Severe Spasticity Research Articles

Are Cannabis and Cannabinoids Effective for Symptomatic Treatment in People With Multiple Sclerosis?: A Cochrane Review Summary With Commentary.

Are Cannabis and Cannabinoids Effective for Symptomatic Treatment in People With Multiple Sclerosis?: A Cochrane Review Summary With Commentary.

HPDL mutations identified by exome sequencing are associated with infant neurodevelopmental disorders.

BackgroundRecent research found that biallelic HPDL variants can cause neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA), with only a few reports. Clinical phenotypic information on individuals with damaging HPDL variants may also be incomplete. The phenotype of NEDSWMA is characterized by severe neurodevelopmental delay, brain atrophy, and spasticity in infancy.MethodsExome sequencing was used in the proband and his parents to identify the underlying genetic cause. Candidate mutations were validated by classic Sanger sequencing. The clinical presentation of the infant who carried HPDL variants was summarized.ResultsWe identified a novel compound heterozygous variants in HPDL, c.995delC (p.T332Mfs) and c.1051C>T (p.Q351*) in the patient a 6‐month‐old boy presenting with global developmental delay, seizures, hypertonia, and limb spasticity. Brain magnetic resonance imaging (MRI) showed thin corpus callosum, ventriculomegaly, white matter volume reduction, bilateral frontotemporal subarachnoid widening, and sulcus deeping.ConclusionOur results provided important information for the associations of variants in HPDL with the neurodevelopmental disorder in infants, and broaden the genetic spectrum of HPDL‐related disease. This is the second report of the HPDL mutation causing infant neurodevelopmental disorders in a Chinese population.

Implications of the First Ex Vivo Gene Therapy Approved for Treating Early-Onset Metachromatic Leukodystrophy

Laura Campbell from Orchard Therapeutics, London, UK, opened the session by explaining the objectives of the symposium and providing some background information on metachromatic leukodystrophy (MLD). MLD is a rare and life-threatening inherited disease of the body’s metabolic system. MLD is caused by a mutation in the ARSA gene, which results in the accumulation of fats called sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and spleen. Over time, the nervous system is damaged and children with MLD experience progressive neurological symptoms, including motor, behavioural and cognitive regression, severe spasticity, and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat, and see. MLD is estimated to occur in approximately one in every 100,000 live births.1,2 The prognosis for MLD is extremely poor. Most children within the late infantile (LI) form die by the age of 5 years; the juvenile (JU) form progresses to death within 10–20 years; and those affected by the adult form typically die 25 years following the onset of symptoms.1 Approval of Libmeldy (atidarsagene autotemcel, [arsa-cel]; Orchard Therapeutics, London, UK), a gene therapy containing an autologous CD34+ cell enriched population, which contains haematopoietic stem and progenitor cells transduced ex vivo using a lentiviral vector encoding the human ARSA gene, for the treatment of early-onset MLD,3 opens up tremendous new possibilities for eligible children with MLD faced with this devastating disease, where previously no approved treatment options existed. Libmeldy is the first product approval for Orchard Therapeutics, a global gene therapy leader dedicated to rare diseases through the development of gene therapies.4 Francesca Fumagalli from the Paediatric Immunohematology Unit and Department of Neurology, Ospedale San Raffaele – Telethon Institute for Gene Therapy (OSR-TIGET), Milan, Italy, shared the evidence on the efficacy and safety of Libmeldy in patients with MLD. The clinical trial investigating Libmeldy started more than 10 years ago at OSR-TIGET. Campbell closed the symposium by providing several educational resources to support clinicians managing children with MLD.

Intrathecal Drug Delivery: Advances and Applications in the Management of Chronic Pain Patient.

Advances in our understanding of the biology of spinal systems in organizing and defining the content of exteroceptive information upon which higher centers define the state of the organism and its role in the regulation of somatic and automatic output, defining the motor response of the organism, along with the unique biology and spatial organization of this space, have resulted in an increased focus on therapeutics targeted at this extracranial neuraxial space. Intrathecal (IT) drug delivery systems (IDDS) are well-established as an effective therapeutic approach to patients with chronic non-malignant or malignant pain and as a tool for management of patients with severe spasticity and to deliver therapeutics that address a myriad of spinal pathologies. The risk to benefit ratio of IDD makes it a useful interventional approach. While not without risks, this approach has a significant therapeutic safety margin when employed using drugs with a validated safety profile and by skilled practioners. The present review addresses current advances in our understanding of the biology and dynamics of the intrathecal space, therapeutic platforms, novel therapeutics, delivery technology, issues of safety and rational implementation of its therapy, with a particular emphasis upon the management of pain.

