Neuropsychologia 44 (2006) 2569–2572
Note
Evidence of a developmental cerebello-cerebral disorder Varda Gross-Tsur a , Dafna Ben-Bashat b , Ruth S. Shalev a,∗ , Miriam Levav c , Liat Ben Sira b a
b
Neuropediatric Unit, Shaare Zedek Medical Center, Jerusalem 91031, Israel The Wohl Institute for Advanced Imaging, Radiology Department, Sourasky Medical Center, Israel c Pediatric Neuropsychology Unit, Tel Hashomer Medical Center, Tel Aviv, Israel Received 22 December 2005; received in revised form 27 April 2006; accepted 28 April 2006 Available online 13 June 2006
Abstract The objective of this study was to examine the cognitive and neuroanatomical features of an adolescent with developmental hypoplastic left cerebellum who presented with executive and visuo-spatial deficits, nonverbal learning disabilities and interpersonal difficulties. He underwent a neuropsychological assessment, MRI and diffusion tensor imaging MRI. The neuropsychological impairments were primarily in executive functions, spatial and visual perception, graphomotor skills, arithmetic, social perception and comprehension. Fractional anisotropy, which is measured by diffusion tensor imaging and enables assessment of axonal integrity, was reduced in the right cerebral peduncle and right hemisphere white matter (p < 0.001). Based on the results, we hypothesize that disruption of neural circuits linking the hypoplastic left cerebellum to the right hemisphere may contribute to the evolution of a neurocognitive syndrome with characteristics of the developmental right hemisphere syndrome and suggestive of the cerebellar cognitive-affective syndrome. © 2006 Elsevier Ltd. All rights reserved. Keywords: Cerebellum; Cognition; Affective; Behavior; Hypoplasia; Developmental right hemisphere syndrome
1. Introduction Lesions in the cerebellum cause cognitive and behavioral deficits in addition to the known perturbations of motor control and specific neurobehavioral profiles have been localized to the site of the cerebellar lesions. Right cerebellar lesions can result in auditory sequential memory and language processing deficits, left cerebellar lesions with spatial and visual sequential memory deficits while vermal lesions may lead to speech, language or behavioral disturbances (Riva & Giorgi, 2000; Scott et al., 2001). The cerebellar cognitive-affective syndrome (CCAS), characterized by impaired executive functions, visuo-spatial and language deficits and personality changes can result from lesions in the lateral hemisphere of the posterior cerebellum or in the vermis (Schmahmann, 2004; Schmahmann & Sherman, 1998). We present an adolescent with congenital left cerebellar and vermal hypoplasia and a neuropsychological profile characterized primarily by executive and visuo-spatial deficits, nonverbal
∗
Correspondence to: Neuropediatric Unit, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel. Tel.: +972 2 6666141; fax: +972 2 6422481. E-mail address:
[email protected] (R.S. Shalev). 0028-3932/$ – see front matter © 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropsychologia.2006.04.028
learning disabilities and interpersonal difficulties. This profile is similar to that of the developmental right hemisphere syndrome (DRHS) and has certain features in common with the CCAS (Gross-Tsur, Shalev, Manor, & Amir, 1995; Schmahmann, 2004). We speculated that the DRHS symptomatology may result from the cerebellar malformations and/or abnormalities in the neural circuits connecting to the right hemisphere. Since conventional MRI did not delineate structural supratentorial abnormalities, we used diffusion tensor MRI (DTI), a technique that measures the anisotropy of water diffusion. This technique enables assessment of the microstructure of white matter pathways, organization and architecture of white matter fibers and demonstrates pathological white matter conditions (Neil, Miller, Mukherjee, & Huppi, 2002). DTI demonstrated disruption of circuits that link the left cerebellar hemisphere and right cerebrum. 2. Case report A 14-year-old boy with ataxic-athetoid cerebral palsy was born to non-consanguineous parents after a normal pregnancy and birth, head circumference 34.5 cm. Visual focusing and tracking appeared late, crawling and first words at 2 years and
