Effects of Baclofen on Central Paroxysmal Positional Downbeat Nystagmus.

Paroxysmal positional nystagmus frequently occurs in lesions involving the cerebellum, and has been ascribed to disinhibition and enhanced canal signals during positioning due to cerebellar dysfunction. This study aims to elucidate the mechanism of central positional nystagmus (CPN) by determining the effects of baclofen on the intensity of paroxysmal positional downbeat nystagmus due to central lesions. Fifteen patients with paroxysmal downbeat CPN were subjected to manual straight head-hanging before administration of baclofen, while taking baclofen 30 mg per day for at least one week, and two weeks after discontinuation of baclofen. The maximum slow phase velocity (SPV) and time constant (TC) of the induced paroxysmal downbeat CPN were analyzed. The positional vertigo was evaluated using an 11-point numerical rating scale (0 to 10) in 9 patients. After treatment with baclofen, the median of the maximum SPV of paroxysmal downbeat CPN decreased from 30.1°/s [interquartile range (IQR) = 19.6-39.0°/s] to 15.2°/s (IQR = 11.2-22.0°/s, Wilcoxon signed rank test, p < 0.001) with the median decrement ratio at 40.2% (IQR = 28.2-50.6%). After discontinuation of baclofen, the maximum SPV re-increased to 24.6°/s (IQR = 13.1-34.4°/s, Wilcoxon signed rank test, p = 0.001) with the median increment ratio at 23.5% (IQR = 5.2-87.9%). In contrast, the TCs of paroxysmal downbeat CPN remained unchanged at approximately 3.0 s throughout the evaluation. The positional vertigo also decreased with the medication (Wilcoxon signed rank test, p = 0.020), and remained unchanged even after discontinuation of medication (Wilcoxon signed rank test, p = 0.737). The results of this study support the prior presumption that paroxysmal CPN is caused by enhanced responses of the semicircular canals during positioning due to cerebellar disinhibition. Baclofen may be tried in symptomatic patients with paroxysmal CPN.

Intrathecal baclofen efficacy for managing motor function and spasticity severity in patients with cerebral palsy: a systematic review and meta-analysis.

BACKGROUND: Spasticity can significantly affect a patient's quality of life, caregiver satisfaction, and the financial burden on the healthcare system. Baclofen is one of only a few options for treating spasticity. The purpose of this study is to investigate the impact of intrathecal baclofen (ITB) therapy on severe40.23 spasticity and motor function in patients with cerebral palsy. METHODS: We conducted a systematic review in PubMed, Scopus, Ovid, and the Cochrane Library in accordance with the PRISMA guidelines. We included studies based on eligibility criteria that included desired participants (cerebral palsy patients with spasticity), interventions (intrathecal baclofen), and outcomes (the Ashworth scales and the Gross Motor Function Measure [GMFM]). The within-group Cohen's d standardized mean differences (SMD) were analyzed using the random effect model. RESULTS: We screened 768 papers and included 19 in the severity of spasticity section and 6 in the motor function section. The pre-intervention average spasticity score (SD) was 3.2 (0.78), and the post-intervention average score (SD) was 1.9 (0.72), showing a 40.25% reduction. The SMD for spasticity reduction was - 1.7000 (95% CI [-2.1546; -1.2454], p-value < 0.0001), involving 343 patients with a weighted average age of 15.78 years and a weighted average baclofen dose of 289 µg/day. The SMD for the MAS and Ashworth Scale subgroups were - 1.7845 (95% CI [-2.8704; -0.6986]) and - 1.4837 (95% CI [-1.8585; -1.1088]), respectively. We found no relationship between the participants' mean age, baclofen dose, measurement time, and the results. The pre-intervention average GMFM (SD) was 40.03 (26.01), and the post-intervention average score (SD) was 43.88 (26.18), showing a 9.62% increase. The SMD for motor function using GMFM was 0.1503 (95% CI [0.0784; 0.2223], p-value = 0.0030), involving 117 patients with a weighted average age of 13.63 and a weighted average baclofen dose of 203 µg/day. In 501 ITB implantations, 203 medical complications were reported, including six new-onset seizures (2.96% of medical complications), seven increased seizure frequency (3.45%), 33 infections (16.26%), eight meningitis (3.94%), and 16 cerebrospinal fluid leaks (7.88%). Delivery system complications, including 75 catheter and pump complications, were also reported. CONCLUSION: Despite the risk of complications, ITB has a significant impact on the reduction of spasticity. A small but statistically significant improvement in motor function was also noted in a group of patients.

