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Arginine test is not reliable for diagnosing cerebellar multiple system atrophy.

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ANNALS
of Neurology
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Arginine Test Is Not Reliable
for Diagnosing Cerebellar
Multiple System Atrophy
Raquel C. Gardner, MD
and Jeremy D. Schmahmann, MD
We evaluated the arginine growth hormone (GH) stimulation test for the diagnosis of cerebellar-type multiple
system atrophy (MSAc) in patients with ataxia. Fourteen
subjects with MSAc, 11 with idiopathic late-onset cerebellar ataxia (ILOCA), 10 with familial ataxia, and 10
healthy controls were tested. After pituitary GH deficiency was excluded, subjects underwent arginine testing. Peak serum GH response was analyzed. No significant differences in peak GH response were found
between subject populations. Thirty-three percent of
MSAc subjects mounted responses ⬎10␮g/l GH. Thirtysix percent of ILOCA subjects and 40 percent of healthy
controls mounted responses ⬍4␮g/l GH. Arginine thus
appears to be unreliable for the diagnosis of MSAc.
ANN NEUROL 2010;67:404 – 408
A
dults with insidious-onset progressive cerebellar
ataxia, negative family history, and negative evaluation for identifiable causes carry a diagnosis of idiopathic
From the Department of Neurology, Massachusetts General Hospital
and Harvard Medical School, Boston, MA.
Address correspondence to Dr Schmahmann, Massachusetts General
Hospital, 175 Cambridge Street, Suite 340, Boston, MA 02114. E-mail:
jschmahmann@partners.org
Received Jan 24, 2008, and in revised form Sep 27, 2009. Accepted
for publication Oct 6, 2009.
Published online, in Wiley InterScience (www.interscience.wiley.com).
DOI: 10.1002/ana.21898
404
1
late-onset cerebellar ataxia (ILOCA). Up to 3 of these patients may develop extracerebellar symptoms, fulfilling diagnostic criteria for possible or probable cerebellar-type
multiple system atrophy (MSAc), an idiopathic neurodegenerative disorder characterized by cerebellar ataxia, autonomic dysfunction, Parkinsonism, and corticospinal
dysfunction. It has been proposed that ILOCA and MSAc
represent overlap disorders,1– 4 but MSAc is debilitating
and usually leads to death within 5 to 8 years, whereas
ILOCA may be slowly progressive over decades. The diagnosis of definite MSAc can be made only postmortem
with identification of alpha-synuclein–containing glial cytoplasmic inclusions. There is an urgent need to develop
objective clinical tests that distinguish ILOCA from
MSAc.
In a small cohort of Italian patients, arginine, a
growth hormone (GH) secretagogue, distinguished MSA
(n ⫽ 5 MSAc and 5 parkinsonian MSA [MSAp]) from
ILOCA (n ⫽ 8) with 100% sensitivity and specificity at a
cutoff GH level of 3.6mU/l.5 All MSA patients mounted
a negligible serum GH surge in response to intravenous
arginine. ILOCA patients mounted a response similar to
healthy controls. The same investigators subsequently
confirmed that at a cutoff level of 4␮g/l, the arginine test
distinguishes MSAc (n ⫽ 26) from idiopathic Parkinson
disease (n ⫽ 35) with 96% sensitivity and 91% specificity.6
The absence of a GH response to arginine in MSA
is thought to be based on the following pathophysiology.
Hypothalamic GH release is promoted by GH-releasing
hormone (GHRH) and inhibited by somatostatin. Arginine inhibits somatostatin, thus stimulating GH release,
an effect mediated by cholinergic activation.7,8 In MSA,
there is depletion of catecholaminergic neurons in the
brainstem and hypothalamus,9,10 thus blocking downstream effects of the arginine-induced inhibition of somatostatin.
In this study we attempt to validate reports that arginine can distinguish MSAc from other cerebellar ataxias.
