e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 2 9 5e3 0 0

Official Journal of the European Paediatric Neurology Society

Original article

Cortical thickness at the time of the initial attack intwo patients with paediatric relapsingeremittingmultiple sclerosis

Alberto Fernandez-Jaen a,b,*, Daniel Martın Fernandez-Mayoralas a,b,Ana Laura Fernandez-Perrone a,b, Mar Jimenez de la Pena d,e,f,Manuel Recio Rodrıguez d,e,f, Beatriz Calleja-Perez c, Nuria Munoz Jareno g,Rafael Arroyo h, Jacobo Albert i

aDepartment of Neuropediatrics, Hospital Universitario Quiron, Madrid, SpainbDepartment of Neurology, Hospital Universitario Quiron, Madrid, SpaincPaediatric Primary Care, Centro de Salud Doctor Cirajas, Madrid, SpaindRadiodiagnostics Department, Hospital Universitario Quiron, Madrid, SpaineDepartment of Neuro-radiology, Hospital Universitario Quiron, Madrid, SpainfDepartment of Magnetic Resonance, Hospital Universitario Quiron, Madrid, SpaingDepartment of Neuropediatrics, Hospital Infanta Leonor de Vallecas, Madrid, SpainhDepartment of Neurology, Hospital Universitario Quiron, Madrid, SpainiHuman Brain Mapping Unit, Complutense University of Madrid, Spain

a r t i c l e i n f o

Article history:

Received 18 May 2013

Received in revised form

27 November 2013

Accepted 10 December 2013

Keywords:

Atrophy

Cortical

Gray matter

Multiple sclerosis

Paediatric

* Corresponding author. Department of NeurMadrid, Spain. Tel.: þ34 902151016; fax: þ34

E-mail address: aferjaen@telefonica.net (1090-3798/$ e see front matter ª 2013 Europhttp://dx.doi.org/10.1016/j.ejpn.2013.12.002

a b s t r a c t

Background: Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous

system with a low incidence in the paediatric population; cortical atrophy is often striking,

even in the early stages of the disease. Evidence of cortical thinning in childhoodMS is scant.

Aims: This study aimed to assess cortical thickness in paediatric patients during the initial

attack of remittingerelapsing MS.

Methods: Wereport twocasesof remittingerelapsingMS,with initial attacks at 12and16years

of age.We analysed brain cortical thickness (CTh) in these patients and compared these data

to the CTh of a control group comprised of six 12-year-old females and six 16-year-oldmales.

Results: Both cases exhibited a total brain CTh significantly below that of the control group.

This difference was also observed when analysing the CTh of all lobes except the left pa-

rietal lobe in one of the cases.

Conclusions: Cortical atrophy is already present at the time of onset of MS. Studies with

larger patient populations that have a more homogenous clinical presentation could

identify the time of onset of cortical atrophy and use this parameter as a prognostic and/or

treatment marker of MS.

ª 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

ology, Hospital Universitario Quiron, C/ Diego de Velazquez, 1, 28223 Pozuelo de Alarcon,913 517 311.A. Fernandez-Jaen).ean Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 2 9 5e3 0 0296

1. Introduction

Multiple sclerosis (MS) is a chronic demyelinating disease of

the central nervous system that is rare in children (0.51/

100,000 person-year).1e3 Between 3 and 10% of individuals

with MS are children under the age of 16 years.4e7

MS affects cortical and subcortical white and graymatter of

the central nervous system.8e12 Neocortical atrophy is prom-

inent in MS, and synaptic loss is particularly striking. These

features may independently contribute to the expression of

neuronal disease in MS patients.13e16

Cortical atrophy can appear in the early stages of MS.13,15

Cortical thinning is an early, diffuse phenomenon in adult pa-

tients who receive an early diagnosis of MS based on clinical

signs in the initial stages of the disease13,15,17e19; however, few

studies evaluated cortical thickness (CTh) and atrophy in

childhood-onset MS.8,12,20

The purpose of this study is to report two paediatric clinical

cases with prospective follow-up that meet the diagnostic

criteria for the remittingerelapsing form of MS.2,21,22 These

cases presented distinct cortical atrophy, which was already

discernible at the time of the initial attack.

