In: Trends in Autism Research
Editor: O. T. Ryaskin, pp. 109-132
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Chapter V
COGNITIVE AFFECTIVE DISORDER
ASSOCIATED WITH
RHOMBENCEPHALOSYNAPSYS
Annapia Verri*, Carla Uggetti, Enrico Alfonsi,
Alessandra Ramponi and Valeria Destefani
Neurological Institute C. Mondino Foundation
Pavia, Italy.
ABSTRACT
Rhombencephalosynapsys (RS) is a rare cerebellar malformation in which the cerebellum
is severely underdeveloped. The condition is associated in Gomez Lopez Hernandez
syndrome with congenital trigeminal anaesthesia and a self injurious behavior . The
cognitive-affective disorder associated with rhomboencephalosynapsis seems to be linked
to brain dysfunction: this report supports the theory of a cerebellar contribution to non
motor functions (Shachmann, 1998).
1. THE CEREBELLAR COGNITIVE
AFFECTIVE SYNDROME (CCAS)
The cerebellum is involved in many cognitive functions, such as level of attention,
sensory discrimination, working memory, semantic association, verbal learning and memory,
and complex problem solving (Allen, 1997). Attentional and motor task involve different
regions of the cerebellum: "cerebellum is not designed to perform a single neurobehavioral
function, such as motor control or attention, but instead is a system composed of different
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
regions that distinctly influence different neurobehavioral functions" (Allen, 1997). Vermis
agenesis is experimentally involved in affective control of behavior and in the coordination of
fear related somatic and autonomic conditioned responses (Ghelarducci, 1997).
Definition
The cerebellar cognitive affective syndrome is a pattern of behavioural abnormalities
(Schmahmann & Sherman,1998) that includes:
• impairments of executive function (deficient planning, set-shifting, abstract
reasoning, working memory, decreased verbal fluency) often with perseveration,
• distractibility or inattention;
• visuo-spatial disorganization and impaired visuo-spatial memory;
• personality change with blunting of affect or disinhibited and inappropriate behavior;
• difficulties with language production including dysprosodia, agrammatism and mild
anomia.
The net effect of these disturbances in cognitive abilities appears to be a general lowering
of intellectual function.
This syndrome has been first described by Schmahmann & Sherman (1998) in a
population of 20 patients with lesions confined to the cerebellum.
The Role of Cerebro-Cerebellar Connections
The constellation of deficits in the cerebellar cognitive affective syndrome is suggestive
of disruption of the cerebellar modulation of neural circuits that link prefrontal, posterior,
parietal, superior temporal and limbic cortices with the cerebellum. In particular, posterior
lobe lesions are mostly important in the generation of the syndrome, and the vermis is
consistently involved in patients with pronounced affective presentation, while more
pronounced disturbances are present in patients with bilateral and acute disease
(Schmahmann & Sherman, 1998).
It has been hypothesized (Schmahmann & Sherman, 1998) that the multiple highly
organized anatomical subsystems that constitute the cerebrocerebellar circuit represent
functional subsystems that facilitate cerebellar processing in many different functional
domains, be they motor, sensory, cognitive, affective or autonomic. The proposed net effect
of these multiple streams of diverse information, reaching into and being sent back from the
cerebellum is that the cerebellum is able to integrate multiple internal representations with
external stimuli and self-generated responses. The cerebellar modulation of these different
subsystems permits the ultimate production of harmonious motor, cognitive and
affective/autonomic behaviours. The loss of the cerebellar component of these neural circuits
produces a dysmetria of thought (Schmahmann, 1991, 1996) that results in the cerebellar
cognitive affective syndrome.
*
Address for correspondence: Dr. Verri Annapia, IRCCS. Neurological Institute C. Mondino, via Palestro
3, 27100–Pavia, EMAIL ADDRESS: [email protected]
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
111
Clinical Presentation
The cerebellar cognitive affective syndrome shows the clinical relevance of the nonmotor functions of the cerebellum and supports the evidence for a correlation between
cerebellar damage and changes in behavior.
The original arguments supporting the view that the cerebellum might play a significant
role in cognitive functions - traditionally the domain of areas such as the prefrontal cortex –
come from anatomy, physiology and functional neuroimaging studies.
These arguments are:
1. the observation, during evolution, of the roughly parallel expansion of cerebellar
hemispheres with the great enlargement of the neocortex in the primates (Ramnani,
2001);
2. the consideration of the cerebrocerebellar circuits that link the cerebellum with
associative and paralimbic cerebral areas that are producing evolving theoretical
notions addressing the fundamental role of the cerebellum in motor, sensory,
cognitive and affective and autonomic behaviours (Dolan, 1998);
3. the growing collection of a wealth of physiological and behavioural data in
experimental animals which confirm the hypothesis of a close interrelation of motor
development and cognitive development and of the cerebellum and prefrontal cortex
(Diamond, 2000);
4. the hypotization of a similar role of the neocerebellum (vermal and hemispheric
portion) in animals, for the regulation of fear related behaviours (Ghelarducci, 1997),
and in humans, for the control of affective reactions such as anxiety and fear
(Sacchetti, 2002);
5. the findings from functional imaging studies that have shown how the lateral
cerebellum becomes active during cognitive tasks that are far removed from control
of movement (Ramnani, 2001).
