1  

Cognitive and affective disturbances following focal cerebellar damage in

adults: A neuropsychological and SPECT study

Hanne Baillieux1, Hyo Jung De Smet1, André Dobbeleir2, Philippe F. Paquier1, 3, Peter P. De

Deyn 4, & Peter Mariën1, 4

1 Department of Linguistics, Vrije Universiteit Brussel, Brussels, Belgium 2 Department of Nuclear Medicine, ZNA-AZ Middelheim, Antwerp, Belgium and Universitair

Ziekenhuis Gent, Ghent, Belgium 3 Department of Neurology, Hôpital Universitaire Erasme ULB, Brussels, Belgium and Unit of

Neurosciences, Universiteit Antwerpen, Antwerp, Belgium 4Department of Neurology, ZNA-AZ Middelheim, Antwerp, Belgium and Laboratory of

Neurochemistry and Behaviour, Institute Born-Bunge, Universiteit Antwerpen, Antwerp,

Belgium

Correspondence address: Prof. Dr. Peter Mariën

ZNA - Middelheim

Department of Neurology

Lindendreef 1

B-2020 Antwerp

Belgium

Tel: 0032/3/280.31.36

Fax: 0032/3/281.37.48

E-mail: peter.marien5@telenet.be

Acknowledgements: This study was supported by grant G.0209.05 of the Fund for Scientific

Research – Flanders (F.W.O. – Vlaanderen), by Onderzoeksraad (OZR-VUB), by Nationale

Vereniging tot Steun aan Gehandicapte Personen (NVSG-ANAH), by Stichting Integratie

Gehandicapten (SIG), and by Deloitte Belgium.

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Abstract

The traditional view on cerebellar functioning has recently been challenged by results from

neuroanatomical, neuroimaging and clinical studies. In this contribution, eighteen patients with

primary cerebellar lesions (vascular: n=13; neoplastic: n=5) were systematically investigated by

means of an extensive neuropsychological test battery. Fifteen patients (83%) presented with a

broad variety of cognitive and linguistic deficits following cerebellar damage. Disturbances of

attention (72%), executive functioning (50%) and memory (50%) were most commonly found.

Analyses of our results tend to support the hypothesis of a lateralization of cognitive modulation

within the cerebellum, the right cerebellar hemisphere being associated with logical reasoning

and language processing and the left cerebellum mediating right-hemispheric functions including

attentional and visuo-spatial skills. In addition, nine patients (50%) presented with frontal-like

behavioural and affective alterations. In an attempt to determine the working-mechanism

underlying cerebellar induced cognitive and affective disturbances, all patients were investigated

by means of quantified ECD-SPECT studies. From a semiological point of view, damage to the

cerebellum can cause a broad spectrum of clinically significant cognitive and affective

disturbances. From a pathophysiological point of view, quantified SPECT data, reflecting the

phenomenon of cerebello-cerebral diaschisis, support the functional impact of the cerebellar

lesion on cortical functioning through disruption of cerebello-cerebral connections.

Keywords: cerebellum, adults, cognition, cognitive-affective syndrome, SPECT

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Introduction

At the beginning of the 20th century, neurophysiologists such as Luigi Rolando and

Marie-Jean-Pierre Flourens observed coordination difficulties, clumsiness and staggering gait

following isolated cerebellar ablation in animals (Fine et al., 2002). Additionally, Gordon Holmes

studied a family with hereditary cerebellar degeneration and described the family members as

small in stature with poor coordination and an unsteady walk. A decade later, Holmes (1922)

published his famous “Croonian Lectures” in which he reported hypotonia, dysmetria and

abnormal speech, characterized by an indistinct articulation in patients with acute cerebellar

lesions. As a result, coordination, balance and motor speech regulation were defined as the core

functions of the cerebellum. This view persisted during the 20th century.

Recently, however, results from neuroanatomical, neuroimaging and clinical studies have

challenged this traditional view on the cerebellum’s functions. Neuroanatomical studies have

shown bidirectional pathways between the cerebellum and cortical structures involved in

cognitive regulation. More specifically, the prefrontal cortex sends information to the cerebellum

via pontine nuclei, while the cerebellum sends information back to the prefrontal areas through

dentatothalamic pathways (Leiner et al., 1986; Middleton & Strick, 1994; Murdoch, this issue).

However, the functional implications of the cerebello-cerebral connectivity still evoke many

questions. There is no consistency with regard to the precise clinical consequences of acquired

cerebellar lesions and the pathophysiological substrate remains unclear. Numerous reports of a

broad variety of linguistic, cognitive and affective disturbances following isolated cerebellar

damage have been published (for a review see Baillieux et al., 2008). Clinical investigations of

patients with acquired cerebellar lesions have demonstrated cerebellar involvement in attentional

disturbances (Baillieux et al., 2006; Gottwald et al., 2004), executive dysfunctioning

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(Schmahmann & Sherman, 1998), visuo-spatial disturbances (Molinari et al., 2004) and a variety

of language disorders such as agrammatism (Silveri et al., 1994), anomia (Schmahmann &

Sherman, 1998), adynamia (Mariën et al., 1996) and reading/writing disorders (Vlachos et al.,

2007) (see De Smet et al., 2007 for a review).

In this contribution, we describe the neurocognitive symptoms and behavioural

characteristics of eighteen patients with isolated cerebellar damage. In addition, functional

neuroimaging by means of quantified ECD-SPECT studies was conducted to evaluate the

pathophysiological hypothesis that cerebellar-induced cognitive and affective disturbances

constitute a diaschisis phenomenon (Mariën et al., 1996, 2001; Baillieux et. al., 2006).

Method

Population

All patients with focal cerebellar lesions admitted to the neurology department of ZNA

AZ-Middelheim hospital between January 2006 and November 2007 were included in this study.

Exclusion criteria consisted of: 1) lesions involving cortical or subcortical non-cerebellar

damage, 2) a neurological status that did not allow reliable neurocognitive testing, 3) age younger

than 18 years, 4) a history of psychiatric disease and 5) a history of substance abuse. Approval by

the local Ethics Committee was obtained. All patients were given a standard neurological

evaluation within 24 hours of onset of the symptoms.

