Comprehensive Summaries of Uppsala Dissertations
from the Faculty of Medicine 1332
Rolandic Epilepsy
A Neuroradiological, Neuropsychological
and Oromotor Study
BY
STAFFAN LUNDBERG
ACTA UNIVERSITATIS UPSALIENSIS
UPPSALA 2004
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List of Papers
The thesis is based on the following papers, which will be referred to in the
text by their Roman numerals:
I
Lundberg S, Eeg-Olofsson O, Raininko R, Edebol EegOlofsson K. Hippocampal asymmetries and white matter
abnormalities on MRI in benign childhood epilepsy with
centrotemporal spikes. Epilepsia 1999;40:1808-15.
II
Lundberg S, Weis J, Eeg-Olofsson O, Raininko R. Hippocampal region asymmetry assessed by 1H-MRS in rolandic epilepsy. Epilepsia 2003;44:205-10.
III
Croona C, Kihlgren M, Lundberg S, Eeg-Olofsson O,
Edebol Eeg-Olofsson K. Neuropsychological findings in
children with benign childhood epilepsy with centrotemporal spikes. Developmental Medicine & Child Neurology 1999;41:813-18.
IV
Lundberg S, Frylmark A, Eeg-Olofsson O. Children with
rolandic epilepsy have abnormalities of oromotor and dichotic listening performance (submitted).
V
Lundberg S, Eeg-Olofsson O. Rolandic epilepsy
– a challenge in terminology and classification. European
Journal of Paediatric Neurology 2003;7:239-41.
Reprints were made with the permission of the publishers.
Contents
Introduction.....................................................................................................9
Background ...................................................................................................10
History......................................................................................................10
Definition and prevalence ........................................................................11
Seizures and other clinical manifestations in RE .....................................12
EEG in RE................................................................................................13
Cerebral lesions and RE ...........................................................................16
Neuroimaging in RE.................................................................................17
Magnetic Resonance Imaging (MRI) ..................................................17
Proton Magnetic Resonance Spectroscopy (1H-MRS) ........................18
Positron Emission Tomography (PET)................................................20
Neuropsychological evaluation in RE......................................................20
Oromotor disturbances in RE ...................................................................21
Family history and genetics in RE ...........................................................22
Treatment of RE .......................................................................................23
Prognosis of RE........................................................................................23
Benignity of RE and atypical RE .............................................................24
Relations to other idiopathic epilepsy syndromes in childhood ...............24
Aims of the study:.........................................................................................27
Subjects.........................................................................................................28
Study I ......................................................................................................31
Study II.....................................................................................................31
Study III ...................................................................................................32
Study IV ...................................................................................................32
Methods ........................................................................................................33
Study I ......................................................................................................33
Study II.....................................................................................................33
Study III ...................................................................................................34
Study IV ...................................................................................................35
Statistics ...................................................................................................37
Results...........................................................................................................38
Study I ......................................................................................................38
Study II.....................................................................................................43
1
H-MRS ...............................................................................................43
MRI......................................................................................................45
Study III ...................................................................................................46
Study IV ...................................................................................................48
Dichotic listening test ..........................................................................49
Paper V.....................................................................................................50
Discussion .....................................................................................................51
Classification and diagnosis of RE, inclusion and exclusion criteria
(Study V) ..................................................................................................51
Magnetic resonance imaging (Study I) ....................................................54
1
H-MRS (Study II) ...................................................................................56
Neuropsychological assessment (Study III) .............................................57
Oromotor assessments (Study IV)............................................................58
Dichotic listening (Study IV) ...................................................................59
Neurophysiology and summary................................................................61
Limitations of Study I–IV ........................................................................62
Conclusions...................................................................................................63
Future directions ...........................................................................................65
Acknowledgements.......................................................................................66
References.....................................................................................................68
Abbreviations
ABPE
AED
BCECTS
Cho
Cr
CSWS
CT
EEG
ESES
FDG
Glx
GTCS
HIBM
1
H-MRS
ILAE
MEG
MRI
NAA
OPL
PET
ppm
RAVLT
RD
RE
RS
SE
Shw
TLE
VOI
Atypical benign partial epilepsy
Antiepileptic drug
Benign childhood epilepsy with centrotemporal spikes
Choline containing compounds
Creatine
Continuous spikes and waves during slow-wave sleep
Computerized tomography
Electroencephalogram
Electrical status epilepticus during slow sleep
18
F-fluorodeoxyglucose
Glutamine and glutamate
Generalized tonic-clonic seizure(s)
Hereditary impairment of brain maturation
Proton magnetic resonance spectroscopy
International League Against Epilepsy
Magnetoencephalography
Magnetic resonance imaging
N-acetyl aspartate
Oropharyngolaryngeal
Positron emission tomography
Parts-per-million
Rey Auditory-Verbal Learning test
Rolandic discharges
Rolandic epilepsy
Rolandic seizure (s)
Status epilepticus
Sharp wave(s)
Temporal lobe epilepsy
Volume of interest
Introduction
Epilepsy syndromes are clusters of signs and symptoms customarily occurring together. Rolandic epilepsy (RE) is the most common focal epilepsy
syndrome in the pediatric age group. Since it was described in 1958 (1), the
syndrome has had a variety of denominations throughout the years. The
name, proposed by the Commission on Classification and Terminology of
the International League Against Epilepsy (ILAE) 1989, is ‘benign childhood epilepsy with centrotemporal spikes’ (BCECTS) according to clinical
and electro-encephalographic features (2). The prefix ‘benign’ is included in
most of the synonyms (3) due to the excellent prognosis regarding the seizures which usually resolve at puberty as well as normalization of the EEG.
