Early ReportDistinction of idiopathic Parkinson's disease from multiple-system atrophy by stimulation of growth-hormone release with clonidine
Introduction
Idiopathic Parkinson's disease is a major cause of neurological disability, with about 100 000 cases in the UK.1 The morbidity and mortality in idiopathic Parkinson's disease, however, is favourable compared with that in multiple system atrophy (MSA) in which most patients have extrapyramidal features.2 At necropsy, up to 25% of patients diagnosed during life as having idiopathic Parkinson's disease have histopathological evidence of MSA.3 In MSA, parkinsonian features are common, either at presentation or with progression of disease; cerebellar and pyramidal deficits also occur.4, 5 Most people with MSA have generalised autonomic dysfunction but this may not appear until later in the disease process, so an accurate early diagnosis is difficult. Clinical differentiation of MSA from idiopathic Parkinson's disease is important since prognosis, complications, and response to antiparkinsonian treatment in MSA are poorer2, 5 and inclusion of people thought to have idiopathic Parkinson's disease, but who actually have MSA, in pallidotomy or cerebral implantation trials6 may confound results.
The number of approaches used to distinguish idiopathic Parkinson's disease from MSA reflects the difficulty in differentiating these disorders. Cardiovascular autonomic function testing,7 urethral sphincter electromyography,8 magnetic resonance scanning, positron emission tomography,9, 10 and proton magnetic resonance spectroscopy11 have been used for diagnosis but may be limited in their specificity (where known) or practicality. Ideally, a widely available, reproducible, sensitive, specific, and acceptable test is needed to aid early diagnosis.
Clonidine has emerged as a promising lead: it is a centrally active α2-adrenoceptor agonist that raises growth hormone (GH) concentrations in normal people and those with pure autonomic failure with a peripheral autonomic deficit, but not in those with MSA, who have central lesions.12 We postulate that in idiopathic Parkinson's disease without central autonomic abnormalities, unlike MSA, the GH response to clonidine is preserved and thus distinguishes idiopathic Parkinson's disease from MSA. Therefore, we studied the GH responses to clonidine in idiopathic Parkinson's disease and compared the results with those from age-matched people with MSA. Additionally, in MSA where there is an abnormal clonidine-GH response, the responses to another GH secretagogue, levodopa, were measured because GH stimulation via non-α2-adrenergic pathways may provide further insight into the central autonomic disorder in MSA.
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Participants and methods
Patients of comparable age with idiopathic Parkinson's disease, MSA, and pure autonomic failure (table 1), were studied along with 27 healthy participants (controls). All participants underwent detailed physiological and biochemical testing of autonomic function7 to confirm diagnosis when applicable; participants with secondary causes of autonomic dysfunction were excluded.13
14 participants fulfilled UK Parkinson's Disease Society Brain Bank diagnostic criteria for idiopathic Parkinson's
Clonidine studies
Basal serum GH was similar in all groups. After clonidine, GH increased in patients with idiopathic Parkinson's disease (maximum 45 min, 11·9 [SE 2·4] mU/L, p<0·005, paired t test). There was no rise in GH concentration in patients with MSA, in either the parkinsonian or cerebellar forms (table 2, figure 1). GH concentrations rose in the controls (peak 45 min, 18·6 [3·6] mU/L) and patients with pure autonomic failure (peak 60 min 15·3 [4·5] mU/L, p<0·05). Because of individual variation in
Discussion
These studies on the GH response to clonidine indicate that idiopathic Parkinson's disease with no central autonomic deficit can be clearly separated from MSA-P. Results from idiopathic Parkinson's disease were similar to those from patients with pure autonomic failure and normal participants, which indicated preservation of the hypothalamic α2-adrenoceptor response to clonidine. Furthermore, the abnormal GH response in each of the major neurological types of MSA (MSA-P and MSA-C) was different
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2019, Handbook of Clinical NeurologyCitation Excerpt :However, growth hormone secretion response to levodopa and insulin-induced hypoglycemia are normal in patients with MSA, who have no clinical or biochemical evidence of panhypopituitarism. This suggests that in MSA there is a specific deficit of GHRH release via α2-adrenoceptors and cholinergic central systems in the absence of destruction of GHRH neurons or pituitary somatotrophs (Kimber et al., 1997; Pellecchia et al., 2005; Zhang et al., 2010). Both idiopathic Parkinson's disease and MSA are pathologically defined as synucleinopathies, but the distribution of phosphorylated α-synuclein (pSNCA) deposition in peripheral postganglionic neurons and in CNS glial cells and neurons is different in these disorders.
Cardiovascular autonomic testing performed with a new integrated instrumental approach is useful in differentiating MSA-P from PD at an early stage
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