Pediatric Movement Disorders and Neuromodulation: An Overview
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.302474
Source of Support: None, Conflict of Interest: None
Keywords: Deep brain stimulation, movement disorder, neuromodulation
Movement Disorders in pediatric population are complex disease entities with diagnostic dilemmas due to their sequential presentation, genotypic variation, and clinical pleiotropy. These disorders are diverse in terms of etiology, severity, disability, comorbidities and evolution. Getting an accurate diagnosis is critical in determination of appropriate treatment. The spectrum of pediatric movement disorder encompasses various conditions like chorea, dystonia, tics, myoclonus, etc., Dystonia is the most frequent, severe, and difficult to treat movement disorder. Movement disorders are challenging due to the difficulty in their identification, localization, evolution with changing patterns, varied etiology and lack of evidence in terms of treatment. Therapeutic options in children are lacking robust clinical trials. Also movement disorders in pediatrics are predominantly secondary with multiple comorbidities and showing variable evolution during development as against in adults. Most of the drugs tried are off label and have difficulties in their introduction, titration, and discontinuation.
A then-new technique of invasive neuromodulation was introduced in 1960 for adult movement disorder i.e., deep brain stimulation (DBS) for essential tremors and Parkinson's disease (PD). In children, when pharmacological management fails, surgical interventions like pallidotomy, deep brain stimulation may be considered with promising results following successful trials in adult population. Lesioning surgeries are still an option in pediatric movement disorders.
Classification and definitions of pediatric movement disorder
Movement disorders in children are broadly classified into two main groups
1- Hyperkinetic and movement disorders
2- Hypokinetic movement disorders.
The hyperkinetic disorders are further subdivided into chorea, dystonia, dyskinesia, myoclonus, stereotypies, tics, tremors whereas hypokinetic disorders are predominantly Parkinson spectrum with rigidity, initiation issues and slowness of movements
Pediatric vs Adult movement disorders: Developing Pediatric brain shows evolution in symptomatology with variable manifestations according to the age and developmental stage. The etiology of pediatric movement disorder is quite variable, static as well as progressive disorders presenting early in life show similar manifestations in different combinations needing a pattern recognition leading to complexity in diagnosis especially in young infants. Another important distinction in pediatric and adult movement disorders is the anatomical localization in adult disorders as against global and multifocal insult in children with specific cells or receptor damage.,
Pathophysiology of pediatric movement disorder
In general movement disorders are understood as failure to initiate desired movements with poverty and slowness of movements or failure to inhibit unwanted movements Majority of movement disorders are secondary to disruption of the various connections in motor cortex, pallidostriatal systems, cerebellum, spinal cord. The center or initiation of movement occurs in basal ganglia consisting of corpus striatum (caudate nucleus and lenticular nucleus comprising putamen and pallidum and other Subcortical allied nuclei like subthalamic nucleus (STN), substantia nigra (SN – pars compacta (SNc), pars reticularis (SNr)) and the pedunculopontine tegmental nucleus (PPTg). Striatum and STN being the primary input structures receiving excitatory inputs from motor cortex. The globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr) are the output nuclei sending inhibitory output to thalamus and brainstem [Figure 1].
In normal state, putamen receives afferents from cortex and projects on to GPi/SNr through a direct inhibitory (GPe) or an indirect pathway via STN. Dopamine acts by inhibiting indirect and facilitating direct pathways. Hyperkinetic disorders are associated with hypoactivity of STN leading to disinhibition of GPi output to thalamocortical projections. Parkinson's disease with dopamine deficiency is associated with increased inhibition from putamen onto GPe and STN disinhibition which in turn have excitation of GPi/Sr with inhibition of thalamocortical pathways [Figure 1].
[Figure 1]: Basal Ganglia circuit in Normal, Hyperkinetic and Hypokinetic Disorders.
