Nusinersen Initiation After Onset of Weakness Does Not Prevent Progression of Hip Instability.

BACKGROUND: We report changes in the natural history of hip instability with nusinersen treatment among patients with spinal muscular atrophy (SMA) type II after onset of weakness, historically wheelchair-bound but now potentially ambulatory in the era of disease-modifying therapy. METHODS: Patients with genetically confirmed diagnoses of SMA type II who received intrathecal nusinersen from January 1, 2018, to June 30, 2022, were screened for inclusion. Patients with less than 6 months of follow-up, or prior hip surgeries were excluded. Primary clinical outcome measures included scores from Hammersmith motor functional scale expanded (HMFSE), revised upper limb module (RULM), 6-minute walk test (6MWT), and ambulatory status. Radiographic outcomes, including Reimer migration index, the presence of scoliosis, and pelvic obliquity, were also assessed. Secondary outcomes involved comparisons with a historical cohort of SMA type II patients treated at our institution who never received nusinersen. RESULTS: Twenty hips from 5 boys and 5 girls were included in the analysis, with a mean follow-up of 3 years and 8 months. The median age at time of nusinersen initiation was 6.8 years old, ranging between 2.5 and 10.3 years. All patients developed lower limb motor weakness before nusinersen initiation. After treatment with nusinersen, 1 previously stable hip (5%) developed subluxation, 15 hips (75%) remain subluxated, 3 hips (15%) remain dislocated, and 1 hip (5%) remained stable, with a statistically significant difference between the pretreatment and posttreatment groups ( P <0.01). Six patients (60%) were ambulatory at latest follow-up. Six patients (60%) had improved ambulatory ability; 2 had static ambulatory ability (20%); and 2 had deterioration in their walking ability. The median HFMSE score improved from 18.5 (range 0 to 46) to 22 (range 0 to 49) ( P =0.813), whereas the median RULM score improved from 17 (range 2 to 28) to 21.5 (range 5 to 37), which was statistically significant ( P =0.007). CONCLUSIONS: Hip instability persists despite treatment with nusinersen among patients with SMA type II who received nusinersen after onset of lower limb weakness. LEVEL OF EVIDENCE: Therapeutic Level IV.

Perioperative opioid-minimization approach as a useful protocol in the management of patients with Ehlers-Danlos syndrome-hypermobility type, craniocervical instability and severe chronic pain who are to undergo occipito-cervical fixation.

Patients suffering from connective tissue disorders like Ehlers-Danlos syndrome hypermobility type/joint hypermobility syndrome (EDS-HT/JHS) may be affected by craniocervical instability (CCI). These patients experience myalgic encephalomyelitis, chronic fatigue, depression, extreme occipital-cervical pain, and severe widespread pain that is difficult to relieve with opioids. This complex and painful condition can be explained by the development of chronic neuroinflammation, opioid-induced hyperalgesia, and central sensitization. Given the challenges in treating such severe physical pain, we evaluated all the analgesic methods previously used in the perioperative setting, and updated information was presented. It covers important physiopathological aspects for the perioperative care of patients with EDS-HT/JHS and CCI undergoing occipital-cervical/thoracic fixation/fusion. Moreover, a change of paradigm from the current opioid-based management of anesthesia/analgesia in these patients to the perioperative opioid minimization strategies used by the authors was analyzed and proposed as follow-up considerations from our previous case series. These strategies are based on total-intravenous opioid-free anesthesia, multimodal analgesia, and a postoperative combination of anti-hyperalgesic coadjuvants (lidocaine, ketamine, and dexmedetomidine) with an opioid-sparing effect.

A protocol for a randomized clinical trial assessing the efficacy of hypertonic dextrose injection (prolotherapy) in chronic ankle instability.

