Brain Advance Access originally published online on October 21, 2003
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Brain, Vol. 127, No. 1, 175-181, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh013
MRI-based volumetric differentiation of sporadic cerebellar ataxia
Departments of 1 Neurology, 2 Neuroradiology and 3 Medical Biometry, University of Tübingen and 4 Institute of Human Genetics, University of Lübeck, Germany
Correspondence to: K. Bürk, Department of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, D-72076 Tübingen, Germany E-mail: buerk{at}uni-tuebingen.de
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Summary |
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The term idiopathic cerebellar ataxia (IDCA) designates a variety of cerebellar syndromes that may present with a purely cerebellar syndrome (IDCA-C) or with additional extracerebellar features (IDCA-P). Multiple system atrophy is also a sporadic neurodegenerative disorder of unknown origin that may cause prominent cerebellar symptoms (MSA-C). The final neuropathological answer to the question whether IDCA-P and MSA-C represent different varieties of one disease or two distinct entities is still lacking. Three-dimensional MRI-based volumetry allows morphological investigations intra vitam. Volumetric analysis of cerebellum, brainstem and basal ganglia was therefore performed in 46 patients with sporadic cerebellar ataxia and 16 age-matched healthy controls. Patients with dementia were excluded from the study since cognitive impairment is an exclusion criterion for the diagnosis of MSA. Cerebellar patients were clinically divided into two groups: 33 patients with multiple system atrophy with prominent cerebellar symptoms (MSA-C) and 13 patients with extracerebellar features not corresponding to MSA-C (IDCA-P). There was evidence for substantial cerebellar atrophy in both cerebellar groups while additional brainstem atrophy was significantly more pronounced in MSA-C patients. Absolute caudate and putamen atrophy was found to be restricted to single MSA-C individuals while group comparisons of mean volumes did not yield significant differences from controls. Based on the volumetric data, diagnosis could be correctly predicted in 94% of control, 82% of MSA-C and 100% of IDCA-P individuals. The finding of specific imaging characteristics strengthens (i) the value of MRI volumetry in separating MSA-C from other types of sporadic cerebellar ataxia, and (ii) the hypothesis of two independent neurodegenerative disorders in MSA-C and IDCA-P.
Key Words: idiopathic cerebellar ataxia; multiple system atrophy; olivopontocerebellar atrophy; cerebellar atrophy
Abbreviations: ANOVA = analysis of variance; CCA = cortical cerebellar atrophy; IDCA = idiopathic cerebellar ataxia; IDCA-C = IDCA with a purely cerebellar syndrome; IDCA-P = IDCA with additional extracerebellar features; MRI = magnetic resonance imaging; MSA = multiple system atrophy; MSA-C = MSA of the cerebellar type; MSA-P = MSA of the striatonigral type; OPCA = olivopontocerebellar atrophy; SCA = spinocerebellar ataxia; TurboSE = turbo spin echo
Received January 22, 2003. Revised May 15, 2003. Second revision August 11, 2003. Accepted August 16, 2003 .
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Introduction |
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The term ‘sporadic cerebellar ataxia’ comprises a variety of non-hereditary cerebellar syndromes of unknown origin. Neuropathological features vary from isolated cerebellar degeneration (cortical cerebellar atrophy, CCA) to combined neuronal degeneration and gliosis in the inferior olives, pons and cerebellum (olivopontocerebellar atrophy, OPCA) (Gilman and Quinn, 1996
). Clinically, patients may present with a purely cerebellar syndrome (IDCA-C) or with additional extracerebellar features (IDCA-P).
Combined cerebellar and pontine atrophy is also a neuropathological hallmark of multiple system atrophy (MSA) (Schulz et al., 1994), a sporadic unrelentlessly progressive neurodegenerative disorder leading to incapacity and a reduced life expectancy. Neuronal loss is not restricted to the inferior olives, pontine nuclei and Purkinje cells in MSA brains, but may also be found in the putamen, caudate nucleus, substantia nigra and the autonomic nuclei of the brainstem and the intermediolateral cell columns in the spinal cord and is accompanied by the presence of glial cytoplasmic inclusions (Gilman et al., 1999). Clinically, MSA is associated with various combinations of cerebellar ataxia, basal ganglia symptoms and severe autonomic dysfunction (Gilman et al., 1999). Many MSA patients initially develop basal ganglia symptoms (MSA of the striatonigral type, MSA-P) while others start with a cerebellar syndrome (MSA of the cerebellar type, MSA-C). The question whether MSA-C and idiopathic cerebellar ataxia with extracerebellar presentation (IDCA-P) represent the same disease has been discussed controversially in the literature (Penney, 1995; Rinne et al., 1995; Gilman and Quinn, 1996; Quinn and Daniel, 1996; Gilman et al., 2000). Meanwhile, it seems commonly accepted that sporadic ataxia is a heterogeneous disorder with at least two subgroups of patients, those who evolve to MSA-C and those who continue to show progressive deterioration of cerebellar function without developing signs of MSA-C. However, the neuropathological proof of this hypothesis has not yet been established.
