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Parkinson's disease (PD) is a chronic progressive movement disorder with severe reduction in patients' health-related quality of life (HR-QoL). Motor and cognitive symptoms are especially linked with decreased PD patients' HR-QoL. However, the relationship of these symptoms to caregiver burden is relatively unclear. Influence of the Montreal Cognitive Assessment scale (MoCA) as a cognitive screening tool and Movement Disorders Society Unified Parkinson's disease Rating Scale MDS-UPDRS symptoms in relation to patients' HR-QoL and caregivers' burden was analyzed. PD patients (n = 124) completed MDS-UPDRS, MoCA, and the PD questionnaire 8 (PDQ-8) as a measure of quality of life. Caregivers (n = 78) were assessed by the PD caregiver burden inventory (PDCB). PDQ-8 and PDCB scores were regressed on MDS-UPDRS subscales and MoCA subscores. PDQ-8 correlated with attention (R2 0.1282; p < 0.001) and executive (R2 0.0882; p 0.001) MoCA subscores and all parts of the MDS-UPDRS. PDCB correlated most strongly with MDS-UPDRS part III motor symptoms (R2 0.2070; p < 0.001) and the MoCA attention subscore (R2 0.1815; p < 0.001). While all facets of PD symptoms assessed by the MDS-UPDRS relate to PD patients' quality of life, motor symptoms are the most relevant factor for the prediction of caregiver burden. In addition, patients' attentional symptoms seem to affect not only them, but also their caregivers. These findings show the potential of a detailed analysis of MDS-UPDRS and MoCA performance in PD patients. [ABSTRACT FROM AUTHOR]

Background and purpose Conventional scales measure the effect of botulinum toxin ( BT) therapy only at specific points in time. The Dystonia Discomfort Scale ( DDS), a novel, easy-to-use, self-assessment scale to record temporal profiles of the effect of BT therapy in cervical dystonia ( CD), is introduced and evaluated against the Toronto Western Spasmodic Torticollis Rating Scale ( TWSTRS). Methods Seventy-six patients with CD (age 54.4 ± 10.9 years, 34% male) receiving ≤5 cycles of incobotulinumtoxinA (Xeomin®; Merz Pharmaceuticals, Frankfurt am Main, Germany) injections at intervals ≥10 weeks used DDS to record the severity of their symptoms daily. DDS data were compared with TWSTRS-Total scores and patients' subjective estimation ( SE) of the onset ( TO) and waning ( TW) of the treatment effect. Results The Toronto Western Spasmodic Torticollis Rating Scale − Total scores correlated significantly with DDS ( P ≤ 0.028 at all visits evaluated). TO- DDS and TO- SE were 7.9 ± 8.6 and 7.1 ± 4.1 days, respectively; TW- DDS and TW- SE were 41.8 ± 19.2 and 45.1 ± 21.5 days, respectively. Conclusion The Dystonia Discomfort Scale is a novel, easy-to-use, self-assessment scale for valid and sensitive monitoring of the temporal profile of the effect of BT therapy in patients with CD. DDS provides important additional information about onset, duration, waning, stability and reproducibility of the effects of BT therapy. [ABSTRACT FROM AUTHOR]

Background and purpose Abnormalities of the lenticular nucleus ( LN) on transcranial sonography ( TCS) are a characteristic finding in idiopathic segmental and generalized dystonia. Our intention was to study whether TCS detects basal ganglia abnormalities also in spasmodic dysphonia, an extremely focal form of dystonia. Methods Transcranial sonography of basal ganglia, substantia nigra and ventricles was performed in 14 patients with spasmodic dysphonia (10 women, four men; disease duration 16.5 ± 6.1 years) and 14 age- and sex-matched healthy controls in an investigator-blinded setting. Results Lenticular nucleus hyperechogenicity was found in 12 spasmodic dysphonia patients but only in one healthy individual (Fisher's exact test, P < 0.001) whilst other TCS findings did not differ. The area of LN hyperechogenic lesions quantified on digitized image analysis correlated with spasmodic dysphonia severity (Spearman test, r = 0.82, P < 0.001). Conclusion Our findings link the underlying pathology of spasmodic dysphonia to that of more widespread forms of dystonia. [ABSTRACT FROM AUTHOR]

