The Molecular Neuroimaging of Tremor

Purpose of Review Tremor is a hyperkinetic movement disorder most commonly encountered in essential tremor (ET) and Parkinson’s disease (PD). The purpose of this review is to summarize molecular neuroimaging studies with major implications on pathophysiological and clinical features of tremor. Recent Findings Oscillatory brain activity responsible for tremor manifestation is thought to originate in a cerebello-thalamo-cortical network. Molecular neuroimaging has helped clarify metabolic aspects and neurotransmitter influences on the main tremor network. In ET, recent positron emission tomography (PET) studies are built on previous knowledge and highlighted the possibility of investigating metabolic brain changes after treatments, in the attempt to establish therapeutic biomarkers. In PD, molecular neuroimaging has advanced the knowledge of non-dopaminergic determinants of tremor, providing insights into serotonergic and noradrenergic contributions. Summary Recent advances have greatly extended the knowledge of tremor pathophysiology and it is now necessary to translate such knowledge in more efficacious treatments for this symptom.

“Restlessness” After Cancer Diagnosis and Treatment

A 76-year-old woman sought care for unintentional weight loss, hematuria, and fatigue. She was diagnosed with plurimetastatic renal cell carcinoma. After resection of the primary tumor and metastases, she was treated with pembrolizumab, an immune checkpoint inhibitor. The patient experienced involuntary tongue and face movements with dysphagia and weight loss. She was also described as “restless.” At that point, the patient was in cancer remission with ongoing immune checkpoint inhibitor treatment. Blood testing was unremarkable. Brain magnetic resonance imaging showed basal ganglia T2/fluid-attenuated inversion recovery hyperintensities without gadolinium enhancement. Cerebrospinal fluid testing showed slightly increased protein concentration and 8 cerebrospinal fluid-restricted oligoclonal bands. Serum and cerebrospinal fluid testing for neural autoantibodies showed immunoglobulin G immunoreactivity in a mouse tissue indirect immunofluorescence assay, predominantly staining the basal ganglia. The immunoglobulin G was subsequently identified to bind to phosphodiesterase 10A. The patient was diagnosed with paraneoplastic phosphodiesterase 10A-immunoglobulin G autoimmunity manifesting as hyperkinetic movement disorder triggered by immune checkpoint inhibitor treatment. Given the patient’s cancer remission, the immune checkpoint inhibitor treatment was discontinued. She was treated with high-dose intravenous corticosteroids, with improvement of her hyperkinetic movement disorder but persistence of some dystonic movements. Further treatment with oral prednisone did not produce further improvement. The patient was treated symptomatically with onabotulinumtoxinA injections and tetrabenazine, which ameliorated her dystonic movements. Three years after her cancer diagnosis, she was alive and in cancer remission with minimal residual movements. Immune checkpoint inhibitors are monoclonal antibodies targeting “stop signs” of the immune response, which lead to enhanced endogenous responses, including those against cancer. Autoimmune complications are consequences of the enhanced immunity and can affect all organs, including the nervous system.

Non-Ketotic Hyperglycemia-Induced Hemichorea-Hemiballism, A Case Presentation

Hemiballism is a rare hyperkinetic movement disorder characterized by repetitive, uncontrolled movements unilateral /or bilateral extremities, develops as a result of insult to the contralateral basal ganglia. The leading source for this disorder is ischemia, followed by non-ketotic hyperglycemia with poorly controlled diabetes. Non-ketotic hyperglycemic induced hemichorea-hemiballism is an uncommon but unique etiology of unilateral neuro-parenchymal findings restricted to corpus striatum (caudate nucleus and putamen). Nonketotic hyperglycemia-induced hemichorea-hemiballism diagnosed by Cross-sectional imaging modalities (Computed tomography and Magnetic resonance imaging), Clinical results (hemichorea-hemiballism), Laboratory tests (elevated blood glucose and hemoglobin A1c levels).

Propranolol Relieves L-Dopa-Induced Dyskinesia in Parkinsonian Mice

Background: Parkinsonism is caused by dopamine (DA) insufficiency and results in a hypokinetic movement disorder. Treatment with L-Dopa can restore DA availability and improve motor function, but patients can develop L-Dopa-induced dyskinesia (LID), a secondary hyperkinetic movement disorder. The mechanism underlying LID remains unknown, and new treatments are needed. Experiments in mice have shown that DA deficiency promotes an imbalance between striatal acetylcholine (ACh) and DA that contributes to motor dysfunction. While treatment with L-Dopa improves DA availability, it promotes a paradoxical rise in striatal ACh and a further increase in the ACh to DA ratio may promote LID. Methods: We used conditional Slc6a3DTR/+ mice to model progressive DA deficiency and the β-adrenergic receptor (β-AR) antagonist propranolol to limit the activity of striatal cholinergic interneurons (ChIs). DA-deficient mice were treated with L-Dopa and the dopa decarboxylase inhibitor benserazide. LID and motor performance were assessed by rotarod, balance beam, and open field testing. Electrophysiological experiments characterized the effects of β-AR ligands on striatal ChIs. Results: LID was observed in a subset of DA-deficient mice. Treatment with propranolol relieved LID and motor hyperactivity. Electrophysiological experiments showed that β-ARs can effectively modulate ChI firing. Conclusions: The work suggests that pharmacological modulation of ChIs by β-ARs might provide a therapeutic option for managing LID.