The missing evidence suggesting a role for the cerebellum in higher order functions
(Dolan, 1998) was a convincing demostration of clinically relevant behavioural changes in
patients with lesions restricted to the cerebellum; this clinical evidence has been obtained by
studies of patients with degenerative diseases of the cerebellum and by the accurate
description of their impaired cognitive function and behavioural change (Schmahmann &
Sherman, 1998).
These behavioural changes that have been diagnosed at bedside and quantified by
neuropsychological tests conform to an identifiable clinical syndrome that is consistent with
predictions derived from anatomy, physiology and functional neuroimaging studies.
In affected patients, arousal and alertness are not depressed. Remote episodic and
semantic memory are preserved and new learning is only mildly affected. Cerebellar
cognitive affective syndrome patients have difficulty with planning and integration of
cognitive responses; these deficits are clinically relevant, noted by family members and
nursing and medical staff. Other cortical phenomena such as aphasia, apraxia and agnosia are
largely absent. Furthermore, the cerebellar cognitive affective syndrome is distinguishable
from other subcortical syndromes by virtue of the symptom complex consisting of
disturbances in executive, spatial, linguistic and affective functions. The core features of
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
executive, spatial, linguistic and affective changes set the cerebellar cognitive affective
syndrome apart from non specific confusional states or dementia states and other subcortical
syndromes.
How to Study CCAS
A complete screening for detecting the main features of the cerebellar cognitive affective
syndrome should compraise (Schmahmann 1998):
1. Neurological examinations
2. Bedside mental state tests
3. Neuropsychological testing
Neurological Examinations
The starting point for a diagnosis of cerebellar cognitive affective syndrome is the
presence of a cerebellar-related documented deficit in function.
Neurological observation is important because it can detect different movement disorders
according to the localization of the cerebellar damage.
On this purpose, neuroimaging investigations can best focus the cerebellar damage while
functional brain imaging is very informative in revealing the portion of cerebellum that is
activated by a large number of cognitive tasks (devoid of movement) and can help in
distinguish the contribution of the lesioned cerebellum to the new abnormal behaviour
observed in affected patients.
Bedside Mental State Tests
The CCAS includes alterations in behaviour that extend beyond cognition. Affected
patients may experience altered regulation of mood and personality, display obsessivecompulsive tendencies, and demonstrate psychotic thinking (Schmahmann, 2003). A recent
review of studies assessing the potential cognitive deficit and personality changes associated
with cerebellar disease has pointed out the role of the cerebellum in schizophrenia, dementia,
and other psychiatric disorders (Rapoport et al., 2000). The first reports in the 1800’s of the
behavioural consequences of cerebellar lesions focused on psychiatric manifestations; cases
of intellectual impairment and aberrant behavior in patients with cerebellar disease were
described as early as 1831 (Schmahmann, 1997). Later clinical studies identified a
relationship between the cerebellum and personality, aggression and emotion, and linked
psychosis and schizophrenia in particular with enlargement of the fourth ventricle, smaller
cerebellar vermis and cerebellar atrophy. Current studies show changes in cerebellar
symmetry and volume in schizophrenics and functional imaging studies reveal differences in
metabolic activity in the cerebellum of schizophrenics during tests of language and memory.
Vermal and hemispheric atrophy are evident on some MRI studies of autistic subjects,
although other investigators conclude that the cerebellar volume is larger than in controls
(Schmahmann, 2003). Recent findings suggest that researchers should consider the role of the
cerebellum to understand the neurological substrates of behavior (Rapoport et al., 2000)
because personality changes of either flattening of affect or disinhibited and inappropriate
behavior in patients with CCAS are common. Moreover depression has been shown to be a
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
113
recurring problem and it has been hypothesized that cerebellar vermal atrophy may be a late
degenerative event in those who have multiple affective episodes (Schmahmann, 2003).
Useful instruments adopted in order to evaluate mental state parameters of psychophatology
in patients affected by cerebellar cognitive affective syndrome are vermal atrophy may be a
late degenerative event in those who have multiple affective episodes (Schmahmann &
Sherman, 1998):
•
•
•
•
DSM III-R (SCID II; semi-structured interview for the diagnosis of personality
disorders; Spitzer et al., 2000).
CBA (CBA-2.0 – II edition: Cognitive Behavioural Assessment; Bertolotti et al.,
1986).
ABC (Aberrant Behaviour Cheklist; Aman et al., 1985).
ABI (Adaptive Behavior Inventory) (Brown & Leigh, 1987).
Neuropsychological Testing
The major functional category suggested to be addressed in the neuropsychological
testing for cerebellar cognitive affective syndrome are:
1.
2.
3.
4.
5.
6.
7.
