Identification of Novel Variants in 8 Families With Meige Syndrome Using Whole-exome Sequencing

Background: Meige syndrome is a type of cranial dystonia characterized by blepharospasm and infraorbital dystonia and may be related to movement disorders of the mandibular and facial muscles, mouth, jaw, tongue, pharynx and cervical muscles. However, the etiopathogenesis of this disease condition remains unknown. Our present study aimed to find clues to the pathogenic factors of Meige Syndrome using whole-exome sequencing. Results: The study included 13 clinically diagnosed patients with Meige syndrome, a subtype of facial dystonia, from eight families (marked as Family 1 to Family 8) and two matched controls in two of the eight families. The genomic DNA was extracted from peripheral blood for whole-exome sequencing (WES). Quality control filtering, genome repeat filtering, genomAD/1000g filtering, exonic & splicing site filtering, hazard filtering, Varsome (ACMG) filtering were used to find the genes predicted to be damaging in Meige Syndrome. Among 582,715 SNP or indel variants. One variant in PALM3 (rs374267554, NC_000019.9:g.14167249G>A) passed our analysis and detection criteria. We verified the variant site using Sanger sequencing in another 48 patients. Structural analysis of the PALM3 variant predicted its potential effects on pathogenicity.Conclusions: Our findings contribute to a better understanding of the impact of the PALM3 variant on the pathogenicity of Meige Syndrome. Sequencing PALM3 in larger Meige Syndrome cohorts and functional studies will need to be performed to further elucidate the association between PALM3 and the disease.

Regional metabolic and network changes in Meige syndrome

To contribute to the understanding of the aetiology and pathogenesis of Meige syndrome, the metabolic networks of patients with Meige syndrome were investigated using 18F-fluoro-D-glucose positron emission tomography (18F-FDG-PET) imaging of cerebral glucose metabolism. Fifty right-handed and unmedicated primary Meige syndrome patients enrolled between September 2017 and September 2020 at the Department of Neurosurgery, Peking University People’s Hospital, and 50 age- and sex-matched healthy control subjects participated in the study. Metabolic connectivity and graph theory analysis were used to investigate metabolic network differences based on 18F-FDG-PET images. Glucose hypometabolism was detected in the left internal globus pallidus and parietal lobe, right frontal lobe and postcentral gyrus, and bilateral thalamus and cerebellum of patients with Meige syndrome. Clustering coefficients (Cps) (density threshold: 16–28%; P < 0.05) and shortest path lengths (Lps) (density threshold: 10–15%; P < 0.05) were higher in Meige syndrome patients than in healthy controls. Small-worldness was lower in Meige syndrome patients than in healthy controls, and centrality was significantly lower in the right superior occipital gyrus and pallidum and higher in the right thalamus. Hypometabolism in the globus pallidus and thalamus may indicate basal ganglia-thalamocortical motor circuit abnormalities as a pathogenic mechanism of Meige syndrome, providing a possible explanation for the efficacy of deep brain stimulation (DBS) in improving symptoms. Meige syndrome patients had abnormal small-world properties. Centrality changes in the right pallidus and thalamus verified the important roles of these regions in the pathogenesis of Meige syndrome.

Rescue Subthalamic Deep Brain Stimulation for Refractory Meige Syndrome

Meige syndrome is a segmental form of dystonia. It is a disabling disease, especially when refractory to treatment with botulinum toxin. A well-established therapeutic option is deep brain stimulation (DBS), and the target in bilateral globus pallidus internus (GPi DBS) demonstrated satisfactory short- and long-term efficacy. However, some patients present minor or suboptimal responses after GPi DBS, and in those cases, rescue DBS may be appropriate. The present case illustrates a good outcome after subthalamic nucleus (STN) and not after GPi DBS (considering that both were well positioned and had adequate programming). The larger dimension of the GPi and its somatotopic organization, with the stimulation outside the “face region,” could explain our outcomes.

Pallidal versus subthalamic deep-brain stimulation for meige syndrome: a retrospective study

Deep-brain stimulation (DBS) is an effective treatment for patients with Meige syndrome. The globus pallidus interna (GPi) and the subthalamic nucleus (STN) are accepted targets for this treatment. We compared 12-month outcomes for patients who had undergone bilateral stimulation of the GPi or STN. Forty-two Asian patients with primary Meige syndrome who underwent GPi or STN neurostimulation were recruited between September 2017 and September 2019 at the Department of Neurosurgery, Peking University People’s Hospital. The primary outcome was the change in motor function, including the Burke–Fahn–Marsden Dystonia Rating Scale movement (BFMDRS-M) and disability subscale (BFMDRS-D) at 3 days before DBS (baseline) surgery and 1, 3, 6, and 12 months after surgery. Secondary outcomes included health-related quality of life, sleep quality status, depression severity, and anxiety severity at 3 days before and 12 months after DBS surgery. Adverse events during the 12 months were also recorded. Changes in BFMDRS-M and BFMDRS-D scores at 1, 3, 6, and 12 months with DBS and without medication did not significantly differ based on the stimulation target. There were also no significant differences in the changes in health-related quality of life (36-Item Short-Form General Health Survey) and sleep quality status (Pittsburgh Sleep Quality Index) at 12 months. However, there were larger improvements in the STN than the GPi group in mean score changes on the 17-item Hamilton depression rating scale (− 3.38 vs. − 0.33 points; P = 0.014) and 14-item Hamilton anxiety rating scale (− 3.43 vs. − 0.19 points; P < 0.001). There were no significant between-group differences in the frequency or type of serious adverse events. Patients with Meige syndrome had similar improvements in motor function, quality of life and sleep after either pallidal or subthalamic stimulation. Depression and anxiety factors may reasonably be included during the selection of DBS targets for Meige syndrome.