However, several studies during the last decade have shown previous unattended cognitive deficits in children with RE, so that the favorable prognosis
has been challenged. The definition and delineation of the syndrome has also
been discussed over the last years.
9
Background
History
The name rolandic epilepsy alludes to the central sulcus of Rolando, named
after the Italian anatomist Luigi Rolando (1773-1831). However, according
to a historical review of the syndrome published by van Huffelen 1989 (4),
this was an erroneous tribute to Rolando, who never contributed any scientific work concerning epilepsy. The first clinical description of RE can be
ascribed to the Bavarian physician Martinus Rulandus (1532-1602). In one
of his medical publications from 1597, he described the history of a 10-yearold boy presenting a ‘terrible epileptic disorder’ with brief seizures both day
and night with convulsions of the left eye, mouth and arm, arrest of speech
and a transitory paralysis of his left arm but without falling. Rulandus treated
the boy with a concoction of lime tree blossom and brandy, and the boy was
cured (!). The long-term outcome, however, is not told. This description of
the seizure corresponds quite well to that occurring in RE and van Huffelen
thus suggested the name Rulandic epilepsy instead of Rolandic epilepsy (4).
However, the last-mentioned denomination has formed out to be the current
one.
In modern times, the syndrome was not described and defined until the
1950s. The EEG features of what would later be called rolandic spikes or
sharp waves (shw), were first reported by Y Gastaut in 1952, who called the
discharges ‘prerolandique’ (5). Gibbs and Gibbs in the same year (6) and
Gibbs et al. 1954 (7), entitled the spikes ‘mid-temporal’. The first accurate
description of the electro-clinical syndrome was presented in 1958 by Nayrac and Beaussart (1) and this was followed by several other reports in the
1960s and 1970s. The most prominent authors in the delineation of this idiopathic focal syndrome were Gibbs and Gibbs (8, 9), Beaussart (10, 11),
Lombroso (12), Loiseau (13-16), and Lerman (17, 18). In Scandinavia, Blom
and Brorsson (19) and Blom and Heijbel (20-22) made important contributions and they also introduced the term “centro-temporal” and proposed the
prefix “benign” (21).
10
Definition and prevalence
The current definition of RE is that of the Commission on Classification and
Terminology of the ILAE 1989 (2), which is presented in full:
Idiopathic localization-related epilepsies are childhood epilepsies with
partial seizures and focal EEG abnormalities. They are age-related, without
demonstrable anatomic lesions, and are subject to spontaneous remission.
Clinically, patients have neither neurologic and intellectual deficit nor a history of antecedent illness, but frequently have a family history of benign epilepsy. The seizures are usually brief and rare, but may be frequent early in the
course of the disorder. The seizure patterns may vary from case to case, but
usually remain constant in the same child. The EEG is characterized by normal background activity and localized high-voltage repetitive spikes, which
are sometimes independent multifocal. Brief bursts of generalized spikewaves can occur. Focal abnormalities are increased by sleep and are without
change in morphology.
Benign childhood epilepsy with centrotemporal spikes is a syndrome of
brief, simple, partial, hemifacial motor seizures, frequently having associated
somatosensory symptoms which have a tendency to evolve into generalized
tonic-clonic seizure (GTCS). Both seizure types are often related to sleep.
Onset occurs between the ages of 3 and 13 years (peak 9-10 years), and recovery occurs before the age of 15-16 years. Genetic predisposition is frequent, and there is male predominance. The EEG has blunt high-voltage centrotemporal spikes, often followed by slow waves that are activated by sleep
and tend to spread or shift from side to side.
This definition does not take into consideration several new aspects of the
syndrome, which have been reported and discussed over the last decade, as
neuropsychological abnormalities and different expressions of the syndrome.
For instance, there is common agreement that the focal (partial) seizures
quite often are accompanied by some impairment of consciousness. Consequently, there have been somewhat different inclusion criteria for RE
amongst epileptologists when studying populations of children with epilepsy. This has resulted in a varying range of prevalence figures.
The prevalence figures of RE in childhood epilepsy populations comprising children up to 15/16 years, excluding neonates are:
Heijbel et al. 1975 (23) 15.7 % and Sidenvall et al. 1996 (24) 17.4 %
(both Umeå, Sweden); Panayiotopoulos in Athens, Greece 1989/1993 (25,
26) 15.3/14.6 %, and Larsson and Eeg-Olofsson, Uppsala, Sweden 2001
17.6% (personal communication).
In children between 5 to 14 years, Cavazzuti, Italy 1980 (27) reported a
prevalence of 23.9 % and Panayiotopoulos (25, 26) 24.6 %. Doose and
Sitepu studied children aged 0 to 8 years in Northern Germany 1983 (28)
and found a prevalence of 8 %. A slight male predominance is reported (16,
29, 30).