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walking at 9 years. Neuropsychological evaluation at age 10 showed normal language skills, including length of utterance, syntax, vocabulary and comprehension, dysarthric but comprehensible speech, low average intelligence, attention deficit hyperactivity disorder (ADHD), severe dyscalculia and motor dysgraphia. He misinterpreted social cues and did not have friends of his own age in spite of his efforts to communicate with peers. On neurologic examination, he was alert, communicative, dysarthric with athetoid movements and ataxic gait, head circumference in the 50th percentile. He had bucco-facial dyspraxia, right external strabismus, low muscle tone and mild left hemiparesis. Deep tendon reflexes were alert, slightly more pronounced on the left. EEG showed rare bursts of spike/wave activity. Auditory evoked potentials, metabolic workup and karyotype were normal. 2.1. Neuropsychological assessment The assessment was carried out over several sessions. He was cooperative, with a sense of humor, showed impulsivity, obsessive symptoms, perseverative discourse and difficulty in planning and regulation of behavior. Verbal IQ was 87 (Wechsler Intelligence Scale for ChildrenRevised, WISC-R) and the score on the Raven Coloured Matrices was compatible with an IQ of 74; WISC-R performance subtests were not used because of his motor problems and subsequent difficulties interpreting the results. His performance in the following areas was impaired (i.e. ≤−1.8S.D. below the mean or at least −1.0S.D. below his verbal IQ) (Table 1): executive functions (planning, organization, inhibition control, parent assessment of working memory and verbal fluency); spatial and visual perception; graphomotor skills; arithmetic skills; social perception and comprehension (Baron, 2004; Dorris, Espie, Knott, & Salt, 2004; Ekman & Friesen, 1976). On the Child Behavior Checklist, he scored at the 98th percentile on the social, thought and attention problem narrow band scales (Silber, Auerbach, & Lerner, 1994). Cognitive areas that were within the low average range (>−1.0S.D.) included verbal working memory of the Differential Abilities Scales (0.0), memory of sentences from the Developmental Neuropsychological Assessment-NEPSY (−0.6), recognition of word lists from the Rey Auditory Verbal Learning Test [RAVLT] (0.9), similarities (0.0) and information (0.2) from the WISC-R subtests. The score achieved on the vocabulary subtest of the WISC-R was −1.4 and word list learning from the RAVLT was −1.3 (Baron, 2004). 3. Neuroimaging Conventional brain MRI demonstrated severe hypoplasia of the left cerebellar hemisphere, with residual tissue visualized; the right cerebellar hemisphere was normal. The vermis was malformed with only its superior aspect identifiable and mild hypoplasia of the right midbrain and pons (Fig. 1a). T1 and T2 weighted images showed normal symmetric cerebral hemispheres and normal sized ventricles with normal
Table 1 Results of neuropsychological assessment Domains
Areas assessed IQ*
z-Scores
Procedures
Intelligence
Verbal Non verbal IQ
−0.8 −1.5
WISC-R RCM
Executive
Planning
−2.6
Tower test (DKEFS)
Functions
Organization Inhibition Control Parent assessment of working memory Verbal fluency*
−2.0 −2.6 −2.6
BRIEF BRIEF BRIEF
−1.8
COWAT
Spatial
−2.0
Visual
−2.6
Matching (WRAVMA) MFVPT-R
Motor skills Number skills
Graphomotor Arithmetic
−2.0 −1.8
Clock drawing Number skills (DAS)
Social perception and comprehension
Simple emotions
14/35 impaired −2.0 −2.0
Ekman faces
Perception
Complex emotions Comprehension
Eyes test WISC-R
The table presents z-scores of neuropsychological tests that were considered abnormal, that is when the score was ≤−1.8S.D. below the mean. Where z-scores were unavailable, results are presented and noted as impaired. * Time limited test; BRIEF: Behavior Rating Inventory of Executive Functions; COWAT: Controlled Word Association Test (action verbs); DAS: Differential Abilities Scales; DKEFS: Delis–Kaplan-Executive Function Scale; MFVPT-R: Motor Free Visual Perception Test Revised; RCM: Raven Colored Matrices; WRAVMA: Wide Range Assessment of Visual and Motor Abilities.
myelinization as detected by the gray/white matter contrast (Fig. 1b). DTI was performed on a 1.5T GE scanner, with b = 1000 s/mm2 measured in six non-collinear gradient directions (xy, xz, yz, −xy, −xz and y–z) to demonstrate white matter tracts. Single-shot spin-echo echo-planar diffusion weighted imaging sequences were carried out with echo time (TE) 105 ms and repetition time (TR) 7160 ms. Forty-eight, contiguous slices of 3 mm thickness were prescribed on the whole brain. Fractional anisotropy (FA) maps were obtained from the DTI data set according to the procedure described by Basser and Pierpaoli (1998). FA values correlate with microstructural features including the integrity of axonal cell membranes, the coherence of axonal orientation and the number and size of axons (Neil et al., 2002). FA maps were calculated from the level of the cerebral peduncles up to the cortex and were measured on selected regions of interest (ROI) on each slice bilaterally. Mean FA values of the ROI of the right hemisphere were significantly lower than that of the left hemisphere, from the level of the cerebral peduncle, to the internal capsule (Rt 0.61 ± 0.002, Lt 0.67 ± 0.001, N (number of slices) = 11, p < 0.0001) and the corona radiata up to the subcortical level (Rt 0.47 ± 0.001, Lt 0.52 ± 0.001, N = 6, p < 0.001) [Student’s t-test, two-tailed, assuming unequal variances]. Fig. 2a–c shows three slices of axial T2 -weighted images and a correlate FA map at the same levels of the cerebral crus (a and b) and internal capsule (c).
