Evidence of cerebral hypoperfusion in scleroderma patients

M. Cutolo, F. Nobili1, A. Sulli, C. Pizzorni, M. Briata, F. Faelli, P. Vitali1, G. Mariani2, F. Copello3, B. Seriolo, C. Barone and G. Rodriguez1

Division of Rheumatology
1 Clinical Neurophysiology Service
2 Nuclear Medicine Service, Department of Internal Medicine, University of Genova,
3 Department of Occupational Medicine, S. Martino Hospital, Genova, Italy


    Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Objectives. To investigate regional cerebral blood flow by 99mTc-hexamethylpropylenamineoxime (HMPAO) single photon emission computed tomography (SPECT) in a series of 40 patients (mean age 58.5±11.5 yr) affected by systemic sclerosis (SSc) in comparison with age-matched healthy controls.

Methods. Subjects affected by concomitant severe pathologies that might interfere with the interpretation of the SPECT results were excluded. SPECT findings were correlated with the severity of peripheral microvascular involvement, as assessed by nailfold videocapillaroscopy (NVC). Whenever possible, patients underwent magnetic resonance imaging (MRI) of the brain.

Results. Twenty-one SSc patients (52%) showed hypoperfusion in two or more regions of interest (ROIs) at the SPECT analysis. MRI was available in 14 of these patients, and was shown to be altered in eight of them (57%). One patient with both abnormal SPECT and abnormal MRI was affected by mild cognitive impairment. Transcranial Doppler sonography was normal in all but one of these patients with hypoperfusion. Nineteen patients exhibited a normal brain SPECT scan, but the MRI was shown to be altered in 3/12 of them (25%). No significant differences were found between the group of SSc patients showing hypoperfusion and those showing a normal SPECT scan regarding age, the duration of disease, the presence of vascular risk factors or damage of other organs typically involved in the disease, and the severity of peripheral microvascular involvement (NVC).

Conclusions. Focal or diffuse cerebral hypoperfusion was found in more than half of the neurologically asymptomatic SSc patients studied, paralleling the incidence of altered brain MRI. The hypoperfusion was not linked to ageing and possibly reflects the cerebral location of the microangiopathic process characterizing the disease.

KEY WORDS: Single photon emission computed tomography (SPECT), Magnetic resonance imaging (MRI), Videocapillaroscopy, Systemic sclerosis, Cerebral blood flow.


    Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Systemic sclerosis (SSc) is a diffuse connective tissue disease characterized by proliferation of the vascular tissue, obliterative microvascular lesions and diffuse interstitial fibrosis. Several organs are affected, with a severity of involvement that is often heterogeneous [1]. Current theories hold that the vascular lesions are the consequence of endothelial damage; however, the early mechanisms remain to be established [2, 3]. With increasing severity of the disease, the accumulation of extracellular matrix leads to thickening of the skin and to interstitial fibrosis of the organs, the severity of which is generally correlated [4]. The microangiopathy therefore seems to be the main pathogenic marker of the disease, although macrovascular lesions have also been reported [5]. The peripheral nervous system is often involved during SSc, usually in the form of mononeuropathy or multiple neuropathy. The involvement of the brain vessels has been reported less frequently and it has usually been thought to be related to concomitant arterial hypertension, renal failure or other systemic complications of the disease [6].

However, beyond the rare cases of acute vasculitis of the major cerebral vessels, there is increasing evidence of SSc patients suffering from central nervous system (CNS) involvement, most often in the form of transient ischaemic attacks and cognitive impairment [5, 7, 812]. These events are not clearly related to common vascular risk factors or to the failure of other organs or systems. Recently, calcinosis of the small vessels in several brain areas, including the cerebral cortex, has been reported in two autopsy SSc cases [13].

Therefore, the hypothesis may be advanced that vascular involvement in the brain occurs to some extent in SSc patients, in the form of macro- or microangiopathy or both [5, 10]. We therefore investigated regional cerebral blood flow (rCBF) in a large number of SSc patients by 99mTc-hexamethylpropylene amine oxime (HMPAO) single photon emission computed tomography (SPECT). In addition, the SPECT findings were correlated with the severity of the peripheral microvascular involvement, as assessed by nailfold videocapillaroscopy (NVC) and, whenever possible, by magnetic resonance imaging (MRI) of the brain.


    Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients
During a period of 3 yr, 47 consecutive patients (46 women, one man, mean age 58.5±12 yr, range 32–77 yr) were recruited. The patients had been referred to the Division of Rheumatology of the Department of Internal Medicine of the University of Genova, and had SSc according to the American Rheumatism Association criteria [14]. Patients with either limited or diffuse cutaneous involvement were considered for inclusion in the study [4].

Clinical and pathological conditions associated with SSc were investigated. Exclusion criteria included severe or uncontrolled arterial hypertension; uncontrolled diabetes mellitus; relevant renal, respiratory or hepatic failure; and severe anaemia. Seven patients matched one or more of these criteria and therefore were excluded.

The remaining 40 patients (39 women and one man, mean age 58.7±11.5 yr, range 32–75 yr) entered the study after they had given informed consent. The duration of the disease was derived from the clinical medical history and an interview. The major clinical features of these patients are shown in Table 1Go. Twenty-one patients in this series had already been included in a previous study that used the planar xenon-133 method [15, 16]. Twenty per cent of the patients included in the study showed associated mild hypertension (diastolic blood pressure <105 mmHg), slight hypercholesterolaemia (total serum cholesterol <250 mg/dl) or low-degree anaemia (Hb level <12 g/l).


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TABLE 1. Clinical features of the 40 SSc patients and summary of brain SPECT and MRI results

 

Methods
99mTc-HMPAO SPECT.
The SPECT equipment we used (Ceraspect; Digital Scintigraphics, Waltham, Massachusetts, USA) acquired cerebral perfusion images of 99mTc-HMPAO by means of an annular crystal [17]. The sensitivity of the cylindrical-shaped, low-energy, high-resolution lead collimator was 190 c.p.s./MBq (7.0 c.p.s./Ci) with a point source in air, with a spatial resolution at 140 keV of 99mTc <8.5 mm at the centre of rotation and 6.3 mm in the peripheral regions (full width half maximum).

SPECT acquisitions were performed 30–90 min after the i.v. injection of 740–925 MBq of freshly prepared 99mTc-HMPAO (Ceretec, Amersham Medical, Amersham, UK). Sensory input was minimized whilst the tracer was injected in a quiet, dimly lit room, the patient lying on a reclining chair (eyes closed and ears unplugged).

Sixty-four axial slices parallel to the anterior–posterior commissure (AC–PC) line, 1.67 mm thick, were reconstructed on a 128x128 matrix (1 pixel=1.67 mm) using a 2-dimensional Butterworth-filtered back-projection (cut-off 0.80 cm, order 10), according to the method described by Minoshima et al. [18] and corrected for attenuation with Chang's first-order method, using an attenuation coefficient of 0.15/cm [19]. SPECT data were analysed on two transaxial sections (8.3 mm thick: five slices summed), as identified with the aid of a widely used anatomical atlas [20]. The first (lower) section was constructed by summing the five most intermediate of all the slices parallel to the AC–PC line, which included the thalami (Fig 1Go, left). The second (upper) section was constructed by summing the first five transaxial slices tangential to the lower border of the cingulate gyrus (Fig 1Go, right), as identified in the coronal section at the level of the thalami. In each section, the cortical ribbon was automatically delimited similarly, as suggested by Mountz et al. [21], and was then divided into twelve 30° sectors to identify twelve regions of interest (ROIs) in each section. For each hemisphere, there were two frontal, three temporal and one occipital area in the lower section, and three frontal, two parietal and one occipital area in the upper section. Irregular but symmetrical ROIs were hand-drawn around the thalami and the basal ganglia in the lower section (Fig 1Go, left). Therefore, 28 ROIs were analysed in each patient: 10 frontal, six temporal, four parietal and four occipital areas, the two thalami and the two basal ganglia.



