Neuropsychological status in
children with agenesis of
corpus callosum
P. Martelli 1, E. Fazzi1,2, C. Guuva2, S. Micheletti1,3, L.
Pinelli4, C. Ambrosi 4, C. Groli5, P. Moretti5, P. Accorsi 1
1 Unit of Child Neurology and Psychiatry, Brescia, Italy
2 Department of Clinical and Experimental Sciences, Unit of Child Neurology and Psychiatry,
Spedali Civili, University of Brescia, Brescia, Italy
3 Cognition Psychology Neuroscience Lab., University of Pavia, Pavia, Italy
4 Neuroradiology Unit, Department of Diagnostic Imaging, University of Brescia, Brescia, Italy
5 Prenatal Diagnosis Unit, Department of Obstetrics and Gynecology, University of
Brescia,Brescia, Italy
Introduction
The agenesis of corpus callosum (ACC) is the most frequent
commissural malformation of the central nervous system.
The prevalence of ACC (complete and partial) is reported to be
1.4 per 10,000 live births (California Birth Defect Minitoring
Program Santo S.- Ultrasound Obstet Gynecol -2012) but 2-3% in
neuropaediatric population.
ACC can be isolated (absence of other extraneurological and
neurological abnomalities observed by postnatal MRI, normal
karyotype testing and normal virus screening) or complex
(associated with other cerebral and extracerebral
abnormalities, including genetic syndromes, cromosomal
anomalities, viral infection or toxic syndromes).
ISOLATED AGENESIS of CORPUS
CALLOSUM
Fetal MRI
(31.3 w)
ISOLATED AGENESIS of CORPUS
CALLOSUM
DTI
(FA map)
Post-natal MRI
(6 days old)
AGENESIS of CORPUS CALLOSUM
WITH INTEREMISPHERIC CYSTS + PMG
Fetal MRI
(27 w)
AGENESIS of CORPUS CALLOSUM
WITH INTEREMISPHERIC CYSTS + PMG
Post-natal MRI
(2 days old)
Acc: state of art
• The prenatal diagnosis agenesis of corpus callosum is a
problem within parental counseling due to its uncertain
prognosis
• Prenatal counseling is currently based on scattered data
coming mainly from small cases series.
• In most studies assessment was made in preschool
period and/or it represented only an evaluation of
DQ/IQ.
•
•
•
•
•
•
•
•
Few studies
Most studies report a small number
of cases
Imaging protocol different : prenatal
diagnosis by echography or by fetal
MRI; postnatal diagnosis by TC or
MRI
Different terminology about complex
or isolated ( f.e.: ACC isolated with
interemisferic cystis)
Incomplete studies: studies not
provide karyotyping information
Many study report short follow-up
Outcome assess by different tool:
formal assessment with standardized
and validated tool or informal
assessment , interviews, non
standardized questonnaires, …
Lack of distinction on the severity of
neurodevelopmental delay
•
•
•
•
•
•
•
•
Prevalence of associated brain abnormalities is 45,8%
RMI allows direct visualization of C.C ( false-positive by ultrasound 0%-20%)
and confirm whether partial or complete detect coexisting brain abnormalities (additional
abnormalities in 22,5% of cases compared with ultrasonography)
The overall rate of chromosomal abnormality is 17,8% but a recent study suggests that this
high risk of chromosomal abnormalities is confined to complex cases also the comparative
genomic hybridization shold be considered
ACC has been associated with several syndromes AD, AR, X-linked.
Bedeschi found that 33% had a recognizable syndrome. Schell-Apacik 12%
ACC has been reported in association with CMV,TOXO,rubella, influenza but other associated
anomalies usually coexist
Prognosis in ACC is dependent on the coexistence of other abnormalities, which can only
be assessed with advancing gestation
In 15,1% of cases thought to be isolated prenatally were found to have associated
abnormalitie after birth
The rate of neurodevelopmental delay in infant with a prenatal diagnosis of isolated ACC is
about 25-30% and this appears to be similar in complete and partial ACC.