BACKGROUND: Lateral ankle sprain (LAS) is a common injury. Conservative care is not uniformly effective. Chronic ankle instability (CAI) results in up to 70% of patients with LAS in the physically active population. LAS, together with subsequent osteochondral lesions and pain in many patients, leads to the development of post-traumatic osteoarthritis, resulting in a substantial direct and indirect personal and societal health burden. Dextrose prolotherapy (DPT) is an injection-based therapy for many chronic musculoskeletal conditions but has not been tested for CAI. This protocol describes a randomized controlled trial to test the efficacy of DPT versus normal saline (NS) injections for chronic ankle instability (CAI). METHODS AND ANALYSIS: A single-center, parallel-group, randomized controlled trial will be conducted at a university-based primary care clinic in Hong Kong. A total of 114 patients with CAI will be randomly allocated (1:1) to DPT and NS groups. The primary outcome will be the Cumberland Ankle Instability Tool scores at 1 year. The secondary outcomes will be the number of re-sprains in 1 year, the Star Excursion Balance Test, the 5-level of EuroQol 5-dimension questionnaire, and the Foot and Ankle Ability Measure. All outcomes will be evaluated at baseline and at 16, 26, and 52 weeks using a linear mixed model. DISCUSSION: We hypothesized the DPT is a safe, easily accessible, and effective treatment for patients with CAI. This RCT study will inform whether DPT could be a primary non-surgical treatment for CAI. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000040213 . Registered on 25 November 2020.

Arterial tortuosity syndrome causing recurrent transient ischemic attacks in young adult: a case report.

BACKGROUND: Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive disorder characterized by elongated and tortuous arteries. Although ATS showed a significant clinical and pathophysiological overlap with other syndromes involving connective tissues, only few cases of cerebrovascular events related to this syndrome have been described so far. CASE PRESENTATION: We report the case of a 33-years-old male diagnosed with ATS since childhood, that experienced three sudden episodes of expressive aphasia and right hemiparesis with spontaneous resolution. He was treated with recombinant tissue plasminogen activator (r-TPA) at a dosage of 0.9 mg/kg with a complete recovery. Brain Magnetic Resonance Imaging (MRI) showed the absence of acute ischemic lesions and the patient was diagnosed with recurrent transient ischemic attacks (TIA). Intracranial and supra-aortic trunks Magnetic Resonance Angiography (MRA) and Angio-CT scan of the thoracic and abdominal aorta showed marked vessel tortuosity without stenosis. To our knowledge, this is the first reported case of an ATS patient with TIA in young age that was treated with intravenous thrombolysis with recombinant plasminogen activator. CONCLUSION: Our report strengthens the relationship between ATS and juvenile cerebrovascular events, suggesting that an extensive study of body vessels in order to detect potential stenoses or occlusions in these cases is needed. The greater predisposition to cerebrovascular events in ATS could benefit from a more aggressive primary and secondary prevention therapy.

Perioperative Botulinum Toxin A in the Surgical Management of Seizure-Related Shoulder Instability: A Case Report.

CASE: A 20-year-old woman presented with recurrent bilateral shoulder instability concurrent with severe, treatment-refractory epilepsy. Imaging revealed glenoid bone loss of 25% to 28% and large Hill-Sachs defects bilaterally. Bone graft augmentation of the glenoid and infill of the Hill-Sachs defects was performed bilaterally. Perioperative neuromuscular paralysis of shoulder girdle muscles with botulinum toxin was performed to facilitate recovery. Both shoulders at 2.5 and 4 years, respectively, demonstrate excellent stability and radiographic union despite continued seizure activity. CONCLUSION: Perioperative neuromuscular paralysis with botulinum toxin may provide early graft protection after the surgical treatment of glenohumeral instability because of seizures.

Vague Posterior Knee Discomfort in a Soccer Player: A Clinical Vignette.

A 24-yr-old male soccer player presented with a 7-yr history of left posterior knee "looseness." Evaluation 7 yrs ago, at the time of initial injury, revealed atraumatic anterior and posterior cruciate ligament sprains. On representation, the patient described the pain as a constant, dull ache, 3/10, but his biggest complaint was this feeling of "instability" and looseness where his knee would "buckle" 3-4 times a week. Physical examination was positive for grade 1 posterior drawer and grade 1 posterior sag signs. Reverse KT-1000 testing showed a 3-mm side-to-side difference. Sonographic evaluation confirmed magnetic resonance imaging findings of posterior cruciate ligament laxity and buckling and a small cystic lesion abutting the posteromedial margin of the distal 1/3 of the posterior cruciate ligament. After a trial of physical therapy, the patient elected to undergo experimental injection of dextrose hyperosmolar solution. This resulted in resolution of the cyst and reverse KT-1000 measurements improved to a side-to-side difference of 1 mm. The patient's subjective feeling of looseness and instability resolved by 7 wks.

