Background: Huntington disease (HD) is an inherited neuropsychiatric condition with progressive neurodegenerative changes, mainly affecting the striatum. Pathological processes within the striatum are likely to lead to alterations in dopamine and glutamate activity in frontostriatal circuitry, resulting in characteristic motor, behavioural and cognitive symptoms.Methods: We conducted a systematic literature search in order to identify and review randomised, double-blinded, placebo-controlled trials of anti-dopaminergic and anti-glutamatergic therapy in HD.Results: Ten studies satisfied our selection criteria. These studies investigated a range of agents which act to antagonise dopamine (tetrabenazine, typical and atypical antipsychotics) or glutamate (amantadine, riluzole) transmission.Discussion: Although most agents showed efficacy in terms of amelioration of chorea, the available evidence did not allow us to identify a universally effective treatment. One difficulty associated with analysing the available evidence was a high prevalence of side effects, which prevented the full therapeutic potential of the medications from being adequately investigated. A further limitation is that many studies evaluated treatment effectiveness only in relation to patients' motor symptoms, even though behavioural and cognitive changes may negatively impact patients' quality of life. There is a clear need for further higher-level evidence addressing the effects of dopaminergic and glutamatergic agents on global functioning in HD.

Sumeer K. Mittal

Clare Eddy

The Role of Dopamine and Glutamate Modulation in Huntington Disease

Background: Restless legs syndrome (RLS) is a relatively common neurological disorder affecting sleep and health-related quality of life. Neuroimaging studies, autopsy investigations and experimental studies using animal models have been conducted to investigate the potential causes of RLS, resulting in the generation of multiple pathophysiological hypotheses.Methods: This paper reviews the neurobiology and pharmacotherapy of RLS, with a critical analysis of the heterogeneity and methodological limitations of the existing scientific literature.Results: Although several neurotransmitter systems dysfunction and neuroanatomical abnormalities have been implicated in RLS pathogenesis, dopamine dysfunction within basal ganglia pathways, iron deficiency and opioid system abnormalities have consistently been found to be involved. Their involvement is further strengthened by the therapeutic effectiveness of dopaminergic agents, iron supplementation and opioid medications.Discussion: Converging evidence from neuroimaging, autoptic and animal studies points towards dopamine dysregulation and iron metabolism alterations as the main contributors to RLS pathophysiology. The possible interactions between different neurotransmitter systems should guide further neuropharmacological research in order to improve therapeutic efficacy for this disabling condition.

Ruth Jones

Andrea Eugenio Cavanna

The Neurobiology and Treatment of Restless Legs Syndrome

Objectives: The pharmacotherapy of Parkinson&#x2019;s disease (PD) is often challenging as clinicians have to find a favourable balance between the efficacy on motor symptoms and side effect profiles of different dopaminergic medications. We aimed to assess the available evidence on the role of dopamine agonist monotherapy as an alternative to Levodopa in the treatment of motor symptoms of PD, along with the role of dopamine antagonists in the treatment of PD-related psychosis.Methods: We performed a systematic literature review using the databases MEDLINE, EMBASE, PsycINFO and the Cochrane Library Central register of controlled trials. Two searches were performed, &#x2018;Search 1&#x2019; extracting trials on dopamine agonists, and &#x2018;Search 2&#x2019; on atypical antipsychotics. Eligible studies were Double-blind Randomised Controlled Trials (RCTs) using the Unified Parkinson&#x2019;s Disease Rating Scale (UPDRS) and the Brief Psychiatric Rating Scale (BPRS) as outcome measures for Search 1 and 2, respectively.Results: 16 relevant RCTs were extracted from the search results. Overall, dopamine agonists were shown to significantly improve UPDRS scores, with a mean percentage improvement of 14.4&#x25; compared to &#x2212;1.9&#x25; in the control arm (P value &#x3C; 0.05)However, their side effect profile illustrated they were associated with twice the incidence of psychotic symptoms in comparison to the controls. The results on the efficacy of atypical antipsychotics for the treatment of PD-related psychosis were
not significant.Conclusions: This evidence-based review confirmed that dopamine agonists can be an effective and safe treatment as monotherapy in PD, however psychotic symptoms remain a significant side effect. Atypical antipsychotics may not be relied upon for the correction of these symptoms due to inconsistent results about their efficacy.

Hajar Alobaidi

Hardev Pall

The Role of Dopamine Replacement on the Behavioural Phenotype of Parkinson&#x2019;s Disease

Introduction: The basal ganglia are interconnected with cortical areas involved in behavioural, cognitive and emotional processes, in addition to movement regulation. Little is known about which of these functions are associated with individual basal ganglia substructures.Methods: Pubmed was searched for literature related to behavioural, cognitive and emotional symptoms associated with focal lesions to basal ganglia structures in humans.Results: Six case-control studies and two case reports were identified as relevant. Lesion sites included the caudate nucleus, putamen and globus pallidus. These were associated with a spectrum of behavioural and cognitive symptoms, including abulia, poor working memory and deficits in emotional recognition.Discussion: It is often difficult to precisely map associations between cognitive, emotional or behavioural functions and particular basal ganglia substructures, due to the non-specific nature of the lesions. However, evidence from lesion studies shows that most symptoms correspond with established non-motor frontal-subcortical circuits.

