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Papers by Allison Brashear

Clinical trials have established the efficacy and safety of botulinum toxin type A (BTX-A) in pat... more 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. 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. A retrospective chart review was undertaken at an academic center and a private neurology practice. At each site, > or =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 > or =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. 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. BTX-A the controls symptoms of cervical dystonia for 12 to 24 weeks, with a mean duration of effect per patient of 15.5 weeks.

gressive back pain. Case Description: 3 months prior to admission, the patient had a gradual onse... more gressive back pain. Case Description: 3 months prior to admission, the patient had a gradual onset of low back pain following urologic stent placement and antibiotic therapy. He was diagnosed as having degenerative disk disease at L1-2 following numerous imaging studies and orthopedic referral. Physical therapy and epidural block did not relieve his pain. He was admitted to the hospital due to worsening pain that prohibited ambulation. The patient noted a 13.5kg (30lb) weight loss but denied bowel and bladder incontinence or fever and chills. Magnetic resonance imaging (MRI) on admission demonstrated significant spinal stenosis at L1-2, edema of the L1-2 disk space, and destruction of the L1 and L2 vertebrae. Differential diagnosis included metastatic tumor versus osteomyelitis. Assessments/Results: The initial plan by a neurosurgeon was open surgical decompression. On review with an interventional physiatrist, a less invasive fluoroscopically guided percutaneous approach was performed. Using Kyphon biopsy devices, traditional spinal injection approaches were utilized to biopsy the L1 and L2 vertebrae and decompress the L1-2 disk. Cultures grew Candida albicans, and the patient was treated with intravenous fluconazole for 4 weeks, followed by oral therapy. Postoperatively and at follow-up visits, the patient was pain free. Follow-up MRI at 9 months revealed fusion of the L1-2 vertebrae and excellent decompression of the spinal canal. Discussion: This case illustrates the value of a cooperative, team approach among surgeons and interventional pain physicians. The patient's pain and fungal infection were treated without an open surgery. Conclusions: Fungal osteomyelitis and diskitis are uncommon yet treatable causes of low back pain. Modern minimally invasive techniques using fluoroscopy may assist both with diagnosis and treatment, while decreasing morbidity and mortality when compared to traditional open surgeries. Objective: To examine the effects of a novel injection technique on procedure time, radiation exposure, anesthetic use, and intraprocedure pain. Design: Prospective randomized controlled study. Setting: University spine clinic. Participants: 8 patients scheduled for symmetric bilateral lumbar facet joint and adjacent transforaminal epidural steroid injections. Interventions: Participants received injections by a "traditional" technique on 1 side, and a single needle for multiple injections (SIMI) technique on the contralateral side. All were blinded to the technique. Traditional technique involves needles placed independently for each injection, beginning with the epidural injection and ending with the facet injection. SIMI technique uses a single needle and a single insertion site to first perform the epidural injection, then withdraw and redirect the needle to the ipsilateral facet after adjusting the c-arm to a favorable view. One nonblinded physician (Ͼ5y experience) performed every injection. Injections started on the right, alternating between traditional and SIMI technique to begin. Main Outcome Measures: An independent third party recorded procedure time, fluoroscopy time, and needles used. The treating physician recorded volume of local anesthetic and intraprocedure pain on a 10-point verbal analog scale (VAS). Results: The SIMI technique reduced procedure time by 25% (mean, 148Ϯ42s vs 207Ϯ89s; PϽ.05) and fluoroscopy time by 37% (14.6Ϯ3.3s vs 23.1Ϯ11.8s; PϽ.05). The SIMI tech-nique used 33% less local anesthetic (mean, 1.0Ϯ0.3mL vs 1.6Ϯ0.3mL; PϽ.01) and half as many needles (PϽ.01). Last, VAS scores were lower for the SIMI technique (mean, 5.9Ϯ1.9 vs 7.6Ϯ2.7; PϾ.05). Conclusions: The SIMI technique was less painful and safer than traditional techniques when performing concomitant facet joint and transforaminal epidural injections. Objective: To evaluate the efficacy and safety of repeated botulinum toxin type A (BTX-A) (Botox) treatment of focal upperlimb poststroke spasticity in reducing pain frequency and intensity. Design: Multicenter, open-label, repeated dose study. Setting: 35 clinical sites in North America. Participants: Patients with upperlimb poststroke spasticity were enrolled in a 12-month study of BTX-A (Nϭ279). A post hoc subgroup analysis of 73 patients (mean age, 56.8y; 56.2% women) who scored Ն2 on the pain component of the 4-point Disability Assessment Scale (DAS; 0 [no pain] to 3 [severe pain]) at baseline was performed. Interventions: Patients received up to 5 treatments of 200 to 400U of BTX-A in the elbow, wrist, finger, and/or thumb flexors of the affected limb. Successive treatments were administered at least 12 weeks after the previous injection. Patients were assessed every 6 weeks for 12 months. Main Outcome Measures: Change from baseline in pain frequency (0 [none of the time] to 4 [all of the time]), pain intensity (0 [no pain] to 10 [pain as bad as it can be]), DAS (pain domain), and muscle tone (Ashworth Scale) following BTX-A treatment.

