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EDITOR’S PICKS 10

Zonisamide as an Adjunct to Levodopa for DLB Parkinsonism Neurology

Take-home message • Parkinsonism is an important component of the dementia with Lewy bodies (DLB) phenotype. It is difficult to treat because the dopaminergic drugs effective against these symptoms tend to exacerbate the psychiatric features of the disease. Zonis- amide is an anti-epileptic drug that has shown efficacy as an adjunct therapeutic agent for motor symptoms of Parkinson’s through several proposed mechanisms. This is a phase II, placebo-controlled randomized double-blind study assessing the role of zonisamide as an adjunct to levodopa in DLB therapy. The reductions in the UPDRS part III (motor) scores at week 12 were (least squares mean) 2.1 points in the placebo group, 4.4 points in the zonisamide 25-mg dose group, and 6.2 in the zonisamide 50-mg dose group, both active arms meeting significance thresholds. The most common drug-related adverse events were weight loss, reduced appetite, and rash. There was no difference in severe adverse events between the groups. There was no worsening of cognition or psychiatric symptoms. • Overall, zonisamide appeared to be well-tolerated and effective in treating parkinsonism in DLB. Codrin Lungu MD

COMMENT By Mark Hallett MD Z onisamide was first noted to be helpful for motor symptoms in Parkinson’s disease when it was given to a patient to control epilepsy. Subsequently, it has been studied in a number of patients and the utility has been confirmed, particularly with a reduction in wearing off. More recently, it has become clear that zonisamide is also helpful for non-motor features of Parkinson’s disease such as impulse control disorders. The current article shows that, although there are a vari- ety of mild side effects with zonisamide, there is no worsening of cognitive function or psychiatric manifestations in patients with Lewy Body Dementia parkinsonism. It certainly seems that it should be considered as an adjunct in the treatment of patients with Parkin- son’s disease. It is not clear how zonisamide is helpful, but there are many theories, largely based on animal models. Monoamine oxidase is inhibited and dopamine turnover is reduced. Increased dopamine release has been found. Levodopa-induced quinone formation is reduced, mitochondria are protected, and alpha-synuclein neurotoxicity is blocked. Zonisamide reduces endoplasmic reticulum stress and may be neuroprotective of dopaminergic neu r on s . Ano t he r po s s i b l e neuroprotective mechanism is an increase in brain-derived neurotrophic factor (BDNF) signaling. The mechanism of action of zonisamide in epilepsy is also unknown, but the most likely mechanism is blockade of sodium and T-type calcium channels. Thus, the most straightforward explanation of how it might work in Parkinson’s disease is by blocking the T-type calcium channel in the subthalamic nucleus, reducing its firing rate, and favorably modulating the overactive basal ganglia circuit.

" It certainly seems that it should be considered as an adjunct in the treatment of patients with Parkinson’s disease. "

Abstract OBJECTIVE To investigate the efficacy and safety of zonisamide as an adjunct to levodopa ther- apy for parkinsonism in patients with dementia with Lewy bodies (DLB). METHODS This phase 2, placebo-controlled, randomized, double-blind study consisted of run-in (placebo, 4 weeks) and treatment (pla- cebo or zonisamide 25 or 50 mg once daily, 12 weeks) periods. Outpatients diagnosed with probable DLB were eligible for inclusion. The primary endpoint was the change from base- line in Unified Parkinson’s Disease Rating Scale (UPDRS) part 3 total score at week 12. Cognitive function, behavioral and psychological symp- toms of dementia (BPSD), caregiver burden, other UPDRS parts as secondary endpoints, and safety were also assessed. RESULTS Overall, 158 patients with DLB received the study drug; 21 discontinued during treatment and 137 completed treatment. Improvement in UPDRS part 3 total score at week 12 was signif- icantly greater in the zonisamide 50 mg group compared with placebo (between-group differ- ence -4.1; 95% confidence interval -6.8 to -1.4;p=

0.003). Zonisamide did not worsen cognitive function, BPSD, or caregiver burden. The overall incidence of adverse events was higher in the zonisamide 50 mg than the 25 mg and placebo groups (65.3%, 43.1%, and 50.0%, respectively); similar rates of serious adverse events were observed among all groups. CONCLUSION Zonisamide (adjunctive to levo- dopa) improved parkinsonism accompanying DLB without worsening cognitive function or psychiatric symptoms. CLINICAL TRIAL REGISTRATION JapicCTI-122040. CLASSIFICATION OF EVIDENCE This study provides Class I evidence that zonisamide (adjunctive to levodopa) improves parkinsonism and is well-tolerated in patients with DLB. Adjunct Zonisamide to Levodopa for DLB Parkinsonism: A Randomized Double-Blind Phase 2 Study. Neurology 2018 Feb 20;90(8) e664-e672, MMurata, T Odawara, K Hasegawa, et al. www.practiceupdate.com/c/64546

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