11
Seizures and other clinical manifestations in RE
The seizures in connection with RE are called rolandic seizures (RS). The
onset occurs between the ages of 3 and 13 years, in 76 % between 5-10
years, with a peak at 9 years (18). Seizures only during sleep are most frequent (70-80 %), in the majority in nocturnal sleep, typically arising shortly
after the child has fallen asleep or before awakening in the morning. Seizures
exclusively when awake are less frequent (10-20%) (18), and seizures when
both awake and during sleep occur in approximately 15 % (18) to 23 % (16).
The first seizure is typically observed by the parents as GTCS during
sleep, and this may bring the family to the hospital. The genuine RS is a
focal seizure, which originates from the rolandic area. The consciousness is
most often unimpaired but may be blurred, which can be difficult to evaluate
for observers. An appropriate description of the seizure semiology is crucial
for a correct diagnosis.
The characteristic features of a RS includes:
Hemisensory symptoms as paraesthesias with numbness and tickling sensations from the face, mouth, lips, inner cheek, tongue, gum and throat and
hemimotor symptoms from the face, lips and mouth which consists of brief,
rhythmic contractions. The hemifacial symptoms occur in about a third of
the children (31). Both hemimotor symptoms and paraesthesias may also
progress to the arm ipsilaterally but the leg is very rarely involved.
Oropharyngolaryngeal (OPL) symptoms are classical RS manifestations
and occurs in more than 50 % (31) . The symptoms are mainly motor but
may also be sensory. They are described as guttural, moaning, gurgling,
chuckling, grunting, roaring, gasping, and wheezing sounds. The child may
describe a feeling of strangulation or choking. However, usually the child is
unconscious, and the described sounds will often draw the attention of the
parents to the child in the bedroom.
An associated very characteristic symptom is speech arrest, which occurs
in more than 40% of the seizures (12, 15, 17). The child is conscious but
becomes frustrated because of the inability to speak, except for producing
some OPL sounds. This can be explained as an ictal anarthria, i.e. loss of
power and co-ordination to articulate words (12, 15, 17, 31).
Hypersalivation is also a common ictal phenomenon occurring in about
one third of the children (31). The drooling is thought not only to be a consequence of swallowing difficulties but also a genuine sialhorrhea as an
autonomic ictal manifestation which, according to Lüders , probably is “due
to involvement of the superior bank of the sylvian fissure” (29).
The focal seizure has a strong tendency to secondary generalization, which
most often occurs during sleep. Thus, a focal seizure onset will often not be
12
witnessed. Secondarily generalized seizures are reported in one to two thirds
of the children.
A so called Todd’s paralysis, i.e. a postictal paralysis most often of one
arm, has been reported in 7-16 % (15, 32, 33).
The frequency of RS is highly variable irrespective of treatment. Some authors include children with only one verified RS in their series (16, 17)
which is strictly not in accordance with the definition of epilepsy. It is quite
common that seizures occur in clusters for some days up to a few weeks
followed by a seizure-free interval of several months. In 10-20 % the seizures may be frequent and resistant to treatment (18).
Precipitating factors are in correspondence with epilepsy in general (e.g.
sleep deprivation, fatigue, minor illness, fever), but most often the RS occur
unprovoked. Focal status epilepticus in children with RE is reported by a few
authors (31, 32, 34-38).
EEG in RE
The interictal EEG findings are essential for the diagnosis of RE. The hallmark is the rolandic spike or sharp wave (shw) with a characteristic morphology. The shw is also called ‘benign focal shw’, referring to the absence
of corresponding (cortical) morphological lesions and are also described in
other idiopathic epilepsies (39), as well as occurring in individuals without
seizures (40). By definition, the distinction between a spike and a shw is the
duration of the discharge. A spike has a duration less than 70 ms and a shw
above 70 ms but not exceeding 200 ms. However, this discrimination is not
of any practical importance for the epileptologist when considering RE, and
the terms are most often used interchangeably.
The morphology of the shw can be described as follows: A low amplitude
positive wave is generally followed by the characteristic high negative wave
with a peak amplitude often exceeding 200 µV, but this can be smaller or
markedly higher. The average amplitude has been estimated to 160 µV
(41).Then three positive or negative slow waves follows and this constitutes
the so-called “five-component shw” according to Doose (39). However, the
shape can be altered depending on localization, age, tendency to generalization, and by sleep activation.
The shw constituting the electrographic sign of RE will in the following
be called rolandic discharge (RD).
13
Figure 1. Interictal EEG of a 6-year-old girl (case 18) during drowsiness. The EEG
was performed four months after onset of characteristic left-sided RS, which were
initially frequent during several days until she was successfully treated with carbamazepine. The EEG shows typical RD in the right centrotemporal area (phase
reversal C4), and contralateral synchronous RD of lower amplitudes.
14
Figure 2. Interictal EEG of a 9-year-old girl (case 14) during drowsiness. She had
RE onset at age 7 years and was successfully treated with valproate. Frequent RD in
clusters are seen with typical morphology with maximum at electrode C3 on the left
side.