Neuroimaging

Each patient underwent structural neuroimaging by means of Computed Tomography

(CT) and/or Magnetic Resonance Imaging (MRI) scan on admission to determine the precise

localization and nature of the cerebellar lesion. Based upon the templates provided by Savoiardo

  5  

et al. (1987) and Cormier et al. (1992), vascular lesions were attributed to the following vascular

territories independently of the neuropsychological data: superior cerebellar artery (SCA),

posterior inferior cerebellar artery (PICA) or anterior inferior cerebellar artery (AICA). In

addition, a quantified Tc-99m-ECD SPECT study was administered in the acute phase and during

follow-up after onset of the cerebellar damage. Using a previously fixed butterfly needle 740

MBq (20 mCi) Tc-99m-ECD was administered to the patient sitting in a quiet and dimmed room,

eyes open and ears unplugged. Acquisition was started 40 min after injection using a three-

headed rotating gamma camera system (Triad 88; Trionix Research Laboratory, Twinsburg,

Ohio, USA) equipped with lead super-fine fanbeam collimators with a system resolution of 7.3

mm FWHM (rotating radius 13 cm). Projection data were accumulated in a 128 x 64 matrix,

pixel size 3.56 mm, 15 seconds per angle, 120 angles for each detector (3° steps, 360° rotation).

Projection images were rebinned to parallel data, smoothed and reconstructed in a 64 x 64 matrix,

using a Butterworth filter with a high cut frequency of 0.7 cycles/cm and a roll-off of 5. No

attenuation or scatter correction was performed. Trans-axial images with a pixel size of 3.56 mm

were anatomically standardized using SPM and compared to a standard normal and SD image

obtained from 15 normal ECD perfusion studies in healthy adults. Using a 31 ROI template, the

z-scores (SD) were then calculated for each region. A regional z-score of >2.0 was considered

significant.

Neuropsychological assessment

All patients were extensively investigated by means of a neuropsychological protocol.

Patients with vascular lesions were evaluated following the time frame model of Mazzochi &

Vignolo (1979) for the study of vascular aphasia and were examined during the lesion phase with

an average of 30 days following onset of the cerebellar lesion. Follow-up examinations were

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conducted during the late phase with an average of 6 months and 24 days post-onset. Patients

with cerebellar tumours were investigated before the surgical resection of the tumour and with an

average of 3 weeks after removal of the tumour.

The Wechsler Memory Scale-Revised (Wechsler, 1987) was administered to assess

general memory skills in patients below 74 years of age. Patients above the age of 74 were tested

with the Hierarchic Dementia Scale (HDS, Cole & Dastoor, 1983) or the Repeatable Battery for

the Assessment of Neuropsychological Status (R-BANS, Randolph, 1998). In addition, executive

functioning and problem solving were investigated by means of the Wisconsin Card Sorting Test

(WCST) (Heaton et al., 1993), the Stroop Color-Word Test (Hammes, 1971), and the

Trailmaking Test (Reitan, 1958). The D2 test of attention (Brickenkamp & Zilmer, 1998) was

used to evaluate visual-motor attention and a copy of the Rey-Osterrieth Figure (Osterrieth, 1944)

was used to examine visuo-constructive praxis. Working memory was assessed by verbal and

visual memory spans (WMS-R), while the Raven Matrices tests (Raven Progressive and Raven

Coloured) were used to evaluate non-verbal problem solving (Raven, 1938, 1958).

Neurolinguistic assessments consisted of a semantic verbal fluency test (1 minute generation of

four semantic categories: animals, transportation, vegetables and clothing; unpublished norms)

and the Boston Naming Test (BNT) (Kaplan et al., 1983; Mariën et al., 1998). In addition, to

evaluate possible behavioural-affective abnormalities and personality changes, the patient’s

behaviour and emotional coping were observed and family members of all patients were

interviewed.

Results

Group characteristics

Demographic data

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Eighteen patients matching our criteria were included in the study. Demographic

characteristics and neurological symptoms are summarized in Table 1.

Insert Table 1 near here

Twelve patients were men with an average age of 64 years (X=63.6; SD=11; range 50-88)

and six patients were women with an average age of 67 years (X=67.1; SD=12; range 50-86). All

patients were right-handed as formally assessed by the Edinburgh Handedness Inventory

(Oldfield, 1971).

Lesion localization

Eight patients (patients 1 to 8) presented with right-sided cerebellar lesions, of whom six

patients had a vascular lesion: three were located in the PICA territory (patient 2, 3, 6; Figure

1A), while three patients presented with lesions in the SCA territory (patient 1, 4, 5; Figure 1B).

Two patients presented with a right-sided cerebellar tumour (patient 7 and 8).

Insert Figure 1A-B-C near here

Six patients (patients 9 to 14) had lesions confined to the left cerebellar hemisphere, of

whom five patients presented with vascular lesions: four located in the PICA territory (patient 10,

11, 13, 14; Figure 2A), while one patient had an infarction in the SCA territory (patient 9). MRI

in one patient showed a left cerebellar tumour (patient 12; Figure 2B).

Insert Figure 2A-B

One patient (patient 14) presented with bilateral cerebellar infarctions in the SCA

territory.

In addition, three patients presented with lesions confined to the vermis (AVM rupture in

patient 17 and tumours in patient 16 and 18; Figure 3).

Insert Figure 3 near here

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Neuropsychological results

Three patients (patients 3, 5 and 8) obtained normal neuropsychological and

neurolinguistic results and had no affective disturbances. Analysis of neuropsychological data

revealed cognitive symptoms and/or behavioural-affective abnormalities in fifteen patients

(83%). Statistical analysis by means of the chi-square test revealed no significant relation

between gender and neuropsychological outcome (Pearson χ2=1.80; p=0.18). Cognitive and

affective symptoms are summarized in Table 2.

Insert Table 2 near here

Speech was characterized by dysarthria and an indistinct articulation in nine patients

(50%; patient 1, 2, 4, 5, 7, 13-15, 17). Comprehension however was normal in all patients.