High Doses of Botulinum Toxin Type A for the Treatment of Post-Stroke Spasticity: Rationale for a Real Benefit for the Patients.

In the past few years, there was a great interest in the use of higher doses of botulinum toxin type A, especially in case of upper and lower limb severe spasticity. To date, only one prospective, non-randomized, single-arm, multicenter, open-label, dose-titration study with the employment of incobotulinum toxin up to 800 U has been published, and the authors investigated safety and tolerability. Other researches showed efficacy in spasticity reduction, but there is a lack of evidence about the reasons to use high doses of botulinum toxin. This short communication highlights the benefits of higher doses for subjects with upper and lower limb spasticity.

Treating Mild, Moderate, or Severe Spasticity Matters to People with Multiple Sclerosis - SEEN-MSS Survey (P10-4.006)

Treating Mild, Moderate, or Severe Spasticity Matters to People with Multiple Sclerosis - SEEN-MSS Survey (P10-4.006)

Management of severe spasticity with and without dystonia with intrathecal baclofen in the pediatric population: a cross-sectional study.

To investigate the differences in delivery mode, daily dose, and catheter tip location in pediatric patients using intrathecal baclofen (ITB) pumps with spasticity plus dystonia versus spasticity alone. A single-center, cross-sectional study was performed by collecting retrospective data from electronic medical records. Demographic and diagnostic information was obtained, comparing patients with spasticity with or without dystonia. The data were analyzed for group differences using a two-tailed Student's t-test. Categorical data were analyzed for group differences using Pearson's χ2 test. A total of 137 patients met the criteria. The majority (114) had spasticity plus dystonia whereas only 23 were documented as spasticity alone. Simple continuous dosing was the most common delivery mode, but flex dosing was used more than twice as frequently with spasticity plus dystonia compared with spasticity alone (42% vs 17%). Patients with spasticity plus dystonia also had more rostral catheter tip locations. While it has been discussed anecdotally, this study confirms the supposition that patients with spasticity plus dystonia have increased dose requirements when compared with those with spasticity alone. Although there are no clear standards of care when managing these patients, they are often on higher daily dosages, are more likely to require flexed dosing method, and have higher catheter placements. Still, there are few studies that demonstrate improvements in dystonia with the use of ITB. In general, these patients would benefit from the development of universal standardizations as well as the confirmation that this is an appropriate treatment.

Long-term effect of additional rehabilitation following botulinum toxin-A on upper limb activity in chronic stroke: the InTENSE randomised trial

BackgroundIt is common for people with persistent spasticity due to a stroke to receive an injection of botulinum toxin-A in the upper limb, however post-injection intervention varies.AimTo determine the long-term effect of additional upper limb rehabilitation following botulinum toxin-A in chronic stroke.MethodAn analysis of long-term outcomes from national, multicenter, Phase III randomised trial with concealed allocation, blinded measurement and intention-to-treat analysis was carried out. Participants were 140 stroke survivors who were scheduled to receive botulinum toxin-A in any muscle(s) that cross the wrist because of moderate to severe spasticity after a stroke greater than 3 months ago, who had completed formal rehabilitation and had no significant cognitive impairment. Experimental group received botulinum toxin-A plus 3 months of evidence-based movement training while the control group received botulinum toxin-A plus a handout of exercises. Primary outcomes were goal attainment (Goal Attainment Scale) and upper limb activity (Box and Block Test) at 12 months (ie, 9 months beyond the intervention). Secondary outcomes were spasticity, range of motion, strength, pain, burden of care, and health-related quality of life.ResultsBy 12 months, the experimental group scored the same as the control group on the Goal Attainment Scale (MD 0 T-score, 95% CI -5 to 5) and on the Box and Block Test (MD 0.01 blocks/s, 95% CI -0.01 to 0.03). There were no differences between groups on any secondary outcome.ConclusionAdditional intensive upper limb rehabilitation following botulinum toxin-A in chronic stroke survivors with a disabled upper limb is not more effective in the long-term.Trial RegistrationACTRN12615000616572 (12/06/2015).

