Unmet needs in childhood dystonias

Jean-Pierre Lin,  Nardo Nardocci.  Recognizing the Common Origins of Dystonia and the Development of Human Movement: A Manifesto of Unmet Needs in Isolated Childhood Dystonias. Front. Neurol., 19 December 2016 | https://doi.org/10.3389/fneur.2016.00226

http://journal.frontiersin.org/article/10.3389/fneur.2016.00226/full?utm_source=newsletter&utm_medium=email&utm_campaign=Neurology-w1-2017

A Need to Recognize That Many Different Patterns of Brain Injury Can Cause Dystonia: Emphasizing Dystonia as a Manifestation of a Disturbed Distributed Network

If we accept that dystonia emerges out of an initial developmental cocontraction pattern of movements and postures and that motor development arises from an ab initio hyperkinetic motor condition, it is not difficult to understand why so many disorders with seemingly completely different mechanisms result in dystonia.

Apart from the classical injuries of the developing brain, approximately 17–20% of children with CP have normal neuroimaging, which calls into question “where exactly is the non-progressive injury to the developing brain” said to be the defining hallmark of CP? A feature all the more intriguing when over 50% of children with “dyskinetic CP” have normal brain imaging.

This suggests that the brain in early dystonic motor disorders may fail to develop the efficient and functional connectivity networks underpinning normal motor development. By extension of this hypothesis, the child with early onset dystonia may be utilizing an under-pruned, over-arborized network of connections (rather than a damaged network). This calls into question therapeutic approaches centered on “curing” CP with stem cell therapies, for instance see Graham  for a recent discussion of the role of stem cells in CP. However, it is conceivable that stem cells, not only repair damaged areas of the brain but also facilitate activity-dependent plasticity, which could be associated with promoting functional connectivity.

Connectivity within the brain of the child with dystonia, may be measured by whole white matter fractional anisotropy (FA) estimations using diffusion-weighted imaging methods with the technique of MRI Diffusion Tensor Imaging. This provides information about white matter microstructure integrity and is derived from the differential diffusion of water molecules along fiber tracts. The FA value from 0.0 to 1.0 represents the likelihood of water diffusing along fibers (FA maximum = 1.0) or water diffusing randomly in all directions because there are no fibers (FA minimum = 0.0). The FA value may therefore be a useful marker of the connectivity of the brain: higher FA values corresponding to greater structural connectivity and integrity of the white matter fiber tracts within the brain and vice versa. For instance, in a cohort of children selected on clinical, conventional radiological, and neurophysiological assessments  preparatory to management of dystonia with DBS or ITB, the mean DBS-group FA value was >0.5, but the FA value was <0.5 in the ITB group. Such statistical imaging parameters may in the future, with neurophysiological parameters become a means of appropriately stratifying children with dystonia into prognostic groups suitable for intervention with DBS or ITB...

The Need to Recognize Non-Motor Symptoms in Childhood Dystonia

The focus on the classic motor symptoms of dystonia, i.e., involuntary muscle contractions and abnormal postures has left a gap in research on the non-motor aspects of the dystonic disorders such as abnormalities in sensory and perceptual functions, neuropsychiatric disturbances, and sleep. The comorbidity of non-motor symptoms is increasingly recognized in adults with dystonia. It is not known, if these non-motor symptoms, including poor sleep patterns, are intrinsic to dystonia comorbidities or secondary to the dystonia disorders themselves. Understanding the role of non-motor symptoms in childhood dystonia has potential implications for clinical assessment tools; pre- and post-surgical interventions, e.g., deep brain stimulation (DBS), and treatment targets. Moreover, these non-motor symptoms play a vital role in determining quality of life. Although research has begun to investigate these non-motor phenomena in typically developing children and autistic children, no systematic evaluation of non-motor symptoms exist for the childhood dystonia population…

Further work on the non-motor aspects of living with dystonia is urgently required. These non-motor aspects of dystonia could relate to abnormal sensory processing, body image, cognitive issues, and the social context of physical dependency and lack of opportunity for independence…

Measuring What Matters Most to Children with Dystonia is also an Unmet Need

Most studies fail to report what matters most to children with dystonia and their carers: reduction in pain, improvements in activities of daily living, and manual function. This is a particularly important failing since dystonia worsens in approximately 2/3 of cases and remains severe in a further 1/3 of cases referred for further management after conventional medication…

Exploration of Better Pharmacological Approaches to Managing Dystonia in Childhood as an Unmet Need

Although several medications are regularly used in the first-line management of dystonia, the evidence to support pharmacological agents in childhood dystonia is weak. Trihexyphenidyl has some evidence of efficacy to support its use in adults with dystonia. In a retrospective cohort of 278 children with dystonia referred to a single center from all over the United Kingdom and Republic of Ireland, medication use had been prospectively gathered including adverse drug reactions (ADR).

The commonest drugs used were baclofen (118/278: 42.4%), trihexyphenidyl (98/278: 35.2%), l-dopa (57/278: 20.5%), and diazepam (53/278: 19%). Choice of medication appeared to be influenced by dystonia etiology. ADR had occurred in 171/278 (61.5%) of children: the commonest drugs responsible for ADR being trihexyphenidyl (90/171: 52.3%), baclofen (43/171: 25.1%), and l-dopa (26/171: 15.2%) (70). Unfortunately, pharmacological management of dystonia in children is often disappointing or not tolerated. No medication is licensed for the management of dystonia in childhood . This includes new conceptual approaches to mechanisms of relieving dystonia. Gabapentin has been reported to be beneficial in relieving dystonia in a relatively large open trial in children with often severe dystonia, which was liable to disrupt night sleep, impair the capacity to tolerate sitting comfortably, reduce activities of daily living, disrupt mood and behavior, and very often associated with severe pain. Outcomes were measured using the Dystonia Severity Assessment Plan (DSAP)  and the activities of daily living were mapped on a scale of 0–4 using the WHO International Classification of Function where 0 = no difficulty and 4 = maximum difficulty most of the time. Gabapentin may thus become a new, “re-purposed” medication for routine management of dystonias in childhood subject to further studies with a view to obtaining a license for gabapentin liquid and tablets/capsules in childhood dystonia.