2. Clinical cases

2.1. Clinical case 1

A 12-year-old female with no personal or family history of

note was admitted to the hospital due to acute onset of facial

Fig. 1 e Axial T2-weighted FLAIR images from the clinical cases.

in the periventricular white matter adjacent to the right occipit

compatible with demyelinating lesions. (B) Control MRI perform

arrows) due to reactivation or confluence of new lesions. Clinic

periventricular white matter and in paracallosal areas perpendic

of a multiple sclerosis-type demyelinating disease. (D) Control

(indicated by white arrows), indicating progression.

asymmetry and diplopia. At admission, the neurological ex-

amination revealed left facial paralysis, which was associated

with paralysis of the left VI cranial nerve, with no additional

findings of note.

Upon admission, a cranial computerized tomography was

performed with normal findings. Cerebral magnetic reso-

nance revealed the presence of at least 4 demyelinating

infratentorial lesions: 2 in the left cerebellar hemisphere, 1 in

the pons, and 1 in the mid-brain. There were more than 20

supratentorial lesions; the most significant of these lesions

were as follows: 7 in the periventricular white matter, 5 peri-

callosal lesions, 3 in the corpus callosum, 4 in the centrum

semiovale, and 7 bilateral juxtacortical, frontoparietal lesions

(Fig. 1A). The magnetic resonance of the spinal cord was

normal.

The study also included the following tests23: blood count,

basic metabolic studies, sedimentation rate, PCR, liver func-

tion tests, serum B12 and folate levels, proteinogram,

angiotensin-converting enzyme, and immunological (i.e.,

antinuclear antibodies, TSH, antiDNA anti-Sm, anti RNP, anti

SS-A, and anti SS-B) and virological (i.e., serum agglutination

test for Brucella, Borrelia, HIV, and Epstein Barr titres) studies,

which were all normal.

The cerebrospinal fluid analysis revealed discrete hyper-

proteinorraquia (480 mg/L), with the presence of oligoclonal

bands.

The ophthalmological examination was normal. The

study using visual evoked potentials revealed a discrete

p100 latency in both eyes (p100 right at 121 ms and left at

118 ms).

Clinical case 1 (AeB). (A) Small hyperintense lesions located

al horn and the right ventricular atrium, which are

ed two years later. Increased lesion size (indicated by white

al case 2 (CeD). (C) Hyperintense lesions located in the

ular to the greater ventricular axis, which are characteristic

MRI performed two years later. Appearance of new lesions

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 2 9 5e3 0 0 297

The patient subsequently received care in our department

for two clinical episodes. One episode caused diplopia and

hypoesthesia on the right side of the body, and a second

episode was characterised by mild paresthesia in the left

hand. The patient had a full clinical recovery from all three

episodes after treatment with intravenous methylpredniso-

lone, which was administered in all cases after the magnetic

resonance study was performed.

The patient exhibited no learning disabilities or symp-

tomatic cognitive delays.

Follow-up magnetic resonance studies indicated the

appearance of new lesions similar to the original lesions

(Fig. 1B) in the supratentorial region and on the spinal cord.

One lesionwas at the C2 level, and another was a left posterior

paramedial lesion at the C3eC4 level.

2.2. Clinical case 2

A 16-year-old male with no personal or family history of in-

terest requested a consultation after a 7-day, self-limiting

episode characterised by a lack of sensitivity and a loss of

strength in the left upper and lower limbs. During examina-

tion after the patient had become asymptomatic, no focal

disturbances or relevant anomalies were detected. Cerebral

magnetic resonance revealed 15 demyelinating lesions: 1 in

the middle cerebellar peduncle, 5 in the periventricular white

matter, 3 paracallosal lesions, 4 in the semioval centers, 1 in

the right external capsule, and 1 left frontal juxtacortical

lesion. The lesions did not take up contrast. Spinal magnetic

resonance revealed no relevant alterations (Fig. 1C).