Image-Guided Stereotactic Radiosurgery for the Treatment of Spasticity and Pain: A Preliminary Experience.

BackgroundSpasticity is a major health problem worldwide. Response to current medical and rehabilitation treatments is often poor. Surgical treatment is available only for a very limited number of patients.AimWe recently reported the application of stereotactic radiosurgery as a treatment option for spasticity and related pain. This paper describes a larger experience using image-guided stereotactic radiosurgery targeting the cervical or lumbar spinal roots to relieve spasticity and pain in four patients.MethodsAll the patients had refractory spasticity and related pain, one patient had additional paroxystic neuralgic pain. The cause of spasticity and pain was a traumatic brain and/or spinal cord injury, brain and/or spinal cord surgery, and stroke. Symptoms affected the right superior limb in one patient, and the inferior limbs in three patients (unilaterally in two, bilaterally in one). According to the symptoms, one patient was treated at the cervical level (C7 right sensory root) and three patients at lumbar level (right L4, left S1, and L2 roots bilaterally). The target was selected on constructive interference in steady-state (CISS) MR, focusing the irradiation on the postganglionic sensory segment of the cervical root or the intra-foraminal dorsolateral sensory portion of the lumbar roots. Appropriate spasticity and pain scales were used to assess the patient’s status after the treatment.ResultsThe treatments were tolerated well. Marked symptomatic relief was found in all the treated patients. Improvements in spasticity and pain scales were observed up to the latest follow-up. After 2 years, the mean reduction of the visual analog scale (VAS) and Modified Ashworth Scale (MAS) was 64.3% and 43.7%, respectively, while the median reduction of MAS score was 50%.ConclusionsExcept for a previous case report, this is the first study describing a novel noninvasive technique based on image-guided radiosurgery to treat severe spasticity and pain due to brain and spinal cord injury. This novel technique appears to be safe and effective and deserves to be studied further.

On the recovery of disorders of consciousness under intrathecal baclofen administration for severe spasticity-An observational study.

BackgroundOccasionally, patients show dramatic recovery from disorders of consciousness (DOC) under intrathecal baclofen (ITB), an established treatment option for severe supraspinal spasticity. Anecdotal explanations for ITB‐related recovery of cognition include modulation of afferent impulses at the spinal level, thereby reducing spasticity‐related proprioceptive information overload within cortico–thalamo–cortical connections.ObjectiveIn this retrospective patient chart analysis, we assessed whether a reduction in spasticity would be associated with an increase in Coma Recovery Scale revised (CRS‐R) scores in a larger sample of patients than previously published.MethodsFrom a hospital‐based ITB treatment register, we extracted data from 26 patients with DOC and severe supraspinal spasticity who improved by >2 points on the Coma Recovery Scale revised (CRS‐R) within 6 months after ITB treatment initiation. We assessed Modified Ashworth scale (MAS) scores and CRS‐R scores on admission (PRE) and 3 and 6 months after initiation of ITB treatment (3M, 6M). We performed correlation analysis of the scores and their respective changes (PRE to 3M, 3M to 6M). We also correlated the time from acute event until ITB initiation to CRS‐R scores at 3M and 6M.ResultsITB led to significant improvement in spasticity based on MAS scores, which did not correlate to the improvements seen in CRS‐R total and subscale scores. Daily ITB dose did neither correlate to MAS scores nor to CRS‐total scores in the whole patient group, but after 3 months, ITB dose correlated to some CRS‐R subscale scores in some patient subgroups. Time until ITB treatment did not correlate to CRS‐R scores later on.ConclusionsOur data confirm that ITB may exert beneficial effects in selected DOC patients with respect to improved cognitive functions, which, however, do not correlate to its antispastic effect. The lack of correlation between time to ITB and CRS‐R outcome, but significant CRS‐R improvements following pump implantation, renders spontaneous remissions unlikely and leaves room for alternative pharmacological mechanisms.