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FIG. 1. 99mTc-HMPAO brain SPECT images. ROI drawings in the superficial cortex and (left) around the thalami and the basal ganglia on two transaxial sections parallel to the AC–PC line. (Left) Lower section, crossing the thalami. The deep nuclei ROIs are hand-drawn. (Right) Upper section, tangential to the lower border of the cingulate gyrus. In both sections the ROIs around the cortical ribbon have been drawn automatically. The common visual scale is shown in the rectangle below; decreasing flow values are indicated by the range of tones from right to left. L, left cerebral hemisphere.

 
Counts in the ROIs were normalized by computing ROI/cerebellar ratios (mean count per pixel in each ROI divided by mean count per pixel in the whole cerebellum). If cerebellar asymmetry was greater than 10%, the cerebellar hemisphere with the higher count was considered as the reference region.

Other examinations
All patients were scheduled to undergo MRI of the brain, which was performed with a 0.5-Tesla superconductive apparatus (MR 5000; Esaote Biomedica, Genova, Italy) with the following parameters: bicommissural paraxial planes; DP-(TR/TE=2000/30 ms), T1-weighted (660/20) and T2-weighted (2500/120) sequences. The T1-weighted sequences were also performed after i.v. injection of 0.15 mmol/kg of gadolinium-diethylene-tetraaminopentaacetate (Gd-DTPA) (Magnesvit; Schering, Berlin, Germany). MRI was performed within a 1-month period after SPECT examination.

Duplex scanning of the neck vessels was performed in all patients, and transcranial Doppler sonography (TCD) was performed in patients with an abnormal SPECT scan within 1 month after the abnormal scan. TCD was performed in a supine position with a 2 MHz probe through the temporal windows of either side and the occipital window. The Doppler signal was subjected to automatic on-line fast Fourier transform with a Multi-Dop X device (German Vasculab, Sipplingen, Germany). All vessels of the Willis circle were searched for and insonated at various depths whenever possible.

NVC was carried out with a cold light videocapillaroscope and analogue image analysis software (Videocap; DS Medigroup, Milan, Italy). Each subject had been indoors for a minimum of 15 min before the nailfold was examined and the room temperature was 20–22°C. The nailfolds of all 10 fingers were examined in each patient, after a drop of immersion oil had been placed on the nailfold bed to improve resolution. Fingers affected by recent local trauma were not analysed. The NVC examination was performed by the same operators, without knowledge of the patient's clinical condition and characteristics. During routine clinical NVC analysis, changes in the shape and arrangement of the capillary loops and the loss of capillaries are the most useful features for the diagnosis and follow-up of microangiopathy [22]. Therefore, patients were classified as showing an early (E), active (A) or late (L) pattern, according to recently validated criteria [23]. These criteria include the following: (early pattern) few giant capillaries, few capillary haemorrhages, no evident loss of capillaries; (active pattern) frequent giant capillaries, frequent capillary haemorrhages, moderate loss of capillaries, some avascular areas; (late pattern) irregular enlargement of the capillaries, few or absent giant capillaries, absence of haemorrhages, severe loss of capillaries with extensive avascular areas, ramified/ bushy capillaries.

Controls
Twenty-two subjects (16 females, six males, mean age 61±8.7 yr, range 44–84 yr) out of 52 volunteers were enrolled as controls on the basis of criteria that comprised normal values for serum glucose, creatinine, blood urea nitrogen, complete blood count, and urinalysis. Mild hypertension and hypercholesterolaemia were accepted in 22% of the subjects. Previous or present neurological, psychiatric, metabolic or severe cardiovascular disorders and the use of drugs other than anti-hypertensive agents were exclusion criteria. The controls were informed about the aim of the study and underwent brain SPECT examinations by the same procedure as that used for SSc patients.

Statistics
The Statistical Analysis System (Cary, NC, USA) was employed for statistical procedures. The distribution of values in each ROI was analysed by the Kolmogorov test and yielded a non-Gaussian distribution. ROI values for the patient and control groups were then compared by the non-parametric Wilcoxon rank sum test and the Kruskal–Wallis test. The Bonferroni correction for multiple comparisons was used, and the first level of statistical significance accepted was P<0.002.

