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A 21-year old male presented with ataxia and dysarthria that had appeared over a period of months. Exome sequencing identified a de novo missense variant in ATP1A3, the gene encoding the α3 subunit of Na,K-ATPase. Several lines of evidence suggest that the variant is causative. ATP1A3 mutations can cause rapid-onset dystonia-parkinsonism (RDP) with a similar age and speed of onset, as well as severe diseases of infancy. The patient’s ATP1A3 p.Gly316Ser mutation was validated in the laboratory by the impaired ability of the expressed protein to support the growth of cultured cells. In a crystal structure of Na,K-ATPase, the mutated amino acid was directly apposed to a different amino acid mutated in RDP. Clinical evaluation showed that the patient had many characteristics of RDP, however he had minimal fixed dystonia, a defining symptom of RDP. Successive magnetic resonance imaging (MRI) revealed progressive cerebellar atrophy, explaining the ataxia. The absence of dystonia in the presence of other RDP symptoms corroborates other evidence that the cerebellum contributes importantly to dystonia pathophysiology. We discuss the possibility that a second de novo variant, in ubiquilin 4 (UBQLN4), a ubiquitin pathway component, contributed to the cerebellar neurodegenerative phenotype and differentiated the disease from other manifestations of ATP1A3 mutations. We also show that a homozygous variant in GPRIN1 (G protein-regulated inducer of neurite outgrowth 1) deletes a motif with multiple copies and is unlikely to be causative.

Objective Current botulinum toxin labeling indicates injections once every 12 weeks but few studies have assessed the treatment interval after repeated injections. In a recent double-blind (DB) study followed by an open-label (OL) extension abobotulinumtoxinA (aboBoNT-A, Dysport®) was efficacious and demonstrated a favourable safety profile in adult patients with upper limb spasticity (ULS) after single and repeated injections (Gracies et al. Lancet Neurol 2015; Brashear et al. Am Acad Neurol 2016). This additional analysis focuses on the retreatment intervals after repeated injections of aboBoNT-A. Material/Patients and methods Phase III, international, multicentre, DB, single-treatment study of aboBoNT-A in adults with ULS, followed by a long-term OL extension study with a maximum of 4 additional treatment cycles over a maximum of 18 months. Retreatment was per investigator's clinical judgment and possible at weeks 12, 16, 20, and 24. Results Among the subjects who received aboBoNT-A in the DB study and were treated in cycle 1 of the OL extension, 37% were re-injected at week 16 or later (17% at week 16, 10% at week 20, 10% at week 24 or later). For those who received a second cycle of treatment in the OL phase, 35% of subjects were re-injected at week 16 or later (20% at week 16, 7.0% at week 20, 8% at week 24 or later). For those who received a third cycle of treatment in the OL phase, 24% of subjects were re-injected at week 16 or later (19% were retreated at week 16, 3% at week 20, 2% at week 24 or later). Discussion/Conclusion These data show that 24% to 37% of subjects did not require reinjection before week 16 across multiple cycles. This long duration of clinical effect leads to longer intervals between injections, and thus may reduce the burden associated with frequency of injections for patients and their caregivers/families. This also highlights the needs for a tailored approach in the treatment of patients with ULS.

To evaluate the relationship between disability and both health-related quality of life (HRQoL) and caregiver burden in patients with upper limb poststroke spasticity.Multicenter open-label study.Thirty-five sites in North America.Patients (N = 279) with upper limb poststroke spasticity.Post hoc analyses of data from an open-label study were performed to estimate HRQoL and caregiver burden at study baseline across levels of disability in 4 problem domains: hygiene, dressing, limb posture, and pain. Disability severity in these areas was determined by using the 4-point Disability Assessment Scale rated by the physicians.HRQoL measured by the patient-reported EuroQol 5 Dimensions questionnaire and the Stroke-Adapted Sickness Impact Profile and caregiver burden.At study baseline, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale was associated with diminishing HRQoL scores (P.002) measured by the EuroQol 5 Dimensions. By using the Stroke-Adapted Sickness Impact Profile, greater disability scores in all problem domains were significantly associated with higher overall dysfunction scores (P ≤ .05). Within the physical dimension of the Stroke-Adapted Sickness Impact Profile, significant associations also were observed in all domains. At baseline, caregiver burden was significantly related to increasing levels of hygiene and dressing domain severity (P ≤ .05). Caregiver assistance requirement increased from approximately 9.0-28.2 hours per week in the hygiene domain and 3.3-32.1 hours per week in the dressing domain as disability increased from "none" to "severe."In patients with upper limb poststroke spasticity, increasing disability in the hygiene, dressing, and pain domains of the Disability Assessment Scale were associated with diminishing HRQoL. Furthermore, these patients required caregiver assistance proportionally related to the severity of their disability in the hygiene and dressing domains.