Advances in therapy

Botulinum toxin type A (BoNT/A) is the principal therapy for patients with cervical dystonia. Rep... more 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.

Movement Disorders, 2004

Rapid-onset dystonia-parkinsonism (RDP, DYT12, MIM 128235) is a rare autosomal dominant movement ... more Rapid-onset dystonia-parkinsonism (RDP, DYT12, MIM 128235) is a rare autosomal dominant movement disorder characterized by abrupt onset of slow, dystonic movements and prominent bulbar features. Three families and 1 isolated case have been described in the literature, and linkage to markers on chromosome 19q13 have been reported. Here, we describe the clinical features in a fourth family (the second in Europe) with 4 affected members, suggesting that RDP may be misdiagnosed for years and/or may mimic other dystonic/parkinsonian syndromes. By using haplotype analysis, we show that the family is consistent with linkage to markers on chromosome 19q13.

Parkinsonism & Related Disorders, 2010

The aim of this study was to evaluate the efficacy and safety of intramuscular (IM) administratio... more The aim of this study was to evaluate the efficacy and safety of intramuscular (IM) administration of botulinum toxin type A (Dysport®, Ipsen Biopharm Ltd.) for the treatment of cervical dystonia (CD) and the long-term safety and efficacy of repeated treatments. During the randomized, double-blind, placebo-controlled phase patients were randomized to 500 units Dysport (n = 55) or placebo (n = 61). Efficacy assessments

New England Journal of Medicine, 2002

Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injec... more 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 (P<0.001 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 (P<0.001, P<0.001, 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 (P<0.001). 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.

Neurology, 2006

In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity ... more 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.

Neurology, 2014

ABSTRACT Rapid-onset dystonia-parkinsonism (RDP) occurs in children over 18 months of age, teens,... more ABSTRACT Rapid-onset dystonia-parkinsonism (RDP) occurs in children over 18 months of age, teens, and adults, and alternating hemiplegia of childhood (AHC) occurs in children less 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 age 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.

Neurology, 2008

To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in ... more To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders.

Muscle & Nerve, 1996

The ulnar, hypothenar compound muscle action potential often shows a double-peaked configuration ... more The ulnar, hypothenar compound muscle action potential often shows a double-peaked configuration in the negative phase component while the median, thenar potential has a simple dome shape. To investigate the origin of these differences we evaluated the activity at the belly and tendon electrode locations by referencing those sites to an electrode on the contralateral hand. The tendon sites are not electrically inactive. The ulnar tendon electrode contributes a large amplitude potential which corresponds to the second peak of the ulnar belly-tendon potential. The median tendon electrode contributes only a minimal component to the negative phase of the belly-tendon potential. The distribution of such potentials throughout the hand is evaluated and possible mechanisms for the presence of a tendon potential as well as the differences between ulnar and median sites are discussed.

