ORIGINAL CONTRIBUTION Clinical and Magnetic Resonance Imaging Characteristics of Sporadic Cerebellar

Katrin Bürk, MD; Udo Bühring, MD; Jörg Bernhard Schulz, MD; Christine Zühlke, PhD; Yorck Hellenbroich, MD; Johannes Dichgans, MD

Background: It is unknown whether multiple system spheres was found in both groups. Atrophy of the brain- atrophy of the cerebellar type (MSA-C) and idiopathic stem and middle cerebellar peduncles was significantly cerebellar ataxia with extracerebellar presentation more frequent in patients with MSA-C (PϽ.001). Hy- (IDCA-P) represent distinct entities. perintensities of infratentorial structures were common in patients with MSA-C (middle cerebellar peduncles: Objective: To investigate the discriminative validity of 87%; pons: 97%) but were absent in patients with IDCA-P. magnetic resonance imaging in sporadic cerebellar ataxia. Hypointensities or hyperintensities of basal ganglia struc- tures did not reliably differentiate the groups. Design: Basal ganglia and infratentorial structures were screened for signal abnormalities and atrophic changes. Conclusions: Patients with MSA-C were characterized Magnetic resonance imaging raters were masked to the by a higher frequency and severity of magnetic reso- clinical diagnosis. nance imaging abnormalities (atrophic changes and ad- ditional hyperintense signal changes) of the middle cer- Setting: Outpatient clinic of a university hospital. ebellar peduncles and pons. The presence of these magnetic resonance imaging features points to the diag- Patients: Forty-one individuals were diagnosed as hav- nosis of MSA-C and helps differentiate MSA-C from other ing MSA-C (n=30) or IDCA-P (n=11) based on their clini- types of sporadic cerebellar ataxia with extracerebellar cal features. features.

Results: Shrinkage of the cerebellar vermis and hemi- Arch Neurol. 2005;62:981-985

HE TERM SPORADIC CEREBEL- may also be found in the putamen, cau- lar ataxia comprises a va- date , substantia nigra, and auto- riety of nonhereditary cer- nomic nuclei of the and in the ebellar syndromes of intermediolateral cell columns in the spi- unknown origin. Neuro- nal cord.2 Clinically, MSA is associated pathologicT features vary from isolated cer- with various combinations of cerebellar ebellar degeneration to combined neuro- ataxia, basal ganglia symptoms, and se- nal degeneration and in the inferior vere autonomic dysfunction.2 Many pa- olives, pons, and (olivopon- tients with MSA initially develop basal gan- tocerebellar atrophy).1 Clinically, pa- glia symptoms (MSA of the striatonigral tients may have a purely cerebellar syn- type [MSA-P]), whereas others start with drome (idiopathic cerebellar ataxia a cerebellar syndrome (MSA of the cer- [IDCA-C]) or additional extracerebellar ebellar type [MSA-C]). The question of Author Affiliations: features (IDCA-P). whether MSA-C and IDCA-P represent the Department of , Combined cerebellar and pontine at- same disease has been discussed contro- University of Ulm, Ulm rophy is also a neuropathologic hallmark versially in the literature.1,3-6 However, the (Dr Bürk); Departments of of multiple system atrophy (MSA), a spo- neuropathologic proof of this hypothesis Neurology (Drs Bürk, Schulz, radic and unrelentlessly progressive neu- has not yet been established. and Dichgans) and rodegenerative disorder that leads to in- Modern imaging techniques allow mor- Neuroradiology (Dr Bühring), University of Tübingen, capacity and a reduced life expectancy. phologic studies of central nervous sys- Tübingen; and Institute of Apart from glial cytoplasmic inclusions, tem structures in vivo. The presence of pu- Human Genetics, University of neuropathologic changes are not re- taminal and infratentorial signal changes Lübeck, Lübeck (Drs Zühlke stricted to the inferior olives, pontine nu- has been considered to be predictive of the and Hellenbroich), Germany. clei, and Purkinje cells in MSA brains but diagnosis of MSA-P with respect to Par-