In 2005, incobotulinumtoxinA (Xeomin®), a new botulinum toxin (BT) type A drug without complexing proteins (CPs), became available. This paper reviews the specific features of Xeomin® and the experience gathered with it during the last 5 years. Compared with conventional BT drugs, Xeomin®'s extended shelf live and its simplified temperature restrictions indicate that CPs are not necessary for BT drug stability. Its reduced molecular size does not translate into diffusion differences, and its potency labelling is identical to that of onabotulinumtoxinA (Botox®). With a reduced content of inactivated botulinum neurotoxin, Xeomin® should have reduced antigenicity. Lack of CP's may further reduce antigenicity. Xeomin®'s therapeutic efficacy against cervical dystonia, blepharospasm and spasticity has been proven in large randomised, double-blind and placebo-controlled studies leading to registrations in many countries. Additional successful clinical use in axillary hyperhidrosis, hemifacial spasm, re-innervation synkinesias and hypersalivation as well as in dystonia and spasticity in extended doses and throughout extended observation periods has been documented meanwhile. Lack of reported cases of antibody-induced therapy failure (ABF), as to date, support the hypothesis of an improved antigenicity. [ABSTRACT FROM AUTHOR]

Dystonia may produce co-contractions and constant strain in numerous muscle fibers, including those of the muscle spindles. As proprioceptors, muscle spindles detect dynamic or static changes in muscle length and their afferent projections to the spinal cord play a central role in control of antagonistic muscles. Their parallel arrangement with extrafusal muscle fibers and association with the earlier recruited oxidative motor units allow them to conveniently sample the activity of all motor units and effectively modulate movement. At the same time, fusimotor muscle spindle innervation contracts the striated polar portions of the intrafusal muscle fibers and prevents their slackening during extrafusal muscle contractions. Botulinum toxin remains the most efficient therapy of dystonia. Its muscular mechanism of action is hinged on cholinergic blockade not only of extrafusal, but also of intrafusal muscle fibers. Besides being a targeted muscular therapy, the alteration of the corresponding sensory input following an effect of botulinum toxin on the intrafusal muscle fibers is pivotal in modulating loss of pre-synaptic inhibition in dystonia, including suppression of the tonic vibration reflex. Whether or not trans-synaptic botulinum toxin migration occurs, a modification of the central motor programming is bound to happen in dystonia, with botulinum toxin acting either as another ‘sensory trick’ or as a form of ‘short-term plasticity’. Knowledge of the muscle spindle anatomy and function is key to unify our understanding of abnormal movements and of effects of botulinum toxin therapy. Thus, in dystonia, overactivity of muscles and increased spindle sensitivity are germane to botulinum toxin targets of action. [ABSTRACT FROM AUTHOR]

Botulinum toxin (BT) is used in various medical specialties. However, dystonia is still one of the most important indications for BT therapy. BT drugs consist of botulinum neurotoxin, complexing proteins and excipients. Botox®, Dysport® and Xeomin® are BT type A drugs and produce similar therapeutic and adverse effects (AE). Neurobloc®/MyoBloc® is based upon BT type B. Its use is limited by substantial systemic anticholinergic AE. The potency of BT drugs may be compared as follows: Botox®:Xeomin®:Dysport®:Neuobloc®/MyoBloc® = 1:1:3:40. BT selectively blocks the cholinergic innervation of striate and smooth muscles and exocrine glands. It can produce obligate, local and systemic AE. However, its overall AE profile including long-term safety is excellent. BT can be blocked by antibodies. Risk factors include single doses, interinjection intervals and the immunological quality of the BT drug applied. Planning of BT therapy is based upon target muscle identification and estimation of their dystonic involvement. For planning of BT therapy and BT placement, electromyography and imaging techniques may be used additionally. So far, total Xeomin® and Botox® doses of up to 840 MU have been used without clinically detectable systemic AE. BT can be used to treat focal dystonias including cranial, pharyngolaryngeal, cervical and limb dystonias. In segmental and generalized dystonias, BT therapy has to be focussed on the most relevant target muscles. Combinations with all other treatment options including deep brain stimulation are possible. Recent safety data and availability of immunologically improved BT drugs are now allowing higher BT doses thus expanding the use of BT into more widespread dystonias. [ABSTRACT FROM AUTHOR]