Peter Ward

Stefano Seri

Functional Neuroanatomy and Behavioural Correlates of the Basal Ganglia: Evidence from Lesion Studies

Aims: This review aims to evaluate the most recent evidence on the pathophysiology of impulse control disorders (ICDs) in Parkinson disease (PD).Methods: Computerised searches of Medline, Embase and PsycInfo, along with manual searches for grey literature, were conducted and resulted in a total of 16 studies suitable for review.Results: Evidence was divided into four categories: medication used in PD management, imaging studies, genetic analysis and subthalamic deep brain stimulation (STN-DBS). Analysis of the literature reveals that both intrinsic and extrinsic factors may play a role in the pathophysiology of ICDs in PD. Dysfunction of the mesocorticolimbic pathway and polymorphisms of the dopamine D3 and D4 receptors may increase an individual's susceptibility to the development of ICDs.Discussion: Dopaminergic medication, particularly dopamine agonists (DAs), increases the risk of developing impulsive behaviours in a PD patient. Further evidence, particularly in the form of prospective studies and randomised controlled trials is required to better establish the pathophysiology of ICDs in PD.

Sharmili Balarajah

The Pathophysiology of Impulse control Disorders in Parkinson Disease

Background: Dystonia is a chronic disorder characterised by an aberration in the control of movement. Sustained co-contraction of opposing agonist and antagonist muscles can cause repetitive and twisting movements, or abnormal postures. Cervical dystonia (CD), often referred to as spasmodic torticollis, is a type of focal dystonia involving the muscles of the neck and sometimes the shoulders.Methods: This systematic review collates the available evidence regarding the safety and efficacy of a range of treatments for CD, focusing on their effectiveness as shown by double-blinded, randomised controlled trials.Results: Our review suggests that botulinum toxin type A (BTA), botulinum toxin type B (BTB) and trihexyphenidyl are safe and efficacious treatments for CD. Evidence shows that botulinum toxin therapies are more reliable for symptomatic relief and have fewer adverse effects than trihexyphenidyl. When comparing BTA to BTB, both are found to have similar clinical benefits, with BTA possibly having a longer duration of action and a marginally better side effect profile. BTB is also safe and probably just as efficacious a treatment in those patients who are unresponsive or have become resistant to BTA.Discussion: The current evidence shows that the pharmacological management of CD relies on BTA and BTB, two agents with established efficacy and tolerability profiles.

Sejal Patel

Davide Martino

Cervical Dystonia: From Pathophysiology to Pharmacotherapy

The Behavioural Neurology of Basal Ganglia Disorders

Introduction: Huntington disease (HD) is a progressive neurodegenerative condition characterised by motor, cognitive and behavioural dysfunction, and has an autosomal dominant mode of inheritance. As there is currently no treatment to delay progression of the disease, pharmacological intervention is aimed at symptomatic relief.Methods: We set out to assess the current evidence on the pharmacological treatment of motor and non-motor symptoms in HD by carrying out a systematic literature review across five large scientific databases.Results: The search generated 23 original studies meeting our search criteria. Studies on the following drug classes were obtained: dopamine (DA) depleting agents, neuroleptics, anti-glutamatergic agents, acetylcholinesterase inhibitors, GABA agonists, cannabinoids, antidepressants and potential neuroprotective agents. Tetrabenazine (TBZ), a DA depleting agent, was the only pharmacotherapy shown to have a clinically meaningful, statistically significant effect on chorea. The majority of the reviewed studies focussed on the treatment of motor symptoms of HD.Discussion: Overall, the evidence base for the pharmacological management of HD is poor. There is a clear need for future high quality randomised controlled trials on the symptomatic treatment of HD, particularly on the pharmacotherapy of non-motor symptoms of HD.

Connie Pidgeon

Hugh Rickards

The Pathophysiology and Pharmacological Treatment of Huntington Disease

Introduction: Gilles de la Tourette Syndrome (GTS) is a childhood-onset hyperkinetic movement disorder defined by the chronic presence of multiple motor tics and at least one vocal tic and often complicated by co-morbid behavioural problems. The pharmacological treatment of GTS focuses on the modulation of monoaminergic pathways within the cortico-striato-thalamo-cortical circuitry. This paper aims to evaluate the efficacy and safety profiles of pharmacological agents used in the treatment of tics in patients with GTS, in order to provide clinicians with an evidence-based rationale for the pharmacological treatment in GTS.Method: In order to ascertain the best level of evidence, we conducted a systematic literature review to identify double-blind randomised controlled trials of medications in GTS populations.Results: We identified a large number of pharmacological agents as potentially effective in improving tic symptoms. The alpha-2 agonist Clonidine is amongst the agents with the most favourable efficacy-versus-adverse events ratio, especially in patients with co-morbid attention-deficit hyperactivity disorder, although effect sizes vary evidence-based studies.Discussion: Our results are in line with the findings of uncontrolled open-label studies. However, most trials have low statistical power due to the small sample sizes, and newer agents, such as Aripiprazole, have not been formally tested in double-blind randomised controlled trials. Further research should focus on better outcome measures, including Quality of Life instruments.

Karen Waldon

Jonathan Hill

Cristiano Termine

Umberto Balottin

Trials of Pharmacological Interventions for Tourette Syndrome: A Systematic Review

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Papers are published upon acceptance, regardless of the Special Issue publication date.

Behavioural Neurology

The Behavioural Neurology of Basal Ganglia Disorders

The Behavioural Neurology of Basal Ganglia Disorders

Articles

The Role of Dopamine and Glutamate Modulation in Huntington Disease

The Neurobiology and Treatment of Restless Legs Syndrome

The Role of Dopamine Replacement on the Behavioural Phenotype of Parkinson’s Disease

Functional Neuroanatomy and Behavioural Correlates of the Basal Ganglia: Evidence from Lesion Studies

The Pathophysiology of Impulse control Disorders in Parkinson Disease

Cervical Dystonia: From Pathophysiology to Pharmacotherapy

The Behavioural Neurology of Basal Ganglia Disorders

The Pathophysiology and Pharmacological Treatment of Huntington Disease

Trials of Pharmacological Interventions for Tourette Syndrome: A Systematic Review