Language symptoms mostly consisted of naming deficits (22%; patient 1, 4, 13, 15) and disturbed

semantic verbal fluency (39%; patient 1, 2, 4, 7, 13, 15, 18). Two patients (patients 4 and 15)

presented with apractic agraphia. No ideomotor or ideational apraxia was found in any of the

patients.

Executive dysfunction (disturbed divided attention, mental flexibility, problem solving

and organization skills) was found in nine patients (50%; patient 1, 2, 4, 7, 10, 13, 16, 17, 18). In

addition, attentional deficits were present in thirteen patients (72%; patient 1, 2, 4, 7, 9-17). Five

patients presented with visuo-spatial disturbances including disrupted non-verbal problem-

solving (28%; patient 1, 9, 10, 13, 14). Verbal memory as assessed by WMS-R was disturbed in

five patients (28%, patient 2, 4, 7, 14, 18) and deficient recent memory (WMS-R) was found in

four patients (22%; patient 2, 6, 14, 18). In addition, a disruption of verbal working memory as

assessed by verbal memory span (WMS-R) was found in four patients (22%; patient 1, 2, 4, 7).

Two patients presented with abnormal visual memory spans (11%; patient 9, 11) (Table 2).

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Behavioural-affective disturbances consisted of a variety of frontal-like behavioural

abnormalities and were present in eight patients (45%; patient 1, 2, 4, 6, 10, 16-18). Three

patients (patient 2, 4, 10) presented with a behavioural profile characterized by inhibition, apathy,

flattening of affect and reduced initiative. Five patients (patient 1, 6, 16-18), however, presented

with a disinhibition syndrome characterized by overfamiliarity, irresponsible behaviour,

inappropriate comments and verbal disinhibition. One patient (patient 17) developed a

behavioural profile resembling obsessive-compulsive disorder and was referred to psychiatric

counselling.

Right versus left cerebellar damage

Comparison of right (n=8) versus left (n=6) cerebellar damage revealed a tendency to

lateralization of cerebellar involvement in cognitive processing. Five out of eight patients with

right cerebellar lesions (patients 1, 2, 4, 6, 7) and all six patients with left-sided cerebellar lesions

developed cognitive disturbances. Statistical analysis by means of the chi-squared test revealed

no significant difference between right or left cerebellar damage and the occurrence of

neuropsychological deficits (Pearson χ2= 2.86; p=0.09).

However, a difference was found in the type of neuropsychological impairment following

right versus left cerebellar damage. The majority of the patients with right-sided cerebellar

lesions showed typical left-hemispheric dysfunctions, including disorders in executive functions,

logical reasoning and language skills, such as disturbed verbal working memory, naming deficits

and reduced verbal fluency. By contrast, all six patients with left-sided cerebellar lesions (patients

9 to 14) demonstrated significant deficits in attention, visuo-spatial functioning, non-verbal

problem-solving and/or visual working memory, which are typically associated with right-

hemispheric dysfunctioning. Statistical analysis by means of a chi-squared test revealed a

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significant difference in the type of neuropsychological symptoms following left versus right

cerebellar infarction (Pearson χ2= 11,00; p=0.001).

Analysis of behavioural-affective abnormalities revealed that four patients (patient 1, 2, 4,

6) with right-hemispheric cerebellar damage presented with behavioural-affective abnormalities.

By contrast, only one patient (patient 10) with left cerebellar damage experienced behavioural-

affective symptoms.

Vascular territory: SCA lesions versus PICA lesions

Cerebellar lesions of twelve patients with a vascular aetiology were attributed to a

vascular territory (SCA, PICA, AICA) within the cerebellum. One patient (patient 17) presented

with a vermian AVM. Seven patients had vascular lesions in the territory of the PICA (patients 2,

3, 6, 10, 11, 13, 14) and five patients presented with vascular lesions in the SCA territory

(patients 1, 4, 5, 9, 15).

Comparing the cognitive and affective deficits in relation to the vascular territory reveals

that six out of seven patients (patient 2, 6, 10, 11, 13, 14) with cerebellar lesions in the PICA

territory presented with clinically significant cognitive symptoms and/or behavioural

disturbances. One patient however with a PICA lesion did not develop neurocognitive symptoms

(patient 3). Similar results were obtained regarding the five patients with vascular lesions in the

SCA territory. Four patients out of five (patient 1, 4, 9, 15) developed post-stroke cognitive

and/or behavioural-affective symptoms. One patient remained free of any cognitive or

behavioural disturbances following the SCA infarction (patient 5). Statistical analyses by means

of a chi-square test revealed no significant difference between the vascular territory and the

occurrence of neuropsychological symptoms (Pearson χ2=0.69; p=0.79). In addition, no

difference was found in neuropsychological impairment following infarction in the SCA or PICA

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territory. Attentional deficits were observed five times following PICA infarction and four times

following SCA infarction. Executive deficits were found in three patients following PICA

infarction and in two patients with SCA infarction. Disruption of linguistic skills (naming and

verbal fluency) was observed in two patients with PICA infarction and in three patients with SCA

infarction. Memory disturbances were found four times following PICA infarction and two times

following SCA infarction. Visuo-spatial deficits were observed in three patients with an

infarction in the vascular territory of the PICA and in two patients with an infarction in the SCA

territory.

Functional neuroimaging

Quantified ECD-SPECT studies were conducted in thirteen patients (patient 1, 2, 4, 5, 6,

8, 9, 10, 11, 13, 15, 16, 17). In all patients with vascular lesions a SPECT study was performed

with an average of four weeks after the stroke. In two patients (patient 8 and 16) with cerebellar

tumours a SPECT study was performed before the surgery and four weeks after surgical removal

of the tumour. Results of the quantified ECD-SPECT studies are summarized in table 3.

