Ai-Augmented Management of Pharmacoresistant Insomnia and Restless Legs Syndrome in Park2 Parkinson’s Disease: an N-Of-1 Case Report Integrating Pharmacogenetics, Chronopharmacology, Digital Monitoring, and an Llm Co-Pilot

Ai-Augmented Management of Pharmacoresistant Insomnia and Restless Legs Syndrome in Park2 Parkinson’s Disease: an N-Of-1 Case Report Integrating Pharmacogenetics, Chronopharmacology, Digital Monitoring, and an Llm Co-Pilot | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Ai-Augmented Management of Pharmacoresistant Insomnia and Restless Legs Syndrome in Park2 Parkinson’s Disease: an N-Of-1 Case Report Integrating Pharmacogenetics, Chronopharmacology, Digital Monitoring, and an Llm Co-Pilot Stefano Scapigliati, Sabina De Innocentiis This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8815425/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract We report a case of young-onset PARK2 Parkinson’s disease complicated by severe, persistent insomnia, restless legs syndrome (RLS), and REM sleep behavior disorder (RBD), refractory to multiple conventional strategies. The clinical course included features consistent with levodopa-related rebound and augmentation, culminating in a systemic crisis with near-total sleep deprivation and night eating syndrome (NES). An N-of-1 precision approach was implemented by combining pharmacogenetics, molecule- and time-specific repositioning of medications (chronopharmacology), and continuous monitoring using consumer wearable sleep metrics and continuous glucose monitoring (CGM). Crucially, the optimization was conducted within an iterative human–AI loop in which a large language model (LLM) acted as a cognitive co-pilot to integrate multiplexed data streams, surface interaction risks, and generate prioritized hypotheses that were then clinically validated and implemented under continuous neurologist supervision. Key steps included discontinuation of evening levodopa, a strict pre-dinner ‘gastric-sparing’ window on an empty stomach to optimize absorption, and an evening synergy between low-dose pramipexole, pregabalin, and clonazepam. From September 2025 to February 2026, monthly wearable estimates showed deep sleep increasing from 5–8 min to 42–43 min and REM sleep increasing from 7–10 min to 45–50 min. In parallel, metabolic markers improved (HbA1c 7.2% to 6.8%, ALT/GPT 61 to 34 U/L within 12 months), with a 3 kg weight loss. This case illustrates a pragmatic framework for AI-augmented clinical reasoning in a complex multimorbid patient, demonstrating a path from pharmacoresistance to sustained clinical improvement. Health sciences/Diseases Health sciences/Medical research Health sciences/Neurology Biological sciences/Neuroscience Parkinson’s disease PARK2 insomnia restless legs syndrome REM sleep behavior disorder chronopharmacology pharmacogenetics continuous glucose monitoring wearables large language model clinical decision support Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 1. Introduction Sleep disorders are a pervasive and disabling non-motor feature of Parkinson’s disease (PD), profoundly impacting quality of life [ 1 , 2 ]. The spectrum includes insomnia, restless legs syndrome (RLS) or Willis-Ekbom disease, and REM sleep behavior disorder (RBD), which are particularly frequent and challenging to manage [ 3 , 4 ]. The therapeutic challenge is amplified in patients with young-onset genetic forms, such as those associated with PARK2 gene mutations, where non-motor phenomenology can be complex and intertwined with severe systemic comorbidities [ 1 ]. Standard therapeutic approaches, often centered on dopaminergic replacement for motor control, can paradoxically exacerbate sleep disturbances. Evening administration of levodopa, for instance, may worsen nocturnal symptoms through end-of-dose rebound or induce augmentation, a long-term iatrogenic worsening of RLS [ 5 ]. Furthermore, metabolic comorbidities like type 2 diabetes and the use of incretin-based therapies (e.g., GLP-1 receptor agonists) can interfere with evening drug absorption via delayed gastric emptying, impacting both sleep continuity and nocturnal glucose stability [ 10 ]. While these mechanisms are individually recognized, their real-time intersection in a single patient can be difficult to operationalize during standard episodic clinical encounters. This N-of-1 case report describes a precision medicine strategy developed for a patient with PARK2 PD whose life was dominated by pharmacoresistant insomnia and severe RLS, culminating in a systemic crisis. After numerous therapeutic failures with conventional protocols, we implemented an integrated approach combining pharmacogenetics, chronopharmacology, and data-driven pharmacological synergy, augmented by an AI co-pilot for complex data synthesis. The objective is to illustrate the analytical pathway and methodology that resolved a seemingly intractable clinical picture by shifting the focus from symptomatic treatment to correcting underlying biochemical and pharmacokinetic mechanisms. 2. Case Presentation 2.1. Patient Information and Clinical History The patient is a 56-year-old male with a diagnosis of young-onset PD (diagnosed in 2009), subsequently confirmed to be associated with a PARK2 gene mutation. The clinical picture was complicated by a constellation of severe sleep disorders and significant systemic comorbidities, as summarized in Table 1 . The patient (also the first author) provided written informed consent for the publication of this report and de-identified data sharing. Table 1 Patient characteristics and key comorbidities. Category Description Patient Male, 56 years old Primary Neurological Diagnosis Parkinson's Disease (diagnosed 2009), PARK2 gene mutation Associated Sleep Disorders Chronic pharmacoresistant insomnia, Restless Legs Syndrome (RLS), REM Sleep Behavior Disorder (RBD) Relevant Comorbidities Chronic ischemic heart disease (3 coronary stents), Type 2 Diabetes Mellitus, Arterial Hypertension, Class I Obesity, Diverticulosis, Cervicobrachialgia, Bilateral complete rotator cuff tear Metabolic Management Tirzepatide (GLP-1/GIP receptor agonist) 7.5 mg/week for glycemic control and weight management 2.2. History of Therapeutic Failures The patient's therapeutic journey was marked by a long series of failures that progressively worsened his clinical condition. Initial attempts to manage insomnia with standard benzodiazepines (e.g., diazepam, bromazepam) were ineffective even at high doses, instead producing paradoxical reactions such as sleepwalking and complex parasomnias. This idiosyncratic response was later explained by pharmacogenomic testing (MIFAR test), which identified the patient as an intermediate metabolizer for the CYP2C19 enzyme, a primary metabolic pathway for diazepam [ 11 ]. This genetic profile likely led to altered drug bioavailability and accumulation, providing a scientific basis for the observed inefficacy and toxicity. The management of RLS and motor symptoms with dopaminergic drugs proved to be a double-edged sword. The use of levodopa, particularly with afternoon and evening doses, triggered two deleterious phenomena: augmentation , a paradoxical worsening of RLS characterized by earlier symptom onset and increased intensity, and nocturnal rebound , where the short half-life of levodopa led to a dopaminergic "crash" during the night, causing a violent explosion of RLS symptoms (Fig. 1 ). The crisis culminated in an episode of ten consecutive days of total sleep deprivation. This state of "forced wakefulness" triggered a cascade of systemic consequences, including the activation of Night Eating Syndrome (NES), with a devastating impact on glycemic control and obesity. A vicious cycle was established where chronic insomnia, nocturnal eating, and metabolic dysregulation mutually reinforced each other, bringing the patient to a physical and psychological breaking point. 