Acc: state of art
• The prenatal diagnosis agenesis of corpus callosum is
a problems within parental counseling due to its
uncertain prognosis
• Prenatal counseling is currently based on scattered
data coming mainly from small cases series.
• In most studies assessment was made in preschool
period and/or it represented only an evaluation of
DQ/IQ.
One study has a long follow-up, neuropsychological
tests, school achievement
Follow-up yearly until 6 years of age and every 2 years there after
IQ ( Weschler Intelligence Scale for children WISC III)
Laterality, short-term memory, Long-term memory, Fine motor skills, perception, analysis and
synthesis of complex visual-spatial material and visual memory
Cultural status of parents
Information regarding school placement was collected from interviews with the parents
Aim of our study
To describe
neurodevelopmental
profile in a sample of
children with prenatal
diagnosis of ACC
Study
Between 1998 and 2011, 38 children were referred to
Unit of Child Neurology and Psychiatry of Spedali
Civili, Brescia after prenatal diagnosis of ACC.
Prenatal diagnosis was made, in Prenatal Diagnosis Unit
of Spedali Civili, by ultrasound between 20 w and 36
w of gestation and confirmed by fetal MRI
only in 31 fetuses.
38 children with
prenatal diagnosis of
ACC
30 with
postnatal
MRI
15 isolated ACC
2 drop-out
1died in car crash
3 “normal”
(interview by phone)
-
8 without
postnatal
RMI
14 complex ACC
( with associated cerebral
anomalies and 1 Aicardi
syndrome)
23 children evalueted in this study
9 isolated ACC 14 complex ACC
1 Other
diagnosis
Characteristics of the sample
INCLUSION CRITERIA: PRENATAL DIAGNOSIS OF ACC BY FETAL ULTRASOUND OR FETAL MRI
FROM 1998 TO 2011 , POSTNATAL MRI, NEUROLOGICAL FOLLOW UP OF AT LEAST 18 MONTHS
GENDER
ISOLATED ACC ( 9)
8M
1F
COMPLEX ACC (14)
8M6F
AGE OF OBSERVATION
MEAN (RANGE/SD)
PREGNANCY AND DELIVERY
5 y 6 m ( RANGE 18 m- 15 y
SD 4)
physiological
4y 2 m (RANGE 2 y- 10 y
SD 2,4)
physiological
GESTATIONAL AGE
BIRTH WEIGHT
8 term (38-41 W )
1 late preterm (35 W)
normal for gestational age
13 term (38 -40W)
1 late preterm (35 W)
normal for gestational age
HEAD CIRCUMFERENCE
normal for gestationa age
3 with HC < 2 sd
DYSMORFIC FEATURES
KARYOTYPE
8 absence of features
1 minor facial dysmorphies
normal in all cases
13 absence of features
1 facial dysmorphies
normal in all cases
VIRUS SCREENING
normal in all cases
normal in all cases
FEBRILE SEIZURES
absent
absent
EPILEPSY
PARTIAL/COMPLETE ACC
absent
0 partial / 9 complete
2 focal epilepsy
4 partial/10 complete
METHODS
CLINICAL , NEUROLOGICAL EVALUTION and postnatal MRI
,KARYOTYPE and VIRUS SCEENING
DEVELOPMENTAL/
INTELLIGENCE QUOTIENT
BAYLEY SCALES OF INFANT AND TODDLER DEVELOPMENT