Insert Table 3 near here

Supratentorial perfusional deficits (more than 2SD below average) were observed in ten

of the thirteen patients (77%; patient 1, 2, 4, 5, 6, 8, 9, 13, 15, 17). Three patients presented

exclusively with infratentorial hypoperfusion (patients 10, 11 and 16). Eight patients presented

with frontal hypoperfusion (patients 1, 2, 4-6, 13, 15, 17) and two patients with parietal

hypoperfusion (patients 4 and 15). Analysis of cognitive data revealed an association between

supratentorial hypoperfusion and the observed neuropsychological deficits. Seven out of eight

patients with frontal hypoperfusion presented with associated neuropsychological deficits

(patients 1, 2, 4, 6, 9, 13, 15, 17), including executive dysfunction and/or behavioural

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disturbances. No frontal lobe hypoperfusions were found in patients 10 and 16 despite executive

dysfunctions. Two patients with parietal hypoperfusion (patients 4 and 15) both presented with

apraxic apgraphia, a symptom commonly associated with parietal dysfunctioning (Heilman,

1974). Two patients, however, had normal neuropsychological results despite supratentorial

hypoperfusions (patient 5 and 8).

Figure 4A-B-C shows quantified ECD-SPECT studies following the onset of the

cerebellar lesion in three patients (patient 2, 13 and 17).

Insert Figure 4A-B-C near here

Discussion

In this prospective study, cognitive and functional neuroimaging findings of 18 adult

patients with isolated cerebellar damage are presented. Fifteen patients (83%) presented with

significant cognitive impairment and/or behavioural-affective disturbances. Analysis of the

neuropsychological data revealed a clear tendency to lateralization of cognitive functioning

within the cerebellum: left cerebellar damage relates to right-hemispheric dysfunctioning, such as

attention deficits and visuo-spatial disturbances, while right cerebellar damage relates to typical

left-hemispheric deficits, such as disrupted language skills. In addition, analysis of the

neuropsychological symptoms revealed no significant difference between SCA and PICA lesions.

Functional neuroimaging studies by means of quantified ECD-SPECT showed that supratentorial

hypoperfusional deficits could be related to neuropsychological symptoms, in which frontal

hypoperfusions were associated with executive dysfunctions while two patients with parietal

hypoperfusions presented with apractic agraphia.

In the late 1990s, Schmahmann and Sherman (1998) introduced the concept of cerebellar-

cognitive-affective-syndrome (CCAS) to identify a spectrum of cognitive and affective

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disturbances in patients with isolated cerebellar lesions. Based upon bedside screening and formal

neuropsychological testing of 20 patients, the authors grouped a constellation of cognitive,

linguistic and affective symptoms following cerebellar damage. The core features of this

syndrome consist of executive dysfunctions, disrupted spatial cognition, impaired visual-spatial

memory, language disturbances and personality and behavioural disorders (Schmahmann &

Sherman, 1998). Since the first description of the syndrome, CCAS has been reported in a

number of aetiologically different patients, both children and adults, with acquired (Levisohn et

al., 2000; Baillieux et al., 2006) and congenital cerebellar damage (Duggal, 2005; Mariën et al.,

2008). Analyses of the spectrum of cognitive symptoms and behavioural abnormalities in our

patients revealed full-blown CCAS in only four cases (patient 1, 2, 4 and 10). The majority of our

patients, however, presented with a broad spectrum of cognitive and/or linguistic deficits,

including disturbances in executive functioning (50%), attention (72%), verbal and recent

memory (50%), visuo-spatial skills (28%) and linguistic functions such as naming deficits (22%)

and disrupted verbal fluency (39%). Additionally, various degrees of severity were found in our

patient group, indicating that neuropsychological deficits following cerebellar lesions may vary

among the population.

A possible explanation for the clinical diversity in our patient group might be found in the

functional lateralization (left versus right) and/or topographical organization (SCA versus PICA)

of the cerebellum. Comparing the neurocognitive deficits of our patients with right-sided versus

left-sided cerebellar lesions provides support for a lateralized involvement of cerebellar structures

in cognition. Eight patients presented with right-sided cerebellar damage, of whom five patients

showed typical left hemisphere dysfunction, including disrupted linguistic skills (disrupted

naming and verbal fluency), disturbed verbal working memory, impaired planning and deficits in

logical reasoning (executive dysfunctions). By contrast, only one patient with left-sided

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cerebellar damage presented with linguistic deficits (disturbed verbal fluency), while none of the

patients with left-sided cerebellar damage showed disturbances in verbal working memory. By

contrast, all six patients with left cerebellar damage had typical symptoms of right hemisphere

dysfunctioning, such as visual attention disturbances, visual working memory deficits and

disrupted visuo-spatial skills. In summary, our data show that patients with right-sided cerebellar

lesions were generally more impaired in linguistic processing and logical reasoning than patients

with left-sided cerebellar damage who had significant deficits in attention, visuo-spatial

functioning and non-verbal problem solving, mimicking typical right hemisphere dysfunctioning.

The lateralized functional involvement of the cerebellum in typical dominant and non-dominant

hemisphere dysfunctions is subserved by strong crossed cerebello-cerebral connections. The

cross-wise functional impact of focal cerebellar damage on supratentorial regions subserving

cognitive functioning has been amply documented. Early evidence in support of this finding was

presented by Botez-Marquard et al. (1994) and Mariën et al. (1996). In the early 1990s Botez-

Marquard et al. (1994) described typical right-hemisphere dysfunction, such as attention deficits

and disrupted visuo-spatial skills following a left cerebellar lesion. A few years later, Mariën et

al. (1996) introduced the concept of a lateralized linguistic cerebellum based upon a longitudinal

follow-up study of a patient with cerebellar-induced aphasia following a right cerebellar infarct.

The authors attributed the modulating role of the right cerebellar hemisphere to crossed cerebello-

cerebral connections. Their hypothesis was supported by SPECT results revealing cerebello-

cerebral diaschisis, a phenomenon that represents the functional impact of the cerebellar lesion on

cortical functioning. More recently, neurocognitive studies of Allin et al. (2001), Gottwald et al.