3. Methods 3.1. N-of-1 Study Design and Outcomes A prospective N-of-1 optimization was conducted with stepwise changes and pre-defined outcomes. Primary outcomes were total sleep time, sleep continuity (awakenings), and wearable-derived estimates of deep sleep and REM sleep. Given the known limitations of consumer devices for sleep staging [ 12 , 13 ], these estimates were treated as intra-individual trend indicators rather than polysomnography (PSG)-equivalent measures. Secondary outcomes included nocturnal CGM profiles (Ambulatory Glucose Profile, AGP), laboratory markers (HbA1c, liver enzymes), and patient-reported functional outcomes (gait, balance, tremor, daytime functioning). CGM-derived metrics (including time-in-range targets) were interpreted according to international consensus recommendations [ 9 ]. 3.2. AI-Augmented Clinical Reasoning Framework The therapeutic optimization was structured as a continuous, iterative feedback loop between the patient, the supervising neurologist, and an LLM-based co-pilot (Google Gemini) used for integrative analysis and hypothesis generation (Fig. 2 ). The neurologist maintained full clinical responsibility for all decisions. The patient curated and provided time-stamped data (medication logs, symptom diaries, diet, stressors) and digital monitoring streams (wearable, CGM). The LLM's role was to synthesize this multiplexed information, propose structured differentials for failure modes (e.g., rebound vs. absorption failure vs. glycemic triggers), and generate testable, stepwise adjustments. All LLM outputs were treated as provisional reasoning aids and were implemented only after clinician validation and safety review. 3.3. Therapeutic Interventions and Rationale Faced with the systematic failure of standard protocols, a paradigm shift was necessary, moving from a symptomatic approach to a mechanistic strategy founded on three pillars: 1) targeted molecular selection, 2) rigorous chronopharmacology, 3) strategic management of pharmacological synergies. The key interventions and their rationale are summarized in Table 2 . Table 2 Chronopharmacology optimization timeline and major interventions. Date Major Change Rationale September 2025 (Baseline) Severe insomnia, RLS, RBD. Evening levodopa use. Suspected dopaminergic rebound/augmentation; sleep fragmentation; metabolic triggers. Early October 2025 Replace rotigotine patch with oral pramipexole 0.18 mg (evening). Achieve nocturnal dopaminergic stabilization with a lower augmentation risk profile than levodopa. Oct-Nov 2025 Introduce vortioxetine (daytime). Address affective components with a multimodal antidepressant known for minimal sleep interference. December 5, 2025 Eliminate evening levodopa. Crucial step to remove the primary driver of nocturnal rebound and augmentation. December 28, 2025 Implement "gastric-sparing" chronopharmacology. Administer evening neurological drugs on an empty stomach before dinner to maximize absorption and bypass delayed gastric emptying. January 21, 2026 Reduce evening pregabalin from 150 mg to 125 mg. Assess minimum effective dose to maintain RLS control while reducing next-day sedation. February 2026 Protocol consolidation and monitoring. Verify stability and reproducibility of outcomes. The chronopharmacological reorganization was critical. Activating medications like amantadine were confined to the morning and early afternoon (no later than 15:00) to prevent central nervous system stimulation at night. The evening neurological medications were administered in a "gastric-sparing" window at 19:45, on a strictly empty stomach, with dinner postponed by approximately 60–90 minutes. This strategy was designed to ensure rapid and predictable absorption, bypassing the gastroparesis associated with both PD and tirzepatide therapy (Fig. 3 ). The evening regimen was built on a triple-action molecular synergy. Low-dose pramipexole (0.18 mg) provided a stable dopaminergic foundation for RLS control without the rebound of levodopa. Pregabalin (125 mg) modulated neuronal hyperexcitability by binding to α2-δ subunits of voltage-gated calcium channels. Clonazepam (~ 1.0 mg) was specifically targeted to suppress RBD motor activity and facilitate sleep maintenance by potentiating GABA-A receptor inhibition (Fig. 4 ). The final optimized medication schedule is detailed in Table 3 . Table 3 Final optimized medication schedule under the consolidated protocol. Time Drug Dose Notes 08:00 Amantadine 100 mg Daytime activating effect; avoid in the evening. 08:00 Propranolol 40 mg Tremor control. 15:00 Amantadine + Propranolol 100 mg + 40 mg Second dose within cut-off time to prevent insomnia. 19:45 (empty stomach) Pramipexole 0.18 mg Nocturnal dopamine stabilization for RLS. 19:45 (empty stomach) Pregabalin 125 mg Baseline therapy for RLS. 19:45 (empty stomach) Clonazepam (drops) ~ 1.0 mg Targeted for RBD control; titrated for efficacy vs. hangover. 19:45 (empty stomach) Melatonin RP 2 mg Circadian synchronization. 22:00 Non-neurological therapies As prescribed Administered after the critical absorption window for neurological drugs. 4. Results 4.1. Sleep Architecture and Continuity The implementation of the precision protocol led to a dramatic and sustained improvement in sleep quality and duration. Monthly means for wearable-derived sleep metrics showed a marked increase following the discontinuation of evening levodopa and the implementation of the chronopharmacological strategy in December 2025. As shown in Table 4 and Fig. 5 , average deep sleep duration increased from a baseline of 5–8 minutes per night to 42 minutes, and REM sleep increased from 7–10 minutes to 45 minutes by February 2026. Total sleep time correspondingly increased from an average of under 2 hours to over 4.5 hours. Table 4 Monthly means of wearable-derived sleep metrics (trend indicators). Month Average Sleep Duration (h:mm) Deep Sleep (min) Deep Sleep (%) REM Sleep (min) REM Sleep (%) September 2025 1:48 7 7% 7 6% October 2025 1:44 5 5% 9 9% November 2025 2:16 8 6% 10 7% December 2025 3:52 30 13% 23 10% January 2026 5:08 43 14% 50 16% February 2026 4:42 42 17% 45 18% 4.2. Metabolic and Systemic Outcomes Metabolic improvements occurred in parallel with sleep stabilization. The resolution of NES and the restoration of a physiological circadian rhythm contributed to a reduction in HbA1c from 7.2% to 6.8% and a normalization of liver enzymes (ALT/GPT from 61 to 34 U/L) over a 12-month period. The patient also experienced a weight loss of approximately 3 kg, with body weight falling below 100 kg. CGM data revealed a crucial link between nocturnal glycemic stability and sleep quality. Nights with high glycemic variability and hyperglycemic spikes were associated with fragmented sleep, whereas stable nocturnal glucose in the 85–110 mg/dL range was associated with consolidated sleep architecture (Fig. 6 ). This supported the hypothesis that metabolic dysregulation was a significant trigger for nocturnal arousals. 4.3. Functional Outcomes and Quality of Life The patient reported clinically meaningful daytime improvements, including more stable gait, better balance, reduced nocturnal hyperarousal, and improved overall daytime functioning. Furthermore, the stabilization of sleep architecture and the introduction of vortioxetine coincided with a significant remission of neuropsychiatric symptoms, particularly a drastic reduction in behaviors related to Impulse Control Disorders (ICD), such as compulsive shopping. The patient also reported a marked recovery of executive functions, evidenced by a restored capacity for sustained attention and increased frustration tolerance. These self-reported outcomes, while requiring objective quantification in future work, suggest a functional reactivation of prefrontal cortical circuits previously impaired by sleep fragmentation and dopaminergic dysregulation. 