Cardiac uptake of [¹²³I]MIBG separates Parkinson’s disease from multiple system atrophy

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,4,22-24 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).

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 [¹²³I]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 [¹²³I]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.

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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).

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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 (B). 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 [⁹⁹mTc] methoxyisobutylisonitril (MIBI).

If deficits in cardiac MIBI uptake were found, patients underwent myocardial perfusion scintigraphy under resting conditions at least 3 days after [¹²³I]MIBG imaging to exclude impaired myocardial perfusion. A dose of 370 MBq of [^99mTc]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.

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.

Scintigraphy with [¹²³I]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 own15 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.

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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 [^99mTc]MIBI.

In all 15 IPD patients, results of scintigraphy with MIBI were normal, without evidence of impaired cardiac perfusion.