Subjects and Methods
Patients and Protocol
Thirty-five ataxic subjects (2 definite MSAc, 8 probable MSAc,
4 possible MSAc, 11 ILOCA, 10 familial ataxia) and 10 healthy
controls were tested. Diagnoses of probable or possible MSAc
and ILOCA were based on clinical criteria.11 Diagnoses of definite MSAc were based on pathological criteria in 2 probable
MSAc subjects who died after the study concluded.12 All
ILOCA subjects had a negative family history and workup for
known causes of ataxia and experienced the onset of symptoms
at the age of 23 or older. Of the 10 subjects with familial ataxia,
6 had genetically identified ataxias (spinocerebellar ataxia types
Volume 67, No. 3
Gardner and Schmahmann: Arginine for Diagnosing MSAc
1, 3 [n ⫽ 2], 6, and 7, and Friedreich’s ataxia), 3 had a genenegative family history of autosomal dominant cerebellar ataxia,
and 1 had a gene-negative family history of recessive cerebellar
ataxia. Healthy control subjects underwent screening medical interviews and neurological examinations. No subjects had a history of endocrinological, psychiatric, or neurological illness aside
from those being studied.
The local ethics committee approved the study. Informed
consent was obtained. Subjects were evaluated in the General
Clinical Research Center at Massachusetts General Hospital.
Subjects fasted for 10 hours before each GH test. Dopaminergic
medications were held for at least 2 weeks before testing, because dopaminergic tone may enhance GH secretion.13 Of the 5
probable MSAc subjects taking dopaminergic medications, 2
held medications for only 1 week and were excluded from the
formal data analysis.
At the first study session, subjects received 100␮g/kg
GHRH plus 30g arginine intravenously to rule out pituitary
GH deficiency. An abnormal response was defined as peak GH
⬍4.1␮g/l based on a report from our hospital of 95% sensitivity
and 91% specificity for this cutoff level in healthy controls.14 At
least 5 days later, subjects returned for the second study session
and received 30g arginine. Subjects were scored with a 120point Modified International Cooperative Ataxia Rating Scale
(MICARS).15
GH Testing
Testing was initiated between 9:00 AM and 12:00 PM after a
10-hour fast. A peripheral intravenous catheter was placed. Following 15 to 30 minutes of bed rest, blood was sampled for the
basal GH level. For the GHRH plus arginine test only, a bolus
of 100␮g/kg GHRH (sermorelin acetate, Geref Diagnostic,
Rockland, MA) was injected. For both tests, 30g of arginine
(arginine hydrochloride 10% solution, R-Gene 10, Pfizer Pharmaceuticals, New York, NY) was then infused over 30 minutes.
After the infusion, blood was sampled for the 30-minute GH
level, and then sampled every 30 minutes for 2 hours.
GH Assay
Blood samples were collected and transferred to the Massachusetts General Hospital chemistry lab, where they were centrifuged and the plasma was frozen until the biweekly GH assay
was performed. Serum GH was measured using a commercially
available chemiluminescent Immulite 2000 kit (Siemens, Erlangen, Germany) on an automated analyzer validated for single
determinations. The between-run (interassay) imprecision is
ⱕ6.6% and is based on trilevel quality control materials tested
at the beginning of every run. The chemistry lab carefully monitors variance of the control materials as well as shifts and drifts
that might bias the results. At a 95% confidence level, there was
no evidence of shifts or drift during the entire testing period.
The sensitivity of this assay is 0.5␮g/l.
Statistical Analysis
The basal GH is the GH level measured after 15 to 30 minutes
of bed rest, before administration of the stimulating agent. The
March, 2010
peak GH is the peak measured GH level following administration of the stimulating agent. The data are expressed as raw values in a scatterplot and also as means with standard deviations.
The clinical characteristics of the subject populations are expressed as means with standard deviations or fractions. The data
were analyzed with analysis of variance (ANOVA), Pearson correlations, and analysis of covariance (ANCOVA).
Results
Demographic and clinical characteristics of the subject
groups are displayed in Table 1. Mean GH responses to
the 2 GH stimulation tests are displayed in Table 2. All
subjects mounted a normal GH response to GHRH plus
arginine, thus ruling out pituitary GH deficiency.
Peak postarginine GH responses (Fig) show extensive between-group overlap and within-group variability.