WECHSLER PRE-SCHOOL AND PRIMARY SCALE OF INTELLIGENCE III
WESCHLER INTELLIGENCE SCALE FOR CHILDREN III
NEUROPSYCHOLOGICAL ASSESMENT
ONE NEUROPSYCHOLOGIST IN BLIND
COGNITIVE EVALUTATION
EXECUTIVE FUNCTIONS
DIGITAL RECALL TASK; LISTENING RECALL TASK (BILANCIA & BERTELLI, 1998)
COORDINATION ABILITIES
MOVEMENT ABC
ATTENTION
ATTENTIONAL SCALE CBCL, CANCELLATION TASK
BEHAVIOURAL ASSESSMENT
OBSERVATIONAL SCALES
Child Behaviour Check List 1½-5
Child Behaviour Check List 6-18
ACADEMIC SKILLS
READING SKILLS
WRITING SKILLS
ARITHMETIC SKILLS
Standardized batteries which assess the speed and accuracy in reading,
writing and arithmetic tasks(Cornoldi & Colpo, 1998; Sartori, Job, &
Tressoldi, 2009, Biancardi-Nicoletti, 2004; see Consensus Conference, 2007)
NORMAL: normal neurological exam and
neuropsychological evaluation, DQ/IQ >85, absent
behavioral problems (CBCL <60 T scores)
outcome
COMPLEX ACC
NEURODEVELOPMENTAL OUTCOME
COMPLEX ACC
NORMAL OUTCOME
MILD IMPAIRMENT
PATHOLOGICAL OUTCOME
43% (6)
43% (6)
age range 2y -5 y
age range 18m-10 y
14% (2)
age range 5y – 7 y
COMPLEX ACC outcome
NORMAL
MINOR SIGNS
DEVELOPMENT
1
2
3
4
5
6
7
8
+
+
+
+
+
+
+
IQ 70
FOCAL
EPILEPSY
MILD
IMPAIRMENT
PATHOLOGICAL
OUTCOME
+
10
12
13
14
CP
NORMAL
OUTCOME
9
11
IQ < 50
+
+
+
+
+
+
++
++
+
+
+
++
++
OUTCOME/ POSTNATAL MRI
ASSOCIATED MALFORMATION
1
multiple interhemispheric cysts, polymicrogiria, cortical abnormality
2
8
septo optic dysplasia
interhemispheric cyst, complex cortical abnormality developmental with
polymicrogiria and heterotopia
mild hypoplasia vermis
focal cortical dysplasia
ventriculomegaly
interhemispheric cysts, cortical abnormality developmental
cortical dysplasia, voluminous cysts arachnoid of the vermian cistern
9
multiple interhemispheric cysts, polymicrogiria
10
malformation of the cerebellar vermis, hydrocephalus
multiple interhemispheric cysts, polymicrogiria, heterotopy, choroid
plexus cysts, optic nerve coloboma (Aicardì syndrome)
ventriculomegaly, hypoplasia vermis
white matter atrophy, hypoplasia trunk, gyration disorders
multiple interhemispheric cysts, metabolic encephalopaty
3
4
5
6
7
11
12
13
14
NORMAL
OUTCOME
MILD
IMPAIRMENT
PATHOLOGICAL
OUTCOME
COMPLEX ACC
COGNITIVE ABILITIES
RANGES OF IQ/DQ
PERCENTAGE OF THE SAMPLE
100
80
60
40
20
0
EXTREMELY
LOW (<70)
BORDERLINE LOW AVARAGE AVARAGE (90- HIGH AVARAGE
(70-79)
(80-89)
109)
(110-119)
SUPERIOR
(>120)
BAYLEY SCALES
(2-3)
WPPSI 3
(4-6)
WISC 3
(>6)
N. OF PATIENTS
5
4
3
FIQ/DQ
87,6 (55-106)
110,7 (109-112)
55 (50-70)
LANGUAGE
83,2 (50-100)
MOTOR
88,8 (53-107)
VERBAL IQ
107,3 (104-114)
54,7 (55-69)
PERFORMANCE IQ
115,7 (107-120)
57,2 (55-79)
ISOLATED ACC
NEURODEVELOPMENTAL OUTCOME
ISOLATED ACC
NORMAL OUTCOME
PATHOLOGICAL OTUCOME
11%