Movement Disorders, 2000

Despite widespread commercial acceptance of botulinum toxin (BTX) for idiopathic cervical dystoni... more Despite widespread commercial acceptance of botulinum toxin (BTX) for idiopathic cervical dystonia (ICD), no follow up has been performed to determine when and why some patients stop therapy. It has been suggested that some patients who stop BTX treatment may do so because of permanent improvement. We surveyed 155 patients with ICD who were treated over 6 years with BTX to determine when and why patients stopped treatment with BTX, and what adverse events and changes in dose and/or frequency of treatments occurred in those who continued treatment. Of the 133 (86.6%) individuals returning the surveys, 104 continued on BTX treatment and 29 had stopped therapy. Of the 29 subjects

Movement Disorders, 1998

To compare clinical parameters of patients treated with botulinum toxin type A (BTX) for treatmen... more 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 seventy 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 f 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.

Movement Disorders, 1996

Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder characterized by the ra... more 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 symp-toms 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.

Movement Disorders, 2001

Cervical dystonia (CD) is characterized by sustained contractions of the neck musculature, result... more Cervical dystonia (CD) is characterized by sustained contractions of the neck musculature, resulting in abnormal head postures. The Cervical Dystonia Severity Scale (CDSS) was developed to provide a reliable measure of treatment response in patients with CD. The CDSS uses a protractor and wall chart to rate the severity of the head's deviation from neutral in each of three planes of motion (rotation, laterocollis, anterocollis/retrocollis), which is then scored in 5 degree intervals (1 degree to 5 degrees deviation ‫ס‬ 1; 86 degree to 90 degrees deviation ‫ס‬ 18).

The Lancet Neurology, 2014

Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the ... more Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.

Journal of Pediatric Orthopaedics, 2000

Increased gastrocnemius/soleus muscle tone in children with cerebral palsy may cause an equinus o... more Increased gastrocnemius/soleus muscle tone in children with cerebral palsy may cause an equinus of the ankle. Botulinum toxin type A (BTX), a neuromuscular blocking agent, reduces muscle tone in various neuromuscular disorders. The safety and short-term efficacy of BTX injections were evaluated in a prospective, 3-month, double-blind, randomized clinical trial involving 114 children with cerebral palsy and dynamic equinus foot deformity. Outcome was determined by observational gait analysis, ankle range-of-motion measurements, and quantification of muscle denervation by nerve conduction. Patients in the BTX group demonstrated improved gait function and partial denervation of the injected muscle. No serious adverse events were reported.

Journal of Neurology, Neurosurgery & Psychiatry, 2008

Background: While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) ... more Background: While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) injection, these treatments have not been systematically compared. Methods: This study performed a randomised, doubleblind, 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 upperlimb 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;

Clinical Therapeutics, 2000

Clinical trials have established the efficacy and safety of botulinum toxin type A (BTX-A) in pat... more 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. 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. A retrospective chart review was undertaken at an academic center and a private neurology practice. At each site, > or =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 > or =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. 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. BTX-A the controls symptoms of cervical dystonia for 12 to 24 weeks, with a mean duration of effect per patient of 15.5 weeks.