(2004) and Hokkanen et al. (2006) have provided evidence that patients with right-sided

cerebellar lesions are generally more impaired in verbal functions, while patients with left-sided

cerebellar lesions show more difficulty in visuo-spatial tasks. It may be hypothesized that the

  15  

cerebellar involvement in cognitive functioning reflects a lateralized functional organization of

the cerebellum: left cerebellar lesions lead to right-hemisphere dysfunction, whereas in right

cerebellar lesions left-hemispherical symptoms are more prominent. In addition, functional

neuroimaging studies by means of SPECT (Baillieux et al., 2006; Mariën et al., 2007) and fMRI

(Fink et al., 2000; Jansen et al., 2005) have convincingly shown the importance of the

contralateral cerebello-cerebral network in cognitive modulation.

A second factor that can possibly account for the various clinical expressions in our

patient group is the topographical organization of the cerebellum (Exner et al., 2004; Mariën et

al., 2008). Based upon neuroanatomical and neuroimaging studies, the anatomic specificity of the

cerebellar-cerebral connections implies a functional topography of cognitive modulation within

the cerebellum in which different cerebellar areas interact with specific and different cortical

areas. According to Schmahmann (2004), these anatomical subcircuits consist of the feed-

forward loop of the cortico-ponto-cerebellar system and the feed-back loop of the cerebello-

thalamo-cortical pathway. These anatomical subcircuits constitute the structural basis for

functional subunits reflecting a topographic organization of motor and cognitive functions within

the cerebellum: the posterior parts of the cerebellum seem to be predominantly involved in

cognitive modulation, while the anterior cerebellar lobe is mainly involved in motor functions.

Recently, Exner et al. (2004) investigated the hypothesis that vascular lesions in different

vascularization areas of the cerebellum result in differential cognitive and affective impairments.

According to their results, patients with SCA lesions generally did not present with cognitive

symptoms or affective abnormalities, while patients with PICA lesions presented with a variety

of cognitive, linguistic and affective disturbances, including memory deficits, executive

disturbances and emotional withdrawal. These conclusions are supported by other studies (Paulus

et al., 2004; Willert et al., 2005). Additionally, Schmahmann and Sherman (1998) showed that

  16  

the majority of their patients (10/13) presented with CCAS following PICA-lesions. However,

neuropsychological findings in our patients challenge these results. No statistically significant

difference was found between cognitive and/or affective symptoms following cerebellar lesions

in the PICA or SCA territory. Two patients out of 13 with vascular lesions (cases 3 and 5) had

normal neuropsychological results. One of these patients had an infarction in the vascular

territory of the PICA and the other patient had an SCA infarction. In addition, full-blown CCAS

was found four times in our patient group, twice after a SCA infarction and twice after lesions

within the PICA territory. Additionally, the majority of the patients with cerebellar lesions

confined either to the SCA territory (80%) or the PICA territory (87%) presented with clinically

significant neuropsychological disturbances. No indications of a difference in the type of

neuropsychological impairment following ischaemic damage in the SCA or PICA territory were

found. Infarction in the territory of the SCA and PICA were both associated with deficits in

executive functioning, attention, linguistic skills, memory and visuo-spatial abilities.

Accordingly, Mariën et al. (2008) recently reported cognitive, linguistic and affective

disturbances in a patient with a SCA lesion and Neau et al. (2000) found no significant

differences between the neuropsychological consequences of vascular lesions in the PICA or

SCA territory. From an anatomical point of view, there is still no consistency in findings with

regard to the parts of the cerebellum that subserve cognitive modulation. Several studies and case

reports, including our own, demonstrate that variability may exist with regard to the functional

anatomy of the cerebellum (Neau et al., 2000; Mariën et al., 2008).

In addition to cerebellar involvement in language and cognition, 19th century reports

anecdotally mentioned behavioural alterations and affective abnormalities in patients with

isolated cerebellar damage (Combettes, 1831; Otto, 1873). Due to lack of standardized

investigations and pathological verification these observations did not receive much attention

  17  

(Dow & Moruzzi, 1958). However, the introduction of the CCAS (Schmahmann & Sherman,

1998), renewed interest in the role of the cerebellum in behavioural and affective regulation. In

our study group, frontal-like behavioural abnormalities were present in nine patients. Three

patients presented with an inhibitory behavioural profile, characterized by apathy, flattening of

affect and reduced initiative (patient 2, 4, 10) and five patients presented with the opposite

behavioural condition consisting of a disinhibition syndrome characterized by overfamiliarity,

irresponsible behaviour, inappropriate comments and verbal disinhibition (patient 1, 6, 16-18).

Schmahmann and Sherman (1998) observed that behavioural and affective symptoms in their

patient group were most notable when the lesion involved the vermis or paravermian region. This

finding is supported by the affective disturbances in patients with vermian malformations

(Steinlin, 1997) and in children following posterior fossa tumour resection who have undergone

surgical splitting of the vermis. In our patient group only two patients presented with isolated

lesions of the vermis. Patient 16 presented with severe behavioural-affective disturbances

following vermian tumour resection, while patient 17 presented with obsessive-compulsive

behavioural symptoms that needed psychiatric counselling.

Finally, the cerebello-cerebral diaschisis phenomenon is advanced as a possible

explanation for cerebellar-induced cognitive symptoms, linguistic deficits and behavioural

abnormalities (Mariën et al., 2001). It reflects a disturbance of the excitatory impulses from deep

cerebellar nuclei through dentatothalamic connections to the cortical areas subserving cognitive

processes. Data in support of this hypothesis comes from SPECT studies, evidencing perfusional

deficits in cortical areas which are crucially involved in cognitive functioning (Hassid, 1995;

Mariën et al., 1996, 2001; Zettin et al., 1997; Baillieux et al., 2007). To test this hypothesis, we

conducted ECD-SPECT studies in the immediate and follow-up phase in the vascular and

tumoural patient group. An association between the hypoperfusional deficits and the

  18  

neuropsychological profile was found in the majority of patients. Patients with frontal

hypoperfusions presented with executive dysfunctions and /or behavioural abnormalities, while

parietal hypoperfusions in two patients were associated with apractic agraphia, a rare writing

disorder often linked to parietal dysfunctioning (Valenstein & Heilman, 1979). However, some

inconsistency could be observed: patient 5 for example had normal neuropsychological results

while a SPECT study conducted two weeks post-stroke revealed discrete bilateral medial frontal

hypoperfusions. In addition, patient 10 presented with executive dysfunctions and behavioural

abnormalities in the absence of frontal hypoperfusions. Similar inconsistencies were observed by

Gasparini et al. (1999), Pollack et al. (1995) and Ersahin et al. (2002). In addition, it is likely that

post-infarction phenomena such as oedema or tissue swelling influence supratentorial perfusional

blood-flow and can account as a possible explanation for the observed inconsistency in SPECT

data following acquired cerebellar lesions. It seems plausible that the relation between

supratentorial hypoperfusion following an acquired cerebellar lesion and the neuropsychological

outcome is not a strict causal relationship, but an important part of a complex network underlying

cerebellar-induced cognitive and behavioural symptoms.

