Treatment Approaches for Altered Facial Expression: A Systematic Review in Facioscapulohumeral Muscular Dystrophy and Other Neurological Diseases.

Background: Facial weakness is a key feature of facioscapulohumeral muscular dystrophy (FSHD) and may lead to altered facial expression and subsequent psychosocial impairment. There is no cure and supportive treatments focus on optimizing physical fitness and compensation of functional disabilities. Objective: We hypothesize that symptomatic treatment options and psychosocial interventions for other neurological diseases with altered facial expression could be applicable to FSHD. Therefore, the aim of this review is to collect symptomatic treatment approaches that target facial muscle function and psychosocial interventions in various neurological diseases with altered facial expression in order to discuss the applicability to FSHD. Methods: A systematic search was performed. Selected studies had to include FSHD, Bell's palsy, Moebius syndrome, myotonic dystrophy type 1, or Parkinson's disease and treatment options which target altered facial expression. Data was extracted for study and patients' characteristics, outcome assessment tools, treatment, outcome of facial expression and or psychosocial functioning. Results: Forty studies met the inclusion criteria, of which only three studies included FSHD patients exclusively. Most, twenty-one, studies were performed in patients with Bell's palsy. Studies included twelve different therapy categories and results were assessed with different outcomes measures. Conclusions: Five therapy categories were considered applicable to FSHD: training of (non-verbal) communication compensation strategies, speech training, physical therapy, conference attendance, and smile restoration surgery. Further research is needed to establish the effect of these therapies in FSHD. We recommend to include outcome measures in these studies that cover at least cosmetic, functional, communication, and quality of life domains.

Clinical, genetic, and histological features of centronuclear myopathy in the Netherlands.

Centronuclear myopathy (CNM) is a genetically heterogeneous congenital myopathy characterized by muscle weakness, atrophy, and variable degrees of cardiorespiratory involvement. The clinical severity is largely explained by genotype (DNM2, MTM1, RYR1, BIN1, TTN, and other rarer genetic backgrounds), specific mutation(s), and age of the patient. The histopathological hallmark of CNM is the presence of internal centralized nuclei on muscle biopsy. Information on the phenotypical spectrum, subtype prevalence, and phenotype-genotype correlations is limited. To characterize CNM more comprehensively, we retrospectively assessed a national cohort of 48 CNM patients (mean age = 32 ± 24 years, range 0-80, 54% males) from the Netherlands clinically, histologically, and genetically. All information was extracted from entries in the patient's medical records, between 2000 and 2020. Frequent clinical features in addition to muscle weakness and hypotonia were fatigue and exercise intolerance in more mildly affected cases. Genetic analysis showed variants in four genes (18 DNM2, 14 MTM1, 9 RYR1, and 7 BIN1), including 16 novel variants. In addition to central nuclei, histologic examination revealed a large variability of myopathic features in the different genotypes. The identification and characterization of these patients contribute to trial readiness.

LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

OBJECTIVE: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. METHODS: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. RESULTS: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. CONCLUSIONS: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

Posterior drooling in children with cerebral palsy and other neurodevelopmental disorders.

AIM: To evaluate the effect of botulinum neurotoxin A (BoNT-A) injections, submandibular gland excision (SMGE), and bilateral submandibular duct ligation (2DL) for the control of posterior drooling in children with neurological impairment. METHOD: In a retrospective cohort, children with neurological impairment (e.g. cerebral palsy) treated between 2000 and 2016 were identified. Mean age at time of surgery was 9 years (range 1-21y). The primary outcome was posterior drooling severity by a visual analogue scale (VAS; 0-10) at baseline, 8-weeks, and 32-weeks follow-up. The secondary outcome was lower respiratory tract infections during the follow-up period. RESULTS: Ninety-two patients (out of 475; 47 males, 45 females) were identified. They were undergoing three different treatments: BoNT-A (n=63), SMGE (n=16), and 2DL (n=13). A significant reduction in VAS over time was observed in the total group of 92 patients. After SMGE, VAS decreased significantly from 6.82 (SD 3.40) at baseline to 2.29 (SD 1.93) at 8 weeks, and 2.17 (SD 2.58) at 32 weeks (F[2.34]=11.618, p<0.001). There was no significant decrease after both BoNT-A and 2-DL. INTERPRETATION: Posterior drooling is an unfamiliar, potentially life-threatening condition that is treatable with medication, BoNT-A injections, or surgery. Although all treatments reduced signs and symptoms of posterior drooling, there is a greater effect after SMGE compared to BoNT-A and 2-DL. What this paper adds Submandibular gland excision has better results for posterior drooling than botulinum toxin A or submandibular duct ligation.