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 kinson disease and other basal ganglia disorders.7,8 In- hypotension (orthostatic decline of Ն30 mm Hg in systolic blood fratentorial signal changes, especially cruciform signal ab- pressure immediately [0 minutes] after having been supine for normalities in the pons on T2- and proton-weighted 5 minutes and 3 minutes after assumption of the upright po- magnetic resonance images (MRIs) (the “cross sign”) that sition). Diagnosis of the parkinsonian syndrome required at least are thought to result from degeneration of pontine neu- 2 of the following features: akinesia, rigidity, tremor, and poor or no response to levodopa therapy. The finding of dementia rons and transverse , have been or limited gaze excluded the diagnosis of MSA-C. claimed to be highly predictive of the diagnosis of MSA. 2. Cerebellar ataxia with additional extracerebellar fea- On the other hand, these signal abnormalities have been tures (IDCA-P): Patients with extracerebellar symptoms who documented in several types of hereditary olivoponto- did not fulfill the criteria for MSA, in particular without auto- cerebellar atrophy.9,10 The predictive value of qualita- nomic failure. tive variables has, therefore, been questioned.11 The present study was undertaken to investigate the MRI STUDIES discriminative validity of MRI signal changes in various types of sporadic cerebellar ataxia. To address this ques- All MRI measurements were performed using a 1.5-T scanner tion, basal ganglia and infratentorial structures were (Magnetom Vision; Siemens AG, Erlangen, Germany) with a screened for the presence of hypointense and hyperin- standard coil. Two MRI series were acquired. We scanned tense MRI signal abnormalities and atrophic changes in a 3-dimensional Fourier transform fast low-angle shot se- 41 patients with sporadic cerebellar ataxia. Individuals quence that produced isotropic T1-contrasted image sets in high were diagnosed as having MSA-C or IDCA-P based on resolution (repetition time, 15 milliseconds; echo time, 5 mil- their clinical features. liseconds; flip angle, 30°; number of excitations, 1; section thick- ness, 0.9 mm; and pixel size, 0.9ϫ 0.9 mm). A double- contrast 2-dimensional Fourier transform turbo spin echo was METHODS acquired twice in interleaved section positions to obtain a gap- less set of images (repetition time, 5800 milliseconds; echo time, PATIENTS 15/75 milliseconds; number of excitations, 2; section thick- ness, 2 mm; gap, 2 mm; and pixel size, 0.9ϫ0.9 mm). To investigate the differentiation of MSA-C and IDCA-P in pa- Fast low-angle shot images were used for cerebellar and brain- tients with cerebellar symptoms with clinical presentations as stem abnormalities, and signal changes were rated on T2- similar as possible, those with evidence of cognitive impair- weighted images. Anonymous images were evaluated indepen- ment were excluded from the study (dementia has to be ab- dently by 2 experienced raters (K.B. and U.B.). In cases of sent in MSA according to the Guideline of the International Con- differing evaluations, the images were reanalyzed by both rat- sensus Statement of MSA2). Forty-six patients with cerebellar ers and consensus was reached. Qualitative and semiquantita- symptoms (mean±SD age, 60.5±7.2 years; age range, 41-75 tive analyses of central nervous system structures were per- years; mean±SD age at onset, 54.8±8.5 years; age range at on- formed visually. set, 30-70 years; mean±SD disease duration, 5.7±3.6 years; range T2-weighted axial MRIs were screened for the presence of of disease duration, 1-19 years) fulfilled the following inclu- (1) signal hypointensity of the , (2) signal hy- sion criteria: (1) chronic progressive cerebellar dysfunction; (2) pointensity of the substantia nigra, (3) signal hypointensity of disease onset after age 35 years (patients who were younger at the , (4) signal hyperintensities along the lateral onset were excluded because MSA-C usually starts after age 35 boundary of the putamen, (5) signal hyperintensities along the years2); (3) the absence of any neurodegenerative disorders in medial boundary of the putamen, and (6) signal hypointensi- relatives, no evidence of consanguinity of parents, and nega- ties of the putamen (defined as areas of signal intensity equal tive molecular genetic testing for Friedreich ataxia and spino- to or lower than the signal intensity of the globus pallidus). cerebellar ataxia types 1, 2, 3, and 6; and (4) the exclusion of The extent of the following variables was assessed semi- symptomatic causes of ataxia, such as gluten sensitivity, infec- quantitatively by applying scores of absent (score 0), mild (score tious disease, multiple sclerosis, paraneoplastic disease, dis- 1), moderate (score 2), and severe (score 3): cruciform signal ease of the thyroid, Wilson disease, hypovitaminosis, - hyperintensities in the pons (the