Introduction/Background Patients with chronic hemiparesis following stroke or traumatic brain injury (TBI) often experience restricted walking performance. Our previous double-blind (DB) trial of 388 patients demonstrated that abobotulinumtoxinA (aboBoNT-A) treatment improves muscle tone and functional outcomes in adults with lower limb spastic paresis. This sub-analysis from the open-label (OL) study extension phase assesses changes in walking speed (WS), step length (SL) and cadence in these patients. Material and method Phase 3, prospective, multicentre, double-blind (DB), randomised study (single injection of aboBoNT-A 1000U or 1500U or placebo; NCT01249404 ), followed by an OL study extension (≤ 4 cycles of aboBoNT-A 1000U or 1500U; NCT01251367 ). Participants were ambulatory adults with spastic hemiparesis causing gait dysfunction, comfortable barefoot WS 0.1–0.8 m/s in 10-metre WS test without walking aids, and stroke or TBI ≥ 6 months before study enrolment. Patients receiving either aboBoNT-A dose were assessed relative to DB baseline for WS, SL and cadence using 10-metre WS tests under different conditions (maximal and comfortable WS, barefoot and with shoes). Week 12 data are shown for the last treatment cycle with available data (cycle 3). Results Relative to baseline, improvements in WS, SL and cadence by OL Cycle 3 Week 12 were observed in all four categories ( Table 1 ). Mean percentage of improvements in WS were +19.7–23.6% across categories. Mean percentage improvements of +9.4–13.8% and +7.2–9.7% were observed for SL and cadence, respectively. The highest mean percentage improvements were at comfortable barefoot WS for WS and SL, and at maximal barefoot WS for cadence. The least improvements from DB baseline were observed with shoes compared with barefoot, across all categories. Conclusion Substantial improvements in WS, SL and cadence were achieved over time in hemiparetic adults with repeated administration of aboBoNT-A.

Introduction/Background Long-term safety and efficacy of repeated abobotulinumtoxinA (aboBoNT-A) injections in patients with upper limb spasticity (ULS) after stroke or traumatic brain injury have been described in an open-label study (Gracies et al. Muscle Nerve, 2018). Continuous improvements in active movements, and perceived and active function were reported, with no unexpected safety signals identified. Here, we describe the frequency of repeated aboBoNT-A injections over the open-label study. Material and method A phase 3, international, double-blind, single-treatment study ( NCT01313299 ) of aboBoNT-A in the hemiparetic upper limb, followed by a 12-month open-label extension study ( NCT01313312 ) with up to four additional treatment cycles, at least 12 weeks apart. Re-treatment was per investigator's clinical judgement, based on muscle tone, spasticity measures and other findings. Patients not requiring re-treatment completed the study. Results A total of 254 patients entered in open-label cycle 1 ( Table 1 ). In cycle 1, 14/254 patients withdrew and 240 completed the cycle. After cycle 1, 10 patients completed the study without subsequent aboBoNT-A injections. In cycle 2, 219/229 patients completed the cycle (10 withdrew) and 44 did not require subsequent injections. Of 175 patients entered cycle 3, six withdrew and 169 completed the cycle, 88 of whom did not require subsequent injections. Overall, 55.9% (n = 142) of patients required three or fewer injections of aboBoNT-A over the course of the 12-month study, 21.6% required two or fewer injections, and 3.9% required one injection. Conclusion Over half of the patients (55.9%) enrolled in this phase 3 study required three or fewer injections of aboBoNT-A over the course of a year, based on physician clinical assessment. This decreased injection frequency, with respect to usual practice, may reduce the burden associated with treatment for patients and their caregivers/families.

Allison BrashearDept of Neurology, Wake Forest University Baptist, Medical Center, Winston Salem, NC, USAAbstract: Dystonia is an involuntary movement involving twisting and turning of agonist and antagonist muscles. Cervical dystonia is isolated to neck musculature. Botulinum toxin type A is a safe and effective treatment of this disabling and often painful syndrome. Three forms of botulinum toxin type A are available worldwide to treat patients with cervical dystonia. This is a review of the studies of botulinum toxin type A to treat cervical dystonia.Keywords: dystonia, botulinum toxin type A, cervical dystonia

Treatment of spasticity requires a team approach, including the patient and caregivers, therapists, physicians, and surgeons. The team needs to determine what component of the spasticity interferes with function. Traditional therapy continues to dominate the therapy provided to patients who are living with spasticity. Treatment of increased tone must be part of the overall treatment plan for the patient. The plan may also include physical and occupational therapy, oral medication, injections of botulinum toxin, use of an intrathecal baclofen pump, or surgery. For patients with limited improvement from therapy, injections of botulinum toxin are often first-line treatment for focal spasticity involving overactive muscle groups. Botulinum toxin is safe when used at recommended doses and has limited side effects. The benefits of oral medications in patients with focal spasticity may be limited by adverse effects at higher doses. Refractory spasticity may be treated with intrathecal baclofen. Surgery is reserved for patients in whom the other modalities fail to provide meaningful improvement. Continued communication from all members of the team can assure the best spasticity management plan for the individual patient, but patients need to have realistic expectations about outcome.

