More on Scanning Technology - Scintigraphy with MIBG - 3

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Neurology

Volume 53 . Number 5 . September 11, 1999

Copyright © 1999 American Academy of Neurology

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Articles

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Cardiac uptake of [123 I]MIBG separates Parkinson's disease from multiple

system atrophy

S. Braune MD, M. Reinhardt MD, R. Schnitzer, A. Riedel MD, C. H. Lucking MD

From Neurologische (Drs. Braune, Schnitzer, Riedel, and Lucking) and Abt.

Nuklearmedizin der Radiologischen (Dr. Reinhardt), Universitatsklinik

Freiburg, Germany.

Received December 18, 1998.

Accepted in final form April 24, 1999.

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Address correspondence and reprint requests to Dr. S. Braune, Neurologische

Universitatsklinik Freiburg, Breisacherstr. 64, 79106 Freiburg, Germany.

Objective: To improve the differential diagnosis between patients with

multiple system atrophy (MSA) and idiopathic PD (IPD) with autonomic

failure.

Background: Some patients diagnosed with IPD are discovered to have

alternative diseases such as MSA, despite the application of stringent

diagnostic criteria. This differentiation is particularly difficult if

patients with IPD also show symptoms of autonomic failure. In IPD, autonomic

failure is caused by damage of the postganglionic part of the autonomic

nervous system, whereas in MSA, degeneration of preganglionic and central

autonomic neurons is revealed histopathologically.

Methods: Scintigraphy with [123 I]metaiodobenzylguanidine (MIBG) enables the

quantification of postganglionic sympathetic cardiac innervation. Fifteen

patients with IPD and 5 patients with MSA underwent standard autonomic

function tests and scintigraphy with MIBG.

Results: In all patients, cardiovascular testing showed evidence of

autonomic failure of varying severity. In all patients with IPD, the

heart-mediastinum (H/M) ratio of MIBG uptake was pathologically impaired,

independent of duration and severity of autonomic and parkinsonian symptoms.

All patients with MSA had a regular H/M ratio. Each patient could be

assigned to the correct diagnostic group based on the results of the MIBG

scintigraphy, even if the duration of the disease was only 2 years or less.

Conclusions: This population assessment of the heart-mediastinum ratio of

[123 I]metaiodobenzylguanidine uptake showed a high sensitivity for the

detection of autonomic involvement in patients with idiopathic IPD and also

a high specificity for the discrimination between idiopathic PD and MSA.

Key words: Autonomic failure; PD; Multiple system atrophy;

Metaiodobenzylguanidine.

Introduction

In the last few years, it has become possible to visualize and quantify

cardiac sympathetic innervation in vivo with [123 I]metaiodobenzylguanidine

(MIBG) scintigraphy and SPECT. MIBG is a derivative of urea, with a

biochemical structure similar to noradrenaline but without pharmacologic

activity. Both substances compete for the same cellular transport mechanisms

on postganglionic adrenergic neurons. MIBG has been shown to be incorporated

into adrenergic cells by the same active uptake mechanism as norepinephrine.

[1] It is stored in granules [2] [3] and is secreted after stimulation by

acetylcholine. [1] Therefore, the concentration of [123 I]MIBG reflects not

only the localization of postganglionic adrenergic neurons in organs but

also is an index of their integrity and function. [4] [5] [6] In animal

experiments, its myocardial uptake is reduced after destruction of the

stellate ganglions or of the sympathetic efferents locally at the

epicardium. [7] This underscores the specificity of this technique for the

detection of postganglionic lesions of sympathetic efferents.

An established method for diagnosis and therapy of pheochromocytoma,

neuroblastoma, and carcinoid tumors in oncology, MIBG scintigraphy was

introduced into the field of neurology as a diagnostic tool for the

involvement of the autonomic nervous system in diabetes. [8] [9] [10]

Studies soon reported that cardiac MIBG uptake also may be impaired in some

patients with neurologic disorders of the central and peripheral nervous

system with autonomic failure. [11] [12] Recently, several studies [13] [14]

[15] showed evidence of gross impairment of MIBG uptake in patients with

idiopathic Parkinson's disease (IPD) and autonomic failure, independent of

the severity of extrapyramidal or autonomic symptoms. This points to a

predominantly postganglionic involvement of the autonomic nervous system in

these patients. This had been reported first by Senard et al. [16] based on

reduced norepinephrine resting levels and denervation hypersensitivity. In

multiple system atrophy (MSA), autonomic failure is caused by degeneration

of preganglionic and central neurons of the autonomic nervous system, as

shown in histopathologic [17] [18] and in vivo studies. [19]