Peter Oswald Derrick Pharoah, 1934–2021

... I knew Peter when he was head of the Department of Public Health at the University of Liverpool and worked closely with him for >10 years. My interest in paediatric and perinatal epidemiology was nurtured and developed by him, and I eventually took over the running of the Merseyside and Cheshire Cerebral Palsy register. He was also Editor of the International Journal of Epidemiology during this time (1991–2000)—a responsibility he took seriously, spending many hours reading submitted papers, often before sending them out for review. My personal knowledge of Peter comes from the many stories he would tell of himself, of his wife Margaret, of his four children and of his many grandchildren. He was proud of all of them, and clearly loved them dearly. Peter was born in India, where his parents were teachers. He trained as a doctor at St Mary’s Hospital Medical School, London, where he met his wife Margaret, also a doctor and who predeceased him. He qualified in 1958. While a student, he occasionally worked as a film extra. Peter’s first ambition was (as he told it) to become a physician but he had some difficulty passing the MRCP and so, in 1963, with his wife and young family, he took up a post as a medical officer in Rabaul, Papua New Guinea (PNG), followed by positions in Mount Hagen, Wewak and Goroka. While based in Mount Hagen, Peter learnt there were areas in the highlands where goitre and cretinism were common and the cause had not been identified. On his visit to one of these areas, the Jimi Valley, he was told that goitre had been present for many years, but endemic cretinism (which is characterized by severe spasticity of the legs, a squint, profound deafness and mental disability, affecting infants and young children) was new. According to the local inhabitants, this problem was seen for the first time after the arrival of ‘the White man’ (in 1959).

Successful long-term management of spasticity in people with multiple sclerosis using a software application: Results from a randomized, controlled, multicenter study.

Successful long-term treatment of spasticity in people with multiple sclerosis (pwMS) is challenging. We investigated the effects of multidisciplinary inpatient rehabilitation (MIR) and an individualized self-training program delivered by an app on spasticity in pwMS. First, we assessed the efficacy of 4-week MIR in ambulatory pwMS (Expanded Disability Status Scale < 7.0) with moderate to severe lower limb spasticity (defined by ≥4 points on the Numeric Rating Scale for spasticity [NRSs]) in a cohort of 115 pwMS at seven rehabilitation centers in Austria. In the case of a clinically relevant improvement in spasticity of ≥20% on the NRSs following MIR (n=94), pwMS were randomly allocated in a 1:1 ratio to either the newly designed MS-Spasticity App or to a paper-based self-training program for 12weeks. The primary outcome was change in NRSs (German Clinical Trials Registry DRKS00023960). MIR led to a significant reduction of 2.0 points on the NRSs (95% confidence interval [CI] = 2.5-2.0, p<0.000). MIR was further associated with a statistically significant improvement in spasticity on the Modified Ashworth Scale, strength, and all mobility outcomes. Following MIR, self-training with the MS-Spasticity App was associated with a sustained positive effect on the NRSs, whereas paper-based self-training led to a worsening in spasticity (median NRSs difference = 1.0, 95% CI = 1.7-0.3, p=0.009). The MS-Spasticity App was also associated with a significantly better adherence to self-training (95% vs. 72% completion rate, p<0.001). In pwMS, MIR is able to significantly improve lower limb spasticity, strength, and mobility. Following MIR, an individually tailored antispasticity program delivered by an app leads to sustained positive long-term management.

Reliability and diagnostic accuracy of corrected slack angle derived from 2D-SWE in quantitating muscle spasticity of stroke patients

BackgroundTo explore the feasibility of corrected slack angle acquired from two-dimensional shear wave elastography (2D-SWE) for quantitating the spasticity of medial gastrocnemius (MG) in stroke patients.MethodsConsecutive stroke patients with spastic MG and matched healthy controls were recruited. Intra- and interobserver reliability of 2D-SWE measurement were evaluated, and the correlation between corrected slack angle and modified Ashworth scale (MAS) score was examined. The corrected slack angle before and after botulinum toxin A (BoNT-A) injection was compared and its diagnostic performance in classifying the severity of spasticity were assessed with receiver operating characteristic (ROC) curve analysis.ResultsThe intra- (0.791 95% CI 0.432–0.932) and interobserver (0.751 95% CI 0.382–0.916) reliability of slack angle acquired with 2D-SWE were good. Significant correlation was found between corrected slack angle and MAS score (R = − 0.849, p < 0.001). The corrected slack angle increased after BoNT-A injection. The cutoff value of MAS ≥ 3 had the highest sensitivity (100%) and specificity (93.33%). The positive predictive value (PPV) for classification of MAS ≥ 1+ and the negative predictive value (NPV) for classification of MAS ≥ 3 were greater than 90%.Conclusion2D-SWE was a reliable method to quantitate the post-stroke spasticity. The corrected slack angle had advantage in classifying the severity of spasticity, especially in early identification of mild spasticity and confirmation of severe spasticity.