Status Dystonicus in Children with Secondary Dystonia: Reporting 3 Cases of Cerebral Palsy, Leigh Disease and Molybodynum Co Factor Deficiency

Objective: Patients with primary and secondary dystonic syndromes occasionally develop severe episodes of generalized dystonia and rigidity which is known as status dystonicus (SD) or dystonic storm. This is a frightening hyperkinetic movement disorder and it is an emergency. Marked, rapid exacerbation of dystonia requires prompt intervention and admission in the hospital. It is critical to recognize early and differentiate dystonic storm from other hyperkinetic movement disorder as it may lead to metabolic complications such as rhabdomyolysis, leading to acute renal failure. This paper has been written to describe three cases of SD, all having secondary dystonia with different etiologies to highlight the mode of presentation, diagnosis, treatment and outcome. Methodology: We report 3 cases of severe secondary dystonia culminating in SD necessitating management in hospital setting. All the three cases were admitted in a tertiary care hospital and evaluated. Results: One patient was treated in intensive care unit. In brief 1st case was a 5 year boy with dyskinetic CP who was treated with trihexiphenidyl (THP), baclofen and midazolam infusion. Second case was a 15 month old boy, diagnosed case of mitochondrial encephalopathy (Leigh disease) who was treated with THP, baclofen, haloperidol, clonazepam and infusion midazolam. The third case was a 13 month old boy, diagnosed case of Molybdenum Cofactor deficiency who was treated with THP, tizanidine but they refused to take midazolam. Conclusion: In this case series, three cases with SD with different etiology have been described with clinical features, modalities of treatment and outcome.

Fifteen-minute consultation: Approach to investigation and management of childhood dystonia

Dystonia is a hyperkinetic movement disorder characterised by sustained or intermittent muscle contractions causing abnormal movements, postures or both. Dystonia is a challenging condition to diagnose and treat. Dystonia is often under-recognised in children, particularly in cerebral palsy, and frequently coexists with spasticity. This guide aims to simplify the approach to diagnosis, investigation and treatment of childhood-onset dystonia. The principle of treatment is similar regardless of the underlying aetiology: identification of potential triggers and consideration of both pharmacological and surgical options.

Treatment of Dystonia Using Trihexyphenidyl in Costello Syndrome

Costello syndrome (CS), a rare syndrome with multisystemic involvement inherited as a dominant trait, is characterized by developmental delay, coarse facial appearance, cardiac defects including hypertrophic cardiomyopathy, skin abnormalities, brain complications, and a predisposition to certain malignancies. The musculoskeletal system is particularly affected in CS, with peculiar orthopedic anomalies that impact posture and gait. Dystonia has been recently documented to contribute to abnormal postures and musculoskeletal anomalies characterizing CS, suggesting the possible use of pharmacological treatments to treat these complications. We report the case of a child affected by CS displaying a particularly severe musculoskeletal involvement with dystonic posture especially in the arms and legs. The Movement Disorder-Childhood Rating Scale (MD-CRS) and a gait analysis were used to assess clinical patterns of hyperkinetic movement disorder and dystonia. The child was further treated with trihexyphenidyl for six months with a final dosage of 14 mg. MD-CRS and gait analysis assessments provided evidence for a significant improvement of posture and the related musculoskeletal problems with no side effects. Our preliminary study report provides first evidence that pharmacological anti-dystonia treatment significantly improves movement and posture disorders in patients with CS. Further studies enrolling larger cohorts of patients should be performed to validate these preliminary observations.

A Review of the Current Treatment of Tourette Syndrome

Tourette syndrome is a hyperkinetic movement disorder that presents before age 18 years and involves motor and phonic tics that may present with a wide range of severity. The severity and presentation of tics in an individual may fluctuate over time. Tourette syndrome may affect social relationships and school attendance, and may result in depression. Comorbidities are common, with attention-deficit/hyperactivity disorder and obsessive-compulsive disorder being most common. The literature supporting optimal treatment is limited but provides a framework for clinical decision-making. The focus of this review is to discuss the symptoms and possible causes of Tourette syndrome and current non-pharmacologic and pharmacologic treatment options, to help practitioners optimize care for pediatric patients with this disease.