Still, the differential diagnosis in vivo between IPD and MSA based only on

clinical grounds can be difficult in a single patient. [20] This is

particularly so if a patient with IPD also shows symptoms typical of

autonomic failure. The assumption that selective investigation of

postganglionic cardiac neurons possibly enables a safe differentiation is

supported by a recent 6-[18 F]fluorodopamine PET study with reduced uptake

in two patients with IPD and regular uptake in nine patients with MSA. [21]

Patients and methods.

Patients.

Fifteen patients with IPD and autonomic failure and 5 patients with MSA were

included in this study (for details see table 1). Some of the patients with

IPD had already been described. [15] Because there are conflicting data on

the influence of age on cardiac MIBG uptake, [4] [22] [23] [24] the two

groups were age matched with no significant statistical difference (p <

0.07). The mean age was 70.7 years (SD 6.3) in the IPD group and 64.4 years

(SD 7.6) in the MSA group. As expected, the mean duration of neurologic

symptoms was longer in IPD patients (mean 9.2 years, range 1 to 24 years)

than in MSA patients (mean 2.2 years, range 1 to 3 years).

Table 1. Demographic and clinical data of patients with idiopathic PD (IPD)

and multiple system atrophy (MSA) Patient Age/sex Symptoms of autonomic

failure, y Other neurologic symptoms, y Levodopa/DIH type mg/d H/M ratio

IPD

1 72 /M 3 11 200/50 B 1.01

2 69 /F <1 4 300/75 C 1.06

3 71 /M 2 22 500/125 C 1.49

4 61 /F CS 3 600/150 B 1.04

5 69 /M 1 3 350/87.5 C 1.02

6 62 /M CS 2 400/100 C 1.14

7 70 /F <1 <1 None 1.12

8 72 /M CS 7 600/150 B 1.06

9 65 /M CS 7 450/112.5 B 1.11

10 86 /M 1 3 250/62.5 B 0.94

11 78 /M <1 20 350/87.5 B 1.11

12 74 /F 4 20 400/100 C 1.05

13 76 /F 4 9 250/62.5 B 1.00

14 67 /F 8 15 300/75 B 0.97

15 68 /M 4 7 400/100 C 1.13

MSA

16 60 /F 1 3 No indication 2.72

17 69 /M 2 1 500/125 B 1.78

18 56 /F 3 2 No indication 1.95

19 75 /F 1 3 No indication 1.82

20 62 /F <1 1 None 1.90

The duration of clinical symptoms is given in years.

DIH = dopa-decarboxylase inhibitor; B = DIH benseradine; C = DIH carbodopa;

CS = clinically silent; H/M ratio = heart-mediastinum ratio.

Definite confirmation of MSA or IPD is possible only by post mortem

histopathologic examination of the CNS. However, certain combinations of

clinical symptoms enable a high predictive accuracy of the correct

diagnosis. All patients, with the exception of Patient 4, fulfilled the

criteria of clinically definite PD according to the classification scheme

published by Calne et al. [25] Patient 4 was rated as clinically probable

PD. All 15 patients in the IPD group showed a marked response to levodopa,

which could be observed over 3 years or more in 13 patients.

All patients in the MSA group fulfilled the diagnostic criteria for probable

MSA published by Quinn. [26] Three patients (Patients 16, 18, and 19) showed

a combination of cerebellar, extrapyramidal, and autonomic symptoms, which

is typical for the olivo-ponto-cerebellar form of MSA. MRI demonstrated

atrophy of cerebellum and pons. Patient 17 presented with a parkinsonian

syndrome, responding only poorly to levodopa, and autonomic failure.

Spontaneous activity shown by electromyography of the external anal

sphincter muscle, pathologic findings seen on electronystagmography, and

impaired glucose metabolism evidenced in both parietal hemispheres during

PET investigation made the diagnosis of MSA likely. Patient 20, who

presented less than 1 year after onset of symptoms, showed signs of

beginning bulbar palsy, cerebellar symptoms, mild bilateral akinesia, and

autonomic failure without evidence of another etiology. She did not respond

to levodopa.