Local controlled release of corticosteroids extends surgically induced joint instability by inhibiting tissue healing.

BACKGROUND AND PURPOSE: Corticosteroids are intra-articularly injected to relieve pain in joints with osteoarthritis (OA) or acute tissue damage such as ligament or tendon tears, despite its unverified contraindication in unstable joints. Biomaterial-based sustained delivery may prolong reduction of inflammatory pain, while avoiding harmful peak drug concentrations. EXPERIMENTAL APPROACH: The applicability of prolonged corticosteroid exposure was examined in a rat model of anterior cruciate ligament and medial meniscus transection (ACLT + pMMx) with ensuing degenerative changes. KEY RESULTS: Intra-articular injection of a bolus of the corticosteroid triamcinolone acetonide (TAA) resulted in enhanced joint instability in 50% of the joints, but neither instability-induced OA cartilage degeneration, synovitis, nor the OA-related bone phenotype was affected. However, biomaterial microsphere-based extended TAA release enhanced instability in 94% of the animals and induced dystrophic calcification and exacerbation of cartilage degeneration. In healthy joints, injection with TAA releasing microspheres had no effect at all. In vitro, TAA inhibited cell migration out of joint tissue explants, suggesting inhibited tissue healing in vivo as mechanisms for enhanced instability and subsequent cartilage degeneration. CONCLUSIONS AND IMPLICATIONS: We conclude that short-term TAA exposure has minor effects on surgically induced unstable joints, but its extended presence is detrimental by extending instability and associated joint degeneration through compromised healing. This supports a contraindication of prolonged corticosteroid exposure in tissue damage-associated joint instability, but not of brief exposure.

Characterizing adolescents with heavy menstrual bleeding and generalized joint hypermobility.

Patients with generalized joint hypermobility (JHM) may experience excessive bruising/bleeding, with heavy menstrual bleeding (HMB) commonly reported. We performed a retrospective review of 30 adolescents seen in a Young Women's Hematology Clinic with both HMB and JHM. We found that (1) a significant delay (mean 36 months, range 5-72) occurred between menarche and referral to specialty care, (2) HMB had moderate to severe impact on school and physical activities in 60% of patients, and (3) most patients (68%) required escalation of their initial therapy. We suggest providers consider JHM as a risk factor for a more complex clinical course.

Predictors for progression of two different types of cervical lesions in rheumatoid arthritis treated with biologic agents.

BACKGROUND: Biologic agents (BAs) enabled not only a reduction of disease activity but also a slowing down of structural damage to the joints in patients with rheumatoid arthritis (RA). However, the incidence of cervical lesions in patients with RA is still high. PURPOSE: To elucidate the predictors for the progression of two different cervical lesions in patients with RA under BA treatment. METHODS: Of 151 subjects who received more than two years of continuous BA treatment, 101 subjects who had cervical X-ray images taken at baseline and final visit were enrolled. The mean disease duration and mean radiography interval were 10.6 years and 4.4 years, respectively. The existence and progression of cervical lesions (atlanto-axial subluxation [AAS], vertical subluxation [VS], and subaxial subluxation [SS]) were investigated. And predictors for the AAS or VS progression were analyzed by multivariate logistic regression analysis. RESULTS: The incidence of cervical lesions at baseline were no pre-existing cervical lesion (none) in 50 cases (50%), AAS only in 32 (32%), both AAS and VS in 12 (12%), and VS only in 7 cases (7%). In the none group, only 4 cases of AAS progression (8%) was observed during the follow-up. In contrast, in the groups with pre-existing cervical lesions, a high incidence of VS progression was observed (63% in the AAS only group, 58% in the AAS + VS group, and 71% in the VS only group). Multivariate regression analysis demonstrated that the DAS-CRP value at baseline (odds ratio [OR] = 9.23) and matrix metaloprotease-3 level at baseline (OR = 1.01) were significant predictors for the progression of AAS, and pre-existing AAS (OR = 18.38) was a sole significant predictor for the progression of VS. CONCLUSIONS: Cervical lesions progressed irrespective of disease activity after AAS development. Strict disease control before the development of AAS is crucial for preventing further progression and development of cervical lesions.