Further information on the topography of hypoperfusion in individual SSc patients was obtained by computing the standardized normal deviate Z with respect to the control group. ROI values exceeding two standard deviations below the mean value of controls for a given ROI were considered to indicate hypoperfusion. Only patients with at least two ROIs with reduced values were regarded as hypoperfused.

Age and the duration of the disease were compared between patients with a normal SPECT scan and those with hypoperfusion by the t-test and the Mann–Whitney U-test. The presence of common vascular risk factors (i.e. arterial hypertension, diabetes mellitus, habitual smoking, hypercholesterolaemia and ischaemic heart disease), the impairment of other organs that are frequently affected in SSc (oesophagus, lung, kidney and joints) and the severity of microvascular impairment (NVC pattern) were compared between patients with a normal SPECT scan and those with hypoperfusion by the {chi}2-test.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Groups
Statistically significant differences between patient and control groups were found in the lower brain section in two of the four frontal ROIs, in five of the six temporal ROIs (except the left posterior ROI) and in both the occipital ROIs (P<0.001). No significant difference was found for the thalami and the basal ganglia. In the upper section, statistical significance was reached in four of the six frontal ROIs, whereas no difference was found for either the parietal or the occipital ROIs. In summary, significant differences were found between patients and controls in 13 (46%) out of 28 ROIs.

No significant difference between patients with a normal SPECT scan and patients with hypoperfusion was found for age [patients with a normal scan, 57±13 (S.D.) yr; patients with an abnormal scan, 61±9.9 yr] or the duration of the disease (patients with a normal scan, 6.41±4.2 yr; patients with an abnormal scan, 6.63±4.7 yr). Similarly, the presence of vascular risk factors, involvement of other organs and the single NVC pattern did not differ significantly between patients with a normal SPECT scan and patients with hypoperfusion. The same frequency of cutaneous telangiectasia was detected in both SPECT-positive and SPECT-negative patients and no relationship was observed (Table 1Go).

Patients with normal brain SPECT scan
Nineteen patients (48%) exhibited a normal brain SPECT scan (Table 1Go). All patients had a normal neurological examination and no neurological episode was found in their history. MRI was available in 12 cases. In nine of them the MRI was normal, while it showed small signal abnormalities in the white matter of both hemispheres in the remaining three. Among these three patients, one (patient 1) showed a 70% stenosis of the left internal carotid artery at its origin, and one (patient 18) showed multiple atherosclerotic plaques at both common carotid bifurcations, with a degree of stenosis ranging from 20 to 30% of the vessel lumen; in the third patient no carotid abnormalities were observed. Among the remaining 16 patients of this group, four had unilateral (three patients) or bilateral (one patient) carotid plaques with a degree of stenosis less than 20%.

Patients with abnormal brain SPECT scan
Twenty-one patients (52%) showed two or more hypoperfused ROIs (Table 1Go). The number and the location of hypoperfusion were heterogeneous among these 21 patients. Eight patients showed hypoperfusion in all ROIs, whereas in the remaining 13 patients the number of hypoperfused ROIs ranged between two and 27. In three cases (patients 5, 11 and 35) the hypoperfusion was also located in the basal ganglia and/or in the thalami. MRI was available for five of eight patients with diffuse hypoperfusion. In one of them the MRI was normal, whereas in four patients the MRI showed multiple signal abnormalities of different sizes in the white matter of both hemispheres. In particular, in patient 3 (affected by non-stenosing atherosclerotic plaques at both carotid bifurcations), multiple lesions involving extensively the white matter of both the parieto-occipital lobes were detected. Furthermore, in patient 3 (the only patient showing TCD abnormalities), TCD signal abnormalities were consistent with moderate stenosis at the intracranial bifurcation of the left internal carotid artery. Patients 27, 33 and 36 showed multiple white-matter hyperintensities in frontal and parietal lobes. Duplex scanning of neck vessels disclosed mild (<30% stenosis) plaques in both internal carotid arteries in another three patients (patients 27, 36 and 39) and was normal in the remaining four patients.