Basal ganglia dysfunction, the major culprit in movement disorder can occur at many levels for example – i) destruction of specific nuclei with resultant specific movement disorder. The etiology could be focal like stroke or may be due to multiple nuclei injury as in hypoxia, metabolic disorder ii) destruction of particular neurons as in Huntington's or Parkinson's disease iii) cellular dysfunction rather than destruction as in Primary dystonia. Caudate lesions are associated with chorea or dystonia in addition to behavioral disturbances. Putaminal lesions are associated with dystonia or Parkinsonism More Details. Similarly globus pallidal lesions present with dystonia, parkinsonism or both. Unilateral subthalamic nuclear involvement can lead to hemiballismus or smaller amplitude chorea. Ataxia results from either cerebellar disorder or its afferent or efferent pathways. Tic disorder localizes to basal ganglia or cortex; similar is the case with myoclonus. But in general pediatric movement disorders are seldom with focal pathology.
Etiology of pediatric movement disorder
The list of movement disorders aetiologies is extensive and ever expanding. These can be classified as primary and secondary where in primary is one in which there is no structural abnormality in brain and may be due to some genetic causes and secondary are due to identifiable pathology in the brain which could be static brain damage or progressive neurodegeneration, metabolic disorders, immune-mediated disorders, demyelinating disorders, drug-induced or toxin-induced movement disorders.
Cerebral Palsy is the most common cause of secondary pediatric movement disorders with vivid presentations. Prevalence is 2 per 1000. Though static insult the presentation and type of movement disorder may change with age and development.
Approach to diagnosing these movement disorders is based primarily on detailed description or observation (Video) of these abnormal movements with identification of the predominant abnormal movement (in case of multiple abnormal movements) in addition to the routine neurologic and non-neurologic history. Developmental milestones, family history, drug history are also essential in coming to the diagnosis of the neurological condition. The detailed examination includes various scales used to classify and characterize abnormal movements. The examination also is extended to evaluate various other functional assessments like speech, feeding, overall severity and degree of disability.
Neuroimaging (magnetic resonance imaging) determines the further pattern of work-up with lesion positive and negative cases. This is followed by extensive metabolic, biochemical, electrophysiological, genetic work up as per need of the case. Functional imaging in form of PET is obtained in specific cases.
Management of pediatric movement disorders
The management of pediatric movement disorders has two main goals – 1- management of the etiology if treatable e.g., Wilson's disease, Glut 1 transporter disease 2- Management of symptomatology. Most of the pediatric movement disorders require symptomatic treatment The goal is to disrupt the connection between the pathophysiology and expression of clinical impairment. The symptomatic management ideally should be goal specific which addresses at limitation of functional disability.
The pediatric movement disorder requires multidisciplinary approach with goal-specific progress monitoring approach in a supportive environment with adaptive equipment. Treatment option are many including pharmacotherapy, invasive neuromodulation, surgery experimental gene therapy or stem cell therapy. But identification of appropriate treatment is challenging because of the dearth of knowledge of pathophysiology and developmental influence.
A. Pharmacotherapy- A variety of options are available for management of pediatric movement disorders including botulinum toxin but all these are off-label uses and high-quality evidence of treatment protocols are lacking. Pharmacotherapy has variable efficacy and is limited by adverse effects. A general guideline suggests initiation of medications at low dose, gradually titrate them to get the best benefit without side effects. Tapering is recommended rather than abrupt withdrawal in order to minimize the risk of side effects.
Overview of the Medications [Table 1]:
1- Anticholinergic Drugs – Trihexyphenidyl – It is centrally acting anticholinergic drug used in management of segmental and generalized dystonia. Its use in young children is documented by randomized control trials. It has been also shown to be beneficial in pediatric patients with cerebral palsy. Benztropine is another anticholinergic drug usually used in combination with antihistaminic for management of drug-induced movement disorder secondary to dopamine receptor blockage. Side effects of anticholinergic drugs are constipation, urinary retention, irritability, dryness of mouth, but in general are well tolerated in high doses up to 50 mg/day in pediatric population.