5. Discussion This N-of-1 case study demonstrates that a multi-modal, data-driven precision strategy can successfully resolve severe, pharmacoresistant sleep disorders in a complex patient with PARK2 PD. The success did not stem from a novel molecule but from a strategic redesign of the therapeutic regimen based on the patient's individual biology, pharmacokinetics, and real-time digital monitoring data. The first critical insight was the identification of evening levodopa as a primary iatrogenic agent driving the vicious cycle of RLS augmentation and rebound [ 5 ]. Its elimination was the cornerstone of the intervention, "cleaning" the nocturnal biochemical environment and increasing the brain's receptivity to sedative medications. This confirms that in PD patients with comorbid RLS, dopaminergic therapy must be carefully timed and balanced to avoid paradoxical effects on sleep. The second key element was the implementation of a rigorous chronopharmacological protocol. The "gastric-sparing" empty-stomach window was essential to overcome the delayed gastric emptying caused by both PD-related dysautonomia and tirzepatide therapy [ 10 ]. This highlights that medication timing and management of food-drug interactions can be as impactful as the choice of molecule itself, especially in polymedicated patients with metabolic comorbidities. Third, the approach was guided by pharmacogenetics, which explained the patient's paradoxical response to standard benzodiazepines and steered therapy towards more predictable options [ 11 ]. The final evening combination of low-dose pramipexole, pregabalin, and clonazepam created a powerful molecular synergy, addressing the distinct pathophysiological mechanisms of RLS (dopaminergic deficit, neuronal hyperexcitability) and RBD (REM atonia failure) simultaneously [ 3 , 6 , 8 ]. This strategy aligns with recent clinical guidelines that advocate for gabapentinoids as a first-line therapy for RLS to mitigate the long-term risk of augmentation associated with dopaminergic agents [ 7 , 14 ]. Finally, this work provides a real-world proof-of-concept for AI-augmented clinical reasoning. The LLM co-pilot enabled the rapid synthesis of heterogeneous data streams (pharmacogenetics, CGM, wearables, clinical notes) and the systematic exploration of interaction hypotheses that had previously been addressed in a fragmented manner. This approach preserved full clinician authority while leveraging AI's capacity for pattern recognition and complex data integration, representing a pragmatic model for human-AI collaboration in personalized medicine. Limitations This study has several limitations. As an N-of-1 case report, the findings lack generalizability and are subject to potential confounders (e.g., stress, diet). The therapeutic optimization involved multiple simultaneous interventions, making it impossible to isolate the causal contribution of each component. The use of consumer wearable devices for sleep staging, while useful for intra-individual trend analysis, is not equivalent to the gold standard of PSG. Future studies should incorporate standardized pre/post assessment scales (e.g., ISI, IRLS, PDSS-2, UPDRS) and validated clinical actigraphy or PSG. AI-specific limitations include dependence on prompt framing and the risk of generating plausible but incorrect suggestions, underscoring the absolute necessity of expert clinical supervision and validation. 6. Conclusion This case report illustrates a successful, AI-augmented precision medicine approach to managing complex, pharmacoresistant non-motor symptoms in a patient with PARK2 Parkinson's disease. By integrating pharmacogenetics, chronopharmacology, synergistic polypharmacy, and continuous digital monitoring, we achieved a sustained resolution of severe insomnia, RLS, and RBD, leading to significant improvements in metabolic health and quality of life. This N-of-1 study provides a pragmatic framework for leveraging AI as a cognitive co-pilot to navigate clinical complexity and personalize therapy, shifting the paradigm from symptom management to the correction of underlying pathophysiological mechanisms. Declarations Author Contribution Author Contributions: Stefano Scapigliati: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Visualization, Writing - original draft. Sabina De Innocentiis: Methodology, Literature review, Validation, Writing - review & editing. All authors read and approved the final manuscript. Funding This research received no external funding. Ethics, Conflicts, Data Availability, and AI Tool Disclosure Ethics: Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. Conflicts of interest: The authors declare no conflicts of interest. Data availability: De-identified raw wearable/CGM data and a summarized AI-assisted decision-log are available upon reasonable request, subject to privacy constraints. AI disclosure: A commercially available LLM (Google Gemini; cloud-hosted, accessed during Oct 2025–Feb 2026) was used as a decision-support co-pilot for data synthesis and hypothesis generation. No protected health information was intentionally shared beyond what is included in this de-identified report. References Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature . 1998;392(6676):605-608. doi:10.1038/33416. Ratti PL, Joubert S, Pereira B, et al. Self-reported sleep dysfunction and insomnia symptoms in Parkinson’s disease: the French CoPark cohort. Parkinsonism Relat Disord . 2015;21(11):1323-1329. doi:10.1016/j.parkreldis.2015.09.025. Alatriste-Booth V, Rodríguez-Violante M, Camacho-Ordoñez A, Cervantes-Arriaga A. Prevalence and correlates of sleep disorders in Parkinson’s disease: a polysomnographic study. Arq Neuropsiquiatr . 2015;73(3):241-245. doi:10.1590/0004-282X20140228. Trenkwalder C, Allen R, Högl B, Paulus W, Winkelman JW. Restless legs syndrome associated with major diseases: a systematic review and new concept. Neurology . 2016;86(14):1336-1343. doi:10.1212/WNL.0000000000002542. Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep . 1996;19(3):205-213. doi:10.1093/sleep/19.3.205. Allen RP, Chen C, Soaita A, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med . 2014;370(7):621-631. doi:10.1056/NEJMoa1303646. American Academy of Sleep Medicine. Treatment of restless legs syndrome and periodic limb movement disorder: an AASM clinical practice guideline. J Clin Sleep Med . 2024. doi:10.5664/jcsm.11390. American Academy of Sleep Medicine. Management of REM sleep behavior disorder: an AASM clinical practice guideline. J Clin Sleep Med . 2023;19(4):759-768. doi:10.5664/jcsm.10424. Battelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care . 2019;42(8):1593-1603. doi:10.2337/dci19-0028. Urva S, Quinlan T, Landry J, et al. The novel dual GIP and GLP-1 receptor agonist tirzepatide transiently delays gastric emptying in type 2 diabetes patients. Diabetes Obes Metab . 2020;22(10):1886-1891. doi:10.1111/dom.14110. Inomata S, Nagashima A, Itagaki F, et al. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. Clin Pharmacol Ther . 2005;78(6):647-655. doi:10.1016/j.clpt.2005.08.020. Birrer V, et al. Evaluating reliability in wearable devices for sleep staging. npj Digital Medicine . 2024. doi:10.1038/s41746-024-01016-9. Lee T, Cho Y, et al. Accuracy of 11 wearable, nearable, and airable consumer sleep trackers: a prospective multicenter validation study. JMIR mHealth and uHealth . 2023;11:e50983. doi:10.2196/50983. Winkelman JW, Wipper B. Restless legs syndrome: a review. JAMA . Published online January 21, 2026. doi:10.1001/jama.2025.23247. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8815425","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":589515150,"identity":"7763f1fd-8356-43e6-b030-8c86d421b5c5","order_by":0,"name":"Stefano Scapigliati","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABE0lEQVRIiWNgGAWjYPACCQY+ZiCVUMHAwAYV4mFgJqCFjZmBsSHhDIoW/HpAKhkbGNtQxLBrkW9gf/jh5w4LuzZ25ucPHs47nMcndvjZhx8Vd2QY2PkPYNNicIDHWLL3jERyGzObYUPitsPFbNJpxjN7zjzD6TADBh42Bt42iWSgX8BaEtukE4yZGdsO49QCdNgzxr9gLewfGxLngLSkf8arheEAgxkz0BY7NmYeoC0NIC05+G0xOMxjLC17RiIBqKVwRsKxdJCWYsaeM4d52JiZDbA6rL394ce3O+rs+fmPb/j4o8Y6cf7s9M0MPyoOA0UOPsBqDchyxgaGxAYMGTYMESQA1GKPT34UjIJRMApGOAAAvnhS6o5cKHsAAAAASUVORK5CYII=","orcid":"","institution":"Marconi University","correspondingAuthor":true,"prefix":"","firstName":"Stefano","middleName":"","lastName":"Scapigliati","suffix":""},{"id":589515153,"identity":"41e154ba-1414-4b21-8cb9-1d244d2a1549","order_by":1,"name":"Sabina De Innocentiis","email":"","orcid":"","institution":"Institute for Environmental Protection and Research (ISPRA)","correspondingAuthor":false,"prefix":"","firstName":"Sabina","middleName":"","lastName":"De Innocentiis","suffix":""}],"badges":[],"createdAt":"2026-02-07 12:24:40","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8815425/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8815425/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102599797,"identity":"64f92957-c54e-404e-a3d4-58d974c2bbeb","added_by":"auto","created_at":"2026-02-13 12:46:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":228383,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eThe Dopaminergic Paradox: Rebound and Augmentation.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Panel A illustrates the acute \"rebound\" effect, where a rapid drop in levodopa plasma levels below the therapeutic threshold triggers a severe spike in RLS symptoms during the night. Panel B illustrates the chronic \"augmentation\" effect, where, over months, the onset of RLS symptoms shifts progressively earlier in the day.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8815425/v1/2a15d9680f7a9dd49cefa61c.png"},{"id":102599799,"identity":"1a42eeea-6870-41bc-9239-0c6edd8df0c9","added_by":"auto","created_at":"2026-02-13 12:46:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":358575,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eHuman–AI Clinical Reasoning Loop (Conceptual).\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e Patient data, contextual factors, and digital monitoring data are fed into an LLM co-pilot for synthesis and hypothesis generation. The output is reviewed, validated, and checked for safety by a neurologist. Approved protocol updates are then implemented under clinician oversight, with the results feeding back into the system to close the loop.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8815425/v1/7ab2460c65e89a883804aadc.png"},{"id":102747331,"identity":"de24d57b-1197-4396-89a7-366e6af1f51f","added_by":"auto","created_at":"2026-02-16 09:04:32","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":844288,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eOptimized Chronopharmacology Protocol.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e The therapeutic regimen is structured to segregate activating agents (Day Phase) from sedative agents (Night Phase). A \"Wash-out\" period clears stimulants before the \"Critical Window\" for evening medication intake on an empty stomach (19:45) to ensure optimal absorption and synchronize peak drug concentration with sleep onset.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-8815425/v1/0c989c3a471438dccdb1ad80.png"},{"id":102599803,"identity":"dadcf410-4a9c-49ce-9958-75d89b6a41b2","added_by":"auto","created_at":"2026-02-13 12:46:10","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":694665,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003ePre- and Post-Synaptic Molecular Synergy for Neuronal Silencing.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e This mechanism illustrates the combined action of the evening medications. Pregabalin acts pre-synaptically to reduce the release of excitatory neurotransmitters (e.g., glutamate) by blocking voltage-gated calcium channels. Clonazepam acts post-synaptically to enhance the inhibitory effect of GABA at the GABA-A receptor. The net effect is a stable neuronal silencing conducive to sleep onset and maintenance.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-8815425/v1/944f508958659f9859f6fd70.png"},{"id":102962382,"identity":"de57c88f-489d-4f15-8abb-77f1dc02cf33","added_by":"auto","created_at":"2026-02-19 04:07:54","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67064,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMonthly Mean Minutes of Wearable-Derived Deep and REM Sleep.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e The chart shows a clear inflection point in December 2025, corresponding to the elimination of evening levodopa and chronopharmacological reorganization, with sustained improvements in both deep and REM sleep in the subsequent months.\u003c/em\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-8815425/v1/743df5706240bbddf0c0d2f7.png"},{"id":102962486,"identity":"11707ca0-7ba7-4f33-84e8-6864a9ea3975","added_by":"auto","created_at":"2026-02-19 04:09:18","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":907806,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eComparative Analysis of Sleep Architecture and Metabolic Stability.\u003c/strong\u003e\u003c/em\u003e\u003cem\u003e The top panel (\"Failure\") shows a night with fragmented sleep architecture (frequent arousals, minimal deep/REM sleep) and high glycemic variability (red line). The bottom panel (\"Success\") shows a night under the optimized protocol, characterized by consolidated sleep cycles with robust deep (N3) and REM stages, and stable nocturnal glycemia (green line).\u003c/em\u003e\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-8815425/v1/ddcddf698a5fa06bbc3ff50a.png"},{"id":104397163,"identity":"e6071380-4350-4afb-aa77-c1cdd6ce2cb5","added_by":"auto","created_at":"2026-03-11 11:38:19","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4588997,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8815425/v1/7512a091-c612-44d4-8216-59cb5dcaa895.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eAi-Augmented Management of Pharmacoresistant Insomnia and Restless Legs Syndrome in Park2 Parkinson’s Disease: an N-Of-1 Case Report Integrating Pharmacogenetics, Chronopharmacology, Digital Monitoring, and an Llm Co-Pilot\u003c/p\u003e","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eSleep disorders are a pervasive and disabling non-motor feature of Parkinson\u0026rsquo;s disease (PD), profoundly impacting quality of life [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe spectrum includes insomnia, restless legs syndrome (RLS) or Willis-Ekbom disease, and REM sleep behavior disorder (RBD), which are particularly frequent and challenging to manage [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe therapeutic challenge is amplified in patients with young-onset genetic forms, such as those associated with PARK2 gene mutations, where non-motor phenomenology can be complex and intertwined with severe systemic comorbidities [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eStandard therapeutic approaches, often centered on dopaminergic replacement for motor control, can paradoxically exacerbate sleep disturbances.\u003c/p\u003e \u003cp\u003eEvening administration of levodopa, for instance, may worsen nocturnal symptoms through end-of-dose rebound or induce augmentation, a long-term iatrogenic worsening of RLS [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, metabolic comorbidities like type 2 diabetes and the use of incretin-based therapies (e.g., GLP-1 receptor agonists) can interfere with evening drug absorption via delayed gastric emptying, impacting both sleep continuity and nocturnal glucose stability [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile these mechanisms are individually recognized, their real-time intersection in a single patient can be difficult to operationalize during standard episodic clinical encounters.\u003c/p\u003e \u003cp\u003eThis N-of-1 case report describes a precision medicine strategy developed for a patient with PARK2 PD whose life was dominated by pharmacoresistant insomnia and severe RLS, culminating in a systemic crisis.