MRI was available for nine of 13 patients with focal or multifocal hypoperfusion (Table 1Go), and was found to be altered in four, in whom there were multiple signal abnormalities of different sizes in the white matter of both hemispheres. Moreover, in patient 12 a left cerebellar hyperintensity was found. In one patient (patient 6; SPECT images shown in Fig 2Go) mild signs of dementia were detected (Mini-Mental State Examination score 23/30) [24]. This patient underwent detailed neuropsychological evaluation that confirmed cognitive deterioration, and the MRI disclosed large, confluent signal abnormalities in the periventricular white matter of both hemispheres. In three patients (patients 5, 12 and 31) small carotid plaques (less than 20% stenosis) were found bilaterally by duplex scanning.



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FIG. 2. Brain SPECT scan of a patient (patient 6) with reduced tracer uptake in multiple ROIs, as derived from Z-statistics, in comparison with normal controls (those in the right frontal and temporal cortexes are indicated by arrowheads). All other details as in Fig 1Go.

 
Overall, MRI showed abnormalities in eight of 14 patients (57%) with an abnormal brain SPECT scan and in three of 12 patients (25%) with a normal SPECT scan.


    Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The present study shows that 52% of patients affected by SSc present focal or diffuse cerebral hypoperfusion, as assessed by 99mTc-HMPAO SPECT. These results confirm the findings already reported by our group, obtained by the planar quantitative xenon-133 clearance method in a smaller SSc sample [16].

The incidence of multiple white-matter MRI hyperintensities was higher in patients with cerebral hypoperfusion, especially in those with diffuse hypoperfusion. On the other hand, whereas our previous study showed that the hypoperfusion was more frequent in patients with an ‘active’ pattern of NVC [16], this trend was not confirmed in the present investigation. Therefore, the cerebral vascular involvement does not seem to reflect merely the peripheral microvascular alterations as assessed by NVC.

In addition, the ageing process should not have influenced the SPECT results, since an age-matched control group was preselected for the statistical comparisons and no significant age difference between SSc patients with a normal SPECT scan and those with hypoperfusion was found. Furthermore, it is unlikely that the impairment of other organs and systems, such as renal failure and hypertension, could have caused the SPECT abnormalities, as concomitant severe pathologies represented exclusion criteria. Finally, no significant difference regarding the presence of common vascular risk factors and the involvement of other organs was found between SSc patients with and without cerebral hypoperfusion. Therefore, when the possible influences of all these confounding variables on cerebral perfusion are excluded or minimized, the hypothesis that vascular involvement per se is the leading factor contributing to the hypoperfusion in SSc is reinforced.

Accordingly, the SPECT abnormalities may be limited to the microangiopathic damage of brain vessels. It is currently believed that complex endothelial cell dysfunction leading to typical non-inflammatory microangiopathy, characterized by vascular tissue proliferation and obliterative microvascular lesions, might alter the function of the nervous system during SSc, although the mechanism causing endothelial damage is poorly explained [3, 25, 26]. It is known that collagen types I, III and IV contained in the basement membranes of vessel walls, including the brain, are overproduced in SSc and are involved in the process of vascular narrowing and occlusion [27, 28]. Nevertheless, the rarity of clinical CNS involvement in SSc has been attributed to the limited presence of extracellular matrix proteins (i.e. collagens) into the cerebral tissue with the consequent spareness of media and adventitia in cerebral arteries and limited progression of the vascular obliteration [10, 29]. However, according to the hypothesis of non-inflammatory microangiopathy, it may be hypothesized that the progressive obliterative lesions of the small cerebral arteries might well be present in patients showing SPECT abnormalities. On the other hand, the role of macrovascular involvement, which has been reported previously [5, 30], is not supported by our data, which show few cases of extracranial or intracranial carotid involvement.