Thirty-three percent of MSAc subjects mounted responses
to arginine ⬎10␮g/l GH. Thirty-six percent of ILOCA
subjects, 40% of familial ataxia subjects, and 40% of
healthy controls mounted responses ⬍4␮g/l GH.
ANOVA of the peak postarginine GH revealed no
significant difference between the 5 subject groups ( p ⫽
0.43). When all MSA subjects were pooled into a single
group, there was no significant difference in peak postarginine GH between the resulting 4 subject groups ( p ⫽
0.42). When only ataxia subjects were analyzed in 2
groups (all MSA, all other ataxias), there was no significant difference in peak postarginine GH between groups
( p ⫽ 0.18).
Significant negative correlations were found between
peak postarginine GH and weight (R ⫽ ⫺0.55, p ⫽
0.0001) and between peak postarginine GH and body
mass index (BMI) (R ⫽ ⫺0.52, p ⫽ 0.0004). Significant
positive correlation was found between peak post-GHRH
GH and peak postarginine GH (R ⫽ 0.45, p ⫽ 0.002).
When healthy controls were excluded, significant positive
correlations were found between peak postarginine GH
and MICARS score (R ⫽ 0.42, p ⫽ 0.015) and between
peak postarginine GH and disease duration (R ⫽ 0.36,
p ⫽ 0.04).
ANCOVA with significant correlates, including
BMI and weight, revealed no significant differences between groups, whether all subjects were evaluated in 5
groups or only ataxia subjects were evaluated in 2 groups
(all MSA, all other ataxias). When all subjects with BMI
of ⱖ28 were excluded, the mean BMI of the resultant
subject groups were essentially identical (mean BMI for
each group ⫽ 23 or 24), and ANOVA of the peak postarginine GH level revealed no significant difference between groups ( p ⫽ 0.43).
Regarding the 2 definite MSAc subjects, 1 mounted
a peak postarginine GH of 10.4␮g/l (BMI ⫽ 16.9). The
405
ANNALS
of Neurology
TABLE 1: Demographic and Clinical Characteristics of Subject Groups
Characteristic
Controls
Familial
Ataxia
ILOCA
Definite/Probable MSAc
Possible
MSAc
No.
Sex (M/F)
Avg age (yr) ⫾ SD
Avg BMI (kg/m2) ⫾ SD
Avg weight (kg) ⫾ SD
Avg disease duration (yr)
⫾ SD
Cerebellar atrophy on MRI
(fraction)
Pontine atrophy on MRI
(fraction)
10
6/4
49.5 ⫾ 11.5
10
8/2
58.6 ⫾ 13.1
11
8/3
49.1 ⫾ 10.7
8
4/4
59.5 ⫾ 6.5
4
4/0
59.0 ⫾ 5.7
23.6 ⫾ 3.5
70.1 ⫾ 13.2
Not
applicable
Not imaged
26.6 ⫾ 4.0
79.6 ⫾ 12.5
17.5 ⫾ 10.3
28.3 ⫾ 5.9
86.9 ⫾ 21.7
10.2 ⫾ 3.6
26.4 ⫾ 6.1
76.8 ⫾ 25.5
5.8 ⫾ 1.4
31.7 ⫾ 3.3
93.4 ⫾ 13.1
5.5 ⫾ 0.6
8/10a
11/11
8/8
4/4
Not imaged
1/10
1/11
7/8b
2/4
Orthostatic hypotension
(fraction)
0/10
1/10
0/11
8/8
0/4c
Urinary dysfunction
(fraction)
Avg MICARS score ⫾ SD
0/10
3/10
1/11
8/8
3/4
48.2 ⫾ 16.7
36.7 ⫾ 13.2
58.0 ⫾ 19.8
49.5 ⫾ 11.1
0.9 ⫾ 1.1
Orthostatic hypotension is defined as a drop of 30mmHg systolic or 15mmHg diastolic blood pressure after 2 minutes of
standing. Urinary dysfunction is defined as urgency, frequency, or incontinence.
a
Two patients did not having brain imaging available.
b
Only the MRI written report was available for 1 patient, and it did not comment on pontine atrophy.
c
None of the patients with possible MSAc fulfilled Quinn’s full criteria for orthostatic hypotension, but 3 experienced a drop of
20mmHg in systolic blood pressure, fulfilling Quinn’s feature for orthostatic hypotension.