Baclofen and Tizanidine Adverse Effects Observed Among Community-Dwelling Adults Above the Age of 50 Years: A Systematic Review.

OBJECTIVE: This review highlights adverse effects of baclofen and tizanidine in older community-dwelling adults. DATA SOURCES: A literature search was conducted, including search terms of "adverse effect," "baclofen," "elderly," "falls," "fractures," and "tizanidine." Studies were included if they described community-dwelling adults aged 50 years and older who received oral baclofen or tizanidine. The Federal Drug Administration Adverse Event Reporting System (FAERS) data were compiled for adverse effect incidence. STUDY SELECTION AND DATA EXTRACTION: The literature search was completed in July 2019 and updated in June 2023. Reviews performed by 2 independent reviewers yielded 15 records. FAERS identified 486 (baclofen) and 305 (tizanidine) adverse effects of interest. DATA SYNTHESIS: Two retrospective cohort studies evaluating baclofen use in older adults showed increased hospitalizations for encephalopathy in chronic kidney disease (7.2% vs 0.1%) and end-stage renal disease (daily dose 20 mg or more; relative risk [RR] 19.8, 95% CI = [14.0-28.0]). Other articles were case reports; 10 articles reported dyskinesias, encephalopathy or disorientation, and drowsiness associated with baclofen, and 5 articles reported bradycardia and/or hypotension with tizanidine. The FAERS Public Dashboard revealed 12.1% and 28.7% overall incidence of adverse effects of interest, with a 27.8% and 29.2% incidence of falls for baclofen and tizanidine, respectively. Baclofen and tizanidine are associated with concerning adverse effects in older adults. Alternative agents should be considered, but, if necessary, providers should start at lower doses and increase slowly. CONCLUSIONS: This review highlights the importance of using baclofen and tizanidine with caution in older adults.

Downregulation of PMP22 ameliorates myelin defects in iPSC-derived human organoid cultures of CMT1A.

Charcot-Marie-Tooth disease is the most common inherited disorder of the PNS. CMT1A accounts for 40-50% of all cases and is caused by a duplication of the PMP22 gene on chromosome 17, leading to dysmyelination in the PNS. Patient-derived models to study such myelination defects are lacking as the in vitro generation of human myelinating Schwann cells has proved to be particularly challenging. Here, we present an induced pluripotent stem cell-derived organoid culture, containing various cell types of the PNS, including myelinating human Schwann cells, which mimics the human PNS. Single-cell analysis confirmed the PNS-like cellular composition and provides insight into the developmental trajectory. We used this organoid model to study disease signatures of CMT1A, revealing early ultrastructural myelin alterations, including increased myelin periodic line distance and hypermyelination of small axons. Furthermore, we observed the presence of onion-bulb-like formations in a later developmental stage. These hallmarks were not present in the CMT1A-corrected isogenic line or in a CMT2A iPSC line, supporting the notion that these alterations are specific to CMT1A. Downregulation of PMP22 expression using short-hairpin RNAs or a combinatorial drug consisting of baclofen, naltrexone hydrochloride and D-sorbitol was able to ameliorate the myelin defects in CMT1A-organoids. In summary, this self-organizing organoid model can capture biologically meaningful features of the disease and capture the physiological complexity, forms an excellent model for studying demyelinating diseases and supports the therapeutic approach of reducing PMP22 expression.

Positive allosteric modulators of the GABAB receptor: a new class of ligands with therapeutic potential for alcohol use disorder.

