Dominant ACO2 mutations are a frequent cause of isolated optic atrophy.

Biallelic mutations in ACO2, encoding the mitochondrial aconitase 2, have been identified in individuals with neurodegenerative syndromes, including infantile cerebellar retinal degeneration and recessive optic neuropathies (locus OPA9). By screening European cohorts of individuals with genetically unsolved inherited optic neuropathies, we identified 61 cases harbouring variants in ACO2, among whom 50 carried dominant mutations, emphasizing for the first time the important contribution of ACO2 monoallelic pathogenic variants to dominant optic atrophy. Analysis of the ophthalmological and clinical data revealed that recessive cases are affected more severely than dominant cases, while not significantly earlier. In addition, 27% of the recessive cases and 11% of the dominant cases manifested with extraocular features in addition to optic atrophy. In silico analyses of ACO2 variants predicted their deleterious impacts on ACO2 biophysical properties. Skin derived fibroblasts from patients harbouring dominant and recessive ACO2 mutations revealed a reduction of ACO2 abundance and enzymatic activity, and the impairment of the mitochondrial respiration using citrate and pyruvate as substrates, while the addition of other Krebs cycle intermediates restored a normal respiration, suggesting a possible short-cut adaptation of the tricarboxylic citric acid cycle. Analysis of the mitochondrial genome abundance disclosed a significant reduction of the mitochondrial DNA amount in all ACO2 fibroblasts. Overall, our data position ACO2 as the third most frequently mutated gene in autosomal inherited optic neuropathies, after OPA1 and WFS1, and emphasize the crucial involvement of the first steps of the Krebs cycle in the maintenance and survival of retinal ganglion cells

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial - study protocol

Introduction: Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. Methods and analysis: Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. Ethics and dissemination: TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. Trial registration number: NCT01962571