Intellectual functioning
Executive functioning
Reasoning and abstraction
Visuo-spatial/visual construction
Language
Attention and orientation
Verbal and visual memory
In literature, several instruments are reported to be indicated for the specific evaluation of
these domains. See the tests listed below:
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Wechsler Adult Intelligence Scale – Revised (WAIS – R; Wechsler, 1981)
Wechsler Memory Scale – Revised (WMS – R; Wechsler, 1987)
Rey/Taylor Complex Figure Test (Rey, 1941; Kolb and Whishaw, 1985)
Controlled Oral Word Association Test (FAS; Yeudell et al., 1986; Spreen and
Straus, 1991)
Animal Naming Test (Spreen and Straus, 1991)
Stroop Color and Word Test (Golden, 1978)
Trail Making Test (Army individual Test Battery, 1994)
Wisconsin Card Sorting Test (Heaton et al., 1993)
Porteus Maze Test (Porteus, 1965)
Hooper Visual Organization Test (Hooper, 1983)
Boston Naming Test (Kaplan et al., 1983)
Peabody Picture Vocabulary Test – Revised (Dunn & Dunn, 1981)
California Verbal Learning Test (CVLT; Delis et al., 1987)
Rey Auditory Verbal Learning Test (RAVLT; Rey, 1958)
Written Fluency Test (H-words, Reitan, 1979)
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
•
•
•
•
•
•
Verbal Fluency Test (Novelli et al., 1986)
Raven’s Standard Progressive Matrices (Raven et al., 1976)
Benton Judgment of Line Orientation Test (Benton et al., 1983)
Benton Face Ricognition Test (Benton et al., 1983)
Tower of Hanoi Test (Shallice, 1982; Shallice and Burgess, 1991)
Wide Range Achevement Test (Wilkinson, 1993)
2. ROMBENCEPHALOSYNAPSYS
Rhombencephalosynapsys (RS) has been considered a rare malformation with an
estimate frequency of 0,13%, but MRI has diagnosed it in many children and adults
(Jellinger, 2002).
RS was first described by Obersteiner, on the post mortem examination of a 28 year old
suicide victim (Obersteiner, 1916) and called RS by Gross and Hoff in 1959. RS essential
features are the absence of the incisura cerebelli posterior, fusion of cerebellar hemispheres,
agenesys of the vermis, absence of the velum medullare anterius and nuclei fastigii, and
fusion of the dentate nuclei, which are shifted towards the midline (Schachenmeyr, 1982).
The first observation and four subsequent cases were all reported in Vienna and for this
reason RS was called a “Viennese malformation” (ibidem).
Severe behavioural disorders have been described in most cases (Jellinger ,2002).
Pathogenesis
Rhombencephalosynapsis (RHS) is a rare congenital condition in which the cerebellum is
severely underdeveloped. In this anomaly, vermian hypogenesis or agenesis is present and it
is not associated with disconnected cerebellar hemispheres, as in Dandy-Walker
malformation, “molar-tooth” malformation (an anomaly presented in case of Joubert
syndrome), or tecto-cerebellar dysraphia. On the contrary, the cerebellar hemispheres are
fused, and the dentate nuclei are closely apposed.
The pathogenesis of this unique malformation of the posterior fossa remains unclear, also
because occasional cytogenetic studies in patients with RHS resulted negative. Sarnat (2001)
suggested that RHS is probably a genetic disease, representing an underexpression of a
dorsalizing organizer gene.
Embryologically, RHS is likely to represent an early developmental derangement,
probably occurring at Carnegie stages 14-17 (28-41 days of gestation).
Rhombencephalon (hindbrain), the most caudal part of the encephalon, formed at stage
11, promptly divides in metencephalon (future pons and cerebellum) and myelencephalon
(future medulla oblongata). The embryonic cerebellum (tuberculum cerebelli) first appears as
a proliferation of cells in the alar laminae of the metencephalon: it consists of a band of tissue
in the dorsal part of the first rhombomere and straddles the midline in the shape of an inverted
“V”. During the thirds gestational month, the midline component shows accelerated growth
and begins to fill the acute angle between the limbs of the inverted V. The two cerebellar
primordes unite dorsally to form a median, worm-like mass, the vermis.
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
115
The lateral parts, i.e. the cerebellar hemispheres, grow rapidly. The cerebellar fissures
begin to form at about the 12th week of gestation in the transverse axis of the cerebellum. The
primary fissure divides the medial part of the cerebellum into the anterior vermis and the
posterior vermis, so that vermian differentiation occurs first in the most posterior (caudal) part
and proceeds toward the anterior (rostral) part. Finally, the cerebellum becomes connected to
the midbrain, pons and medulla by bundles of fibres called the superior, middle and inferior
cerebellar peduncles respectively.
In RHS, absence of the vermis finally results in abnormal cerebellar hemispheric fusion,
malorientation of folia and a unique horseshoe-shaped dentate nucleus, that appears to be
draped posteriorly to the fourth ventricle.
While cerebellar findings are quite similar in all patients affected by RHS, associated
supratentorial abnormalities can be very different. Hydrocephalus, secondary to aqueductal
stenosis, absence or hypoplasia of the corpus callosum, the anterior commissura, and the
septum pellucidum, nodular heterotopia, fused fornices, fused thalami, and hypoplasia of the
temporal lobes were also described. These supratentorial anomalies, which often dominate the
clinical features, are consistent with the suggested gestational timing of RHS. They all, in
fact, may represent malformation in ventral induction, which occur at the same time the
cerebellum is developing.
It is worthwhile to be noticed that development of the posterior fossa differs significantly
from that of the supratentorial brain. Whereas the telencephalon undergoes a normal cleavage
process known as diverticulation, following a midline to lateral pathway, the cerebellum
arises from two distinct embryonic primordia, and the median vermis forms in a second time
from the lateral hemispheres following a lateral to midline direction. So, the vermis represents
the only cerebellar interhemispheric connection, whereas the peduncles allow cerebellar
communication with the brainstem and the remainder of the central system.
Neuropathology
The first report of rhombencephalosynapsis was described by Obersteiner in 1916.
