Claudia Celletti

Natural History and Manifestations of the Hypermobility Type Ehlers-Danlos Syndrome: A Pilot Study on 21 Patients

Hypermobility type Ehlers–Danlos syndrome (HT‐EDS) is a relatively frequent, although commonly misdiagnosed variant of Ehlers–Danlos syndrome, mainly characterized by marked joint instability and mild cutaneous involvement. Chronic pain, asthenia, and gastrointestinal and pelvic dysfunction are characteristic additional manifestations. We report on 21 HT‐EDS patients selected from a group of 40 subjects with suspected mild hereditary connective tissue disorder. General, mucocutaneous, musculoskeletal, cardiovascular, neurologic, gastrointestinal, urogynecological, and ear–nose–throat abnormalities are investigated systematically and tabulated. Six distinct clinical presentations of HT‐EDS are outlined, whose tabulation is a mnemonic for the practicing clinical geneticist in an attempt to diagnose this condition accurately. With detailed clinical records and phenotype comparison among patients of different ages, the natural history of the disorder is defined. Three phases (namely, hypermobility, pain, and stiffness) are delineated based on distinguishing manifestations. A constellation of additional, apparently uncommon abnormalities is also identified, including dolichocolon, dysphonia, and Arnold–Chiari type I malformation. Their further investigation may contribute to an understanding of the pathogenesis of the protean manifestations of HT‐EDS, and a more effective approach to the evaluation and management of affected individuals.

Management of pain and fatigue in the joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome, hypermobility type): Principles and proposal for a multidisciplinary approach

Joint hypermobility syndrome (JHS), or Ehlers–Danlos syndrome (EDS) hypermobility type (EDS‐HT), is a underdiagnosed heritable connective tissue disorder characterized by generalized joint hypermobility and a wide range of visceral, pelvic, neurologic, and cognitive dysfunctions. Deterioration of quality of life is mainly associated with pain and fatigue. Except for the recognized effectiveness of physiotherapy for some musculoskeletal features, there are no standardized guidelines for the assessment and treatment of pain and fatigue. In this work, a practical classification of pain presentations and factors contributing in generating painful sensations in JHS/EDS‐HT is proposed. Pain can be topographically classified in articular limb (acute/subacute and chronic), muscular limb (myofascial and fibromyalgia), neuropathic limb, back/neck, abdominal and pelvic pain, and headache. For selected forms of pain, specific predisposing characteristics are outlined. Fatigue appears as the result of multiple factors, including muscle weakness, respiratory insufficiency, unrefreshing sleep, dysautonomia, intestinal malabsorption, reactive depression/anxiety, and excessive use of analgesics. A set of lifestyle recommendations to instruct patients as well as specific investigations aimed at characterizing pain and fatigue are identified. Available treatment options are discussed in the set of a structured multidisciplinary approach based on reliable outcome tools.

Ehlers–Danlos syndrome hypermobility type and the excess of affected females: Possible mechanisms and perspectives†

Ehlers–Danlos Syndrome Hypermobility Type and the Excess of Affected Females: Possible Mechanisms and Perspectives Marco Castori,* Filippo Camerota, Claudia Celletti, Paola Grammatico, and Luca Padua Medical Genetics, Department of Molecular Medicine, Sapienza University, San Camillo-Forlanini Hospital, Rome, Italy Physical Medicine and Rehabilitation Division, Sapienza University, Umberto I Hospital, Rome, Italy Don Carlo Gnocchi Onlus Foundation, Milan, Italy Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy

Focal Muscle Vibration in the Treatment of Upper Limb Spasticity: A Pilot Randomized Controlled Trial in Patients With Chronic Stroke