It is not clear which investigations may be most useful in differentiating MSA-C from other cerebellar patients. This seems the more important as prognosis of MSA is poor (Schulz et al., 1994; Gilman et al., 2000). The reliability of three-dimensional MRI-based volumetry has been demonstrated in earlier intra vitam studies (Luft et al., 1996, 1998; Schulz et al., 1999). This method is characterized by a higher exactness and reproducibility than two-dimensional planimetric evaluation or voxel-based volumetry.
We have therefore performed a comparative study of the clinical and morphological characteristics in patients with sporadic cerebellar ataxia. Individuals were diagnosed as MSA-C or IDCA-P based on their clinical features. Morphological analysis included MRI-based volumetry of cerebellum, brainstem, caudate nucleus and putamen.
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Patients and methods |
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Patients
In order to investigate the discernment of MSA-C and IDCA-P in cerebellar patients with a clinical presentation as similar as possible, cerebellar patients with evidence for cognitive impairment were excluded from the study [dementia has to be absent in MSA according to the Guideline of the International Consensus Statement of MSA (Gilman et al., 1999
)]. Forty-six cerebellar patients (mean age 60.5 ± 7.2 years, range 41–75 years; mean age of onset 54.8 ± 8.5 years, range 30–70 years; mean disease duration 5.7 ± 3.6 years, range 1–19 years) were selected from a larger patient pool.
They fulfilled the following inclusion criteria: (i) chronic progressive cerebellar dysfunction with cerebellar ataxia and dysarthria; (ii) disease onset after the age of 35 years [patients with a lower age of onset were excluded since MSA-C usually starts after the age of 35 years (Gilman et al., 1999)]; (iii) absence of any neurodegenerative disorder in relatives, no evidence for consanguinity of parents and negative molecular genetic testing for Friedreich’s ataxia and the most frequent spinocerebellar ataxias (SCA1, SCA2, SCA3, SCA6) (Orr et al., 1993; Kawaguchi et al., 1994; Campuzano et al., 1996; Pulst et al., 1996; Zhuchenko et al., 1997); (iv) exclusion of symptomatic causes of ataxia such as gluten sensitivity (negative testing for antigliadin antibodies), infectious disease (negative serological testing for neurotropic viruses, negative VDRL), multiple sclerosis (normal cell count, protein, albumin, immunoglobin, lactate contents and electrophoresis of the CSF, no white matter lesions on MRI), paraneoplastic disease (in patients with a disease duration of <4 years normal thoracic and abdominal CT scan, in female patients no evidence for breast or ovarian cancer, normal differential blood cell count, negative testing for anti-Hu and anti-Yo antibodies), disease of the thyroid (normal L-thyroxine, L-thyronine and thyroid-stimulating hormone levels), Wilson’s disease (normal ceruloplasmin levels), hypovitaminosis (normal cobalamin and alpha-tocopherol levels), alcoholism, chronic anticonvulsive therapy and intracranial ischaemia or neoplasm.
Clinical rating
Individuals were interviewed and examined using a standardized examination procedure. Severity of cerebellar symptoms was rated on a scale ranging from zero (absent) to five (most severe) (Klockgether et al., 1990). The age of onset was defined as the onset of motor symptoms as experienced by the patient.
Classification
Patients were separated into the following diagnostic categories.
