Epidemiology, methods of diagnosis, and clinical management of patients with arginase 1 deficiency (ARG1-D): A systematic review.

BACKGROUND: Arginase 1 Deficiency (ARG1-D) is a rare, progressive, metabolic disorder that is characterized by devastating manifestations driven by elevated plasma arginine levels. It typically presents in early childhood with spasticity (predominately affecting the lower limbs), mobility impairment, seizures, developmental delay, and intellectual disability. This systematic review aims to identify and describe the published evidence outlining the epidemiology, diagnosis methods, measures of disease progression, clinical management, and outcomes for ARG1-D patients. METHODS: A comprehensive literature search across multiple databases such as MEDLINE, Embase, and a review of clinical studies in ClinicalTrials.gov (with results reported) was carried out per PRISMA guidelines on 20 April 2020 with no date restriction. Pre-defined eligibility criteria were used to identify studies with data specific to patients with ARG1-D. Two independent reviewers screened records and extracted data from included studies. Quality was assessed using the modified Newcastle-Ottawa Scale for non-comparative studies. RESULTS: Overall, 55 records reporting 40 completed studies and 3 ongoing studies were included. Ten studies reported the prevalence of ARG1-D in the general population, with a median of 1 in 1,000,000. Frequently reported diagnostic methods included genetic testing, plasma arginine levels, and red blood cell arginase activity. However, routine newborn screening is not universally available, and lack of disease awareness may prevent early diagnosis or lead to misdiagnosis, as the disease has overlapping symptomology with other diseases, such as cerebral palsy. Common manifestations reported at time of diagnosis and assessed for disease progression included spasticity (predominately affecting the lower limbs), mobility impairment, developmental delay, intellectual disability, and seizures. Severe dietary protein restriction, essential amino acid supplementation, and nitrogen scavenger administration were the most commonly reported treatments among patients with ARG1-D. Only a few studies reported meaningful clinical outcomes of these interventions on intellectual disability, motor function and adaptive behavior assessment, hospitalization, or death. The overall quality of included studies was assessed as good according to the Newcastle-Ottawa Scale. CONCLUSIONS: Although ARG1-D is a rare disease, published evidence demonstrates a high burden of disease for patients. The current standard of care is ineffective at preventing disease progression. There remains a clear need for new treatment options as well as improved access to diagnostics and disease awareness to detect and initiate treatment before the onset of clinical manifestations to potentially enable more normal development, improve symptomatology, or prevent disease progression.

Perspective of an International Online Patient and Caregiver Community on the Burden of Spasticity and Impact of Botulinum Neurotoxin Therapy: Survey Study.

BACKGROUND: Patient- and caregiver-reported data are lacking on the burden of spasticity, and the impact of botulinum neurotoxin type A (BoNT-A) treatment for this condition, on patients' daily lives. As recommended in recent guidance from the US Food and Drug Administration, online patient communities can represent a platform from which to gather specific information outside of a clinical trial setting on the burden of conditions experienced by patients and caregivers and their views on treatment options in order to inform evidence-based medicine and drug development. OBJECTIVE: The objective of our study is to characterize spasticity symptoms and their associated burdens on Western European and US patients and caregivers in the realms of work, daily activities, quality of life (QoL), as well as the positive and negative impacts of treatment with BoNT-A (cost, time, QoL) using Carenity, an international online community for people with chronic health conditions. METHODS: We performed a noninterventional, multinational survey. Eligible participants were 18 years old or older and had, or had cared for, someone with spasticity who had been treated with BoNT-A for at least 1 year. Patients and caregivers were asked to complete an internet-based survey via Carenity; caregivers reported their own answers and answered on behalf of their patients. Questions included the burden of spasticity on the ability to work, functioning, daily-living activities, and QoL, the impact of BoNT A therapy on patients' lives, and the potential benefits of fewer injections. RESULTS: There were 615 respondents (427 patients and 188 caregivers). The mean age of patients and caregivers was 41.7 years and 38.6 years, respectively, and the most commonly reported cause of spasticity was multiple sclerosis. Caregivers were most often the parents (76/188, 40%) or another family member (51/188, 27%) of their patients. Spasticity had a clear impact on patients' and caregivers' lives, including the ability to work and injection costs. For patients, spasticity caused difficulties with activities of daily living and reduced QoL indices. The median number of BoNT-A injections was 4 times per year, and 92% (393/427) of patients reported that treatment improved their overall satisfaction with life. Regarding the BoNT-A injection burden, the greatest patient-reported challenges were the cost and availability of timely appointments. Overall, 86% (368/427) of patients believed that a reduced injection frequency would be beneficial. Caregivers answering for their patients gave largely similar responses to those reported by patients. CONCLUSIONS: Spasticity has a negative impact on both patients' and caregivers' lives. All respondents reported that BoNT A treatment improved their lives, despite the associated challenges. Patients believed that reducing the frequency of BoNT-A injections could alleviate practical issues associated with treatment, implying that a longer-acting BoNT-A injection would be well received.