In summary, converging evidence from numerous clinical reports and neuroimaging

studies shows that the cerebellum is crucially involved in cognitive functioning, behavioural

processing and affective regulation. However, many questions concerning the functional

cerebello-cerebral connectivity remain unanswered. In order to determine the extent and the

precise nature of the cerebellar contribution more systematic studies are necessary to unravel this

complex network.

  19  

Table 1: Demographic and neurological data of the patient group

Pt. Nr.

Gender/ Age/

Hand.

Aetiology R vs. L

Terri-tory

Neurological symptoms at onset

1 de laet

M/58/R infarction R SCA right-sided ataxia, dysmetria, dysarthria gait disturbances

2 matthé

M/52/R infarction R PICA right-sided hypotonia, disequilibrium, dysarthria

3 DERWA

EL??

M/50/R infarction R PICA gait disturbances, disequilibrium,

4 schelkens

M/75/R infarction R SCA right-sided ataxia, hypotonia, gait disturbances, disequilibrium, dysarthria

5 schellens

M/61/R infarction R SCA disequilibrium, gait disturbances, vertigo, dysarthria

6 vleugels

M/67/R infarction R PICA left-sided paresthesia and dysmetria, vertigo, gait disturbances

7 VAN

AGGELPEOL??

F/53/R tumour R - disequilibrium, visual disturbances, dysarthria, nausea

8 florus

M/55/R tumour R - disequilibrium

9

M/88/R infarction L SCA left-sided ataxia, hypotonia, discrete facial palsy, gait disturbances, vertigo

10 verschuer

en???

F/68/R infarction L PICA gait disturbances, left-sided paresthesia, dysmetria, ataxia

11

smet

M/52/R infarction L PICA disequilibrium, gait disturbances

12 langenhu

yzen

F/68/R tumour L - disequilibrium, nausea

13 janssens

M/80/R infarction L PICA dizziness, disequilibrium, dysarthria

14 palinckx

F/78/R infarction L PICA disequilibrium, hypotonia, dysarthria

15 geerts

F/86/R infarction BL SCA right-sided hemiparesis, disequilibrium, dysarthria

16 M/57/R tumour verm - disequilibrium, gait disturbances, ataxia

  20  

william

is

17 jooris

F/50/R AVM vermis

- disequilibrium, ataxia, gait disturbances, dysarthria

18 hendricks

M/68/R tumour vermis

- disequilibrium, gait disturbances, nausea

Legend: Hand.= handedness; M= male; F=female; R=right; L=left; BL=bilateral; PICA= posterior inferior cerebellar artery; SCA= superior cerebellar artery; AVM= arrterio-venous malformation

Table 2: Cognitive and affective symptoms following cerebellar damage

Pt Nr. Lesion site Cognitive deficits in: Affective symptoms

1 infarction R SCA

executive functions, verbal WM, naming, visuo-spatial functions, attention and verbal fluency

disinhibition, overfamiliarity and irresponsible behaviour

2 infarction R PICA

executive functions, verbal and recent memory, verbal WM, attention and verbal fluency

behavioural inhibition, irresponsible behaviour, flattening of affect, apathy

3 infarction R PICA

normal normal

4 infarction R SCA

executive functions, verbal memory, verbal WM, attention, naming, verbal fluency and apractic agraphia

reduced initiative, flattening of affect

5 infarction R SCA

normal normal

6 infarction R PICA

recent memory verbal and behavioural disinhibition

7 R-sided tumour

executive functions, verbal memory, verbal WM, attention and verbal fluency

normal

8 R-sided tumour

normal normal

9 infarction L SCA

attention and non-verbal problem-solving normal

10 infarction L PICA

executive functions, attention, visual WM and visuo-spatial functions

behavioural inhibition, reduced initiative, apathy

11 infarction L PICA

attention normal

12 L-sided tumour

attention, visual WM normal

13 infarction L PICA

executive functions, attention, naming, non-verbal problem-solving, verbal fluency and visuo-spatial functions

normal

  21  

14 infarction L PICA

verbal and recent memory, visuo-spatial functions and attention

normal

15 BL infarction SCA

attention, naming, verbal fluency and apraxic agraphia

normal

16 vermian tumour

executive functions, attention disinhibition and overfamiliarity

17 vermian AVM

executive functions, attention and severe logorrhea

verbal disinhibition, behavioural profile resembling obsessive-compulsive disorder

18 vermian tumour

executive functions, verbal and recent memory and verbal fluency

verbal disinhibition

Legend: L= left; R= right; BL= bilateral; PICA= posterior inferior cerebellar artery; SCA= superior cerebellar artery; AVM= arterio-venous malformation; WM= working memory

  22  

Table 3: Results from quantified SPECT studies in patients with vascular or neoplastic lesions

Pt Nr. Lesion site X weeks

po Hypoperfusional deficits (x standard-scores below average)

supratentorial infratentorial 1 infarction

R SCA 5w po frontal medial L (-2.21) cerebellum R (-3.15)

2 infarction R PICA

10w po bilateral frontal medial (-5.38 R, -4.15 L); motor cortex R (-2.62)

/

4 infarction R SCA

3w po premotor cortex L (-2.82) parietal lobe L (-4.41)

cerebellum R (-2.41)