Hypermobility in individuals with Kabuki syndrome: The effect of growth hormone treatment.

Kabuki syndrome (KS) is a multiple congenital malformation syndrome which has been described across all ethnic groups. Most KS patients possess two genetic subtypes: KMT2D-associated, autosomal-dominant KS type 1 (KS1; OMIM 147920); and KDM6A-associated, X-linked-dominant KS type 2. Generalized joint hypermobility is one feature of KS, but its exact incidence and pattern is not well described in the literature. As part of our prospective study on the metabolic and growth effect of GH treatment, we assessed children from our Dutch Kabuki cohort who were eligible for growth hormone therapy. We assessed severity and pattern of joint hypermobility, both before and after 24 months of growth hormone replacement therapy. The prevalence of hypermobility was 31% in boys and 14% in girls using the Beighton score and 69% in boys and 57% in girls using the Bulbena score. This varies from the general population where girls are more affected. After 2 years of growth hormone treatment, there was a statistically significant decrease in the presence of joint hypermobility to 6% using the Bulbena score and none with respect to the Beighton score. We hypothesized that this result suggests a direct effect of growth hormone on connective tissue in patients with KS.

Pharmacological resources, diagnostic approach and coordination of care in joint hypermobility-related disorders.

INTRODUCTION: Joint hypermobility (JH) is the hallmark of many hereditary soft connective tissue disorders, including Ehlers-Danlos syndromes and related disorders, disorders of the TGFß-pathway, lateral meningocele syndrome, arterial tortuosity syndrome, and cutis laxa syndromes. Contemporary practice separates individuals with isolated, non-syndromic JH from patients with Mendelian syndromes and those with hypermobility spectrum disorders. The latter is a new nosologic entity grouping together individuals with JH and related musculoskeletal manifestations, but lacking inclusion criteria for well-defined and/or single-gene disorders. Area covered: Nomenclature of JH and JH-related disorders are summarized on a practically oriented perspective. Critical areas of clinical management comprise pain; cardiovascular and respiratory issues; fatigue and dysautonomia; bone fragility; and capillary, skin and soft tissue fragility. Medical management stands on low-evidence data. Ongoing preclinical and clinical studies are aimed to reach a more personalized pharmacological approach to the management of the cardiovascular risk, musculoskeletal pain, and reduced bone mass. Expert commentary: Correct classification of patients with JH-related disorders needs a systematic approach, in which a wide array of molecular tests should be intermingled with strong clinical competences in highly specialized settings. A multispecialty, hierarchical approach should be encouraged for optimal coordination of care in systemic phenotypes.

The efficacy of dextrose prolotherapy over placebo for temporomandibular joint hypermobility: A systematic review and meta-analysis.