OBJECTIVE To examine the clinical effect of repetitive focal muscle vibration (rMV) on the motor function of the upper extremity 1 month after treatment in patients with chronic stroke. DESIGN We performed a pilot randomized controlled trial using a double-blind, parallel-group study design. SETTING Medical center. PARTICIPANTS Patients with chronic stroke (N=49). INTERVENTIONS Patients randomly assigned to the study group (SG) received rMV, while patients in the control group (CG) received a placebo vibratory treatment. The patients and the clinical examiner were blind to the intervention. MAIN OUTCOME MEASURES The primary endpoint was an improvement of more than .37 points on the Functional Ability Scale of the Wolf Motor Function Test (WMFT FAS). The Modified Ashworth Scale and the visual analog scale were the secondary outcome measures. All measures were administered before the treatment (t0) and 1 week (t1) and 1 month (t2) after the treatment. RESULTS Twenty-eight patients were allocated to the SG and 21 to the CG. The analysis of variance for repeated measurements revealed a significant difference in the expression of the WMFT FAS score over time only in the SG (P=.006). The treatment was successful for 7 (33%) of 21 patients recruited in the SG and for 2 (13%) of 15 patients recruited in the CG. The relative risk was 2.5 (95% confidence interval, .60-10.39), and the number needed to treat was 5. The Wilcoxon test showed a statistically significant difference between t0 and t2 in the SG (P=.02). No adverse event was observed in the 2 groups. CONCLUSIONS Our results suggest that rMV treatment of the upper limb may improve the functional ability of chronic stroke patients, but a larger, multicenter, randomized controlled study is needed.

Measuring regularity of human postural sway using approximate entropy and sample entropy in patients with Ehlers-Danlos syndrome hypermobility type.

Ligament laxity in Ehlers-Danlos syndrome hypermobility type (EDS-HT) patients can influence the intrinsic information about posture and movement and can have a negative effect on the appropriateness of postural reactions. Several measures have been proposed in literature to describe the planar migration of CoP over the base of support, and the most used in clinical field are the CoP excursions in antero-posterior and medio-lateral direction. In recent years a growing number of studies have been designed to explore the complexity of the COP trajectories during quiet standing. We assessed 13 adults with EDS-HT (EDSG) and 20 healthy adults (CG) during static posture, evaluating the CoP using time and frequency domain analysis and entropy analysis (SampEn and ApEn parameters). Higher values of CoP displacements in medio-lateral and anterior-posterior directions for EDSG than CG were found; no differences were observed in CoP frequency. The entropy analysis showed lower value for EDSG than CG, pointing out the needing of EDSG to concentrate more attention on postural control, loosing complexity and reflecting a less automatized postural control.

Gynecologic and obstetric implications of the joint hypermobility syndrome (a.k.a. Ehlers–Danlos syndrome hypermobility type) in 82 Italian patients†‡

Joint hypermobility syndrome (JHS) emerges as likely the most common clinical form of Ehlers–Danlos syndrome. Given the striking predominance of affected women, practitioners often face gynecologic and obstetric issues. However, their decisions are still based on personal experience rather than literature due to the lack of a consistent body of evidence. We collected a set of gynecologic and obstetric features in 82 post‐puberal women with JHS attending two Italian centers. Common gynecologic findings were dysmenorrhea (82.9%), meno/metrorrhagias (53.7%), irregular menses (46.3%), and dispareunia/vulvodinia (31.7%). Forty women were nulliparous and 42 had one or more pregnancy for a total of 93 diagnosed conceptions. Of them, 16.1% were spontaneous abortions, 6.5% voluntary interruptions, 10.7% preterm deliveries, and 66.7% deliveries at term. Overall outcome of proceeding pregnancies was good with no stillbirth and fetal/neonatal hypoxic/ischemic event. Non‐operative vaginal delivery was registered in 72.2%, forceps/vacuum use in 5.5% and cesarean in 22.3%. Local/total anesthesia was successfully performed in 17 pregnancies without any problem. Major post‐partum complications included abnormal scar formation after cesarean or episiotomy (46.1%), hemorrhage (19.4%), pelvic prolapses (15.3%), deep venous thrombosis (4.2%), and coccyx dislocation (1.4%). Prolapses were the most clinically relevant complication and associated with episiotomy. Gathered data were discussed for practically oriented considerations.