\u003c/p\u003e \u003cp\u003eAfter numerous therapeutic failures with conventional protocols, we implemented an integrated approach combining pharmacogenetics, chronopharmacology, and data-driven pharmacological synergy, augmented by an AI co-pilot for complex data synthesis.\u003c/p\u003e \u003cp\u003eThe objective is to illustrate the analytical pathway and methodology that resolved a seemingly intractable clinical picture by shifting the focus from symptomatic treatment to correcting underlying biochemical and pharmacokinetic mechanisms.\u003c/p\u003e"},{"header":"2. Case Presentation","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Patient Information and Clinical History\u003c/h2\u003e \u003cp\u003eThe patient is a 56-year-old male with a diagnosis of young-onset PD (diagnosed in 2009), subsequently confirmed to be associated with a PARK2 gene mutation.\u003c/p\u003e \u003cp\u003eThe clinical picture was complicated by a constellation of severe sleep disorders and significant systemic comorbidities, as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The patient (also the first author) provided written informed consent for the publication of this report and de-identified data sharing.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics and key comorbidities.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCategory\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDescription\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePatient\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale, 56 years old\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003ePrimary Neurological Diagnosis\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParkinson's Disease (diagnosed 2009), PARK2 gene mutation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAssociated Sleep Disorders\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic pharmacoresistant insomnia, Restless Legs Syndrome (RLS), REM Sleep Behavior Disorder (RBD)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eRelevant Comorbidities\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic ischemic heart disease (3 coronary stents), Type 2 Diabetes Mellitus, Arterial Hypertension, Class I Obesity, Diverticulosis, Cervicobrachialgia, Bilateral complete rotator cuff tear\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMetabolic Management\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTirzepatide (GLP-1/GIP receptor agonist) 7.5 mg/week for glycemic control and weight management\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. History of Therapeutic Failures\u003c/h2\u003e \u003cp\u003eThe patient's therapeutic journey was marked by a long series of failures that progressively worsened his clinical condition. Initial attempts to manage insomnia with standard benzodiazepines (e.g., diazepam, bromazepam) were ineffective even at high doses, instead producing paradoxical reactions such as sleepwalking and complex parasomnias.\u003c/p\u003e \u003cp\u003eThis idiosyncratic response was later explained by pharmacogenomic testing (MIFAR test), which identified the patient as an intermediate metabolizer for the CYP2C19 enzyme, a primary metabolic pathway for diazepam [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis genetic profile likely led to altered drug bioavailability and accumulation, providing a scientific basis for the observed inefficacy and toxicity.\u003c/p\u003e \u003cp\u003eThe management of RLS and motor symptoms with dopaminergic drugs proved to be a double-edged sword.\u003c/p\u003e \u003cp\u003eThe use of levodopa, particularly with afternoon and evening doses, triggered two deleterious phenomena: \u003cb\u003eaugmentation\u003c/b\u003e, a paradoxical worsening of RLS characterized by earlier symptom onset and increased intensity, and nocturnal \u003cb\u003erebound\u003c/b\u003e, where the short half-life of levodopa led to a dopaminergic \"crash\" during the night, causing a violent explosion of RLS symptoms (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe crisis culminated in an episode of ten consecutive days of total sleep deprivation.\u003c/p\u003e \u003cp\u003eThis state of \"forced wakefulness\" triggered a cascade of systemic consequences, including the activation of Night Eating Syndrome (NES), with a devastating impact on glycemic control and obesity.\u003c/p\u003e \u003cp\u003eA vicious cycle was established where chronic insomnia, nocturnal eating, and metabolic dysregulation mutually reinforced each other, bringing the patient to a physical and psychological breaking point.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Methods","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.1. N-of-1 Study Design and Outcomes\u003c/h2\u003e \u003cp\u003eA prospective N-of-1 optimization was conducted with stepwise changes and pre-defined outcomes.\u003c/p\u003e \u003cp\u003ePrimary outcomes were total sleep time, sleep continuity (awakenings), and wearable-derived estimates of deep sleep and REM sleep.\u003c/p\u003e \u003cp\u003eGiven the known limitations of consumer devices for sleep staging [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], these estimates were treated as intra-individual trend indicators rather than polysomnography (PSG)-equivalent measures.\u003c/p\u003e \u003cp\u003eSecondary outcomes included nocturnal CGM profiles (Ambulatory Glucose Profile, AGP), laboratory markers (HbA1c, liver enzymes), and patient-reported functional outcomes (gait, balance, tremor, daytime functioning). CGM-derived metrics (including time-in-range targets) were interpreted according to international consensus recommendations [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.2. AI-Augmented Clinical Reasoning Framework\u003c/h2\u003e \u003cp\u003eThe therapeutic optimization was structured as a continuous, iterative feedback loop between the patient, the supervising neurologist, and an LLM-based co-pilot (Google Gemini) used for integrative analysis and hypothesis generation (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe neurologist maintained full clinical responsibility for all decisions.\u003c/p\u003e \u003cp\u003eThe patient curated and provided time-stamped data (medication logs, symptom diaries, diet, stressors) and digital monitoring streams (wearable, CGM).\u003c/p\u003e \u003cp\u003eThe LLM's role was to synthesize this multiplexed information, propose structured differentials for failure modes (e.g., rebound vs. absorption failure vs. glycemic triggers), and generate testable, stepwise adjustments.\u003c/p\u003e \u003cp\u003eAll LLM outputs were treated as provisional reasoning aids and were implemented only after clinician validation and safety review.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Therapeutic Interventions and Rationale\u003c/h2\u003e \u003cp\u003eFaced with the systematic failure of standard protocols, a paradigm shift was necessary, moving from a symptomatic approach to a mechanistic strategy founded on three pillars:\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003e1) targeted molecular selection,\u003c/h3\u003e\n\n\u003ch3\u003e2) rigorous chronopharmacology,\u003c/h3\u003e\n\n\u003ch3\u003e3) strategic management of pharmacological synergies.\u003c/h3\u003e\n\u003cp\u003eThe key interventions and their rationale are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChronopharmacology optimization timeline and major interventions.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDate\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMajor Change\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eRationale\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSeptember 2025 (Baseline)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSevere insomnia, RLS, RBD. Evening levodopa use.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSuspected dopaminergic rebound/augmentation; sleep fragmentation; metabolic triggers.