While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) injection, these treatments have not been systematically compared.This study performed a randomised, double-blind, placebo-controlled trial to compare injection of BoNT-Type A into spastic upper limb muscles versus oral tizanidine (TZD), or placebo, in 60 subjects with upper-limb spasticity due to stroke or traumatic brain injury (TBI). Wrist flexors were systematically injected, while other upper limb muscles were injected as per investigator judgement. Participants were randomised into three groups: (1) intramuscular BoNT plus oral placebo; (2) oral TZD plus intramuscular placebo; (3) intramuscular placebo plus oral placebo. The primary outcome was the difference in change in wrist flexor modified Ashworth score (MAS) between groups. Other outcome measures included MAS at elbow and finger joints, Disability Assessment Scale (DAS) and adverse events (AE).BoNT produced greater tone reduction than TZD or placebo in finger and wrist flexors at week 3 (p0.001 vs TZD; p0.02 vs placebo) and 6 (p = 0.001 vs TZD; p = 0.08 vs placebo), and greater improvement in the cosmesis domain of the DAS at week 6 (p0.01). TZD was not superior to placebo in tone reduction at either time point (por=0.09). The incidence of AE related to study treatment was higher with TZD than in the BoNT (p0.01) or placebo groups (p = 0.001).BoNT is safer and more effective than TZD in reducing tone and disfigurement in upper-extremity spasticity, and may be considered as first-line therapy for this disorder.

The expanding uses of botulinum neurotoxin (BoNT) for a growing number of clinical indications, including cervical and other dystonias, adult and childhood spasticity, and hyperhidrosis, in conjunction with the emergence of new formulations of BoNT, prompt discussion of the differences in formulations, serotypes, and indications for different neurologic diseases.This review will evaluate evidence from preclinical studies, prospective treatment studies, and direct comparative trials to discuss the differences among BoNTs and the clinical implications of using these different drugs. Data from these sources indicate that formulations of BoNT are distinct; even the same serotype formulations of BoNT serotype A have different molecular structures and sizes and therapeutic indices (reflected in different safety and efficacy profiles).Taken together, these findings confirm that the different BoNT serotypes, including the different BoNTA formulations, are distinct therapeutic entities.

Rapid-onset dystonia-parkinsonism (RDP) (also known as DYT12) is characterized by the abrupt onset of dystonia and parkinsonism and is caused by mutations in the ATP1A3 gene. We obtained clinical data and sequenced the ATP1A3 gene in 49 subjects from 21 families referred with 'possible' RDP, and performed a genotype-phenotype analysis. Of the new families referred for study only 3 of 14 families (21%) demonstrated a mutation in the ATP1A3 gene, but no new mutations were identified beyond our earlier report of 6. Adding these to previously reported families, we found mutations in 36 individuals from 10 families including 4 de novo mutations and excluded mutations in 13 individuals from 11 families. The phenotype in mutation positive patients included abrupt onset of dystonia with features of parkinsonism, a rostrocaudal gradient, and prominent bulbar findings. Other features found in some mutation carriers included common reports of triggers, minimal or no tremor at onset, occasional mild limb dystonia before the primary onset, lack of response to dopaminergic medications, rare abrupt worsening of symptoms later in life, stabilization of symptoms within a month and minimal improvement overall. In comparing ATP1A3 mutation positive and negative patients, we found that tremor at onset of symptoms, a reversed rostrocaudal gradient, and significant limb pain exclude a diagnosis of RDP. A positive family history is not required. Genetic testing for the ATP1A3 gene is recommended when abrupt onset, rostrocaudal gradient and prominent bulbar findings are present.

Botulinum toxin type A (BoNT/A) is the principal therapy for patients with cervical dystonia. Repeated treatments over many years are required in most cases. This retrospective review evaluates the dose of BoNT/A used to treat cervical dystonia and the interval between treatments during a 2-year observation period. Outcomes data were abstracted from the medical records of 172 patients at 3 different sites who had received BoNT/A between January and December 1998. A total of 1059 treatments were assessed. Mean per-treatment doses throughout the 2-year study ranged from 241.80 to 254.07 units. The mean interval between treatments was 108.48 days during the first year of observation and 114.14 days during the second year. These findings indicate that doses of and intervals between BoNT/A treatments for cervical dystonia were consistent throughout 2 years of observation.

Childers MK, Brashear A, Jozefczyk P, Reding M, Alexander D, Good D, Walcott JM, Jenkins SW, Turkel C, Molloy PT. Dose-dependent response to intramuscular botulinum toxin type A for upper-limb spasticity in patients after a stroke. Arch Phys Med Rehabil 2004;85:1063–9. Objective To test the hypothesis that intramuscular (IM) botulinum toxin type A (BTX) reduces excessive muscle tone in a dose-dependent manner in the elbow, wrist, and fingers of patients who experience spasticity after a stroke. Design Randomized, double-blind, placebo-controlled, multicenter, 24-week trial. Setting Six academic and 13 private US outpatient medical centers. Participants Ninety-one patients with a mean age of 60 years (range, 30–79y). Mean time elapsed from ischemic or hemorrhagic stroke to study enrollment was 25.8 months (range, 0.9–226.9mo). Interventions Up to 2 treatments of placebo, or 90, 180, or 360U of BTX. Concurrent splinting and physical therapy protocols were permitted, but no changes were allowed during the study. Main outcome measures Wrist, elbow, and finger flexor tone assessed by the Modified Ashworth Scale, physician and patient global assessments, pain, FIM instrument, and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). Results Muscle tone decreased more with injections of BTX than with placebo in the wrist flexors at weeks 1, 2, 3, 6, and 9 ( P ≤.026); in the elbow flexors at weeks 1, 2, 3, 4, 5, and 9 ( P ≤.033); and in the finger flexors at weeks 1 and 3 ( P ≤.031). A dose-dependent response was generally observed in tone reduction but not in pain, FIM, or SF-36 measures. Conclusions IM BTX reduced muscle tone in a dose-dependent manner in the elbow, wrist, and fingers of patients who experience spasticity after a stroke but did not appear to affect global quality of life or disability.