A closer look at the paralyzed face; a narrative review of the neurobiological basis for functional and aesthetic appreciation between patients with a left and a right peripheral facial palsy.

BACKGROUND: The facial nerve or n. facialis (NVII) is the seventh cranial nerve and it is responsible for the innervation of the mimic muscles, the gustatory organ, and the secretomotor function to the salivary, lacrimal, nasal and palatine glands. Clinical presentation of Facial Palsy (FP) is characterized by unilateral facial asymmetry and may present with a change in taste, decreased saliva production, and dysarthria. A facial palsy has a notable effect on the facial appreciation by both the patient and the environment and also affects quality of life and emotional processing. There appear to be differences in the appreciation of people with a left and right facial palsy. PURPOSE OF THIS REVIEW: The purpose of the review is to give an overview of the anatomy of the facial nerve, neuro-anatomy of face processing, and hemispheric specialization and lateralization. Further,an overview is given of the clinical studies that translated the neuro-anatomical and neurobiological basis of these concepts into clinical studies. What this review adds: This review emphasizes the neurobiological evidence of differences in face processing between the left and right cerebral hemisphere, wherein it seems that the right hemisphere is superior in emotional processing. Several theories are proposed; 1) a familiarity hypothesis and 2) a left-right hemispheric specialization hypothesis. In clinical studies, promising evidence might indicate that, in patients with FP, there is indeed a difference in how left and right FP are perceived. This might give differences in decreased quality of life and finally in occurrence of depression. Further research must aim to substantiate these findings and determine the need for altering the standard therapeutic advice given to patients.

An evaluation of predictors for success of two-duct ligation for drooling in neurodisabilities.

BACKGROUND: Drooling is dependent on various clinical variables. However, while drooling proves refractory to two-duct ligation in 40% of patients, predictors for treatment success are sparse and to date there is little evidence why some respond well while others are non-responders. We aim to find predictors for treatment success and study the effectiveness of two-duct ligation for drooling in neurodisabilities. METHODS: Fifty-four patients with moderate to severe drooling who had undergone two-duct ligation were screened for inclusion. Four patients were excluded due to missing or unreliable primary outcomes. The average age at the time of surgery was 12 years. Predictors were evaluated for treatment success which was defined as ≥ 50% visual analog scale for severity of drooling and/or drooling quotient reduction from baseline. Treatment effect was measured after 8 and 32 weeks compared to baseline. RESULTS: Age (more mature), adequate posture (no anteflexion), and normal speech are predictors for treatment success. Compared to baseline, drooling quotient was significantly lower at 8 (difference 18.6%, 95% confidence interval 12.3-24.9%) and 32 weeks (difference 10.1%, 95% confidence interval 3.9-16.4%). Compared to baseline, visual analog scale was significantly lower at 8 (difference 45.0, 95% confidence interval 37.0-52.9) and 32 weeks (difference 32.9, 95% confidence interval 25.0-40.7). CONCLUSIONS: Age, adequate posture, and a normal speech are predictors for treatment success, are easily determined pre-operatively, and help the clinician providing patient-specific probability of treatment success. There is a significant subjective and objective decrease of drooling after two-duct ligation.

Clinical, morphological and genetic characterization of Brody disease: an international study of 40 patients.

