Journal of Clinical Neuroscience 21 (2014) 1002–1006

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Clinical Study

Profile of extrapyramidal manifestations in 85 patients with spinocerebellar ataxia type 1, 2 and 3 Ketan Jhunjhunwala a, M. Netravathi a, Meera Purushottam b, Sanjeev Jain b, Pramod Kumar Pal a,⇑ a b

Department of Neurology, National Institute of Mental Health & Neurosciences, Hosur Road, Bangalore 560029, Karnataka, India Department of Psychiatry, National Institute of Mental Health & Neurosciences, Bangalore, Karnataka, India

a r t i c l e

i n f o

Article history: Received 11 July 2013 Accepted 5 October 2013

Keywords: Dystonia Extrapyramidal signs Movement disorders Parkinsonism Spinocerebellar ataxia Tremor

a b s t r a c t This study aimed to determine the prevalence and type of extrapyramidal signs (EPS) in spinocerebellar ataxia (SCA) type 1, 2 and 3. Eighty-five patients with genetically confirmed SCA (SCA1 = 40, SCA2 = 28, SCA3 = 17) were evaluated for the prevalence and types of EPS. Forty-one SCA patients (48.2%) had one or more types of EPS. The prevalence of EPS was 60.7% in SCA2, 52.9% in SCA3, and 37.5% in SCA1. Among SCA2 patients, bradykinesia was the most frequent (35.3%), followed by reduced facial expression, postural tremor and dystonia (29.4% each), rest tremor, titubation and rigidity (23.5% each), and lip/ jaw tremor and chorea (11.8% each). In SCA3 the common EPS were bradykinesia (44.4%), staring look, postural tremor and dystonia (33.3% each), and reduced facial expression and rigidity (22.2% each). In SCA1, staring look was the most common (53.3%), followed by dystonia and bradykinesia (33.3% each), and postural tremor (26.7%). In all three groups, there was no significant difference in the mean length of repeat of the abnormal allele between those with and without EPS. To conclude bradykinesia, staring look, dystonia and postural tremor were the most frequent EPS observed in SCA. In SCA1, these signs were seen more often in younger patients with early onset of symptoms. Ó 2013 Elsevier Ltd. All rights reserved.

1. Introduction The spinocerebellar ataxias (SCA) are a heterogeneous group of inherited disorders characterized by progressive ataxia. They were previously known as autosomal dominant cerebellar ataxias. Currently, SCA consist of 36 genetically distinct progressive neurodegenerative disorders [1]. The more prevalent types of SCA – SCA1, SCA2, SCA3 and SCA6 – are caused by expansion of a CAG repeat that encodes a polyglutamine tract in the affected protein [2]. SCA type 1, 2 and 3 are late onset autosomal dominant neurodegenerative disorders characterized by cerebellar ataxia associated with variable degrees of oculomotor abnormalities, pyramidal and extrapyramidal features, peripheral neuropathy, and cognitive impairment. Various types of hypokinetic and hyperkinetic movement disorders are reported among SCA. In fact, movement disorders appear to be very common in SCA. Except for tics, all types of movement disorders can been observed in many types of SCA [3]. A variety of extrapyramidal signs (EPS) have been reported in SCA2 and SCA3, but less often in SCA1 [4]. In some patients, a non-ataxia manifestation may be the dominant or presenting feature, which ⇑ Corresponding author. Tel.: +91 80 2699 5147; fax: +91 80 2656 4830. E-mail address: [email protected] (P.K. Pal). http://dx.doi.org/10.1016/j.jocn.2013.10.021 0967-5868/Ó 2013 Elsevier Ltd. All rights reserved.

at times presents a diagnostic challenge. Some movement disorders are more often seen in a specific subtype of SCA, and this knowledge may help in prioritizing genetic analysis for the patient [3]. Parkinsonian features are more common in SCA2 [5] and a Huntington’s chorea-like presentation is more common in SCA17 [6]. When cerebellar ataxia is mild or even absent, SCA may not at first glance be suspected as a possible cause. Cerebellar atrophy on brain imaging or a family history suggesting dominant disease are useful clues in clinical practice to raise suspicion of SCA. In a patient with an isolated movement disorder without cerebellar ataxia, genetic mutation testing should be carefully selected due to the low yield of these tests, with the two exceptions of SCA2 and SCA17 [3]. SCA17 is caused by the expansion above 44 units of a CAG/CAA repeat in the coding region of the TATA box binding protein (TBP) gene leading to an abnormal expansion of a polyglutamine stretch in the corresponding protein. SCA2 is a CAG repeat disorder leading to abnormal expression of the ATXN 2 gene resulting in abnormal ataxin 2 protein. There are sparse data on EPS in large cohorts of SCA patients from a single ethnic group in the literature. It is also not clear if EPS correlate with age at symptom onset or the size of repeat lengths of the abnormal allele. The aims of our study were to (i) determine the prevalence and type of EPS in SCA type 1, 2 and 3, (ii) compare the findings between the patients with SCA1, SCA2,

