Arginine test for differential diagnosis of multiple system atrophy

Annamaria Colao

BARONE, Paolo

PELLECCHIA, MARIA TERESA

Rosario Pivonello

English

PIVONELLO, ROSARIO

COLAO, ANNAMARIA

BARONE, PAOLO

Archivio della ricerca - Università degli studi di Napoli Federico II

Is arginine test a reliable tool for differential diagnosis of multiple system atrophy?

Archivio della Ricerca - Università di Salerno

LETTERSIs Arginine Test a Reliable Tool for DifferentialDiagnosis of Multiple System Atrophy?Maria Teresa Pellecchia, MD, PhD,1Rosario Pivonello, MD, PhD,2 Annamaria Colao, MD,2and Paolo Barone, MD, PhD1,3Gardner et al evaluated the arginine growth hormone (GH)stimulation test in cerebellar-type multiple system atrophy(MSA-C) patients as compared with those with idiopathic late-onset cerebellar ataxia (ILOCA) and familial ataxia.1 In contrastto our previous results,2 they did not find any correlationbetween GH response to arginine and diagnosis.There are several aspects of the Gardner et al study thatdeserve attention.The case series investigated is too small to draw any con-clusion. In the study in which we proposed the arginine test asa diagnostic tool for the differential diagnosis between idio-pathic Parkinson disease (PD) and MSA, we enrolled a numberof MSA-C patients that was double that of Gardner’s study.The lack of results in Gardner’s study could be due to the smallseries studied. Moreover, Gardner and coworkers concludedthat the arginine test is not reliable for diagnosing MSA-C onlyon the basis of absence of any significant difference in peakGH response to arginine. In our study, 25 of 26 patients(96%) with MSA-C had GH peak after arginine under the cut-off level of 4lg/l, established by receiver operating characteristic(ROC) analysis.2 Gardner et al did not calculate a cutoff level;however, by carefully analyzing their Figure, we observed that 8of 12 (67%) MSA-C patients had a GH peak lower or close to4l/l, as compared to 8 of 21 (38%) patients with ILOCA andfamilial ataxia.The inclusion of obese patients is a major methodologicalflaw, as body weight is a strong predictor of GH response toany stimulation test.3–5 Considering the significant negativecorrelation between peak postarginine GH and weight, observedin their study, it is thus highly likely that weight is the majordeterminant for the variability of GH response to arginine. In asubanalysis, they excluded subjects with a body mass index(BMI) 28 (about 50% of all ataxic patients), further reducingthe sample size to the point that no statistical analysis wouldhave any value.The authors stated that GH deficiency (GHD) had beenexcluded by performing growth hormone-releasing hormone(GHRH) plus arginine test. To exclude GHD, they used a cut-off of 4.1l/l, based on a report on a US population of 39patients with hypothalamic-pituitary disease and 34 healthycontrols.3 This is surprising, considering that GHRH plus argi-nine test is a very potent test, inducing the release of the com-plete pituitary reserve of GH. In a series of 408 healthy subjectsof our region who performed the GHRH plus arginine test, aGH cutoff value ranging from 4 to 11.5lg/l according to ageand BMI was found for a diagnosis of GHD.5 On analysis ofthe mean levels of GH peak after GHRH plus arginine reportedby Gardner et al in their Table 2, the large standard deviationsin both patients and controls demonstrated that a consistentnumber of subjects had abnormal GH peak, making it unlikelythat they can be considered normal and not GHD.Recently, the reliability of the arginine test in the differ-ential diagnosis of MSA has been confirmed by Zhang et al,who studied GH response to arginine and clonidine in 24patients with parkinsonian MSA (MSA-P) as compared with 26patients with PD.6 By ROC analysis, they found that the argi-nine test had a sensitivity of 78% and a specificity of 73%,whereas the clonidine test had a sensitivity of 82% and a speci-ficity of 76%. When these tests were combined, the specificity inthe differential diagnosis of MSA-P from PD increased to 92%.6In conclusion, we still consider the arginine test a validresearch tool that deserves further analysis to understand itspotential role in the differential diagnosis between MSA-C andILOCA.Potential Conflicts of InterestNothing to report.Departments of 1Neurological Sciences and 2Molecular andClinical Endocrinology and Oncology, Federico II University,and 3IDC Hermitage Capodimonte, Naples, ItalyReferences1. Gardner RC, Schmahmann JD. Arginine test is not reliable fordiagnosing cerebellar multiple system atrophy. Ann Neurol 2010;67:404–408.2. Pellecchia MT, Longo K, Pivonello R, et al. Multiple system atro-phy is distinguished from idiopathic Parkinson’s disease by the ar-ginine growth hormone stimulation test. Ann Neurol 2006:60:611–615.3. Biller BM, Samuels MH, Zagar A, et al. Sensitivity and specificityof six tests for the diagnosis of adult GH deficiency. J Clin Endo-crinol Metab 2002;87:2067–2079.4. Corneli G, Di Somma C, Baldelli R, et al. The cut-off limits of theGH response to GH-releasing hormone-arginine test related tobody mass index. Eur J Endocrinol 2005;153:257–264.5. Colao A, Di Somma C, Savastano S, et al. A reappraisal of diag-nosis GH deficiency in adults: role of gender, age, waist circumfer-ence, and body mass index. J Clin Endocrinol Metab 2009;94:4414–4422.6. Zhang K, Zeng Y, Song C, et al. The comparison of clonidine, ar-ginine and both combined: a growth hormone stimulation test todifferentiate multiple system atrophy from idiopathic Parkinson’sdisease. J Neurol 2010 April 20 [Epub ahead of print].DOI: 10.1002/ana.22148VC 2010 American Neurological Association 1

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Is arginine test a reliable tool for differential diagnosis of multiple system atrophy?

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Archivio della ricerca - Università degli studi di Napoli Federico II

Archivio della Ricerca - Università di Salerno