Functional Neurological Disorder during Foscarbidopa/Foslevodopa Infusion in <scp> <i>PRKN</i> </scp> ‐Associated Parkinsonism

Functional neurological disorder (FND) can express with a range of motor disturbances such as weakness, tremors, and gait abnormalities, as well as non-motor manifestations.1 FND can occur in isolation or coexist with other neurological disorders, including Parkinson's disease, dementia with Lewy bodies, and paroxysmal kinesigenic dyskinesia.2, 3 Here, we report a 25-year-old woman with PRKN-associated Parkinsonism who developed FND after the initiation of foscarbidopa/foslevodopa infusion. While the diagnostic odyssey leading to her genetic diagnosis was recently reported,4 here we focus on the recognition of FND developing within the context of infusion therapy, and the improvement after its recognition with cognitive behavioral therapy (CBT) and targeted physical therapy (PT). This 25-year-old woman with a history of anxiety, autoimmune hypothyroidism and factor VII deficiency was diagnosed with dopa-responsive dystonia at age 12. She subsequently manifested features of juvenile-onset Parkinsonism at age 18. Whole exome sequencing (WES) confirmed a homozygous pathogenic variant in the PRKN gene.4 Initially, she demonstrated an excellent response to levodopa. However, she later developed significant levodopa sensitivity, characterized by severe dyskinesias triggered by small dose increases and sleep disruption due to nighttime wearing off. At age 19, she underwent bilateral subthalamic nucleus deep brain stimulation (STN-DBS) for disabling motor and non-motor complications, including peak-dose dyskinesia and unpredictable wearing-off episodes. Postoperatively, she experienced an excellent initial lesion effect, with improvement in tremor, rigidity, dyskinesia, and gait. However, 3 weeks later, the benefit diminished, and she developed severe left-arm hemiballismus with suspected functional overlay.4 Following discontinuation of stimulation, the hemiballismus was initially replaced with intermittent choreiform right leg dyskinesias and eventually resolved. Since age 24, her medication regimen had consisted of carbidopa/levodopa 25/100 mg, 1.25 tablets six times daily, taken every 3 h between 7:00 AM and 10:00 PM, with 1–2 additional doses as needed for wearing-off symptoms. Because the severity of her fluctuations, peak-dose dyskinesia, and unpredictable wearing-off were inadequately addressed with optimization of oral treatments, we elected to proceed continuous subcutaneous foscarbidopa/foslevodopa infusion therapy. During the initial loading dose (0.7 ml foscarbidopa/foslevodopa, equivalent to 125 mg levodopa), she developed severe generalized dyskinesia lasting approximately 2 h. Lower infusion rates resulted in frequent off episodes, but she responded well to gradual titration. Once reaching the optimal therapeutic rate of 0.36 ml/h, she developed random involuntary large-amplitude, variable, suppressible, and distractible ballistic non-choreic leg movements (Video 1: first segment), fundamentally different from the ballistic chorea observed while on STN-DBS. These clinical features were consistent with the emergence of FND, now observed in the context of continuous subcutaneous infusion therapy. Upon debriefing the patient and her parents about the nature of this new complication, CBT and targeted PT led to a reduction in both the frequency and severity of her symptoms within 2 months, without any infusion rate changes (Video 1: second segment). This case highlights how PRKN-associated Parkinsonism is vulnerable to variable involuntary movements fulfilling criteria for FND. This is the first report of FND emerging after foscarbidopa/foslevodopa infusion in advanced PRKN-associated Parkinsonism. FND has previously been reported after DBS in Parkinson's disease, with surgery proposed as a physical precipitating factor for the onset of functional symptoms in vulnerable individuals.5 In our case, a hyperkinetic expression of FND emerged within 2 months after both DBS and foscarbidopa/foslevodopa infusion, suggesting that procedural interventions may have served as triggers for symptom onset. Recognizing such triggers may provide valuable clinical clues for both diagnosis and therapeutic management.6 Consistent with prior reports, our patient's initial episode of FND improved after DBS was turned off. FND emerging after foscarbidopa/foslevodopa infusion responded to CBT and targeted PT, independently from infusion rate modifications. It is also worth noting that severe levodopa-induced dyskinesia may represent a potential predisposing factor for the later development of FND in PRKN-associated Parkinsonism. FND is a potentially reversible cause of disability.1 A randomized clinical trial has shown that multidisciplinary treatment with PT and CBT is more effective in improving functional symptoms and physical quality of life than psychological support alone.7 A multidisciplinary care model that incorporates PT, psychological support, and neurology follow-up can optimize outcomes while reducing healthcare costs. In summary, this case highlights the excellent levodopa responsiveness of PRKN-associated Parkinsonism, while underscoring the potential for FND to emerge as a complication of advanced therapies, and the responsiveness of this source of disability to CBT and PT. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. Z.Y.: 1A, 1B, 1C, 3A, 3B. N.O.C.P.: 1A, 3A, 3B. P.M.P.: 1A, 3A, 3B. B.T.D.L.E.: 1C, 3B. M.A.K.: 3A. A.J.E.: 1A, 1B, 3A, 3B. L.M.: 1A, 1B, 1C, 3A, 3B. We thank the patient for her participation in the study. Ethical Compliance Statement: Institutional Review Board approval was not required for this work. Written informed consent was obtained directly from the patient for participation in this work and for publication of the clinical details. In the form, the patient has given consent for her clinical information, video, and images to be reported in the journal. The patient understands that names and initials will not be published and that due efforts will be made to conceal identity, but anonymity cannot be guaranteed. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. All study procedures were performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: ZY declares that there are no additional disclosures to report. NOChP declares that there are no additional disclosures to report. DPMP declares that there are no additional disclosures to report. BTdlE declares that there are no additional disclosures to report. MAK is an employee of the CONICET and has received grant support from the Ministry of Science and Technology of Argentina and the Ministry of Health of Buenos Aires. AJE has received grant support from the NIH and the Michael J. Fox Foundation; personal compensation as a consultant/scientific advisory board member for Mitsubishi Tanabe Pharma America (formerly, Neuroderm), Amneal, Acorda, Abbvie, Bial, Supernus (formerly, USWorldMeds), NeuroDiagnostics, Inc (SYNAPS Dx), Intrance Medical Systems, Inc., Merz, Praxis Precision Medicines, Citrus Health, and Herantis Pharma; Data Safety Monitoring Board (chair) of AskBio; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He is co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies.” He cofounded REGAIN Therapeutics to fund preclinical studies but relinquished the right to any personal income from future treatments. LM has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support, and personal compensation as a consultant/scientific advisory board member for Acadia, ExpertConnect, and Mirum Pharmaceuticals. LM has received a grant (collaborative research agreement) from the International Parkinson and Movement Disorders Society for the MDS-UTRS Validation Program (Role: PI), Non-Profit. The data that support the findings of this study are available from the corresponding author upon reasonable request.