Agenesis of the Corpus Callosum: A Case Study

Agenesis of the Corpus Callosum: A Case Study and
Investigation of Characteristics and Long Term
Outcomes
By:
Fern S. Daniels
Doctorate Candidate
University of New Mexico School of Medicine
Physical Therapy Program
Class of 2013
Advisor:
Kathy Dieruf, PT, PhD, NCS
Printed Name
Signature
Date
Approved by the Program in Physical Therapy, School of Medicine, University of
New Mexico in partial fulfillment of the requirements for the degree of Doctor of
Physical Therapy.
1
ABSTRACT
Background/Purpose: Agenesis of the corpus callosum (ACC) is a congenital brain anomaly involving
either complete or partial absence of the corpus callosum [Doherty 2006]. It is a common in up to 1% of the
population. This malformation of the brain creates varying effects within the affected population. Patients
with this diagnosis typically demonstrate numerous delays in gross motor activities that affect the individual
from the time they are born. As such, they are commonly seen and treated through early intervention and
within the public schools setting for their gross motor delays, as well as other impairments. Due to the
variable presentation of the diagnosis there are no a set practice guidelines within physical therapy for this
population. This case study sets out to review current studies and identify characteristics and long-term
outcomes within the population in order to better serve this group in the rehabilitative setting.
Case Description: The patient is a 3-year-old female with a diagnosis of developmental delay with
agenesis of the corpus callosum. She was diagnosed in utero using sonagraphy. Due to impairments in
gross motor skills, socialization, and self-care, as well as medical complexity including a gastro-jejunal
feeding tube, the patient has need for physical, occupational, and speech therapy within the public schools
setting. During her time at the pre-kindergarten, she is seen by physical, occupational, and speech
therapists. She was evaluated for gross motor impairment using the Gross Motor Functional Measure
(GMFM-88) by the school’s physical therapist. A treatment plan was designed to assist in areas of
impairment including balance, strength, bilateral coordination, and gait training.
2
Outcomes: An extensive and comprehensive evidence based literature search was conducted using two
different databases which included PubMed® and CINAHL Plus. A thorough literature search for studies
related to agenesis of the corpus callosum was applied. After databases were searched, a pool of articles
was reviewed for topic relevance, power, validity, study design, and accessibility and placed into two
subgroupings according to topic, either characteristics or long-term outcomes. Articles best suited to
answer the clinical question, and were then thoroughly reviewed, analyzed and discussed.
Discussion/Conclusion: Evidence based findings report high variability in patient presentation, but identify
certain characteristics, such as reduced capacity in balance, crawling, and walking, as frequently occurring
within the population. Findings also discuss difficulty with problem solving and verbal processing delays
[Hinkley]. Other challenges reported include sleep disturbances, difficulties eating, and bi-manual
coordination. No research was found to indicate which outcome measures were most successful when
evaluating this population. Rehabilitative suggestions focused on identifying the most common challenges
and working to provide assistance in those areas.
3
TABLE OF CONTENTS
Chapter 1: Background/Purpose ………………………………………………………...Page 5
Chapter 2: Case Description……………………………………………………………..Page 6
Examination
Evaluation
Intervention
Outcome
Chapter 3: Evidence Based Analysis…………………………………………………..Page 11
Literature Review
Chapter 4: Discussion and Conclusion..………………………………………………Page 27
References……….……………..………………………………………………………..Page 29
Appendices……………………………………………………………………………..Page 31
4
CHAPTER 1: BACKGROUND AND PURPOSE
There is a growing population of developmentally delayed children surfacing within the general population
[Boyle 2011]. With this increase, there is an increasing need for therapy services within the public schools.
One such population with a need of assistance is children with agenesis of the corpus callosum. Its
prevalence is an estimated 3-7 per 1000 births [Doherty]. However, in children with developmental
disabilities the estimate is 2-3 per 100. The corpus callosum is the largest white matter tract in the brain,
connecting the bilateral hemispheres. Children with a diagnosis of agenesis of the corpus callosum (ACC)
can be identified from the mid-trimester onwards by expert sonography [Chiappedi].
Once born, children with ACC present with a variety of concerns for adapting with their neuroanatomy.
Gross motor delays affect many activities of daily living. As such therapeutic intervention is needed in
order to assist in the child’s ability to adapt via neural plastic changes as they grow and change.
Therefore, the purpose of this literature analysis and case study is to answer the following clinical
question: In children with agenesis of the corpus callosum what are the most common characteristics and
expected long term outcomes within the population?
5
CHAPTER 2: CASE STUDY
Introduction
The case subject is a 3-year-old female. She lives at home with her two siblings, Mom, and
grandmother. She is seen for her diagnosis of agenesis of the corpus callosum within the public schools in
the pre-kindergarten setting. The educational intervention plan includes physical, occupational, and speech
therapists. Each year she is evaluated using the GMFM-88 in order to follow her gross motor development.
