Botulinum toxin (BoNT) is highly effective in the treatment of cervical dystonia (CD), yet a significant proportion of patients report low levels of satisfaction following treatment and fail to follow up for repeated treatments. The goal of this study was to determine the reasons that some patients have unsatisfactory responses. A total of 35 subjects who came to our center requesting alternative treatments due to unsatisfactory responses following BoNT treatment for CD were evaluated. Included were 26 women and 9 men with an average age of 57.1 years (range 25–82 years), and an average duration of illness of 12.5 years (range 1–55 years). Details of unsatisfactory BoNT treatments were methodically collected by a movement specialist using a standardized intake form, including provider subspecialty, product used, the number of satisfactory or unsatisfactory trials, doses given, specific muscles treated, the use of electromyographic guidance, side effects, and tests of resistance. The specialist then provided repeat treatments if indicated, and followed each case until the reasons for unsatisfactory outcomes could be determined. Multiple reasons for unsatisfactory outcomes were found. They included suboptimal BoNT doses, suboptimal muscle targeting, intolerable side effects, complex movement patterns, discordant perceptions, and incorrect diagnoses. Only one patient was functionally resistant to BoNT. Of 32 subjects who received repeat BoNT treatments, 25 (78 %) achieved satisfactory responses after revision of the original treatment plan. These results indicate that the majority of unsatisfactory responses to BoNT treatment of CD were caused by correctible factors and imply a need for improved education regarding optimal treatment methods.

Cervical dystonia (CD) is a neurological disorder characterized by abnormal movements and postures of the head. The brain regions responsible for these abnormal movements are not well understood, because most imaging techniques for assessing regional brain activity cannot be used when the head is moving. Recently, we mapped brain activation in healthy individuals using functional magnetic resonance imaging during isometric head rotation, when muscle contractions occur without actual head movements. In the current study, we used the same methods to explore the neural substrates for head movements in subjects with CD who had predominantly rotational abnormalities (torticollis). Isometric wrist extension was examined for comparison. Electromyography of neck and hand muscles ensured compliance with tasks during scanning, and any head motion was measured and corrected. Data were analyzed in three steps. First, we conducted within-group analyses to examine task-related activation patterns separately in subjects with CD and in healthy controls. Next, we directly compared task-related activation patterns between participants with CD and controls. Finally, considering that the abnormal head movements in CD occur in a consistently patterned direction for each individual, we conducted exploratory analyses that involved normalizing data according to the direction of rotational CD. The between-group comparisons failed to reveal any significant differences, but the normalization procedure in subjects with CD revealed that isometric head rotation in the direction of dystonic head rotation was associated with more activation in the ipsilateral anterior cerebellum, whereas isometric head rotation in the opposite direction was associated with more activity in sensorimotor cortex. These findings suggest that the cerebellum contributes to abnormal head rotation in CD, whereas regions in the cerebral cortex are involved in opposing the involuntary movements.

Parkinson's disease (PD), an intractable condition impairing motor and cognitive function, is imperfectly treated by drugs and surgery. Two priority issues for many people with PD are OFF-time and cognitive impairment. Even under best medical management, three-fourths of people with PD experience “OFF-time” related to medication-related motor fluctuations, which severely impacts both quality of life and cognition. Cognitive deficits are found even in newly diagnosed people with PD and are often intractable. Our data suggest that partnered dance aerobic exercise (PDAE) reduces OFF-time on the Movement Disorders Society Unified Parkinson Disease Rating Scale-IV (MDS-UPDRS-IV) and ameliorates other disease features, which motivate the PAIRED trial. PDAE provides AE during an improvisational, cognitively engaging rehabilitative physical activity. Although exercise benefits motor and cognitive symptoms and may be neuroprotective for PD, studies using robust biomarkers of neuroprotection in humans are rare. We propose to perform a randomized, controlled trial in individuals with diagnosed mild–moderate PD to compare the efficacy of PDAE vs. walking aerobic exercise (WALK) for OFF-time, cognition, and neuroprotection. We will assess neuroprotection with neuromelanin-sensitive MRI (NM-MRI) and iron-sensitive (R2*) MRI sequences to quantify neuromelanin loss and iron accumulation in substantia nigra pars compacta (SNc). We will use these biomarkers, neuromelanin loss, and iron accumulation, as tools to chart the course of neurodegeneration in patients with PD who have undergone long-term (16 months) intervention. We will randomly assign 102 individuals with mild–moderate PD to 16 months of PDAE or WALK. The 16-month intervention period will consist of Training (3 months of biweekly sessions) and Maintenance (13 months of weekly sessions) phases. We will assess participants at baseline, 3 months (immediately post-Training), and 16 months (immediately post-Maintenance) for OFF-time and behaviorally and physiologically measured cognition. We will acquire NM-MRI and R2* imaging data at baseline and 16 months to assess neuroprotection. We will (1) examine effects of Training and Maintenance phases of PDAE vs. WALK on OFF-time, (2) compare PDAE vs. WALK at 3 and 16 months on behavioral and functional MRI (fMRI) measures of spatial cognition, and (3) compare PDAE vs. WALK for effects on rates of neurodegeneration.

