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.

IL-6 and TNF are Potential Inflammatory Biomarkers in Facioscapulohumeral Muscular Dystrophy.

Background: FSHD is a highly prevalent inherited myopathy with a still poorly understood pathology. Objective: To investigate whether proinflammatory cytokines are associated with FSHD and which specific innate immune cells are involved in its pathology. Methods: First, we measured circulating cytokines in serum samples: IL-6 (FSHD, n = 150; HC, n = 98); TNF (FSHD, n = 150; HC, n = 59); IL-1α (FSHD, n = 150; HC, n = 66); IL-1ß (FSHD, n = 150; HC, n = 98); MCP-1 (FSHD, n = 14; HC, n = 14); VEGF-A (FSHD, n = 14; HC, n = 14). Second, we tested trained immunity in monocytes (FSHD, n = 15; HC, n = 15) and NK cells (FSHD, n = 11; HC, n = 11). Next, we explored the cytokine production capacity of NK cells in response to different stimuli (FSHD, n = 39; HC, n = 22). Lastly, we evaluated the cytokine production of ex vivo stimulated MRI guided inflamed (TIRM+) and paired MRI guided non inflamed (TIRM-) muscle biopsies of 21 patients and of 8 HC muscle biopsies. Results: We included a total of 190 FSHD patients (N = 190, 48±14 years, 49% men) and of 135 HC (N = 135, 44±15 years, 47% men). We found that FSHD patients had higher concentrations of IL-6 and TNF measured (a) in the circulation, (b) after ex-vivo stimulation of NK cells, and (c) in muscle specimens. Besides, IL-6 circulating concentrations, as well as its production by NK cells and IL-6 content of FSHD muscle specimens, showed a mild correlation with disease duration, disease severity, and muscle weakness. Conclusion: These results show that IL-6 and TNF may contribute to FSHD pathology and suggest novel therapeutic targets. Additionally, the activation of NK cells in FSHD may be a novel pathway contributing to FSHD pathology.

Five-year follow-up study on quantitative muscle magnetic resonance imaging in facioscapulohumeral muscular dystrophy: The link to clinical outcome.

BACKGROUND: It is unclear how changes in quantitative muscle magnetic resonance imaging (MRI) relate to changes in clinical outcome in facioscapulohumeral muscular dystrophy (FSHD), although this information is crucial for optimal use of MRI as imaging biomarker in trials. We therefore assessed muscle MRI and clinical outcome measures in a large longitudinal prospective cohort study. METHODS: All patients were assessed by MRI at baseline and at 5-year follow-up, employing 2pt-Dixon and turbo inversion recovery magnitude (TIRM) sequences, after which fat fraction and TIRM positivity of 19 leg muscles were determined bilaterally. The MRI compound score (CoS) was defined as the mean fat fraction of all muscles weighted for cross-sectional area. Clinical outcome measures included the Ricci-score, FSHD clinical score (FSHD-CS), MRC sumscore (MRC-SS), and motor-function-measure (MFM). RESULTS: We included 105 FSHD patients [mean age 54 ± 14 years, median Ricci-score 7 (range 0-10)]. The median change over 5 years' time in the MRI-CoS was 2.0% (range -4.6 to +12.1; P < 0.001). The median change over 5 years' time in clinical outcome measures was small in all measures, with z-scores ranging from 5.0 to 7.2 (P < 0.001). The change in MRI-CoS correlated with change in FSHD-CS and Ricci-score (ρ = 0.25, respectively; ρ = 0.23, P < 0.05). The largest median increase in MRI-CoS was seen in baseline subgroups with an MRI-CoS 20-40% (6.1%), with ≥2 TIRM positive muscles (3.5%) or with an FSHD-CS 5-10 (3.1%). CONCLUSIONS: This 5-year study showed significant changes in MRI and clinical outcome measures and a significant correlation between changes in MRI-CoS and changes in clinical outcome measures. In addition, we identified subgroups of patients that are most prone to radiological disease progression. This knowledge further establishes quantitative MRI parameters as prognostic biomarkers in FSHD and as efficacy biomarkers in upcoming clinical trials.

Assessment of the burden of outpatient clinic and MRI-guided needle muscle biopsies as reported by patients with facioscapulohumeral muscular dystrophy.

