Prescribing issues in spasticity and dystonia Professor Rajat Gupta Consultant Paediatric Neurologist Birmingham Children s Hospital
Cerebral palsy is common, affecting about 2-3 per 1000 children Surveillance of cerebral palsy in Europe, Dev Med Child Neurol 2000 About 75% of children with CP have spasticity Murphy NA, et al, Phys Med Rehabil 2002 Around 10 to 15% will have dystonia (often together with spasticity)
Spasticity Spasticity is a motor disorder characterized by a velocity dependent increase in tonic stretch reflexes ( muscle tone ) with exaggerated tendon jerks, resulting from hyper-excitability of the stretch reflex, as one component of the upper motor neurone syndrome Lance 1980
Spasticity results from a lack of descending impulses that normally stimulate the release of the inhibitory neurotransmitter GABA which acts presynaptically to inhibit the release of excitatory neurotransmitters
Dystonia Dystonia is defined as a syndrome of sustained muscle contraction that frequently causes twisting and repetitive movements or abnormal postures; it is often increased during voluntary movement Fahn S, et al, 1998
Dystonic movements are characterized by the co-contraction of antagonist muscles and overflow of activity into surrounding muscles resulting in an abnormal pattern of muscle activation during voluntary movement or the maintenance of posture. Dystonia originates in the basal ganglia and involves deficient inhibition at the level of the motor cortex and probably also at the levels of the brainstem and spinal cord.
Spasticity in under 19s management Oral drugs NICE July 2012 Consider oral diazepam or baclofen if spasticity is contributing to one or more of the following: discomfort or pain muscle spasms functional disability
If oral diazepam is initially used because of its rapid onset of action, consider changing to oral baclofen if long-term treatment is indicated. Continue using oral diazepam or oral baclofen if they have a clinical benefit and are well tolerated, but think about stopping the treatment whenever the child or young person's management programme is reviewed and at least every 6 months.
If adverse effects (such as drowsiness) occur with oral diazepam or oral baclofen, think about reducing the dose or stopping treatment. If the response to oral diazepam and oral baclofen used individually for 4 6 weeks is unsatisfactory, consider a trial of combined treatment using both drugs.
If a child or young person has been receiving oral diazepam and/or baclofen for several weeks, ensure that when stopping these drugs the dose is reduced in stages to avoid withdrawal symptoms. In children and young people with spasticity in whom dystonia is considered to contribute significantly to problems with posture, function and pain, consider a trial of oral drug treatment, for example with trihexyphenidyl, levodopa or baclofen.
Baclofen Baclofen binds to GABA B receptors in Rexed laminae I to IV of the spinal cord leading to a reduction in the release of excitatory neurotransmitters (such as glutamate and aspartate), as well as substance P. Important side effects of baclofen include drowsiness, orthostatic hypotension and withdrawal symptoms such as seizures, fever, hallucinations, and rebound spasticity.
Oral baclofen has poor penetration of the bloodbrain barrier with cerebrospinal fluid (CSF) drug levels 10-fold lower than serum concentrations. Commonly oral dose escalation leads to side effects before full therapeutic efficacy is reached. Intrathecal delivery of baclofen may then be considered.
Benzodiazepines Benzodiazepines facilitate the binding of existing GABA to the GABA A receptor, found in high concentrations in the reticular formation and polysynaptic spinal tracts. Activation of the GABA A receptor causes an increase presynaptic inhibition and reduces monosynaptic and polysynaptic reflexes throughout the spinal cord
Different benzodiazepine compounds are available with different routes of administration and different half-lives. Oral diazepam often used. Initial dose is 250 mcg/kg tds with a maximum dose of 20 mg tds. If nocturnal spasticity is the major problem consider a single dose at night. The most important side effect is sedation. Additionally, habituation and tolerance may develop.
Clonidine and Tizanidine These are alpha 2, nonadrenergic receptor agonists that release excitatory neurotransmitters and inhibit supraspinal facilitatory pathways. Tizanidine is given orally and selectively decreases tone and spasm frequency in only the spastic muscles, eliminating the unwanted side effect of generalised muscle weakness.
Tizanidine is an imidazoline derivative similar to clonidine but without the cardiovascular effects when appropriately titrated. Potential side effects include drowsiness (particularly with tizanidine), dry mouth, dizziness, nausea and vomiting. Also hypotension with clonidine. Clonidine dose 0.5 1mcg/kg tds (max 25mcg/kg/d)
Dantrolene sodium Dantrolene works peripherally directly on the skeletal muscle, hindering the release of calcium from the sarcoplasmic reticulum, thereby preventing the excitation-contraction coupling mechanism. This decreases the force of muscle contraction. However, this mechanism is not selective and the resulting generalised muscle weakness may weaken respiratory muscles. It is less sedative than the other antispasticity agents
Dantrolene dosing in children 0.5 mg/kg orally once daily for 7 days, then 0.5 mg/kg three times a day for 7 days, then 1 mg/kg three times a day for 7 days, then 2 mg/kg three times a day.