Background: Injectable daxibotulinumtoxinA (an investigational botulinum toxin, RT002) may offer a more prolonged duration of response—and therefore less frequent dosing—than onabotulinumtoxinA. Objectives: To perform a phase 2, open-label, dose-escalation study to assess the efficacy and safety of daxibotulinumtoxinA in cervical dystonia. Methods: Subjects with moderate-to-severe isolated cervical dystonia were enrolled in sequential cohorts to receive a single open-label, intramuscular dose of injectable daxibotulinumtoxinA of up to 200 U (n = 12), 200–300 U (n = 12), or 300–450 U (n = 13; clinicaltrials.gov identifier NCT02706795). Results: Overall, 33/37 enrollees completed the trial. DaxibotulinumtoxinA was associated with mean reductions in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score of 16.8 (38%) at week 4, 21.3 (50%) at week 6, and 12.8 (30%) at week 24. The proportion of subjects who were responders (achieved ≥ 20% reduction in TWSTRS-Total score) was 94% at week 6 and 68% at week 24. The median duration of response (time until > 20% of the improvement in TWSTRS-Total score achieved at week 4 was no longer retained or re-treatment was needed) was 25.3 weeks (95% CI, 20.14–26.14 weeks). There were no serious adverse events and there was no apparent dose-related increase in the incidence of adverse events. The most common treatment-related adverse events were dysphagia (14%) and injection site erythema (8%). Conclusions: Preliminary assessments suggest that injectable daxibotulinumtoxinA at doses up to 450 U is well tolerated and may offer prolonged efficacy in the treatment of cervical dystonia. Further studies involving larger numbers of patients are now warranted.

Low blood docosahexaenoic acid (DHA) is reported in patients with phenylketonuria (PKU); however, the functional implications in adolescents and adults are unknown. This pilot study investigated the effect of supplemental DHA on cognitive performance in 33 females with PKU ages 12-47 years. Participants were randomly assigned to receive DHA (10 mg/kg/day) or placebo for 4.5 months. Performance on cognitive processing speed and executive functioning tasks was evaluated at baseline and follow up. Intention-to-treat and per protocol analyses were performed. At follow up, biomarkers of DHA status were significantly higher in the DHA-supplemented group. Performance on the cognitive tasks and reported treatment-related adverse events did not differ. While no evidence of cognitive effect was seen, a larger sample size is needed to be conclusive, which may not be feasible in this population. Supplementation was a safe and effective way to increase biomarkers of DHA status (www.clinicaltrials.gov; Identifier: NCT00892554).

Diet therapy for phenylketonuria (PKU) requires restricted phenylalanine (Phe) intake, with the majority of protein and other nutrients coming from synthetic medical food. The fatty acid docosahexaenoic acid (DHA) is important in brain development and function; however, there are reports of low blood DHA concentrations in people treated for PKU. Although the implications of this low blood DHA are unclear, subtle cognitive deficits have been reported in those treated early and continuously for PKU. For this study, we investigated the relationship between DHA status and cognitive performance in 41 females 12 years and older with PKU. Participants were attending the baseline visit of a research-based camp or a supplementation trial. We assessed the domains of verbal ability, processing speed, and executive function using standardized tests, and the proportions of DHA in plasma and red blood cell (RBC) total lipids using gas chromatography/mass spectrometry. Percent plasma and RBC total lipid DHA were significantly lower in the participants compared with laboratory controls (P < .001), and participants consumed no appreciable DHA according to diet records. Plasma and RBC DHA both negatively correlated with plasma Phe (P < .02), and performance on the verbal ability task positively correlated with RBC DHA controlling for plasma Phe (R=.32, P=.03). The relationship between DHA and domains related to verbal ability, such as learning and memory, should be confirmed in a controlled trial. Domains of processing speed and executive function may require a larger sample size to clarify any association with DHA.

