Increased Growth Hormone Response to Apomorphine in Parkinson Disease Compared with Multiple System Atrophy

ORIGINAL CONTRIBUTION Increased Growth Hormone Response to Apomorphine in Parkinson Disease Compared With Multiple System Atrophy Elisabeth Friess, MD; Tania Kuempfel, MD; Juliane Winkelmann, MD; Dagmar Schmid, MD; Manfred Uhr, MD; Rainer Rupprecht, MD; Florian Holsboer, MD, PhD; Claudia Trenkwalder, MD Background: Parkinson disease (PD) is often difficult to Results: The GH response to the low dose of apomor- distinguish from parkinsonian syndromes of other causes phine was significantly increased in patients with PD when in early stages of the disease. In search of a suitable endo- compared with patients with multiple system atrophy or crinologic challenge test, we investigated dopaminergic sen- the control subjects (multivariate analyses of covari- sitivity in patients with de novo parkinsonian syndromes. ance; univariate F test, all P,.05). In contrast, there were no significant group differences with use of the higher Objective: We measured the growth hormone (GH) re- dose of apomorphine or in the somatorelin-induced GH sponse to a subthreshold dose of the dopamine 1–dopa- release. mine 2 receptor agonist apomorphine hydrochloride to differentiate parkinsonian syndromes from PD. Conclusions: The GH response to a subthreshold dose of apomorphine appears to be a useful tool to identify Patients and Methods: Seventeen patients with a clini- patients with PD vs multiple system atrophy. The en- cal diagnosis of PD, 16 patients with a clinical diagnosis hanced GH response to a subthreshold dopaminergic of multiple system atrophy, and 11 healthy controls. The stimulus may reflect a hypersensitivity of the extrastria- GH response to a subthreshold dosage of apomorphine tal dopamine receptors in PD. and to somatorelin (GH-releasing factor) was tested in a randomized order; on the third day the protocol was repeated with a clinically effective dose of apomorphine. Arch Neurol. 2001;58:241-246 HE CLINICAL differentia- tients with PD and healthy subjects.2 How- tion of patients with par- ever, an attempt to replicate these findings kinsonian syndromes (PSs) was unsuccessful.3 involves a high risk of false- The GH response to dopaminergic positive diagnosis of Par- substances is a well-established neuroen- kinson disease (PD), particularly in early docrine test to investigate the sensitivity of T 4 stages of the disease. Twenty-five per- the overall central dopaminergic system. cent of patients with clinically diagnosed The present study aimed to distinguish PD PD had clear evidence of a multiple sys- from nonidiopathic PS, particularly MSA, tem atrophy (MSA) at postmortem exami- with an endocrinologic challenge test re- nation.1 With respect to appropriate treat- flecting the central dopamine receptor func- ment regimens, the distinction of PD from tion. We therefore investigated the GH re- MSA is of increasing importance. The out- sponse to the strong dopamine 1–dopamine come of treatment studies using possibly 2 receptor agonist apomorphine hydro- “neuroprotective” drugs is weakened by chloride in patients with new clinical di- the inclusion of patients with nonidio- agnoses of PD or MSA and compared the pathic PS, especially when patients with results with those for a healthy control de novo cases are investigated. group matched for age. In search of a reliable and practi- cable method for differentiating PD from RESULTS PS of other causes, a recent study by Kim- ber et al2 focused on the dysregulation of LOW-APOMORPHINE TEST the central noradrenergic pathways in pa- From the Neurology Section, tients with MSA. The blunted response of The analysis of covariance showed both Max Planck Institute of growth hormone (GH) to clonidine dif- a significant time main effect and Psychiatry, Munich, Germany. ferentiated patients with MSA from pa- group3time interaction effect (Wilks mul- (REPRINTED) ARCH NEUROL / VOL 58, FEB 2001 WWW.ARCHNEUROL.COM 241 ©2001 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 PATIENTS AND METHODS [sensitivity, 4160 pmol/L]; corticotropin: Nichols Insti- tute [sensitivity, 0.22 pmol/L]). The interassay and intra- assay variation coefficients of the radioimmunoassays were PATIENTS all less than 8%. All samples from a given subject were measured in duplicate in 1 assay. The study design, experimental procedure, and recruit- The experimental protocol was approved by the Eth- ment of patients are diagrammed in Figure 1. ics Committee for Human Experiments of the Bayerische We recruited 38 patients with PS who had never been Landesa¨rztekammer (Munich, Germany). treated with dopaminergic agents. Before participating in the experiments, all subjects gave informed consent. The CLINICAL DIAGNOSES clinical classification was made by experienced