Subacute Painful Axonal Polyneuropathy Associated with Foslevodopa/Foscarbidopa Subcutaneous Infusion in Advanced Parkinson's Disease

Abstract

Polyneuropathy (PNP) is a known side effect of levodopa (LD) treatment for Parkinson's disease (PD), particularly with intestinal gel infusion, with a prevalence of up to 42%. Approximately a third of cases have acute or subacute onset, and approximately 90% being sensory axonal PNPs. LD-associated PNP is linked to deficiencies in vitamins B6, B12, and folate, as well as elevated homocysteine and methylmalonic acid levels (MMA). Although the underlying mechanism remains unclear, it may involve drug-related impact on vitamin metabolism or absorption.1 Foslevodopa/foscarbidopa subcutaneous infusion (FLFCI) was recently approved in many countries for treatment of motor fluctuations in advanced PD. Safety and efficacy have been reported in two studies that excluded patients with low or low-normal vitamin B12 and elevated MMA. In a randomized active controlled 12-week phase 3 trial, two of 74 patients in the FLFCI group experienced PNP.2 In a combined analysis of a 52-week open-label study of FLFCI in 244 subjects and its 96-week extension, five subjects had at least one PNP event, with a median onset at 74 days.3, 4 At screening, most of these subjects had low vitamin B6 levels, elevated homocysteine or elevated MMA and relevant confounding comorbidities. Detailed descriptions are not published. Current prescribing guidelines do not require screening for vitamin deficiencies before or during the treatment with FLFCI. A 71-year-old woman with a 6-year history of PD experienced uncontrolled motor fluctuations with approximately 8 hours of off time despite treatment with levodopa/benserazide 200 mg/50 mg 5 times daily, levodopa/carbidopa 200 mg/50 mg for the night, rasagiline 1 mg, rotigotine CR 12 mg, and amantadine 50 mg twice daily. To improve the motor fluctuations, oral levodopa was replaced with FLFCI, titrated gradually to doses of 0.81 mL/h during daytime and 0.65 mL/h at night-time, totaling to approximately 4358 mL of FLFCI per day, equivalent to approximately 3360 mg of oral levodopa, resulting in near-complete reduction of off time, initially without major adverse effects. After 7 months of FLFCI treatment, the patient developed symmetrical numbness in the feet, worsening over 2 months and presenting also in the fingers. Physical examination revealed 5 kg weight loss over 6 months, symmetric reduction in distal tendon reflexes, temperature and vibration sensitivity, and allodynia from the knees down and in the fingertips. Electroneuromyography showed severe axonal, predominantly sensory PNP combined with chronic motor fiber damage, without demyelination. Blood count, kidney, liver, thyroid function tests, celiac disease screening, fasting glucose, inflammatory markers, protein electrophoresis, borreliosis antibodies, and paraneoplastic antibodies were normal. Vitamin B12 was normal, whereas vitamin B6 and folate were low with strongly elevated homocysteine (Table 1). Oral supplementation with vitamins B6, B12, and folate, along with duloxetine, led to clinical improvement within 2 weeks and improvement of vitamin and homocysteine levels without discontinuation of FLFCI treatment (Table 1). Our case demonstrates that FLFCI can be associated with severe subacute axonal sensory PNP linked to B-vitamin deficiency and elevated homocysteine. Because FLFCI unlikely interferes with intestinal vitamin absorption, the impact of LD metabolism on vitamin and homocysteine levels appears as a more plausible mechanism. Monitoring vitamins B12 and B6, folate, homocysteine, and/or MMA levels, along with timely B-vitamin supplementation, is advisable to reduce the risk of PNP associated with FLFCI. (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. A.V.V: 1C, 3A F.S.: 1A,B, 3B Open access publishing facilitated by Helsingin yliopisto, as part of the Wiley - FinELib agreement. A.V.V. has nothing to declare. F.S. reports consultancies (AbbVie, Orion Pharma, Teva, Adamant Health, MRM Heath), honoraria (AbbVie, Teva, Biocodex), grants (Emil Aaltonen Foundation, Konung Gustav V:s och Drottning Victorias Stiftelse, Sigrid Juselius Foundation, Research Council of Finland, Hospital District of Helsinki and Uusimaa, Orion Pharma), stock (NeuroInnovation Oy, NeuroBiome Oy, Axial Biotherapeutics, MRM Health). Research data are not shared.

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