Acute and Chronic Pain in Children and Adolescents With Cerebral Palsy: Prevalence, Interference, and Management.

OBJECTIVE: To determine the prevalence, interference, and management of acute and chronic pain among youth with cerebral palsy (CP) aged 5-18 years attending outpatient rehabilitation services. DESIGN: A cross-sectional study using the Faces Pain Scale-Revised, Patient Reporting Outcomes Measurement Information System Pediatric Pain Interference Scale, and the Cerebral Palsy Quality of Life questionnaire. Where children were unable to self-report, parent or caregiver proxy was obtained. SETTING: Outpatient rehabilitation. PARTICIPANTS: Participants (N=280) with CP aged 5-18 years and their parent or caregiver. Self-report was obtained by 45.7% (n=128) and proxy-report was obtained by 54.3% (n=152) of the cohort. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Presence or absence of acute pain and chronic pain. Secondary measures were pain intensity, pain interference, pain management, and quality of life. RESULTS: Acute pain and chronic pain were reported by 67.1% and 31.4% of participants, respectively. Of those reporting acute pain, 42% also experienced chronic pain. Factors that increased the odds of chronic pain were: predominately dyskinesia (odds ratio [OR]=3.52; 95% confidence interval [CI], 1.64-7.55); mixed spasticity-dyskinesia (OR=1.93; 95% CI, 1.07-3.47); bilateral involvement (OR=3.22; 95% CI, 1.844-5.61) and Gross Motor Function Classification System level IV (OR=2.32; 95% CI, 1.02-5.25), and V (OR=3.73; 95% CI, 1.70-8.20). Pain frequently interferes with sleep, attention, ability to have fun, and quality of life. Short-acting pharmacologic analgesics, thermotherapy, hydrotherapy, and massage were commonly used for pain management. CONCLUSIONS: Routine screening for pain is critical for early identification and intervention. Multimodal interventions are needed to address the biopsychosocial model of pain, and should be tailored for all abilities across the CP spectrum.

Prevalence, Patterns, and Cost of Care for Children with Cerebral Palsy Enrolled in Medicaid Managed Care.