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEarly October 2025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReplace rotigotine patch with oral pramipexole 0.18 mg (evening).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAchieve nocturnal dopaminergic stabilization with a lower augmentation risk profile than levodopa.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eOct-Nov 2025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntroduce vortioxetine (daytime).\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAddress affective components with a multimodal antidepressant known for minimal sleep interference.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDecember 5, 2025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eEliminate evening levodopa.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eCrucial step to remove the primary driver of nocturnal rebound and augmentation.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDecember 28, 2025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eImplement \"gastric-sparing\" chronopharmacology.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003eAdminister evening neurological drugs on an empty stomach before dinner to maximize absorption and bypass delayed gastric emptying.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eJanuary 21, 2026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReduce evening pregabalin from 150 mg to 125 mg.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAssess minimum effective dose to maintain RLS control while reducing next-day sedation.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFebruary 2026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eProtocol consolidation and monitoring.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eVerify stability and reproducibility of outcomes.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe chronopharmacological reorganization was critical.\u003c/p\u003e \u003cp\u003eActivating medications like amantadine were confined to the morning and early afternoon (no later than 15:00) to prevent central nervous system stimulation at night.\u003c/p\u003e \u003cp\u003eThe evening neurological medications were administered in a \"gastric-sparing\" window at 19:45, on a strictly empty stomach, with dinner postponed by approximately 60\u0026ndash;90 minutes.\u003c/p\u003e \u003cp\u003eThis strategy was designed to ensure rapid and predictable absorption, bypassing the gastroparesis associated with both PD and tirzepatide therapy (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe evening regimen was built on a triple-action molecular synergy.\u003c/p\u003e \u003cp\u003eLow-dose pramipexole (0.18 mg) provided a stable dopaminergic foundation for RLS control without the rebound of levodopa.\u003c/p\u003e \u003cp\u003ePregabalin (125 mg) modulated neuronal hyperexcitability by binding to α2-δ subunits of voltage-gated calcium channels.\u003c/p\u003e \u003cp\u003eClonazepam (~\u0026thinsp;1.0 mg) was specifically targeted to suppress RBD motor activity and facilitate sleep maintenance by potentiating GABA-A receptor inhibition (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe final optimized medication schedule is detailed in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eFinal optimized medication schedule under the consolidated protocol.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDrug\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDose\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNotes\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e08:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmantadine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDaytime activating effect; avoid in the evening.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e08:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePropranolol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eTremor control.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e15:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAmantadine\u0026thinsp;+\u0026thinsp;Propranolol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e100 mg\u0026thinsp;+\u0026thinsp;40 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eSecond dose within cut-off time to prevent insomnia.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e19:45 (empty stomach)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePramipexole\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.18 mg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eNocturnal dopamine stabilization for RLS.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e19:45 (empty stomach)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003ePregabalin\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e125 mg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eBaseline therapy for RLS.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003e19:45 (empty stomach)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eClonazepam (drops)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e~\u0026thinsp;1.0 mg\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003eTargeted for RBD control; titrated for efficacy vs. hangover.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e19:45 (empty stomach)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMelatonin RP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2 mg\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCircadian synchronization.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e22:00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNon-neurological therapies\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAs prescribed\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdministered after the critical absorption window for neurological drugs.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"4. Results","content":"\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e4.1. Sleep Architecture and Continuity\u003c/h2\u003e \u003cp\u003eThe implementation of the precision protocol led to a dramatic and sustained improvement in sleep quality and duration.\u003c/p\u003e \u003cp\u003eMonthly means for wearable-derived sleep metrics showed a marked increase following the discontinuation of evening levodopa and the implementation of the chronopharmacological strategy in December 2025.\u003c/p\u003e \u003cp\u003eAs shown in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e, average deep sleep duration increased from a baseline of 5\u0026ndash;8 minutes per night to 42 minutes, and REM sleep increased from 7\u0026ndash;10 minutes to 45 minutes by February 2026.\u003c/p\u003e \u003cp\u003eTotal sleep time correspondingly increased from an average of under 2 hours to over 4.5 hours.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eMonthly means of wearable-derived sleep metrics (trend indicators).