OBJECTIVE: The aim of the systematic review was to analyse the available evidence in order to assess the efficacy of dextrose prolotherapy in improving outcomes in temporomandibular joint (TMJ) hypermobility patients as compared to placebo. METHODS: An electronic search of PubMed, Scopus, CENTRAL and Google scholar databases was performed for English language papers published up to February 2018. Randomised clinical trials (RCTs) and controlled clinical trials (CCTs) comparing dextrose prolotherapy with placebo for TMJ hypermobility were included. RESULTS: Three RCTs were included in the review. Frequency of subluxation/dislocation was reported by two trials which found no difference between dextrose and placebo. A statistical significant difference in reduction of MMO with the use of dextrose prolotherapy was seen on pooling of data (random: MD = -3.32, 95% CI -5.26 to -1.28; P = 0.0008; I2  = 0%). A statistical significant difference in pain reduction was also seen with dextrose as compared to placebo (random: MD = -1, 95% CI -1.58 to -0.42; P = 0.0007; I2  = 0%). CONCLUSION: Within the limitations of the study, dextrose prolotherapy may cause significant reduction in mouth opening and pain associated with TMJ hypermobility. Conclusions with regard to reduction of episodes of subluxation/dislocation cannot be drawn. There is a need of more high-quality RCTs with larger sample size and homogenous prolotherapy protocol to draw stronger conclusions on the effect of dextrose prolotherapy in patients with TMJ hypermobility.

Long-term therapeutic effects of dextrose prolotherapy in patients with hypermobility of the temporomandibular joint: a single-arm study with 1-4 years' follow up.

The aim was to analyse the short-term and long-term therapeutic efficacy of dextrose prolotherapy for dislocation or subluxation (hypermobility) of the temporomandibular joint (TMJ). Sixty-one patients with symptomatic hypermobility of the TMJ were included in this single-arm prospective study, in which they were each given four sessions of intra-articular and pericapsular injections six weeks apart. Each injection comprised 10% dextrose/mepivacaine solution 3ml. Clinical outcomes including severity of pain on movement according to the numerical rating scale (NRS), maximal interincisal opening, clicking, and frequency of locking were measured before treatment (T1), during treatment (T2) (just before the third session of injections), at the short-term follow-up (T3) (three months after treatment), and at the long-term follow-up (T4) (1-4 years after treatment). Condylar translation and osseous changes of each joint were evaluated at T1 and T4 using tomography. There was significant reduction in all variables by T2 (p<0.001, p<0.001, p=0.006, and p<0.001). The pain scores (p<0.001) and clicking (p<0.001) had decreased significantly by T3. Linear tomograms of each joint at T1 and T4 showed no alteration in the morphology of the bony components of the joint, and at T4, tomographic open views of all joints showed condylar hypertranslation. Dextrose prolotherapy provided significant and sustained reduction of pain and recovery of constitutional symptoms associated with symptomatic hypermobility of the TMJ without changing either the position of the condyle or the morphology of the bony components of the joint.

[THE ROLE OF TRANSFORMING GROWTH FACTOR-B IN IMMUNOPATHOGENESIS OF DISEASES OF CONNECTIVE TISSUE].

The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-ß (TGFß). The involvement of TGFß in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem.

Arterial Tortuosity Syndrome reveals function of dehydroascorbic acid in collagen and elastin synthesis: Implications for skin care.

Some investigations in Arterial Tortuosity Syndrome (ATS) suggest that impaired intracellular transport of the oxidized form of vitamin C (dehydroascorbic acid, DHAA) is at the core of the pathogenesis. Lack of vitamin C for lysyl- and prolyl-hydroxylase activity may explain the defects in collagen and elastin formation found in ATS, and draws strong parallels between ATS and scurvy. Topically applied vitamin C has a well-established basis in the field of skin care, and part of its benefit is attributed to proper collagen formation in the skin. The ATS studies suggest that DHAA transport is necessary for normal skin collagen formation, and this has implications as to the forms of vitamin C best-suited for topical skin care.

Corneal Cross-Linking for Brittle Cornea Syndrome.

PURPOSE: To describe corneal cross-linking (CXL) as a treatment option for brittle cornea syndrome (BCS). METHODS: Case report. RESULTS: Ethical decision making enabled bilateral sequential transepithelial CXL in an 11-year-old girl with BCS. Postoperative courses were uneventful with a bilateral stromal demarcation line, unchanged corneal transparency, constant endothelial cell density, and stable topography 2 years after intervention. CONCLUSIONS: Modified CXL can safely be performed in patients with BCS. Ethical review may be helpful for interventions deviating from standard practice.

Diffuse neonatal hemangiomatosis in a very low-birthweight infant treated with erythropoietin.