BACKGROUND: Positive allosteric modulators (PAMs) of the GABAB receptor constitute a new class of GABAB-receptor ligands. GABAB PAMs reproduce several pharmacological effects of the orthosteric GABAB receptor agonist, baclofen, although displaying a better safety profile. AIMS: This paper reviews the reducing or, frequently, even suppressing effects of all GABAB PAMs tested to date on multiple alcohol-related behaviours in laboratory rodents exposed to validated experimental models of human alcohol use disorder. RESULTS: Acute or repeated treatment with CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669 reduced excessive alcohol drinking, relapse- and binge-like drinking, operant alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced conditioned place preference in rats and mice. CONCLUSIONS: These effects closely mirrored those of baclofen; notably, they were associated to remarkably lower levels of tolerance and toxicity. The recent transition of ASP8062 to clinical testing will soon prove whether these highly consistent preclinical data translate to AUD patients.

Surgical treatment options for spasticity in children and adolescents with hereditary spastic paraplegia.

PURPOSE: To provide an overview of outcome and complications of selective dorsal rhizotomy (SDR) and intrathecal baclofen pump implantation (ITB) for spasticity treatment in children with hereditary spastic paraplegia (HSP). METHODS: Retrospective study including children with HSP and SDR or ITB. Gross motor function measure (GMFM-66) scores and level of spasticity were assessed. RESULTS: Ten patients were included (most had mutations in ATL1 (n = 4) or SPAST (n = 3) genes). Four walked without and two with walking aids, four were non-walking children. Six patients underwent SDR, three patients ITB, and one both. Mean age at surgery was 8.9 ± 4.5 years with a mean follow-up of 3.4 ± 2.2 years. Five of the SDR patients were walking. Postoperatively spasticity in the legs was reduced in all patients. The change in GMFM-66 score was + 8.0 (0-19.7 min-max). The three ITB patients treated (SPAST (n = 2) and PNPLA6 (n = 1) gene mutation) were children with a progressive disease course. No complications of surgery occurred. CONCLUSIONS: SDR is a feasible treatment option in carefully selected children with HSP, especially in walking patients. The majority of patients benefit with respect to gross motor function, complication risk is low. ITB was used in children with severe and progressive disease.

Intraventricular baclofen for palliative management of acquired generalized dystonia in pediatric patients: a case series and literature review.

Dystonia represents a significant source of disability in children. Generalized dystonia, which involves multiple body regions, leads to impaired mobility and motor function, resulting in substantial challenges in daily activities. Surgical treatments are used when medical treatments fail. Intrathecal baclofen (ITB) or deep brain stimulations (DBS) are the most employed surgical therapies. When these options are not feasible or ineffective, some authors have explored the use of intraventricular baclofen (IVB). In this report, we present four cases of pediatric patients with generalized dystonia who underwent treatment with IVB, resulting in notable improvements. To further explore the potential of this treatment modality, we conducted a comprehensive literature review. The findings from our study provide a comprehensive overview that can guide palliative management in similar cases.

Outcomes, complications, and dosing of intrathecal baclofen in the treatment of multiple sclerosis: a systematic review.

OBJECTIVE: The purpose of this systematic review was to evaluate empirical outcomes of studies in the literature that investigated effectiveness of intrathecal baclofen (ITB) in the treatment of multiple sclerosis (MS)-related spasticity (MSRS) based on various metrics. Since the first description of this route of baclofen delivery for MS patients by Penn and Kroin in 1984, numerous studies have contributed to the medical community's knowledge of this treatment modality. The authors sought to add to the literature a systematic review of studies over the last 2 decades that elucidates the clinical impact of ITB in treating MSRS with the following endpoints: impact on patient-centered outcomes, such as spasticity reduction (primary), complications (secondary), and dosing (secondary). METHODS: The authors queried three databases (PubMed, Scopus, and Cochrane Library) using the following search terms: (intrathecal baclofen) AND (multiple sclerosis). The set inclusion criteria were as follows: 1) original, full-text article; 2) written in the English language; 3) published between and including the years 2000 and 2023; 4) discussion of pre- and post-ITB pump implantation outcomes (e.g., reduction in spasticity and improved comfort) in MSRS patients with long-term ITB treatment; and 5) contained a minimum of 5 MS patients. Data on study type, patient demographics, follow-up periods, primary outcomes, and secondary outcomes were extracted from the included studies. RESULTS: The authors' search yielded 465 studies, of which 17 met inclusion criteria. Overall, they found evidence for the effectiveness of ITB in treating MSRS patients whose condition was refractory to oral medications, with significant reported changes in spasm frequency from pre- to postimplantation. They also found evidence supporting the positive impact of ITB on MSRS patients' quality of life. Moreover, the authors found that most complications were surgical rather than pharmacological. In addition, the average 1-year dose of ITB (reported in 7 of the included studies) was 191.93 µg/day, which is substantially lower than ITB doses reported in the literature for patients with central (non-MS) or spinal origins of spasticity at 1-year follow-up. CONCLUSIONS: The evidence supports ITB as a clinically effective treatment for MSRS, particularly in patients in whom oral antispasmodics and physiotherapy have failed. This systematic review contributes a comprehensive synthesis of clinical benefits, complications, and dosing of ITB reported over the past 2 decades, which furthers an understanding of ITB's clinical utility in practice.