A discrete hyperproteinorraquia (530mg/L) was detected in

the cerebrospinal fluid analysis, with the presence of oligo-

clonal banding.

The study also included the blood analyses described for

the previous case,23 which revealed normal results. The

ophthalmological examination was normal.

Eight months after the first episode, the patient again

presented with a self-limiting episode of paresthesia in the

upper left limb. Magnetic resonance (Fig. 1D) revealed two

additional lesions, which were similar to the original lesions.

However on this occasion, the lesions did take up contrast.

Another small lesion that did not take up contrast was

detected on the cervical spine at the C2 level. Visual evoked

potentials were normal. Both episodes were treated with

intravenous methylprednisolone after the MRI was

performed.

This patient had no clinical learning or cognitive disabil-

ities, and he was a university student with good grades.

2.3. Control group

The control group included six 12-year-old females (female

control group) and six 16-year-old males (male control group)

with a history of normal neurological development. Each child

was examined by a paediatric neurologist to rule out any

neurological abnormalities.

All of the subjects (i.e., both cases and controls) were

evaluated from a general medical perspective and a neuro-

logical perspective. Appropriate consent was obtained prior to

each child’s evaluation and neuroimaging studies.

3. Methods

3.1. MRI acquisition and image analysis

MRI scans were visually inspected by a radiologist for move-

ment artefacts before inclusion in the analysis. CTh analysis

was performed by two technicians trained to use the software

used in this study; neither of the technicians knew the pa-

tients or their diagnoses.

The following equipment and sequences were used: Gen-

eral Electric 1.5t Signa HDx equipment (Milwaukee, MI, US);

1.5 T; T1 3D SPGR (spoiled gradient echo) sequence in plane

axial, TE (echo delay time) 1 ms in phase, automatic TR

(repetition time), flip angle 10�, bandwidth 31.25 Hz, FOV (field

of view) 28, slice thickness 1.4 mm; zip (“speed” compression

system): 512; phase FOV: 0.8; 2NEX (number of excitations);

matrix: 228 � 228; duration: 6.25 min.

The sequential method for analysing CTh was previously

described by our group.24 Three steps were performed suc-

cessively: 1) automated removal of non-brain tissue using the

Bet extraction tool,25 2) automatic segmentation of the

selected brain tissue into tissue types, including grey matter,

white matter and cerebrospinal fluid, using the FSL’s FAST

tool, and 3) CTh measurement for each subject using the

Laplace method, as implemented in BrainVoyager.26 Prior to

this analysis, anatomical data from each subject was resam-

pled and transformed into ACPC space and Talairach standard

space. An advanced segmentation was also performed to

obtain a highly accurate cortex representation. After individ-

ual CTh maps were calculated, the reconstructed cortices

were aligned into a spherical representation to improve the

spatial correspondence across the subjects’ brains. CTh was

analysed within lobes, within hemispheres and within the

whole brain.

4. Results

4.1. Total brain CTh and CTh by hemisphere

An analysis of total cerebral CTh indicated that patients with

MS have smaller thicknesses than patients in the control

group, regardless of gender (Table 1). The analysis of CTh by

hemisphere indicated that this relationship was maintained

in the right hemisphere in both clinical cases; the left hemi-

sphere CTh in Case 1 was also smaller than that of the control

group comprised of girls of the same age. However, the left

hemisphere CTh in Case 2 was greater than the mean CTh of

the control group comprised of males of the same age as the

patient.

4.2. CTh by brain lobe (Table 1)

Case 1 versus the female control group. All of the right lobular

CTh values recorded in Case 1 were at least 1.5 standard de-

viations below the values recorded in the control group. The

left lobular CTh values of the same patient were also lower

than those observed in the control group, exhibiting values

between 0.73 and 2.3 standard deviations below those of the

Table 1 e Mean cortical thicknesses (in millimetres) and standard deviations (SD), presented according to group.