There is increasing evidence of CNS involvement in SSc. Recently, foci of ischaemic neuronal necrosis and calcification of the small deep cerebral arteries without glial or inflammatory reaction were reported at autopsy in two cases of SSc with the CREST syndrome, presenting with severe dementia or focal cerebrovascular accident [13]. Vascular abnormalities were found in the basal ganglia, hippocampus and dentate nuclei, but also in the walls of the small arteries of cortical areas, especially the frontal lobes, the cerebellar cortex and the mammillary bodies [13]. Other reports of brain involvement, mainly represented by focal cerebrovascular accidents, dementia and psychosis, not explainable by the systemic complications of the disease, have been published recently [5, 10, 31].

Brain hypoperfusion detected by SPECT has been reported in several rheumatic conditions, including fibromyalgia and chronic fatigue syndrome (CFS) characterized by a high incidence of depression, although the finding in CFS was not confirmed by another group [3236]. It has been suggested that repeated peripheral nociceptive stimuli in fibromyalgia patients may lead to altered CNS function that would be reflected by rCBF reduction in the thalamus and the head of the caudate nucleus [32]. However, abnormal pain perception and/or painful associated conditions are not usually reported in SSc patients, which makes their possible influence on the observed SPECT abnormalities unlikely.

Defects in brain perfusion have been reported by different techniques in patients with neuropsychiatric systemic lupus erythematosus, in whom the involvement of the CNS is often related to anticardiolipin (aCL) antibodies or to antibodies directed against the neuronal components [3739]. However, the SSc patients evaluated in the present study were negative for aCL antibodies.

Therefore, several combinations of rCBF defects, both in the cortical regions and in the deep grey structures, have been reported in different rheumatic diseases and a specific pattern of hypoperfusion cannot be identified [36, 37].

The increasing incidence of white-matter MRI abnormalities in SSc patients with hypoperfusion fits the hypothesis of cerebral microangiopathy. Moreover, it should be taken into account that the real extent of MRI abnormalities may have been underestimated in the present study, because of the use of a rather old imager working at 0.5 Tesla. Recent MRI data obtained by ourselves with more sensitive equipment confirmed the higher rates of both large and small signal abnormalities in the white matter in SSc patients than in age-matched healthy controls [40]. These alterations were not significantly related to age or to the duration of the disease, as for the SPECT data [40].

Concerning the MRI/SPECT relationships, it should be appreciated that perfusional 99mTc-HMPAO SPECT, like the other most commonly employed blood flow tracers, is not a suitable method of studying CBF in the white matter. The finding of cortical hypoperfusion in patients with deep white-matter lesions may be explained by assuming functional deafferentation (diaschisis) of the cerebral cortex from the deep structures, through the ascending neural pathways such as the thalamocortical projections, as observed in cerebral ischaemia [41]. Alternatively, the cortical hypoperfusion could be the consequence of the narrowing of small vessels within the cerebral cortex itself. These two interpretations could be checked by a provocative test able to overcome the hypoperfusion due to a deafferentation mechanism, such as the acetazolamide test [42].

Whatever the underlying pathogenic mechanism, the involvement of the cerebral (micro)vascular of the CNS seems to be essentially a subclinical process, since the CNS syndromes have been reported in a minority of patients, as in the present study. Impairment of CNS function in SSc patients in the absence of clinical symptoms has already been reported by classical neurophysiological techniques, such as conventional electroencephalography and the use of visual evoked potentials [31, 43].

According to this interpretation, and supported by the data of the present and other recent studies, the severity of cerebral microvascular impairment during SSc might be viewed as a continuum whose largest part remains at the subclinical level but which can be revealed by appropriately sensitive techniques, such as high-resolution perfusional SPECT of the brain [16, 40].

In conclusion, focal or diffuse cerebral hypoperfusion has been found in a large number of neurologically asymptomatic SSc patients, paralleled by an increased incidence of abnormalities in the brain MRI. The hypoperfusion seems to be unrelated to age or the severity of the peripheral microvascular involvement.


    Notes
 
Correspondence to: M. Cutolo, Division of Rheumatology, Department of Internal Medicine, Viale Benedetto XV No. 6, 16132 Genova, Italy Back


    References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Submitted 13 January 2000; Accepted 27 June 2000