Markus Naumann

Assessment: Botulinum neurotoxin in the treatment of autonomic disorders and pain (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Objective: To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of autonomic and urologic disorders and low back and head pain. Methods: A literature search was performed including MEDLINE and Current Contents for therapeutic articles relevant to BoNT and the selected indications. Authors reviewed, abstracted, and classified articles based on the quality of the study (Class I–IV). Conclusions and recommendations were developed based on the highest level of evidence and put into current clinical context. Results: The highest quality literature available for the respective indications was as follows: axillary hyperhidrosis (two Class I studies); palmar hyperhidrosis (two Class II studies); drooling (four Class II studies); gustatory sweating (five Class III studies); neurogenic detrusor overactivity (two Class I studies); sphincter detrusor dyssynergia in spinal cord injury (two Class II studies); chronic low back pain (one Class II study); episodic migraine (two Class I and two Class II studies); chronic daily headache (four Class II studies); and chronic tension-type headache (two Class I studies). Recommendations: Botulinum neurotoxin (BoNT) should be offered as a treatment option for the treatment of axillary hyperhidrosis and detrusor overactivity (Level A), should be considered for palmar hyperhidrosis, drooling, and detrusor sphincter dyssynergia after spinal cord injury (Level B), and may be considered for gustatory sweating and low back pain (Level C). BoNT is probably ineffective in episodic migraine and chronic tension-type headache (Level B). There is presently no consistent or strong evidence to permit drawing conclusions on the efficacy of BoNT in chronic daily headache (mainly transformed migraine) (Level U). While clinicians’ practice may suggest stronger recommendations in some of these indications, evidence-based conclusions are limited by the availability of data.

Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial

BACKGROUNDnSevere forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial.nnnMETHODSnIn the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259).nnnFINDINGSnAn intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae.nnnINTERPRETATIONn3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia.nnnFUNDINGnMedtronic.

Long-term treatment with botulinum toxin type A in cervical dystonia has low immunogenicity by mouse protection assay†

To evaluate the immunogenicity of botulinum toxin type A (BoNTA; BOTOX) in cervical dystonia (CD). Subjects diagnosed with CD for ≥1 year and previously naïve to BoNTs were treated with BoNTA in a prospective, open‐label, multicenter study. Serum samples were analyzed for BoNTA neutralizing antibodies using the Mouse Protection Assay (MPA). Clinical resistance was assessed with a test injection of 20 U BoNTA placed unilaterally into the frontalis (Frontalis Antibody Test; FTAT) or corrugator muscle (Unilateral Brow Injection; UBI). Efficacy was assessed and adverse events were recorded. Of 326 subjects enrolled, 251 (77%) completed the study. Subjects received a median of 9 BoNTA treatments (mean dose per session ranged from 148.4 to 213.0 U over a mean of 2.5 years [range: 3.2 months–4.2 years]). Only 4 of 326 subjects (1.2%) tested positive for antibodies in the MPA; three of these subjects stopped responding clinically to BoNTA (of whom one also showed clinical resistance in the FTAT) and one continued to respond. Consistent improvements in the signs/symptoms of CD were noted. The most frequent treatment‐related adverse events were mild to moderate weakness, dysphagia, neck pain, and injection‐site pain. The current formulation of BoNTA rarely causes neutralizing antibody formation in CD subjects treated ≤4 years.

Meta-analysis of neutralizing antibody conversion with onabotulinumtoxinA (BOTOX®) across multiple indications.