Examination
The patient’s medical history began nearly 4 years ago in utero. In February 2009, the patient’s
mother was evaluated while pregnant, as she was a mother at risk for birth abnormalities. A sonographic
report was flagged for a fetal brain anomaly. Her mother spent the final month of gestation on bed rest due
to complications. The female child was born one month premature weighing 5lbs, 15oz. Following birth,
the child was jaundice, had hydrocephalus, and demonstrated hypoplasia of the corpus callosum via
sagittal MRI. The family received counseling through the children’s hospital where the mother and child
were receiving care. The child remained in the hospital for two weeks following her birth for monitoring.
She displayed visibly reduced posterior parietal shape, for which she was given a helmet for some time.
The child has a history of seizures, and is medicated for a seizure disorder. She has a reportedly high
pallet, but is able to eat some soft solids. She has a jujenal feeding tube. The patient presents with mild left
sided scoliosis and wears bilateral ankle foot orthosis’.
Evaluation
After the patients birth, Early Intervention provided services within the home. Inteventions included
physical therapy to stimulate the patient and assist in her gross motor development. On 9/20/12, she
began attending a pre-kindergarten in a special needs classroom. At this time she was evaluated using the
Gross Motor Functional Assessment Tool, GMFM-88 by the schools physical therapist. The GMFM was
originally used to evaluate children with cerebral palsy; it has since been validated for children with Down
6
Syndrome and has application for other children with significant gross motor delay. The GMFM has five
dimensions, each dimension is scored based on a 4 point system.
Lying and Rolling: the subject demonstrates abilities in supine and prone positions, head lift to 45
degrees, rolling from supine to prone and back again. In prone she can support herself on forearms and on
hands with elbows straight. She at times requires assistance to weight bear on her left palm rather than the
back of her hand. She demonstrates some emerging skills as well. She is able to support herself on one
forearm while in the prone position while extending the other arm forward. While in supine, she can reach
across midline to grab for a toy or other object with her right hand, but sometimes struggles to reach across
with left hand. She also has difficulty using her extremities to pivot while in prone.
Sitting: the subject can perform the following tasks well in seated. She can sit on a mat and
maintain her head at midline and upright. She can sit upright with arms free and unsupported while she
reaches. She can also maintain a side-seated position to either side. She also has some emerging skills.
She can attain seated position by rolling over either side, she prefers to come straight up. She can also
maintain a high kneel position for ten seconds and lower herself with control from seated to prone. She has
yet to attain a seated position on a bench from standing or from the floor.
Crawling and Kneeling: the subject can creep forward on her stomach at least 6 feet using her
upper extremities. She can creep on her hands and knees for at least one foot. The subject has the
following emerging skills. She can reach for with either hand to get a toy over her head. While in four point
she can pivot either direction 90 degrees using only her lower extremities.
Standing: the patient can maintain her balance for 2-3 seconds and pull up to standing at the
couch. She has yet to develop the following skills in standing, lift either foot and balance one hand
supported, stand up through half kneel, stand unsupported for any length of time, squat in standing and
pick up a toy.
7
Walking, Running, and Jumping: the patient has yet to begin developing any skills within
this category, as defined by this clinical measure. We are working on the precursors to this category within
standing, kneeling and crawling categories.
Considerations for Educationally Relevant Therapy (CERT) is a tool used to assist therapists in
determining a students need of OT or PT services in the school setting. The CERT is a summary of
educational considerations based on a review of student records, evaluations, observations, progress
notes, parent teacher information, and other data. A score of 1 indicates total independence, and a score of
4 indicated complete need for services.
Student Profile
Points
Personal Care
4
Mobility
4
Gross Motor
4
Fine Motor/Visual Motor
4
Sensory Processing
4
Total Points 20
8
Therapy Profile
Points
Number of Years Student has Received Educationally Relevant Therapy
3
Potential Response to Educationally Relevant Therapy
4
Students Learning Environment
4
Therapy Services to be Provided to Student
4
Support Services to be Provided to School Staff/Parents
4
Total Points 19
Summary of the CERT: Student Profile, score of 20=intensive therapy needed. Therapy Profile, score of
19=intensive therapy needed.
Summary of Findings/Interpretation of Evaluation Results: From the GMFM-88 and the CERT, it is
apparent that the student is not yet functional in the educational environment and is unable to assess her
school environment without constant adult supervision for safety. Her needs are addressed by significant
modifications to the classroom curriculum and other existing services. Physical therapy was strongly
recommended due to the student’s diagnosis and performance levels, in order to improve gross motor
skills, safety awareness, maintenance of acquired skills and independent mobility around her school
environment.