ervical dystonia is an abnormal involuntary movement f the head and neck that is frequently associated with ain. Typically presenting in middle to late adulthood and sually with no identifiable cause, cervical dystonia (also eferred to in some texts as “spasmodic torticolli”) often esults in permanent disability caused by a decreased ange of motion, involuntary movements, and pain in the eck and head muscles. The prevalence of cervical dysonia has been estimated to be 9 per 100,000, but this stimate is thought to be conservative because it is based n a retrospective chart review. In the United States, The ystonia Medical Research Foundation estimates that 50,000 people suffer from cervical dystonia; however, it is uspected that many more are undiagnosed and/or unreated. The discovery of botulinum toxin produced by Clostridum botulinum as a localized injectable treatment to relax veractive muscles is one of the interventional neuroloist’s most potent tools in treating dystonia. The introuction of botulinum toxin type A in 1989 in the United tates has dramatically improved the ability of physicians o treat dystonic movements of the head and neck. The ddition of botulinum toxin type B as an alternative treatent, particularly in those patients who develop resisance to type A, has further expanded the resources availble to treat this disabling disease. The bacteria Clostridium botulinum produces 7 immunoogically distinct serotypes, but only serotype A, B, nd F have been used in clinical practice. There are 2 orms of botulinum toxin type A (BTX-A)—BOTOX (Alergan, Irvine, CA), available worldwide, and Dysport Ipsen), available outside of the United States. Serotype B s available as botulinum toxin type B (BTX-B; formulated s MyoblocTM in the United States and NeuroBloc elsehere), and serotype F (BTX-F) is available only on a imited basis in Japan. Each of the 7 toxins is synthesized as a single-chain olypeptide with a molecular weight of 150 kDa. The isulfide bond holding the heavy chain and light chain ogether must be cleaved and the light chain internalized nto the cytosol by the process of chemodenervation. Chemical denervation is a 3-step process. First, after njection into the target muscle, the heavy chain of the oxin recognizes a specific receptor on the presynaptic erve terminal in the neuromuscular junction. Second, the oxin is internalized by endocytosis and translocated to the ytosol of the presynaptic nerve terminal. Third, the light

Brashear A, McAfee AL, Kuhn ER, Fyffe J. Botulinum toxin type B in upper-limb poststroke spasticity: a double-blind, placebo-controlled trial. Arch Phys Med Rehabil 2004;85:705-9. Objective To determine whether botulinum toxin type B (BTX-B) is effective in controlling upper-limb spasticity. Design A single-site, double-blind, placebo-controlled, randomized trial and open-label study. Setting Outpatient. Participants Subjects with an Ashworth Scale score of 2 or more at the elbow, wrist, and fingers. Interventions Subjects were injected with 10,000U of BTX-B or placebo at the elbow, wrist, and finger flexors. Main outcome measures Measures recorded at weeks 0, 2, 4, 8, 12, and 16, with a 12-week open-label study. Ashworth Scale score, a global assessment of change (GAC), adverse events and mouse neutralization antibody testing. Results BTX-B did not decrease muscle tone in the elbow, wrist, or finger flexors at 10,000U over the 16-week period. A decrease in Ashworth Scale score for the BTX-B patient group was present at the wrist at week 2 of the double-blind study ( P =.003) but was not statistically significant at other visits. In the open-label study, improvement was noted at week 4 for the elbow ( P =.039), wrist ( P =.002), finger ( P =.001), and thumb flexors ( P =.002). In the double-blind study, the Physician GAC did not reach significance. Dry mouth was reported by 8 of 9 BTX-B subjects in the double-blind study. Mouse neutralization antibodies were negative. Conclusions Our study does not show a significant decrease in tone from 10,000U of BTX-B. Dry mouth was common.

Brashear A, Zafonte R, Corcoran M, Galvez-Jimenez N, Gracies J-M, Gordon MF, Mcafee A, Ruffing K, Thompson B, Williams M, Lee C-H, Turkel C. Inter- and intrarater reliability of the Ashworth Scale and the Disability Assessment Scale in patients with upper-limb poststroke spasticity. Arch Phys Med Rehabil 2002;83:1349-54. Objective: To evaluate the reliability of the Ashworth Scale and the Disability Assessment Scale (DAS) in poststroke patients with upper-limb spasticity and functional disability. Design: Single-center trial. Setting: University medical center. Participants: Nine patients ≥6 months poststroke with upper-limb spasticity and impairment in the areas of hygiene, dressing, limb posture, or pain were included in the analysis. Interventions: Ten experienced medical professionals rated each patient in randomized order twice on the same day (results based on mean of evaluations at times 1 and 2). Elbow, wrist, finger, and thumb flexion tones were assessed by using the Ashworth score (range, 0–4), and functional disability was assessed using the DAS (range, 0–3). Main Outcome Measures: Intra- and interrater reliability of the Ashworth Scale and DAS. Results: For the Ashworth parameters, 38 of 40 evaluations indicated excellent (weighted κ≥.75) or good (weighted κ≥.4) intrarater reliability. For DAS parameters, 31 of 40 evaluations indicated excellent or good intrarater reliability. The interrater reliability was also good for both the Ashworth Scale (Kendall W=.598–.792) and DAS (Kendall W=.494–.772) with statistically significant agreement found among raters (all P .001). Conclusions: In patients with upper-limb spasticity after stroke, the Ashworth Scale and DAS had good intra- and interrater reliability when used by trained medical professions. © 2002 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation

Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injections of botulinum toxin type A reduce disability in persons with spasticity of the wrist and fingers after a stroke.We performed a randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of one-time injections of botulinum toxin A (200 to 240 units) in 126 subjects with increased flexor tone in the wrist and fingers after a stroke. The primary outcome measure was self-reported disability in four areas: personal hygiene, dressing, pain, and limb position (on a four-point scale ranging from no disability to severe disability) at six weeks; at base line, each subject selected one of these areas in which there was moderate-to-severe disability as the principal target of treatment.Subjects who received botulinum toxin A had greater improvement in flexor tone in the wrist and fingers at all follow-up visits through 12 weeks than did subjects who received placebo (P0.001 for all comparisons). Subjects treated with botulinum toxin A had greater improvement in the principal target of treatment at weeks 4, 6, 8, and 12 (P0.001, P0.001, P=0.03, and P=0.02, respectively); at week 6, 40 of the 64 subjects in the botulinum-toxin group (62 percent), as compared with 17 of the 62 in the placebo group (27 percent), reported improvement of at least one point on the Disability Assessment Scale in the principal target of treatment (P0.001). There were no major adverse events associated with injection of botulinum toxin A.Intramuscular injections of botulinum toxin A reduce spasticity of the wrist and finger muscles and associated disability in patients who have had a stroke.

Objective There are limited data on improvements of active limb movement and function following treatment with botulinum toxin in chronic spastic paresis. We report the effect of repeated injections of abobotulinumtoxinA (aboBoNT-A) on these parameters from two Phase III multicenter open-label (OL) trials in adults with spasticity post-stroke/traumatic brain injury; one trial in upper limb spasticity, the other in lower limb spasticity. These are extensions to respective double-blind studies (DB) in which adults received a single aboBoNT-A injection (Gracies et al. Lancet Neurol 2015; Esquenazi et al. AAPM&R 2016). Material/Patients and methods Subjects (18–78 years) received aboBoNT-A (500 to 1500U) over a year (injections ≥ 12 weeks apart) in their affected limb. Active movement was assessed by active range of motion (XA) against elbow, wrist and finger flexors or active ankle dorsiflexion. Active function was assessed by Modified Frenchay Scale (MFS) (upper limb) or the 10-meter walking speed test (lower limb). Results for cycle 4 week 4 of the OL phase are presented. Results Eighty-one subjects received 5 injections in their UL and 139 subjects in their LL. XA improved in the upper limb across injection cycles, with active finger extension (most frequently injected muscle group) increasing by a mean (SD) of +38.0 (53.4)°. The overall increase in MFS was +0.40 (0.75), an improvement that was more pronounced with 1500U (500U in shoulder muscles): +0.62 (0.48) vs. +0.30 (0.83) for 1000U. Active ankle dorsiflexion improved by +6.5(10.9)° with knee extended. Comfortable walking speed improved by +0.088 (0.144) (mean increase of 25% from baseline of DB phase). Discussion/Conclusion Improvement in active movement and function in subjects with chronic upper or lower limb spasticity was observed following repeat injections of aboBoNT-A over a year. A more pronounced efficacy with 1500U versus 1000U aboBoNT-A for active function in the upper limb may suggest the importance of shoulder muscle injections.