This meta‐analysis evaluated the frequency of neutralizing antibody (nAb) conversion with onabotulinumtoxinA (BOTOX®; Allergan) across five studied indications. The analysis was based on large, controlled or prospective, open‐label trials (durations 4 months to ≥2 years). Serum samples were analyzed for nAbs using the Mouse Protection Assay. Subjects who were antibody negative at baseline and had at least one analyzable postbaseline antibody assay result were included. The 16 clinical studies included 3,006 subjects; of these, 2,240 met the inclusion criteria for this analysis. Subjects received 1–15 treatments (mean 3.8 treatments) with onabotulinumtoxinA. Total doses per treatment cycle ranged from 10 or 20 units in glabellar lines to 20–500 units in cervical dystonia. The numbers of subjects who converted from an antibody‐negative status at baseline to antibody‐positive status at any post‐treatment time point were: cervical dystonia 4/312 (1.28%), glabellar lines 2/718 (0.28%), overactive bladder 0/22 (0%), post‐stroke spasticity 1/317 (0.32%), and primary axillary hyperhidrosis 4/871 (0.46%). Across all indications, 11/2,240 subjects (0.49%) converted from antibody negative at baseline to positive at one or more post‐treatment time points, but only three subjects became clinically unresponsive to onabotulinumtoxinA at some point following a positive assay. Based on these large trials, the frequency of antibody conversion after onabotulinumtoxinA treatment is very low, and infrequently leads to loss of efficacy.

Primary Focal Hyperhidrosis: Disease Characteristics and Functional Impairment

Background: There are few published data on the clinical characteristics of hyperhidrosis. Objective: To describe the functional impairment caused by primary focal hyperhidrosis. Methods: Patients with hyperhidrosis (n = 345) were enrolled at the Department of Dermatology, University of Würzburg. Controls (n = 154) were a convenience sample of subjects without hyperhidrosis. Hyperhidrosis characteristics, health-related quality of life and functional impairment were assessed. Results: Patients with axillary hyperhidrosis reported a later age at onset and a higher prevalence of a family history of hyperhidrosis than patients with palmar hyperhidrosis. Sixty-three percent of patients reported occupational impairment related to hyperhidrosis. Hyperhidrosis patients reported emotional and physical impairment, with a greater proportion of the axillary group reporting impairment. More than 50% of patients reported moderate to extreme impairment in personal relationships and in social situations. Conclusion: Primary focal hyperhidrosis is a serious medical condition, affecting work productivity, daily activities, emotional well-being and personal relationships.

Immunogenicity of botulinum toxins

Botulinum neurotoxins are formulated biologic pharmaceuticals used therapeutically to treat a wide variety of chronic conditions, with varying governmental approvals by country. Some of these disorders include cervical dystonia, post-stroke spasticity, blepharospasm, migraine, and hyperhidrosis. Botulinum neurotoxins also have varying governmental approvals for cosmetic applications. As botulinum neurotoxin therapy is often continued over many years, some patients may develop detectable antibodies that may or may not affect their biological activity. Although botulinum neurotoxins are considered “lower risk” biologics since antibodies that may develop are not likely to cross react with endogenous proteins, it is possible that patients may lose their therapeutic response. Various factors impact the immunogenicity of botulinum neurotoxins, including product-related factors such as the manufacturing process, the antigenic protein load, and the presence of accessory proteins, as well as treatment-related factors such as the overall toxin dose, booster injections, and prior vaccination or exposure. Detection of antibodies by laboratory tests does not necessarily predict the clinical success or failure of treatment. Overall, botulinum neurotoxin type A products exhibit low clinically detectable levels of antibodies when compared with other approved biologic products. This review provides an overview of all current botulinum neurotoxin products available commercially, with respect to the development of neutralizing antibodies and clinical response.

Transdermal rotigotine for the perioperative management of Parkinson’s disease

Continuous delivery of antiparkinsonian medication during a perioperative period is desirable to avoid ‘off’-symptom complications in surgical patients with concomitant Parkinson’s disease (PD). Fourteen PD patients undergoing surgery under general anesthesia were switched from oral dopaminergic medication to transdermally delivered 24-h rotigotine (median dose 12xa0mg/24xa0h) for the perioperative period. Rotigotine treatment was considered feasible by patients, their anesthesiologists and neurologists with good control of PD symptoms and easy switching and re-switching of PD medication.

Listeria Meningitis Complicating Alemtuzumab Treatment in Multiple Sclerosis—Report of Two Cases

Alemtuzumab, a humanized monoclonal antibody targeting the surface molecule CD52, leads to a rapid depletion of immune cells in the innate and adaptive immune system. In phase 2 and 3 trials in multiple sclerosis (MS), infections have been reported more frequently in alemtuzumab than in interferon beta treated patients. Here we report two patients treated with alemtuzumab for MS developing Listeria meningitis few days after the first infusion cycle. Both patients recovered completely after prompt diagnosis and adequate treatment. Physicians and patients should be aware of this serious, but treatable complication.