Interventions
The child participates in physical therapy three times per week. One session is one on one with a
physical therapist. The other two sessions are in small peer groups. During individual and group sessions,
balance, bilateral coordination, postural control, and locomotion are all stimulated. Techniques for postural
9
control are used in prone, seated, side lying, quadruped, standing, and during assistive walking. Cruising
along objects is frequently used during sessions as a compensatory locomotive form in order to encourage
maximal initiation and challenge of musculature as well as balance for the patient. When crawling the
patient prefers to scoot, this is another area for intervention. The child is encouraged to crawl and given
tactile and verbal cues to use her bilateral upper and lower extremities equally and at midline. During group
sessions the child is facilitated in peer interaction in order to participate in therapeutic activities. Sign
language is used during therapy sessions along with verbal and nonverbal interaction. The patient uses
cooing, humming and buzzing to convey a variety of sentiments. Obstacle courses, scooter boards,
tricycles, slides, swings, and climbers are all used to stimulate the challenge areas listed above.
Outcomes
The GMFM-88 is the outcome measure used for the child’s evaluation, as well as her development
of skills. Using the gross motor functional classification system she would be considered a level 3.
Complete scores from Gross Motor Functional Measure (GMFM) in Table 1.
Table 1. Gross Motor Functional Measure-88
Pre-K Admission
Lying and Rolling
47/51= 92.16%
Sitting
40/60= 66.67%
Kneeling and
15/42= 35.71%
Crawling
Standing
9/39= 23.08%
Walking, Jumping,
5/72= 6.94%
and Running
Total Score
224.56/5= 44.912%
Discharge
NT
NT
NT
NT
NT
NT
10
CHAPTER 3: EVIDENCE BASED ANALYSIS
Methods
An extensive and comprehensive evidence based literature search was conducted for the literature
review. Two different databases were used in order to search for the answer to the clinical question which
included PubMed® and CINAHL Plus. PubMed® (MEDLINE) is a database provided by the National
Library of Medicine and is “the premier database for medical, nursing, dental, and related literature.” The
MeSH or Medical Subject Headings database was used as a specific method to search for evidence, and is
“the NLM controlled vocabulary thesaurus used for indexing articles for PubMed.” CINAHL Plus with Full
Text is a database described as the “cumulative index to nursing and allied health.”
Search Methods:
A comprehensive literature search for studies related to the agenesis of the corpus callosum in
humans. The search strategy for conducting this literature review/analysis consisted of searching the two
previously described databases and was unique to each database.
To search within PubMed, the MeSH database was utilized. The keywords used were different
combinations of agenesis of the corpus callosum, callosal abnormalities, and rehabilitation; the limits used
were English, and human, and articles published within the last 10 years. This search yielded 67 articles.
From this article collection, all titles were reviewed and those which investigated the patients with agenesis
of the corpus callosum or function in some manner, whether compared to another form of intervention or
not, were kept. This resulted in 12 articles.
To search CINAHL Plus, the following keywords were used in different combinations: agenesis of
the corpus callosum, callosal abnormalities, and rehabilitation, with the limitations of English language and
humans. This resulted in 15 hits. Of these four articles were kept.
From a pool of 82 articles, 16 articles had relevant titles and were saved.
11
Once the pool of articles was created and the articles had been saved within RefWorks, the articles
were compared and any duplicates were deleted. Next, the articles with the most relevant titles were
selected. The article topics were variable, with common themes centering on mapping characteristics
and/or long-term outcomes within the population. This resulted in a total of 10 articles that were selected
from the larger pool to be reviewed and analyzed in order to answer the clinical question. Five articles
were chosen for characteristics and five for long-term outcomes. Articles were organized presenting
characteristics first and then outcomes with the two groups of five alphabetized.
12
Figure 1. Part I Methods: Articles Included and Excluded for Analysis
PubMed
CINAHL
Some keywords:
Agenesis of the Corpus
Callosum;
AgCC and rehab
67
15
Keyword Search
Keyword Search
One keyword
Two key words & no
limitations
combinations & 1 limits
12
Selected based on
appropriateness/
relevance of title
in relation to
PICO question
4
16
6 Excluded:
Total Articles (Relevant to Topic)
Literature
Review
4
+
Prospective Cohort
Study
1
+
Case
Study
2
13
Lower level research,
Non-similar
population
+
Interviews/
Questionnaires
1
+
Other
3
=
10 Total Studies
-Reviewed
-Analyzed
-Compared to PICO
Literature Review: Articles which investigate agenesis of the corpus callosum, in its 1-5 characteristics,
and 6-10 long-term outcomes.
1. Chiappedi and Bejor. Corpus callosum agenesis and rehabilitative treatment. Italian Journal of Pediatrics
2010 36:64.
Level of Evidence: 5
Pedro Score: NA
Purpose: In this paper, research findings are reviewed using a MedLine search in an effort to present the
potential impact on children with AgCC and the potential for rehabilitative treatment.
Methods: This article was a review and synthesis of the current research. Articles within the last five
years were emphasized, however, additional articles were utilized for background information.
Results: Some suggestions can be drawn from current scientific literature concerning CCA. The treatment
should be started as soon as possible, in order to prevent secondary complications (e.g. social exclusion
due to the above described difficulties) and to exploit CNS plasticity as much as possible.