Schachenmayr described the absence of the olfactory tracts, bulbs and septum pellucidum in
concert with the posterior fossa malformation (Schachenmayr, 1982). Rhombencephalosynapsis appears to represent a unique malformation of the posterior fossa, however variable
supratentorial anomalies have occasionally been reported such as abnormal gyri,diminished
white matter, fused cerebral peduncles, thalami and fornices, hydrocephalus, agenesis of the
septum pellucidum, hypoplasia or aplasia of anterior commissure, agenesis of olfactory tracts,
dysgenetic corpus callosum, meningoencephalocele, schizencephaly, anomalies related to
hypothalamic–hypophyseal axis, and thalamic fusion (Taori, 2003). Moreover, in the reports
by Gross and Kepes, rhombencephalosynapsis was associated with thalamic fusion and third
ventricular deficiency. It is interesting to know that the hypothalamic-pituitary axis appeared
normal in all cases but one (Taori, 2003). In that case, the posterior pituitary lobe was absent,
the septum pellucidum was absent, and the optic nerves, chiasm, and tracts were markedly
hypoplastic, fulfilling the pathologic diagnosis of septo-optic dysplasia [Michaud, 1982;
Truwit, 1991]. Nevertheless, in only two cases the corpus callosum was described as
hypoplastic or dysgenetic (Taori 2003). Rhombencephalosynapsis thus appears to represent a
unique malformation of the posterior fossa with occasional supratentorial, midline anomalies,
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
most likely related to the gestational age at the time of insult to the developing
rhombencephalon. The severity of clinical manifestations and the prognosis of
rhombencephalosynapsis generally depend on the associated supratentorial anomalies.
Cakirer (2003) summarizes both the similarities and differences between Joubert syndrome
and rhombencephalosynapsis in terms of their clinical and radiological aspects. The main
common feature of these two anomalies is aplasia or hypoplasia of the cerebellar vermis
associated with a malformed cerebellum and fourth ventricle. Distinguishing features include:
(a) apposition of cerebellar hemispheres that may be associated with a vermian cleft in
Joubert syndrome vs the fusion of cerebellar hemispheres across the midline in
rhombencephalosynapsis; (b) the thickened and elongated superior cerebellar peduncles
causing molar tooth sign in Joubert syndrome versus the fusion of peduncles in
rhombencephalosynapsis; (c) the absence of vermian folial pattern in Joubert syndrome
versus abnormal orientation of folia in rhombencephalosynapsis; (d) the dysplasia and
heterotopia of dentate nuclei in Joubert syndrome versus fusion of nuclei across the midline;
(e) the presence of isthmic dysgenesis and brain stem tract and nucleus anomalies in Joubert
syndrome; (f) the fusion of inferior colliculi in rhombencephalosynapsis; (g) the more
common
association
of
supratentorial
anomalies
and
hydrocephalus
in
rhombencephalosynapsis; and (h) the more common association of extracranial anomalies in
Joubert syndrome make the differentiation of these two developmental anomalies easy with
neuroimaging studies, especially MRI.
Genetics
All published cases have been sporadic. A single instance of consaguineity was signaled
by Romanengo (1997), who suggests the possibility of autosomal recessive inheritance.
Karyotype was normal in all reported cases except in a case reported by Truwit (1991) where
an interstitial deletion of the long arm of chromosome 2 has been detected.
The pathogenesys of RS is obscure, however recently an animal model, Dreher Lmx 1a
gene mutant mouse, has been proposed (Jellinger, 2002). This model shows agenesis of the
vermis with fusion of cerebellar hemispheres and inferior colliculi due to dorsal patterning
defects in the hindbrain, resembling human RS. The autosomal recessive mutation of the
recently identified LIM homebox gene includes misplaced neurons in numerous patterns of
the CNS which mimic a spectrum of neuronal migration disorders in human, probably due to
disruption of the glial limiting membrane (Costa, 2000). LIM – home box genes play an
essential role in patterning and differentiation of different cell types during embryonic
development (Zhao, 2000). Experimental studies on the genetic control of early regional
specification of brain stem structures have identified a critical organizer center for cerebellar
development: the isthmic organizer (Hatten, 1995) which is localized at the hind-midbrain
transition and controls anterior hindbrain and midbrain regionalization (Martinez, 2000). It is
possible that mutations of genes that regulate early specification of cerebellar domain
,particularly the homeotic genes that establish the dorsal isthmic region,might produce the
alterations found in RS (Yachnis, 2002).
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
117
Associated Anomalies
The clinical presentation associated with RS is extremely variable ranging from mild
truncal ataxia to severe cerebral palsy and mental retardation (Toelle, 2002). The degree of
mental retardation is also very variable, from mild to severe. Reported cases were from
different age groups, the youngest being reported antenatally (Litherland, 1993) and the oldest
being a 39 years old living patient (Montull, 2000; Taori, 2003).
The last author reviewed from literature 23 cases with sufficient clinical data and
signalled 6 new cases. All published cases have been sporadic. Ataxia was reported in 12/23
patients. Head rolling was reported in 4 patients. Epilepsy was reported in 7 patients. Seizures
were also present in one of the autopsy cases reported by Gross (1959).
Hand anomalies have been reported by Aydingoz (1997) in a RS subject, namely
phalangeal hypoplasia and occult polydactyly in the right hand and syndactyly in the left.
Outside the central nervous system,the muscoskeletal system is the commonest site of
associated anomalies in case with RS: Michaud (1982) described a case of RS in a severely
malformed newborn who died in the first day of life with hypoplasia of the right hand and
multiple segmentation defect of the cervical and thoracic vertebrae and left upper ribs. Facial
anomalies have been described by Romanengo (1997): low set ears, long philtrum,
hypertelorism and strabismus.