Safety and efficacy of continuous intrathecal baclofen via cervical catheter tip: a retrospective case series.

OBJECTIVE: Intrathecal baclofen (ITB) is an effective treatment for hypertonia in children involving the implantation of a pump and catheter system. The highest concentration of ITB is at the catheter tip. The catheter tip location is most commonly within the lumbar or thoracic spine. The cervical tip location has traditionally been avoided because of concerns of hypoventilation and pneumonia; however, these complications in cervical compared with thoracic or lumbar placement have not been reliably proven. Some studies have suggested that cervical ITB location better treats upper-extremity hypertonia. There are limited data describing the safety and efficacy of cervical ITB on hypertonia. The authors present a single-institution retrospective case series highlighting the safety and efficacy of using cervical ITB location for the treatment of hypertonia. METHODS: Retrospective data analysis was performed for children who underwent continuous dosing cervical ITB between April 2022 and October 2023. Nonmodifiable risk factors, clinical variables, operative characteristics, and adverse outcomes were collected. RESULTS: This study included 25 patients (8 female). The mean age at implantation was 12.4 years, and the mean operative duration was 90 minutes. The mean Barry-Albright Dystonia Scale score decreased by 9.5 points (p = 0.01). The mean aggregated modified Ashworth scale score in the upper extremities decreased by 2.14 points (p = 0.04), and that in the lower extremities decreased by 4.98 points (p < 0.01). One patient each (4%) had infection and baclofen toxicity. Two patients (8%) had respiratory depression requiring continuous positive airway pressure. There was no incidence of pneumonia or wound dehiscence. CONCLUSIONS: The cervical catheter tip location for ITB is safe, is effective to control tone, and should be considered for the treatment of hypertonia. Larger studies with longer follow-up are necessary to further determine upper-limit dosing safety along with long-term functional benefits in these patients.

Uncovering the rate and risk factors of intrathecal baclofen pump-associated complications in the adult population.

OBJECTIVE: The aim of this study was 1) to describe the rate of intrathecal baclofen (ITB)-associated complications at a large tertiary center, and 2) to evaluate the impact of patient-related factors on the likelihood of developing such complications. METHODS: A retrospective single-center study was carried out. A total of 301 eligible patients were included in the analysis. Univariate regression models were used to evaluate the impact of age, sex, diagnosis, ambulation status, modified Ashworth scale score, body mass index, diabetes status, and pain level on the likelihood of developing a device-related infection, pump malfunction, catheter malfunction, and other clinically significant complications. RESULTS: Overall, 27% of patients experienced an ITB-related complication. The most common complications included infection (6%, 18/301), pump malfunction (7.3%, 22/301), and catheter malfunction (14%, 42/301). The univariate analyses revealed that the patient's ambulatory status had a significant impact on the likelihood of developing a catheter-related malfunction. Furthermore, a trend toward significance was identified between patients' preoperative body mass index and device-related infection. Finally, the risk of suffering any ITB-related complications was statistically correlated with the number of years that had passed since the initial pump implantation. CONCLUSIONS: The authors' analysis reveals a previously underrecognized association between ambulatory status at the time of ITB pump implantation and the incidence of catheter-related complications, and confirms the impact of time since surgery on the risk of developing any ITB-related complication. The patient's age, sex, diagnosis, diabetes status, or pain level at baseline were not associated with the risk of complications. Collectively, these insights contribute novel information to the existing literature, providing practical value for physicians in guiding patient selection for ITB therapy.