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and SCA3, and (iii) determine whether the length of the CAG repeat, age at disease onset or disease duration correlate with EPS in a specific SCA.

Table 1 Demographics of patients with spinocerebellar ataxia type 1, 2 and 3

Women:Men Age, years AAO, years Duration

2. Subjects and methods 2.1. Patients This study was conducted in the Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India. It was approved by the Institute’s Ethics Committee, NIMHANS. The nature and design of the study was explained to patients and informed consent was obtained. All patients who had signs of cerebellar dysfunction with or without a positive family history were first clinically evaluated by a movement disorder specialist and then genetic testing was carried out to characterize the type of SCA. After informed consent was given, DNA was extracted from samples of peripheral blood leukocytes. All patients were genetically tested for the trinucleotide repeat expansions causing SCA1, SCA2 and SCA3 using a previously reported method [7]. 2.2. Clinical evaluation A detailed clinical evaluation was performed in each patient prior to genetic testing. Emphasis was given to the accurate and detailed documentation of EPS in addition to cerebellar and other neurological signs. The severity of ataxia was assessed in the majority of patients using the International Cooperative Ataxia Rating Scale (ICARS). The following EPS were specifically examined: rigidity, bradykinesia, reduced facial expression, staring look (bulging eyes), rest and action tremor, head, lip and jaw tremor (in addition to intention tremor of cerebellar dysfunction), myoclonic jerks, dystonia, athetosis and chorea. Eighty-five patients who were found to be positive for SCA1, 2 and 3 were taken for analysis in the current study (SCA1 = 40, SCA2 = 28, SCA3 = 17). The prevalence and characterization of EPS and a comparison of those with and without EPS were done for each type of SCA. 2.3. Statistical analysis The demographics and clinical characteristics of the patients with and without EPS were compared using unpaired t-tests. Comparative analysis of the prevalence of different types of EPS among the three subgroups of SCA was performed using the chi-squared test and Fisher’s exact test. Results are reported as mean ± standard deviation.

SCA1 (n = 40)

SCA2 (n = 28)

SCA3 (n = 17)

20:65 36.2 ± 12.5 31.1 ± 12.1 5.2 ± 4.5

10:30 35.3 ± 12.1 30.4 ± 10.3 5.1 ± 5.0

5:23 34.1 ± 14.1 28.5 ± 14.1 5.7 ± 4.4

5:12 40.2 ± 8.8 36.2 ± 10.9 4.4 ± 3.1

Data are presented as mean ± standard deviation. AAO = age at onset of symptoms, SCA = spinocerebellar ataxia.

each). In SCA3 the common EPS were bradykinesia (44.4%), staring look, postural tremor and dystonia (33.3% each), and reduced facial expression and rigidity (22.2% each) (Table 2). 3.1. Prevalence of different types of EPS in SCA1, 2 and 3 3.1.1. Dystonia Thirteen of the 85 patients (15.2%) had evidence of dystonia, which was seen more often in SCA2 (17.9%) and SCA3 (17.6%) than in SCA1 (12.5%), though the difference was not statistically significant. Types of dystonia included five patients with generalized dystonia (SCA1 = 1, SCA2 = 1, SCA3 = 3), three patients with dystonia of the neck (one each in each SCA), three patients with facial dystonia in the form of grimacing (SCA1 = 2, SCA2 = 1), and one patient of SCA2 with lingual and foot dystonia. Using Fisher’s exact test, there was no significant difference between SCA type 1, 2 and 3 for the presence of focal dystonia. 3.1.2. Rigidity Only six patients (7.1%) had rigidity of their limbs. Rigidity was found in four (14.3%) SCA2 patients and in two (11.3%) SCA3 patients, but no rigidity was seen in the SCA1 group (p = 0.01 for SCA2 versus SCA1, and p = 0.03 for SCA3 versus SCA1). 3.1.3. Bradykinesia Fifteen patients (17.6%) had appendicular and generalized bradykinesia. The sign was most often seen in SCA3 (n = 4, 23.5%) and SCA2 (n = 6, 21.4%) patients and was less common in SCA1 (n = 5, 12.5%). The differences were not statistically significant. 3.1.4. Tremor Rest tremor was uncommon in SCA (4.7%) and all four patients with rest tremor belonged to the SCA2 group (14.3%; p = 0.01 for SCA2 versus SCA1). Postural tremor was present in 13 patients

