Objective: To examine the histology of subcutaneous nodules after continuous subcutaneous apomorphine infusion (CSAI).

Background: CSAI has been used successfully in advanced Parkinson’s disease (PD). However, CSAI is commonly associated with cutaneous side-effects (i.e. formation of subcutaneous nodules with or without erythema), which cause distress to patients and caregivers, and may impair drug absorption. However, the pathogenesis of these apomorphine-induced subcutaneous nodules is not fully understood.

Methods: Punch skin biopsies were taken from subcutaneous nodules in 7 patients with CSAI. The biopsies were taken with different intervals, lasting from 1 day up to several weeks after CSAI was terminated. Histologic analysis of all biopsies was performed, which was compared with 15 cases from the literature.

Results: In total, 8 biopsies were taken from subcutaneous nodules after CSAI, with a duration of infusion varying from a week to 6.5 years in 7 different PD patients. Patients’ clinical characteristics are summarized in table 1.

Table 1. Clinical characteristics of patients and nodule appearance

Patient	Gender	Age (years)	PD duration (years)	Duration of CSAI (months)	Apomorphine dose (mg/day)	Maturity of nodule (days)	Nodule diameter (cm)
1	Female	68	14	66	88	Weeks to months	Plaque
		69	15	77	88	1	5
2	Female	71	26	42	58	Weeks to months	Plaque
3	Male	52	4	0	104	1	4
4	Female	73	7	26	132	Weeks to months	3
5	Male	60	21	1	60	1	5
6	Male	61	9	12	80	2	4
7	Male	63	8	0	84	3	3

The histology of subcutaneous biopsies, taken <4 days after termination of CSAI showed a predominantly eosinophilic infiltrate in the subcutaneous tissue, along with fat necrosis. Biopsies taken after a longer period (weeks to months) showed an infiltrate with macrophages, loaded with dark melanin-like pigment. These results are in accordance with 23 biopsies in 15 PD patients treated with CSAI in literature. This dark melanin-like pigment is very likely the end product of fast auto-oxidation of the highly unstable apomorphine solution, forming ortho-quinones, which in turn can polymerize into melanin-like pigment. Although ortho-quinones are invisible compounds with histology, the formation of ortho-quinones is indisputable given the pigment. Ortho-quinones are known as potent allergens involved in type IV allergic reactions. Allergic tests with apomorphine and its preservatives were negative, while ortho-quinones were not tested.

Conclusions: It seems that apomorphine infusion causes an early allergic reaction, accompanied by the deposition of ortho-quinones, which are known as potent allergens. Improving the stability of the apomorphine solution very likely will reduce the formation of ortho-quinones and the prevalence of subcutaneous nodules.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/histology-of-subcutaneous-nodules-in-pd-patients-treated-with-continuous-apomorphine-infusion-case-series-and-review-of-the-literature/