2-GABAergic drugs – Benzodiazepine group of drugs act as GABA agonists or they modulate allosteric GABA receptors thereby enhancing the inhibitory neurotransmission in the spinal cord and basal ganglia. In pediatrics clonazepam either alone or in combination with baclofen is used in dystonia management with added benefit in concomitant spasticity or myoclonus. In case of status dystonicus, the sedative effect of benzodiazepine is considered beneficial as sleep abolishes the dystonia. Baclofen – a GABAergic drug is also shown to be effective in spasticity, dystonia and myoclonus. In case of severe and refractory spasticity or dystonia, intrathecal preparations could be tried.
Gabapentin does not have direct GABAergic effect but it inhibits synthesis of glutamatergic excitatory synapses and have shown some benefit in children with dystonia.
Cannabinoids inhibit glutamatergic and enhance GABAergic transmission through cannabinoid receptors in basal ganglia are shown to have some benefit in patients with refractory Tics.
3-Dopaminergic drugs - Firstline treatment in childhood dystonia comprise levodopa combined with inhibitor of peripheral aromatic L amino acid decarboxylase. Promising results are seen in dopa-responsive dystonia but other disorders like Juvenile Parkinson's disease, dystonia secondary to tyrosine hydroxylase deficiency may show improvement In Dyskinetic CP, the benefit of levodopa is not much marked. Dopamine agonists can be tried in levodopa refractory juvenile parkinsonism or in aromatic amino acid decarboxylase deficiency. The antiviral drug Amantadine is known to increase dopamine release and inhibit its uptake by inhibition of NMDAR.
4-Antidopaminergic drugs – Some movement disorders may be benefitted with suppression of dopaminergic pathways. The monoamine inhibitor, tetrabenazine reversibly inhibits monoamine transporter 2 (VMAT2) hindering its passage from cytosol into the vesicles. This drug helps in management of tics and unlike other neuroleptics like haloperidol carries a minimal risk of tardive dyskinesia thus making it useful in Tourette's syndrome. It is also used in management of chorea in Huntington's disease, other pediatric choreiform disorders, and dystonia. Neuroleptics like haloperidol, pimozide, atypical antipsychotics like risperidone, aripiprazole with affinity of D2 receptors are used in management of tics.
5- Anticonvulsants – These are used in management of myoclonus and tremors, chorea. Most commonly used are levetiracetam, piracetam, valproic acid, topiramate, clonazepam
6- Alpha-adrenergic drugs – Presynaptic alpha 2 receptor agonist – clonidine, guanfacine is useful in management of tics, dystonia.
7- Beta Blockers are useful in adults with essential tremors but the evidence is lacking in children.
B. Surgical Management – Lesional surgeries for dystonia, chemopallidectomy were introduced in early sixties. Pallidotomies are an alternative option to DBS in children as it is cheaper but permanent method and without any implant. There are case reports in 4 children who underwent pallidotomy up to GPi for dystonia showed significant improvement. Another case of glutaric aciduria underwent pallidotomy at 18 months., But the exact role of this surgical option is yet to be discovered.
Neuromodulation – Modulation of the pathological brain activity in pediatric movement disorders by deep brain stimulation seems to offer a promising new therapeutic strategy, though not curative or disease specific. The field of invasive neuromodulation is rapidly expanding and getting translated from adult experience into pediatrics. In adults safety and efficacy of DBS for Parkinson's disease, essential tremors and epilepsy are time tested and approved by FDA. In pediatrics also DBS has been is established and approved as an effective modality of treatment of pharmaco-resistant monogenic isolated dystonia but Tourette, Obsessive-compulsive disorder (OCD) and epilepsy are also potential targets. The role of DBS in acquired, neurodegenerative or neurometabolic disorders not yet clear. Cooper (1922-1985) was the pioneer in functional neurosurgery who developed several novel techniques for managing movement disorders and epilepsy (a cryosurgical probe to conduct thalamotomy cerebellum stimulation to manage spasticity and cerebral palsy,,, and deep brain stimulation (DBS) of the thalamus or internal capsule to manage tremor, spasticity, and dystonia.,, With technological advancement especially structural and functional imaging modalities, better understanding of the neuronal networks and access to validated rating scales for various disorders functional neurosurgery has advanced by leaps and bounds.