Critique/Bottom Line: The subject’s functioning can be described in terms of body structures (eventually
altered, as in CCA) and functions (i.e. physiological functions performed by one or more structures), but
also in terms of activities (i.e. actions the subject can or cannot perform) and participation (defined as the
possibility to be involved in life situations).
14
2. Hanna, Marsh, et al. Distinguishing 3 Classes of Corpus Callosal Abnormalities in Consanguineous
Families. Neurology 76 January 25, 2011
Level of Evidence: 5
Pedro Score: NA
Purpose: Currently, no classification system for pediatric corpus callosal abnormalities (CCA) exists. This
research attempts to create a system based upon midline sagittal brain MRI within families affected by
malformation of the corpus callosum.
Methods: They focused recruitment toward multiplex consanguineous families, gathering 30 patients from
19 consanguineous families, and analyzed clinical features together with brain imaging.
Results: There were 3 major classes identified, including hypoplasia, hypoplasia with dysplasia, and
complete agenesis. Affected individuals within a given multiplex family usually displayed the same variant
of the class of abnormality and they always displayed the same class of abnormality within each family, or
they displayed complete agenesis. The system was validated among a second cohort of 10 sporadic
patients with CCA.
Critique/Bottom Line: This study was unable to acquire consistent resolution for the quality of MRI
images, and this may pose a threat to the study’s validity. The ability to select patients for evaluation at
newly identified genes based upon similarities in the appearance of the CC could improve the ability to
molecularly classify CCA patients. Future studies are needed.
15
3. Hinkley, Marco, Findlay et al. The Role of Corpus Callosum Development in Functional Connectivity and
Cognitive Processing. PLoS One 2012; (7:8).
Level of Evidence:
Pedro Score: NA
Purpose: To examine resting-state functional connectivity in 18 individuals with agenesis of the corpus
callosum (AgCC) with matched controls. (mean age: 31, SD= 12.1)
Methods: Used magnetoencephalographic imaging (MEG-I) of coherence in the alpha (8–12 Hz), beta
(12–30 Hz) and gamma (30–55 Hz) bands.
Results: In AgCC individuals, alpha band GC was significantly reduced in the dorsolateral pre-frontal
(DLPFC), posterior parietal (PPC) and parieto-occipital cortices (PO). No significant differences in GC were
seen in either the beta or gamma bands. Data suggests that reduced connectivity in these regions is driven
by faulty coupling in both inter- and intra- hemispheric connectivity.
Critique/Bottom Line: This study provides compelling evidence that the absence of a fully developed
corpus callosum impacts functional interactions both within each hemisphere and between the two
hemispheres in the resting alpha frequency range (8–12 Hz). It was also found that the degree of
diminished connectivity in specific cortical regions was directly correlated with verbal processing speed and
executive performance in individuals with AgCC.
16
4. Moes P, Schilmoeller K, Schilmoeller G. Physical, motor, sensory and developmental features
associated with agenesis of the corpus callosum. Child: Care, Health & Development [serial online].
September 2009;35(5):656-672.
Level of Evidence: 4
Pedro Score: NA
Purpose: This study focuses on individuals with previously diagnosed agenesis of the corpus callosum
(ACC). The objective was to develop a profile of characteristics and diagnostic indicators of agenesis of the
corpus callosum (ACC) using a large sample of individuals with ACC and their siblings.
Methods: A 70 item questionnaire was sent to 2100 families of the ACC Network. 720 questionnaires
were returned (34%). Follow up questionnaires were mailed to the 509 families that indicated they had one
or more siblings. 219 of these follow up questionnaires were returned (37%). Of these 219, 204 siblings
with no medical conditions n=204 were analyzed as the control.
Results: Significant differences were not found for sleep disturbances. However, those patients with
partial ACC were more likely to have sleep disturbances than were individuals with complete ACC.
Difficulties with simple motor functions were not as pronounced as those reported previously. Yet,
difficulties with more complex motor activities are consistent with previous reports. Additionally, among the
‘gross motor’ activities requiring balance seemed to be particularly problematic. Reduced pain perception
appears unrelated to a reduction of sensory processing, as individuals with ACC demonstrate increased
touch sensitivity. The reduced responsiveness to cold could possibly be related to an increase in
hypothermia reported by Jeret and colleagues, which they speculated was related to changes in noncallosal structures.
Critique/Bottom Line: The present study did not find consistent differences between individuals with
complete or partial ACC.
17
5. Paul. Developmental Malformation of the Corpus Callosum: a Review. Journal of Neurodevelopmental
Disorders (2011) 3:3–27.
Level of Evidence: 5
Pedro Score: NA
Purpose: This review provides an overview of the involvement of the corpus callosum (CC) in a variety of
developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or
behavior. It is suggested that a new way of categorizing these disorders be developed based on
neuroanatomy.
Methods: The process by which these articles were collected and integrated was not presented. This is a
point of weakness within the paper. There is no qualitative analysis of the previous research.
Results: The inventory of callosal contributions to the developmental disorders collected in this review
points to the need for future studies and broader review of this topic. The author states that future research
will need to discover the precise functional contributions of the corpus callosum in developmental disorders.