Spinal catheter revision in pediatric intrathecal baclofen pumps: risk factors and postoperative outcomes.

OBJECTIVE: Intrathecal baclofen (ITB) pumps are commonly used in pediatric patients with cerebral palsy (CP) and medically refractory spasticity. However, catheter malfunction and associated risk factors are not well understood. The aim of this study was to examine potential risk factors for spinal catheter malfunction and characterize postoperative follow-up to understand the clinical consequences. METHODS: Patients who received ITB pump replacement or revision at Boston Children's Hospital between 2010 and 2023 were retrospectively reviewed. The spinal catheter revision cohort (SCRC) included patients whose spinal catheter was occluded requiring lumbar catheter revision. The second cohort included abdominal pump replacements only (APRC). Between-group comparisons and multivariable regression identified factors associated with catheter revision and postoperative outcomes. RESULTS: Forty-one (33.6%) patients underwent spinal catheter revision and were compared with 81 patients (66.4%) who underwent abdominal pump replacement only. Younger age at surgery and an elevated preoperative lower-extremity modified Ashworth scale grade were associated with spinal catheter revision (p < 0.05). Catheter model type, tip location, and history of spinal fusion were not associated with obstruction. Postoperatively, SCRC patients experienced a higher rate of infection (17.1%) relative to APRC patients (0%) within 30 days from their ITB pump replacement procedure (p < 0.05) and greater likelihood of subsequent ITB system removal compared with the APRC (24.4% vs 7.4%, p < 0.05). Although not differing preoperatively, SCRC patients had lower postoperative ITB doses when compared with the APRC group (median dose 143 vs 350 µg/day, p < 0.05) at hospital discharge and remained statistically different at the 6-month and 1-year follow-ups (p < 0.05). There were no postoperative differences in baclofen overdose, withdrawal, or median number of hospital readmissions within 30 days. Overall, 31.7% of spinal catheter revisions were unanticipated by the clinical team at time of surgery. CONCLUSIONS: Younger age at surgery and increased preoperative lower-extremity tone may be risk factors for catheter obstruction, resulting in a higher rate of postoperative infection and subsequent ITB pump removal compared with pump replacement alone. Spinal catheter occlusion can complicate revision or replacement procedures, especially when unanticipated. Routine clinical assessment may be inadequate for diagnosing insidious catheter malfunction. Catheter occlusion deserves further study, and routine assessment of catheter patency may be warranted to prevent suboptimal tone therapy.

History and evolution of surgical treatment for spasticity: a journey from neurotomy to selective dorsal rhizotomy.

The evolution of neurosurgical approaches to spasticity spans centuries, marked by key milestones and innovative practitioners. Probable ancient descriptions of spasmodic conditions were first classified as spasticity in the 19th century through the interventions of Dr. William John Little on patients with cerebral palsy. The late 19th century witnessed pioneering efforts by surgeons such as Dr. Charles Loomis Dana, who explored neurotomies, and Dr. Charles Sherrington, who proposed dorsal rhizotomy to address spasticity. Dorsal rhizotomy rose to prominence under the expertise of Dr. Otfrid Foerster but saw a decline in the 1920s due to emerging alternative procedures and associated complications. The mid-20th century saw a shift toward myelotomy but the revival of dorsal rhizotomy under Dr. Claude Gros' selective approach and Dr. Marc Sindou's dorsal root entry zone (DREZ) lesioning. In the late 1970s, Dr. Victor Fasano introduced functional dorsal rhizotomy, incorporating electrophysiological evaluations. Dr. Warwick Peacock and Dr. Leila Arens further modified selective dorsal rhizotomy, focusing on approaches at the cauda equina level. Later, baclofen delivered intrathecally via an implanted programmable pump emerged as a promising alternative around the late 1980s, pioneered by Richard Penn and Jeffrey Kroin and then led by A. Leland Albright. Moreover, intraventricular baclofen has also been tried in this matter. The evolution of these neurosurgical interventions highlights the dynamic nature of medical progress, with each era building upon and refining the work of significant individuals, ultimately contributing to successful outcomes in the management of spasticity.

Intraventricular baclofen for intractable spasticity and secondary dystonia: a frame-based stereotactic approach and case series.