Deep brain stimulation (DBS) is one of the early invasive brain stimulation techniques described since 1960 for various neurological and psychiatric disorders. It has its foundation in two seminal papers by Benabid et al. (Grenoble group 1987) describing thalamotomy and stimulation and Pollok et al. (1993) describing DBS for Parkinson's disease.,
DBS is a more conservative and adjustable neuromodulation technique validated in adults as well as children. It is one of the invasive brain stimulation techniques in which lead is placed in the targeted area of the brain and is connected to the extracranially implanted impulse generator. Direct electrical stimulation leads to neurochemical change with alteration in neurotransmitters. There are four main components of the deep brain stimulator: (1) the intracranial electrodes which are inserted surgically into the deep brain Gray matter (2) an anchoring system (plastic ring) fixing the electrode, (3) a single or double channel Implantable Pulse Generator and (4) an extension cable that connects the DBS electrodes to the pulse generator which is implanted in the chest wall or abdomen., This procedure can be performed in a single surgical day or can be staged, with the connection of the pulse generator and electrodes done on another day.
DBS technique use various continuous frequencies (high >100 Hz and low <60 Hz with various pulse widths (narrow- 60–90 microseconds and wide 210-450 microseconds), combination of amplitudes and monopolar or bipolar stimulations. In dystonia high stimulation frequency stimulation is more effective than low frequency. This stimulation mimics the effects of surgical lesioning of the target structures. It suppresses or overrides pathological oscillatory networks in cortico - pallido- thalamo- cortical pathways., The most common targets are STN and GPi. It is associated with symptomatic improvement of disabling symptoms like muscle spasms, various involuntary movements, pain and abnormal postures, respiratory and feeding issues.
1. Dystonia: When medical management fails to provide improvement, symptomatic benefit of invasive modalities like pallidotomy and DBS are tried to reduce the burden of disabling dystonia. Most consistent benefit is seen in early-onset primary dystonia (DYT1) with improvement in Burke Fahn – Marsden Dystonia rating scale (BFMDRS) upto 60-70%., Haridas and colleagues have shown a superior efficacy in primary generalized dystonia patients under 21 years of age (n = 22). They have shown an improvement of BFMDRS scores up to 94% at three years follow-up. The Globus Pallidus Interna (GPi) is the main target in dystonia management which is same in children and adults. There are studies targeting Subthalamic nucleus and thalamic ventralis intermedius. The stimulation frequencies could be higher (100 Hz) but lower frequencies also have been studied.
Several factors have been identified as good prognostic factors. Overall, data suggest that DYT1-carrier status, younger age (before skeletal maturation), shorter duration of disease and absence of fixed contractures are thought to be positive outcome predictors.,,,, However there are no validated selection criteria for DBS in Pediatric dystonia. 1.b DBS is also useful (GPi or ventralis intermedius nucleus of thalamus stimulation) in myoclonic dystonia (DYT 11)
1.c GPi stimulation is also beneficial in neuronal iron accumulation in symptomatic betterment though the disease progression is not heralded. anteroventral GPi is shown benefit in movements and behavior in Lesch Nyhan Syndrome.