Critique/Bottom Line: This review did a great job of collecting, synthesizing, and presenting information
on callosal malformations and their associated disorders. However, there was little or no analysis of these
research articles for the discernment of the research quality.
18
6. Hsu, et al. Anatomical and Electrophysiological Manifestations in a Patient with Congenital Corpus
Callosum Agenesis. Brain Topogr (2013) 26:171–176.
Level of Evidence: 3b
Pedro Score: NA
Purpose: The study evaluated a 27-year- old man with agenesis of the corpus callosum without detectable
motor function deficits and compared him with age similar controls, in an effort to identify neuro-anatomic
differences and potentially how the brain had adapted to ACC.
Methods: The study used diffusion tensor imaging (DTI) and two electrophysiological tests, movementrelated cortical potential (MRCP) and interhemispheric inhibition (IHI), provoked by transcranial magnetic
stimulation (TMS), to evaluate the patient and controls.
Results: The patient demonstrated enhanced fibers connecting the bilateral anterior commissures.
Suggesting enhanced transcommissural fibers form an alternative route connecting the two hemispheres.
Critique/Bottom Line: The article demonstrates good methodology, despite their small sample. This
information is a good start. However, it is not generalizable without replication on a larger sample.
19
7. Khanna, et al. Preserved Interhemispheric Functional Connectivity in a Case of Corpus Callosum
Agenesis. Neuroradiology (2012) 54:177–179.
Level of Evidence: 4
Pedro Score: NA
Purpose: This case study explored the functional connectivity in a patient with near-complete ACC.
Methods: The patient, a 6-year-old male, was imaged under anesthesia using a 3 T system with a 32channel head coil. Diffusion tensor imaging and resting state fcMRI were taken. Then anterior and posterior
commissures were assessed using the fcMRI. Anisotropy was confirmed, with fiber continuity followed for
several millimeters. The fibers lacked clear laminar organization and it was difficult to follow tracts to
specific cortical regions.
Results: Findings suggest that the callosum is not necessarily required for fcMRI connectivity between
hemispheres. “Extracallosal neural pathways involving “lower-level” subcortical connections may provide
some interhemispheric connectivity”.
Critique/Bottom Line: Functional networks develop from focal to peripheral regions with in the brain. One
of the next challenges will be to understand how these patterns change across development and in a range
of anatomic malformations that affect hemispheric integration. These concepts represent areas of need
within research to come.
20
8. Marco, Harrell, Brown et al. Processing Speed Delays Contribute to Executive Function Deficits in
Individuals with Agenesis of the Corpus Callosum. Journal of the International Neuropsychological Society.
May 2012. 18(3).
Level of Evidence: 4
Pedro Score: NA
Purpose: This study examines rapid complex problem solving and reasoning by isolating the impact of time
constraints (i.e., processing speed) from the executive skills, specifically cognitive inhibition and mental
flexibility, which are necessary for these tasks.
Methods: Color-Word Interference Test (CWIT) is based on the Stroop procedure and is designed to
evaluate response inhibition and cognitive flexibility. The CWIT has four conditions, each resulting in a
completion time score: Color Naming, Word Reading, Inhibition and Inhibition/Switching.
Results: Nonparametric test of trend for ranks revealed a statistically significant effect of rank for all three
executive tasks, CWIT Inhibition (z = 4.39; p=.001), CWIT Inhibition/Switching (z = 4.85; p<.001), and TMT
Number-Letter Switching (z = 3.32; p = .001), such that the cAgCC group scores lowest, the HC group
scores highest, and the pAgCC group is consistently intermediate in performance.
Critique/Bottom Line: The cohort of children, adolescents, and adults with isolated AgCC (FSIQ ≥ 80),
performed significantly worse than matched controls in timed tasks of cognitive inhibition and flexibility.
However, while individuals with agenesis of the corpus callosum demonstrated deficits on tasks of
executive function, this impairment appeared to be primarily a consequence of slow cognitive processing.
21
9. Moutard et al. Agenesis of corpus callosum: prenatal diagnosis and prognosis. Childs Nervous System.
2003 Aug;19 (7-8):471-6.
Level of Evidence: 4
Pedro Score: NA
Purpose: Prospective study monitoring 17 children with isolated agenesis of the corpus callosum with
evaluations at 2, 4, and 6 years of age in an effort to provide improved insight into the outcome of patients
with ACC.
Methods: The neuropsychological evaluation protocol included an intellectual quotient (IQ) measure using
Brunet-Lezine revised for children, the Wechsler pre-school and primary scale of intelligence revised
(WPPSI-R). Laterality was determined using the Dellatolas protocol. Evaluation was completed using the
KABC subtests (movements of hands, picture recognition, vocabulary, and people and places recognition).
For children aged 6 years, we evaluated fingertip dexterity with the Purdue Pegboard, and reading with the
KABC subtest.