BACKGROUND: In the United States, many children with cerebral palsy (CP) obtain health care coverage through managed Medicaid, but little is known about the current demographics or management of this high-need, complex population. OBJECTIVE: To develop U.S. population-level information about the prevalence of CP, management patterns, and costs. METHODS: Data (2013-2015) were analyzed from a managed Medicaid database with coverage of children and adolescents in 15 states. Analyses included demographic information and use of 10 prespecified CP management options often used to manage spasticity. Code-based algorithms were applied to indicate presence of spasticity and determine the likely ambulatory status. RESULTS: In this claims analysis, the prevalence estimate of CP was 1.78 per 1,000 patients. Most (69.8%) children with CP had spasticity, of which 20.8% had hemiplegia, 15.6% diplegia, 32.9% quadriplegia, and 30.5% CP unspecified. Overall, 42.4% of children with CP were not treated with any of the 10 CP management options via Medicaid. Among treated children, the most common management options were physical therapy (37.1%), orthotics (29.9%), oral baclofen (13.5%) and botulinum toxins (9.4%). Overall annualized Medicaid costs were higher for children with CP versus children in the overall database population ($22,383 vs. $1,358). Within the CP population, costs were higher for those children who were likely nonambulatory than for those who were likely ambulatory ($43,687 vs. $10,368, respectively). CONCLUSIONS: Most children with CP have spasticity, and the costs of care are high. This study highlights wide variation in the way CP is managed, with many young patients not receiving CP management options via Medicaid. DISCLOSURES: This analysis was funded by Ipsen Biopharmaceuticals and conducted by Milliman. Pulgar and Bains were employees of Ipsen Biopharmaceuticals during the conduct of this study. Chambers is a consultant for OrthoPediatrics and an employee of the University of California. Pyenson and Ferro are employees of Milliman, as was Sawhney during the analysis. Gooch, Noritz, and Wright report no conflicts of interest. Part of this work was presented as a poster at TOXINS 2017: Basic Science and Clinical Aspects of Botulinum and Other Neurotoxins, held January 18-21, 2017, in Madrid, Spain.

A retrospective study to assess resource utilization and costs in patients with post-stroke spasticity in the United Kingdom.

OBJECTIVE: Post-stroke spasticity (PSS) is a common complication following stroke. This study describes the differences in healthcare resource utilization between patients who do and do not develop PSS in the UK. METHODS: Adults registered in The Health Improvement Network database with a recorded stroke between 2007 and 2011 were included. PSS was identified through Read codes; machine learning was used to retrospectively identify unrecorded PSS events. Patients with diagnosed or predicted PSS in the 12 months after stroke were matched to those with no PSS on age, sex, number of strokes, socioeconomic status, and comorbidities using the nearest neighbor algorithm. Utilization and costs associated with general practitioner visits, nurse visits, hospitalizations, referrals to specialists, laboratory tests, and medications in the 12 months after stroke were compared. RESULTS: Overall, 2,951 PSS cases were matched to 37,753 controls. During the first year, more PSS cases visited a physiotherapist (19% vs 7%) and occupational therapist (12% vs 5%) compared to controls. A greater proportion of cases were also referred to specialists (76% vs 64%) and hospitalized (33% vs 9%) compared to controls. Medication for spasticity was, on average, 14.68 prescriptions for cases and 5.64 for controls. Total mean costs per patient were £1,270 (standard deviation [SD] = 772) and £635 (SD = 273) for cases and controls, respectively. CONCLUSION: Costs after stroke for patients developing PSS are twice as high compared to patients who do not develop it, with the major driver being the number of hospital admissions. This highlights the need for better recording and closer management of PSS.

Regional disparities in botulinum toxin A (BoNT-A) therapy for spasticity in Sweden: budgetary consequences of closing the estimated treatment gap.

OBJECTIVES: As no national treatment guidelines for spasticity have been issued in Sweden, different regional treatment practices may potentially occur. This study examines botulinum toxin A (BoNT-A) treatment for spasticity on a regional level in Sweden and presents budgetary consequences of closing the estimated treatment gap. MATERIALS AND METHODS: Prevalence of spasticity in Sweden was estimated from published data. Regional sales data for BoNT-A were acquired from IMS Health. A set proportion of hospital BoNT-A use was assumed to represent treatment of spasticity. Total intervention cost of BoNT-A treatment was gathered from healthcare regional tariffs, while costs associated with spasticity were derived from publications on multiple sclerosis and stroke. RESULTS: Results show that the regional variation in treatment of spasticity with BoNT-A is large, with approximately every fourth patient being treated in Southern healthcare region compared to every tenth in the Stockholm-Gotland or Western healthcare regions. The incremental cost of filling the reported treatment gap was also assessed and was estimated at around 9.4 million EUR. However, for the incremental cost to be offset by savings in spasticity-related costs, only a small proportion of treatment responders (defined as patients transitioning to a lower severity grade of spasticity) was required (12%). CONCLUSIONS: The study revealed apparent regional disparities of BoNT-A treatment for spasticity in Sweden. The results further suggest that the incremental cost of eliminating the treatment gap has a high probability of being offset by savings in direct costs, even at a low proportion of the patients reaching clinical improvement.