Intrathecal baclofen therapy in the management of drug-resistant muscle spasticity in patients with traumatic spinal cord injury

Neurorehabilitation of patients with spinal cord injury and severe muscle spasticity have always been one of the most challenging tasks for neurologists. Muscle spasticity significantly impairs patients’ quality of life and is often resistant to pharmacotherapy. Over the last 10 years, intrathecal baclofen therapy has become the most effective treatment for spasticity in Russia. In this study, we tried to systematize the data on intrathecal baclofen therapy in patients with spinal cord injury complicated by spasticity and to evaluate their treatment outcomes, as well as the incidence of adverse events. Our findings will ultimately help to clarify the need for intrathecal baclofen therapy in routine clinical practice.

Real Life Experience with Individualized Doses of Incobotulinumtoxina in Patients with Severe Spasticity Due to Acquired Brain Injury

The objective of the present study was to evaluate the effectiveness and tolerability of incobotulinumtoxinA, at doses according to individual needs, in 10 patients with acquired brain injury and severe upper and lower limb spasticity. Patients received a multipattern periodic treatment with ultrasound-guided injections of incobotulinumtoxinA at doses of 800-900 U in the upper and lower limbs. The mean number of injection cycles per patient was 4.2. The 0-10 visual analogue scale for pain score decreased significantly from pre-injection (mean: 4.7) to four-week post-injection (mean: 0.7). Similarly, the mean Ashworth Scale score (muscular tone assessment) at four-week post-injection (mean: 1.4) was significantly lower than at injection (mean: 2.5). Except for two patients in one pattern, all cases showed an improvement in passive range of motion assessments using goniometry. All patients reported maximum satisfaction with the treatment, all reporting “much improved” after the treatment. No treatment-related adverse effects were observed during the study. Individualized doses of incobotulinumtoxinA are effective and well-tolerated for this type of patients and allow better management of their severe spasticity. Therefore, individualization of doses should be taken into account for optimizing clinical outcomes and improving the patients’ treatment satisfaction.

Intrathecal baclofen therapy and Covid-19 infection - report of three cases

Introduction. Patients with severe spasticity are effectively treated with intrathecal baclofen therapy (ITB), but because of their invalidity, in case of infection, prognosis is poor. Case outline. We present three cases (two men and one woman) of patients treated with baclofen intrathecal therapy due to spasticity of all four extremities who underwent SARS-CoV2 virus infection. Two of them have multiple sclerosis, and one has trauma of the cervical segment of the spinal cord. In all three patients, the clinical presentation of COVID-19 infection occurred within six months of implantation of the pump for ITB. They were successfully treated in hospital with same dose of the drug and without exacerbation of neurological status. Barthel index (BI) and modified Rankin score were same before and after COVID-19 infection. In two cases BI was 20, and in one 69; and modified Rankin score (mRS) was 3 in one case, and 5 in two cases. Conclusion. Patients with severe spasticity who require intrathecal baclofen therapy can be safely treated regardless of the pandemic.

A rare case of the complex phenotype of hereditary spastic paraparesis due to a mutation in a novel gene variant