5 infarction R SCA

2w po bilateral frontal medial (-2.34 R, -3.28 L)

/

6 infarction R PICA

1w po bilateral frontal medial (-3.17 R, -4.02 L), caudate nucl L (-2.20); thalamus L (-2.09)

8

R-sided tumour

4w post-op

bilateral temporal (-2.81 R, -2.85 L)

/

9 infarction L SCA

3w po occipital lobe R (-3.42), caudate nucl L (-2.74); thalamus L (-2.44)

10 infarction L PICA

12w po caudate nucl L (-2.88); thalamus L (-2.73)

cerebellum left (-3.83); vermis (-2.63)

11 infarction L PICA

2w po caudate nucl L (-4.27); thalamus L (-2.32)

13 infarction L PICA

2w po bilateral frontal medial (-2.09 R, -2.82 L); motor cortex L (-2.52), bilateral caudate nucl (-2.13 R; -4.8 L); thalamus L (-4.38)

vermis (-2.20) cerebellum L (-4.75)

15 BL infarction SCA

1w po frontal medial R (-3.24); motor cortex R (-4.81); parietal R (-4.91)

cerebellum R (-3.09)

16 vermian tumour

4w post-op

bilateral caudate nucl (-2.39 R, -2.88 left); thalamus R (-2.37)

vermis (-5.04)

17 vermian AVM

10w po bilateral frontal medial (-3.86 R, -3.74 left)

/

Legend: w=weeks; po=post-onset; post-op.= post-operative; R=right; L=left; BL=bilateral; PICA= posterior inferior cerebellar artery; SCA= superior cerebellar artery; AVM= arterio-venous malformation; nucl.=nucleus

  23  

References

Allin M, Matsumoto H, Santhouse AM, Nosarti C, Alasady MH, Stexard AL, Rifkin L and

Murray RM. Cognitive and motor functions and the size of the cerebellum in adolescents

born very pre-term. Brain, 124: 60-66, 2001

Baillieux H, De Smet HJ, Lesage G, Paquier PF, De Deyn PP and Mariën P. Neurobehavioral

alterations in an adolescent following posterior fossa tumor resection. The Cerebellum, 5:

289-295, 2006.

Baillieux H, Weyns F, Paquier PF, De Deyn PP and Mariën P. Posterior fossa syndrome after a

vermian stroke: a new case and review of the literature. Pediatric Neurosurgery, 43: 386-

395, 2007

Baillieux H, De Smet HJ, Paquier PF, De Deyn PP, and Mariën P. Cerebellar neurocognition:

insights into the bottom of the brain. Clinical Neurology and Neurosurgery, 110 : 763-773,

2008

Botez-Marquard T, Léveillé J and Botez MI. Neuropsychological functioning in unilateral

cerebellar damage. Canadian Journal of Neurological Sciences, 21: 353-357, 1994.

Brickenkamp R and Zillmer E. D2 Test of Attention. Göttingen: Hogrefe, 1998.

Cole M, and Dastoor D. The hierarchic dementia scale. Journal of Clinical and Experimental

Gerontology, 5: 219-234, 1983.

Combettes M. Absence complete du cervelet, des pédoncules postérieures et de la protubérance

cérébrale chez une jeune fille morte dans sa onzième année. Bulletin de la Société Anatomique

Paris, 5: 148-157, 1831.

Cormier PJ, Long ER. and Russell EJ. MR imaging of posterior fossa infarctions: vascular

territories and clinical correlates. Radiographics, 12 : 1079-1096 , 1992

De Smet HJ, Baillieux H, Mariën P, De Deyn PP, and Paquier PF. The cerebellum and language:

the story so far. Folia Phoniatrica et Logopaedica, 59: 165-170, 2007

Dow RS and Moruzzi G. The Physiology and Pathology of the Cerebellum. Minneapolis:

University of Minnesota Press, 1958.

Duggal HS. Cognitive affective psychosis syndrome in a patient with sporadic

olivopontocerebellar atrophy. Journal of Neuropsychiatry and Clinical Neurosciences, 17:

260-261, 2005.

  24  

Ersahin Y, Yararbas U, Duman Y, and Mutluer S. Single photon emission tomography following

posterior fossa surgery in patients with and without mutism. Child’s Nervous System, 18:

318-325, 2002

Exner C, Weniger G and Irle E. Cerebellar lesions in the PICA but not SCA territory impair

cognition. Neurology, 63: 2132-2135, 2004.

Fine EJ, Ionita CC, and Lohr L. The history of the development of the cerebellar

examination. Seminars in Neurology, 22: 375-384, 2002

Fink GR, Marshall JC, Shah NJ, Weiss PH, Haligan PW, Gros-Ruyken M, Ziemons K, Zilles K

and Freund HJ. Line bisection judgments implicate right parietal cortex and cerebellum as

assessed by fMRI. Neurology, 54: 1342-1331, 2000

Folstein M, Folstein S, and McHugh P. Mini-Mental State Examination. USA : Psychological

Assessment Resources, Inc, 2000

Gasparini M, Di Piero V, Ciccarelli O, Cacioppo MM, Pantano P. and Lenzi GL. Linguistic

impairment after right cerebellar stroke: a case report. European Journal of Neurology, 6:

353-356, 1996

Gottwald B, Mihajlovic Z, Wilde B and Mehdorn HM. Does the cerebellum contribute to specific

aspects of attention? Neuropsychologia, 41: 1452-1460, 2003.

Gottwald B, Wilde B, Mihajlovic, Z and Mehdorn HM. Evidence for distinct cognitive deficits

after focal cerebellar lesions. Journal of Neurology, Neurosurgery and Psychiatry, 74:

1524-1531, 2004

Hammes JGW. Stroop Kleur Woord Test. Swets & Zeitlinger B.V.: Lisse, 1971.

Hassid EI. A case of language dysfunction associated with cerebellar infarction. Journal of

Neurological Rehabilitation, 9: 157-160, 1995

Heaton RK, Chelune GJ, Talley JL, Kay GG and Curtiss, G. Wisconsin Card Sorting Test:

Revised and expanded. Psychological Assessment Resources Inc.: Lutz, 1993.