Background and purpose: Based upon large and carefully performed studies Xeomin® was first registered in 2005. However, its real potential can only be assessed, when it is used outside of study design restrictions, in an independent setting, in off-label indications and during continued use. Methods and results: Two hundred and sixty-three patients (91 with dystonia, 84 with spasticity, 17 with hemifacial spasm and re-innervation synkinesias, 64 with hyperhidrosis, 7 with hypersalivation), who were previously treated with Botox® for at least 1 year under stable conditions, were converted in a blinded fashion to Xeomin® using a 1:1 conversion ratio and identical treatment parameters. Therapeutic outcome and adverse effects were monitored by neurological examination and structuralised interviews. In 223 patients (all except those with axillary hyperhidrosis) Xeomin® was used continuously throughout a 3 year period. Altogether 1050 injection series were performed. Patients with dystonia received 261.5 ± 141.0 MU Botox®/Xeomin®, patients with spasticity 450.5 ± 177.1 MU, patients with hemifacial spasm and reinnervation synkinesias 44.7 ± 19.5 MU and patients with hyperhidrosis 286.9 ± 141.6 MU. The maximum botulinum toxin dose applied was 840 MU. There were no subjective or objective differences between Botox® and Xeomin® treatments with respect to onset latency, maximum and duration of their therapeutic effects and their adverse effect profiles. Long-term use did not reveal additional safety relevant aspects. None of the patients lost therapeutic efficacy during the observation period. Conclusions: Xeomin® can be used safely in doses of up to 840 MU. Even when applied in high doses it did not produce secondary therapy failure. There were no diffusion differences between Botox® and Xeomin®. Using a conversion ratio of 1:1 Xeomin® and Botox® can easily be exchanged in a continued treatment. [ABSTRACT FROM AUTHOR]

Urinary dysfunction is very common in idiopathic Parkinson's disease (PD) and manifests primarily with symptoms of overactive bladder (OAB). Affection of central serotonergic systems has been suggested to play a role in OAB. The objective of this study was to evaluate whether in PD patients with OAB symptoms a specific alteration of the brainstem raphe (BR), which contains serotonergic neurons, can be detected with transcranial sonography (TCS). Of 116 PD patients enrolled, 19 had PD-related OAB symptoms (OAB+) unlike remaining 97 patients (OAB−). Patients were examined by a sonographer blinded to the clinical data. Reduced echogenicity of BR was found in 12 (63%) OAB+ patients but only in 18 (19%) of 93 assessable OAB− patients (Mann–Whitney U-test, P < 0.001). In OAB+ patients, lower raphe echogenicity score was associated with longer duration of OAB symptoms (anova, P = 0.033). Other TCS findings such as echogenicity of substantia nigra, thalami, lenticular and caudate nuclei, and widths of third and lateral ventricles did not differ between OAB+ and OAB− patients. TCS findings suggest a pathogenetic role of BR in OAB related to PD. Alterations may reflect disturbance of its central serotonergic system. [ABSTRACT FROM AUTHOR]