Cardiovascular, respiratory, and urinary system anomalies are very rarely associated
extracranial findings (Taori, 2003).
MR Imaging
The MR features of RS are characteristic. The posterior fossa is small; no cyst is present.
In a sagittal section, the fourth ventricle appears narrowed. The fastigium is formed, and the
nodulus seems to be the only component of the vermis, and determinates a protuberance
below the fastigium. On axial sections, the fourth ventricle does not appear with the normal
crescentic shape, but it is deformated, with a typical diamond-shaped morphology described
as tear-drop, or keyhole. This abnormal configuration of the fourth ventricle results from the
dorsal and rostral convergence of the dentate nuclei, the cerebellar peduncles, and the inferior
colliculi. It is also due to the absence of the vermis, that normally shapes the floor of the
fourth ventricle. Further distinctive features are a flat and uninterrupted continuity of the base
of the cerebellar hemispheres, clearly evident in coronal sections, transversely orientated folia
and fissures in the inferior cerebellum, that extend directly across the midline, and large
corpus medullare, all of which represent the single-lobed cerebellum.
Behavioral Disorders, RS and Gomez Lopez Hernandez Syndrome
Behavioral disturbances have been reported in RS. The first report of
rhombencephalosynapsis, was about the post mortem examination of a 28 year old suicide
victim (Obersteiner, 1916). No clinical data were known about the patient. However ,we
know his profession (Kanzleigehilfe), so we suppose he had no mental retardation.
Compulsive head rolling was signaled by Demarel (1994) in a 6-year old boy affected by RS
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
and a behavioral disorder-associated with psychomotor epilepsy has been described in
another RS patient, diagnosed with MRI (Savolaine ,1991). Autoaggressive behaviour has
been described by Toelle in his second patient (2002).
Self injurious behavior has been reported in all patients with Gomez Lopez Hernandez
(GLH) syndrome, characterized by RS, congenital trigeminal anaesthesia and alopecia. GLH
syndrome, also called cerebello-trigeminal dermal dysplasia, has been described for the first
time by Gomez in 1979. A few patients with GLH have been described since 1979 (Gomez
1979 ; Lopez-Hernandez 1982; Pascual Castroviejo 1983; Gomez 1987; Munoz 1997 ;Brocks
2000). It is interesting to note that Gross in the autopsy of his two RS patients in 1959,
signalled in both cases two symmetric circumscribed areas of hair loss (symmetrische
umschriebene Defekte der Kopfbehaarung). Normal chromosomal analysis has been reported
in all the patients. The syndrome seems to be sporadic or autosomal recessive (OMIM).
Physical examination is characterized by towerlike skull, flat forehead and occiput-bilateral
parietal areas of alopecia. Craniosynostosis has been described in all patients. Other
dysmorphic features are midfacial hypoplasia, bilateral corneal opacities, ocular
hypertelorism-telecanthus, low set ears. Clinodactyly of fifth fingers is reported frequently.
Growth is impaired: all patients range less than the third percentile in height and weight.
From the neurological point of view, cerebellar ataxia and corneal and facial anaestesia of
trigeminal distribution have been described in all subjects. A MRI imaging of
rhombencephalosynapsis associated with hypoplasia of trigeminal nuclei is present in all
subjects. Cognitive aspects are characterized by mild to severe mental retardation.
Hyperactivity, depression, self injurious behavior, bipolar disorders have been reported in
these subjects. Self injurious behavior may be partially due to the lack of sensory sensation to
the face and eyes (Brocks, 2000). Life expectancy is not known, but all the described cases
are very young (the oldest is 19 yrs old).
Case Report
Since 1996 we are following a young patient (S.A.) affected by RS who came to
observation for oral self mutilation (Verri, 2000): now he is becoming increasingly alcohol
addicted (with a week-end modality).
The patient was born on the 30th week of pregnancy: neonatal weight was 2 kg. Delayed
psychomotor development was evident since early neonatal period; he was able to walk alone
only at the age of 2; he had however problems with balance till the age of 3.
Learning problems were evident at the primary school. During late infancy, compulsive
head rolling was signaled. The patient is actually working as labourer.
From the age of 19 yrs, he started to compulsively touch his teeth and his gums. For this
reason he developed oral infections followed by lost of all his teeth. He got recurrent
implantology.
At the age of 22 he was hospitalized because of a suspected neoplasm of the mouth (Fig
1). An oral mucosal biopsy documented a granuloma with a secondary infection.
Subsequently, he was hospitalized in our Neurological Institute, to clarify his clinical
symptomatology.
The objective evaluation documented dysmorphic features (little dysmorphic ears,
cubitum valgum, hypertelorism, pes cavum) and bitemporal balding (Fig.2 and Fig. 3)
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
119
Neurological evaluation showed a slight truncal ataxia and right trigeminal hypoestesia.
Bilateral keratoconus has been signalled by the ophthalmologist.
Fig.1: Presenting oral lesion of the patient S.A.
Fig 2: The 28yrs old patient (frontal view): see hypertelorism and bitemporal balding.
120
A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
Fig 3: The 28yrs old patient (lateral view): see lower face hypoplasia.
Chromosomal analysis was normal. Routine biochemical analyses were normal.
Neurophysiological Evaluation
To evaluate trigeminal function, the patient was submitted to an electromyographic
(EMG) study of masseter muscle by coaxial-needle electrode, exteroceptive suppression
reflexes of masseter muscle by infraorbital foramen stimulation, and blink reflex. Neurogenic
findings represented by an increased area of motor unit action potentials (MUAPs) and poor
recruitments of the interference pattern were observed in the right masseter muscle; normal
EMG findings were obtained in left muscle.