Results: Gross and fine motor skills were normal in all patients. Children were able to sit at 9 months and
autonomous walk appeared at a mean age of 14 months (10–18 months). Median full-scale intellectual
quotient (FSIQ) was in the normal range (between 90 and 109) and stable over the years with verbal and
performance IQ. At 6 years, the median verbal IQ was in the lower range.
Critique/Bottom Line: This article represents preliminary results that isolated ACC could have a favorable
outcome independent of sex and type of ACC (complete or partial).
22
10. Sotiriadis A, Makrydimas G. Neurodevelopment after prenatal diagnosis of isolated agenesis of the
corpus callosum: an integrative review. American Journal of Obstetrics and Gynecology 2012; 206:337.
Level of Evidence: 5
Pedro Score: NA
Purpose: To systematically review published data on the neurodevelopment of children that were
diagnosed prenatally with isolated agenesis of the corpus callosum.
Methods: Medline and Scopus searches (1960-July 2011); cross-referencing of retrieved articles.
Results: Prenatally diagnosed, isolated agenesis of the corpus callosum is usually associated with a
favorable outcome. Larger, prospective series are required, as current data are limited, inconsistent, and
prevent subgroup analyses (e.g. complete verse partial agenesis of the corpus callosum).
Critique/Bottom Line: The available data from published reports indicates that in isolated ACC the
medium- to long-term neurodevelopmental outcome is expected to be normal in approximately 75% of
cases. This rate reaches 83% for isolated CACC. However, MRI is required to confirm the sonographic
diagnosis of isolated ACC, as many (> 20%) apparently isolated cases may have additional findings on
MRI, which could deteriorate the patients’ prognosis.
23
Table 4. Results / Article Summaries
#
1
2
3
Study
&
Origin
Oxford
Level of
Evidence
Pedro
Score
Purpose of
Study
Outcome
Measures
Chiappedi and
Bejor. Corpus
callosum
agenesis and
rehabilitative
treatment. Italy.
5
NA
Recent findings are
reviewed in view of the
potential impact on
children’s global functioning
and on the possible
rehabilitative treatment, with
an emphasis on the
possibility to exploit brain
plasticity and on the use of
the ICF-CY framework.
NA: review of current literature
The model proposed in the
International Classification of
Functioning, Disability and
Health can be useful as a frame
to guide the rehabilitative
treatment.
Rehabilitative interventions can include: speech therapy,
physiotherapy, psychomotor therapy, occupational or
educational therapy, psychotherapy, parent training, and
counseling for teachers.
Hanna et al.
Distinguishing 3
Classes of
Corpus Callosal
Abnormalities in
Consanguineous
Families. CA,
USA.
5
NA
The authors sought to
create a classification
system for pediatric corpus
callosal abnormalities
(CCA) based upon midline
sagittal brain MRI.
Focused on recruitment toward
multiplex consanguineous
families, ascertained 30 patients
from 19 consanguineous
families, and analyzed clinical
features together with brain
imaging. For analysis, midline
sagittal MRI were cropped 2– 4
cm anterior to the genu,
posterior to the splenium, and
inferior to IV ventricle to ensure
uniform visualization of the CC
and the adjacent structures.
The authors adopted the term CCA to encompass all forms of
CC abnormalities as well as complete agenesis. Three major
CCA classes were identified, including hypoplasia, hypoplasia
with dysplasia, and complete agenesis
Yes
Hinkley et al.
The role of
corpus callosum
development in
functional
connectivity and
cognitive
processing.
Netherlands.
4
NA
To examine resting-state
functional connectivity in 18
individuals with agenesis of
the corpus callosum
(AgCC) with matched
controls. (mean age: 31,
SD= 12.1)
Used
magnetoencephalographic
imaging (MEG-I) of coherence in
the alpha (8–12 Hz), beta (12–
30 Hz) and gamma (30–55 Hz)
bands.
In AgCC individuals, alpha band GC was significantly reduced
in the dorsolateral pre-frontal (DLPFC), posterior parietal
(PPC) and parieto-occipital cortices (PO). No significant
differences in GC were seen in either the beta or gamma
bands. Data suggests that reduced connectivity in these
regions is driven by faulty coupling in both inter- and
intrahemispheric connectivity.
Yes
24
Results
Accept
Results to
Answer
Clinical
Question
Yes
4
5
6
Moes et al.
Physical, motor,
sensory and
developmental
features
associated with
agenesis of the
corpus callosum.
ME, USA.
5
NA
This study focuses on
individuals with previously
diagnosed agenesis of the
corpus callosum (ACC).
The objective was to
develop a profile of
characteristics and
diagnostic indicators of
agenesis of the corpus
callosum (ACC) using a
large sample of individuals
with ACC and their siblings.
Surveys with data on diagnoses,
physical characteristics,
developmental patterns and
physical functioning.
Some information can be gleaned from this study on the
prevalence of characteristics for AgCC in its different forms.
This information could be used in the creation of goals for
patients with AgCC and/or determining prognosis for this
population.