Clinical Therapeutics, 2007

The purpose of this study was to investigate the incidence of neutralizing antibody (NAb) formati... more The purpose of this study was to investigate the incidence of neutralizing antibody (NAb) formation in patients with poststroke spasticity treated with a specific formulation of botulinum toxin type A (BoNTA). Data from 3 previous clinical trials of BoNTA in patients with upper and/or lower limb spasticity were pooled and evaluated. Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial of BoNTA in patients aged >/=21 years who had experienced a stroke >6 months before the initiation of the study. Study 2 was an open-label extension of study 1. Study 3 was a randomized, double-blind, multicenter trial of a specific BoNTA formulation in patients aged >/= 21 years who had experienced a stroke >/=6 weeks before study entry. Patients with a fixed contracture of the studied limb were excluded from participation in studies 1 and 2. Serum samples were obtained from each patient before each BoNTA treatment and at the end of each study. The mouse protection assay (MPA) was used for detection of NAbs to BoNTA in serum. A total of 235 individual patients with post-stroke spasticity were enrolled in the 3 trials, including 126, 111 (all of whom participated in study 1), and 109 in studies 1, 2, and 3, respectively. Study 1 had an equal (50.0%) distribution of male and female patients (63/63). The distribution of male and female patients was 56 (50.5%) and 55 (49.5%), respectively, in study 2, and 55 (50.5%) and 54 (49.5), respectively, in study 3. The mean (SD) ages of patients in studies 1, 2, and 3 were 61.4 (13.8), 61.5 (14.1), and 58.5 (13.9) years, respectively. The MPA was used for detection of NAbs to BoNTA in the serum samples of 191 patients, including 64 from study 1, 111 from study 2 (55 of these patients were placebo recipients and 56 received their first BoNTA injection in study 1), and 72 (a sample was not obtained for 1 patient who had not received an injection) from study 3. The median number of BoNTA treatments received by these patients was 2 (range, 1-4 treatments) over a period lasting from 12 to 42 weeks. The mean dose of BoNTA was 241 U (range, 100-400 U), with a maximum dose of 960 U in any 1 patient. NAbs to BoNTA were detected in the serum sample of 1/191 (0.5%) patient who had participated in studies 1 and 2. Based on muscle-tone scores (3 and 4 for wrist and fingers, respectively) on a 5-point Ashworth Scale (0 = none to 4 = severe), the patient did not appear to exhibit a clinical response to BoNTA at any time during the studies. Formation of NAbs was rare (1/191) in this group of adults with poststroke spasticity from three 12- to 42-week clinical trials who received >/=1 treatment with a specific BoNTA formulation at doses ranging from 100 to 400 U.

Clinical trials have established the efficacy and safety of botulinum toxin type A (BTX-A) in pat... more 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. 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. A retrospective chart review was undertaken at an academic center and a private neurology practice. At each site, > or =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 > or =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. 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. BTX-A the controls symptoms of cervical dystonia for 12 to 24 weeks, with a mean duration of effect per patient of 15.5 weeks.