15
The localization of the RD is classically a horizontal dipole with maximal
electronegativity in the centrotemporal (midtemporal) area and with the electropositivity in the frontal regions (42, 43). It may also be located in the
centro-parietal, fronto-central or centro-occipital areas. The localization of
RD in general is age dependent with parieto-occipital foci usually occurring
before the age of four while centrotemporal (midtemporal) RD peak around
the age of eight (6, 44). Drury et al. (45) found RD outside the centrotemporal area in 21 % of children with a typical history of RE and stated that the
most important feature is the monomorphic shw and not the location. The
RDs are located unilaterally in around 60 % and bilaterally in around 40 %
with the foci tending to shift from side to side asynchronously (18) and synchronously (12, 29). There is a tendency of the RD to appear in clusters with
a rhythm of 1.5 to 3 Hz (46). They typically increase in frequency during
drowsiness and sleep and tends to become bilateral, usually with unchanged
morphology (20). In approximately 30 % of the children with RE, shw appear only in sleep (12, 20). This emphasizes the importance of getting a
sleep EEG that usually is obtained by sleep deprivation. Activation with
hyperventilation or photic stimulation does not influence the frequency of
discharges. Lerman and Kivity (17) found no correlation between the intensity of the discharges and frequency, length or duration of the RS.
The background activity should by definition be normal. However, there are
some reports of focal (47, 48) or bilateral (49) episodic slow activity.
Several ictal recordings in RE have been reported since the first one of Dalla
Bernadina 1975 (50-54) and there are also some reports when awake (18, 50,
55-57). The semiology has been described as typical of RS with EEG showing fast, repetitive spikes from the centrotemporal (midtemporal) area unilaterally, with or without preictal decrement and postictal slowing of activity,
respectively.
Cerebral lesions and RE
RE has been reported in children with cerebral lesions with different aetiologies and clinical presentations. Blom et al. (21) described in their series of 40
children two with slight hemiparesis. Santanelli et al. (58) reported three
patients with electro-clinical findings in accordance with RE. However, CT
scans showed agenesis of the corpus callosum, a lipoma of the corpus callosum, and congenital toxoplasmosis, respectively. Lerman and Kivity (17)
found three of 100 children with RE suffering from cerebral palsy and another from microcephaly. Lerman considered RE in the children described in
these reports as “fortuitously superimposed or ‘grafted’ on to an injured
brain,” and the prognosis concerning RE as good as in normal children (18).
16
Shevell and coworkers described five children with suggestive RE where
MRI or CT revealed mass lesions with variable locations (59). Stephani and
Doose (60) reported a girl with severe head trauma in the neonatal period
resulting in spastic tetraplegia, mental retardation and simple focal seizures
occurring from the right orofacial region from 28 months of age. At the age
of five she had typical RS with a benign course. As her sister showed RD on
EEG, the authors concluded that the proband did not just have a ‘phenocopy’
due to the brain lesion. Thus, the genetic predisposition of RD underlying
RE, can be involved also in the pathogenesis of seemingly pure symptomatic
epilepsies. Gelisse et al. (61) reported enlargement of the lateral ventricle in
five children of whom two had shunted hydrocephalus.
Other structural lesions exclusively revealed by MRI will be presented in
the following.
Neuroimaging in RE
Neuroimaging of idiopathic epilepsies has been regarded as superfluous due
to the good prognosis concerning seizure outcome according to many authors (10, 11, 62, 63). However, it is recommended if any atypical electroclinical features are found (55, 61). MRI is today the imaging method of first
choice for identifying the structural basis of epilepsy, and the technique is
still improving. Prior to the MRI era or in the early years of MRI, i.e. mid
1980s, CT was the only imaging technique that was available. Systematic
CT studies of benign focal epilepsy have not been performed to my knowledge. However, CT has been used now and then in RE series in selected
cases excluding gross morphological abnormalities. Because of its availability, CT is nowadays used only in the very acute or initial phase of epilepsy to
exclude tumor or haemorrhage.
Magnetic Resonance Imaging (MRI)
Over the last years, a few case reports of MRI studies in children with RE
have been reported. Gelisse et al. (64) presented a 10-year-old boy with
clinically typical RE, the MRI disclosing a very marked right sided hippocampal atrophy. However, because of absent clinical correlates and no apparent cause to the atrophy, they concluded that the seizure disorder could
not be ascribed to this abnormality. Cortical dysplasia has also been found in
children with typical RE (65, 66). Shet et al. (65) reported cortical dysplasia
in the suprasylvian region, which was regarded as an incidental finding. In a
case of unilateral opercular macrogyria (unspecified location), this malformation was supposed to provide an epileptogenic zone causing rolandic discharges (66).
17
Proton Magnetic Resonance Spectroscopy (1H-MRS)
1
H-MRS provides a non-invasive means of investigating the biochemistry in
various tissues. The brain has been one of the most studied organs and the
clinical applications are mainly brain tumors, degenerative or neurometabolic brain disorders and epilepsy. The application of 1H-MRS, in attempt
to delineate the epileptogenic zone in epilepsy, has mainly concerned presurgical evaluation of temporal lobe epilepsy (TLE), but it has also been
performed in extra-temporal epilepsies. 1H-MRS, however, is not used in
common clinical routine. In research, 1H-MRS studies in focal idiopathic
epilepsies including RE have so far not been performed.
1
H-MRS background
H-MRS, in contrary to MRI, does not primarily produce an image but spectra showing peaks of metabolites. The spectra are achieved by excitation of
protons in a strong magnetic field by a specific radio frequency (RF) pulse.