Hereditary spastic paraplegia (HSP), is a heterogeneous group of corticospinal tract disorders leading to progressive lower limb weakness and spasticity. Recessive mutations in DDHD2 characteristically involve early onset delay in motor and cognitive milestones coupled with spasticity. The complex nature of HSP is always confounding for appropriate management. An 11-year-old boy was brought by his parents for developmental delay noticed from 7 months of age and was diagnosed to have possible spastic cerebral palsy initially. Due to increasing spasticity, he underwent tendon release surgery for achilles and iliopsoas at 4 years of age. Now, he presented to us with increasing stiffness in his lower limbs even after regular physical therapy and myoclonic jerks. He had severe spasticity in the lower limbs with a power of 4/5. His activities of daily living were restricted due to severe spasticity. The lower limb deep tendon reflexes are exaggerated with positive Babinski sign and Scissoring of gait. He also had a mild intellectual disability. He was started on symptomatic management with muscle relaxants. Clinical exome sequencing showed a novel homozygous nonsense variation in exon 6 of DDHD2 gene. Prenatal genetic counseling was given for the next pregnancy and hence chorionic villus sampling for the variant testing of the developing fetus was done. The reports revealed a heterozygous state and asymptomatic carrier, unlikely to be affected by DDHD2-associated phenotype (spastic paraplegia genes 54). HSP should be considered when there is global developmental delay and increasing spasticity in lower limbs despite rehabilitation therapies.

Intrathecal Baclofen Pump Perioperative Management: Case Report and Literature Review

The use of intrathecal baclofen pumps (ITBP) has become increasingly common worldwide for the treatment of severe spasticity. Increased prevalence of patients using ITBPs makes encounters ever more common with surgical teams, these surgical interventions may be related to ITBP manipulation or completely unrelated to these devices. The anesthetist must be familiar with the normal functioning of ITBPs and be aware of baclofen pharmacokinetics in the cerebrospinal fluid, the occurrence of baclofen overdosing or withdrawal, and the potential pharmacological interactions between baclofen and drugs commonly used intraoperatively.

Triceps Surae Muscle Characteristics in Spastic Hemiparetic Stroke Survivors Treated with Botulinum Toxin Type A: Clinical Implications from Ultrasonographic Evaluation.

Equinovarus foot is one of the most commonly spasticity related conditions in stroke survivors, leading to an impaired gait and poor functional performances. Notably, spastic muscles undergo a dynamic evolution following typical pathophysiological patterns. Botulinum Neurotoxin Type A (BoNT-A) is the gold standard for focal spasticity treatment, and ultrasound (US) imaging is widely recommended to guide injections and monitor muscle evolution. The role of BoNT-A in influencing muscle fibroadipose degeneration is still unclear. In this study, we analyzed medial gastrocnemius (MG) and soleus (SOL) US characteristics (cross-sectional area, muscle thickness, pennation angle, and mean echo intensity) in 53 patients. MG and SOL alterations, compared to the unaffected side, depend on the spasticity only and not on the BoNT-A treatment. In functionally preserved patients (functional ambulation classification, FAC > 3; modified Ashworth scale, MAS ≤ 2), the ultrasonographic changes of MG compared to ipsilateral SOL observed in the paretic limb alone seems to be due to histological, anatomical, pathophysiological, and biomechanical differences between the two muscles. In subjects with poor walking capability and more severe spasticity, such ipsilateral difference was found in both calves. In conclusion, BoNT-A does not seem to influence muscle degeneration. Similar muscles undergo different evolution depending on the grade of walking deficit and spasticity.

A Neuro-Metabolic Syndrome that Needs to Be Discovered: A Child with Late Onset Asparagine Synthetase Deficiency

AbstractAsparagine synthetase (ASNS) deficiency is a rare inborn error of metabolism caused by a defect in ASNS—a gene encoding asparagine synthetase. It has mainly been described as a neurological phenotype manifesting as severe developmental delay, congenital microcephaly, spasticity, and refractory seizures; it is not associated with any specific dysmorphisms. ASNS deficiency leads to the inability to synthesize a nonessential amino acid in the brain, this explains why the symptoms are primarily neurological. The accumulation of aspartate/glutamate causes increased neuronal apoptosis leading to brain atrophy and increased neuronal excitability leading to seizures. Asparagine levels in plasma and cerebrospinal fluid are not reliable biomarkers for this disorder, therefore diagnosis is mainly obtained by molecular genetics. This disorder is associated with a poor prognosis and there is no treatment except supportive therapy. Prenatal diagnosis is possible. We report a case of a later onset form, c.146G &gt; A (p.Arg49Gln) variant in the ASNS gene detected by molecular analysis using next-generation sequencing; the patient's clinical presentation included microcephaly, regression of developmental milestones, epilepsy, and hyperthermia.