gressive back pain. Case Description: 3 months prior to admission, the patient had a gradual onse... more gressive back pain. Case Description: 3 months prior to admission, the patient had a gradual onset of low back pain following urologic stent placement and antibiotic therapy. He was diagnosed as having degenerative disk disease at L1-2 following numerous imaging studies and orthopedic referral. Physical therapy and epidural block did not relieve his pain. He was admitted to the hospital due to worsening pain that prohibited ambulation. The patient noted a 13.5kg (30lb) weight loss but denied bowel and bladder incontinence or fever and chills. Magnetic resonance imaging (MRI) on admission demonstrated significant spinal stenosis at L1-2, edema of the L1-2 disk space, and destruction of the L1 and L2 vertebrae. Differential diagnosis included metastatic tumor versus osteomyelitis. Assessments/Results: The initial plan by a neurosurgeon was open surgical decompression. On review with an interventional physiatrist, a less invasive fluoroscopically guided percutaneous approach was performed. Using Kyphon biopsy devices, traditional spinal injection approaches were utilized to biopsy the L1 and L2 vertebrae and decompress the L1-2 disk. Cultures grew Candida albicans, and the patient was treated with intravenous fluconazole for 4 weeks, followed by oral therapy. Postoperatively and at follow-up visits, the patient was pain free. Follow-up MRI at 9 months revealed fusion of the L1-2 vertebrae and excellent decompression of the spinal canal. Discussion: This case illustrates the value of a cooperative, team approach among surgeons and interventional pain physicians. The patient's pain and fungal infection were treated without an open surgery. Conclusions: Fungal osteomyelitis and diskitis are uncommon yet treatable causes of low back pain. Modern minimally invasive techniques using fluoroscopy may assist both with diagnosis and treatment, while decreasing morbidity and mortality when compared to traditional open surgeries. Objective: To examine the effects of a novel injection technique on procedure time, radiation exposure, anesthetic use, and intraprocedure pain. Design: Prospective randomized controlled study. Setting: University spine clinic. Participants: 8 patients scheduled for symmetric bilateral lumbar facet joint and adjacent transforaminal epidural steroid injections. Interventions: Participants received injections by a "traditional" technique on 1 side, and a single needle for multiple injections (SIMI) technique on the contralateral side. All were blinded to the technique. Traditional technique involves needles placed independently for each injection, beginning with the epidural injection and ending with the facet injection. SIMI technique uses a single needle and a single insertion site to first perform the epidural injection, then withdraw and redirect the needle to the ipsilateral facet after adjusting the c-arm to a favorable view. One nonblinded physician (Ͼ5y experience) performed every injection. Injections started on the right, alternating between traditional and SIMI technique to begin. Main Outcome Measures: An independent third party recorded procedure time, fluoroscopy time, and needles used. The treating physician recorded volume of local anesthetic and intraprocedure pain on a 10-point verbal analog scale (VAS). Results: The SIMI technique reduced procedure time by 25% (mean, 148Ϯ42s vs 207Ϯ89s; PϽ.05) and fluoroscopy time by 37% (14.6Ϯ3.3s vs 23.1Ϯ11.8s; PϽ.05). The SIMI tech-nique used 33% less local anesthetic (mean, 1.0Ϯ0.3mL vs 1.6Ϯ0.3mL; PϽ.01) and half as many needles (PϽ.01). Last, VAS scores were lower for the SIMI technique (mean, 5.9Ϯ1.9 vs 7.6Ϯ2.7; PϾ.05). Conclusions: The SIMI technique was less painful and safer than traditional techniques when performing concomitant facet joint and transforaminal epidural injections. Objective: To evaluate the efficacy and safety of repeated botulinum toxin type A (BTX-A) (Botox) treatment of focal upperlimb poststroke spasticity in reducing pain frequency and intensity. Design: Multicenter, open-label, repeated dose study. Setting: 35 clinical sites in North America. Participants: Patients with upperlimb poststroke spasticity were enrolled in a 12-month study of BTX-A (Nϭ279). A post hoc subgroup analysis of 73 patients (mean age, 56.8y; 56.2% women) who scored Ն2 on the pain component of the 4-point Disability Assessment Scale (DAS; 0 [no pain] to 3 [severe pain]) at baseline was performed. Interventions: Patients received up to 5 treatments of 200 to 400U of BTX-A in the elbow, wrist, finger, and/or thumb flexors of the affected limb. Successive treatments were administered at least 12 weeks after the previous injection. Patients were assessed every 6 weeks for 12 months. Main Outcome Measures: Change from baseline in pain frequency (0 [none of the time] to 4 [all of the time]), pain intensity (0 [no pain] to 10 [pain as bad as it can be]), DAS (pain domain), and muscle tone (Ashworth Scale) following BTX-A treatment.

Advances in therapy

Botulinum toxin type A (BoNT/A) is the principal therapy for patients with cervical dystonia. Rep... more 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.

Movement Disorders, 2004

Rapid-onset dystonia-parkinsonism (RDP, DYT12, MIM 128235) is a rare autosomal dominant movement ... more Rapid-onset dystonia-parkinsonism (RDP, DYT12, MIM 128235) is a rare autosomal dominant movement disorder characterized by abrupt onset of slow, dystonic movements and prominent bulbar features. Three families and 1 isolated case have been described in the literature, and linkage to markers on chromosome 19q13 have been reported. Here, we describe the clinical features in a fourth family (the second in Europe) with 4 affected members, suggesting that RDP may be misdiagnosed for years and/or may mimic other dystonic/parkinsonian syndromes. By using haplotype analysis, we show that the family is consistent with linkage to markers on chromosome 19q13.

Parkinsonism & Related Disorders, 2010

The aim of this study was to evaluate the efficacy and safety of intramuscular (IM) administratio... more The aim of this study was to evaluate the efficacy and safety of intramuscular (IM) administration of botulinum toxin type A (Dysport®, Ipsen Biopharm Ltd.) for the treatment of cervical dystonia (CD) and the long-term safety and efficacy of repeated treatments. During the randomized, double-blind, placebo-controlled phase patients were randomized to 500 units Dysport (n = 55) or placebo (n = 61). Efficacy assessments

New England Journal of Medicine, 2002

Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injec... more 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 (P<0.001 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 (P<0.001, P<0.001, 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 (P<0.001). 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.