Rapid-onset dystonia parkinsonism (RDP) is a rare disorder characterized by abrupt onset of dystonia and parkinsonism. The condition is the result of mutations in ATP1A3. Careful characterization of neurological manifestations associated with ATP1A3 mutations, which can cause RDP and alternating hemiplegia of childhood (AHC), is important to understand how specific mutations can lead to different presentations. This case of RDP is notable because (1) the patient harbored an ATP1A3 variant at the c.2267G>A site, resulting in a nonsynonymous p.R756H mutation, which has not been reported in typical adolescent-onset RDP, and (2) reports of Asian cases are very rare and this is the first patient of pure Chinese descent. Our patient, of pure Southern Chinese ancestry, was previously healthy until 9 May 2002 (at the age of 10 years), when she became clumsy. This was preceded by a self-limited febrile episode a week earlier. The next day, she had dysarthria, drooling, unsteady gait, and poor handwriting. This progressed over 10 days to a state of being unable to speak, swallow, or walk. She was recognized to have a severe dystonic syndrome when assessed by a pediatric neurologist 3 weeks later. By this time, she had made some recovery and was able to walk with assistance and swallow. Investigations were unremarkable, including routine blood tests, cerebrospinal fluid analysis, brain MRI, and EEG. Slit-lamp examination was negative for Kayser-Fleischer rings. She was diagnosed with postviral encephalitis and given levodopa/carbidopa (100/25 mg, 2 tablets three times daily [TID]), but this was ineffective. The patient was first assessed at the University of Malaya, Kuala Lumpur, in August 2011, at age 19. She had made gains in functional activities (e.g., no longer falling frequently and able to type fairly quickly on a computer). She was eating a normal diet without choking episodes. The patient was a top scorer in her school examinations, and there were no psychiatric manifestations. There was no relevant family history and no parental consanguinity. Her parents were also examined by us and confirmed to be neurologically intact. Examination revealed facial grimacing and jaw-opening dystonia, especially when speaking, severely slurred speech, and antecollis. There was severe and generalized nonpainful dystonia affecting all limbs and the trunk. Her movements were slow, but this was considered to probably be a result of the severe dystonia and there were no other parkinsonian features, such as rigidity or tremor (limb tone at rest was, in fact, reduced; these findings were confirmed by S.-Y.L. and A.E.L.). There was no ataxia, upper motor neuron signs, or abnormalities of eye movements or hearing. The patient’s DNA was analyzed for ATP1A3 mutations, and she was found to have a mutation in exon 17 at cDNA position c.2267G>A (NM_152296.4), resulting in a p.R756H amino acid substitution (NP_689509; laboratory of L.J.O.). Neither of the patient’s parents had this mutation. DNA profiling was performed using short tandem repeat (STR) analysis at 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA) by an accredited national forensics laboratory; this confirmed that the patient was the biological child of the parents in question. Benzhexol 2 mg TID subjectively reduced limb stiffness and improved speech, but caused sleepiness and dizziness and was stopped. Her condition has remained stable (see accompanying Video 1 from November 2013), with a Burke-Fahn-Marsden Dystonia Rating Scale Movement Scale score of 67, a Disability Scale score of 13; an RDP Severity Scale score of 4; and the following UPDRS scores (largely felt to be a result of the severe dystonia; see Video 1): Total of 55.5, Parts I of 0, II of 16, III of 38.5, and IV of 1; and Montreal Cognitive Assessment score of 29/30. To our knowledge, the ATP1A3 p.R756H mutation has not been reported in typical adolescent-onset RDP. This mutation

Background: Clinical trials have established the efficacy and safety of botulinum toxin type A (BTX-A) in patients with cervical dystonia. To maintain the clinical benefits of BTX-A, injections need to be repeated whenever patients' symptoms begin to recur. Objective: The purpose of this study was to determine, in clinical practice settings, the mean duration of effect of BTX-A in the treatment of adult patients with cervical dystonia. Methods: A retrospective chart review was undertaken at an academic center and a private neurology practice. At each site, ≥50 patients being treated for cervical dystonia were identified and randomized for chart review. Patients had to have received the first assessable injection of BTX-A between January 1, 1998, and March 31, 1998, to coincide with the clinical availability of the most current formulation of the neurotoxin. A chart was eligible for review if the patient was aged ≥18 years, had a documented diagnosis of idiopathic cervical dystonia, was being treated with BTX-A, and had been under the continuous care of investigators from January 1, 1998, to August 31, 1999. Of the 102 patients initially identified, the first 30 from each site who met the study inclusion criteria were assessed for (1) age and sex; (2) severity of dystonia; (3) years of BTX-A use; (4) dates of first, second, third, and fourth BTX-A injections; (5) drug dose; (6) use of electromyography; (7) use of other prescribed therapies; (8) laboratory tests; and (9) adverse events. The mean interval between each visit and mean per-patient duration of effect were calculated and stratified by patient characteristics. Results: The mean age of the patients was 56.4 years. Two thirds of the patients were women. Forty-one of the 60 patients (68.3%) had either moderate or severe disease, and 48 (80.0%) had experienced cervical dystonia for >5 years. The mean per-patient duration of effect across the 4 visits was 15.5 weeks (range, 12.2–24.3 weeks). The duration of effect did not differ significantly between study sites despite the differences in disease severity, drug dose, and use of adjunctive therapy. Conclusion: BTX-A controls the symptoms of cervical dystonia for 12 to 24 weeks, with a mean duration of effect per patient of 15.5 weeks.

Rapid-onset dystonia-parkinsonism (RPD) is an autosomal dominant movement disorder characterized by sudden onset of persistent dystonia and parkinsonism, generally during adolescence or early adulthood. Symptoms evolve over hours or days, and generally stabilize within a few weeks, with slow or no progression. Other features include little or no response to L-dopa, and low levels of homovanillic acid in the central nervous system. Neuroimaging studies indicate no degeneration of dopaminergic nerve terminals in RDP, suggesting that this disorder results from a functional deficit, as in dystonia, rather than neuronal loss, as in Parkinson's disease. We studied 81 members of two midwestern US families with RDP, 16 of whom exhibited classic features of RDP. We found significant evidence for linkage in these two families to markers on chromosome 19q13, with the highest multipoint LOD score at D19S198 (z = 5.77 at theta = 0.0). The flanking markers D19S587 and D19S900 define a candidate region of approximately 8 cM. Although RDP itself is a rare condition, it is important because it has clinical and biochemical similarities to both Parkinson's disease and dystonia. Identification of the genetic defect in RDP holds promise for understanding the underlying disease processes of both of these more common diseases.