neurolo- gists who were unaware of the results of the endocrino- Parkinson disease was diagnosed according to the United logic tests. The results of only the 33 patients diagnosed Kingdom Parkinson’s Disease Society Brain Bank criteria.8 as having PD or MSA were included in the subsequent data We diagnosed PD if the patient showed a positive or equivo- analysis and compared with an age-matched healthy con- cal response in the high-apomorphine test and a clear mo- trol group. The patients with vascular PS or with progres- tor improvement after 3 months of the dopaminergic treat- sive supranuclear palsy were excluded (see Figure 1). ment. We diagnosed MSA according to the consensus statement of the American Autonomic Society and Ameri- EXPERIMENTAL PROCEDURE can Academy of Neurology.9 The clinical features included (1) a PS with autonomic failure proved by either The tests with somatorelin (GH-releasing factor), a low dose tilt-table test10 or clinically relevant urinary dysfunction; of apomorphine (low-apomorphine test), or a high dose (2) negative dopaminergic treatment response in the high- of apomorphine (high-apomorphine test) were per- apomorphine test and a negative or equivocal response to formed on 3 consecutive days. The somatorelin test and a 3-month dopaminergic treatment period; (3) presence of the low-apomorphine test were performed on the first 2 days additional pyramidal tract signs, cerebellar signs, predomi- (randomized schedule). On the third day, the patients par- nant gait disorder, falling, and dizziness (Table 1). All pa- ticipated only in the high-apomorphine test. Eleven patients underwent magnetic resonance imaging to detect vas- tients with PD and 14 patients with MSA participated in cular lesions and atrophy. the somatorelin test. According to the protocol described by Corn et al,5 the subjects received either apomorphine STATISTICAL ANALYSIS hydrochloride, 0.005 mg/kg of body weight subcutaneously (Teclapharm GmbH, Lu¨ neburg, Germany), or so- The statistical differences in hormone responses were tested matorelin, 1 µg/kg of body weight subcutaneously (Fer- for significance by a 2-factorial multivariate analysis of co- ring Arzneimittel GmbH, Kiel, Germany). The high- variance (MANCOVA, Wilks multivariate test of signifi- apomorphine test6,7 (3 mg subcutaneously) was performed cance) for repeated measures with time as a within- with a pretreatment of domperidone, 20 mg 3 times daily subject factor and group (PD, MSA, and control group) as orally (Motilium; Byk Gulden Lomberg Chemische Fab- a between-subject factor. Age, sex, and hormone concen- rik GmbH, Konstanz, Germany), that started after the trations at time 0 (baseline) were entered as covariates in completion of the preceding endocrine challenge. The re- all subjects, and duration (in years) and the severity of the sponse to the high-apomorphine injection was evaluated disease (in Hoehn and Yahr stages11) only when the pa- by a clinical rating according to the Unified Parkinson’s Dis- tient groups were compared. The MANCOVAs were ap- ease Rating Scale, Part III (motor examination), before and plied for the hormone levels at single time points and ad- 20 minutes after the injection: a score of 30% or more was ditionally with the use of 2 robust profile characteristics: rated as positive; 10% to 30%, equivocal; and 10% or less the area under the time course curve of the hormone con- or an increase, negative.6 All patients were treated subse- centration (trapezoidal integration) and the D values (dif- quently with levodopa at a dosage of at least 400 mg 3 times ferences between baseline and maximum values). The lat- daily or an equivalent dose of a dopamine agonist (caber- ter MANCOVA was done with a 1-factorial MANCOVA for goline or pergolide mesylate, at least 3 mg 3 times daily). each experimental condition, with group as the only be- A positive levodopa response included a subjective and ob- tween-subject factor. In case of a significant main or inter- jective change in the clinical symptoms within a period of action effect of group and/or time, post hoc tests (univari- at least 3 months (improvement of the Unified Parkin- ate F tests and tests with contrasts) were performed to son’s Disease Rating Scale, Part III, score $30%). identify the pairs of groups or time points with significant The blood specimens were analyzed with commer- differences. To approach normality and homogeneity, all cially available radioimmunoassay kits (Figure 1) (GH: Ni- variables entered in the MANCOVAs were log n–trans- chols Institute, San Juan Capistrano, Calif [sensitivity, 8.8 formed. As a nominal level of significance, a=.05 was ac- pmol/L]; prolactin: ICN Pharmaceuticals, Costa Mesa, Calif cepted and corrected (post hoc tests) according

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