cross sign) and signal hyper- ism, chronic anticonvulsive therapy, ischemia, or . intensities in the middle cerebellar peduncles on T2-weighted axial images; atrophy of the cerebellar vermis, atrophy of the cerebellar hemispheres, and atrophy of the brainstem on T1- CLINICAL RATING weighted sagittal images; and atrophy of the middle cerebellar peduncles on T1-weighted axial images. Individuals were examined using a standardized examination procedure. The severity of the cerebellar symptoms was rated on a scale from 0 (absent) to 5 (most severe).12 Age at onset STATISTICAL ANALYSIS was defined as the age at which the onset of motor symptoms was experienced by the patient. A software package (JMP; SAS Institute Inc, Cary, NC) was used for statistical analysis. Statistical comparisons of clinical and ␹2 CLASSIFICATION qualitative MRI variables were conducted using tests. The analysis of semiquantitative variables was performed using analy- sis of variance (ANOVA). Post hoc paired-group comparisons Patients were separated into the following diagnostic categories: were explored using the Tukey test or, in the case of nonpara- 1. Multiple system atrophy of the cerebellar type (MSA- metric distribution, the Wilcoxon rank sum test. Differences C): Patients fulfilling the modified criteria of the International were considered statistically significant at PϽ.05. For corre- Consensus Statement of MSA2: cerebellar ataxia with addi- lation studies of disability and semiquantitative MRI scores, tional severe autonomic failure or a parkinsonian syndrome un- Spearman rho was applied. To achieve a global significance level responsive or poorly responsive to levodopa therapy. Severe au- of 5%, P values were corrected by applying the modified Bon- tonomic failure was diagnosed based on the presence of postural ferroni-Holm adjustment.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 Table 1. Clinical Characteristics of the 41 Study Patients Table 2. Qualitative Abnormalities on T2-Weighted Magnetic Resonance Images Patients Patients With Patients, No. (%) With MSA-C IDCA-P P (n = 30) (n = 11) Value* MSA-C IDCA-P P (n = 30) (n = 11) Value* Age, mean ± SD, y 61 ± 4 57 ± 8 .04 Age at onset, mean ± SD, y 56 ± 4 49 ± 10 .002 Atrophy of the cerebellar vermis 30 (100) 10 (91) .09 Disease duration, mean ± SD, y 5 ± 3 8 ± 5 .009 Atrophy of the cerebellar 29 (97) 10 (91) .45 Cerebellar symptoms, No. (%) hemispheres Ͻ 15 (50) 2 (18) .07 Atrophy of the middle cerebellar 28 (93) 2 (18) .001 Cranial symptoms, No. (%) peduncles Ͻ Spontaneous nystagmus 2 (7) 4 (36) .02 Brainstem atrophy 30 (100) 2 (18) .001 Gaze-evoked nystagmus 23 (77) 9 (82) .72 Hypointensity of the dentate 17 (57) 0 .001 Impaired smooth pursuit 30 (100) 11 (100) NA nuclei Pale discs 2 (7) 2 (18) .27 Hypointensity of the red nucleus 2 (7) 0 .38 Double vision 7 (23) 4 (36) .40 Hypointensity of the substantia 2 (7) 0 .38 nigra Gaze palsy 0 2 (18) .02 Hyperintensities of the lateral 13 (43) 5 (46) .90 Slowed horizontal saccades 8 (27) 1 (9) .23 putamen Square wave jerks 5 (17) 0 .15 Hyperintensities of the medial 3 (10) 0 .28 Facial atrophy 2 (7) 0 .38 putamen Dysphagia 18 (60) 4 (36) .18 Hypointensity of the putamen 6 (20) 0 .11 Hypacusis 4 (13) 6 (55) .007 Atrophy of the cervical spinal 1 (3) 0 .54 Autonomic dysfunction, No. (%) cord Postural hypotension 25 (83) 0 Ͻ.001 Cross sign 29 (97) 0 Ͻ.001 Bladder dysfunction 27 (90) 6 (55) .01 Hyperintensities of the middle 26 (87) 0 Ͻ.001 Sleep behavior disorders 23 (77) 3 (27) .004 cerebellar peduncles Constipation 19 (63) 2 (18) .01 Motor signs, No. (%) Abbreviations: IDCA-P, idiopathic cerebellar ataxia with extracerebellar Myoclonus 1 (3) 1 (9) .45 presentation; MSA-C, multiple system atrophy of the cerebellar type. Akinesia 16 (53) 0 .002 *Using the ␹2 test. Boldface entries indicate statistical significance. Rigidity 20 (67) 0 Ͻ.001 Dystonia 4 (13) 1 (9) .71 Reduced tendon reflexes 7 (23) 2 (18) .72 Muscle fasciculations 4 (13) 2 (18) .70 CLINICAL FEATURES Amyotrophy 2 (7) 0 .38 Pyramidal tract signs 20 (67) 4 (36) .08 Muscle cramps 8 (27) 6 (55) .10 All patients had ataxia of stance, gait, and limbs and dys- Sensory system symptoms, No. (%) arthria (Table 1). Although impaired smooth pursuit and Impaired 21 (70) 7 (64) .70 gaze-evoked nystagmus were present in both cerebellar Impaired exteroception 4 (13) 2 (18) .70 groups, spontaneous nystagmus was uncommon in MSA-C. Autonomic dysfunction (bladder dysfunction, Abbreviations: IDCA-P, idiopathic cerebellar ataxia with extracerebellar presentation; MSA-C, multiple system atrophy of the cerebellar type; NA, not sleep behavior disorders, and constipation) was a char- applicable. acteristic finding in the MSA-C group but could also been *Using the ␹2 test. Boldface entries indicate statistical significance. found in the IDCA-P group. Pyramidal tract signs and sensory deficits were found in both groups.