Brody disease is an autosomal recessive myopathy characterized by exercise-induced muscle stiffness due to mutations in the ATP2A1 gene. Almost 50 years after the initial case presentation, only 18 patients have been reported and many questions regarding the clinical phenotype and results of ancillary investigations remain unanswered, likely leading to incomplete recognition and consequently under-diagnosis. Additionally, little is known about the natural history of the disorder, genotype-phenotype correlations, and the effects of symptomatic treatment. We studied the largest cohort of Brody disease patients to date (n = 40), consisting of 22 new patients (19 novel mutations) and all 18 previously published patients. This observational study shows that the main feature of Brody disease is an exercise-induced muscle stiffness of the limbs, and often of the eyelids. Onset begins in childhood and there was no or only mild progression of symptoms over time. Four patients had episodes resembling malignant hyperthermia. The key finding at physical examination was delayed relaxation after repetitive contractions. Additionally, no atrophy was seen, muscle strength was generally preserved, and some patients had a remarkable athletic build. Symptomatic treatment was mostly ineffective or produced unacceptable side effects. EMG showed silent contractures in approximately half of the patients and no myotonia. Creatine kinase was normal or mildly elevated, and muscle biopsy showed mild myopathic changes with selective type II atrophy. Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) activity was reduced and western blot analysis showed decreased or absent SERCA1 protein. Based on this cohort, we conclude that Brody disease should be considered in cases of exercise-induced muscle stiffness. When physical examination shows delayed relaxation, and there are no myotonic discharges at electromyography, we recommend direct sequencing of the ATP2A1 gene or next generation sequencing with a myopathy panel. Aside from clinical features, SERCA activity measurement and SERCA1 western blot can assist in proving the pathogenicity of novel ATP2A1 mutations. Finally, patients with Brody disease may be at risk for malignant hyperthermia-like episodes, and therefore appropriate perioperative measures are recommended. This study will help improve understanding and recognition of Brody disease as a distinct myopathy in the broader field of calcium-related myopathies.

Unsuccessful submandibular duct surgery for anterior drooling: Surgical failure or parotid gland salivation?

OBJECTIVES: To evaluate if drooling recurrence after surgery of the submandibular ducts is due to surgical failure or other variables. METHODS: Historic cohort with prospective collected data of all patients with severe drooling who underwent unsuccessful submandibular duct surgery with subsequent re-intervention between 2003 and 2018. A reference cohort was used for comparison of clinical variables. RESULTS: Six males and 4 females were included (cerebral palsy n = 8, neurodevelopmental disorders n = 2). All patients underwent submandibular gland surgery as a primary intervention (duct ligation n = 8, submandibular duct relocation n = 2) followed by re-intervention (submandibular gland excision n = 7, parotid duct ligation n = 3). One patient underwent tertiary surgery (parotid duct ligation after re-intervention by submandibular gland excision). Three patients were successful after re-intervention. No difference was found between both re-intervention techniques. There was significantly more severe dental malocclusion (50% vs. 21%, P value = 0.047) and severe speech disorders (80% vs. 42%, P value = 0.042) in the current cohort when compared to the reference cohort. CONCLUSION: Recurrence of drooling surgery is most likely not caused by surgical failure of the primary intervention, because re-intervention (submandibular gland excision) did not lead to more success. Dysarthria and dental malocclusion might negatively influence treatment outcome.

Randomized controlled trial comparing botulinum vs surgery for drooling in neurodisabilities.

OBJECTIVE: To compare the effect of submandibular duct ligation (2-DL) and submandibular botulinum neurotoxin type A (BoNT-A) for drooling in children and adolescents with neurodevelopmental disabilities. METHODS: A randomized, interventional, controlled, and partly single-blinded study was performed in which submandibular BoNT-A was compared with 2-DL to treat excessive drooling. Main outcomes included a Visual Analog Scale (VAS), drooling quotient (DQ), drooling severity (DS) scale and drooling frequency (DF) scale. Each was obtained at baseline, and 8 and 32 weeks post treatment. RESULTS: Fifty-seven patients (mean age: 11 years, mean baseline VAS score 7.9, mean baseline DQ 27.3%) were randomized to the 2-DL or BoNT-A group. Four patients were excluded from analyses, leaving 53 patients for intention-to-treat analyses. Response to treatment, defined as a ≥50% reduction in DQ or VAS score, was higher for 2-DL after 32 weeks (63.0% vs 26.9%, p = 0.008). Both VAS score (24.5, p < 0.001) and DQ (-9.3%, p = 0.022) were significantly lower at follow-up after 2-DL vs BoNT-A. The total number of adverse events (p = 0.088, 40.7% vs 19.2%) and postoperative complaints was higher (p < 0.001, mean 9.6 vs 3.6 days) for 2-DL than for BoNT-A. CONCLUSION: The 2-DL procedure is a more effective treatment for drooling than botulinum toxin, but carries a slightly greater risk of complications and morbidity. TRIALREGISTERNL IDENTIFIER: NTR3537. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for children and adolescents with neurodevelopmental disabilities and severe drooling, 2-DL compared to a one-time intraglandular BoNT-A injection is more effective at reducing drooling at 32 weeks.