The protons then emit a RF signal of a characteristic resonance frequency,
which is dependent on the chemical environment, i.e. in which molecule the
proton finds itself. The differences of the resonance frequencies are referred
to as ‘chemical shift’ and are presented along a horizontal axis (x-axis) plotted in ‘parts-per-million’ (ppm). The area under the peak represents the relative concentration of protons giving origin to the peak signal. Mainly two
localization methods are used: STEAM (Stimulated Echo Acquisition Mode)
and PRESS (Point-Resolved Spectroscopy), both providing localization in
three dimensions. These methods can be applied to two spectroscopic techniques; single voxel and multiple voxels or chemical shift imaging.
1
The main metabolites in gray and white matter detected by 1H-MRS in epilepsy assessments are:
N-acetyl aspartate (NAA) and N-acetyl aspartyl-glutamate (NAAG) (occuring at 2.02 ppm) are often mentioned as total NAA (tNAA). NAA is considered as a marker of neuronal function and is confined to neurons and neuronal processes both in gray and white matter. Decreased signal intensity
indicates neuronal loss or neuronal dysfunction. The exact functional role of
NAA is still not completely understood.
Creatine (Cr) and phosphocreatine (3.03 ppm) (total creatine; tCr) are involved in the generation of ATP. The concentration is considered as quite
stable but deviations are observed in tumors, stroke and in some metabolic
diseases.
Choline containing compounds (Cho) (3.21 ppm) is required for synthesis
of acetylcholine and of phosphatidylcholine, a major constituent of membranes. It is also considered as mainly stable, though alterations can be observed in neoplasms and in ischemic and neurometbolic disturbances.
18
Glutamate (Glu) and glutamine (Gln) (together termed Glx; 2.2-2.4 ppm).
Glu is the main excitatory amino acid in human brain and Gln its precursor
and storage form. To obtain a satisfying resolution, a short echo time acquisition is required. Theoretically, measurements of Glx would contribute in
evaluating epilepsy, however, up to now few studies have been published
using Glx as an epileptic marker (67-74).
The metabolites are measured quantitatively or qualitatively. In qualitative
studies, NAA/Cr or NAA/ Cr + Cho ratios are most often used as indicators
of neuronal function. As mentioned, the most studied individuals with epilepsy are those with intractable TLE. There is a voluminous literature concerning TLE in adults, and in some reports children are included. Few studies concerns solely children (75-80). The main issues are lateralization and a
more thorough localization of the epileptic focus and prognosis of TLE,
which is mostly post-surgery. There is an unanimous opinion that 1H-MRS
provides a sensitive tool of detecting neuronal dysfunction by measurement
of relative or absolute concentrations of the NAA in the temporal lobes including hippocampi. This also includes dynamic properties of NAA levels.
These can be below normal level even contralaterally to the TLE. Cendes et
al. (81) and Hugg et al. (82) have shown, mainly in adults with TLE, a normalization of NAA ratios on the opposite side after successful epilepsy surgery. Cendes et al. hypothesize that it is the seizure activity itself that lowers
the NAA. However, Li et al. (83), examining individuals with focal epilepsies successfully treated with antiepileptic drugs (AED), did not find recovery of the NAA ratios. They concluded that absence of seizures is not necessarily coupled to NAA improvement.
There are some 1H-MRS studies in normal children with the purpose of
studying the age development of the metabolites. Van der Knaap et al. (84)
studied predominantly white matter with single-voxel technique and found
the most rapid increase of NAA ratios to occur during the first three years of
life. Kadota et al. (85), used multivoxel 1H-MRS to calculate NAA/Cho ratios in the human cerebrum. However, individuals in the first four years of
life were not included. The results demonstrated a rapid increase of the ratio
in white matter during the first decade. In contrast, in isocortical gray matter
the ratio showed a gradual decline with age. Choi et al. (86) compared allocortex, i.e. mainly hippocampal formation, and isocortex (neocortex) in the
frontal and parietal lobe in 30 healthy children aged 3-14 years with a singlevoxel (5 in allocortex and 7.2 ml in isocortex). They found a lower NAA/Cr
ratio in allocortex compared to isocortex, but no significant hemispheric
asymmetry in allocortex and no significant correlation between age and
metabolic ratios in either allocortex or isocortex.
19
Positron Emission Tomography (PET)
Very few functional neuroimaging studies utilizing PET have been performed in children with idiopathic partial epilepsy. De Saint-Martin et al.
(87) reported a longitudinal study of a child with RE using 18Ffluorodeoxyglucose (FDG) PET. They found a bilateral increase of glucose
metabolism in the temporal opercular regions interictally during the ‘active’
phase of the epilepsy. Van Bogaert et al. (88) using FDG-PET in eleven
children with RE could not demonstrate any interictal side differences in
glucose metabolism.
Neuropsychological evaluation in RE
In earlier studies of RE, the children were described as ‘neurologically normal’ because the condition was considered ‘benign’. In some larger studies,
children with behavioral and neuropsychological problems were excluded a
priori (11) and few systematic neuropsychological studies have been published (89). Some remarks of behavior and learning problems have been
reported, but these were attributed to psychosocial factors, or to adverse
effects caused by treatment with barbiturates (17, 18). Panayiotopoulos (31)
states in his comprehensive survey of RE: “The general view is that children
with RS are not different from other normal children regarding intelligence,
school performance, behaviour and development. This is also my view.”