Diffuse neonatal hemangiomatosis (DNH) is a rare condition characterized by the concomitant development of multiple cutaneous infantile hemangiomas (IH) and visceral hemangiomas. Recently, an association between erythropoietin treatment and an increased incidence of infantile hemangioma was noted. A Japanese male infant was born via cesarean section at 27 weeks of gestation. Following the commencement of erythropoietin treatment for anemia of prematurity, he developed multiple cutaneous hemangiomas, high cardiac output heart failure and hepatomegaly. Abdominal imaging indicated comorbidity of diffuse infantile hepatic hemannigomas, resulting in the final diagnosis of DNH. The discontinuation of erythropoietin treatment and long-term therapy with propranolol improved the hepatic lesions and cutaneous hemangiomas. The possibility of multiple organ involvement and the exacerbating effects of erythropoietin treatment should be considered in cases in which multiple cutaneous hemangiomas develop in preterm infants receiving erythropoietin treatment.

Modified dextrose prolotherapy for recurrent temporomandibular joint dislocation.

Conservative interventions with simple procedures and predictable benefits are expected by patients with recurrent dislocation of the temporomandibular joint (TMJ). We have introduced a modified technique of prolotherapy that comprises injection of lignocaine and 50% dextrose at a single site in the posterior periarticular tissues. We studied the effects in 45 younger patients (age range 17-59 years) with non-neurogenic recurrent dislocation of the TMJ, and confirmed the therapeutic effect after more than a year's follow-up. There were appreciable improvements in the number of episodes of dislocation and clicking after the injection. The overall success rate, defined as the absence of any further dislocation or subluxation for more than 6 months, was 41/45 (91%). Of the 41 rehabilitated patients, 26 (63%) required a single injection, 11 (27%) had 2 treatments, and 4 (10%) needed a third injection. All patients tolerated the injections well. The modified dextrose prolotherapy is simple, safe, and cost-effective for the treatment of recurrent dislocation of the TMJ.

Predictors for the progression of cervical lesion in rheumatoid arthritis under the treatment of biological agents.

STUDY DESIGN: Retrospective cohort analysis. OBJECTIVE: To clarify the effect of biological agents (BAs) on the development and progression of cervical lesions in patients with rheumatoid arthritis (RA) and to identify biomarkers that accurately predict disease progression. SUMMARY OF BACKGROUND DATA: The introduction of BAs changed the paradigm of RA treatment. However, their effects on cervical lesions in patients with RA have not been studied. METHODS: Ninety-one subjects who had received BAs for 2 years or more were enrolled. Mean radiographical interval was 3.9 years. Disease activity was evaluated by disease activity score-C-reactive protein levels, and matrix metalloproteinase-3 levels. Cervical lesions were defined as an atlantodental interval more than 3 mm for atlantoaxial subluxation (AAS), Ranawat value less than 13 mm for vertical subluxation (VS), and anterior or posterior listhesis more than 2 mm for subaxial subluxation. Disease progression was defined radiographically as an increase in the atlantodental interval more than 2 mm for AAS, a decrease in both Ranawat and Redlund-Johnell values more than 2 mm for VS, and an increase in listhesis more than 2 mm for subaxial subluxation. We used multivariate regression techniques to assess predictors of disease progression. RESULTS: Baseline radiographical evaluation showed no pre-existing cervical lesion in 44 patients, AAS in 29, and VS in 18. Radiological progression occurred in 7% patients without baseline lesions, 79% in the AAS group, and 72% in the VS group. The incidence of progression was significantly lower in patients without lesions at baseline. Multivariate regression analysis demonstrated pre-existing cervical lesions, disease activity score-C-reactive protein levels at baseline and metalloproteinase-3 levels at final visit as good predictors of RA progression. CONCLUSION: BAs prevented de novo cervical lesions in patients with RA but failed to control progression in patients with pre-existing cervical lesions. Disease activity score-C-reactive protein levels at baseline were related to pre-existing joint destruction, and metalloproteinase-3 levels accurately predicted ongoing bone destruction during BA treatment. LEVEL OF EVIDENCE: 3.