Effectiveness of submandibular duct relocation in 91 children with excessive drooling: A prospective cohort study.

OBJECTIVE: To evaluate the effectiveness of submandibular duct relocation (SMDR) in drooling children with neurological disorders. DESIGN: Prospective cohort study. SETTING: Academic Outpatient Saliva Control Clinic. PARTICIPANTS: Ninety-one children suffering from moderate to severe drooling. MAIN OUTCOME MEASURES: Direct observational drooling quotient (DQ; 0-100) and caretaker Visual Analogue Scale (VAS; 0-100). Secondary outcome measures were drooling severity (DS) and frequency rating scales. RESULTS: The DQ at baseline, 8 and 32 weeks postoperatively was 26.4, 12.3 and 10.8, respectively. VAS score decreased from 80.1 at baseline to 28.3 and 37.0 at 8 and 32 weeks after surgery. Median DS at baseline, 8 and 32 weeks was 5, 3 and 4, whereas the drooling frequency median scores were 4, 2 and 2, respectively. Five children required prolonged intubation due to transient floor of the mouth swelling, two of whom developed a ventilator-associated pneumonia. Another child developed atelectasis with postoperative pneumonia. Two more children needed tube feeding because of postoperative eating difficulties for 3 days or suprapubic catheterisation for urinary retention. Children aged 12 years or older (OR = 3.41; P = 0.03) and those with adequate stability and position of the head (OR = 2.84; P = 0.09) appeared to benefit most from treatment. CONCLUSIONS: Submandibular duct relocation combined with excision of the sublingual glands appears to be relatively safe and effective in diminishing visible drooling in children with neurological disorders, particularly in children aged 12 years and older and those without a forward head posture.

Recessive mutations in ATP8A2 cause severe hypotonia, cognitive impairment, hyperkinetic movement disorders and progressive optic atrophy.

BACKGROUND: ATP8A2 mutations have recently been described in several patients with severe, early-onset hypotonia and cognitive impairment. The aim of our study was to characterize the clinical phenotype of patients with ATP8A2 mutations. METHODS: An observational study was conducted at multiple diagnostic centres. Clinical data is presented from 9 unreported and 2 previously reported patients with ATP8A2 mutations. We compare their features with 3 additional patients that have been previously reported in the medical literature. RESULTS: Eleven patients with biallelic ATP8A2 mutations were identified, with a mean age of 9.4 years (range 2.5-28 years). All patients with ATP8A2 mutations (100%) demonstrated developmental delay, severe hypotonia and movement disorders, specifically chorea or choreoathetosis (100%), dystonia (27%) and facial dyskinesia (18%). Optic atrophy was observed in 78% of patients for whom funduscopic examination was performed. Symptom onset in all (100%) was noted before 6 months of age, with 70% having symptoms noted at birth. Feeding difficulties were common (91%) although most patients were able to tolerate pureed or thickened feeds, and 3 patients required gastrostomy tube insertion. MRI of the brain was normal in 50% of the patients. A smaller proportion was noted to have mild cortical atrophy (30%), delayed myelination (20%) and/or hypoplastic optic nerves (20%). Functional studies were performed on differentiated induced pluripotent cells from one child, which confirmed a decrease in ATP8A2 expression compared to control cells. CONCLUSIONS: ATP8A2 gene mutations have emerged as the cause of a novel neurological phenotype characterized by global developmental delays, severe hypotonia and hyperkinetic movement disorders, the latter being an important distinguishing feature. Optic atrophy is common and may only become apparent in the first few years of life, necessitating repeat ophthalmologic evaluation in older children. Early recognition of the cardinal features of this condition will facilitate diagnosis of this complex neurologic disorder.

The impact of submandibular duct relocation on drooling and the well-being of children with neurodevelopmental disabilities.

