Levodopa-Induced Dyskinesia in Long-Standing Hemiparkinsonism Secondary to a Midbrain Cavernous Malformation

Authors:
Preprint
Publisher website
Google Scholar
Abstract
Late-onset progressive hemiparkinsonism may emerge years or even decades after an acute midbrain insult, such as hemorrhage secondary to a cavernous malformation. Two complementary hypotheses may explain this delayed onset: an initial loss of dopaminergic neurons in the substantia nigra, with surviving neurons compensating for striatal function until age-related decline reaches the clinical threshold, and a delayed neurodegenerative process, such as trans-synaptic degeneration of the substantia nigra following striatal injury. Although post-midbrain lesion parkinsonism may mimic Parkinson’s disease and initially respond dramatically to low-dose levodopa, these patients have an increased risk of motor fluctuations and levodopa-induced dyskinesias. While approximately 50% of patients with idiopathic Parkinson’s disease develop dyskinesias within 5 years, those with acute midbrain injury may develop wearing-off and peak-dose dyskinesias within the first year of levodopa therapy. This rapid onset likely results from severe pre-existing nigral denervation combined with chronic pulsatile dopaminergic stimulation due to levodopa’s short half-life. Clinically, the focal and unilateral nature of the brainstem cavernoma results in asymmetric dyskinesias and dystonia, predominantly affecting the hemibody most involved in the initial parkinsonism. Pharmacological management of dyskinesias without worsening parkinsonian symptoms includes levodopa dose fractionation, addition of dopaminergic agonists to reduce pulsatile stimulation, and amantadine, an NMDA receptor antagonist that reduces striatal glutamatergic hyperactivity involved in levodopa-induced dyskinesias and may decrease dyskinesia duration by up to 60% without compromising motor benefit. In cases refractory to pharmacological treatment, surgical options may be considered to control dyskinesias, including unilateral pallidotomy and deep brain stimulation targeting the subthalamic nucleus or internal globus pallidus.