OBJECTIVE: Intraventricular baclofen has been reported as an alternative to intrathecal baclofen for managing refractory spasticity and dystonia in some circumstances. In this report, we described a frame-based stereotactic approach for precisely positioning of the infusion catheter into the third ventricle. MATERIAL AND METHODS: High resolution contrast-enhanced anatomical MR sequences was acquired prior to surgery for pre-planning. Catheter trajectory was planned to pass from the lateral ventricle to the third ventricle through the Foramen of Monro. The surgical procedure was adapted from the frame-based deep brain stimulation surgery. The Touch-Loc kit (SceneRay, China) was used to temporarily secure the catheter in place during the surgery. From July 2022 to December 2022, three patients suffering from intractable spasticity and/or secondary dystonia received IVB successfully using the described technique. RESULTS: No severe adverse events, including death, intracranial hemorrhage, infection, catheter migration or fracture, were documented at the last follow-up (range: 12‒24 months). Transient side effects included mild nausea following the initiation of infusion or the increase in infusion rate. All three patients responded to the IVB. CONCLUSIONS: The described frame-based stereotactic technique for IVB catheter implant is feasible and could be quickly mastered by neurosurgeons in related fields. Larger prospective cohorts with longer follow-up periods are necessary to further evaluate the long-term safety and efficacy of this procedure.

Postoperative outcomes and stimulation responses for sectioned nerve roots during selective dorsal rhizotomy in cerebral palsy.

BACKGROUND: Cerebral palsy (CP) is the most cause of motor dysfunction in children. Selective dorsal rhizotomy (SDR) plays a major role in long term spasticity control. However, limited data exists on the effect of SDR on postoperative spasticity treatment requirements and supraspinal effects, and the stimulation responses of dorsal nerve roots in those with CP. METHODS: The current study included the outcome for 35 individuals undergoing SDR for motor functional outcome, spasticity, baclofen dose changes, botulinum toxin injection frequency, and spasticity related orthopedic procedures. We also report on the stimulation responses in 112 individuals who underwent SDR at our institution. RESULTS: There was a significant difference in gross motor function measures (GMFM)-66 scores at last follow up that remained present when considering only ambulatory children but not with non-ambulatory children. Ashworth scores were significantly decreased for both upper and lower extremities after SDR at all follow up points. There was a significant decrease in Baclofen dose and botulinum toxin injections requirements after SDR, but no significant difference in the need for orthopedic intervention. A total of 5502 dorsal nerve roots were tested showing a decrease in stimulation intensity and increase in grade on the right side and for descending lumbosacral levels. CONCLUSIONS: SDR improves gross motor scores during short term follow up but has additional benefits in decreasing baclofen dosing and botulinum toxin injections requirements after surgery. They stimulation responses of sectioned dorsal nerve roots adds to the limited available data and our understanding of the pathological changes that occur in CP.

Whiteness, redness, blueness and greenness profile assessment and design of experiments approach to microwave-aided sensitive and green spectrofluorophotometric determination of baclofen.

As a gamma amino butyric acid-ergic agonist, Baclofen is often prescribed to adults and children for the treatment of severe spasticity that originates in the brain or spinal cord. Even after reviewing the literature extensively, no one has documented a method for estimating baclofen using microwave-assisted stability-indicating spectrofluorimetric techniques, despite the abundance of options for baclofen stability, assay, and bioanalysis. Organic solvents, which are typically necessary for current procedures but may be costly and toxic, have a severe effect on aquatic life and the environment. Using green solvents and 4-chloro-7-nitrobezofuran as a fluorescent probe, this work conducted a stability-indicating spectrofluorimetric estimate of baclofen. Through the use of a design-of-experiments technique, a reliable microwave-aided spectrofluorimetric method was developed, with little solvent consumption and time for sample analysis. Prior to conducting response surface analysis and optimizing important variables and responses, a fractional factorial design was used to screen method variables and responses. A central composite design was then employed for these purposes. This flexible spectrofluorimetric technique was used to assess baclofen concentrations in forced degraded samples and marketed formulations. For baclofen determination, the suggested spectrofluorimetric approach was found to be green, quick, easy to use, economical, and user-friendly.

Should the French approval of baclofen for alcohol dependence be extended to abstinence maintenance?