Listed in order from most to least frequent, the following afterbirth characteristics appear to be strongly associated early
markers for ACC: delayed completion of motor developmental
milestones – in particular, standing, crawling, walking, walking
up stairs and riding a bike; reduced pain perception; large
head size; atypical cold sensitivity (mostly reduced, but could
be
increased)
poor
muscle;tone (i.e. ‘floppy’); having an
atypical body size (smaller or larger); increased sensitivity to
touch; the presence of unusual physical features, such as eyes
set wide
apar
-set
ears
t,low
or unusual head shape.
Yes
Paul.
Developmental
Malformation of
the Corpus
Callosum: a
Review. CA,
USA.
5
NA
Literature review and
discussion of research
methods for agenesis of the
corpus callosum.
NA: review of current literature.
Taken together, the neuropsychological findings in Primary
AgCC highlight a pattern of deficits in problem solving,
processing speed, and the social pragmatics of language and
communication, which may result in significant complications
of daily life.
Yes
Hsu, et al.
Anatomical and
Electrophysiologi
cal
Manifestations in
a Patient with
Congenital
Corpus Callosum
Agenesis.
Taiwan, China.
3b
NA
The study evaluated a 27year- old man with ACC but
no detectable motor
function deficits using
diffusion tensor imaging
(DTI), movement-related
cortical potential (MRCP),
and interhemispheric
inhibition (IHI).
The MRCP was analyzed at the
electrodes of C3, FCZ, and C4.
IHI was measured using paired
transcranial magnetic
stimulation over the hand area
of the primary motor cortex at
both hemispheres.
Findings suggest that in the ACC patient, the abnormal
transcommissural fibers might be functional and serve as an
alternative pathway connecting the bilateral hemispheres.
Yes
25
7
8
9
10
Khanna et al.
Preserved
interhemispheric
functional
connectivity in a
case of corpus
callosum
agenesis. WA,
USA.
4
NA
This is a published letter to
the editor exploring
functional connectivity of
the brain in a patient with
agenesis of the corpus
callosum. The letter reports
the methods of this case
study using functional MRI
to demonstrate differences
in the brain of this patient
as compared to that of a
normal.
The patient, a 6-year-old male,
was imaged under anesthesia
on a 3 T system using a 32channel head coil. The case
study used fMRI to produce
imaging of a brain with agenesis
of the corpus callosum and then
used auditory stimulus to
observe the response and then
compare it to a normal
response.
In this patient with near-complete agenesis of the callosum,
strong interhemispheric connectivity was observed. This may
correlate with our patient’s fairly good functional level and
would represent a compelling direction for future research.
Yes
Marco et al.
Processing
Speed Delays
Contribute to
Executive
Function Deficits
in Individuals
with Agenesis of
the Corpus
Callosum. CA,
USA.
4
NA
This study examines rapid
complex problem solving
and reasoning by isolating
the impact of time
constraints (i.e., processing
speed) from the executive
skills, specifically cognitive
inhibition and mental
flexibility, which are
necessary for these tasks.
Color-Word Interference Test
(CWIT) is based on the Stroop
procedure and is designed to
evaluate response inhibition and
cognitive flexibility. The CWIT
has four conditions, each
resulting in a completion time
score: Color Naming, Word
Reading, Inhibition and
Inhibition/Switching.
Nonparametric test of trend for ranks revealed a statistically
significant effect of rank for all three executive tasks, CWIT
Inhibition (z = 4.39; p=.001), CWIT Inhibition/Switching (z =
4.85; p<.001), and TMT Number-Letter Switching (z = 3.32; p
= .001), such that the cAgCC group scores lowest, the HC
group scores highest, and the pAgCC group is consistently
intermediate in performance.
Yes
Moutard.
Agenesis of
corpus callosum:
prenatal
diagnosis and
prognosis.
Barcelona, Spain
4
NA
This study reports a
prospective study of 17
children (11 boys, 6 girls)
with prenatally diagnosed
isolated ACC.
Neuropsychological evaluation
was performed each year and
results at the ages of 2, 4, and 6
years were compared.
This study demonstrates that if outcome of isolated ACC is
favorable, a long follow-up is necessary: with age, IQ in the
lower range and behavioral troubles are linked to difficulties in
school.
Yes
Sotiriadis et al.
Neurodevelopme
nt after prenatal
diagnosis of
isolated
agenesis of the
corpus callosum:
an integrative
review.
5
NA
To systematically review
published data on the
neurodevelopment of
children that were
diagnosed prenatally with
isolated agenesis of the
corpus callosum.
Medline and Scopus searches
(1960-July 2011); crossreferencing of retrieved articles.
Prenatally diagnosed, isolated agenesis of the corpus
callosum is usually associated with a favorable outcome.
Larger, prospective series are required, as current data are
limited, inconsistent, and prevent subgroup analyses (eg,
complete vs partial agenesis of the corpus callosum).
