Validation of “laboratory-supported” criteria for functional (psychogenic) tremor

Background

In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity.

Objectives

This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a “laboratory-supported” level of certainty.

Methods

For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor.

Results

We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%.

Conclusion

We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice.

 Movement Disorders 2016

Long-term effect of epoetin alfa on clinical and biochemical markers in friedreich ataxia

Friedreich ataxia is an autosomal recessive disease with no available therapy. Clinical trials with erythropoietin in Friedreich ataxia patients have yielded conflicting results, and the long-term effect of the drug remains unknown.

We designed a double-blind, placebo-controlled, multicenter trial to test the efficacy of epoetin alfa on 56 patients with Friedreich ataxia. The primary endpoint of the study was the effect of epoetin alfa on peak oxygen uptake (VO₂ max) at the cardiopulmonary exercise test. Secondary endpoints were frataxin levels in peripheral blood mononuclear cells, improvement in echocardiography findings, vascular reactivity, neurological progression, upper limb dexterity, safety, and quality of life. Epoetin alfa or placebo (1:1 ratio) was administered subcutaneously at a dose of 1200 IU/Kg of body weight every 12 weeks for 48 weeks.

A total of 56 patients were randomized; 27 completed the study in the active treatment group, and 26 completed the study in the placebo group[KG1]. VO₂ max was not modified after treatment (0.01 [−0.04 to 0.05]; P = .749), as well as most of the secondary endpoint measures, including frataxin. The 9-hole peg test showed a significant amelioration in the treatment group (−17.24 sec. [−31.5 to −3.0]; P = .018). The treatment was safe and well tolerated.

Although results are not in favor of an effect of epoetin alfa in Friedreich ataxia, this is the largest trial testing its effect. It is still possible that epoetin alfa may show some symptomatic effect on upper-limb performance. This study provides class I evidence that erythropoietin does not ameliorate VO₂ max in patients with Friedreich ataxia. 

 Movement Disorders 2016

Auditory neuropathy — neural and synaptic mechanisms

Sensorineural hearing impairment is the most common form of hearing loss, and encompasses pathologies of the cochlea and the auditory nerve. Hearing impairment caused by abnormal neural encoding of sound stimuli despite preservation of sensory transduction and amplification by outer hair cells is known as 'auditory neuropathy'. This term was originally coined for a specific type of hearing impairment affecting speech comprehension beyond changes in audibility: patients with this condition report that they “can hear but cannot understand”. This type of hearing impairment can be caused by damage to the sensory inner hair cells (IHCs), IHC ribbon synapses or spiral ganglion neurons. Human genetic and physiological studies, as well as research on animal models, have recently shown that disrupted IHC ribbon synapse function — resulting from genetic alterations that affect presynaptic glutamate loading of synaptic vesicles, Ca²⁺ influx, or synaptic vesicle exocytosis — leads to hearing impairment termed 'auditory synaptopathy'. Moreover, animal studies have demonstrated that sound overexposure causes excitotoxic loss of IHC ribbon synapses. This mechanism probably contributes to hearing disorders caused by noise exposure or age-related hearing loss. This Review provides an update on recently elucidated sensory, synaptic and neural mechanisms of hearing impairment, their corresponding clinical findings, and discusses current rehabilitation strategies as well as future therapies.

Nature Reviews Neurology 2016

Ultrasound treatment of neurological diseases — current and emerging applications

Like cardiovascular disease and cancer, neurological disorders present an increasing challenge for an ageing population. Whereas nonpharmacological procedures are routine for eliminating cancer tissue or opening a blocked artery, the focus in neurological disease remains on pharmacological interventions. Setbacks in clinical trials and the obstacle of access to the brain for drug delivery and surgery have highlighted the potential for therapeutic use of ultrasound in neurological diseases, and the technology has proved useful for inducing focused lesions, clearing protein aggregates, facilitating drug uptake, and modulating neuronal function. In this Review, we discuss milestones in the development of therapeutic ultrasound, from the first steps in the 1950s to recent improvements in technology. We provide an overview of the principles of diagnostic and therapeutic ultrasound, for surgery and transient opening of the blood–brain barrier, and its application in clinical trials of stroke, Parkinson disease and chronic pain. We discuss the promising outcomes of safety and feasibility studies in preclinical models, including rodents, pigs and macaques, and efficacy studies in models of Alzheimer disease. We also consider the challenges faced on the road to clinical translation.