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Fig. 1. Sagittal T1 weighted image demonstrating hypoplastic dysmorphic vermis (a) and coronal T2 weighted image demonstrating symmetric cerebral hemispheres and hypoplastic, rudimentary left cerebellar hemisphere and residual vermal tissue (b).
Fig. 2. T2 -weighted MRI (top row) and correlating FA images (lower row). The first two images (a and b) are at the level of the cerebral crus and the last (c) at the level of the internal capsule. The arrows points to the cerebral crus, which is smaller on the right side and also has lower FA values. At the level of the internal capsule, the FA measurement was also lower on the right side but is not well visualized.
The ROI analyses were based on FA maps by defining areas with high FA values that most probably represented multiple projection fibers either descending or ascending between the cortex and brainstem, such as the corticopontine, corticobulbar, corticospinal tract and thalamic radiation (Mori, Wakana, Nagae-Poetscher, & van Zijl, 2005). 4. Discussion Our patient, with congenital hypoplasia of the left cerebellar lobe and vermis, manifests the cognitive and behavioral features of the developmental right hemisphere syndrome (DRHS) as well as certain facets of the CCAS. His case is unique in that it is developmental and its symptomatology was primarily associated with right hemisphere functions, specifically visualspatial deficits, interpersonal social and behavioral difficulties,
dyscalculia, dysgraphia and impaired executive functions such as ADHD (Gross-Tsur et al., 1995; Levisohn, Cronin-Golomb, & Schmahmann, 2000; Riva & Giorgi, 2000; Ronning, Sundet, Due-Tonnessen, Lundar, & Helseth, 2005; Schmahmann and Sherman, 1998; Scott et al., 2001,). The presumably intact right cerebellar-left cerebral subcircuits may explain his language skills, appropriate for his level of intelligence; the vermal involvement may play a role in his dysarthria and interpersonal disorders (Levisohn et al., 2000; Schmahmann, 2004; Scott et al., 2001). Although suggestive of autism, his behavioral problems did not derive from qualitative impairments of social interaction and communication, but rather were a combination of his interpersonal difficulties and the response of peers to his overall neurological condition. Furthermore, the cerebellar malformation in this patient was not characteristic of those seen in the autistic spectrum disorders (Palmen et al., 2004).
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The cerebro-cerebellar circuitry projects to areas important for higher cognitive functions. Indeed, our current understanding is that crossed cerebro-cerebellar connections are important in modulation of executive processes, attentional mechanisms, visual-spatial processing, memory and learning (Aarsen, Von Dongen, Paquier, Van Mourik, & Catsman-Berrevoets, 2004). This correlation has been seen in children who have suffered lateralized cerebellar lesions: right cerebellar lesions often result in auditory sequential memory and language processing deficits, left cerebellar lesions with spatial and visual sequential memory deficits while vermal lesions can result in speech, language or behavioral disturbances (Levisohn et al., 2000; Riva & Giorgi, 2000; Schmahmann & Sherman, 1998; Scott et al., 2001). In cases with lateralized congenital damage to the cerebellum, cognitive functions, such as linguistic processes or visuo-spatial skills, subserved by the contralateral cerebral hemisphere may be selectively impaired (Scott et al., 2001). In our patient, DTI delineated decreased signal in the white matter from the right cerebral peduncle to the right hemisphere. This reduction was measured in pathways connecting the right cortex and thalami and cortex to midbrain. The pathways from the cerebellum to the thalamus could not be measured because of the cerebellar malformation at this level. The term, CCAS, describes a combination of cognitive, non-motor symptoms caused by damage to the cerebellum in adults, representing a “dysmetria of thought” (Schmahmann, 2004; Schmahmann & Sherman, 1998). In children, symptoms attributable to this syndrome were reported with acquired lesions of the cerebellum secondary to resection, chemo- or radiotherapy. Clinical heterogeneity in pediatric cases of CCAS may result from developmental and acquired causes. Ontogenetically, there may be incomplete lateralization of cerebro-cerebellar pathways or other non-specific cerebral wiring abnormalities due to the lack of sufficient afferent inputs from the malformed cerebellum. Acquired causes include resection of large unilateral lesions ultimately affecting both cerebral hemispheres or non-specific effects of chemo- or radiotherapy to the cerebral cortex (Aarsen et al., 2004; Riva & Giorgi, 2000). Although issues pertinent to the developmental aspects of the syndrome have been discussed, evidence for cognitive topography within the cerebellum has not been provided (Levisohn et al., 2000; Riva & Giorgi, 2000; Schmahmann & Sherman, 1998; Scott et al., 2001). However, according to Schmahmann, damage to the lateral hemispheres of the posterior cerebellum or vermis, as seen in our patient, can result in CCAS. In our patient, the constellation of interpersonal and social difficulties, visuo-spatial deficits, impaired executive functions, ADHD, dyscalculia in the presence of normal language functions, is consistent with DRHS and has many of the features characteristic of CCAS. Therefore, we hypothesize that this cognitive and behavioral profile is secondary to left cerebellar damage since the left cerebellar hemisphere projects to, and receives inputs from the right cerebral cortex (Scott et al., 2001).