Yes
26
CHAPTER 4: DISCUSSION / CONCLUSION
Review of Findings
A total of 10 articles were reviewed and analyzed. These articles naturally lent themselves to one
of two categories: long term outcomes for patients with agenesis of the corpus callosum. Of the articles that
examined characteristics, such as functional deficits and physical impairments, complex motor tasks and
balance were found to be particularly problematic [Moes]. Additionally, pain perception decreased and
touch sensitivity appeared to be increased within individuals w isolated AgCC [Moes]. Other characteristics
outlined in current research describe deficits in problem solving, processing speed, and social pragmatics
of language and communication [Paul]. In one study on recommendations for rehab, it is stated that
therapy should begin as soon as possible in order to exploit neuroplasticity as much as possible
[Chiappeddi]. In an article by Khanna et al, there are preliminary findings of the use of transcommisural
fiber adaptations that may indicate how the brain might change in order to communicate between
hemispheres without the corpus callosum.
Of the articles that looked at the effects of agenesis of the corpus callosum on long-term outcomes,
three studies reported significantly decreased function in high-level cerebral tasks; one reported a nonsignificant decrease in flexibility of mental task. Overall outcomes of isolated AgCC are favorable and
medium to long-term outcomes are expected normal in approximately 75% of cases [Sotiriadis].
Application of Findings
There is still a great deal of research that needs to be completed within this population in order to
definitively apply any of the information reviewed. Much of the research available is of small isolated
populations. With that said, there is a somewhat small and limited population of individuals with isolated
27
agenesis of the corpus callosum to recruit. The diagnosis is often secondary and presents with a host of
confounding factors. Despite these challenges, we can still draw from the information available.
Clinical Significance
The research available is of low level and presents no cohesive recommendations that are of major use for
application in the physical therapy setting. However, two characteristics that were a common impairment in
one study was difficulty with complex motor tasks and balance [Moes]. These are areas that can and
should be stimulated during therapy.
Conclusion (Bottom Line Report)
Neuroplasticity can be exploited in this population. Therapy should be started as soon as possible, within
the first year of life. Physical therapy focus can support the development of bimanual coordination,
reciprocal ambulation, and improving balance within individuals with agenesis of the corpus callosum
[Moes]. This is a topic of fair complexity and growing research is needed to support physical therapy
intervention in schools and other pediatric settings.
28
REFERENCES
1. Doherty, et al. Health-Related Issues in Individuals with Agenesis of the Corpus Callosum. Child: Care,
Health & Development (2006) 32:3 333–340.
2. Boyle. Trends in the Prevalence of Developmental Disabilities in US Children, 1997–2008. PEDIATRICS
(June 2011) 127:6.
3. Chiappedi and Bejor. Corpus callosum agenesis and rehabilitative treatment. Italian Journal of
Pediatrics (2010) 36:64.
4. Moutard. Agenesis of corpus callosum: prenatal diagnosis and prognosis. Childs Nervous System. (2003
Aug) 19(7-8): 471-6.
5. Moes P, Schilmoeller K, Schilmoeller G. Physical, motor, sensory and developmental features
associated with agenesis of the corpus callosum. Child: Care, Health & Development. (September 2009);
35(5): 656-672.
6. Hsu, et al. Anatomical and Electrophysiological Manifestations in a Patient with Congenital Corpus
Callosum Agenesis. Brain Topography (2013) 26: 171–176.
7. Hinkley, Marco, Findlay et al. The Role of Corpus Callosum Development in Functional Connectivity and
Cognitive Processing. PLoS One (2012) 7:8.
8. Vasudevan, McKechnie, Levene. Long term outcome of antenatally diagnosed agenesis of corpus
callosum and cerebellar malformation. Seminars in Fetal & Neonatal Medicine (2012). 17:295-300.
9. Marco, Harrell, Brown et al. Processing Speed Delays Contribute to Executive Function Deficits in
Individuals with Agenesis of the Corpus Callosum. Journal of the International Neuropsychological Society.
(May 2012). 18(3).
29
10. Sotiriadis A, Makrydimas G. Neurodevelopment after prenatal diagnosis of isolated agenesis of the
corpus callosum: an integrative review. American Journal of Obstetrics and Gynecology (2012) 206-337.
11. Francesco P, Maria-Edgarda B, et al. Prenatal diagnosis of agenesis of corpus callosum: what is the
neurodevelopmental outcome? Pediatrics International (2006) 48: 298-304.
12. Khanna, et al. Preserved Interhemispheric Functional Connectivity in a Case of Corpus Callosum
Agenesis. Neuroradiology (2012) 54: 177–179.
13. Paul. Developmental Malformation of the Corpus Callosum: a Review. Journal of Neurodevelopmental
Disorders (2011) 3: 3–27.
14. Hanna, Marsh, et al. Distinguishing 3 Classes of Corpus Callosal Abnormalities in Consanguineous
Families. Neurology 76 (January 2011)
30
APPENDICES
Appendix A. Oxford Centre For Evidence Based Medicine
31
Appendix B. Physiotherapy Evidence Database
32
33
34