POSITRON EMISSION TOMOGROPHY (PET) IN CHRONIC FATIGUE SYNDROME: PRELIMINARY
Umberto Tirelli* MD, Franca Chierichetti° MD,
Marcello Tavio* MD, Cecilia Simonelli* MD, Gianluigi Bianchin€ MD,
Pierluigi Zanco° MD and Giorgio Ferlin° MD.
* Division of Medical Oncology and
AIDS, Centro di Riferimento Oncologico, Aviano - Italy.
° Nuclear Medicine Department
- PET Center, General Hospital - Castelfranco Veneto - Italy.
€ Psychiatry Department, General
Hospital - Castelfranco Veneto - Italy.
|Prof. Umberto Tirelli
Division of Medical Oncology and AIDS
Centro di Riferimento Oncologico
Via Pedemontana Occ. 12,
33081 Aviano (PN) - Italy
Background and objective: Chronic fatigue
syndrome (CFS) has been widely studied by neuroimaging techniques in recent
years with conflicting results. In particular, by single photon emission
computed tomography (SPECT) and perfusion tracers it has been found hypoperfusion
in several brain regions, although the findings vary across the research
centres. Objective of the study was to investigate brain metabolism of
patients affected by CFS, by using 18Fluorine-deoxygluxose (18FDG) positron
emission tomography (PET).
Methods: We performed 18FDG PET in 18 patients
who fulfilled the criteria of working case definition of CFS. Twelve of
the 18 patients were females; the mean age was 34 ± 50 (range 15-68)
and the median time from CFS diagnosis was 16 months (range 9-138). Psychiatric
diseases and anxiety neurosis were excluded in all CFS patients. CFS patients
were compared with a group of 6 patients affected by depression (according
to DSM IV R) and 6 age matched healthy controls. The CFS patients were
not taking any medication at the time of PET, while depressed patients
were drug-free for at least one week prior to the PET examination. PET
images were examined considering 22 cortical and subcortical areas.
Results: CFS patients showed a significant
hypometabolism in right medium frontal cortex (p = 0.010) and brain stem
(p = 0.013) in comparison to the healthy controls. Moreover, comparing
patients affected by CFS and depression, the latter group showed a significant
and severe hypometabolism of a medium and upper frontal regions bilaterally
(p = ranging from 0.037 to 0.001), while the metabolism of brain stem was
Conclusion: Brain- 18FDG PET showed peculiar
metabolism abnormalities in patients with CFS in comparison both with healthy
controls and depressed patients. The most relevant result of our study
is the brain stem hypometabolism which , as already reported in a perfusion
SPECT study, seems to be an marker for the in vivo diagnosis
Chronic Fatigue Syndrome (CFS) is a debilitating
disorder of unknown etiology characterized by unexplained, deep fatigue
lasting more than six months. The cause of CFS has not been identified,
and no specific diagnostic tests are available to date. The first case
definition of CFS did not effectively help physicians to distinguish CFS
from other types of unexplained fatigue (1). For this reason, the revised
case definition provided additional guidelines to researchers for subgrouping
cases of CFS and other types of unexplained prolonged fatigue (2). Nevertheless
CFS is not still recognized as an independent syndrome by most neurologists
and psychiatrists, being depression the most common final diagnosis also
in patients with genuine CFS (3). Diagnosis of depression is usually based
on the neuro-psychological evaluation but, in CFS setting, it is not easy
to distinguish between a primary depressive disorder and a secondary, reactive
one. Neuro-functional imaging techniques such as single photon emission
computed tomography (SPECT) and positron emission tomography (PET) have
already been extensively used to study neurologic and psychiatric disorders,
especially to differential diagnosis purposes (4). In a recent review CFS
has been included in a group of problematic syndromes in which SPECT may
be useful in the differential diagnosis (5).
We herewith present the results of a study aiming
to evaluate brain metabolism of CFS patients without signs of depression
by using PET and 18Fluorine-deoxygluxose (18FDG) as tracer. The study was
based on a previous experience by perfusion SPECT in a mixed group
of CFS, neurological and psychiatric disorders that proved a relevant hypoperfusion
of brain stem in CFS (6). As depression is the most frequent neurological
diagnosis in cases of CFS, we examined subject suffering from major depression,
too, but no other psychiatric patients. The aim of our study was to evaluate
glucose brain metabolism to assess a possible role of central nervous system
in the pathogenesis of CFS, and to confirm the data of perfusion SPECT
by a higher resolution method like PET, able to detect small structures
such as brain stem. Patients affected by CFS were evaluated at the Aviano
cancer center, meanwhile patients with depression as well as healthy volunteers
were evaluated at the Castelfranco general hospital, where PET procedure
was performed to all the patients.