Area analysed Controlgroup girls(N ¼ 6)

Case 1 Standarddeviations

(SD)

Controlgroup boys

(N ¼ 6)

Case 2 Standarddeviations

(SD)

Right Hemisphere

Frontal Lobe 3.50 (0.15) 2.92 �3.86 SD 3.29 (0.25) 2.97 �1.28 SD

Parietal Lobe 2.83 (0.26) 2.43 �1.53 SD 2.81 (0.37) 2.23 �1.57 SD

Temporal Lobe 3.74 (0.31) 2.82 �2.96 SD 3.56 (0.35) 3.07 �1.40 SD

Occipital Lobe 3.43 (0.34) 2.27 �3.41 SD 3.01 (0.41) 2.53 �1.17 SD

Total right 3.36 (0.18) 2.67 �3.83 SD 3.19 (0.31) 2.73 �1.4 SD

Left Hemisphere

Frontal Lobe 3.51 (0.16) 3.13 �2.3 SD 3.28 (0.32) 2.96 �1.00 SD

Parietal Lobe 2.87 (0.53) 2.48 �0.73 SD 2.82 (0.38) 4.46 4.31 SD

Temporal Lobe 3.63 (0.33) 3.17 �1.39 SD 3.66 (0.46) 3.36 �0.65 SD

Occipital Lobe 3.21 (0.60) 2.64 �0.95 SD 3.59 (1.44) 2.46 �0.78 SD

Total left 3.32 (0.34) 2.89 �1.26 SD 3.29 (0.39) 3.46 0.43 SD

Both Hemispheres

Total 3.34 (0.17) 2.79 �3.23 SD 3.24 (0.31) 3.10 �0.45 SD

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 2 9 5e3 0 0298

control group. The CTh of both frontal lobes in Case 1

exhibited the most significant differences from the measure-

ments of the corresponding control group (i.e., values more

than 2 standard deviations below the control group values).

Case 2 versus the male control group. All of the right lobe

CTh measurements obtained in Case 1 were at least 1 stan-

dard deviation below the values observed in the control group.

Analysis of the left hemisphere indicated that the CTh of the

frontal, temporal, and occipital lobes in Case 2 were smaller

than the measurements recorded in the corresponding con-

trol group. The CTh values of the right parietal lobe and the

left frontal lobe in Case 2 exhibited the most significant dif-

ferences from the values recorded for the control group, (i.e.,

values 1.57 and 1 standard deviations below the control group

values, respectively).

The comparative analysis of the mean CTh values (in

millimetres) according to cerebral lobe between patients with

multiple sclerosis (cases) and patients in the control group is

presented in Fig. 2.

Fig. 2 e Comparative analysis of mean cortical thicknesses

(inmillimetres) according to cerebral lobe between patients

with multiple sclerosis (cases) and patients in the control

group. R [ right; L [ left.

