benefit for the patients.

Introduction: Botulinum A toxin (BTX-A) acts primarily at peripheral cholinergic synapses, inhibiting the release of acetylcholine. Initially it has been used to block the neuromuscular junction in focal dystonic and spastic syndromes. Recently there has been suggestions for potential clinical indications in non-muscular diseases where cholinergic terminals play a role., Gustatory Sweating: In 1995 physicians reported a long-lasting anhidrotic effect of intracutaneous BTX-A injections in patients suffering from gustatory sweating (Frey's syndrome). Consequently, a number of clinical studies demonstrated good efficacy of intradermal injections of botulinumtoxin in patients with focal hyperhidrosis., Focal Hyperhidrosis of the Palms and Axillae: Focal hyperhidrosis is usually confined to the palms and axillae. Excessive sweating may be a social handicap and an occupational hazard. The management of focal hyperhidrosis remains controversial. Topical antiperspirants are only effective in very mild cases. Iontophoresis with tap water or anticholinergic drugs is messy and time consuming with only short-lived effect. Sympathectomy, the cornerstone of surgical management, is usually effective in palmar hyperhidrosis. Complications of this technique include surgical risks, postoperative and cosmetic problems and compensatory hyperhidrosis., Axillary Hyperhidrosis: Several studies confirmed that intracutaneous injections of botulinum toxin are useful in the majority of patients with axillary hyperhidrosis resistant to conventional treatment. In axillary hyperhidrosis total doses are ranging from 200-400 mU Dysport or from 80 to 130 mU Botox to reach a good clinical response. Injections are usually well tolerated and no serious side-effects have been observed. The mean duration of anhidrotic effect ranges between 3 and 9 weeks., Palmar Hyperhidrosis: The use of botulinumtoxin in patients with palmar hyperhidrosis is rather difficult. The therapeutic window is smaller because injections are complicated by transient weakness of the small hand-muscles. Furthermore the injections at the palms are painful which can be overcomed by application of local anaesthetics or the blockade of the ulnar and median nerves. The duration of anhidrotic effect ranges from 20 to 50 weeks., Conclusion: Intracutaneous injections of botulinum-toxin should be offered to patients with focal hyperhidrosis of the palms and axillae causing serious social, psychologic and occupational problems, resistant to other conventional treatment options.

Local injection of botulinum toxin A (BTX) is considered as the treatment of choice for spasmodic torticollis (ST), blepharospasm (BS) and, with certain limitations, for hemifacial spasm (HFS). Long-term data from 89 patients with ST, 39 patients with BS and 15 patients with HFS were evaluated and subgroups of patients who received at least three (60 ST, 17 BS, 9 HFS), six (35 ST, 10 BS, 8 HFS) and nine (26 ST) re-injections were formed. These groups were investigated in regard of increases in the dosage of BTX and in regard of shorter treatment intervals in cases of repeated treatment. Annual drug costs were calculated from these data. Patients treated at least three times were asked to fill out a questionnaire concerning satisfaction and the quality of life after BTX treatment. Furthermore, the patients' "willingness to pay" for BTX treatment was investigated. Our calculations showed neither a significant increase in the dosage of BTX nor a significant reduction in the length of treatment intervals after 3 or 6 treatment sessions. Annual drug costs for BTX for the treatment of ST were 10,542 ATS, of BS 2847 ATS and of HFS 1029 ATS. 86.1% of patients with ST, 88.9% with BS and 100% with HFS were very satisfied or satisfied with the BTX treatment. In all 3 diagnostic groups, a significant mean improvement of quality of life was measured on a visual analogue scale (p < 0.001). We conclude that the injection of botulinum toxin A is a highly effective and cost effective treatment for ST, BS and HFS, and significantly increases the quality of life of all these patients.