In this preliminary study we enrolled 24 right-handling
individuals composed of 18 patients (12 females and 6 males) who fulfilled
the criteria of working case definition of CFS and 6 patients (4 females
and 2 males) affected by major depression according to the DSM IV R, and
we compared both groups with a group of healthy controls. All patients
underwent a complete diagnostic work-up that included history, physical
and neuropsychiatric examination, and brain CT or MRI. In all CFS cases
psychiatric diseases were excluded by BPRS (Brief Psychiatric Rating Scale)
and PSE (Present State Examination). We performed also Hamilton Rating
Scale for Anxiety and 24-item Hamilton Rating Scale for Depression, before
PET study, to exclude depression and anxiety neurosis. Their mean
age was 34 ± 15 years (range, 15 to 68) and they were drug-naive.
Patients affected by major depression were older (mean age 48 ±
7 years, range 41 to 59) and the mean duration of the disease was 8 +-4
years. They were drug-free for at least 4 weeks prior to entering the study.
Previous head trauma, and/or cerebrovascular diseases were excluded for
both. Median time from CFS diagnosis was 16 months (range 9-138). The main
symptoms of CFS patients are shown in table I.
We included a control group comprising 6 age-matched
healthy subjects (4 females and 2 males) (mean age 38 ± 12) who
were entirely normal on physical examination, with negative history for
neurological and psychiatric diseases. We chose a small group of controls
who were composed of a similar percentage of males and females and age
matched respect to CFS cases. They were young enough to exclude the effect
of age even if this is still controversial as the findings seen on PET
in normal aging are not yet unique (7-8). All subjects or their relatives
gave informed consent to participate into the study.
PET studies were performed using a whole-body, high
resolution PET scanner (ECAT EXACT 47 Siemens CTI). This 24-ring bismuth
germinate tomograph produces 47 simultaneous slices 3.38 mm thick and the
resolution (FWHM) is 6.1 mm along the transaxial plane and 4.8 mm along
the axial plane. The correct positioning of the head was assessed by a
laser device to define the orbitomeatal line. A transmission scan was performed
(10 min acquisition) to obtain the attenuation correction, using orbiting
68Ge rod sources. 210-270 MBq of 18FDG were injected into an antecubital
vein in resting condition, ear unplugged and eyes closed. Emission scan
data were acquired 45 min post injection. In controls, depressed patients
and 10 out of 18 CFS subjects we obtained also the cardiac input functions
for calculating rCMRgl following a methodology described in a previous
experience (9). Transaxial, coronal and sagital slices were reconstructed
from raw data both for qualitative (non parametric) and quantitative (parametric)
studies. On 6 mm thick transaxial slices (about 16 per
study) we performed a region of interest (ROI) analysis positioning several
anatomical ROIs, based on isocontour techniques, comparing the PET images
to a standard brain atlas (10) and outlining the entire region on each
image. The ROIs, 50-54 per study, were used to sample the different brain
areas of the cortex, basal ganglia, thalamus, cerebellum and brain stem.
At least three contiguous slices were used to obtain information from each
area by averaging the data from these planes. The resulting 22 cortical
and subcortical areas were: 1. left inferior frontal (comprising orbito-frontal
region); 2. right inferior frontal; 3. left medium frontal (comprising
medium frontal gyrus and the lower region of superior frontal gyrus); 4.
right medium frontal; 5. left superior frontal; 6. right superior frontal;
7. left parietal; 8. right parietal; 9. left inferior temporal (comprising
hyppocampus and mesial cortex); 10. right inferior temporal; 11. left superior
temporal (comprising primary auditive cortex); 12. right superior temporal;
13. left occipital cortex (included primary visual cortex); 14. right occipital
cortex; 15. left nucleus caudate; 16. right nucleus caudate; 17. left putamen;
18. right putamen; 19. left thalamus; 20. right thalamus; 21. brain stem;
22. cerebellum (taken as a whole). The same set of ROIs was used for both
parametric and non parametric PET images to obtain the mean values of all
areas in rGMRgl and microCi per pixel, respectively. Then, for each study,
we computed the mean brain activity (MBA), as mean value of all ROIs, and
we normalised each cortical and subcortical area to this mean. E.g. left
inferior frontal A = mean value of the ROIs on left inferior frontal cortex/MBA.
Group means were compared using the two-tailed Student's
t test for unpaired comparisons. The level of statistical significance
was set at p < 0.05.
Conventional radiological imaging (MRI and CT) was
normal in both groups of patients showing no focal defects or significant
brain atrophy. For visual inspection of PET imaging, the reduction of metabolism
was considered to be mild (< 10% of the color scale), moderate (10-20%
less) or severe (>20%). CFS patients, respect to controls, showed moderate
hypometabolism of brain stem, especially pons (fig. 1). In depressed subjects
a severely impaired glucose metabolism in frontal areas was evident (fig.
2). Normalised non parametric PET data revealed in CFS a significant hypometabolism
of right medium frontal cortex (p = 0.010) and brain stem (p = 0.013) respect
to healthy subjects. Comparing major depression and CFS, in the first group
of patients the whole frontal cortex was affected (except the left inferior
frontal) with p ranging from 0.037 to 0.001, while in CFS patients brain
stem was severely and significantly hypometabolic, with p value of 0.009
(table II). Absolute, quantitative 18FDG PET showed normal values for the
mean (40± 12 micronmol/100 g/min) rCMRgl both in depressed and CFS
patients. The normalization of parametric images, by using the same set
of ROIs of the non parametric studies, demonstrated the same involvement
of previous reported brain areas.