BACKGROUND Rapid-onset dystonia-parkinsonism (RDP) is a genetic movement disorder characterized by abrupt onset over hours to days of bradykinesia, postural instability, dysphagia, dysarthria, and severe dystonic spasms with decreased levels of the dopamine metabolite, homovanillic acid (HVA), in cerebrospinal fluid (CSF). METHODS We imaged the dopamine re-uptake system with [O-methyl-11C]β-CFT ([11C]β-CFT) in three severely affected individuals with RDP and four patients with idiopathic Parkinson's disease (IPD). Results were compared with those of age-matched normal volunteers. RESULTS Positron emission tomography images from those patients with IPD demonstrated a dramatic reduction in the volume of distribution of [11C]β-CFT whereas patients with RDP showed slightly elevated values. CONCLUSIONS The data suggest that patients with RDP do not have a decrease in the number of dopamine re-uptake sites. Our findings suggest that, unlike the situation in IPD, low CSF HVA concentrations seen in RDP patients are not the result of degeneration of striatal dopamine terminals or loss of dopamine re-uptake sites.

The determination of the safety of a patient with dementia who continues to drive is a difficult task for the physician who cares for geriatric patients. This study used the Traffic Sign Recognition Test (TSRT) discrimination between dementia patients who continue to drive and normal elderly volunteers. Thirty-seven subjects with dementia who continue to drive and 47 normal elderly volunteers were recruited to participate in the study. Each group was tested with the TSRT similar to that used for licensing in the state of Indiana. The difference in total number of signs correctly identified between the two groups was determined using the Wilcoxon Rank Sum Test. The difference between groups of each individual sign recognition was determined using a Chi Square test. The affected group was also tested with a neuropsychological battery (NB) designed to measure skills thought to be needed for driving. Drivers with dementia correctly identified 5.95 (± 2.17) of the 10 traffic signs used in licensing as compared to the normal elderly volunteers who correctly identified 8.77 (± 1.58) total signs (p < 0.0001). The “Slow Moving Vehicle” sign provided the largest difference between the two groups; demented drivers correctly identified the sign 39 percent of the time, compared with 89 percent in the normal volunteers (X2= 15.333, df= 1, p < 0.005). Only 76 percent of the demented drivers correctly identified a “Stop” sign compared with 98 percent of the normal elderly drivers. The percentage of correctly identified signs on the TSRT also correlated with several tests in the NB. Drivers with dementia who continue to drive perform worse on traffic sign recognition than normal elderly drivers. While our current screening tool did not assess the driving safety of either group, it suggests that demented patients who still drive may not recognize common traffic signs and may thus pose a risk to society.

To compare clinical parameters of patients treated with botulinum toxin type A (BTX) for treatment of idiopathic cervical dystonia (ICD) and for tardive cervical dystonia (TCD), we studied 156 patients (149 with ICD and 7 with TCD) who were treated with serial injections of BTX over 5 years. We hypothesized that patients with TCD and ICD would demonstrate similar improvement in severity scores after treatment with BTX. The diagnosis, dates, dosages, and frequency of BTX injected and severity assessments were recorded into a computerized database. Nonparametric Wilcoxon rank sum and signed-rank tests were used to assess statistical significance. The change in severity scores between the first treatment and last treatment in both groups was not statistically significant (p = 0.4859), indicating similar improvement. The difference in BTX doses was significant (p = 0.0045). ICD patients (n = 149) received an average of 219.8 +/- 63.5 units and those with TCD (n = 7) were treated with an average dose of 287.4 +/- 60.3 units. The average number of days between treatments for individuals with ICD was 142.9 +/- 85.8, similar to that for persons with TCD (144.7 +/- 64.5) (p = 0.6075). Our analysis provides preliminary evidence that the improvement from the administration of BTX for patients with ICD and TCD is similar.

In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity of botulinum toxin type B (BTX-B) and correlated the clinical response with the presence of blocking antibodies (Abs) using a novel mouse protection assay. One-third of the patients who were negative for BTX-B Abs at baseline became positive for BTX-B Abs at last visit. Thus, the high antigenicity of BTX-B limits its long-term efficacy.

Rapid-onset dystonia-parkinsonism (RDP) occurs in children older than 18 months of age, teens, and adults, and alternating hemiplegia of childhood (AHC) occurs in children younger than 18 months. They appear to be different diseases, but both are caused by mutations in ATP1A3 .1–4 ATP1A3 encodes the α subunit of the Na+/K+-ATPase that is partially responsible for maintaining the electrical gradient in neurons. Motor symptoms, particularly dystonia, are obvious in both RDP and AHC, but RDP is predominantly fixed and AHC is known for its episodic and fluctuating course. There is now a broader phenotypic spectrum of RDP than originally described in 1993,5,6 including psychosis,7 new phenotypes in children,8 and late onset.9 The nonmotor phenotypes of both RDP (cognitive and psychiatric) and AHC (developmental delay, cognitive, and behavioral)10,11 suggest that ATP1A3 mutations may play a role in other neurologic and psychiatric disorders. Mutations causing RDP or AHC cause symptoms such as dystonia, parkinsonism, epilepsy (including status epilepticus), hemiplegic episodes, abnormal ocular movements, developmental delay, psychosis, depression, anxiety, and gait disorders in ages ranging from newborns to 87 years. It is likely that there will be a broad continuum of patients found, and even a role for the gene in polygenic disorders.