(i) Multiple system atrophy of the cerebellar type (MSA-C)
Patients fulfilling the diagnostic criteria of probable MSA-C based on the guidelines of the International Consensus Statement of MSA (Gilman et al., 1999): cerebellar ataxia with additional severe autonomic failure and/or a levodopa-unresponsive or a poorly responsive parkinsonian syndrome. Severe autonomic failure was diagnosed on the presence of postural hypotension (orthostatic drop of 30 mm Hg or more in systolic blood pressure immediately (0 min) after having been supine for 5 min and 3 min after assumption of the upright position) and/or urinary incontinence (after exclusion of other causes). Diagnosis of the parkinsonian syndrome required at least two of the features akinesia, rigidity, tremor and poor or no response to levodopa. The finding of vertical supranuclear gaze palsy excluded the diagnosis of MSA-C.
(ii) Cerebellar ataxia with additional extracerebellar features (IDCA-P)
Patients who presented with at least one of the following symptoms: pale discs, gaze palsy, slowed saccades, dystonia, reduced tendon reflexes, pyramidal tract signs, mild bladder dysfunction.
MRI studies
MRI sequences
MRI based volumetry was performed by using the method of Schulz (Schulz et al., 1999). All measurements were performed on a Siemens Magnetom Vision 1.5 T scanner (Siemens AG, Erlangen, Germany), using the standard head coil. Two MRI series were acquired. A 3D Fourier transform fast low-angle shot sequence producing isotropic T1-contrasted image sets in high resolution [repetition time (TR) = 15 ms; echo time (TE) = 5 ms; flip angle = 30°; number of excitations (NEX) = 1; slice thickness = 0.9 mm; pixel size = 0.9 x 0.9 mm] was scanned. A double-contrast Fourier transform turbo spin echo (TurboSE) was acquired twice in interleaved slice positions to obtain a gapless set of images (TR = 5800 ms; TE = 15/75 ms; 2 NEX; slice thickness = 2.0 mm; gap = 2 mm; pixel size = 0.9 x 0.9 mm). As the TurboSE sequence included two echos, two image sets of different contrast (TE = 15 ms, proton density contrast; TE = 75 ms, T2-weighted contrast) but equal slice position were obtained. Fast low-angle shot sequence images were used for cerebellar and brainstem volumetry, while the total intracranial and basal ganglia volumes were measured by using TurboSE data.
Volumetric analysis
Volumetric analysis consisted of manual landmark defined presegmentation followed by an automated region growing-based detailed segmentation and calculation of volume considering partial volume effects. Interactive presegmentation was necessary wherever the boundaries between structures were not contrasted and could therefore not be segmented automatically by the region growing algorithm. Manual presegmentation of brainstem and cerebellum included definition of the posterior, superior and inferior borders by planes adjusted for landmarks. After interactive definition of all boundaries, automated segmentation was applied and the volumes were calculated by adding the volumes of all segmented voxels. The basal ganglia were measured by using the first and second echos of the TurboSE dataset. The additional information from the second contrast allowed better identification of each nucleus (multispectral analysis). After manual presegmentation, in which the putamen was separated from insular cortex, region growing was applied and the volume of the caudate nucleus and putamen was calculated as described above. The total intracranial volume was estimated by using the proton density contrast (TE = 15 ms) of the TurboSE sequence.
Statistical analysis
JMP software 4.0 (SAS Institute, Cary, NC, USA) was used for statistical analysis. Individual volumes were standardized for inter-individual variation of head size by dividing the individual structure volume by the individual total intracranial volume. The paired Student’s two-tailed t-test did not reveal any significant differences between the putamen and caudate volumes of both sides. Therefore, the sum of the right and left volumes was taken for further analysis. The comparison of the group means of age, age of onset, disease duration and standardized volumes was performed by an analysis of variance (ANOVA). Post hoc paired-group comparisons were explored with Tukey’s honestly significant difference. Normal values of cerebellum, brainstem, putamen and caudate volumes were defined as the mean control value minus two standard deviations. Volumes were calculated as a percentage of total intracranial volume. Disability scores, frequencies of clinical symptoms and atrophic changes were analysed using the 
2-test. Discriminant analysis was used to discern between the groups and to predict the diagnosis based on the standardized volumes of brainstem, cerebellum, caudate and putamen. As a measure of agreement between the ‘diagnosis’ and the ‘predicted diagnosis’, Kappa statistics were used. Kappa measures the degree of agreement on a scale from minus one to one. For correlation studies, the Pearson correlation coefficient was used. Overall, differences were considered significant when P < 0.05. In order to achieve a global significance level of 5% in case of multiple testing, P-values were corrected applying the modified Bonferoni–Holm Adjustment.
