Treatment & Management
Treatment of Motor Manifestations in patients with dopa-responsive dystonia
Levodopa (L-dopa). Primary manifestations in patients with autosomal dominant and recessive forms of dopa-responsive dystonia are predominantly motor; these symptoms are most effectively treated with levodopa. Optimal dosing requirements may vary with age, physical activity and growth. L-dopa must be used in conjunction with an inhibitor of AADC activity such as carbidopa in order to allow the precursor to effectively cross the blood-brain barrier, where it can be converted to dopamine in neuronal cells.
In more severely affected individuals who have L-dopa dose-related dyskinesia, other therapies may help augment the L-dopa therapy, thus reducing the sometimes significant peak and trough fluctuations in motor function associated with the short half life of L-dopa. Slow release formulations are available for adults but not children.
Because patients with neurotransmitter deficiency disorders may have been deficient for prolonged periods before treatment, they can be extremely sensitive to initiation of neurotransmitter precursors. Patients with TH deficiency seem particularly susceptible in this regard. Starting with extremely conservative dosages, increasing the dosage slowly over weeks or months, and ensuring that peripheral aromatic L-amino acid decarboxylase is fully blocked by providing ample carbidopa can make the transition to treatment much easier. The rate or degree to which children respond depends on a variety of factors including age of diagnosis, specific disorder and mutation, presence or absence of elevated phenylalanine levels, and presence or absence of central BH4 deficiency. In general, optimism regarding improvement is warranted.
Institution of neurotransmitter precursor treatment may lead to new problems, such as intermittent dyskinesia related to a peak dose effect, changes in appetite, gastroesophageal reflux, diarrhea, or constipation. These problems, greatest in the first few weeks of institution of treatment, tend to improve with time. With regard to replacement of L-dopa, use of a slow release form of the medication may theoretically be ideal. However, such formulations are not dosed for use in children, but for use in adults with Parkinson's disease. In addition, dividing standard dosage forms marketed for adults make adequate dosing in infants and young children a significant challenge. Thus, ideal dosage forms may need to be formulated in compounded preparations, rather than via commercially marketed dosage preparations. Support for parents and children during this often difficult period of transition from initiation of treatment to adjustment of medications is critical, because these patients will likely require neurotransmitter precursor replacement throughout their lifetimes.
Other. The monoamine oxidase B (MAO-B) inhibitor selegeline slows the catabolism of dopamine and significantly augments the effectiveness of levodopa/carbidopa therapy in some individuals. Anticholinergic agents, such as trihexyphenidyl and amantidine, have also proved modestly helpful in augmenting motor benefit of levodopa/carbidopa, and in smoothing out motor fluctuations.