1.d DBS in cerebral palsy- Children with dyskinetic cerebral palsy have limited therapeutic options. Many studies of DBS of GPi in dyskinetic cerebral palsy have shown 20-24% improvement of dystonia scores (BFMDRS)
2. DBS in Tourette Syndrome -
The limiting factor of DBS in TD is temporal decline in symptom severity by adulthood with complete resolution in 30% and significant reduction in 75% over a period of time. There is scarce evidence in children for the utility of deep brain stimulation for tics and the optimum brain target for the stimulation itself is under debate. A case report by Shaded showed reduction in tic severity by 76% for motor and 68% for vocal tics after bilateral GPi DBS stating its efficacy in a 16-year-old patient with intractable Tourette's syndrome. Servello et al. also demonstrated a similar benefit with the stimulation of Centro- median perifascicular (CM-POF) nucleus of thalamus. But Dueck and colleagues reported no benefit with bilateral GPi DBS in a girl with severe Tourette's syndrome and intellectual disability.
3- Obsessive-compulsive disorder – Obsession and compulsions are secondary to disturbances in cortico-striato-thalamo cortical circuits. This disorder has a prevalence of 3% and has a good spontaneous remission rate by adulthood so DBS which is used in adults with stimulation of anterior capsule and the nucleus accumbens, remains as a last resort in medically refractory cases.,, There is a case report of 16-year-old girl with bilateral GPi – DBS showing improvement.
4- DBS in Juvenile Parkinson's disease (PD) – In adult PD there are four possible targets for electrode placement. VIM thalamic nucleus stimulation has clear benefit in tremors but DBS of STN or GPi has broader influence on Parkinsonian symptoms., A patient with juvenile PD due to tyrosine hydroxylase deficiency was benefitted with reduction of tremors DBS of the ventralis intermedius nucleus, zona incerta, or radiation prelemniscalis can be beneficial for adult patients with pharmacotherapy-refractory essential tremor. Thalamic deep brain stimulation might also be considered for children with other intractable tremor symptoms.
Patient selection: Validated selection criteria as in adults with Parkinson's disease (response to medication and Quantified severity criteria) are lacking in pediatrics. Pharmaco- resistance and impairment of quality of life can be considered in recruitment. PEDiDBS is an international registry of patient data from children undergoing deep brain stimulation that has been established to allow data sharing.
Complications of DBS: – includes complication of the hardware such as infection or intracerebral bleeding. Other complications include dysarthria, paraesthesia or loss of balance.
Vagal nerve stimulation: Electrical stimulation of vagus nerve (10th Cranial Nerve) is another invasive neuromodulation technique used in management of resistant epilepsy and depression. It was approved in adults and children over 12 years of age in 1997 but the age limit was lowered to 4 years of age in patients with focal onset pharmaco- resistant epilepsy in 2017. This neuromodulation in addition to seizure control also shown to improve sleep quality, behavior and mood in resistant epilepsy patients. The complications though high in percentage are mild and include hoarseness of voice (1%), dyspnoea (<1%), fluid collection around the stimulator, infection (3%). Occasionally arrhythmia and vocal cord dysfunction are encountered.,
Movement disorder and epilepsy are important disabling neurological disorders in children with a myriad of aetiologies. The management is multidisciplinary and goal specific. It includes symptomatic and definitive pharmacotherapy supported by physical therapy. In Resistant cases Neuromodulation techniques like Deep brain stimulation, vagal nerve stimulation has emerged as therapeutic modalities Initially established in adults, the techniques are extended to be offered in pediatric patients with similar symptomatic indications. At present, the evidence with systematic studies in pediatrics is lacking. There are ethical and neurodevelopmental concerns while offering such invasive neuromodulation in children. Further research and better understanding of the neuro circuitries and systematic pediatric registries and further research of these complex neurological disorders may lead to our common goal of helping the kids attain maximum functional abilities improving the quality of life of our patients and their families.
Supported by the CEO (Dr. Minnie Bodhanwala) and MD (Dr. Shakuntala Prabhu) and Dr. Milind Deogaonkar, Professor, Department of neurosurgery, West Virginia University (helping conceptualizing the paper).
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