Cervical dystonia is a common neurological movement disorder characterised by muscle contractions causing abnormal movements and postures affecting the head and neck. The neural networks underpinning ...this condition are incompletely understood. While animal models suggest a role for the superior colliculus in its pathophysiology, this link has yet to be established in humans. The present experiment was designed to test the hypothesis that disrupted superior collicular processing is evident in affected patients and in relatives harbouring a disease-specific endophenotype (abnormal temporal discrimination). The study participants were 16 cervical dystonia patients, 16 unaffected first-degree relatives with abnormal temporal discrimination, 16 unaffected first-degree relatives with normal temporal discrimination and 16 healthy controls. The response of participant's superior colliculi to looming stimuli was assessed by functional magnetic resonance imaging. Cervical dystonia patients and relatives with abnormal temporal discrimination demonstrated (i) significantly reduced superior collicular activation for whole brain and region of interest analysis; (ii) a statistically significant negative correlation between temporal discrimination threshold and superior collicular peak values. Our results support the hypothesis that disrupted superior collicular processing is involved in the pathogenesis of cervical dystonia. These findings, which align with animal models of cervical dystonia, shed new light on pathomechanisms in humans.
A 38-year-old right-handed man was referred for investigation of a 20-year history of progressive behavior change and involuntary movements. Symptom onset was in his late teens. Up until that time he ...had achieved age-appropriate motor and cognitive milestones and had completed normal schooling. There was no family history of dementia or movement disorders.
The temporal discrimination threshold (TDT) is the shortest time interval at which an individual detects two stimuli to be asynchronous (normal = 30-50 ms). It has been shown to be abnormal in ...patients with disorders affecting the basal ganglia including adult onset idiopathic focal dystonia (AOIFD). Up to 97% of patients have an abnormal TDT with age- and sex-related penetrance in unaffected relatives, demonstrating an autosomal dominant inheritance pattern. These findings support the use of the TDT as a pre-clinical biomarker for AOIFD. The usual stimulus presentation method involves the presentation of progressively asynchronous stimuli; when three sequential stimuli are reported asynchronous is taken as a participant's TDT. To investigate the robustness of the 'staircase' method of presentation, we introduced a method of randomised presentation order to explore any potential 'learning effect' that may be associated with this existing method. The aim of this study was to investigate differences in temporal discrimination using two methods of stimulus presentation. Thirty healthy volunteers were recruited to the study (mean age 33.73 ± 3.4 years). Visual and tactile TDT testing using a staircase and randomised method of presentation order was carried out in a single session. There was a strong relationship between the staircase and random method for TDT values. This observed consistency between testing methods suggests that the existing experimental approach is a robust method of recording an individual's TDT. In addition, our newly devised randomised paradigm is a reproducible and more efficient method for data acquisition in the clinic setting. However, the two presentation methods yield different absolute TDT results and either of the two methods should be used uniformly in all participants in any one particular study.
The temporal discrimination threshold (TDT) is a proposed pre-clinical biomarker (endophenotype) for adult onset isolated focal dystonia (AOIFD). Age- and sex-related effects on temporal ...discrimination demonstrate that women, before the age of 40 years, have faster temporal discrimination than men but their TDTs worsen with age at almost three times the rate of men. Thus after 40 years the TDT in women is progressively worse than in men. AOIFD is an increasingly female-predominant disorder after the age of 40; it is not clear whether this age-related sexually-dimorphic difference observed for both the TDT and sex ratio at disease onset in AOIFD is a hormonal or chromosomal effect. The aim of this study was to examine temporal discrimination at weekly intervals during two consecutive menstrual cycles in 14 healthy female volunteers to determine whether physiological hormonal changes affected temporal discrimination. We observed no significant differences in weekly temporal discrimination threshold values during the menstrual cycles and no significant correlation with the menstrual cycle stage. This observed stability of temporal discrimination during cyclical hormonal change raises interesting questions concerning the age-related sexually-dimorphic decline observed in temporal discrimination. Our findings pave the way for future studies exploring potential pathomechanisms for this age-related deterioration.
“JUMP” is a multidisciplinary program based at the Pitie-Salpêtrière Hospital Paris that transitions young adults with chronic neurological conditions from paediatric to adult healthcare. ...Transitional care programs have been shown to improve medical, educational and psychosocial outcomes for adolescent patients.
Demographic details and health-related variables of all patients referred to the JUMP program were collected. Satisfaction outcome measures were the 18-item On Your Own Feet Transfer Experience Scale (OYOF-TES) and a visual analogue scale, which assessed overall satisfaction with the transfer process. Scales were sent to JUMP patients attending the JUMP day hospital (n = 94) and their parents (n = 94).
Since its inception, 111 patients have been seen in the JUMP program. Nine neurological clinical syndromes and four main underlying etiologies were identified. Approximately half of all questionnaires and scales (86/188) sent to patients and parents were returned. Eighty-nine percent of patients and 91% of parents were very satisfied with their transfer experience. There was a strong, positive correlation between patient and parent satisfaction r = 0.910; p < 0.0001.