Table 2 Extrapyramidal signs in patients with spinocerebellar ataxia type 1, 2 and 3

3. Results Men (76.5%) outnumbered women (23.5%) in our cohort of 85 patients with SCA. The mean age of the group was 35.6 ± 12.4 years, and the mean disease duration at the time of evaluation was 5.2 ± 4.5 years. The mean age, age at onset and disease duration in the three SCA groups were comparable (Table 1). Forty-one patients (48.2%) had one or more types of EPS. EPS was present in 17 SCA2 patients (60.7%), nine SCA3 patients (52.9%) and 15 SCA1 patients (37.5%). In patients with EPS in SCA1, staring look was the most common (53.3%), followed by dystonia and bradykinesia (33.3% each), and postural tremor (26.7%). Among EPS in SCA2, bradykinesia was the most frequent (35.3%), followed by reduced facial expression, postural tremor and focal or segmental dystonia (29.4% each), rest tremor, titubation and rigidity (23.5% each), and lip/jaw tremor, chorea and jerks (11.8%

SCA (n = 85)

Any EPS Dystonia Rigiditya Bradykinesia Rest tremorb PT Lip tremor Chorea Titubationb Head thrust Staring look Hypomimiac a

SCA (n = 85)

SCA1 (n = 40)

SCA2 (n = 28)

SCA3 (n = 17)

41 (48.2) 13 (15.2) 6 (7.1) 15 (17.6) 4 (4.7) 13 (15.3) 3 (3.5) 2 (2.3) 4 (4.7) 1 (1.2) 14 (16.5) 8 (9.4)

15 (37.5) 5 (12.5) 0 (0) 5 (12.5) 0 (0) 4 (10) 0 (0) 0 (0) 0 (0) 1 (2.5) 8 (20) 1 (2.5)

17 (60.7) 5 (17.9) 4 (14.3) 6 (21.4) 4 (14.3) 6 (20.9) 2 (7.1) 2 (7.1) 4 (14.3) 0 (0) 3 (10.7) 5 (17.9)

9 3 2 4 0 3 1 0 0 0 3 2

(52.9) (17.6) (11.3) (23.5) (0) (17.6) (5.9) (0) (0) (0) (23.5) (11.8)

SCA1 versus SCA2 (p = 0.01), SCA1 versus SCA3 (p = 0.03). SCA1 versus SCA2 (p = 0.01). SCA1 versus SCA2 (p = 0.04). Data are presented as n (%). EPS = extrapyramidal sign, PT = postural tremor, SCA = spinocerebellar ataxia. b

c

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(15.3%), and was most commonly seen in SCA2 patients (n = 6, 20.9%), followed by SCA3 patients (n = 3, 17.6%) and was seen least frequently in SCA1 patients (n = 4, 10%). Three patients had lip tremor (two SCA2 [7.1%] patients and one SCA1 patient [5.9%]).

Table 4 Comparison of spinocerebellar ataxia patients with and without extrapyramidal signs

3.1.5. Reduced facial expression Hypomimia was observed in only 9.4% of SCA patients. This was most often seen in SCA2 patients (n = 5, 17.9%) followed by SCA3 patients (n = 2, 11.8%) and was least frequent in SCA1 (n = 1, 2.5%). The difference between SCA2 and SCA1 was statistically significant (p = 0.04). 3.1.6. Staring look Fourteen patients (16.5%) had a staring look, and this feature was seen most often in SCA1 patients (n = 8, 20%), followed by SCA3 patients (n = 3, 23.5%) and was seen least often in SCA2 patients (n = 3, 10.7%). 3.1.7. Titubation Four patients (14.3%) with SCA2 had titubation which was absent in the other two SCA groups (p = 0.01 for SCA2 versus SCA1). 3.1.8. Chorea Two patients (7.1%) with SCA2 had significant chorea but none of the other SCA patients had chorea.