The pathophysiology and management of writer's cramp is one of the most challenging amongst the various forms of focal dystonias. Frequently, the dystonic postures are confounded by compensatory muscle activity. Correct identification of target muscles for botulinum toxin (BT) injections determines the treatment success. The dosages of different preparations vary, with 1 unit of Botox® roughly equalling 3.5 units of Dysport®. Electromyographic guided injections yield better results and may also decrease the amount of toxin required. Weakness of target muscles interfering with other non-writing activities is a frequently encountered adverse effect. Studies have shown that BT is a safe long-term therapy option. [ABSTRACT FROM AUTHOR]

Different types of botulinum neurotoxin (BoNT) block different proteins of the soluble N-ethylmaleimide sensitive factor attachment protein receptor (SNARE) protein complex within cholinergic nerve terminals, producing blockade of cholinergic neuromuscular and autonomic synapses. Animal studies indicate the longest duration of action for BoNT type A (BoNTA) followed by types B, F, and E. Diffusion to adjacent and remote muscles may be related to protein composition, dilutions, volume, target muscle selection, and injection technique. A review of head-to-head, randomized, controlled trials of BoNTA preparations (Botox® and Dysport®) suggests that Dysport® tends to have higher efficacy, longer duration, and higher frequency of adverse effects. Conversion factors between the preparations varied, however, and remain controversial. In clinical settings, a Botox®:Dysport® conversion ratio of 1:3 may be appropriate. Animal studies suggest a conversion ratio of 1:2.5–3. When therapeutic effects between these preparations are attempting to be equalized, Dysport® seems to produce more adverse effects. In mice, Botox® appears to have a better safety margin than Dysport® and BoNTB. In rats, diffusion margins are similar for Botox® and Dysport®. Jitter derived from stimulation single-fiber EMG of injected and remote muscles show no differences between Botox® and Dysport®. Atrophy of extrafusal muscle fibers of injected and remote muscles do not differ between the BoNTA preparations. [ABSTRACT FROM AUTHOR]

Hemifacial spasm (HFS) is characterized by involuntary irregular clonic or tonic movements of the muscles innervated by cranial nerve VII on one side of the face, and is most often a result of vascular compression of the facial nerve at the root exit zone ( Muscle and Nerve 1998; 21:1740). Disability associated with this disorder ranges from social embarrassment to interference with vision resulting from involuntary eye closure. Treatment of HFS most often involves botulinum toxin injections, but may also include medications and surgery. We describe treatment with the three types of botulinum toxin currently commercially available – Botox®, Dysport® and Myobloc®/NeuroBloc®. [ABSTRACT FROM AUTHOR]