Gabapentin The exact mechanism of action of Gabapentin is relatively unknown Thought to act at the alpha-2 δ1 subunit of voltage-dependent calcium channels, thus inhibiting calcium currents. A study by Gruenthal et al (1997) showed that using gabapentin alone, compared to a placebo, demonstrated a reduction in the Ashworth scale and in the spasticity Likert scale scores. Adverse effects include somnolence, tremor, and nystagmus
Gabapentin dosing 10 mg/kg once daily (max. per dose 300 mg) on day 1, then 10 mg/kg twice daily (max. per dose 300 mg) on day 2, then 10 mg/kg 3 times a day (max. per dose 300 mg) on day 3 (usual dose 25 35 mg/kg daily in 3 divided doses)
Oral medications used to treat spasticity Levitt and Browd, 2015
Approach to treatment of dystonia Aetiology-specific: treatment of underlying disease Anatomy-specific: treat sensory, basal ganglia, frontal, or cerebellar origin Nonspecific: reduce stretch reflexes
Medicines for dystonia Medicines for spasticity will also generally improve dystonia, particularly if spasticity and dystonia co-exist in the patient. reduce stretch reflexes Baclofen, Intrathecal Baclofen, Benzodiazepines, Botulinum Toxin
Medicines for dystonia These include Trihexyphenidyl, Levodopa and Clonazepam Consider these when anti-spasticity medications not adequately controlling symptoms or if patient predominantly has dystonia and not spasticity
Approach to Treatment Anatomy-specific: treat sensory, basal ganglia, frontal, or cerebellar origin Levodopa, Trihexyphenidyl, Deep-Brain Stimulation
Trihexyphenidyl An anticholinergic agent. It is a muscarinic acetylcholine receptor antagonist. The therapeutic dose varies considerably. Children tend to tolerate this better than adults. Central side effects include memory loss, confusion, restlessness, insomnia, and nightmares. Children may experience chorea, or exacerbation of a pre-existing tic disorder. Peripheral side effects include blurred vision, dry mouth, constipation, and urinary retention.
Trihexyphenidyl dosing For Child 3 months 17 years Initially 1 2 mg daily in 1 2 divided doses, then increased in steps of 1 mg every 3 7 days, dose to be adjusted according to response and sideeffects; maximum 2 mg/kg per day (up to maximum 20mg/d)
Levodopa Study results with Levodopa in treating generalised dystonias have been variable. (Cloud and Jinnah, 2010). One small subset of patients with substantial improvement with levodopa is dopa-responsive dystonia (DRD), which may represent up to 5% of childhood dystonias. DRD is characterised by childhood onset, gait disturbance, muscle cramps and diurnal fluctuations. It is often misdiagnosed as cerebral palsy. Levodopa is administered in combination with the decarboxylase inhibitor carbidopa.
Levodopa Side effects include nausea, orthostasis, and constipation. Unlike adult patients with Parkinson s disease, children with dystonia rarely develop confusion, hallucinations, or dyskinesias. Most children with DRD will respond to low doses. But for dystonia with CP may require doses as high as 20 mg/kg/day. (Cloud and Jinnah 2010) For Child 3 months 17 years (BNFc) Initially 250 micrograms/kg 2 3 times a day, dose to be increased according to response every 2 3 days, increased if necessary up to 1 mg/kg 3 times a day.
Clonazepam Studies have shown Clonazepam to be effective in treating generalised and focal dystonias. (Cloud and Jinnah 2010) A typical starting dose is 0.5 mg at night. The dose is slowly increased to an average daily dose of 1 4 mg in 3 divided doses. Side effects include sedation, confusion, impaired coordination, and depression. There is also potential for dependence
Summary There is a lack of robust evidence to inform pharmacotherapy for dystonia and spasticity, therefore strict recommendations of first, second and third line medications are not practical. Fernandez-Alvarez E, Nardocci N, 2012 Therapeutic strategies tend to vary with individual clinician preference and experience.
As well as dystonia-specific therapy, identifying and treating precipitating factors is paramount. Spasticity is a common co-morbidity, and it can be difficult to differentiate between spasticity and dystonia in some children. In these cases a pragmatic approach to symptom control should be taken.
Medications should be reviewed periodically, addressing whether the drug has had a positive effect on quality of life and the side effects. If no improvement with second line medication, consider discussion with colleagues. As well as medication, supportive management in a multidisciplinary team including physiotherapy, occupational therapy, speech therapy and psychosocial support is essential.
Epidiolex may be a useful treatment on the horizon
Status dystonicus Status dystonicus is a potentially fatal episode of severe generalised dystonia. Complications include bulbar and respiratory compromise, and metabolic disorders such as rhabdomyolysis leading to acute renal failure. Children with status dystonicus should be managed in a hospital setting, and will often need intensive care. Important to treat complications.
Supportive care such as invasive ventilation and haemofiltration for rhabdomyolysis may be needed. Therapy should be aggressive, with a slow weaning process. Treatment options include benzodiazepines, clonidine, propofol, and deep sedation with barbiturates. Once the dystonia severity has lessened, a slow wean of therapy can begin.
Conclusion Childhood spasticity and dystonia are challenging conditions. They often co-exist. A multitude of external and internal factors often play a part in influencing dystonia. Medications have an important role in managing spasticity and dystonia. However, a pragmatic, multi-disciplinary approach to management is vital
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