Postural analysis in time and frequency domains in patients with Ehlers-Danlos syndrome

The goal of this work is to analyze postural control in Ehlers-Danlos syndrome (EDS) participants in time and frequency domain. This study considered a pathological group composed by 22 EDS participants performing a postural test consisting in maintaining standing position over a force platform for 30s in two conditions: open eyes (OE) and closed eyes (CE). In order to compare pathological group we acquired in the same conditions a control group composed by 20 healthy participants. The obtained center of pressure (COP) signal was analyzed in time and frequency domain using an AR model. Results revealed differences between pathological and control group: EDS participants pointed out difficulties in controlling COP displacements trying to keep it inside the BOS in AP direction and for this reason increased the use of ML mechanism in order to avoid the risk of fall. Also in CE conditions they demonstrated more difficulties in maintaining posture revealing the proprioceptive system is impaired, due to ligament laxity that characterized EDS participants. Frequency domain analysis showed no differences between the two groups, affirming that the changes in time domain reflected really the impairment to the postural control mechanism and not a different strategy assumed by EDS participants. These data could help in decision-making process to establish a correct rehabilitation approach, based on the reinforcing of muscle tone to supply the ligament laxity in order to prevent risks of falls and its consequences.

Gait strategy in patients with Ehlers-Danlos syndrome hypermobility type and Down syndrome.

People suffering from Ehlers-Danlos syndrome (EDS) hypermobility type present a severe ligament laxity that results in difficulties in muscle force transmission. The same condition is present in people suffering from Down syndrome (DS) even if their clumsy movements are due to cerebral and cognitive impairments. The aim of this study was to quantify the gait patterns of subjects with EDS and with DS using Gait Analysis (GA). We quantified the gait strategy in 12 EDS individuals and in 16 participants with DS. Both pathological groups were compared to 20 age-matched healthy controls in terms of kinematics and kinetics. Results showed that DS individuals are characterized by a more compromised gait pattern than EDS participants, even if both groups are characterized by joint hypermobility. All the patients showed significant decreased of ankle stiffness probably due to congenital hypotonia and ligament laxity, while different values of hip stiffness. These findings help to elucidate the complex biomechanical changes due to joint hypermobility and may have a major role in the multidimensional evaluation and tailored management of these patients.

Quality of life in the classic and hypermobility types of Elhers‐Danlos syndrome

highly dynamic within subjects and variable between subjects. Therefore, there is no stable baseline A concentration due to baseline fluctuations. Further, the placebo group’sC13-labeled A production and clearance rates were similar to previous studies, whereas those treated with drug had clearly decreased A production while having no difference in A clearance. This demonstrates that the groups were well matched for A metabolism, and that the effect on A production was due to the drug. The effects of LY450139 on A production are the most accurate and direct measurement in humans to date based on well-established research utilizing isotope tracers. Enzymelinked immunosorbent assay (ELISA) CSF A concentration measurements are confounded by variability and do not directly assess A production, which is the pharmacodynamic target of gamma-secretase inhibitors. Further, A concentration measured only by ELISA is affected by changes in total A pools due to A kinetics and likely underestimates the pharmacodynamic effect in single-dose drug studies. The magnitude of effect of a gamma secretase inhibitor necessary to produce a clinical effect is currently unknown. Direct measurement of A production using the SILK technique provides a highly quantitative measure that can be compared to the clinical outcomes of the ongoing phase III studies of LY450139. Based on these initial comparisons, this technique can be subsequently applied even more effectively to evaluate future compounds that affect A production.

Quantitative Effects of Repeated Muscle Vibrations on Gait Pattern in a 5-Year-Old Child with Cerebral Palsy

Objective. To investigate quantitatively and objectively the effects of repeated muscle vibration (rMV) of triceps surae on the gait pattern in a 5-year-old patient with Cerebral Palsy with equinus foot deformity due to calf spasticity. Methods. The patient was assessed before and one month after the rMV treatment using Gait Analysis. Results. rMV had positive effects on the patients gait pattern, as for spatio-temporal parameters (the stance duration and the step length increased their values after the treatment) and kinematics. The pelvic tilt reduced its anteversion and the hip reduced the high flexion evidenced at baseline; the knee and the ankle gained a more physiological pattern bilaterally. The Gillette Gait Index showed a significant reduction of its value bilaterally, representing a global improvement of the childs gait pattern. Conclusions. The rMV technique seems to be an effective option for the gait pattern improvement in CP, which can be used also in very young patient. Significant improvements were displayed in terms of kinematics at all lower limb joints, not only at the joint directly involved by the treatment (i.e., ankle and knee joints) but also at proximal joints (i.e., pelvis and hip joint).