Bilateral loss of cortical SSEP responses is compatible with good outcome after cardiac arrest

Global cerebral ischemia (GCI) following cardiac arrest (CA) is often associated with a poor prognosis and longterm disorders of consciousness. Bilateral absence of cortical responses of the median nerve somatosensory evoked potentials (SSEP) is believed to predict poor outcome with almost 100 % specificity [1–4]. We report a case of a patient with good outcome despite repeatedly absent cortical SSEP responses and without hypothermia. A 16-year-old student suffered CA while playing soccer. Cardiopulmonary resuscitation began within 3 min. Initial rhythm analysis showed ventricular fibrillation (VF, Fig. 1a). Both pupils were dilated and unresponsive to light. After 25 min of resuscitation, stable cardiac output was reestablished and he was admitted to an intensive care unit. Despite the lack of sedative drugs, he was comatose. The GCS motor score was three and pupils were reactive to light. Because of aspiration pneumonia, the patient was ventilated and sedation was started with propofol, midazolam, and fentanyl for 48 h. Hypothermia was not induced, because this was only optional for children according to the 2005 European resuscitation council guidelines [5]. Neurological assessment after 72 h (with no sedation for the last 24) revealed a GCS of 5 (E1V1M3). At this time, median nerve SSEP were conducted in a specialized neurophysiology lab ([3000 recordings/year). N20 cortical responses were bilaterally absent (Fig. 1b). The EEG showed severe encephalopathy. Serum markers for neuronal damage were not examined. A brain CT scan after 96 h showed slight brain edema and obscuration of the caudate nucleus head (Fig. 1c). Based on the lack of arousal and the unfavourable SSEP results, the parents were informed about the diagnosis of severe GCI and the nearly inevitable poor prognosis. Because of a myoclonic status of the diaphragm, he was treated with repeated single doses of barbiturates and muscle relaxants on days 4–7. Sedation was discontinued on day 7, but again the patient failed to recover consciousness. On day 9, SSEP were repeated and again showed no signs of cortical N20 responses. He was extubated on day 12. On day 27, he was transferred to a specialized neurorehabilitation center in the minimally conscious state. He remained in inpatient rehabilitation for 7 months with constant improvement of neurological function. He was able to leave the rehabilitation facility on foot together with his mother (Fig. 1d). 3 years after cardiac arrest, the patient now lives at home with his parents (Barthel index 90/100 points). He rates his quality of life as 65 % (EuroQol, ranging from 0 to 100 %). Dysarthria and fine motor control problems are his biggest limitations on participation in life. A mutation in the SCN5A-gene was A. Bender (&) K. Howell M. Frey Department of Neurology, Therapiezentrum Burgau, Dr.-Friedl-Str. 1, 89331 Burgau, Germany e-mail: andreas.bender@med.uni-muenchen.de

Evidence-based review and assessment of botulinum neurotoxin for the treatment of urologic conditions

Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain urologic conditions, including detrusor sphincter dyssynergia (DSD), lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), and detrusor overactivity (both neurogenic [NDO] and idiopathic [IDO]), an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for autonomic disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, for the serotypes BoNT-A and BoNT-B, as well as for the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations on the use of BoNT for the management of these urologic conditions based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of DSD, the evidence supported a Level B recommendation for the use of A/Ona; A/Abo, A/Inco, and B/Rima received a Level U recommendation. For the treatment of NDO, there was sufficient clinical evidence to support a Level A recommendation for BoNT-A as well as for both A/Ona and A/Abo; no published data were identified for either A/Inco or B/Rima (Level U). For the treatment of IDO, the evidence supported a Level A recommendation for A/Ona; A/Inco, A/Abo, and B/Rima received a Level U recommendation. For the management of BPH, the evidence supported a Level B recommendation for BoNT and A/Ona; no published studies were identified for A/Abo, A/Inco, or B/Rima, warranting a Level U recommendation for these three formulations. Further studies are needed to evaluate the efficacy and safety of BoNT for the management of urologic conditions.