Exteroceptive suppression (ES) reflexes of the masseter muscle revealed absence of both
first and second inhibitory components (ES1 and ES2) of the right masseter muscle when
stimulating the omolateral infraorbital foramen; normal latencies and duration of ES1 and
ES2 components were obtained in the controlateral muscle when stimulating the left
infraorbital foramen.
The stimulation of the left side showed normal latencies and duration for both ES1 and
ES2.
Blink reflex by stimulating the right side revealed absence of R1 direct component with
latencies of R2 components (direct and controlateral) prolonged,whereas the stimulus of the
left side showed R1 and R2 (direct and controlateral) with normal latency (Fig.4). These
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
121
findings indicate a severe sensory deficit strictly unilateral of the first trigeminal branch. An
alteration of peripheral motor axons of the trigeminal nerve in the side involved was indicated
by the EMG findings of the masseter muscle and by the absence strictly unilateral of ES1 and
ES2 reflexes.
Fig 4: Blink reflex by supraorbital nerve stimulation in patient with Gomez Lopez Hernandez syndrome. D:
direct response; C: controlateral response. Absence of R1 response (R1?) and delayed latency of R2 D
response by stimulating the right side.
Therefore electrophysiological study showed abnormalities in both sensory and motor
pathways of the trigeminal nerve.
Neuroradiological Findings
NMR, performed by a Philips "Gyroscan T5" 0,5 Jesk tool documented a typical picture
of rhombencephalosynapsis, caractherized by fusion of cerebellar hemispheres, abnormal
transversal orientation of cerebellar folia, and vermian agenesis, with narrowing and posterior
pointing of the fourth ventricle (Fig.5,6,7). No associated supratentorial anomalies were
demonstrated.
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
Fig 5: Sagittal T1-IR weighted image shows the abnormal aspect of the cerebellum: on the midline the medial
part of cerebellar hemispheres, instead of the vermis, are evident. The fourth ventricle is narrow.
Fig. 6: Axial T2-weighted image shows the so-called “teardrope” shape of the fourth ventricle.
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
123
Fig. 7: Coronal T1-IR weighted image shows the fusion of the cerebellar hemispheres on the midline, the
transverse orientation of the cerebellar folia and the flat aspect of the basis of the olocerebellum.
Cognitive-Behavioural Assessment
The evaluation with DSM-IV criteria documented an obsessive-compulsive personality
disorder on axis II associated with emotional instability; Cognitive Behavioral Assessment
(C.B.A.) (Sanavio 1986) documented a mild obsessive-compulsive disorder; Aberrant
Behavior Checklist (ABC) (Aman 1985) documented a stereotipic, self injurious behavior.
The patient was sufficiently autonomous and able to work: Adaptive Behaviour Inventory
(Brown-Leigh 1987) points out a good level of autonomy.
During the various sessions of assessment S.A. was generally collaborating: he gladly
participated to the talks and executed the proposed tasks with adequate levels of attention and
concentration. He was sociable and wasn’t frightened of the situation; the language was rather
simple, at times stereotyped and there were some expressive difficulties due to the
consequences of the oral self mutilations. However he answered pertinently to the questions:
he was well oriented in space and time and gladly spoke about his own interests and
activities. Sometimes he appeared uninhibited and his attitude was rather childish: he laughed,
he joked, he spoke loudly and addressed the examiner like a friend, often using expressions
from his dialect. In any case he showed good understanding: he quickly understood the
instructions and he was able to remember them throughout the tasks. Sometimes he looked
like restless, especially when he performed the more complex tasks and he frequently showed
124
A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
the tendency to give impulsive answers; anyway his attention ability and his motivation levels
seemed to be adequate.
The following instruments were administered: Wechsler Adult Intelligence Scale
(WAIS), Token Test; Coloured Progressive Matrices (CPM); Ray Taylor Complex Figure
Test; Rey Auditory Verbal Learning Test (RAVLT); Verbal Fluency; Stroop Test; Trail
Making Test; Wisconsin Card Sorting Test (WCST). (Table 1).
To the Wechsler Adult Intelligence Scale (WAIS) S.A. obtained a Full Scale IQ = 74
(mild mental retardation score) with a light discrepancy among the verbal subtests (Verbal IQ
= 79, low average score) and the performance subtests (Performance I.Q. = 72, mild mental
retardation score).
Verbal subtests showed poor attentive skills and short-term memory (at the “digit span”
S.A. was able to repeat five numbers forward and four in reverse sequence) and a limited fund
of knowledge acquired through school and cultural experience (“information”). Abstract and
understanding, as tested by “similarities” and “comprehension” respectively, where simple,
with limited ability to synthesize verbal relationships and restricted practical information and
social knowledge. S.A. had limited computational skills: at the “arithmetic” he was able to
solve only those tasks requiring the use of one single of the four fundamental arithmetical
operations (addition, subtraction, multiplication and division). But, above all, he had poor
verbal competences and verbal language (at the “vocabulary” he was able to report the meant
of only few simple terms as, for instance, “winter” or “to repair”).
Performance subtests revealed accuracy and speed of visual motor coordination and good
scanning ability (“coding”) but impairments in nonverbal reasoning and logical sequencing
(“picture arrangement”), in visual-spatial organization (“block design”) and, above all, in the
organization of the perception and the reconstruction of concrete shapes (“object assembly”).