Tacrolimus (FK506, Prograf), marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation, is virtually completely metabolized. The major metabolic pathways are P450 3A4-mediated hydroxylation and demethylation. Since P450 hepatic drug-metabolizing enzymes may be impaired in hepatic dysfunction, a study was conducted to characterize oral and intravenous tacrolimus pharmacokinetics in 6 patients with mild hepatic dysfunction and compared with parameters to those from normal subjects obtained in a separate study. Patients received two treatments: a single 0.020 mg/kg ideal body weight (IBW) i.v. dose infused over 4 hours and approximately 0.12 mg/kg IBW orally; normal subjects were dosed at 0.02 mg/kg 4-hour i.v. and 5 mg (0.065 mg/kg) p.o. Mean blood pharmacokinetic parameters with mild hepatic dysfunction were as follows: clearance = 0.035 L/h/kg, terminal exponential volume of distribution = 2.59 L/kg, terminal exponential half-life = 60.6 hours (i.v.), p.o. maximum blood concentration = 48.2 ng/mL, time of p.o. maximum blood concentration = 1.5 hours, and absolute bioavailability = 22.3%. The respective parameters in normal subjects were as follows: 0.040 L/h/kg, 1.91 L/kg, 34.2 hours (i.v.), 29.7 ng/mL, 1.6 hours, and 17.8%. Inasmuch as clearance and bioavailability were not substantially different from that in normal subjects, patients with mild hepatic impairment may initially be treated with conventional tacrolimus doses, with subsequent dosage adjustments based on response, toxicity, and therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Tacrolimus (FK506, Prograf) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. This study investigated the effect of timing of a standardized breakfast meal on both the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol used a randomized, open-label, four-period, four-treatment, four-sequence crossover design in 16 healthy, nonsmoking, drug-free male subjects between the ages of 22 and 45 years who were within 15% of their ideal body weight. The four treatments were the following: (A) fasting for 10 hours, (B) ingestion 1 hour before breakfast, (C) ingestion immediately following consumption of the breakfast, and (D) ingestion 1.5 hours after beginning consumption of the breakfast. The breakfast, which was consumed over 15 minutes, contained 848 kcal, with 30%, 16%, and 54% of calories derived from fat, protein, and carbohydrate, respectively. Tacrolimus absorption in the fasting state provided the greatest relative bioavailability (p < 0.05 compared with all other three treatments). AUC(0-infinity)) averaged 312, 276, 205, and 203 ng x h/mL for treatments A, B, C and D, respectively. In contradistinction to taking the drug 1 hour prior to a meal, which had a relatively minor impact on the relative extent of absorption (approximately 12%) compared to the fasting state, ingestion of tacrolimus immediately after a meal (treatment C) or 1.5 hours subsequent to a meal (treatment D) had a more pronounced influence. Mean AUC(0-infinity) ratios (fasting to either postmeal treatments) were approximately 1.5, indicating that absorption extent was considerably reduced by ingesting tacrolimus capsules immediately after eating or 1.5 hours thereafter. Absorption was also prolonged following drug ingestion after a meal, as indicated by a mean tmax value in the fasting state of 1.84 hours, relative to 3.41 hours (immediately aftermeal, p = 0.0035) and 3.22 hours (1.5 hours postmeal, p = 0.0094). The only discernable difference in parameters between treatments C and D was with Cmax, with values of 7.19 and 9.04 ng/mL, respectively, but was not statistically significantly different (p = 0.231). Based on these results and those from a prior study, it is recommended that under therapeutic conditions, oral tacrolimus be administered in a consistent manner, both with respect to the type of meal as well as timing of ingestion relative to consumption of the meal. [ABSTRACT FROM AUTHOR]

Tacrolimus (FK506, Prograf) is a macrolide lactone antibiotic widely used by the oral route for the prophylaxis of organ rejection in patients who have received allogenic liver or kidney transplants. This study investigated the influence of a high- versus a low-fat meal, relative to the fasting state (three treatments total), on the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol employed a three-period, randomized, crossover design employing 5 x 1 mg capsules in 15 healthy male nonsmoking, drug-free volunteers, 20 to 45 years of age, who were within 15% of their ideal body weight. Food had a clinically significant effect in reducing relative bioavailability, as well as slowing absorption, but did not affect terminal exponential half-life (approximately 34 hours). Mean maximum tacrolimus blood concentration (Cmax) values were 25.6, 5.88, and 9.03 ng/mL for the fasting, high-fat, and low-fat treatments, respectively; mean area under the blood concentration-time curve (AUC(0-infinity) values were 272, 181, and 201 (ng/mL)-h, respectively; and mean time of Cmax (tmax) values were 1.37, 6.47, and 3.20 hours, respectively. Differences in parameters between the fasting and each fed treatment were statistically significantly different (p < 0.05). Statistically significant differences also existed in tmax between the two meals. Results also indicated the safety of single 5 mg oral tacrolimus doses administered to healthy volunteers. [ABSTRACT FROM AUTHOR]

Examines the effect of botulinum toxin (BT) on cervical dystonia. Identification of dystonic muscles between clinical examination and the electromyographic evaluation; Measurement of the amplitudes of dystonic and maximal voluntary activities in sternocleidomastoid; Impact of BT on antibody formation.

A foreword to "European Journal of Neurology" is presented.