Denervation of the wrist : basic principles, technique and clinical results

Die Denervierung des Handgelenks ist eine palliative Methode zur Behandlung schmerzhafter Zustände des Handgelenks unterschiedlicher Ätiologie. Hierbei werden die sensiblen, afferenten Nervenfasern aus der Handwurzel neurotomiert, ohne eine Störung der Oberflächensensibilität oder der Motorik hervorzurufen. An der Berufsgenossenschaftlichen Unfallklinik Tübingen wird die Handgelenkdenervierung seit Mitte der siebziger Jahre mit Erfolg durchgeführt. Die hier vorliegende Arbeit untersucht die Wirksamkeit dieser Methode an dem bislang weltweit größten Patientengut. Zwischen 1977 und 2001 wurden an der Berufsgenossenschaftlichen Unfallklinik Tübingen 375 Patienten denerviert. Wir konnten 362 Akten einsehen. 165 Patienten nahmen an unserer Befragung teil. Dabei wurden die Schmerzen mittels Visueller Schmerzanalogskala, die Handgelenkbeweglichkeit, die Arbeitsfähigkeit, die Patientenzufriedenheit und eventuell aufgetretene Komplikationen untersucht. Darüber hinaus wurden die Patienten gebeten, den DASH-Fragebogen (Disabilities of the Arm, Shoulder and Hand) auszufüllen, mit dessen Hilfe die Globalfunktion der oberen Extremität eingeschätzt werden kann. Der durchschnittliche Beobachtungszeitraum beträgt 12.23 Jahre, das Durchschnittsalter der Patienten 43.5 Jahre. 67,7 Prozent der Patienten waren nach der Denervierung beschwerdefrei. Bei 37,9 Prozent der Patienten traten Beschwerden inzwischen erneut auf. 29,8 Prozent der Patienten sind bis zum Zeitpunkt der Umfrage beschwerdefrei. Präoperativ betrugen die auf der VAS angegebenen Schmerzen im Median 83.5 Punkte, 6 Wochen nach der Denervierung wurden 32 Punkte angegeben. Dies entspricht einer Reduktion um 61,7 Prozent. Nach 12 Jahren betragen die Schmerzen mit 40 Punkten weniger als die Hälfte des präoperativen Wertes. 77 Prozent der Patienten, deren Denervierung mindestens 5 Jahre zurückliegt, geben an, über einen Zeitraum von 10 Jahren keine starken Beschwerden verspürt zu haben. Bei 9,7 Prozent der Patienten brachte die Denervierung nicht den gewünschten Erfolg, so dass eine Arthrodese des Handgelenks durchgeführt werden musste. Die Arthrodese wurde im Median 3.7 Jahre nach der Denervierung durchgeführt. Während dieses Zeitraums konnten die Patienten Nutzen aus der erhaltenen Handgelenkbeweglichkeit ziehen. Überraschenderweise erreichen diese Patienten zum Zeitpunkt der Umfrage schlechtere Ergebnisse auf dem DASH-Fragebogens und der Visuellen Schmerzanalogskala als die übrigen, ausschließlich denervierten Patienten. Erreicht wurde durch die Denervierung eine effektive Schmerzreduktion, eine geringe Arbeitsunfähigkeit und eine Patientenzufriedenheit von 77,5 Prozent. Die Denervierung des Handgelenkes lieferte zumindest in zwei Drittel aller Fälle gute bis sehr gute Ergebnisse. Diese Technik sollte selektiv für Patienten reserviert bleiben, welche an einem bereits ausgebildeten arthrotischen Prozess ohne dynamische Instabilität leiden und gute Beweglichkeit aufweisen. Wir glauben, durch die Denervierung eine gleich gute Schmerzreduktion wie durch andere Methoden, insbesondere die verschiedenen Formen der Handgelenksarthrodesen, erzielen zu können. Dabei wird die Handgelenkbeweglichkeit und Kraft nicht vermindert, die durch Arthrodesen um bis zu 70 Prozent reduziert wird. Diese effektive Schmerzreduktion kann durch eine nur gering traumatisierende Operation herbeigeführt werden, die im Falle eines Misserfolges die Möglichkeit, weitere Operationen durchzuführen, offen lässt. Aus diesen Gründen sollte die Denervierung ihren festen Platz in der Handchirurgie beibehalten.The denervation of the wrist joint is a palliative method in the treatment of painful wrist conditions caused by different etiologies. It consists in the selective interruption of the afferent nerve fibres without alteration of the skin sensibility. This study examines the effectiveness of this method by analysing the course of the disease of 362 patients operated at the BG-Unfallklinik Tübingen (Germany). 362 clinical charts were reviewed, 165 patients answered to our questionnaire that consisted of the DASH-Questionnaire (0 points = best result, 100 points = worst result), the visual analogue scale (VAS, minimum pain = 0, maximal pain = 100) and questions about the wrist mobility, workers compensation status, patients satisfaction and complications. Mean follow-up was 12.23 years. Mean age was 43.5 years. 70% were manual workers, 30% had sedentary occupation. Complete denervation was performed in 89%, partial denervation in 11% of the operations. No other additional operations were performed to the wrist at the same time of the denervation. 67.7% of our patients were free of complaints after the operation. 37.9% reported that some complaints reappeared meanwhile, 29.8% are free of complaints up to today. Median preoperative pain level (VAS) was 83.5 points, 6 weeks after the operation pain was reduced to 32 points. After 12 years pain was reported with 40 points which represents a pain reduction of 52.1%. At a long-term follow-up (more than 5 years), 77% of our patients were without significant complaints for a median period of 10 years. Overall patient-satisfaction rate was 77.5% (would undergo operation again). 86% of our patients were back to work after 1 month. 10 years after wrist denervation only 26.3% reported a mild decrease of wrist-mobility and only 13.2% reported a significant decrease in wrist-mobility. 9.7% underwent wrist arthodesis after a median time period of 3.7 years after wrist-denervation as a result of failed denervation of the joint. If we compare the results of patients having a secondary arthrodesis with the results of simple denervation procedures, we find better results for the denervation group regarding the DASH-score and VAS-scale. In our view wrist denervation gives good results and is adapted to reduce or abolish wrist pain. It may not be successful in about 20% of patients but is in most cases the only alternative to partial or total arthodesis. We recommend to denervate arthrotic wrists before performing intra-articular procedures in order to preserve wrist mobility and patient comfort

Optic neuritis in German children: clinical findings and association with multiple sclerosis

Purpose!#!Analysis of a cohort of pediatric optic neuritis patients concerning the epidemiology, disease progression, and association with multiple sclerosis (MS).!##!Methods!#!Retrospective, observational cohort study. From 2004 to 2018, all electronic medical files of patients younger than 18 years referred to a tertiary care clinic in Germany with the diagnosis optic neuritis have been analyzed.!##!Results!#!Sixty-nine patients were referred in the study period, 16 did not suffer under optic neuritis and were excluded. The median visual acuity of the remaining 53 patients was 0.07 at the baseline examination and 1.0 at the latest follow-up examination (decimal notation, median 2.1 years after baseline). Forty-two percent of the patients developed MS during the study period. Female sex (p = 0.028) as well as higher age (p = 0.0082) proved to be statistically significant risk factors for MS development.!##!Conclusion!#!The prognosis for restoring vision in pediatric optic neuritis was favorable. During the observation period, the risk of developing MS was overall 42% and 8% for patients younger than 11 years. The percentage of MS as underlying cause of optic neuritis does not differ remarkably between children older 10 years and adults