Smoking-induced paradoxical worsening of Parkinsonism in an early onset Parkinson’s Disease patient

A 52-year-old man with a diagnosis of Parkinson’s disease presented with motor fluctuations in the form of wearing-off phenomenon and levodopa-induced dyskinesia. His usual ON period begins 15–30 min after taking one tablet of the levodopa–carbidopa combination, with mild, nondisabling, generalized choreiform dyskinesia, and lasts for approximately 2.5 to 3 h. During his OFF period (when the effect of dopaminergic drugs wanes), he experiences walking difficulty, bradykinesia, and mild hypophonic speech. He has a history of smoking cigarettes for the last 20 years, averaging five cigarettes daily (equivalent to 5 pack-years). He reports rapid worsening of gait and lower-limb stiffness within 15–20 min after smoking a cigarette during the ON period, which is much earlier than his usual expected OFF time. This has been occurring regularly for the past 2 years. There is no worsening of parkinsonism in his upper limbs, speech, or rest tremors during this episode. His current medication include levodopa–carbidopa combination (250 mg/day), amantadine (200 mg/day), and safinamide (100 mg/day). Examination revealed asymmetric (right > left) bradykinetic, rigid parkinsonism, with mild, generalized choreiform dyskinesia during the ON period. Within 10 min of cigarette smoking, his lower-limb toe tapping, foot tapping, and gait worsened, which persisted for another 8–10 min (Video 1) His Unified Parkinson’s Disease Rating Scale part III score was 26 in the OFF period, 4 in the ON period, and worsened to 10 in the partially ON period after smoking. {"href":"Single Video Player","role":"media-player-id","content-type":"play-in-place","position":"float","orientation":"portrait","label":"Video 1","caption":"","object-id":[{"pub-id-type":"doi","id":""},{"pub-id-type":"other","content-type":"media-stream-id","id":"1_zl38tqx5"},{"pub-id-type":"other","content-type":"media-source","id":"Kaltura"}]} Discussion Parkinsonian symptoms are an amalgamation of complex interactions between various neurotransmitters in the basal ganglia. The effect of nicotine on parkinsonian symptom is complex. Worsening of parkinsonism following application of a nicotine patch has been reported previously in a placebo-controlled study.[1] Worsening of cerebellar ataxia was also reported in a patient with multisystem atrophy.[2] One proposed theory for this rare phenomenon is smoking-induced basal ganglia vasospasm.[3] However, this could not be proven radiologically by a change in cerebral blood flow.[3] Another hypothesis is that nicotine binds to alpha-4 beta-2-type nicotinic acetylcholine receptors and causes the release of dopamine. In some Early Onset Parkinson Disease patients, subthreshold dopaminergic stimulation leads to activation of presynaptic D2 autoreceptors, which reduces the release of striatal dopamine, leading to transient worsening of parkinsonian symptoms.[4] Acknowledgement The authors thank the patient and the family members for their active contribution to this study. They also thank the reviewers for their comments and suggestions.