Muscle biopsies are used in clinical trials to measure target engagement of the investigational product. With many upcoming therapies for patients with facioscapulohumeral dystrophy (FSHD), the frequency of biopsies in FSHD patients is expected to increase. Muscle biopsies were performed either in the outpatient clinic using a Bergström needle (BN-biopsy) or in a Magnetic Resonance Imaging machine (MRI-biopsy). This study assessed the FSHD patients' experience of biopsies using a customized questionnaire. The questionnaire was sent to all FSHD patients who had undergone a needle muscle biopsy for research purposes, inquiring about biopsy characteristics and burden, and willingness to undergo a subsequent biopsy. Forty-nine of 56 invited patients (88%) completed the questionnaire, reporting on 91 biopsies. The median pain score (scale 0-10) during the procedure was 5 [2-8], reducing to 3 [1-5] and 2 [1-3] after one and 24 h, respectively. Twelve biopsies (13.2%) resulted in complications, eleven resolved within 30 days. BN-biopsies were less painful compared to MRI-biopsies (median NRS: 4 [2-6] vs. 7 [3-9], p = 0.001). The burden of needle muscle biopsies in a research setting is considerate and should not be underestimated. MRI-biopsies have a higher burden compared to BN-biopsies.

Facioscapulohumeral dystrophy transcriptome signatures correlate with different stages of disease and are marked by different MRI biomarkers.

With several therapeutic strategies for facioscapulohumeral muscular dystrophy (FSHD) entering clinical testing, outcome measures are becoming increasingly important. Considering the spatiotemporal nature of FSHD disease activity, clinical trials would benefit from non-invasive imaging-based biomarkers that can predict FSHD-associated transcriptome changes. This study investigated two FSHD-associated transcriptome signatures (DUX4 and PAX7 signatures) in FSHD skeletal muscle biopsies, and tested their correlation with a variety of disease-associated factors, including Ricci clinical severity score, disease duration, D4Z4 repeat size, muscle pathology scorings and functional outcome measures. It establishes that DUX4 and PAX7 signatures both show a sporadic expression pattern in FSHD-affected biopsies, possibly marking different stages of disease. This study analyzed two imaging-based biomarkers-Turbo Inversion Recovery Magnitude (TIRM) hyperintensity and fat fraction-and provides insights into their predictive power as non-invasive biomarkers for FSHD signature detection in clinical trials. Further insights in the heterogeneity of-and correlation between-imaging biomarkers and molecular biomarkers, as provided in this study, will provide important guidance to clinical trial design in FSHD. Finally, this study investigated the role of infiltrating non-muscle cell types in FSHD signature expression and detected potential distinct roles for two fibro-adipogenic progenitor subtypes in FSHD.

Exploring the influence of smoking and alcohol consumption on clinical severity in patients with facioscapulohumeral muscular dystrophy.

Despite the growing knowledge on the (epi)genetic background of facioscapulohumeral muscular dystrophy (FSHD), the substantial variability in disease severity that exists between FSHD patients is not fully understood. We hypothesized that smoking and alcohol consumption are disease modifiers in FSHD and contribute to the variability in disease severity, because they are both associated with higher levels of oxidative stress in muscle tissue. Oxidative stress is known to influence FSHD muscle tissue. One hundred and ninety-eight genetically confirmed FSHD patients completed a questionnaire from which the number of packyears of smoking and the lifetime cumulative alcohol units consumed were calculated. Disease severity was determined by the FSDH evaluation score. Multiple linear regression analyses showed that both the number of packyears and the amount of alcohol consumption did not influence disease severity (respectively B = 0.025, ΔR2=0.006, p = 0.231; and B = 0.000, ΔR2=0.004, p = 0.406). Although smoking and excessive alcohol consumption are unhealthy habits which should be discouraged, these results show that smoking and alcohol consumption have no clinically meaningful modifying effect on disease severity in FSHD patients. However, prospective data should show whether alcohol consumption and smoking influence disease progression rate.

FSHD type 2 and Bosma arhinia microphthalmia syndrome: Two faces of the same mutation.