Hokkanen, L.S.K., Kauranen V, Roine RO, Salonen O and Kotila M. Subtle cognitive deficits after

cerebellar infarcts. European Journal of Neurology, 13: 161-170, 2006

Holmes G. A form of familial degeneration of the cerebellum. Brain, 30: 466-480, 1907

Holmes G. The cerebellum. The Croonian lectures on the clinical symptoms of cerebellar diseases

and their interpretation. Brain, 44: 522-591, 1922

Jansen A, Flöel A, Van Randenborgh J, Konrad C, Rotte M, Förster A, Deppe M and Knecht S.

  25  

Crossed cerebro-cerebellar language dominance. Human Brain Mapping, 24: 165-172,

2005.

Kaplan E, Goodglass H and Weintraub S. Boston Naming Test. USA: Lei and Febiger, 1983.

Leiner HC, Leiner AL and Dow RS. Reappraising the cerebellum: what does the hindbrain

contribute to the forebrain? Behavioral Neuroscience, 103: 998-1008, 1989.

Levisohn L, Cronin-Golomb A and Schmahmann JD. Neuropsychological consequences of

cerebellar tumor resection in children: cerebellar cognitive affective syndrome in a

pediatric population. Brain, 123: 1041-1050, 2000.

Mariën P, Baillieux H, De Smet HJ, Engelborghs S, Wilssens I, Paquier P, and De Deyn PP.

Cognitive, linguistic and affective disturbances following a right superior cerebellar artery

infarction: a case study. Cortex, Epub, 2008

Mariën P, Engelborghs S, Fabbro F and De Deyn PP. The lateralized linguistic cerebellum: a

review and a new hypothesis. Brain and Language, 7: 580-600, 2001.

Mariën P, Mampaey E, Vervaet A, Saerens J and De Deyn PP. Normative data for the Boston

Naming Test in native Dutch-speaking Belgian elderly. Brain and Language, 65: 447-

467, 1998.

Mariën P, Saerens J, Nanhoe R, Moens E, Nagels G, Pickut BA, Dierckx RA and De Deyn PP.

Cerebellar induced aphasia: case report of cerebellar induced prefrontal aphasic language

phenomena supported by SPECT findings. Journal of the Neurological Sciences, 144: 34-

43, 1996.

Mazzocchi F. and Vignolo LA. Localisation of lesions in aphasia: clinical-CT scan correlations in

stroke patients. Cortex, 15: 627-654, 1979

Middleton FA. and Strick PL. Anatomical evidence for cerebellar and basal ganglia involvement

in higher cognitive function. Science, 266: 458-461, 1994

Molinari M, Petrosini L, and Misciagna S. Visuospatial abilities in cerebellar disorders. Journal of

Neurology, Neurosurgery and Psychiatry, 75: 235-240, 2004

Neau JP, Arroyo-Anllo E, Bonnaud V, Ingrand P and Gil, R. Neuropsychological disturbances in

cerebellar infarctions. Acta Neurologica Scandinavia, 102: 363-390, 2000.

Oldfield RC. The assessment and analysis of handedness; the Edinburgh inventory.

Neuropsychologia, 9: 97-113, 1971

Osterrieth PA. Rey's Complexe Figuur Test. Swets & Zeitlinger Publishers: Amsterdam, 1944.

  26  

Otto A. Ein Fall von Verkummerung des Kleinhirns. Archives fur Psychiatry und Nervenkranken,

4: 730-746, 1873.

Paquier PF and Mariën P. A synthesis of the role of the cerebellum. Aphasiology, 19: 3-19, 2005.

Paulus KS, Magnano I, Conti M, Galistu P, D'Onofrio M, Satta W and Aiello I. Pure post-stroke

cerebellar cognitive affective syndrome: a case report. Neurological Sciences, 25: 220-224, 2004.

Pollack IF, Polinko P, Albright AL, Towbin R. and Fitz C. Mutism and pseudobulbar symptoms after

resection of posterior fossa tumours in children: incidence and pathophysiology. Neurosurgery,

37, 885-893, 1995

Randolph C. Repeatable battery for the assessment of neuropsychological status. San Antonio:

Psychological Corporation, 1998

Raven JC. Raven Standard Progressive Matrices. San Antonio: The Psychological Corporation, 1996

Reitan RM. Validity of the Trail Making Test as an indicator of organic brain damage.

Perceptual and Motor Skills, 8: 271-276, 1958.

Savoiardo M, Bracchi M, Passerini A, and Visciani A. The vascular territories in the cerebellum

and brainstem : CT and MR study. American Journal of Neuroradiology, 8: 199-209, 1987

Schmahmann JD. The cerebrocerebellar system: anatomic substrates of the cerebellar

contribution to cognition and emotion. International Review of Psychiatry, 13: 247-260,

2001

Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought and the cerebellar

cognitive affective syndrome. Journal of Neuropsychiatry and Clinical Neuroscience, 16: 367-

378, 2004.

Schmahmann JD and Sherman JC. The cerebellar cognitive affective syndrome. Brain, 121: 561-

579, 1998.

Silveri MC, Misciagna S, Leggio M and Molinari M. Spatial dysgraphia and cerebellar lesion: a case

report. Neurology, 48: 1529-1532, 1997

Steinlin M. Non-progressive congenital ataxias. Brain and Development, 20: 199-208, 1997

Vlachos F, Papathanasiou I, and Andreou G. Cerebellum and Redding. Folia Phoniatrica et

Logopeadica, 59: 177–183, 2007

Wechsler D. Wechsler Memory Scale - Revised (WMS-R). San Antonio: The Psychological

Corporation, 1987.

Willert C, Schaumann-Kuchling C, Adamaszek M and Spitzer C. Neuropsychological

  27  

dysfunction after cerebellar stroke. Nervenartz, 76: 988-991, 2005.

Zettin M, Cappa SF, D'Amico A, Rago R, Perino C, Perani D, and Fazio F. Agrammatic speech

production after a right cerebellar haemorrhage. Neurocase, 3: 375-380, 1997