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Results |
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Patients’ characteristics
Thirty-three patients fulfilled the diagnostic criteria for MSA-C. Thirteen subjects showed extracerebellar features not corresponding to the diagnostic criteria of MSA-C. Patients’ characteristics and their clinical features are given in Table 1. The mean age at clinical examination did not differ between groups [ANOVA: F(2,59) = 1.5234, P = 0.2264]. MSA-C patients were significantly older at perceived onset of motor symptoms than IDCA-P patients [ANOVA: F(1,44) = 5.3684, P = 0.0252; Tukey-test: P < 0.05]. In IDCA-P, the mean disease duration was significantly longer than in MSA-C at the time of the investigation [ANOVA: F(4,79) = 14.9589, P = 0.0004; Tukey-test: P < 0.05].
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Clinical features
All patients presented with ataxia of stance, gait and limbs as well as dysarthria. The degree of motor disability did not differ between both groups. Further clinical features are given in Table 1. While impaired smooth pursuit and gaze evoked nystagmus were present in both cerebellar groups, spontaneous nystagmus was strikingly rare in MSA-C. Pale discs, gaze palsy and hypacusis were restricted to IDCA-P subjects. Autonomic dysfunction (postural hypotension, bladder dysfunction and constipation), sleep behaviour disorders, rigidity and akinesia were characteristic findings in the MSA-C group.
Volumetric analysis
Group comparison
Standardized cerebellar and brainstem volumes were significantly reduced in all cerebellar groups compared with controls [cerebellum: ANOVA, F(2,59) = 37.6269, P < 0.0001; Tukey-test P < 0.05; brainstem: ANOVA, F(2,59) = 110.6494, P < 0.0001; Tukey-test P < 0.05). Brainstem atrophy was most prominent in MSA-C (Tukey-test P < 0.05) while cerebellar atrophy did not differ between MSA-C and IDCA-P (Figs 1 and 2). Mean volumes of caudate and putamen were not significantly different in controls and cerebellar patients (caudate: ANOVA, F(2,59) = 2.6976, P = 0.0757; putamen: ANOVA, F(2,59) = 2.6724, P = 0.0774) (Figs 3 and 4).
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Individual analysis
When analysed on an individual base, cerebellar atrophy was present in 27 (82%) MSA-C and nine (69%) IDCA-P patients (MSA-C versus IDCA-P; P = 0.3514). 33 (100%) MSA-C, but only nine (69%) IDCA-P patients had brainstem volumes below the limits indicating brainstem atrophy (MSA-C versus IDCA-P; P = 0.0009). No atrophy was found in two (15%) IDCA-P subjects (MSA-C versus IDCA-P; P = 0.0212).
The main patterns of atrophy were: (i) isolated cerebellar atrophy in two (15%) IDCA-P individuals (MSA-C versus IDCA-P; P = 0.0212); (ii) isolated brainstem atrophy in six (18%) MSA-C and two (15%) IDCA-P patients (MSA-C versus IDCA-P; P = 0.8217); (iii) combined cerebellar and brainstem atrophy in 27 (82%) MSA-C and 7 (54%) IDCA-P patients (MSA-C versus IDCA-P; P = 0.0517). While none of the IDCA-P subjects had absolutely reduced basal ganglia volumes, one (3%) MSA-C individual presented with atrophy of the caudate nucleus (MSA-C versus IDCA-P; P = 0.5257) and additional brainstem and cerebellar atrophy. Eight (24%) MSA-C patients had evidence for atrophy of the putamen (MSA-C versus IDCA-P; P = 0.0508). In six of them, there was additional atrophy of both brainstem and cerebellum, while the remaining two MSA-C individuals had brainstem atrophy only.
Prediction of diagnosis
Discriminant analysis allows predicting some level of a one-way classification (‘predicted diagnosis’) based on known values of the responses (‘standardized brainstem, cerebellar, caudate and putamen volumes’). The technique is based on how close a set of measurement variables are to the multivariate means of the levels being predicted. The sensitivity of the mathematical model is assessed by comparing the ‘predicted diagnosis’ – as calculated based on the model – to the ‘diagnosis’. Based on all four volume parameters measured (volumes of cerebellum, brain stem, caudate and putamen), IDCA-P and MSA-C could be well discriminated not only from controls, but also from each other (see Fig. 5). Ninety-four per cent of control subjects, 82% of MSA-C and 100% of IDCA-P patients could be correctly diagnosed (see Table 2). One control subject and six MSA-C individuals were classified as IDCA-P. The Kappa coefficient for the agreement between the clinical diagnosis and the predicted diagnosis was 0.823074, P < 0.0001 (standard error 0.05) indicating an overall correct classification in 82% of all individuals tested.