Token Test showed good understanding of spoken language, while the performance at
Coloured Progressive Matrices (CPM) revealed reduced efficiency in the logical-deductive
and abstract reasoning.
Visual-spatial organizational skills as assessed by the Rey Complex Figure Copy seemed
to be fairly good: S.A. completed the design rather quickly (approximately 300 second), he
copied all the elements of the figure and placed them in the correct position, even if he lost
the proportions between the various parts. On the other hand, his visual-spatial memory
seemed to be severely impaired: in the Rey Complex Figure Memory S.A. only reproduced
the outline of the figure and little elements to its inside; anyway, those that he designed were
correctly placed.
In the Rey Auditory Verbal Learning Test (RAVLT) S.A. showed good ability in verbal
list learning and memory tasks: he was able to immediately remember approximately 11
words out of 15 listed and recalled 10 out of these at 5 min.
Verbal Fluency tasks revealed severe impairment in the phonemic fluency: S.A. was able
to say approximately six word in the specified time (one minute) for each letter of the
alphabet presented (“F”, “P”, “L”). The semantic fluency seemed to be in the norm: in a
minute S.A. was able to name approximately 16 words belonging to each category
(“animals”, “cars”, “fruit”).
Selective and focused attention, mental control and response flexibility as assessed by the
Stroop Test seemed to be fairly good. Also the Trail Making Test task A showed average
attention and visual-motor tracking skills, while the task B revealed a reduced efficiency in
divided attention and ability to shift.
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
125
S.A. performance at the Wisconsin Card Sorting Test (WCST) fell within the average: he
was able to complete all the 6 categories in 86 matching out of 128, even if he took several
trials to establish the first matching criterion, showing reduced cognitive intuition and
difficulties in hypothesis generation. His abstract reasoning seemed to be quite perseverative,
even if there were not large differences in comparison with the performance of the greater
part of the subjects of his age. (T score range 45-54). Moreover, S.A. seemed to be able to
establish and maintain adequate problem-solving strategies and to use response feedback
information to improve his performance.
Table 1: Cognitive Assessment Results for instruments with normative data.
TEST
WAIS
Full Scale IQ
Verbal IQ
Performance IQ
Token Test
CPM
Trail Making Test
Task A
Task B
RAVLT
Repetition
Delayed Recall
Verbal Fluency
Phonological
Semantic
SCORE
NORMATIVE DATA
MEAN ± D.S.
74
79
72
34
20
100 ±15
100 ±15
100 ±15
34.45 ±1.58
36.18 ±7.43
42 (sec)
200 (sec)
28.02 (sec) ±8.78
72.30 (sec) ±28.55
57
10
50.12 ±8.35
11.37 ±2.17
19
46
35.09 ±9.84
42.74 ±6.96
3. DISCUSSION
The cognitive-affective disorder associated with rhomboencephalosynapsis seems to be
linked to brain dysfunction: this report supports the theory of a cerebellar contribution to non
motor functions (Shachmann, 1998).
In our patient, performance IQ is slightly lower than verbal IQ. A difference between
performance IQ and verbal IQ has been reported in congenital ataxia (Steinlin, 1999).
Neuropsychological evaluation documented a disturbance of executive functions (particularly
nonverbal reasoning and planning), impaired visuospatial memory and reduced phonetic
fluency, which have been reported in the cerebellar cognitive affective syndrome
(Schmahmann, 2002). The evaluation with DSM-IV criteria documented an obsessivecompulsive personality disorder on axis II and a stereotypic self injurious behavior.
Behavioral alterations are very severe and are mainly characterized by compulsive
touching of the mouth with consequent infections.
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
Self-injurious behavior occurring in persons with mental retardation is a clinically
significant and poorly understood problem (King, 1998). It is more frequent in subjects with
sensory impairment, autism and severe intellectual disability (Oliver, 1987).
Compulsive self-injurious behavior has been described in disorders with known
dysmethabolic pathogenesis as in Lesh- Nyhan disease (Lesh & Nyhan, 1964) or in other
disorders secondary to chromosomal abnormalities (Cornelia de Lange syndrome, Smith
Magenis syndrome, Prader Willi and so on) (Deb, 1998). Different types of self injurious
behavior have been described in different conditions. Self Injurious Behavior in many
respects is becoming a model for the study of gene-brain-behavior relationships in
developmental disabilities (Schroder, 2001). For example in Smith Magenis syndrome, the
number of different types of self injurious behaviors exhibited was also directly correlated
with level of intellectual functioning (Finucane, 2001).
Nyhan proposed a neurotransmitter hypothesis for the autoaggressive compulsive
behavior in Lesh Nyhan disease suggesting an impaired dopaminergic and serotoninergic
pathways (Nyhan, 1996).
However the autoaggressive behaviour often is evident in disabled subjects and is
considered as a psychopathological answer to their condition probably due to a selective
vulnerability impairment of a specific neuroaxonal systems.
Functional self mutilation is performed knowingly, as a response to certain stimuli and
may or may not serve as a positive purpose (Altom, 1989). On the contrary, we were
impressed by the apparent compulsiveness of the injurious behavior of our patient: he
frequently asked to his parents to be restricted with hands bandages and he became anxious
when the bandages were removed. Self restraint is very common (12-50% from prevalence
studies) in individuals with intellectual disabilities who engage in self injurious behaviour
(Forman, 2002).