ILOCA ⫽ idiopathic late-onset cerebellar ataxia; MSAc ⫽ cerebellar-type multiple system atrophy; Avg ⫽ average; SD ⫽
standard deviation; BMI ⫽ body mass index; MRI ⫽ magnetic resonance imaging; MICARS ⫽ Modified International
Cooperative Ataxia Rating Scale.
other mounted a peak postarginine GH of 2.7␮g/l
(BMI ⫽ 35).
Two further patients with probable MSAc were
tested, but their results were excluded from the formal
analysis because dopaminergic medications were held for
only 1 week. Both of these patients had basal GH levels
of 0.5␮g/l; they then mounted peak postarginine GH responses of 25.1␮g/l and 19.7␮g/l.
TABLE 2: Serum GH Responses
Test
GHRH ⫹ arginine
Basal GH (␮g/l) ⫾ SD
Peak GH (␮g/l) ⫾ SD
Arginine
Basal GH (␮g/l) ⫾ SD
Peak GH (␮g/l) ⫾ SD
Controls
Familial
ILOCA
Definite/Probable MSAc
Possible
MSAc
0.6 ⫾ 0.4
44.1 ⫾ 40.0
0.6 ⫾ 0.1
21.0 ⫾ 11.0
0.5 ⫾ 0.0
41.5 ⫾ 43.0
0.8 ⫾ 0.6
36.3 ⫾ 35.4
0.6 ⫾ 0.1
12.5 ⫾ 11.1
0.5 ⫾ 0.3
10.7 ⫾ 10.8
0.9 ⫾ 0.9
11.2 ⫾ 11.3
2.5 ⫾ 3.9
8.0 ⫾ 5.9
1.6 ⫾ 2.3
7.5 ⫾ 5.0
0.7 ⫾ 0.4
2.3 ⫾ 1.9
Mean serum GH responses ⫾ SD for each subject group is shown. GHRH ⫹ arginine testing ruled out pituitary GH
deficiency.
GH ⫽ growth hormone; ILOCA ⫽ idiopathic late-onset cerebellar ataxia; MSAc ⫽ cerebellar-type multiple system atrophy;
GHRH ⫽ growth hormone-releasing hormone; SD ⫽ standard deviation.
406
Volume 67, No. 3
Gardner and Schmahmann: Arginine for Diagnosing MSAc
Peak GH after Arginine Test
40
36
peak GH level (µg/L)
32
28
24
20
16
12
8
4
0
control
familial
ILOCA
Group
MSAc
definite/
probable
MSAc
possible
FIGURE: Scatterplot of peak growth hormone (GH) levels
for each subject following arginine administration. The 2
circled points denote definite cerebellar-type multiple system atrophy (MSAc) subjects. ILOCA ⴝ idiopathic lateonset cerebellar ataxia.
Discussion
In our study, the arginine GH stimulation test did not
reliably distinguish patients with MSAc from those with
ILOCA or genetic ataxias. Some patients with MSAc
mounted normal GH responses to arginine, whereas some
patients with ILOCA, genetic ataxias, and even healthy
controls mounted depressed GH responses to arginine.
Contrary to previously published studies,5,6 33%
(n ⫽ 4) of our American cohort of MSAc subjects responded at a high level (⬎10␮g/l GH) to arginine. When
only definite and probable MSAc subjects are considered,
this percentage rises to 50%. Importantly, 1 definite
MSAc subject (BMI ⫽ 16.9) mounted a peak postarginine GH of 10.4␮g/l. A further 2 probable MSAc subjects
responded at even higher levels (⬎19␮g/l GH), but were
excluded because dopaminergic medications were held for
only 1 week. It is important to note, however, that these
2 subjects had normal basal GH levels before the stimulation test, making it unlikely that their elevated responses
were due to lingering dopaminergic medications. Possible
explanations for these elevated responses are misdiagnosis
and extrinsic factors that augment GH secretion. Additionally, there are external factors that may augment GH
secretion, such as stress, circadian rhythms, dopaminergic
tone, or estrogen status. Many, but not all, of these factors could be controlled in this study—an important
drawback of relying on the GH system as a diagnostic
tool.