Nature Reviews Neurology 2016

Parkinsonism, movement disorders and genetics in frontotemporal dementia

Frontotemporal dementia (FTD) refers to a group of clinically and genetically heterogeneous neurodegenerative disorders that are a common cause of adult-onset behavioural and cognitive impairment. FTD often presents in combination with various hyperkinetic or hypokinetic movement disorders, and evidence suggests that various genetic mutations underlie these different presentations. Here, we review the known syndromatic–genetic correlations in FTD. Although no direct genotype–phenotype correlations have been identified, mutations in multiple genes have been associated with various presentations. Mutations in the genes that encode microtubule-associated protein tau (MAPT) and progranulin (PGRN) can manifest as symmetrical parkinsonism, including the phenotypes of Richardson syndrome and corticobasal syndrome (CBS). Expansions in the C9orf72 gene are most frequently associated with familial FTD, typically combined with motor neuron disease, but other manifestations, such as symmetrical parkinsonism, CBS and multiple system atrophy-like presentations, have been described in patients with these mutations. Less common gene mutations, such as those in TARDBP, CHMP2B, VCP, FUS andTREM2, can also present as atypical parkinsonism. The most common hyperkinetic movement disorders in FTD are motor and vocal stereotypies, which have been observed in up to 78% of patients with autopsy-proven FTD. Other hyperkinetic movements, such as chorea, orofacial dyskinesias, myoclonus and dystonia, are also observed in some patients with FTD.

Nature Reviews Neurology 2016

Efforts in Epilepsy Prevention in the Last 40 Years Lessons From a Large Nationwide Study

Importance  Prevention of new-onset epilepsy is an important public health issue and presents a pressing unmet need. It is unclear whether progress has been made in preventing new-onset epilepsy.

Objective  To determine whether progress has been made in the prevention of epilepsy in Finland during the last 40 years.

Design, Setting, and Participants  Using a long-term national register study of 5.04 million Finnish individuals, we looked at first-time inpatient admissions in Finland for a diagnosis of epilepsy from 1973 to 2013. Patients with epilepsy were defined by the occurrence of 2 or more unprovoked seizures. This study was conducted on July 29, 2015.

Main Outcomes and Measures  In Finland, patients with epilepsy are routinely hospitalized at time of diagnosis, thus providing evidence for the incidence of epilepsy.

Results  Of the mean 5.04 million Finnish individuals followed up for the development of epilepsy from 1973 to 2013, 100 792 people were identified as having epilepsy. Of these, 46 995 (47%) had focal epilepsy. The mean age for those included in the study was 45 years for men (interquartile range, 24-65 years) and 46 years for women (interquartile range, 23-71 years). We found no change in the incidence of epilepsy in the age range of those younger than 65 years (60 per 100 000 in 1973 and 64 per 100 000 in 2013). However, there was a significant increase in epilepsy among those older than 65 years (from 57 per 100 000 to 217 per 100 000).

Conclusions and Relevance  We found no evidence that progress has been made in preventing new-onset epilepsy in those younger than 65 years in the last 40 years; in fact, there was a nearly 5-fold rise of new-onset epilepsy among the elderly population

JAMA Neurology 2016

Long-Term Results of Stenting versus Endarterectomy for Carotid-Artery Stenosis

BACKGROUND

In the Carotid Revascularization Endarterectomy versus Stenting Trial, we found no significant difference between the stenting group and the endarterectomy group with respect to the primary composite end point of stroke, myocardial infarction, or death during the periprocedural period or any subsequent ipsilateral stroke during 4 years of follow-up. We now extend the results to 10 years.

METHODS

Among patients with carotid-artery stenosis who had been randomly assigned to stenting or endarterectomy, we evaluated outcomes every 6 months for up to 10 years at 117 centers. In addition to assessing the primary composite end point, we assessed the primary end point for the long-term extension study, which was ipsilateral stroke after the periprocedural period.

RESULTS

Among 2502 patients, there was no significant difference in the rate of the primary composite end point between the stenting group (11.8%; 95% confidence interval [CI], 9.1 to 14.8) and the endarterectomy group (9.9%; 95% CI, 7.9 to 12.2) over 10 years of follow-up (hazard ratio, 1.10; 95% CI, 0.83 to 1.44). With respect to the primary long-term end point, postprocedural ipsilateral stroke over the 10-year follow-up occurred in 6.9% (95% CI, 4.4 to 9.7) of the patients in the stenting group and in 5.6% (95% CI, 3.7 to 7.6) of those in the endarterectomy group; the rates did not differ significantly between the groups (hazard ratio, 0.99; 95% CI, 0.64 to 1.52). No significant between-group differences with respect to either end point were detected when symptomatic patients and asymptomatic patients were analyzed separately.

CONCLUSIONS

Over 10 years of follow-up, we did not find a significant difference between patients who underwent stenting and those who underwent endarterectomy with respect to the risk of periprocedural stroke, myocardial infarction, or death and subsequent ipsilateral stroke. The rate of postprocedural ipsilateral stroke also did not differ between groups. (Funded by the National Institutes of Health and Abbott Vascular Solutions; CREST ClinicalTrials.gov number,NCT00004732.)

NEJM 2016