Nevertheless, this opinion has been questioned over the last decade by
several authors, who can be divided into two groups: those who ascribe the
cognitive impairment to ongoing epileptic discharges, i.e. RD, and those
who attribute it to the basic cerebral dysfunction responsible for the epileptic
manifestation. An Italian group (90, 91) studied the influence of epileptic
discharges in EEG on cognitive function and attention in children with RE
by sub-grouping them into left, right and bilateral discharges. They found
that cognitive impairment “appears to be to some extent related to the EEG
focus.” The worst scores were found in the group with bilateral discharges
(90). In a later study, they confirmed a significantly lower score in RE children with a right sided focus or bilateral foci (91).
Binnie and Marston (92) studied 10 children with ‘rolandic spikes’, and
seven of them had seizures in accordance with RE. In connection with an
EEG registration they performed a test of short-term memory for spatial
material. Four of the seven children showed a significantly higher error rate
in trials accompanied by EEG discharges. They concluded that the occurrence of ‘rolandic spikes’ might be accompanied by transient cognitive impairment (TCI). This observation has been cited quite often and has established a still ongoing discussion as to whether ‘interictal’ discharges can
affect brain activities expressed as TCI, and consequently should be treated
with AED.
20
Deonna et al. (93) studied 19 children with typical RE. They found that a
proportion of the children showed mild and transient cognitive difficulties
during the ‘active’ phase of their epilepsy. These difficulties were probably
related to EEG activity, and they concluded that a trial of AED on children
suspected to have cognitive or learning difficulties was advisable. Weglage
et al. (94) investigated 40 children with ‘centrotemporal spikes’, 20 with
seizures and 20 without seizures, i.e. 50 % did not have RE. The performance of these children regarding visual perception, short-term memory and
IQ was significantly impaired compared with matched controls. They also
found a correlation between the number of spikes and deficits in IQ, suggesting that AED should be tried even in children without seizures.
Staden et al. (95) reported impairment of language skills in 13 of 20 children with RE, suggesting the cause to be an interictal dysfunction of the
perisylvian language area.
In a prospective study, Baglietto et al. (96) investigated nine children with
RE and with “marked activation of interictal epileptic discharges during
sleep” compared with matched controls. The patients were seizure-free during the study period. A test battery revealed significantly poorer results in
the RE children concerning visuospatial short-term memory, visuomotor
coordination, picture naming and fluency, attention, and cognitive flexibility.
At remission of the discharges, both spontaneously and after treatment with
diazepam, all patients showed normalization of the results, and also an improvement of IQ. The authors proposed a brief period of diazepam treatment
in order to shorten the time for recovery from the interictal discharges,
thereby improving the neuropsychological condition.
In a retrospective study, Yung et al. (97) reported 56 children with centrotemporal spikes on EEG and seizures compatible with RE. Interestingly,
they found three children with language delay and regression. One child had
abundant bilateral independent shw during sleep but did not fulfill the criteria for continuos spikes and waves during slow-wave sleep (CSWS). Another child had a sister with CSWS. However, neither the second child nor
the third one had EEG features of CSWS. Behavioral problems and/or learning disabilities were found in 14 % of the RE children and mild to borderline
intellectual dysfunction in 12 %. However, the authors admitted that the
study represented a skewed population.
Oromotor disturbances in RE
The characteristic semiology of RS comprises OPL symptoms including
speech problems, hypersalivation or sialorrhea and rhythmic hemifacial contractions. These ictal events are normally of short duration and do not harm
the children otherwise in their daily living apart from the seizure itself.
However, prolonged and severe oromotor dysfunction has been reported in
21
RE children with duration from hours to several weeks. Fejerman and Di
Blasi (34) reported two children with RE and partial status epilepticus (SE)
presenting continuous hemifacial twitching, dysarthria or anarthria and sialorrhea, one of them also having swallowing difficulties. The symptoms
lasted for five days and one month respectively. Since then, similar oral dysfunction symptoms attributed to partial SE in children with RE have been
reported (35, 37, 38, 98). There are also case reports of transient oromotor
deficits, most often correlated with abundant interictal epileptic activity but
not defined as partial SE (36, 87, 99-101). The RDs are almost exclusively
bilateral, which seems to be necessary for these symptoms to occur (87, 99,
100).
Some of the reports of RE with oromotor dysfunction discuss these cases
in terms of a ‘functional anterior opercular syndrome’ (36, 87, 98, 102-104),
also designated Foix-Marie-Chavany syndrome.