EPS present

EPS absent

SCA1 Age, yearsa AAO, yearsb Duration, years RL ICARS

n = 10 30.1 ± 9.2 26.3 ± 7.3 3.9 ± 7.40 54 ± 7.3 38.5 ± 13.4

n = 19 38.5 ± 12.6 31.0 ± 12.0 5.9 ± 5.9 51.2 ± 6.2 29.3 ± 12.3

SCA2 Age, years AAO, years Duration, years RL ICARSc

n = 15 35.7 ± 15.7 30.2 ± 15.2 5.0 ± 4.1 44.2 ± 7.7 42.3 ± 12.5

n=9 31.7 ± 12.7 25.0 ± 12.1 6.8 ± 5.0 41.9 ± 3.9 27.4 ± 11.8

SCA3 Age, years AAO, years Duration, years RL ICARS

n=7 41.4 ± 7.4 9.7 ± 7.1 3.0 ± 2.1 71.2 ± 1.2 24.5 ± 10.0

n=7 39.1 ± 10.3 33.3 ± 13.2 5.9 ± 3.4 72.6 ± 3.5 27.2 ± 12.0

a

p = 0.03. p < 0.05. c p = 0.008. Data are presented as mean ± standard deviation. AAO = mean age at onset of disease, EPS = extrapyramidal signs, ICARS = International Cooperative Ataxia Rating Scale, RL = repeat length, SCA = spinocerebellar ataxia. b

4. Discussion 3.2. Clinical features other than EPS Slow saccades were present in 24 (85.7%) and jerky pursuits were present in seven (41.2%) SCA2 patients. These figures were significantly higher when compared with SCA1 patients, with 21 (52.5%) having slow saccades (p = 0.004) and eight (28.6%) having jerky pursuits (p = 0.01), and when compared with SCA3 patients, with six (35.3%) having slow saccades (p = 0.01) and 17 (20%) having jerky pursuits (p = 0.001) (Table 3). 3.3. Comparison of SCA patients with and without EPS SCA1 patients with EPS were significantly younger and had earlier onset of symptoms than those without EPS (age: 30.1 ± 9.2 versus 38.5 ± 12.6 years; p = 0.03; onset of symptoms: 26.3 ± 7.3 versus 31.0 ± 12.0 years, p < 0.05). In SCA2 and SCA3 subtypes, these differences were not significant. In SCA2 patients, the severity of ataxia as rated by ICARS was significantly higher in those with EPS compared to those without EPS (42.3 ± 12.5 versus 27.4 ± 11.8; p = 0.008). The mean size of the repeat lengths of the abnormal allele between those with and without EPS was comparable in each subtype of SCA. The clinical details of the patients are provided in Table 4.

Table 3 Clinical features present in spinocerebellar ataxia other than extrapyramidal signs

Ataxia Pyramidal Autonomic Tonuge fasciculation Slow saccadesa Jerky pursuitb a

SCA

SCA1

SCA2

SCA3

85 25 13 12 51 32

40 (100) 12 (30) 4 (10) 7 (17.5) 21 (52.5) 8 (28.6)

28 (100) 8 (28.6) 5 (17.9) 3 (10.7) 24 (85.7) 7 (41.2)

17 (100) 5 (29.4) 4 (15.3) 2 (11.8) 6 (35.3) 17 (20)

(100) (29.4) (15.3) (14.1) (60) (37.6)

SCA1 versus SCA2 (p = 0.004), SCA2 versus SCA3 (p = 0.001). SCA1 versus SCA2 (p = 0.01), SCA1 versus SCA3 (p = 0.001). Data are presented as n (%). SCA = spinocerebellar ataxia. b