What is new in MS spasticity research? Poster session highlights.

Each year at the Experts Summit, recent relevant research in the field of multiple sclerosis spasticity is featured in the poster sessions. Highlights of the 2015 poster session are presented.

Clinical case reviews and poster sessions in multiple sclerosis spasticity: main outcomes and highlights.

BACKGROUND: Individuals with multiple sclerosis (MS) spasticity present with a range of symptoms and disability levels that are frequently challenging to manage. Summary : Clinical case reviews in treatment-resistant MS spasticity were presented in five country-specific sessions conducted in parallel at the MS Experts Summit. Attendees at the Norwegian session discussed early response to new treatments for severe spasticity and highlighted the importance of titrating THC:CBD oromucosal spray (Sativex®) when adding it to baclofen. The French group focussed on MS symptoms and patient characteristics that interact with spasticity and agreed on a list of minimum ratings for diagnosis of MS spasticity symptoms. Attendees at the Spanish session concurred that THC:CBD oromucosal spray is effective and well tolerated as add-on therapy in treatment-resistant MS spasticity, particularly for pain, spasms and gait disturbances. The Italian group discussed the use of add-on THC:CBD oromucosal spray and other possible combination therapies for treatment-resistant MS spasticity. Attendees at the German session highlighted the need to address trigger factors for MS spasticity to reduce the potential for impact on activities of daily living (ADL) and quality of life (QoL). Three innovative studies of MS spasticity from the poster session were selected for closer review. The MOVE 1 EU epidemiological study indicated that, across western Europe, patients with MS spasticity continue to have unmet management needs. A literature review demonstrated that symptomatic relief of MS spasticity in patients who respond to THC:CBD oromucosal spray translates into sustainable improvements in ADL and QoL. Enriched-design studies of medications targeting the endocannabinoid system require careful interpretation due to possible pharmacodynamic 'priming', i.e. carry-over effects of successful active treatment during the enrichment phase. Key Messages: Sharing experiences of clinical practice, including experience with the use of THC:CBD oromucosal spray, may be useful to overcome some of the challenges in the overall management of patients with moderate to severe treatment-resistant MS spasticity.

Spasticity in multiple sclerosis: results of a patient survey.

Information regarding the epidemiology of spasticity in patients with multiple sclerosis (MS) in Spain is limited. This cross-sectional survey-based study was undertaken to evaluate the symptoms, severity and consequences of MS-related spasticity (MSS) and to estimate the prevalence of MSS overall and according to the degree of severity (mild/moderate/severe). Adult MS patients (n = 8463) from the two main Spanish MS patients' associations were asked to complete a web-based questionnaire. Two thousand six hundred twenty seven responses were received, of which 2029 were valid for analysis. Two thirds were for women. The mean age of respondents was 40.2 years and the mean MS duration was 8.7 years. MSS was reported by 65.7% of respondents with 40% of these rating it as moderate/severe. MS patients with spasticity experienced more symptoms (including greater difficulty walking), consumed more healthcare resources (including care and rehabilitation sessions), and had a higher degree of disability than patients without spasticity. There was a significant correlation between increasing severity of spasticity and worsening of symptoms. Only 42.4% of patients with moderate spasticity and 52.6% of patients with severe spasticity were currently receiving antispasticity medication compared with 69% and 79%, respectively, reported in a similar survey-based study from the United States; this is likely to reflect regional variations in practice. Early and effective treatment of MSS is important to minimise the consequences of spasticity-related symptoms on patients' quality of life and the economic burden on healthcare systems. In appropriate patients, antispastic treatment, including pharmacotherapy and physiotherapy/rehabilitation, may provide such benefits.