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonth\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAverage Sleep Duration (h:mm)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eDeep Sleep (min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDeep Sleep (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eREM Sleep (min)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eREM Sleep (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeptember 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:48\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOctober 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1:44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNovember 2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2:16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e7%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDecember 2025\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e3:52\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e30\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e13%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e23\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e10%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eJanuary 2026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e5:08\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e43\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e14%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e50\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e16%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFebruary 2026\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003e4:42\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e42\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e17%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e45\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003cb\u003e18%\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003e4.2. Metabolic and Systemic Outcomes\u003c/h2\u003e \u003cp\u003eMetabolic improvements occurred in parallel with sleep stabilization.\u003c/p\u003e \u003cp\u003eThe resolution of NES and the restoration of a physiological circadian rhythm contributed to a reduction in HbA1c from 7.2% to 6.8% and a normalization of liver enzymes (ALT/GPT from 61 to 34 U/L) over a 12-month period.\u003c/p\u003e \u003cp\u003eThe patient also experienced a weight loss of approximately 3 kg, with body weight falling below 100 kg. CGM data revealed a crucial link between nocturnal glycemic stability and sleep quality.\u003c/p\u003e \u003cp\u003eNights with high glycemic variability and hyperglycemic spikes were associated with fragmented sleep, whereas stable nocturnal glucose in the 85\u0026ndash;110 mg/dL range was associated with consolidated sleep architecture (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThis supported the hypothesis that metabolic dysregulation was a significant trigger for nocturnal arousals.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003e4.3. Functional Outcomes and Quality of Life\u003c/h2\u003e \u003cp\u003eThe patient reported clinically meaningful daytime improvements, including more stable gait, better balance, reduced nocturnal hyperarousal, and improved overall daytime functioning.\u003c/p\u003e \u003cp\u003eFurthermore, the stabilization of sleep architecture and the introduction of vortioxetine coincided with a significant remission of neuropsychiatric symptoms, particularly a drastic reduction in behaviors related to Impulse Control Disorders (ICD), such as compulsive shopping.\u003c/p\u003e \u003cp\u003eThe patient also reported a marked recovery of executive functions, evidenced by a restored capacity for sustained attention and increased frustration tolerance.\u003c/p\u003e \u003cp\u003eThese self-reported outcomes, while requiring objective quantification in future work, suggest a functional reactivation of prefrontal cortical circuits previously impaired by sleep fragmentation and dopaminergic dysregulation.\u003c/p\u003e \u003c/div\u003e"},{"header":"5. Discussion","content":"\u003cp\u003eThis N-of-1 case study demonstrates that a multi-modal, data-driven precision strategy can successfully resolve severe, pharmacoresistant sleep disorders in a complex patient with PARK2 PD.\u003c/p\u003e \u003cp\u003eThe success did not stem from a novel molecule but from a strategic redesign of the therapeutic regimen based on the patient's individual biology, pharmacokinetics, and real-time digital monitoring data.\u003c/p\u003e \u003cp\u003eThe first critical insight was the identification of evening levodopa as a primary iatrogenic agent driving the vicious cycle of RLS augmentation and rebound [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIts elimination was the cornerstone of the intervention, \"cleaning\" the nocturnal biochemical environment and increasing the brain's receptivity to sedative medications. This confirms that in PD patients with comorbid RLS, dopaminergic therapy must be carefully timed and balanced to avoid paradoxical effects on sleep.\u003c/p\u003e \u003cp\u003eThe second key element was the implementation of a rigorous chronopharmacological protocol.\u003c/p\u003e \u003cp\u003eThe \"gastric-sparing\" empty-stomach window was essential to overcome the delayed gastric emptying caused by both PD-related dysautonomia and tirzepatide therapy [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis highlights that medication timing and management of food-drug interactions can be as impactful as the choice of molecule itself, especially in polymedicated patients with metabolic comorbidities.\u003c/p\u003e \u003cp\u003eThird, the approach was guided by pharmacogenetics, which explained the patient's paradoxical response to standard benzodiazepines and steered therapy towards more predictable options [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe final evening combination of low-dose pramipexole, pregabalin, and clonazepam created a powerful molecular synergy, addressing the distinct pathophysiological mechanisms of RLS (dopaminergic deficit, neuronal hyperexcitability) and RBD (REM atonia failure) simultaneously [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThis strategy aligns with recent clinical guidelines that advocate for gabapentinoids as a first-line therapy for RLS to mitigate the long-term risk of augmentation associated with dopaminergic agents [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFinally, this work provides a real-world proof-of-concept for AI-augmented clinical reasoning.\u003c/p\u003e \u003cp\u003eThe LLM co-pilot enabled the rapid synthesis of heterogeneous data streams (pharmacogenetics, CGM, wearables, clinical notes) and the systematic exploration of interaction hypotheses that had previously been addressed in a fragmented manner.\u003c/p\u003e \u003cp\u003eThis approach preserved full clinician authority while leveraging AI's capacity for pattern recognition and complex data integration, representing a pragmatic model for human-AI collaboration in personalized medicine.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLimitations\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThis study has several limitations. As an N-of-1 case report, the findings lack generalizability and are subject to potential confounders (e.g., stress, diet).\u003c/p\u003e \u003cp\u003eThe therapeutic optimization involved multiple simultaneous interventions, making it impossible to isolate the causal contribution of each component.\u003c/p\u003e \u003cp\u003eThe use of consumer wearable devices for sleep staging, while useful for intra-individual trend analysis, is not equivalent to the gold standard of PSG.\u003c/p\u003e \u003cp\u003eFuture studies should incorporate standardized pre/post assessment scales (e.g., ISI, IRLS, PDSS-2, UPDRS) and validated clinical actigraphy or PSG. AI-specific limitations include dependence on prompt framing and the risk of generating plausible but incorrect suggestions, underscoring the absolute necessity of expert clinical supervision and validation.\u003c/p\u003e"},{"header":"6. Conclusion","content":"\u003cp\u003eThis case report illustrates a successful, AI-augmented precision medicine approach to managing complex, pharmacoresistant non-motor symptoms in a patient with PARK2 Parkinson's disease.\u003c/p\u003e \u003cp\u003eBy integrating pharmacogenetics, chronopharmacology, synergistic polypharmacy, and continuous digital monitoring, we achieved a sustained resolution of severe insomnia, RLS, and RBD, leading to significant improvements in metabolic health and quality of life.\u003c/p\u003e \u003cp\u003eThis N-of-1 study provides a pragmatic framework for leveraging AI as a cognitive co-pilot to navigate clinical complexity and personalize therapy, shifting the paradigm from symptom management to the correction of underlying pathophysiological mechanisms.