In summary, we present an adolescent with developmental cognitive deficits consistent with DRHS, which may be a unilateral variant of CCAS. His structural lesion was congenital hypoplasia of the left cerebellar hemisphere and vermis. The results of the DTI suggest that disruption of neural circuits linking the hypoplastic left cerebellum to the right hemisphere contributes to the evolution of his cognitive and behavioral deficits usually associated with right cerebral hemisphere dysfunction. References Aarsen, F. K., Von Dongen, H. R., Paquier, P. F., Van Mourik, M., & CatsmanBerrevoets, C. E. (2004). Long-term sequelae in children after cerebellar astrocytoma surgery. Neurology, 62, 1311–1316. Baron, I. S. (2004). Neuropsychological evaluation of the child. New York: Oxford University Press Inc. Basser, P. J., & Pierpaoli, C. (1998). A simplified method to measure diffusion tensor from seven MR images. Magnetic Resonance Medicine, 39, 928–934. Dorris, L., Espie, C. A. E., Knott, F., & Salt, J. (2004). Mind reading difficulties in the siblings of people with Asperger’s syndrome: Evidence for a genetic influence in the abnormal development of a specific cognitive domain. Journal of Child Psychology and Psychiatry, 45, 412–418. Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press. Gross-Tsur, V., Shalev, R. S., Manor, O., & Amir, N. (1995). Developmental right hemisphere syndrome: The clinical spectrum of the nonverbal learning disability. Journal of Learning Disabilities, 28, 80–86. Levisohn, L., Cronin-Golomb, A., & Schmahmann, J. D. (2000). Neuropsychological consequences of cerebellar tumour resection in children. Cerebellar cognitive affective syndrome in a paediatric population. Brain, 123, 1041–1050. Mori, S., Wakana, S., Nagae-Poetscher, L. M., & van Zijl, P. C. M. (2005). MRI atlas of human white matter. Amsterdam: Elsevier R.V. Neil, J., Miller, J., Mukherjee, P., & Huppi, P. S. (2002). Diffusion tensor imaging of normal and injured developing human brain: A technical review. NMR in Biomedicine, 15, 543–552. Palmen, S. J., Pol, H. E., Kemner, C. L., Schnack, H. G., Janssen, J., Kahn, R. S., et al. (2004). Larger brains in medication naive high-functioning subjects with pervasive developmental disorder. Journal of Autism and Developmental Disorders, 34, 603–613. Riva, D., & Giorgi, C. (2000). The cerebellum contributes to higher functions during development. Evidence from a series of children surgically treated for posterior fossa tumours. Brain, 123, 1051–1061. Ronning, C., Sundet, K., Due-Tonnessen, B., Lundar, T., & Helseth, E. (2005). Persistent cognitive dysfunction secondary to cerebellar injury in patients treated for posterior fossa tumors in childhood. Pediatric Neurosurgery, 41, 15–21. Schmahmann, J. D. (2004). Disorders of the cerebellum: Ataxia, dysmetria of thought and the cerebellar cognitive-affective syndrome. Journal of Neuropsychiatry and Clinical Neurosciences, 16, 367–378. Schmahmann, J. D., & Sherman, J. C. (1998). The cerebellar cognitive affective syndrome. Brain, 121, 561–579. Scott, R. B., Stoodley, C. J., Anslow, P., Stein, J. F., Sugden, E. M., & Mitchel, C. D. (2001). Lateralized cognitive deficits in children following cerebellar lesions. Developmental Medicine & Child Neurology, 43, 685–691. Silber, N., Auerbach, J., & Lerner, Y. (1994). Israeli norms for the Achenbach Child Behavior Checklist: Comparison of clinically referred and nonreferred children. Israel Journal of Psychology and Related Sciences, 31, 5–12.