The role of drug abuse as a risk factor for cerebrovascular events has been underestimated, particularly in patients with juvenile stroke. The drug most often associated with acute cerebrovascular events is cocaine. After cocaine hydrochloride abuse intracerebral hemorrhages or subarachnoid hemorrhages--predominantly caused by ruptured aneurysms or arteriovenous malformations--are by far the most frequently observed cerebrovascular complications, whereas on abuse with the alkaloidal form ("crack") intracranial hemorrhages and ischemic strokes are encountered with equal frequency. In most cases, the time interval between drug abuse and the cerebrovascular event is less than 3 hours. Several pathophysiological mechanisms are discussed as serving as triggers for the cerebrovascular event, either alone or in combination. No specific antidote to cocaine is known. Nevertheless drug screening (urine analysis) should be performed immediately to allow optimal management of patients with drug-associated acute cerebrovascular events, especially in cases with juvenile stroke.

The various forms of treatment (drugs as well as non-drug therapy) of patients suffering from tension type headache are presented. Analgesics and non-steroidal antirheumatics are used in the management of episodic tension type headache, as well as acute exacerbation of chronic tension type headache. In view of the presumably multifactorial pathogenesis, a multidimensional therapeutic approach is required in patients with chronic tension type headache. Antidepressive drugs (thymoleptics) are usually prescribed as basic therapy. Additional implementation of non-drug therapeutic measures tailored to individual symptomatology is advisable, such as EMG biofeedback, other relaxation techniques, massage, physiotherapy and--in selected cases--psychotherapy or acupuncture.

The highly potent neurotoxins produced by Clostridium botulinum lead to botulism when ingested in appreciable amounts. However, botulinum toxin injections delivered intramuscularly in very small quantities can produce a therapeutically intended focal paresis while producing only negligible local or systemic side effects. Over the past several years, various neurological disorders, especially those involving increased muscle tone and/or abnormal movements, have been successfully treated with local botulinum A toxin injections. The success of this method has led to a general change in the management of blepharospasm, torticollis spasmodicus, hemifacial spasm, and other disorders. Treatment is usually effective for 4 to 12 weeks; if symptoms recur, the injections can be repeated over a period of several years, usually with the same success. Side effects depend on the site of the injections, and are rare at the optimal dosage and always reversible. For optimum therapeutic results, this treatment must be restricted to specialized centers.

This study presents the history and clinical findings in 80 patients suffering from tension-type headache diagnosed according to the criteria (group 2) proposed in 1988 by the Headache Classification Committee of the International Headache Society (IHS). The aim of this investigation was to evaluate the extent to which the symptomatology in our cases still corresponds with the clinical picture of tension headache described in the older literature. A positive family history of headache was obtained in 59% of the patients; mothers of headache patients were affected five times more often than fathers; a history of migraine was reported as frequently as tension-type headache in the families of the investigated patients. The first manifestation of headaches arose almost exclusively in the first four decades of life, whereby two peaks (15-20 and 35-40 years) were observed in patients with the episodic form. Headache in younger patients showed no distinct diurnal pattern; headache in older patients, however, predominantly occurred immediately after awakening from sleep or in the morning. Changes of weather and psychosocial stress were the most frequent precipitating factors; additionally, the premenstrual period, occupational stress, and sleep deprivation were precipitating factors in female patients. Bilateral pain was most often located in the occipital/nuchal, in the frontal, and the periorbital regions. Headache was usually described as pressing/tightening in quality. Difficulties in concentration and the need of rest were the most important associated symptoms. Photophobia, phonophobia and autonomic symptoms were less frequent and are probably partially drug-related and may also be due to the fact that the selected group of patients suffered from severe forms of headache. 33 of our 80 patients belonged to the subgroup "with disorders of pericranial muscles" (IHS criteria: groups 2.1.1., 2.2.1). A remarkable low percentage of patients, especially of the male sufferers, reported regular smoking and/or drinking habits. Oral contraceptives influenced neither frequency nor intensity of headache attacks. Signs of depressive disorders were present in 28% of the female patients. The differences in symptomatology of tension-type headache between patients with episodic and chronic forms, between female and male patients, and also between younger and elderly patients are documented and have to be taken into account in the diagnostik evaluation of this condition.