5. Discussion

The evaluation of changes in cortical volume using serial

magnetic resonance imaging is a reliable andwell-established

method of estimating the progressive loss of tissue that occurs

as a result of neurodegeneration in patientswithMS.19 Studies

in the early stages of the disease are useful for establishing

prognostic markers and treatment monitoring techniques, as

well as for providing information regarding the pathogenesis

of the disease.18 Quantitative MR studies in adults indicate

that gray matter atrophy (i.e., global cerebral atrophy, cortical

volume, and thalamic atrophy)12,13,17e19,27 begins during the

initial stages of the disease,13,17,18 with white matter devel-

oping more quickly14,28; cortical atrophy is more closely

related to motor disability and cognitive impairment than

white matter lesions.11,12,29

Calabrese et al. reported a subgroup of adults with an iso-

lated clinical syndrome that evolved intoMS during the course

of a 4-year follow-up; this clinical syndrome was charac-

terised by significant gray matter atrophy in cortical regions,

deep brain areas and the cerebellum.11 The same author29

conducted an analysis of CTh in a large group of adults with

the remittingerelapsing form of MS; marked bilateral fronto-

temporal cortical thinning was observed in patients with

normal cognition compared to controls. The patients with

mild cognitive impairment displayed widespread cortical

thinning involving most cortical areas. Although the frontal

and temporal lobes were the most atrophied regions,15 many

other areas appear thinned in adult patients.15,29

These results are similar to those observed in the two

children studied in thiswork. In these patients, the CTh values

of most lobes, including the frontal and temporal lobes, were

distinct from the measurements of the corresponding control

group. The increased CTh in the parietal lobe of the second

case could be coincidental; however, this finding could also be

explained by neural compensation, which has been observed

in MS30,31 and other dysfunctional disorders.32,33 Our data

indicate that graymatter pathology plays an important role in

determining the evolutive course of MS in young patients. In

contrast, Absinta et al.8 reported that gray matter volume did

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 1 8 ( 2 0 1 4 ) 2 9 5e3 0 0 299

not differ between paediatric patients with MS and control

patients or between paediatric and adult patients with MS,

after adjusting the values for age. Mesaros et al.20 studied the

pattern of cortical gray matter loss in patients with remit-

tingerelapsing MS; the atrophy of gray matter appeared to

compromise only the thalamus, sparing the cortex. These two

studies reported inconsistent results for adults11,29 and

differed from our results, which indicated that cortical atro-

phywas present during the initial outbreak of MS in paediatric

patients.

Till et al.12 reported cognitive impairment in 29% of youths

with a paediatric onset of MS; the group with MS displayed

significantly smaller thalamic and total cerebral volumes, and

gray matter volume was also affected, as reported in our

study. The important association between cognitive function

and the gray matter findings in the imaging studies suggest

the existence of a neurodegenerative process early in the

course of the disease.12

It is possible that the etiological-pathogenic mechanisms

that cause the lesions may be present and cause cortical at-

rophy prior to the appearance of clinical episodes. To address

this hypothesis, broad, multicenter, studies in child-

adolescent populations that analyse not only the gray mat-

ter thickness but also the cerebral cortex of each brain lobe

during the initial outbreak of MS are needed. Enhancing the

sensitivity of magnetic resonance, improving the software for

data analysis, collecting neuropsychological testing data, and

reducing heterogeneity among patients will facilitate an

improved understanding of the timing of cortical atrophy and

of the possible use of cortical atrophy as a prognostic marker

in MS, leading to the development of disease-modifying

treatments.11

Financial disclosure/funding

The authors received no financial support for the research

and/or authorship of this article.

Author contributions/roles

Alberto Fernandez-Jaen participated in the conception and

design of the study, as well as the analysis and interpretation

of patient data. He also provided final approval for this

manuscript. Daniel Martın Fernandez-Mayoralas participated

in the conception and design of this study and drafted the first

version of this manuscript. He also provided final approval for

this manuscript. Beatriz Calleja Perez contributed to the study

design and to the analysis and interpretation of the data. She

also provided final approval for this manuscript. Mar Jimenez

de la Pena contributed to the conception and design of this

study and to the analysis and interpretation of data. Manuel

Recio Rodrıguez contributed to the study design and to the

analysis and interpretation of the data. Nuria Munoz Jareno

participated in the data analysis and critically revised this

article for important intellectual content. She also provided

final approval for this manuscript. Rafael Arroyo Gonzalez

made substantial contributions to the conception of this

study, revised this manuscript, and will provide final approval

for the version to be published. Jacobo Albert revised this

manuscript and will provide final approval for the version to

be published.

Declaration of conflict of interests

The authors declare that they have no conflicts of interest or

commercial or other financial relationships. We received no

funding for this study. We have no commercial, financial, or

other associations that could create a conflict of interest

related to the submitted article.

Acknowledgements

Thework presented in this studywas conducted at the Quiron

Hospital in Madrid.

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