Neurology, 2006

In this multicenter study of 100 patients with cervical dystonia, we examined the immunogenicity ... more 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.

Neurology, 2014

ABSTRACT Rapid-onset dystonia-parkinsonism (RDP) occurs in children over 18 months of age, teens,... more ABSTRACT Rapid-onset dystonia-parkinsonism (RDP) occurs in children over 18 months of age, teens, and adults, and alternating hemiplegia of childhood (AHC) occurs in children less 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 age 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.

Neurology, 2008

To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in ... more To perform an evidence-based review of the safety and efficacy of botulinum neurotoxin (BoNT) in the treatment of movement disorders.

Muscle & Nerve, 1996

The ulnar, hypothenar compound muscle action potential often shows a double-peaked configuration ... more The ulnar, hypothenar compound muscle action potential often shows a double-peaked configuration in the negative phase component while the median, thenar potential has a simple dome shape. To investigate the origin of these differences we evaluated the activity at the belly and tendon electrode locations by referencing those sites to an electrode on the contralateral hand. The tendon sites are not electrically inactive. The ulnar tendon electrode contributes a large amplitude potential which corresponds to the second peak of the ulnar belly-tendon potential. The median tendon electrode contributes only a minimal component to the negative phase of the belly-tendon potential. The distribution of such potentials throughout the hand is evaluated and possible mechanisms for the presence of a tendon potential as well as the differences between ulnar and median sites are discussed.

Movement Disorders, 2000

Despite widespread commercial acceptance of botulinum toxin (BTX) for idiopathic cervical dystoni... more Despite widespread commercial acceptance of botulinum toxin (BTX) for idiopathic cervical dystonia (ICD), no follow up has been performed to determine when and why some patients stop therapy. It has been suggested that some patients who stop BTX treatment may do so because of permanent improvement. We surveyed 155 patients with ICD who were treated over 6 years with BTX to determine when and why patients stopped treatment with BTX, and what adverse events and changes in dose and/or frequency of treatments occurred in those who continued treatment. Of the 133 (86.6%) individuals returning the surveys, 104 continued on BTX treatment and 29 had stopped therapy. Of the 29 subjects

Movement Disorders, 1998

To compare clinical parameters of patients treated with botulinum toxin type A (BTX) for treatmen... more 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 seventy 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 f 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.

Movement Disorders, 1996

Rapid-onset dystonia-parkinsonism (RDP) is an autosomal dominant disorder characterized by the ra... more 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 symp-toms 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.

Movement Disorders, 2001

Cervical dystonia (CD) is characterized by sustained contractions of the neck musculature, result... more Cervical dystonia (CD) is characterized by sustained contractions of the neck musculature, resulting in abnormal head postures. The Cervical Dystonia Severity Scale (CDSS) was developed to provide a reliable measure of treatment response in patients with CD. The CDSS uses a protractor and wall chart to rate the severity of the head's deviation from neutral in each of three planes of motion (rotation, laterocollis, anterocollis/retrocollis), which is then scored in 5 degree intervals (1 degree to 5 degrees deviation ‫ס‬ 1; 86 degree to 90 degrees deviation ‫ס‬ 18).

The Lancet Neurology, 2014

Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the ... more Genetic research has shown that mutations that modify the protein-coding sequence of ATP1A3, the gene encoding the α3 subunit of Na(+)/K(+)-ATPase, cause both rapid-onset dystonia parkinsonism and alternating hemiplegia of childhood. These discoveries link two clinically distinct neurological diseases to the same gene, however, ATP1A3 mutations are, with one exception, disease-specific. Although the exact mechanism of how these mutations lead to disease is still unknown, much knowledge has been gained about functional consequences of ATP1A3 mutations using a range of in-vitro and animal model systems, and the role of Na(+)/K(+)-ATPases in the brain. Researchers and clinicians are attempting to further characterise neurological manifestations associated with mutations in ATP1A3, and to build on the existing molecular knowledge to understand how specific mutations can lead to different diseases.