[Epidemiology and clinical assessment of spasticity in multiple sclerosis]. / Épidémiologie et évaluation clinique de la spasticité dans la sclérose en plaques.

Spasticity is a commonly seen symptom in patients with multiple sclerosis (MS). The vast majority of patients will suffer from this symptom during the course of the disease, and one- third of patients considers that spasticity contributes to a greater part of their disability. The symptom is frequently disabling. It can, however, allow some activities to be performed. Treatment of the symptom is sometimes deleterious, which is why strict assessment of the consequences of spasticity and anticipation of the outcome of antispastic treatment are necessary. Clinical scales, such as the Ashworth and Tardieu scales, are used in clinical practice. The essential element is not, however, assessment of the symptom, but its repercussions on activities of everyday life. It is important to make a list of what patients consider to be disabling situations to verify that they are truly consequences of spasticity. Considering the heterogeneity of clinical expression of spasticity in patients with MS, the use of a scale such as goal attainment scaling (GAS) can probably be totally adapted for the assessment of the effects of antispastic treatment.

Use of physical therapy services among middle-aged and older adults with multiple sclerosis.

BACKGROUND: There is limited understanding of the utilization of and perceived need for physical therapy services among middle-aged and older adults with multiple sclerosis (MS). The resulting knowledge gap compromises efforts for physical therapy service planning for this population. OBJECTIVE: The purpose of this study was to examine the use of and need for physical therapy services in a sample of adults with MS living in the Midwestern United States. DESIGN: This was a cross-sectional, descriptive study. METHODS: Data from telephone interviews with 1,065 people with MS, aged 45 to 90 years, were used for the study. A multinomial regression model was used to determine factors associated with use of physical therapy services (never, within the past year, more than a year ago). Logistic regression analysis examined factors associated with unmet needs for these services. RESULTS: Thirty-six percent of the sample reported never using physical therapy services, 33% reported using physical therapy services within the past year, and 31% reported using physical therapy services more than a year prior to the interview. Factors associated with recent use of physical therapy services included living in an urban or suburban community, deteriorating MS status, experiencing problems with spasticity (ie, hypertonicity), having difficulty moving inside the house, being hospitalized in the past 6 months, and seeing a family physician. These same factors were associated with unmet needs. Limitations Physical therapy service use was self-reported. Data were collected in 5 Midwestern states from people 45 years of age or older, which may limit generalizability. CONCLUSIONS: Factors associated with use of and need for physical therapy services reflect issues of access (geographical, referrals), MS status, and mobility difficulties.

Prevalence and management of poststroke spasticity in Thai stroke patients: a multicenter study.

OBJECTIVES: To study the prevalence, associated factors and management of poststroke spasticity in two muscle groups namely elbow flexor and knee flexor. MATERIAL AND METHOD: The Thai stroke rehabilitation registry (TSRR) was conducted among 9 rehabilitation centers. All subjects received the conventional rehabilitation program until they reached their rehabilitation goals or discharge criteria. The Brunnstrom motor recovery stage, Barthel Index, Thai Mental State Examination, Modified Ashworth Scale (MAS), and WHOQOL-BREF-Thai (26 items) questionnaires were used to assess the motor recovery, functional disability, cognition, spasticity and quality of life on admission respectively. The management of spasticity was also recorded. RESULTS: There were 327 patients with a mean age of 62.2-years-old participating in the study. The prevalence of poststroke spasticity was 41.6%. Among these the prevalences of spasticity of both elbow and knee flexors was 31.2% and of either elbow or knee flexor were 4.9% and 5.5% respectively. Spasticity with MAS grade 1 was found in the majority. The patients with spasticity had a significantly longer time to rehabilitation admission interval after the stroke (p = 0.049), had the Brunnstrom motor recovery stages of arm (p < 0.001), hand (p = 0.003) and leg (p < 0.001) significantly lower than the no spasticity group. The factor associated with spasticity was Brunnstrom motor recovery stage 2 and 3 of the arm with the odds ratio being 6.1 (95% CI = 2.5-14.9) and 3.5 respectively (95% CI = 1.3-9.2). Management of spasticity was demonstrated in 83 patients (25.4%). Therapeutic exercise, oral antispastic medication and assistive device were the first three managements frequently prescribed respectively. CONCLUSION: Spasticity was a common complication after stroke. Although the prevalence was quite high, spasticity with MAS grade 1 was found in the majority of cases. The associated factor was the Brunnstrom motor recovery stage of the arm. Therapeutic exercise was the mainstay of the management.