MRI VARIABLES

RESULTS Qualitative Analysis

PATIENT CHARACTERISTICS Shrinkage of the cerebellar vermis and hemispheres was found in both groups. Atrophy of the brainstem and Thirty patients fulfilled the diagnostic criteria for MSA-C. middle cerebellar peduncles was statistically signifi- Eleven patients had extracerebellar features that did not cantly more frequent in patients with MSA-C than in those correspond to the diagnostic criteria of MSA-C. The char- with IDCA-P (Table 2). Nearly all patients with MSA-C acteristics and clinical features of the patients are given showed hyperintensities of the middle cerebellar pe- in Table 1. The mean age at clinical examination dif- duncles and pons, whereas these features were absent in fered between groups, with patients with MSA-C being individuals clinically diagnosed as having IDCA-P. Sig- older than those with IDCA-P (ANOVA: F1,39=4.2996; nal reduction was found in approximately half of the pa- P=.04). Patients with MSA-C were also significantly older tients with MSA-C but not in those with IDCA-P. Hypo- at the perceived onset of motor symptoms than those with intensities of the red nucleus, substantia nigra, and IDCA-P (ANOVA: F1,39=11.3780; P=.002). In patients putamen and hyperintensities of the medial putaminal with IDCA-P, the mean disease duration was signifi- border occurred in a small proportion of patients with cantly longer than in those with MSA-C (ANOVA: F1, 39= MSA-C. The distribution of hyperintensities of the lat- 7.5693; P=.009). eral parts of the putamen did not differ between groups.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 Table 3. Correlation Analysis of Disability Scores and Semiquantitative MRI Features

Disability Score

MRI Feature Stance Gait Dysarthria Atrophy of the cerebellar r = 0.44, r = 0.45, r = 0.54, vermis P = .004 P = .003 PϽ.001 Atrophy of the cerebellar r = 0.51, r = 0.53, r = 0.46, hemispheres PϽ.001 PϽ.001 P = .002 Atrophy of the middle r = 0.54, r = 0.56, r = 0.54, cerebellar peduncles PϽ.001 PϽ.001 PϽ.001 Brainstem atrophy r = 0.53, r = 0.56, r = 0.53, PϽ.001 PϽ.001 PϽ.001 Cross sign r = 0.40, r = 0.41, r = 0.36, P = .01 P = .008 P = .02 Hyperintensities of the r = 0.51, r = 0.57, r = 0.53, cerebellar peduncles PϽ.001 PϽ.001 PϽ.001

Abbreviation: MRI, magnetic resonance imaging.

Table 4. Correlation Analysis of Basal Ganglia Symptoms and Qualitative Magnetic Resonance Imaging Features Figure. Axial T2-weighted magnetic resonance image showing severe atrophy and hyperintensities of the middle cerebellar peduncles and pons.