All patients with MSA reported symptoms of generalized autonomic failure, as

did 11 of the 15 patients with IPD. In all patients of both groups,

cardiovascular function tests showed autonomic failure of varied degree (for

details see Results). None of them had a history of neuropathy, previous

relevant cardiac disease, or any other disease that could secondarily affect

the autonomic nervous system.

Autonomic function tests.

Patients underwent standardized testing of cardiovascular autonomic function

with continuous noninvasive measurement of blood pressure and heart rate.

None of them received antihypotensive medication when being tested. The

protocol consisted of a tilt-table test and active standing over 90 seconds,

Valsalva maneuver over 15 seconds with 50% of individual maximum expiratory

pressure, and deep breathing with six breathing cycles per minute, as

previously reported. [27] Analysis included mean values over 4 minutes at

supine rest; mean values over 10 seconds after 60 seconds' duration of

orthostatic challenge maneuvers; and blood pressure values at phase II, IIe,

and IV of the Valsalva maneuver (for definition see Bennarroch et al.

[28] ), the Valsalva ratio equaling the ratio of absolute maximum heart rate

to the subsequent minimum and heart variability during deep breathing

calculated as the mean differences between maximum and minimum heart rate

values of four to six consecutive breathing cycles.

Scintigraphy with [123 I]MIBG.

Patients did not receive any of the 80 substances that either are known,

expected, or theoretically expected to interfere with uptake of MIBG in

organs and target tissues. [29] Notice that medication with levodopa

(L-3,4-dihydroxyphenylalanine) does not relevantly interfere with MIBG

uptake because the transport of levodopa through catecholamine uptake

carriers plays only a minor role on catecholaminergic neurons. [30]

Therefore, competitive blockade of MIBG uptake or its transport into

vesicles by levodopa itself appears to be unlikely. The combination of

levodopa with extracerebral dopa-decarboxylase inhibitors completely

prevents degradation to dopamine or noradrenaline in extracerebral tissues.

Noradrenaline could interfere with MIBG, at least in high concentrations.

[7] The lack of influence of levodopa medication also is evidenced by the

result in Patient 7, who had not been treated with levodopa at any time

before this study but also showed impaired cardiac uptake. In patients

receiving borderline amounts of carboxylase inhibitors, the theoretical

possibility cannot be totally ruled out that some peripheral conversion of

levodopa to noradrenaline could occur.

MIBG scintigraphy was performed in all patients 30 minutes after blocking

the thyroid with 500 mg sodium perchlorate orally. A dose of 185 MBq of [123

I]MIBG was administered intravenously. Planar images of the thorax in

anterior view over 5 minutes and SPECT images with a 180-degree rotation

over 30 minutes were performed 4 hours post IV injection (p.i.) using a

single-headed gamma camera (Siemens Orbiter, Munich, Germany) equipped with

a low-energy all-purpose collimator. A 20% window centered on 159 keV was

used for imaging. Transversal, coronal, and sagittal slices were

reconstructed using filtered-back projection (Butterworth filter of fifth

order with a cutoff frequency of 0.5 cycles-1 and a matrix size of 64 × 64

pixel) for qualitative SPECT analysis to ensure that small regions of

reduced MIBG uptake were not overseen. Only planar images in thoracic

anterior view were used for quantitative evaluation. MIBG uptake was

quantified by comparing regions of interest over heart and mediastinum. An

irregular region enclosed the heart in case of normal uptake and a similar

region between lungs and liver in case of reduced or missing uptake,

respectively. A rectangular region outside of the lungs and below the

thyroid was used to quantify uptake of the upper and anterior mediastinum.

Their typical localizations on the thoracic anterior view are shown in

figure 1. Examples of the different cardiac uptakes of MIBG in a patient

with IPD and with MSA are shown in figure 2. Based on the regions of

interest, the cardiac MIBG uptake was expressed as heart-mediastinum ratio

(H/M ratio). The ratio was calculated by dividing the counts per pixel in

the region enclosing the heart by the counts per pixel in the mediastinal

area. Because there is little uptake of MIBG in the mediastinum, this region

is a reference area.

Figure 1. Placement of regions of interest enclosing metaiodobenzylguanidine

(MIBG) uptake of the heart (irregularly shaped region labeled with a 1) and

characterizing MIBG uptake in the mediastinum (rectangular region). This

anterior thoracic view also shows uptake in both lungs and the liver (left

bottom).