The neurobiology of repetitive movement disorders (stereotyped, self injurious and
repetitive behavior) in mentally retarded people is supposed to be related to a developmental
insult to central dopamine and serotonine systems (Lewis, 1995). Current findings support a
dopamine deficiency model and suggest the efficacy of serotoninergic medications (ibidem).
These were relativily ineffective in our patient.
King (1998) considers multiple neurotransmitter systems implicated in the pathogenesis
of self injurious behavior, particularly dopaminergic, opioidergic, and serotonergic systems.
Pemoline, a central stimulant, administered systemically at high doses reliably produces selfbiting behavior in the rat. The systemic bolus of pemoline produces sustained neostriatal
levels of pemoline for over 24 h in a continuous infusion paradigm. Studies of the effect of
cortical lesions on pemoline-mediated behaviors reveal that cortical damage, as is common in
profound mental retardation, lowers the threshold for pemoline-induced self-biting behavior.
Data from the corticostriatal slice suggests that sustained exposure to pemoline produces a
shift in N-methyl-D-aspartate receptor-mediated responses rendering them more susceptible
to dopaminergic enhancement. Thus, dopaminergic and glutamatergic interactions appear to
play an important role in the development and expression of self-biting in the pemoline model
(King, 1998).
Though a wide range of self mutilations in mentally retarded as well in psychotic state
have been described, oral self mutilation, particularly autoextraction, is rare (Altom, 1989 ;
Armstrong, 1999). The most common topographies reported are head banding, biting, head
bitting, body hitting and scratching (Hyman, 1990).
Cognitive Affective Disorder Associated with Rhombencephalosynapsys
127
Self injurious behaviour has been reported in all patients affected by GLH and was
characterized by scarring of the face and head banging (Brocks, 2000). The GLH patient
reported by Brocks presented hyperactivity at 4 years, leading to the diagnosis of attention
deficit disorder with age progression. Self injurious behaviour initially noted at 2 year
progressed when he became older. This along with depression (the patient was diagnosed as
having bipolar disorder) and suicidal tendencies necessitated continuos monitoring by age 17.
Behavioural problems and suicidal behaviour have been reported also in individuals with
apparent isolated rhomboencephalosynapsis. Up to date, anomalies of the cerebellar vermis
has been reported in affective disorders (Shah, 1992) and in autism (Hashimoto1989,
Courchesne 1991,1994,1998). Recently, a MRI volumetric study tested the differences in
vermis volume between autistic subjects, Down and fragile X (Kaufmann 2003). Posterior
lobules vermi (lobules VI-VII and VIII-X) were markedly smaller in both Down syndrome
groups and those with fragile X syndrome only, whereas only lobules VI-VII were reduced in
idiopathic autism. The authors conclude that selective posterior vermis hypoplasia is seen not
only in idiopathic autism but also in Down syndrome and some individuals with fragile X
syndrome. However, reductions in vermian lobules VI and VII appear to be specific to
idiopathic autism, whereas increased size of lobules VI and VII is associated with autism in
fragile X syndrome. The latter results are consistent with MRI studies showing lobules VIVII hyperplasia in a subset of subjects with idiopathic autism and cerebral and hippocampal
enlargements in fragile X syndrome (Kaufmann, 2003). Purkinje cell atrophy in autism with
significant neurohistological heterogeneity among individuals diagnosed with this disorder
has been also described (Fatemi, 2002). Neuroanatomic imaging in autism had suggested a
role of cerebellar anomalies in this disorder since many years (Courchesne, 1988) The
cerebellum was the only anatomical structure for which there is both imaging and autopsy
evidence of abnormality based on data gathered by many laboratories (Courchesne, 1991).
Neurophysiologic and neuropsychologic studies of children with hemicerebellar resections
and children with autism present an entirely new picture of the role of the cerebellum in
normal human cognition in general and in the development of the social and communication
deficits in autism in particular (Courchesne, 1991).These studies show that autistic subjects
and patients with acquired cerebellar damage are unable to rapidly shift their mental focus of
attention. In patients with autism, neocerebellar abnormality may directly impair cognitive
functions ; may indirectly affect, through its connections to the brain stem, hypothalamus, and
thalamus, the development and functioning of one or more systems involved in cognitive,
sensory, autonomic, and motor activities; or may occur concomitantly with damage to other
neural sites whose dysfunction directly underlies the cognitive deficits in autism
(Courchesne,1988). Attention to understanding normal and abnormal development of the hind
brain is a key to define the genesis of autism spectrum disorders (Sulik, 2002).
Neocerebellar congenital maldevelopment has to be considered a significant risk factor
not only for neurological but also for cognitive and behavioral disabilities. A global cerebellar
impairment may be diagnosed in RS : dysregulaytion of movement causes ataxia and
dysregulation of thoughts and emotion causes cerebellar cognitive affective syndrome
(Schmahmann, 2002).
The clinical spectrum of anomalies associated with RS will be better evaluated with the
evolution of clinical and genetic research. In particular the connection between sporadic RS
and GLH syndrome needs to be clarified. We recommend that a neurophysiological
evaluation of trigeminal function be performed in all patients with RS: in fact, the GLH
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A. Verri, C. Uggetti, E. Alfonsi, A. Ramponi and V. Destefani
syndrome may be underdiagnosed. An electrophysiological evaluation identifies in the
trigeminal areas objective abnormalities which would otherwise not be recognizable by
clinical investigation since an important intellectual disability is common in these patients.
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