Objective: To explore the association between vitamin B12 (B12)-containing supplement use, low B12 concentrations and biochemically defined B12 deficiency in US adults. Design: A cross-sectional study with adjustment for survey design. Prevalence ratios for two age groups (18–50 and >50 years) were estimated using unconditional logistic models. Outcome measures included prevalence of low serum B12 concentration (<148 pmol/l) and biochemical B12 deficiency (serum B12<148 pmol/l with concomitant homocysteine >10 μmol/l). Setting: A population survey of health and nutritional measures. Subjects: Subjects were non-institutionalized adults, aged 18 years and older, who participated in Phase 2 of NHANES III (Third National Health and Nutrition Examination Survey). Results: Low B12 concentrations were less prevalent among persons consuming B12-containing supplements (P = 0·001) with an adjusted prevalence ratio of 0·6 (95% CI 0·3, 1·0). Biochemical B12 deficiency showed a similar trend (P = 0·0002), with an adjusted prevalence ratio of 0·3 (95% CI 0·1, 0·8). Prevalence ratios were similar in adults >50 years of age, although the prevalence of low B12 and biochemical deficiency was proportionally higher. Conclusions: Consumption of B12-containing supplements was associated with at least 50% lower prevalence of both low serum B12 and biochemical B12 deficiency in a nationally representative sample of US adults, suggesting increased consumption of B12 from supplements or from fortified foods may reduce the prevalence of B12 deficiency. Additionally, the current Recommended Daily Allowance for B12 of 2·4 μg may be insufficient for those aged >50 years.

Background Dystonia is a neurological disorder characterized by involuntary twisting movements and postures. The neck is among the most commonly affected regions, and diagnosis can be made readily through a simple clinical evaluation. The goal of this study was to explore how long it took patients to receive a diagnosis of cervical dystonia after symptom onset. Methods A structured questionnaire was administered at outpatient clinics of a tertiary care academic medical center to 146 consecutively evaluated patients. The questionnaire addressed the length of time from symptom onset to diagnosis, the numbers and types of providers seen before reaching a diagnosis, and treatments attempted prior to receiving botulinum toxin. Results A total of 108 patients saw a mean of 3.5 providers over a mean period of 44 months from symptom onset to diagnosis. For patients with symptom onset in the last decade only, patients saw a mean of 3.0 providers over a mean of 14 months. Conclusions Although cervical dystonia is the most common form of dystonia with clinical features readily identifiable by a simple history and examination, patients typically see multiple providers over more than a year before reaching a diagnosis and receiving optimal therapy. Improved awareness of the clinical features will enable patients to obtain appropriate therapy more rapidly.

Background A role for vitamin D deficiency in Parkinson disease (PD) has recently been proposed. Objective To compare the prevalence of vitamin D deficiency in a research database cohort of patients with PD with the prevalence in age-matched healthy controls and patients with Alzheimer disease (AD). Design Survey study and blinded comparison of plasma 25-hydroxyvitamin D (25[OH]D) concentrations of stored samples in a clinical research database at Emory University School of Medicine. Setting Referral center (PD and AD patients), primary care clinics, and community setting (controls). Participants Participants were recruited into the study between May 1992 and March 2007. Every fifth consecutively enrolled PD patient was selected from the clinical research database. Unrelated AD (n=97) and control (n=99) participants were randomly selected from the database after matching for age, sex, race, APOE genotype, and geographic location. Main Outcome Measures Prevalence of suboptimal vitamin D and mean 25(OH)D concentrations. Results Significantly more patients with PD (55%) had insufficient vitamin D than did controls (36%) or patients with AD (41%; P=.02, χ2 test). The mean (SD) 25(OH)D concentration in the PD cohort was significantly lower than in the AD and control cohorts (31.9 [13.6] ng/mL vs 34.8 [15.4] ng/mL and 37.0 [14.5] ng/mL, respectively; P=.03). Conclusions This report of 25(OH)D concentrations in a predominantly white PD cohort demonstrates a significantly higher prevalence of hypovitaminosis in PD vs both healthy controls and patients with AD. These data support a possible role of vitamin D insufficiency in PD. Further studies are needed to determine the factors contributing to these differences and elucidate the potential role of vitamin D in pathogenesis and clinical course of PD.

Excessive drooling may complicate the care of children with chronic neurological conditions by socially isolating both patients and families and by causing secondary dermatitis and infection. Normal control of saliva requires normal integrity of oral structures, normal oropharyngeal sensation, and motor functioning, as well as normal cognitive awareness and rate of salivary production. Glycopyrrolate is an anticholinergic medication with a quaternary structure that recently received Food and Drug Administration approval to treat sialorrhea due to neurological problems in children ages 3-16 years. This review summarizes the few published studies of safety and efficacy of glycopyrrolate for drooling in children with chronic neurological conditions.