Figure 2. Examples of cardiac uptake of MIBG 4 hours after IV injection of

the radioiodinated solution in a patient with idiopathic PD (A) and with

multiple system atrophy (. The figures show a similar uptake in lungs and

liver (left bottom part) in both patients. The uptake of the heart differs

considerably (for localization of the heart, see figure 1).

Perfusion scintigraphy with [99 mTc] methoxyisobutylisonitril (MIBI).

If deficits in cardiac MIBI uptake were found, patients underwent myocardial

perfusion scintigraphy under resting conditions at least 3 days after [123

I]MIBG imaging to exclude impaired myocardial perfusion. A dose of 370 MBq

of [99m Tc]MIBI was injected intravenously. A 20% window centered at 140 keV

was used. Planar and SPECT images were recorded 90 minutes p.i. using the

same camera and imaging parameters as for the MIBG studies.

Student's t -test was used for statistical comparison of the two patient

groups.

Results.

Autonomic function tests.

The most important results of cardiovascular function tests are shown in

table 2. There was evidence of cardiovascular autonomic failure in all

patients of both groups of varying severity and clinical relevance. In 11

IPD and all MSA patients, falls of blood pressure during passive tilt or

active standing fulfilled the criteria of orthostatic hypotension. [27]

Seventeen of 18 patients in both groups, who were able to perform the

Valsalva maneuver adequately, showed pathologically impaired

counterregulation of blood pressure during phases IIe and IV based on the

laboratory's normal data base. [27] In Patient 12, in whom not all tests

could be performed, cardiac arrhythmia with atrial fibrillation and mild

orthostatic hypotension pointed to autonomic failure. In Patient 4, impaired

Valsalva ratio and reduced heart rate variability provided evidence of

autonomic involvement.

Table 2. Results of autonomic function tests No. type 1 IPD 2 IPD 3 IPD 4

IPD 5 IPD 6 IPD 7 IPD 8 IPD 9 IPD 10 IPD 11 IPD 12 IPD 13 IPD 14 IPD 15 IPD

16 MSA 17 MSA 18 MSA 19 MSA 20 MSA

PT 60 sec

SBP -101 -3 -18 20 -39 -5 -34 -22 -20 -39 -7

* -25 -40 -43 -30 -43 -27 -28 -35

DBP -36 14 -2 14 -8 4 -8 -2 0 -6 0 * -12 -26 -12 -18 -11 -14 -2 -10

HR 0 11 4 17 10 4 -7 5 3 0 0 * 0 27 0 7 9 5 4 7

AS 60 sec

SBP * 15 -13 1 * -11 -48 * 8 -50 -30 -10 * -60 nm * -43 -43 -40 -10

DBP * 13 -5 1 * 14 -9 * -7 -10 -10 -5 * -40 nm * -5 -17 -10 -8

HR * 20 5 20 * 14 10 * 0 0 2 CA * 25 0 * 12 10 0 10

VM

SBP Ile -136 -68 -36 -3 -38 -76 * -58 -56 -50 -30

* -62 -50 -55 -57 -64 -80 -23 -50

DBP Ile -51 -18 -14 5 -15 -24 * -16 -21 -11 0

* -20 -18 -18 -17 -27 -31 -12 -10

Ratio 1.0 1.2 1.0 1.1 1.1 1.2 * 1.1 1.2 1.0 1.0 * 1.3 1.4 1.0 1.1 1.1 1.0

1.1 1.0

DB

HR variability 2 9 6 3 3 4 3 13 9 5 0 * 0 6 0 4 18 7 13 4

Systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) are

given as differences to baseline after 60 sec of active standing (AS) and of

70-degree upright position during passive tilt (PT), during phases Ile and

IV of the Valsalva maneuver (VM), and the heart rate variability during deep

breathing (DB).

CA = cardiac arrhythmias; IPD = idiopathic PD; nm = blood pressure not

measurable because of severe fall; MSA = multiple system atrophy.

* Patient was not able to perform the maneuver adequately.

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Scintigraphy with [123 I]MIBG.