Ever since 2018 France has been the only country to approve the gamma aminobutyric acid type B (GABA-B) receptor agonist baclofen for alcohol dependence. This authorization follows a ten-year period of intensive off-label use during which baclofen was used in doses of up to 300 and even 400mg per day to support the gradual reduction of alcohol consumption in patients suffering from alcohol dependence. However, in international clinical trials, baclofen has mainly been studied to support the maintenance of abstinence. The French use of baclofen was therefore somewhat atypical as it paved the way for drug-supported approaches to reducing alcohol consumption, even before nalmefene was marketed. In line with this specific use of baclofen, approval was granted only for alcohol reduction support. However, a recent Cochrane systematic review and meta-analysis by Agabio et al. found significant efficacy only for abstinence maintenance, while no significant effect was found on alcohol reduction outcomes and no dose-response relationship was identified in the analyses. The safety of baclofen was judged to be good. Based on these substantial new results, the Société française d'alcoologie (SFA) now considers that baclofen should also be approved for the maintenance of abstinence. The extension of approval should not lead to the removal of the initial indication or the possibility of using high doses, as some patients have found this therapeutic regimen particularly useful for them. France, which has been a open skies national laboratory on the use of baclofen in alcohol dependence for over ten years, should let this original therapeutic option available to patients. However, it should update the regulatory framework defining the main conditions of access to treatment for patients based on the latest and highest scientific evidence.

Posterior Occipitocervical Fixation and Intrathecal Baclofen Therapy for the Treatment of Basilar Invagination with Klippel-Feil Syndrome: A Case Report.

Klippel-Feil syndrome (KFS) is characterized by the congenital fusion of the cervical vertebrae and is sometimes accompanied by anomalies in the craniocervical junction. In basilar invagination (BI), which is a dislocation of the dens in an upper direction, compression of the brainstem and cervical cord results in neurological defects and surgery is required. A 16-year-old boy diagnosed with KFS and severe BI presented with spastic tetraplegia, opisthotonus and dyspnea. CT scans showed basilar impression, occipitalization of C1 and fusion of C2/C3. MRI showed ventral compression of the medullocervical junction. Posterior occipitocervical reduction and fusion along with decompression were performed. Paralysis gradually improved postoperatively over 3 weeks. However, severe spasticity and opisthotonus persisted and intrathecal baclofen (ITB) therapy was initiated. Following this, opisthotonus disappeared and spasticity of the extremities improved. Rehabilitation therapy continued by controlling the dose of ITB. Five years after the surgery, self-propelled wheelchair driving was achieved and activities of daily life improved. The treatment strategy for patients with BI and congenital anomalies remains controversial. Posterior reduction and internal fixation using instrumentation were effective techniques in this case. Spasticity control achieved through a combination of surgery and ITB treatment enabled the amelioration of therapeutic efficacy of rehabilitation and the improvement of ADL.

[Intrathecal baclofen therapy: a 30-year experience]. / Intratekal'naya baklofenovaya terapiya: 30 let primeneniya.

BACKGROUND: The first pump for intrathecal administration of baclofen was implanted in 1984. Over thirty years, intrathecal prolonged infusion of muscle relaxants has occupied a worthy niche among all methods for correction of non-focal drug-resistant disabling muscle spasticity. However, this method has not become routine despite high awareness of specialists in Russia and abroad, as well as undeniable advantages for restoring the daily activity, improving the walking pattern and providing care and quality of life in people with limited mobility. This is due to scrupulous analysis of adverse events and accurate attitude towards its use.The purpose of this review was to systematize data on indications, selection criteria, pump implantation technique, subsequent patient management and treatment outcomes over a 30-year history. METHOD: A review of national and foreign literature was performed. RESULTS AND CONCLUSION: Prolonged intrathecal baclofen therapy is perspective for long-term treatment of severe spasticity interfering with quality of life and self-care if oral muscle relaxants are contraindicated or ineffective. This procedure is effective for impaired articulation, chewing and spastic pain syndrome. One can reduce the incidence of side effects via correct dosage of the drug, and tolerance to therapy can be reduced by timely elimination of problems with catheter.

[Features of lung damage in baclofen poisoning]. / Osobennosti povrezhdeniya legkikh pri otravlenii baklofenom.