Family history and genetics in RE
Idiopathic or ‘primary’ epilepsies as RE favour a genetic origin. In 1964,
Bray and Wiser (105) studied the families of 40 index cases with ‘temporalcentral’ spikes, i.e. RD, with or without seizures. The prevalence of RD was
36% in siblings and children compared to 2% in controls. They concluded
that the occurrence of RD follows an autosomal dominant mode of inheritance. In 1975, Heijbel et al. (106) obtained almost the same results when
evaluating the families of 19 children with RE. Eleven of 32 siblings (34%)
showed RD in wake or sleep recordings, and five of them had generalized
seizures. They concluded that the result indicated an autosomal dominant
gene with age-dependent penetrance responsible for the EEG trait. Degen
and Degen (107) studied 69 siblings of 43 children with RE and/or RD and
found RD only in four (5.8%) of the siblings which is close to around 3%
found in normal children age 3–14 (40). Despite this low prevalence, they
agreed to the preceding author’s opinion of inheritance. Doose et al. (108)
proposed a multifactorial inheritance of the EEG trait, which is regarded as a
genetic marker of not only RE but also of other epileptic and non-epileptic
disturbances. This concept is denominated ‘hereditary impairment of brain
maturation’ (HIBM). In 1998, Neubauer et al. (109) found a linkage to
chromosome 15q14 in 22 families with 54 members having RD and 43 of
these having RS. It was concluded that either the alpha 7 AChR subunit gene
or another closely linked gene are implicated in pedigrees with RD and that
the trait is genetically heterogeneous. So, the gene localization of RE is still
to be determined.
22
Treatment of RE
Treatment of RE is optional and may be performed only from psychological
and practical reasons (110, 111). The decision of treatment, which is restricted to pharmacological alternatives, has to be properly discussed with
the child and the family including presentations of pros and cons. One has to
consider that seizures normally are infrequent, brief, and most often nocturnal, thus having a minimal influence on the daily life of the child. Furthermore, pharmacological treatment, i.e. AED, does not influence the prognosis
of RE and, according to some authors, does not easily efface the RD (10).
However, other authors have proposed ‘treatment of the EEG’, i.e. to treat
interictal activity in order to minimize the risk of minor cognitive impairment (92-94, 97, 100).
If treatment is advised, there are several alternatives of AEDs, and literally the same as in other focal epilepsies. Carbamazepine is an effective and
mostly well tolerated drug, but may in exceptional cases aggravate seizures
(37, 104, 112-114) or induce epileptic negative myoclonus (115, 116). A
similar drug is oxcarbazepine, which also has been reported to exacerbate
seizures (117). Sulthiame has been used mainly in Europe, and it is a well
tolerated and an effective alternative in the treatment of RE (118, 119). Additionally, marked improvement of the EEG with normalization in the majority of cases has been found (120, 121). Moreover, valproate, benzodiazepines, phenytoin, phenobarbitarate, lamotrigine and gabapentine have also
been used in the treatment of RE. A small percentage of children with RE
may have refractory seizures (10, 33, 122).
Discontinuation of treatment is generally recommended if the patient is
seizure-free for one or two years (18, 31, 55, 123).
Prognosis of RE
A hallmark of RE is that seizures remit before or during puberty, at the latest
at 16 years of age, usually between 9 to 12 years (10, 16, 124). In a metaanalysis of 20 reports comprising 794 RE children, Bouma et al. (30) found
that the mean duration of active RE was less than three years. Most of the
children had only few seizures and were in remission by the age of 12 or 13
years. They concluded that early prediction of seizure outcome in a new RE
patient cannot be given with certainty because of the fact that the selected
studies showed a highly heterogeneous methodology, and that all were retrospective with biased cohorts. One of the 13 selected study cohorts consisted
of 168 patients in a follow-up study by Loiseau et al. (16). They found a
relation to age at onset of RE, i.e. the earlier the onset, the longer the active
period. Three of the patients had experienced further seizures, all of them
GTCS, after the age of 18 years. The authors stated that the relative risk of
23
such late occurring seizures was 10-fold in the RE population. Other studies
have also described a few individuals with sporadic GTCS in adulthood after
remission of RE (11, 21, 31, 122), and the risk has been estimated to less
than 2 % (16, 31). Focal seizures in the follow-up into adulthood are extremely rare (16, 125, 126), and only one case with relapse of RS has been
reported (126).
The prognosis of social adaptation, school achievement and professional
activity appears to be good according to long-term follow-up studies (16,
122, 125). Loiseau et al. (16) put the phrase “for unknown reasons, social
level seems to be even higher than for nonepileptic people.”
The normalization of EEG occurs usually later than the clinical remission.
Aicardi mentioned the average interval to be two years (127).
Benignity of RE and atypical RE
RE has been considered and also denominated as ‘benign’, mainly according
to the excellent prognosis of RS and the disappearance of RD. Several authors have, principally because of the occurrence of abnormal neuropsychological findings (see previous), questioned the benignity of RE. There
has also been some case reports of intractable seizures in children with possible RE (57) as well as of morphological abnormalities (59, 64-66). Recently, some authors proposed that there are different phenotypes within the
RE group, and the children were separated into ‘typical’ and ‘atypical RE’
(35, 128). The prognosis, especially concerning the neuropsychological outcome, has been found less favorable in the group with the ‘atypical’ form
(35, 128). These observations stress the necessity to make a proper delineation of RE rendering it easier to perform adequate studies of the syndrome.