Rigidity Akinesia Correlation Studies Hypointensity of the putamen r = 0.42, r = 0.52, P = .006 PϽ.001 Hyperintensities of the medial NA r = 0.35, There was a statistically significant positive correlation putamen P = .02 between disability and semiquantitative MRI scores for all anatomic structures studied (Table 3). Putaminal sig- Abbreviation: NA, not applicable. nal abnormalities were positively correlated with rigor and akinesia (Table 4). In a single patient with MSA-C, there was evidence of additional atrophy of the cervical . Examples of MRI Findings

Semiquantitative Analysis The Figure shows characteristic findings with atrophy of the brainstem and middle cerebellar peduncles, with Analysis of semiquantitative variables yielded signifi- additional signal hyperintensities on T2-weighted MRIs cant group differences between MSA-P and IDCA-P for in patients with MSA-C. the vermis (ANOVA: F1,39=3.5061; P =.07), hemi- spheres (ANOVA: F1,39=4.6923; P =.04), brainstem COMMENT Ͻ (ANOVA: F1,39=78.5212; P .001), and middle cerebel- Ͻ lar peduncles (ANOVA: F1,39=32.8775; P .001). Group It had been a matter of a long-standing discussion whether differences were even more pronounced for the com- IDCA-P represents a variation of MSA-C.1,3-6 In the lit- parison of T2 hyperintensities of infratentorial struc- erature, it is commonly assumed that not all cerebellar tures (ANOVA: pons, F1,39=50.1381; and middle cerebel- disorders with extracerebellar symptoms will evolve to Ͻ 3 lar peduncles, F1,39=27.5202; P .001 for both). MSA-C despite the fact that the final neuropathologic The rating scores for the degree of both cerebellar struc- proof for the existence of at least 2 independent disor- tures were higher for patients with MSA-C (vermis: me- ders is still lacking. Gilman et al3 estimated that approxi- dian, 2; range, 1-3; hemispheres: median, 2; range, 0-3) mately 25% of patients with sporadic ataxia with extra- than for those with IDCA-P (vermis: median, 1; range, cerebellar involvement will develop MSA-C within 5 years 0-3; hemispheres: median, 1; range, 0-3) (vermis: P=.13; of the onset of cerebellar symptoms. The predictive va- hemispheres: P=.03). Higher rating scores were also ob- lidity of any clinical or functional characteristics has not tained in patients with MSA-C for atrophy of the brain- been established to date. Electromyographic evidence of stem (MSA-C: median, 2; range, 1-3; IDCA-P: median, chronic reinnervation of the external sphincter has been 0; range, 0-1; PϽ.001) and middle cerebellar peduncles recommended to support the diagnosis of MSA,13 but its (MSA-C: median, 2; range, 0-3; IDCA-P: median, 0; range, validity in MSA-C still remains to be established. Posi- 0-1; PϽ.001). Median scores of hyperintensities in the tron emission tomography studies may provide evi- pons and middle cerebellar peduncles were 1.5 (range, dence of reduced dopamine D2 receptor density, thus re- 0-3) in patients with MSA-C. The latter signal abnor- flecting degeneration of striatal in MSA.14 These malities were not documented in patients with IDCA-P. investigations, however, require extensive technical pre- Therefore, group differences were highly significant for requisites and are not necessarily significant in all pa- these 2 variables (PϽ.001 for both). tients with MSA.

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©2005 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/04/2021 The present MRI analysis thus gives further support script: Bürk, Bühring, Zühlke, and Dichgans. Critical re- to the hypothesis that MSA-C and IDCA-P represent dis- vision of the manuscript for important intellectual content: tinct neurodegenerative disorders because patients with Bürk, Bühring, Schulz, Hellenbroich, and Dichgans. Sta- cerebellar symptoms clinically diagnosed as having tistical analysis: Bürk and Schulz. Administrative, techni- IDCA-P and MSA-C were shown to be characterized by cal, and material support: Bühring, Zühlke, and Hellen- distinct MRI features. There was substantial cerebellar broich. Study supervision: Schulz and Dichgans. atrophy in both groups, whereas atrophy of the brain- Correspondence: Katrin Bürk, MD, Institute of Brain Re- stem and middle cerebellar peduncles was found to be search, University of Tübingen, Calwerstr 3, D-72076 more frequent and more pronounced in patients with Tübingen, Germany ([email protected]). MSA-C. In patients with MSA-C, infratentorial atrophy was typically associated with signal hyperintensities in REFERENCES the pons and middle cerebellar peduncles. Similar ab- 15 normalities were first described by Savoiardo et al in a 1. Gilman S, Quinn NP. The relationship of multiple system atrophy to sporadic ol- heterogeneous group of sporadic and hereditary atax- ivopontocerebellar atrophy and other forms of idiopathic late onset cerebellar ias. Pontine cruciform signal changes are thought to be atrophy. Neurology. 1996;46:1197-1199. contingent on differential involvement of pontocerebel- 2. Gilman S, Low PA, Quinn N, et al. 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