To date no diagnostic tests are available for CFS
which is currently diagnosed by a history of illness suggestive of CFS
along with the systematic exclusion of other possible causes of fatigue.
Applications and limitations of functional neuro-imaging in diagnosis of
CFS have been recently reviewed (11). Magnetic resonance imaging (MRI)
and x-ray computed tomography (CT) are anatomical approaches that gave
in CFS conflicting and substantially inconcludent results (12-13). PET
and SPECT offer non-invasive in vivo methods to assess directly regional
brain functions. Regional brain blood flow, oxygen metabolism and glucose
utilisation, blood-brain barrier permeability, and pre-sinaptic and post-sinaptic
neuro-receptor density and affinity are some of the neuro-physiologic variables
that can be studied by these techniques (14-16). Several studies have been
published using SPECT in CFS, although the results vary across research
centers, probably reflecting a different selection of the patients. First
reported regional SPECT abnormalities involved frontal, parietal, temporal
and occipital areas within a widespread cortical hypoperfusion (17). The
involvement of frontal and temporal regions was successfully described
(18) both in depressed and CFS patients, suggesting important similarities
and also arising the question of the differential diagnosis between these
Recently Costa et al compared brain perfusion of
patients affected by myalgic encephalomyelitis/chronic fatigue syndrome
(ME/CFS) with that of normal volunteers and other patients with major depression
(6). The results indicated that in addition to scattered cortical perfusion
abnormalities, brain stem hypoperfusion (compared to normals) appeared
to be characteristic of ME/CFS patients and it was significantly lower
than that of depressed patients. The brain stem hypoperfusion was the lowest
in those ME/CFS patients who fulfilled the CDC criteria and had no other
In order to describe PET- pattern in CFS patients
and to study PET usefulness in differential diagnosis between CFS and depression,
we measured brain metabolism in patients affected by CFS without depression
and in patients affected by depression without CFS, comparing both groups
of patients with a control group of healthy subjects. Absolute glucose
metabolism data and normalised data showed that the brain glucose metabolism
is impaired in selected and different areas both in CFS and depression.
In CFS, respect to healthy subjects, we found a significant hypometabolism
of right medium frontal cortex, as in agreement with a previous SPECT study
by perfusion tracers (18). Our group of depressed patients presented more
severe and spread frontal alterations, as already reported in depression
(19) and in other psychiatric syndromes, especially schizophrenia, and
obsessive-compulsive disorder (20-25). PET and SPECT studies have not yet
identified specific patterns for each disease, but, generally, the frontal
alterations are not focal as we conversely found in our experience with
CFS. We can argue that this limited involvement of frontal cortex
in CFS may be a feature of the disease. Alternatively, we can consider
it as an expression of reactive, not yet clinically evident, depression.
Hypothetically, taking into account that in our regional analysis, medium
frontal cortex comprised brain areas 9 and 46 (association cortex), this
derangement of right hemisphere may explain some neurocognitive impairments
of the disease.
More specifically, we found a significant hypometabolism
of brain stem, confirming the report of other Authors (see above) and this
seems a typical feature of CFS never reported to our knowledge in psychiatric
diseases. Previous SPECT studies were able to identify such involvement,
even if this technique has an anatomical resolution lower than our high
resolution PET. To date this finding has no clear explanation especially
in order to define such a damage as primary or secondary to CFS. Brain
stem is involved in many functions of the vegetative life. Animal models
have shown (26) a predilection for brain stem and diencephalon by some
herpes virus, and Epstein-Barr virus and herpes virus type 6 have been
often implicated in CFS pathogenesis (12-27). As already suggested by Costa
et al. this virus-mediated brain stem impairment might be rather the cause
than the consequence of the disease and might explain some manifestations
of CFS, by the involvement of the reticular system (i.e. sleep disturbances
and consciousness alterations).
In conclusion, our, even preliminary, study is in
agreement with previous neurofunctional imaging studies supporting an organic
cause for CFS. Because of its cost, PET procedure should not be considered
appropriate for the clinical diagnosis of CFS. Nonetheless, in the near
future, PET cuold become extremely useful in testing new pathogenetic hypothesis
and new therapeutic approches, especially in selected subsets of patients.
Table - I -
MAIN SYMPTOMS OF PATIENTS WITH CFS
|Fatigue (according to case definition)
|Insomnia / ipersomnia
|Photophobia or transient scotomata
|Prolonged periods of low-grade fever
Table - II -
FRONTAL CORTEX-BRAIN STEM/MBA IN CFS AND DEPRESSION
|L medium F
|R medium F
|L superior F
|R superior F
|L = left; R = right; F = frontal.
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Legend figure number 1
CFS patient: PET transaxial and sagittal showing
the low up-take in brain stem.
Legend figure number 2
Depressed patient: PET transaxial and sagittal showing
the low frontal up-take and normal glucose metabolism of the brain stem.
We thank Dr. Maddalena Mosconi for the help with