The therapeutic effects of 4-aminopyridine (4AP) were investigated in a randomized, double-blind, crossover trial in 10 subjects with familial episodic ataxia with nystagmus.
After randomization, ...placebo or 4AP (5 mg 3 times daily) was administered for 2 3-month-long treatment periods separated by a 1-month-long washout period. The primary outcome measure was the number of ataxia attacks per month; the secondary outcome measures were the attack duration and patient-reported quality of life (Vestibular Disorders Activities of Daily Living Scale VDADL). Nonparametric tests and a random-effects model were used for statistical analysis.
The diagnosis of episodic ataxia type 2 (EA2) was genetically confirmed in 7 subjects. Patients receiving placebo had a median monthly attack frequency of 6.50, whereas patients taking 4AP had a frequency of 1.65 (p = 0.03). Median monthly attack duration decreased from 13.65 hours with placebo to 4.45 hours with 4AP (p = 0.08). The VDADL score decreased from 6.00 to 1.50 (p = 0.02). 4AP was well-tolerated.
This controlled trial on EA2 and familial episodic ataxia with nystagmus demonstrated that 4AP decreases attack frequency and improves quality of life.
This crossover study provides Class II evidence that 4AP decreases attack frequency and improves the patient-reported quality of life in patients with episodic ataxia and related familial ataxias.
Mitochondrial dysfunction plays a major role in the pathogenesis of Parkinson disease (PD). Creatine (Cr) is an ergogenic compound that exerts neuroprotective effects in animal models of PD. We ...conducted a 2-year placebo-controlled randomized clinical trial on the effect of Cr in 60 patients with PD. Cr improved patient mood and led to a smaller dose increase of dopaminergic therapy but had no effect on overall Unified Parkinson's Disease Rating Scale scores or dopamine transporter SPECT.
Purpose
LHON is a mitochondrial disease resulting in progressive, severe central vision loss, which is caused by 1 of 3 mitochondrial DNA mutations in >95% of patients. Idebenone, at a dose of ...900 mg/day, is effective and safe in patients with LHON. Here, we report long‐term treatment outcomes in real world clinical practice.
Methods
The Expanded Access Program (EAP) assessed idebenone's therapeutic potential in patients with onset of symptoms within 1 year prior to enrollment. Efficacy was assessed as clinically relevant recovery (CRR) or clinically relevant stabilization (CRS). CRR is defined as improvement from off‐chart to reading 5 letters on the ETDRS chart, or as an improvement of 10 letters. CRS is defined as maintenance of VA <1.0 logMAR (20/200).
Results
85 patients carried one of the 3 most common mutations and had at least 1 post‐baseline (BL) visual acuity (VA) assessment. At BL, median age was 23.6 years and median treatment duration at last observation was 17.3 months. A subset of 25 patients presented with VA <1.0 logMAR, from which 52% experienced CRS. CRR from nadir was observed in 51% of patients. The number of eyes which remained on chart increased from 51% at nadir to 67% at last observation, and those <1.0 logMAR increased from 7% to 27%. At BL, 9% of patients were <1.0 logMAR in both eyes, which increased to 23% following treatment. The proportion of patients with CRR increased with treatment duration, with approximately 50% observed up to 6 months, but extending up to 18 months. CRR and CRS were observed, to different degrees, regardless of mutation.
Conclusions
Idebenone has a good safety profile for the long‐term treatment of LHON, and when initiated early, can stabilize good residual vision and prevent severe vision loss and blindness in a large proportion of patients. Maximal benefit may be achieved by prolonged treatment.
To develop and evaluate a clinical Spastic Paraplegia Rating Scale (SPRS) to measure disease severity and progression.
A 13-item scale was designed to rate functional impairment occurring in pure ...forms of spastic paraplegia (SP). Additional symptoms constituting a complicated form of SP are recorded in an inventory. Two independent patient cohorts were evaluated in a two-step validation procedure.
Application of SPRS requires less than 15 minutes and does not require any special equipment, so it is suitable for an outpatient setting. Interrater agreement of SPRS was high (intraclass correlation coefficient = 0.99). Reliability was further supported by high internal consistency (Cronbach alpha = 0.91). SPRS values were almost normally distributed without apparent floor or ceiling effect. Construct validity was shown by high correlation of SPRS to Barthel Index and the International Cooperative Ataxia Rating Scale (convergent validity) and low correlation to Mini-Mental Status Examination (discriminant validity).
The Spastic Paraplegia Rating Scale is a reliable and valid measure of disease severity.
Purpose
LHON is an orphan mitochondrial disorder affecting the retinal ganglion cells leading to permanent blindness from which recovery is rare. More than 90% of patients harbor one of three ...mitochondrial DNA mutations in the genes coding of complex I of the respiratory chain. Idebenone, a short‐chain benzoquinone, is a potent antioxidant and also interacts with the electron transport chain facilitating mitochondrial electron flux. Due to these properties idebenone (Raxone®) has been investigated for the treatment of LHON and we summarize the evidence available for efficacy based on a placebo controlled trial and from clinical practice.
Methods
Visual acuity data from a randomized study (RHODOS), from case reports, retrospective cohort studies, an Expanded Access Program (EAP) and a natural history case report survey have been collected in a database of approximately 500 patients. The disease progression based on natural history data and from the Placebo treated patients are compared to the outcome for patients treated with idebenone with respect to the prevention of vision loss and the recovery of lost vision.
Results
In RHODOS, the number of patients experiencing a clinically relevant recovery after 6 months of treatment was 10.3% in the Placebo group and 30.2% in the idebenone treated group. Patients in the EAP showed a recovery rate of 30.6% after 6 months of treatment increasing to 49.3% when comparing the final outcome after 15 m (mean treatment) to the VA at nadir. The number of patients experiencing vision loss to above 1.0 logMAR VA was lower in RHODOS and in the EAP when compared to the datasets of untreated patients.
Conclusions
A large body of evidence demonstrates that patients with LHON benefit from Raxone treatment and that the drug is well tolerated.
Pathogenic somatic variants affecting the genes
(
) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently,
germline ...missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying
germline variants.
In this retrospective study, we included individuals with proved
causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range.
Eighteen individuals (10 males, 56%) with
germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation.
Imaging phenotypes in germline
affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles.
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