Journal of Pediatric Orthopaedics, 2000

Increased gastrocnemius/soleus muscle tone in children with cerebral palsy may cause an equinus o... more Increased gastrocnemius/soleus muscle tone in children with cerebral palsy may cause an equinus of the ankle. Botulinum toxin type A (BTX), a neuromuscular blocking agent, reduces muscle tone in various neuromuscular disorders. The safety and short-term efficacy of BTX injections were evaluated in a prospective, 3-month, double-blind, randomized clinical trial involving 114 children with cerebral palsy and dynamic equinus foot deformity. Outcome was determined by observational gait analysis, ankle range-of-motion measurements, and quantification of muscle denervation by nerve conduction. Patients in the BTX group demonstrated improved gait function and partial denervation of the injected muscle. No serious adverse events were reported.

Journal of Neurology, Neurosurgery & Psychiatry, 2008

Background: While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) ... more Background: While spasticity is commonly treated with oral agents or botulinum neurotoxin (BoNT) injection, these treatments have not been systematically compared. Methods: This study performed a randomised, doubleblind, 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 upperlimb 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;

Clinical Therapeutics, 2000

Clinical trials have established the efficacy and safety of botulinum toxin type A (BTX-A) in pat... more 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. 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. A retrospective chart review was undertaken at an academic center and a private neurology practice. At each site, > or =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 > or =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. 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. BTX-A the controls symptoms of cervical dystonia for 12 to 24 weeks, with a mean duration of effect per patient of 15.5 weeks.

Clinical Therapeutics, 2007

The purpose of this study was to investigate the incidence of neutralizing antibody (NAb) formati... more The purpose of this study was to investigate the incidence of neutralizing antibody (NAb) formation in patients with poststroke spasticity treated with a specific formulation of botulinum toxin type A (BoNTA). Data from 3 previous clinical trials of BoNTA in patients with upper and/or lower limb spasticity were pooled and evaluated. Study 1 was a randomized, double-blind, placebo-controlled, multicenter trial of BoNTA in patients aged >/=21 years who had experienced a stroke >6 months before the initiation of the study. Study 2 was an open-label extension of study 1. Study 3 was a randomized, double-blind, multicenter trial of a specific BoNTA formulation in patients aged >/= 21 years who had experienced a stroke >/=6 weeks before study entry. Patients with a fixed contracture of the studied limb were excluded from participation in studies 1 and 2. Serum samples were obtained from each patient before each BoNTA treatment and at the end of each study. The mouse protection assay (MPA) was used for detection of NAbs to BoNTA in serum. A total of 235 individual patients with post-stroke spasticity were enrolled in the 3 trials, including 126, 111 (all of whom participated in study 1), and 109 in studies 1, 2, and 3, respectively. Study 1 had an equal (50.0%) distribution of male and female patients (63/63). The distribution of male and female patients was 56 (50.5%) and 55 (49.5%), respectively, in study 2, and 55 (50.5%) and 54 (49.5), respectively, in study 3. The mean (SD) ages of patients in studies 1, 2, and 3 were 61.4 (13.8), 61.5 (14.1), and 58.5 (13.9) years, respectively. The MPA was used for detection of NAbs to BoNTA in the serum samples of 191 patients, including 64 from study 1, 111 from study 2 (55 of these patients were placebo recipients and 56 received their first BoNTA injection in study 1), and 72 (a sample was not obtained for 1 patient who had not received an injection) from study 3. The median number of BoNTA treatments received by these patients was 2 (range, 1-4 treatments) over a period lasting from 12 to 42 weeks. The mean dose of BoNTA was 241 U (range, 100-400 U), with a maximum dose of 960 U in any 1 patient. NAbs to BoNTA were detected in the serum sample of 1/191 (0.5%) patient who had participated in studies 1 and 2. Based on muscle-tone scores (3 and 4 for wrist and fingers, respectively) on a 5-point Ashworth Scale (0 = none to 4 = severe), the patient did not appear to exhibit a clinical response to BoNTA at any time during the studies. Formation of NAbs was rare (1/191) in this group of adults with poststroke spasticity from three 12- to 42-week clinical trials who received >/=1 treatment with a specific BoNTA formulation at doses ranging from 100 to 400 U.