89%
PERCENTAGE OF THE SAMPLE
ISOLATED ACC
COGNITIVE ABILITIES
RANGES OF IQ/DQ
100
80
60
40
20
0
EXTREMELY BORDERLINE
LOW
AVARAGE (90HIGH
LOW (<70)
(70-79)
AVARAGE (80109)
AVARAGE
89)
(110-119)
SUPERIOR
(>120)
BAYLEY SCALES
(2-3)
WPPSI 3
(4-6)
WISC 3
(>6)
N. OF PATIENTS
5
1
3
FIQ/DQ
92,5 (55-100)
103,5
102 (101,102)
LANGUAGE
89 (53-124)
MOTOR
97 (46-127)
VERBAL IQ
110
101 (96-108)
PERFORMANCE IQ
117
100 (94-107)
ISOLATED ACC
COORDINATION ABILITIES
MOVEMENT ABC
20
CENTILES
15
PZ 1
10
PZ 2
5
PZ 3
PZ 4
0
MABC
manual
dexterity
MABC ball MABC static MABC total
skills
& dinamic
score
balance
ISOLATED ACC
ATTENTIONAL PROBLEMS
ATTENTIONAL PROBLEMS CBCL
90
80
T SCORES
70
60
50
40
30
20
10
0
1
2
3
4
5
PATIENTS
6
7
8
9
ISOLATED ACC
NEURODEVELOPMENTAL OUTCOME
COGNITIVE
DEVELOPMENT LANGUAGE
MOTOR
INTERNALIZING EXTERNALIZING
COORDINATION PROBLEMS
PROBLEMS
ATTENTION
pz1 NORMAL
BORDERLINE
NORMAL
NORMAL
NORMAL
pz2 NORMAL
NORMAL
NORMAL
NORMAL
NORMAL
EXECUTIVE
FUNCTIONS
ACADEMI
C SKILLS
pz3 PATHOLOGIC PATHOLOGIC
pz4 NORMAL
NORMAL
NORMAL
NORMAL
NORMAL
pz5 NORMAL
NORMAL
NORMAL
NORMAL
NORMAL
pz6 NORMAL
NORMAL
BORDERLINE
NORMAL
NORMAL
NORMAL
pz7 NORMAL
NORMAL
BORDERLINE
NORMAL
NORMAL
BORDERLINE BORDERLINE NORMAL
pz8 NORMAL
NORMAL
PATHOLOGIC
PATHOLOGIC BORDERLINE
PATHOLOGIC BORDERLINE NORMAL
pz9 NORMAL
NORMAL
PATHOLOGIC
NORMAL
BORDERLINE BORDERLINE NORMAL
SHORT TERM OUTCOME (<4 years)
MEDIUM TERM (4-6 years)
LONG TERM (> 6 years)
NORMAL
NEURODEVELOPMENTAL OUTCOME
ISOLATED ACC
normal outcome
mild impairment
severe impariment
11%
3y
33%
56%
age range 5y-10y
age range 18m-15y
Neuropsychological performances between -1 sd and -2 sd and/or
behavioral problems (CBCL>60 T Scores)
CONCLUSION
• The outcome of complex ACC is pathological
in half of cases and depending on the
underlying pathology. But we find a
unexpected normal outcome in 46% of cases.
• The outcome of isolated ACC, although this
study has wide range ( 18 months- 15 years),
confirms a normal outcome in 89% of cases.
The severe outcome is evident in the first year
of life
CONCLUSION
• Neuropsychological outcome of isolated ACC
children is normal only in 56% of cases.
• We show a association among problems in
motor coordination, in attention and in
executive functions.
• The “mild impairment” emerges later.
• No children have an adapted school program
OPEN QUESTIONS
• WE NEED SOME PROSPECTIVE RESEARCH WITH A LONG
FOLLOW-UP AND COMPLETE NEUROPSICHOLOGICAL
ASSESSMENT FOR A GOOD PRE AND POSTNATAL COUNSELING
ABOUT ACC, ESPECIALLY IN ISOLATED ACC
• WE NEED TO IMPROVE DEFINITION OF MILD IMPAIRMENT
(NEUROPSYCHOLOGICAL ASSESSMENT MAY HAVE A MAJOR
ROLE IN THE DEFINITION OF THE OUTCOME?)
• THE ROLE OF TRACTOGRAPHY AND DTI- MRI : A NEW
COUNSELING STRATEGY?