Classifying SCA into different subtypes poses a significant challenge. The advent of genetic testing for SCA has made it easy to classify these disorders, but doing the full profile of available tests is expensive and time consuming. Various imaging biomarkers have attempted to classify these disorders but none have been reported to be sufficiently specific. Conventional T1-weighted, T2weighted, and proton density weighted MRI sequences do not distinguish SCA subtypes [8]. Nonconventional imaging methods, such as voxel-based morphometry (VBM), diffusion tensor imaging and proton magnetic resonance spectroscopy, have been used with variable success [9]. Oz et al. attempted to differentiate SCA type 1, 2 and 6 by exploring the neurochemical differences using magnetic resonance spectroscopy in 4 Tesla scanners [8]. Advanced imaging techniques such as VBM and single-photon emission computed tomography have also been used to classify the cerebellar ataxias [10]. In our earlier studies we used VBM to characterize the patterns of atrophy in SCA1, SCA2 and SCA3 and to classify these three SCA subtypes [11]. We have looked into conventional electrophysiological techniques to characterize the peripheral nervous system [12] and evaluated cortical excitability using transcranial magnetic stimulation [13] to differentiate SCA type 1, 2 and 3. None of these techniques were sufficiently specific for subtyping SCA. Classifying these disorders is important in order to predict the prognosis of the disease. In this study we attempted to characterize SCA type 1, 2 and 3 by the prevalence and type of associated EPS. Approximately half of the patients with SCA had one or more type of EPS. The prevalence of EPS was highest in SCA2 (60.7%) followed by SCA3 (52.9%) and SCA1 (37.5%) patients, but there was no statistically significant difference between the three groups, probably due to the small sample size of SCA2 and SCA3. However, when the specific type of EPS was analyzed, there were differences in the prevalence of various EPS among the three subtypes of SCA. The prevalence of rigidity, hypomimia and rest tremor was highest in SCA2, and significantly greater when compared to SCA1. Lee et al. in their cohort of six SCA1, 17 SCA2 and 29 SCA3 patients, found EPS to be most common in SCA3 (53%) followed by SCA2 (12%), and found that no patients with SCA1 had EPS [14].

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4.1. Dystonia in SCA

4.3. Parkinsonism in SCA

Dystonia is a well known symptom in many SCA, including SCA17, SCA3 and SCA2 [15]. Focal and generalized dystonia have been reported in SCA. The presence of cervical dystonia as an initial manifestation is well documented in SCA1 and SCA2 [16]. Cervical dystonia appears to be a common clinical feature in SCA2 and may precede ataxia and gait disturbance [16]. Dragasevic et al. compared the clinical features of 33 SCA1 and nine SCA2 patients and found that SCA2 patients had significantly more dystonia (44.4%) compared to patients with SCA1 (9.1%) [17]. In SCA3, a dopa responsive dystonia-like presentation has been reported [18]. SCA3 should be considered as a differential diagnosis in adult patients who present with a dopa responsive dystonia phenotype and have a positive family history. However in our study neither the prevalence nor the type of dystonia could differentiate any particular SCA. Thirteen patients (15.3%) had dystonia and the prevalence of dystonia was similar in all the three groups. The type or pattern of dytonia did not differ significantly between the three groups of SCA. The involvement of the basal ganglia has been shown in all of these three SCA types by post mortem studies which correlate with the clinical findings [19,20]. The degree and extent of the involvement of these structures determine the predominant phenomenology of the clinical symptoms seen. In patho-anatomical studies of patients with SCA1, Rub et al. found neuronal loss in the primary motor cortex and degeneration of gray matter components of the basal forebrain, thalamus, brainstem, and cerebellum, as well as of white matter components in the cerebellum and brainstem [21]. SCA1 involved the motor cerebello-thalamocortical and basal ganglia-thalamocortical circuits [21]. These pathways have also been implicated in a patient with cervical dystonia [22]. In our study, the presence of dystonia in SCA1 patients correlates with the patho-anatomical studies of Rub et al. [21]. Patients with SCA2 and SCA3 have similar involvement of the cerebello-thalamocortical and basal ganglia-thalamocortical circuits on a larger scale as shown in autopsy studies [21]. These findings correlate with our observation of dystonia in these patients.

Parkinsonian features can be observed in SCA patients, most commonly in those with SCA2, SCA3 or SCA17 [23]. The spectrum varies from limb rigidity with a marked cerebellar syndrome to a levodopa-responsive, almost classic Parkinson’s disease-like picture without any cerebellar signs [3,5,27]. In our study, SCA2 patients predominantly had parkinsonian features such as rigidity, rest tremor and hypomimia. As explained above, this may be associated with the parkinsonism phenotype in SCA2 presenting more commonly in Asian populations compared to Caucasian populations [5]. Thalamic degeneration is known to occur in patients with SCA2 and SCA3 [28]. Thalamic integrity is crucial for the efficient performance of prefrontal, somatomotor and oculomotor basal ganglia circuits plus the thalamo-cortical and cerebello-thalamocortical circuits [28]. The functions of the affected thalamic nuclei provide an appropriate patho-anatomical explanation for some of the disease related symptoms seen in SCA2 and SCA3 patients: gait, stance, truncal and limb ataxia, dysarthria, dysdiadochokinesia and bradykinesia [28]. In our study we found rest tremor in patients with SCA2, but this was absent in patients with SCA3. The latter could have been due to short duration of illness in patients with SCA3 in our cohort (mean