Blepharospasm, Oromandibular Dystonia, and Meige Syndrome: Clinical and Genetic Update

Meige syndrome (MS) is cranial dystonia characterized by the combination of upper and lower cranial involvement and including binocular eyelid spasms (blepharospasm; BSP) and involuntary movements of the jaw muscles (oromandibular dystonia; OMD). The etiology and pathogenesis of this disorder of the extrapyramidal system are not well-understood. Neurologic and ophthalmic examinations often reveal no abnormalities, making diagnosis difficult and often resulting in misdiagnosis. A small proportion of patients have a family history of the disease, but to date no causative genes have been identified to date and no cure is available, although botulinum toxin A therapy effectively mitigates the symptoms and deep brain stimulation is gaining increasing attention as a viable alternative treatment option. Here we review the history and progress of research on MS, BSP, and OMD, as well as the etiology, pathology, diagnosis, and treatment.

Long-term Efficacy of GPi DBS for Cranio Facial Dystonia: a Retrospective Report of 13 Cases

Objective: This study evaluated the long-term efficacy of globus pallidus internus (GPi) deep brain stimulation (DBS) in the treatment of Cranio Facial dystonia (Meige syndrome) and investigated the correlation between the volume of tissue activated (VTA) of the GPi and each subregion and movement score improvement.Methods: We retrospectively analyzed the clinical data of 13 patients with drug-refractory Meige syndrome who were treated with GPi DBS. Pre- and postoperative Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS) scores were compared. Relationships between preoperative baseline variables and improvement in the BFMDRS-Movement (BFMDRS-M) score were analyzed. LEAD-DBS software was used for three-dimensional reconstruction of the GPi and implanted electrodes. Correlations between the GPi-VTA and score improvement were analyzed.Results: The average follow-up period was 36.6±11.0 months (18-55 months). The improvements in the BFMDRS-M score were 58.2% and 54.6% at 3 months after stimulation and at the final follow-up visit, respectively, and the improvements in the BFMDRS-Disability (BFMDRS-D) score were 53.6% and 51.7%, respectively. At the final follow-up visit, the improvements in BFMDRS-M scores for the eye, mouth, and speech/swallowing were significant (P<0.001). Age was an independent predictor of improvement in the BFMDRS-M score after DBS (P=0.005). A decrease in the BFMDRS-M score had significant positive relationships with the GPi-VTA (r=0.757, P=0.003). Conclusions: GPi DBS is an effective method to treat drug-refractory Meige syndrome. LEAD-DBS software can be used as an effective aid for visualization programing after DBS.

Outcome of Injection Botulinum Toxin in Blepharospasm

Introduction: Blepharospasm is a condition of involuntary spasm of the orbicularis oculi muscle which leads to intermittent or complete closure of the eyelids. Botulinum toxin is the currently recommended first line treatment for such blepharospasm. This study aims to find out the outcome of injection Botulinum toxin Type A in Blepharospasm. Materials and methods: It was a hospital based, prospective, interventional study conducted on patients diagnosed as Benign essential blepharospasm (BEB), Meige syndrome (MS) and Hemifacial spasm (HFS) by oculoplastic surgeon at Oculoplasty department OPD, Tilganga Institute of Ophthalmology, from December 2018 to November 2019. After taking all standard precautions for botulinum toxin injections, 6 to 8 sites for injecting 2.5 to 5 IU of the toxin were given. All the patients were evaluated before and after injections according to Jankovic spasm grading and improvement in functional impairment scale and followed on one week, one month, three month and when the symptoms reappeared. Results: A total of 43 cases which included 32 cases of Benign essential Blepharospasm, 9 Hemifacial spasm and 2 Meige syndrome. The mean Jankovic severity score was 3.51 ± 0.51 (range 3-4). The mean improvement in functional score was 2.60 ± 0.54 (range 1-3), was statistically significant (p-value <0.001).The effective period of injection was 130 ± 20.82 (93 – 189) days.38 patients had repeated injections after reappearance of symptoms. 4 patients had side effects of redness and hematoma at one site. Conclusion: This study concludes that Botulinum toxin type A is effective in the management of Benign essential blepharospasm, Hemifacial spasm and Meige syndrome. This along with a good safety profile justifies its role as a first line treatment therapy in blepharospasm. However, it is a temporary treatment option where the effect lasts for a short period of time and repeated injections are required.