Bone strength in multiple sclerosis: cortical midtibial speed-of-sound assessment.

It has been previously suggested that multiple sclerosis (MS) patients are at increased risk for osteoporosis due to reduced mobility, decreased exposure to sunlight and recurrent steroid treatment. In order to systematically evaluate bone strength we assessed 256 MS patients (171 females, 75 males) through quantitative ultrasound measurement of cortical bone. Tibial speed of sound (SOS, m/sec) was measured at midpoint of the tibial shaft using a Soundscan 2000 (Myriad Ultrasound Systems, Rehovot, Israel) and results were compared to age- and gender-matched population norms. T-score distribution in male MS patients was similar to normal population. In contrast, for female MS patients T-score distribution was significantly different from population norms, reflected by increased SOS in 30.4% (T-score intervals 1-2 and >2 above normal values; P=0.001), compared with 7.4% in controls. These findings held true for both female patients younger and older than 45 years of age. Increased neurological disability and specifically motor involvement were more frequent in female patients with increased SOS (P<0.05). Bone strength was preserved in MS patients. In a subgroup of female patients increased SOS was conceivably related to spasticity.

Secondary impairments after spinal cord injury: a population-based study.

OBJECTIVE: To determine the prevalence of secondary impairments among individuals with long-standing spinal cord injury in Quebec and the potential relationships between these impairments and several variables. DESIGN: A review of 2,200 medical files was conducted to determine the target population; 976 patients were selected randomly and mailed questionnaires. The results were based on 482 individuals with spinal cord injury who returned the completed questionnaire. The questionnaire included 14 subsections, such as sociodemographic, medical, psychosocial, and environmental information. The medical section, including the type and level of lesion and the presence of secondary impairments, was analyzed. RESULTS: Urinary tract infection, spasticity, and hypotension were the most frequently reported secondary impairments, regardless of the severity of injury. Relationships between the prevalence of secondary impairments and the duration of injury, as well as perceived health status, were observed. CONCLUSIONS: This is the first study to describe secondary impairments after long-standing spinal cord injury in Quebec. Patients with spinal cord injury still present a high prevalence of secondary impairments many years after their rehabilitation, despite preventive education or medical follow-up visits. Further studies are required to determine the specific impact that these impairments have on the patients' social role and their quality-of-life.

The inter rater reliability of the original and of the modified Ashworth scale for the assessment of spasticity in patients with spinal cord injury.

Thirty patients with spinal cord injury (SCI) were randomly selected to participate in this study which evaluated the inter rater reliability of the original and of the modified Ashworth scale for the assessment of spasticity in the lower limbs. A doctor and a physiotherapist rated the muscle tone of hip adductors, hip extensors, hip flexors and ankle plantarflexors according to the original and to the modified Ashworth scale. The results were analyzed using a Cohen's Kappa statistical test and showed varying levels of reliability for different muscle groups and limbs. Kappa values ranged between 0.21 and 0.61 (mean 0.37). The original scale was slightly more reliable than was the modified scale. However, this difference was not significant (P > 0.05), and was not consistent between the two limbs and between different muscle groups. It was concluded that the Ashworth scale is of limited use in the assessment of spasticity in the lower limb of patients with SCI. Further work is required to establish a standardised speed of muscle stretching during the test, or to find more appropriate grades and descriptions of spasticity for this patient group. The effects of training of the raters in the use of the scales also warrants further investigation.