OBJECTIVE: To determine whether congenital arhinia/Bosma arhinia microphthalmia syndrome (BAMS) and facioscapulohumeral muscular dystrophy type 2 (FSHD2), 2 seemingly unrelated disorders both caused by heterozygous pathogenic missense variants in the SMCHD1 gene, might represent different ends of a broad single phenotypic spectrum associated with SMCHD1 dysfunction. METHODS: We examined and/or interviewed 14 patients with FSHD2 and 4 unaffected family members with N-terminal SMCHD1 pathogenic missense variants to identify BAMS subphenotypes. RESULTS: None of the patients with FSHD2 or family members demonstrated any congenital defects or dysmorphic features commonly found in patients with BAMS. One patient became anosmic after nasal surgery and one patient was hyposmic; one man was infertile (unknown cause) but reported normal pubertal development. CONCLUSION: These data suggest that arhinia/BAMS and FSHD2 do not represent one phenotypic spectrum and that SMCHD1 pathogenic variants by themselves are insufficient to cause either of the 2 disorders. More likely, both arhinia/BAMS and FSHD2 are caused by complex oligogenic or multifactorial mechanisms that only partially overlap at the level of SMCHD1.

Lifetime endogenous estrogen exposure and disease severity in female patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is characterized by large variability in disease severity, that is only partly explained by (epi)genetic factors. Clinical observations and recent in vitro work suggest a protective effect of estrogens in FSHD. The aims of this study were to assess whether the lifetime endogenous estrogen exposure contributes to the variability in disease severity in female patients, and whether female patients experience changes in disease progression during periods of hormonal changes. We calculated the lifetime endogenous estrogen exposure by subtracting periods with high progesterone levels (in which estrogens are counteracted) from the reproductive life span. Multiple linear regression in 85 patients did not show a contribution of the lifetime endogenous estrogen exposure to disease severity (B = 0.063, P-value = 0.517, ΔR2 = 0.003). The majority of women reported an unchanged rate of disease progression through periods of hormonal changes, like menarche, pregnancy or menopause. Women that noticed differences reported accelerations as well as decelerations. These results indicate that differences in estrogen exposure do not have a clinically relevant modifying effect on disease severity. However, a clinically relevant protective effect of greater differences in estrogen levels, or a protective effect caused by a more complex interplay with other reproductive hormones, cannot be ruled out.

Management of sporadic duodenal adenomas and the association with colorectal neoplasms: a retrospective cohort study.

GOALS: To evaluate management, outcome, and follow-up of patients with sporadic duodenal adenomas and assess the presence of colorectal neoplasms. BACKGROUND: With the widespread use of esophagogastroduodenoscopy, an increasing number of sporadic duodenal adenomas are diagnosed. An optimal algorithm for management has not been fully defined. Accumulating data suggest an association with colorectal neoplasms. STUDY: Patients diagnosed with sporadic duodenal adenomas at our institute from 1986 until 2008 were retrospectively reviewed. Data were collected from medical records. RESULTS: Fifty-four patients (28 men, 52%) were diagnosed with a sporadic duodenal adenoma at a median age of 59 years (range, 27 to 84 y); 33 patients (61%) underwent endoscopic or surgical intervention, 5 (9%) were only followed endoscopically, and 16 (30%) underwent no intervention or follow-up. Complete endoscopic removal was accomplished in at least 81% of cases, and no complications were reported; surgical intervention was complicated in 4 patients, with 1 resulting in death. Adenoma recurrence was 20% at a median follow-up of 18 months (range, 4 to 54 mo), but no carcinoma developed. Colorectal neoplasms were found in 16 of 29 patients (55%) who underwent colonoscopy, including 2 cancers (7%), 7 advanced adenomas (24%), and 7 nonadvanced adenomas (24%). CONCLUSIONS: Although no consistent approach to management of sporadic duodenal adenomas was followed, no duodenal carcinoma developed during the follow-up. Endoscopic intervention is preferred over surgical intervention, whenever possible. Once complete removal is ascertained, there is no strict indication for regular follow-up esophagogastroduodenoscopy, especially in elderly patients or patients with relevant comorbidity. Colonoscopic assessment is warranted in all patients diagnosed with sporadic duodenal adenomas.