OBJECTIVE: The aim of this study was to evaluate the impact of a reduction in drooling after bilateral submandibular duct relocation (SMDR) with sublingual gland excision on daily life and care, as well as social and emotional consequences in children and adolescents with neurodevelopmental disabilities. METHODS: This prospective cohort study included 72 children and adolescents (46 males, 26 females) with moderate to severe drooling, and their caregivers. Mean age at the time of surgery was 15 years 2 months (SD 4y 3mo). Fifty-two children were diagnosed with cerebral palsy and 20 had other non-progressive developmental disabilities. A caregiver questionnaire to document the impact of drooling on daily care and economic consequences, social interaction and emotional development and self-esteem was administered before, and 8 and 32 weeks after surgery. RESULTS: Following bilateral SMDR the mean Visual Analogue Scale (VAS, 0-100) scores demonstrated a significant (p < 0.001) reduction in the severity of drooling from 81 at baseline to 28 and 36 after 8 and 32 weeks, respectively. This was accompanied by a decrease in the amount of daily care required and reduced economic consequences. In addition, an increase in social contact with other children and adults was reported by caregivers after surgery. CONCLUSION: Bilateral SMDR with sublingual gland excision provides a significant positive reduction in daily care of children suffering from drooling. Caregivers also report positive changes in their child's social interaction and sense of self-esteem.

Diagnosis and Management of Drooling in Children With Progressive Dystonia: A Case Series of Patients With MEGDEL Syndrome.

Drooling is a common problem in children with progressive dystonia. The authors noted a 58% incidence of drooling in 22/38 children with MEGDEL, a rare neurodegenerative cause of dystonia and report on the clinical course of four patients. Drooling of varying severity and subsequent respiratory problems were treated at the authors' multidisciplinary saliva-control outpatient clinic. One patient improved on antireflux medication, the second after medication with drooling as side effect was changed. Two other patients underwent salivary gland surgery, one of whom significantly improved; the other died shortly after surgery. The heterogeneity of the cases presented shows the need for stepwise and personalized treatment. The authors recommend the following: (1) optimize the treatment of the underlying neurological condition and replace medication that stimulates saliva secretion; (2) treat constipation, scoliosis, and gastroesophageal reflux if there is still a risk of chronic aspiration of saliva; (3) perform more intense/invasive treatment (botulinum toxin, salivary gland surgery).

The role of hypofractionation radiotherapy for diffuse intrinsic brainstem glioma in children: a pilot study.

PURPOSE: Most children with a diffuse intrinsic brainstem glioma will die within 1 year after diagnosis. To reduce patient burden, we investigated the feasibility of a radical hypofractionation radiotherapy schedule, given over 3 weeks, as an alternative to the standard regimen (30 fractions over 6 weeks). METHODS AND MATERIALS: Nine children, ages 3-13, were treated by 13 fractions of 3 Gy (n = 8) or 6 fractions of 5.5 Gy (n = 1) given over 3 weeks. All patients had symptoms for or=2 signs of the neurologic triad (long tract signs, ataxia, cranial nerve deficit). Bilateral involvement of the pons (n = 8), encasement of the basilar artery (n = 7) and extension into the cerebellar peduncle (n = 6) was visible on magnetic resonance imaging. RESULTS: Symptom improvement occurred in all patients within 2 weeks after start of radiotherapy. At a mean follow-up time of 15 months, 7 patients have died. Median time to progression and overall survival was 4.9 and 8.6 months, respectively. Median time to death after progression was 3.6 months. No Grade 3 or 4 toxicity was observed. In a recently published review of clinical trials, median time to progression, overall survival, and time between progression and death ranged from 5.0-8.8, 7.0-16, and 1.0-4.5 months, respectively, with more aggressive regimens. CONCLUSION: This radical hypofractionation radiotherapy regimen for children with diffuse intrinsic brainstem glioma is feasible and associated with no Grade 3 or 4 toxicities. With a minimal overall treatment time, it offers quick symptom relief and outcome results within the range of published data.

Brain metastasis from prostate small cell carcinoma: not to be neglected.

BACKGROUND: Symptomatic brain metastases from prostatic carcinoma are rare (0.05% to 0.5%). CASE REPORT: A 70-year-old man presented with a homonymous hemianopsia due to brain metastatic prostatic carcinoma shortly before becoming symptomatic of prostatic disease. CT and MRI of the brain showed a tumour deep in the right hemisphere near the thalamus and involving the optic radiation. RESULTS: Routine haematological and biochemical tests were normal. The prostate specific antigen level was low on two separate occasions. The prostatic and brain tumours showed identical appearances, namely of a poorly differentiated adenocarcinoma with neuroendocrine differentiation (small cell carcinoma). CONCLUSION: A literature review suggests that small cell carcinoma of the prostate is more likely to spread to the brain compared to adenocarcinoma and that brain metastases indicate a poor prognosis. The prostate gland should be remembered as a possible cause of brain metastases and that a normal serum prostate specific antigen does not exclude this diagnosis.