OBJECTIVE: To reveal pathological lung changes in baclofen poisoning and to assess their dynamics. MATERIAL AND METHODS: The experiment included 20 mature (at age 20 weeks) male rats of Wistar line weighing 290-350 gr. The animals were divided into 3 study groups (5 rats in each) depending on experiment's duration after 85 mg/kg baclofen administration: 3, 4.5 and 24 h in the 1st, 2nd and 3rd groups, respectively. Control group consisted of 5 animals without baclofen administration. RESULTS: A number of pathological reactions, including circulatory disorder (venular and capillary congestion, hemorrhage in interalveolar septa, alveoli, sludge) and the appearance of emphysema loci (interalveolar septa at emphysema loci are thinned), alternating with atelectases and dystelectases. The area taken up by vessels after 4.5 h. baclofen administration was statistically significantly higher than in control group, and after 24 h. - statistically significantly higher than in 4.5 h. The area with white blood cells and WBC/IAP ratio after 4.5 h of baclofen administration were statistically significantly higher than in control group after 3 and 24 h of administration. The number of white blood cells, giving PAS positive reaction, increases during baclofen administration. The complex of pathological lung changes, revealed by ourselves, has a certain dynamics. CONCLUSION: The data on morphological lung changes combined with results of chemical examination can be used to diagnose baclofen poisoning and to determine the time elapsed since this medicine administration.

[Assessment of histological changes in the lungs and Bax and Bcl-2 expression in bronchial epithelium, alveolar type 1 cells and neutrophils of rats in poisoning with baclofen]. / Otsenka gistologicheskikh izmenenii legkikh i ekspressii Bax i Bcl-2 v bronkhial'nom epitelii, al'veolotsitakh 1-go tipa i neitrofilakh krys pri otravlenii baklofenom.

OBJECTIVE: To study the histological changes in lung of rats, evaluate their dynamics and determine the Bax and Bcl-2 genes expression in bronchial epithelium, alveolar type 1 cells and neutrophils at different times after the administration of baclofen. MATERIAL AND METHODS: The experiment was conducted on 20 mature (at the age of 20 weeks) male Wistar rats with a mass of 290-350 g, distributed in 4 groups (5 rats in each). Animals in the control group did not receive baclofen. Rats in experimental groups received baclofen at a dose of 85 mg/kg: in the 1st group, the experiment duration was 3 hours (time to maximum observed blood drug concentration); in the 2nd group - 4.5 h (drug half-life and time to maximum observed concentration of the main drug's metabolite - beta-[p-chlorophenyl])-gamma-hydroxybutyric acid in the blood); in the 3rd group - 24 h. RESULTS: A complex of pathological reactions developed in lungs of experimental animals when baclofen muscle relaxant was administered, namely circulatory disturbances at all levels of the microvasculature (venular and capillary congestion, hemorrhages in the interalveolar septums, alveoli, sludge), emphysema, sites of which punctuated with atelectases and dystelectases. The complex of pathological changes in the lungs had a certain dynamics and reached its highest severity by the 24th hour. Bax expression was strong, while Bcl-2 expression was moderate in the immunohistochemical (IHC) study of bronchical epithelium and alveolar type 1 cells, Bax and Bcl-2 expression in neutrophils was moderate in rats of the 1st group. The expression of Bax and Bcl-2 was strong in the bronchial epithelium and alveolar type 1 cells, the expression of Bax in neutrophils was moderate, and BCL-2 - strong in animals of the 2nd group. The expression of Bax in bronchial epithelium and alveolar type 1 cells was moderate, expression of Bcl-2 in bronchial epithelium and alveolar type 1 cells - strong, expression of Bax in neutrophils - weak and expression of Bcl-2 - strong among the rats of the 3rd group. CONCLUSION: The complex of pathological changes in lungs had a certain dynamic. Data on the histological changes in lungs in combination with the results of the chemical study, can be used to diagnose the poisoning by baclofen and to establish the time since the drug was administered. The results obtained during the IHC study suggest the involvement of apoptosis in the development of lesion of bronchial epithelium and alveolar type 1 cells. In addition, the expression of Bcl-2 in epithelial cells may play a role in the process of their regeneration.