The JUMP program which is rooted in a multidisciplinary and coordinated approach to transitional care encompasses a broad range of neuro-pathologies. Overall, satisfaction levels were high amongst patients within the program, and their parents. The key role played by the coordination nurse specialists throughout the transfer process is a likely key determinant in satisfaction levels.
•JUMP is a transitional care program for young adults with neurological disease.•JUMP employs a multi-disciplinary approach to address patient's medical and psychosocial needs.•The work of the JUMP coordination nurse specialists is central to the JUMP program.•High satisfaction levels were observed amongst patients and parents in the JUMP program.
Understanding the neuronal network dynamics underlying the third most common movement disorder, cervical dystonia, can be achieved using dynamic causal modelling. Current literature establishes ...structures of the midbrain network for covert attentional orienting as dysfunctional in patients with cervical dystonia. One of these structures is the superior colliculus, for which it is hypothesised that deficient GABAergic activity therein causes cervical dystonia. To understand the role that this node plays in cervical dystonia, various connectivity models of the midbrain network were compared under the influence of a loom-recede visual stimulus fMRI paradigm. These models included the thalamus and striatum, crucial nodes in the direct/indirect pathways for motor movement and inhibition. The parametric empirical Bayes approach was used to quantify the difference in connection strengths across the winning models between patients and controls. Our findings demonstrated greater modulation by a looming stimulus event on the strength of connection from the striatum to the superior colliculus in patients. These results offer new means to understanding the pathophysiology of cervical dystonia.
Adult patients with adrenoleukodystrophy have a poor prognosis owing to development of adrenomyeloneuropathy. Additionally, a large proportion of patients with adrenomyeloneuropathy develop ...life-threatening progressive cerebral adrenoleukodystrophy. Leriglitazone is a novel selective peroxisome proliferator-activated receptor gamma agonist that regulates expression of key genes that contribute to neuroinflammatory and neurodegenerative processes implicated in adrenoleukodystrophy disease progression. We aimed to assess the effect of leriglitazone on clinical, imaging, and biochemical markers of disease progression in adults with adrenomyeloneuropathy.
ADVANCE was a 96-week, randomised, double-blind, placebo-controlled, phase 2–3 trial done at ten hospitals in France, Germany, Hungary, Italy, the Netherlands, Spain, the UK, and the USA. Ambulatory men aged 18–65 years with adrenomyeloneuropathy without gadolinium enhancing lesions suggestive of progressive cerebral adrenoleukodystrophy were randomly assigned (2:1 without stratification) to receive daily oral suspensions of leriglitazone (150 mg starting dose; between baseline and week 12, doses were increased or decreased to achieve plasma concentrations of 200 μg·h/mL SD 20%) or placebo by means of an interactive response system and a computer-generated sequence. Investigators and patients were masked to group assignment. The primary efficacy endpoint was change from baseline in the Six-Minute Walk Test distance at week 96, analysed in the full-analysis set by means of a mixed model for repeated measures with restricted maximum likelihood and baseline value as a covariate. Adverse events were also assessed in the full-analysis set. This study was registered with ClinicalTrials.gov, NCT03231878; the primary study is complete; patients had the option to continue treatment in an open-label extension, which is ongoing.
Between Dec 8, 2017, and Oct 16, 2018, of 136 patients screened, 116 were randomly assigned; 62 81% of 77 patients receiving leriglitazone and 34 87% of 39 receiving placebo completed treatment. There was no between-group difference in the primary endpoint (mean SD change from baseline leriglitazone: –27·7 41·4 m; placebo: –30·3 60·5 m; least-squares mean difference –1·2 m; 95% CI –22·6 to 20·2; p=0·91). The most common treatment emergent adverse events in both the leriglitazone and placebo groups were weight gain (54 70% of 77 vs nine 23% of 39 patients, respectively) and peripheral oedema (49 64% of 77 vs seven 18% of 39). There were no deaths. Serious treatment-emergent adverse events occurred in 14 (18%) of 77 patients receiving leriglitazone and ten (26%) of 39 patients receiving placebo. The most common serious treatment emergent adverse event, clinically progressive cerebral adrenoleukodystrophy, occurred in six 5% of 116 patients, all of whom were in the placebo group.
The primary endpoint was not met, but leriglitazone was generally well tolerated and rates of adverse events were in line with the expected safety profile for this drug class. The finding that cerebral adrenoleukodystrophy, a life-threatening event for patients with adrenomyeloneuropathy, occurred only in patients in the placebo group supports further investigation of whether leriglitazone might slow the progression of cerebral adrenoleukodystrophy.
Minoryx Therapeutics.
This chapter covers disorders of vision and hearing. Common presentations that may be encountered when examining the neurologic patient are discussed. A stepwise approach is presented for each part ...of the neurologic examination. First, examination techniques and tips are discussed. Clinical clues to aid diagnosis are then discussed.
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