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Influence of disease duration
Linear regression analysis yielded significant inverse correlations between the disease duration and brainstem (r = – 0.59, P = 0.0003) volumes in MSA-C patients. In IDCA-P subjects, CNS volumes were not correlated to the disease duration.
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Discussion |
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The reliability and usefulness of 3D MRI volumetry had been shown in earlier studies (Luft et al., 1996
, 1998; Schulz et al., 1999). The present findings indicate that MRI volumetry represents a useful diagnostic tool also in patients with sporadic cerebellar ataxia: by using three-dimensional MRI-based volumetry, diagnosis could be correctly predicted in 82% of MSA-C patients. It was also possible to distinguish control and IDCA-P subjects from MSA-C patients. There was evidence for substantial cerebellar atrophy in both types of cerebellar ataxia, while additional brainstem and basal ganglia changes appeared more variable. As expected, brainstem atrophy was most pronounced in MSA-C patients. Caudate and putamen atrophy was restricted to MSA-C, a finding that is consistent with neuropathological findings in MSA-C (Lantos and Papp, 1994; Papp and Lantos, 1994; Lantos, 1997; Papp et al., 1989).
Cerebellar and brainstem volume loss were correlated to disease duration in MSA-C, but not in IDCA-P. This finding may point to heterogeneity in IDCA-P in contrast to MSA-C. It had been a matter of a long-standing discussion whether IDCA-P represents a variety of MSA-C (Penney, 1995; Rinne et al., 1995; Gilman and Quinn, 1996; Quinn and Daniel, 1996; Gilman et al., 2000). In the literature, it is commonly assumed that not all cerebellar patients with extracerebellar symptoms will evolve to MSA-C (Gilman and Quinn, 1996; Gilman et al., 2000) despite the fact that the final neuropathological proof for the existence of at least two independent disorders is still lacking (Gilman and Quinn, 1996; Quinn and Daniel, 1996; Gilman et al., 2000).
Using survival analysis methods, Gilman and coworkers estimated that about one-quarter of sporadic ataxia patients with extracerebellar involvement will develop MSA-C within 5 years of the onset of cerebellar symptoms (Gilman et al., 2000). Based on a mathematical model, the authors also calculated a higher risk for the evolution to MSA-C in patients with a disease onset after the age of 51 years, while evolution to MSA-C was less probable in patients with an onset before that age. Correspondingly, in the present study, the mean age of onset in MSA-C was higher than in IDCA-P. Gilman also described a shorter time from the onset of symptoms to the first presentation in a neurology specialty clinic to be an even stronger predictor of transition to MSA-C. The latter finding points to a rather rapid initial course of the disease.
The predictive validity of other characteristics such as particular clinical signs or abnormal functional tests has not been established to date. Electromyography of external anal and urethral sphincter has often been recommended to support MSA diagnosis showing abnormalities of chronic reinnervation (Eardley et al., 1989; Beck et al., 1994; Palace et al., 1997) but its validity in MSA-C still remains to be established. [123I]Iodobenzamide SPECT or raclopride PET may give evidence for reduced dopamine D2 receptor density, thus reflecting degeneration of striatal neurons in MSA (Brooks et al., 1992; Schulz et al., 1994). These investigations however require extensive technical prerequisite and are not necessarily significant in all MSA patients (Schulz et al., 1994).
The value of MRI in the detection of MSA has been questioned. The presence of striatal, cerebellar and brainstem abnormalities had been postulated to be helpful for the diagnosis of MSA but Schrag reported on normal MRI in up to 20% of MSA patients (Schrag et al., 1998).
In the present study, brainstem measurements allowed clear separation of MSA-C patients from controls and IDCA-P in most cases. The volumetric analysis therefore gives further support to the hypothesis that MSA-C and IDCA-P represent distinct neurodegenerative disorders. Accordingly, not all cerebellar patients with extracerebellar symptoms will necessarily evolve to MSA-C. Regarding the discriminative power of MRI volumetry, this method has the potential to allow early detection of possible patients at risk for MSA-C among sporadic cerebellar ataxia patients.
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References |
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