The mean H/M ratio of the IPD population was significantly lower than the

MSA group (p < 0.002; figure 3). All patients with IPD showed pathologically

reduced H/M ratios (mean 1.08, SD 0.13; see table 1) compared with our own

[15] and others' normal data. [22] [23] All patients with MSA were within

normal ranges (mean 2.03, SD 0.39; see table 1). SPECT data identified no

areas of focally reduced cardiac uptake in the MSA group. Each patient with

IPD differed in H/M ratio from the MSA group. These findings were

independent of the severity of autonomic failure and duration of disease.

Figure 3. Heart-mediastinum (H/M) ratio of MIBG uptake in 15 patients with

idiopathic PD and 5 patients with multiple system atrophy. The box plots

show the median values (thick line), the 25th (lower line of box) and 75th

percentiles (upper line of box), and the maximum and minimum values (T bars)

in each group. One extreme value in each group is indicated separately with

an asterisk and the patient's number. They are defined as values lying

beyond three times of the side length of the box.

Perfusion scintigraphy with [99m Tc]MIBI.

In all 15 IPD patients, results of scintigraphy with MIBI were normal,

without evidence of impaired cardiac perfusion.

Discussion.

In clinical practice, it is difficult to identify the cause of a

parkinsonian syndrome in many patients, in particular when symptoms have

begun recently and are confined to the extrapyramidal system. Even with

longer duration of symptoms, about 24% of patients with parkinsonian

syndrome of other etiology were misdiagnosed as IPD. [20]

Cardiac uptake of MIBG was grossly impaired in all patients with IPD. This

was independent of duration and severity of parkinsonian and autonomic

symptoms, as well as severity of pathologic findings during cardiovascular

function tests. None of the patients with MSA showed impaired cardiac MIBG

uptake. The H/M ratio of the MIBG uptakes differentiated all patients with

IPD from the ones with MSA. This could already be done successfully in an

early stage of the disease, as indicated by the typically reduced cardiac

uptake in three patients with IPD and normal findings in three patients with

MSA, each of the them with a disease duration of 2 years or less. In our

population, scintigraphy with MIBG showed a high specificity for

discrimination between IPD and MSA. This promising approach to separate the

two neurodegenerative disorders needs confirmation using a larger series of

patients.

To avoid false-normal results, it is important to perform the scintigraphy 4

hours after injection of the radioiodinated MIBG solution. After rapid

distribution of MIBG from the vascular compartment within the first hour,

[31] cardiac uptake within the following hours results from both neuronal

and nonneuronal biodistribution. Neuronal uptake is visualized in isolation

after the early clearance phase is completed within 4 hours. [32] [33] The

absolute values of cardiac MIBG uptake are known to have high

interindividual variation, are affected by plasma catecholamine levels

because of the competitive neuronal uptake mechanism, [34] [35] and are

liable to technical variables of different cameras and protocols. The use of

the H/M ratio clearly reduces the influences of these variables, enables

safe discrimination between patients with IPD and with MSA, and allows

comparison of results among different centers. This standard method of

nuclear medicine is more widely available, needs less-sophisticated

equipment and analytical procedures, and is cheaper than PET studies with

[18 F]fluorodeoxyglucose and [18 F]fluorodopa to distinguish IPD from MSA.

These findings underscore the postganglionic pattern of involvement of the

autonomic nervous system in patients with IPD, as recently reported in

several in vivo studies. [13] [14] [15] [16] Because MIBG is actively taken

up by the human norepinephrine transport mechanism into the axon and stored

in granules (see earlier), a morphologic lesion of these neurons in IPD must

be assumed to be the cause of autonomic failure. However, the

pathophysiologic mechanism is unknown. Histopathologic investigations

demonstrate Lewy bodies in sympathetic ganglia of IPD patients, although

their functional relevance remains unclear. It could be speculated that

oxidative stress plays a role because adrenergic pathways are particularly

vulnerable to this mechanism. [36] [37] Additional involvement of central

and preganglionic parts of the autonomic nervous system in IPD cannot be

excluded. The normal cardiac MIBG uptake in MSA patients with degeneration

of central and preganglionic neurons does not support the assumption of an

anterograde postganglionic degeneration of autonomic nerve fibers, as

previously suggested. [38]

The evidence of postganglionic damage in IPD patients independent of

duration of parkinsonian and autonomic symptoms and the degree of

abnormality in cardiovascular function test results question the previously

reported observation that autonomic failure occurs only after more than 5

years of parkinsonian symptoms. [39] It supports the view of frequent

involvement of the autonomic nervous system at an early stage of the

disease. [40]

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