Botulinum toxin (BTX) has become a safe and effective therapeutic tool in the treatment of a variety of neurological disorders, especially dystonias. One major disadvantage, however, is the high cost of a single injection of BTX. In this study of 835 patients, we calculated the cost of treatment with BTX serotype A (BTX-A) for different dystonias and hemifacial spasm. The annual expenditure per patient for BTX-A injections in this cohort totalled (mean +/- standard deviation) 1030 Deutschmarks (DM) [1996 values] +/- DM610 [$US570 +/- $US340; 230 +/- 130 pounds sterling (Pound)] for blepharospasm (n = 158), DM1450 +/- DM1520 ($US800 +/- $US830; 310 Pounds +/- 280 Pounds) for craniocervical dystonia (n = 148), and DM1480 +/- DM780 ($US810 +/- $US430; 330 Pounds +/- 180 Pounds) for oromandibular dystonia (n = 16), while the treatment of cervical dystonia consumed DM4590 +/- DM2060 ($US2520 +/- $US1130; 960 Pounds +/- 420 Pounds) [n = 362] per patient. In order to alleviate symptoms in patients with hemifacial spasm (n = 151), DM510 +/- DM270 ($US280 +/- $US150; 110 Pounds +/- 60 Pounds) had to be spent annually. The expenses for surgical therapy for cervical dystonia were DM10,120 +/- DM1900 (n = 54). No major differences concerning expenditure could be found in this study between the 2 available preparations of BTX. However, there appeared to be a lower rate of adverse effects with the Botox formulation, compared with the Dysport formulation, of BTX-A (this difference was statistically significant, i.e. p < 0.001). Although the cost of an individual injection is high, other cost factors also substantially contribute to the societal costs of adult-onset dystonias. Some of these costs may be attenuated with the use of BTX. The subjective and objective relief of these socially devastating and sometimes painful conditions rewards the expenditure associated with the use of BTX-A.

Rapid-onset dystonia-parkinsonism (RDP), first described in a large Midwestern family, is now reported in a second, apparently unrelated, family in which four individuals have this same syndrome. All four developed sudden onset of dysarthria, dysphagia, severe dystonic spasms, bradykinesia, and postural instability over less than 1 hour to a few days. Three of the four had stable limb dystonia for several years preceding the onset of combined dystonia-parkinsonism. Treatment with levodopa/carbidopa provided little benefit. We propose diagnostic criteria for RDP and further define the spectrum of this unusual disease.

Dystonia is a rare neurologic disorder of the basal ganglia presenting with involuntary twisting or turning spasm of muscles. Movements localized to the face, eyes, or neck generally present during late adulthood. Cranial dystonia is usually idiopathic but may be caused by trauma or medications. Of 148 patients with focal dystonia referred to Indiana University over four years, four women had the onset of face and neck symptoms eight days to 34 months after completing treatment with chemotherapy alone or combined with radiation therapy. Two patients were treated with 5-FU, one received doxorubicin and one was treated with both. Both drugs have been associated with transient parkinsonism, but no chemotherapeutic medications have been reported to cause dystonia. Three patients remain free of demonstrable malignancy. A possible association of chemotherapy and focal dystonia has not been previously described.

Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder characterized by the rapid onset of dystonic spasms and parkinsonism over a period of a few hours to weeks after their onset. We have seen two additional members of this previously reported family with RDP who present with a more gradual progression of their disorder over 6-18 months. One of these individuals experienced the rapid progression of symptoms 2 years after an initial stabilization of his condition. The RDP phenotype is variable, and presentation may be gradual in some cases. Cerebrospinal fluid neurotransmitter levels in these two and other family members suggest involvement of the dopaminergic pathways in RDP.

Peroneal and tibial compound motor action potentials (CMAP) recorded using the standard belly-tendon montage have different configurations. The peroneal CMAP is a smooth dome shape, while the tibial CMAP has a slow-rising initial component followed by a higher amplitude negative peak. To evaluate possible causes of these differences we investigated the individual activity recordable at the belly and tendon electrodes by using a referential montage with the opposite foot as the reference. This type recording shows that the peroneal belly site produces most of the nerve CMAP, whereas the tendon site generates most of the high tibial CMAP. Some features and technical problems of referential CMAP recording using an opposite limb reference are shown. An alternative method using an ipsilateral distal leg reference site is described. A montage which separately records the activity at the belly or tendon electrodes may provide new insight into mechanisms of commonly observed nerve conduction phenomena.

The authors evaluated the long-term efficacy and safety of botulinum toxin type A (BTX-A) in poststroke spasticity patients who completed a 12-week placebo-controlled study and received multiple open-label treatments with 200 to 240 U BTX-A for 42 weeks. Significant and sustained improvements were observed for Disability Assessment and Ashworth scores. Adverse events were generally mild. This extension of a double-blind study demonstrates that repeated treatments of BTX-A significantly improve function and tone in spasticity.