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAuthor Contributions: Stefano Scapigliati: Conceptualization, Methodology, Investigation, Data curation, Formal analysis, Visualization, Writing - original draft. Sabina De Innocentiis: Methodology, Literature review, Validation, Writing - review \u0026amp; editing. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no external funding.\u003c/p\u003e\n\u003cp\u003eEthics, Conflicts, Data Availability, and AI Tool Disclosure\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics:\u003c/strong\u003e Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest:\u003c/strong\u003e The authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u003c/strong\u003e De-identified raw wearable/CGM data and a summarized AI-assisted decision-log are available upon reasonable request, subject to privacy constraints.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAI disclosure:\u003c/strong\u003e\u0026nbsp; A commercially available LLM (Google Gemini; cloud-hosted, accessed during Oct 2025\u0026ndash;Feb 2026) was used as a decision-support co-pilot for data synthesis and hypothesis generation. No protected health information was intentionally shared beyond what is included in this de-identified report.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. \u003cem\u003eNature\u003c/em\u003e. 1998;392(6676):605-608. doi:10.1038/33416.\u003c/li\u003e\n\u003cli\u003eRatti PL, Joubert S, Pereira B, et al. Self-reported sleep dysfunction and insomnia symptoms in Parkinson\u0026rsquo;s disease: the French CoPark cohort. \u003cem\u003eParkinsonism Relat Disord\u003c/em\u003e. 2015;21(11):1323-1329. doi:10.1016/j.parkreldis.2015.09.025.\u003c/li\u003e\n\u003cli\u003eAlatriste-Booth V, Rodr\u0026iacute;guez-Violante M, Camacho-Ordo\u0026ntilde;ez A, Cervantes-Arriaga A. Prevalence and correlates of sleep disorders in Parkinson\u0026rsquo;s disease: a polysomnographic study. \u003cem\u003eArq Neuropsiquiatr\u003c/em\u003e. 2015;73(3):241-245. doi:10.1590/0004-282X20140228.\u003c/li\u003e\n\u003cli\u003eTrenkwalder C, Allen R, H\u0026ouml;gl B, Paulus W, Winkelman JW. Restless legs syndrome associated with major diseases: a systematic review and new concept. \u003cem\u003eNeurology\u003c/em\u003e. 2016;86(14):1336-1343. doi:10.1212/WNL.0000000000002542.\u003c/li\u003e\n\u003cli\u003eAllen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. \u003cem\u003eSleep\u003c/em\u003e. 1996;19(3):205-213. doi:10.1093/sleep/19.3.205.\u003c/li\u003e\n\u003cli\u003eAllen RP, Chen C, Soaita A, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2014;370(7):621-631. doi:10.1056/NEJMoa1303646.\u003c/li\u003e\n\u003cli\u003eAmerican Academy of Sleep Medicine. Treatment of restless legs syndrome and periodic limb movement disorder: an AASM clinical practice guideline. \u003cem\u003eJ Clin Sleep Med\u003c/em\u003e. 2024. doi:10.5664/jcsm.11390.\u003c/li\u003e\n\u003cli\u003eAmerican Academy of Sleep Medicine. Management of REM sleep behavior disorder: an AASM clinical practice guideline. \u003cem\u003eJ Clin Sleep Med\u003c/em\u003e. 2023;19(4):759-768. doi:10.5664/jcsm.10424.\u003c/li\u003e\n\u003cli\u003eBattelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. \u003cem\u003eDiabetes Care\u003c/em\u003e. 2019;42(8):1593-1603. doi:10.2337/dci19-0028.\u003c/li\u003e\n\u003cli\u003eUrva S, Quinlan T, Landry J, et al. The novel dual GIP and GLP-1 receptor agonist tirzepatide transiently delays gastric emptying in type 2 diabetes patients. \u003cem\u003eDiabetes Obes Metab\u003c/em\u003e. 2020;22(10):1886-1891. doi:10.1111/dom.14110.\u003c/li\u003e\n\u003cli\u003eInomata S, Nagashima A, Itagaki F, et al. CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia. \u003cem\u003eClin Pharmacol Ther\u003c/em\u003e. 2005;78(6):647-655. doi:10.1016/j.clpt.2005.08.020.\u003c/li\u003e\n\u003cli\u003eBirrer V, et al. Evaluating reliability in wearable devices for sleep staging. \u003cem\u003enpj Digital Medicine\u003c/em\u003e. 2024. doi:10.1038/s41746-024-01016-9.\u003c/li\u003e\n\u003cli\u003eLee T, Cho Y, et al. Accuracy of 11 wearable, nearable, and airable consumer sleep trackers: a prospective multicenter validation study. \u003cem\u003eJMIR mHealth and uHealth\u003c/em\u003e. 2023;11:e50983. doi:10.2196/50983.\u003c/li\u003e\n\u003cli\u003eWinkelman JW, Wipper B. Restless legs syndrome: a review. \u003cem\u003eJAMA\u003c/em\u003e. Published online January 21, 2026. doi:10.1001/jama.2025.23247.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Parkinson’s disease, PARK2, insomnia, restless legs syndrome, REM sleep behavior disorder, chronopharmacology, pharmacogenetics, continuous glucose monitoring, wearables, large language model, clinical decision support","lastPublishedDoi":"10.21203/rs.3.rs-8815425/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8815425/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eWe report a case of young-onset PARK2 Parkinson\u0026rsquo;s disease complicated by severe, persistent insomnia, restless legs syndrome (RLS), and REM sleep behavior disorder (RBD), refractory to multiple conventional strategies.\u003c/p\u003e \u003cp\u003eThe clinical course included features consistent with levodopa-related rebound and augmentation, culminating in a systemic crisis with near-total sleep deprivation and night eating syndrome (NES).\u003c/p\u003e \u003cp\u003eAn N-of-1 precision approach was implemented by combining pharmacogenetics, molecule- and time-specific repositioning of medications (chronopharmacology), and continuous monitoring using consumer wearable sleep metrics and continuous glucose monitoring (CGM).\u003c/p\u003e \u003cp\u003eCrucially, the optimization was conducted within an iterative human\u0026ndash;AI loop in which a large language model (LLM) acted as a cognitive co-pilot to integrate multiplexed data streams, surface interaction risks, and generate prioritized hypotheses that were then clinically validated and implemented under continuous neurologist supervision.\u003c/p\u003e \u003cp\u003eKey steps included discontinuation of evening levodopa, a strict pre-dinner \u0026lsquo;gastric-sparing\u0026rsquo; window on an empty stomach to optimize absorption, and an evening synergy between low-dose pramipexole, pregabalin, and clonazepam. From September 2025 to February 2026, monthly wearable estimates showed deep sleep increasing from 5\u0026ndash;8 min to 42\u0026ndash;43 min and REM sleep increasing from 7\u0026ndash;10 min to 45\u0026ndash;50 min. In parallel, metabolic markers improved (HbA1c 7.2% to 6.8%, ALT/GPT 61 to 34 U/L within 12 months), with a 3 kg weight loss.\u003c/p\u003e \u003cp\u003eThis case illustrates a pragmatic framework for AI-augmented clinical reasoning in a complex multimorbid patient, demonstrating a path from pharmacoresistance to sustained clinical improvement.\u003c/p\u003e","manuscriptTitle":"Ai-Augmented Management of Pharmacoresistant Insomnia and Restless Legs Syndrome in Park2 Parkinson’s Disease: an N-Of-1 Case Report Integrating Pharmacogenetics, Chronopharmacology, Digital Monitoring, and an Llm Co-Pilot","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-13 12:46:01","doi":"10.21203/rs.3.rs-8815425/v1","editorialEvents":[{"type":"communityComments","content":1}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"87b451da-5291-4331-a18c-bb3919de5fb1","owner":[],"postedDate":"February 13th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":62882627,"name":"Health sciences/Diseases"},{"id":62882628,"name":"Health sciences/Medical research"},{"id":62882629,"name":"Health sciences/Neurology"},{"id":62882630,"name":"Biological sciences/Neuroscience"}],"tags":[],"updatedAt":"2026-03-03T04:08:59+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-13 12:46:01","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8815425","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8815425","identity":"rs-8815425","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}