Further, many of our non-MSA subjects responded
March, 2010
at a very low level (⬍4␮g/l GH) to arginine. Possible explanations are obesity, GH deficiency, misdiagnosis, or
extrinsic factors that may depress GH release. The mean
BMI of our cohort is higher than that of the cohorts in
the previously reported studies.5,6 GH response to stimulating agents is reportedly depressed in overweight patients.16,17 Our finding of a significant negative correlation between GH response and weight confirmed this.
When the effect of weight was controlled, however, there
was still no significant difference between patient populations. Similarly, when subjects with BMIs ⱖ28 were excluded, there were also no significant differences between
patient populations. These patients were not GH deficient, as they responded normally to the gold-standard
GHRH plus arginine test. All ILOCA subjects who responded to arginine at a GH level ⬍4␮g/l reported disease durations of at least 10 years, making progression to
MSAc unlikely.
In the United States, the arginine test is considered
a poor diagnostic tool for the diagnosis of GH deficiency,
as many healthy adults mount a depressed peak GH response. In a study conducted by our hospital of 34
healthy American adults, 59% mounted a peak GH response to arginine of ⬍3␮g/l.14 A virtually identical Italian study of 37 healthy adults, however, reported a mean
peak GH response to arginine of 18␮g/l (range, 2.939.5␮g/l).18 These differing results may be due, in part,
to the higher average BMI of the American subjects as
compared to the Italian subjects in these studies. Similarly, this effect of weight may explain why some of our
overweight or obese non-MSA subjects had depressed
peak GH responses to arginine and may also explain why
1 of our definite MSA subjects with a BMI of 35
mounted a depressed response. A test that is unreliable in
overweight or obese patients with sporadic ataxia is not
helpful. In our study, which drew from a Northeastern
US population and did not recruit based on weight,
nearly 50% of our ataxic subjects had BMIs ⱖ28.
Our conclusions are limited by the possible sources
of error described above, the small sample size, the significant effect of weight, and the geographic homogeneity of
the patient population. A larger prospective multicenter
study of patients with early-stage disease and eventual
pathologic confirmation of MSAc would be needed to definitively rule out or establish the utility of this test. Despite these limitations, given our results and the unreliable
nature of the arginine test in American and overweight/
obese cohorts,14,16,17 we conclude that the arginine test is
impractical for the diagnosis of MSAc in these populations. As we did not test patients with MSAp, we are
407
ANNALS
of Neurology
unable to comment on the utility of the arginine test in
the diagnosis of MSAp.
Diagnostic tools based on morphometric magnetic
resonance imaging analysis of cerebellum and brainstem,19 together with levels of specific biomarkers,20 may
ultimately prove more reliable than measurement of labile
hormonal axes.
This research was supported by the Doris Duke Clinical
Research Fellowship Program (RCG), the Harvard Medical School Pasteur Program and Office of Enrichment
Programs (RCG), the Birmingham Foundation (JDS),
and the Mallinkrodt General Clinical Research Center at
Massachusetts General Hospital (RCG, JDS).
We thank Hang Lee for his assistance with the statistical
analysis, Lisa Nachtigall and Anne Klibanski for their
general neuroendocrine advice, and Karen Pulaski-Liebert
for her assistance with the GH testing protocols.
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Muller EE, Locatelli V, Cocchi D. Neuroendocrine control of
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Giustina A, Veldhuis JD. Pathophysiology of the neuroregulation
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Norbiato G, Bevilacqua M, Righini V, et al. Altered vasopressin
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Gilman S, Wenning GK, Low PA, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology
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form of the ICARS. Mov Disord 2009;24:1820 –1828.
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GH response to GH-releasing hormone-arginine test related to
body mass index. Eur J Endocrinol 2005;153:257–264.
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Qu XD, Gaw Gonzalo IT, Al Sayed MY, et al. Influence
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Abdo WF, van de Warrenburg BP, Munneke M, et al. CSF analysis differentiates multiple-system atrophy from idiopathic lateonset cerebellar ataxia. Neurology 2006;67:474 – 479.
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