Relations to other idiopathic epilepsy syndromes in
childhood
RE belongs to the idiopathic focal epilepsies also including benign partial
epilepsy with affective symptoms (‘benign psychomotor epilepsy’) and benign childhood occipital epilepsy. The last-mentioned consists of both early
onset benign childhood epilepsy with occipital paroxysms or Panayiotopoulos syndrome, and the more rare late onset Gastaut type idiopathic childhood
occipital epilepsy (129). RE and Panayiotopoulos syndrome have specific
semiologies, but have in common that they are age-related, have a favorable
seizure outcome and that EEG shows the typical benign focal shw of RD
type, though the localizations are different. Moreover, these shw are also
seen in acquired epileptic aphasia or Landau-Kleffner syndrome (LKS) and
in the syndrome continuous spikes and waves during slow-sleep (CSWS) or
24
electrical status epilepticus during slow-sleep (ESES) (130). In these syndromes, characterized by behavioral, cognitive and language disturbances,
seizures are absent in up to 30%. RE may exceptionally be transformed into
CSWS (35), sometimes precipitated by carbamazepine (37). Atypical benign
partial epilepsy (ABPE) was reported by Aicardi 1982 (131) also called
pseudo-Lennox syndrome, and is characterized by generalized minor seizures and focal shw similar to RD. The seizure outcome is favorable, but
mental deficits are common (132). There is a broad overlap with
CSWS/ESES and LKS (35, 130, 132). Doose and Baier (108) proposed the
hypothesis of HIBM in view of the common benign focal shw or RD, and
the clinical overlap of the described syndromes. This concept includes also
seizure-free individuals with behavior disorders and slight mental retardation
with RD. In this view, RE, and especially RE ´pure´ is in the very benign
end of a spectrum of clinical entities with a common complex pathogenetic
background.
Additionally, Scheffer et al. (133) reported a rare syndrome, autosomal
dominant rolandic epilepsy with speech dyspraxia, which has electro-clinical
features resembling RE.
Fig 3 presents schematically the syndromes described with their relations
to RE and the difficulties of making exact delineation between syndomes.
The figure includes ‘atypical RE’ which is a diffuse entity discussed in the
previous chapter.
25
Childhood epilepsy
with occipital
paroxysms/spikes
LKS
Rolandic
epilepsy
Benign focal ep
with affective
symptoms
ESES/ CSWS
ABFE
‘Atypical RE’
Figure 3. A schematic presentation of RE, related epilepsies, and conditions similar
to RE. The size of the circles does not represent the prevalence or proportions between the conditions.
LKS: Landau-Kleffner syndrome; CSWS: continuous spikes and waves during
slow-sleep; ESES: electrical status epilepticus during slow-sleep; ABFE: atypical
benign focal (partial) epilepsy.
26
Aims of the study:
Over the last years, some reports describing RE have included individuals
characterized as ‘less benign’, ‘atypical’ and even ‘malignant’. In other reports the presence of cognitive dysfunction has been highlighted.
The general aim of this study was to investigate children with electroclinically typical RE without any obvious signs of neurological or psychological disturbances (RE ‘pure’) using various methods.
The specific aims were:
1. to reveal the presence of morphological brain abnormalities by
magnetic resonance imaging (MRI) (paper I)
2. to reveal the presence of metabolic disturbances or asymmetry of
the hippocampal regions by proton magnetic resonance spectroscopy (1H-MRS) (paper II)
3. to reveal any cognitive dysfunction by neuropsychological assessment using a test battery measuring auditory-verbal, visuospatial and executive functions (paper III)
4. to reveal any speech defect by orofacial motor and sensory tests
and any auditory abnormalities by dichotic listening test (paper
IV)
5. to discuss the delineation of RE (paper V)
27
Subjects
All children with RE were recruited from our epilepsy outpatient clinic at the
University Children’s Hospital, Uppsala, Sweden, and all were living in the
county of Uppsala, with a population of about 60.000 children. They were
asked for participation in the different studies separately. Informed consent
was obtained from the children and their families in Study II, III and IV.
Applications were presented to the Human Ethics Committee of the Medical
Faculty, Uppsala University, and these were approved.
An overview of the participants in Study I-IV is presented in Table 1 and 2.
Thirty-eight children, 18 girls and 20 boys, with a seizure onset between 3
and 11 years (mean 6.8, median 7) participated in at least one of the studies
(I–IV). Three children had participated in all four studies, five in three,
eleven in two, and 19 in one study. Two pairs of siblings were included
(cases 9 + 15 and case 12 + 13). One child was left-handed (case 1), and one
was ambidextrous (case 14).
The RE diagnosis was evaluated and confirmed for each child by the author,
mainly by personal consultation or, in a few cases, after having read the hospital record of the child. Additional information was obtained when needed.
All children had undergone at least one EEG including sleep recording. The
electro-clinical features of RE according to the ILAE criteria (2) had to be
fulfilled. Some of the children included in Studies I–III were excluded in
Study IV as they had been seizure-free with or without AED for five years,
i.e. they did not have ‘active’ epilepsy.
The seizure frequency was mainly low for all children except for some
children who had frequent seizures for a few days in the initial phase. No
one had had status epilepticus. Eight children had never been treated with
AED. Sixteen had been treated with one AED, nine with two, four with three
and one child with four AEDs usually as monotherapy but also in combinations. Thus, at any time 23 children had been treated with carbamazepine, 19
with valproate, four with sulthiame, two with nitrazepame and two with oxcarbazepine.
28
Table 1. Number of participants and overlap in Study I–IV.
Study
RE
Controls
Overlap of RE subjects in the different
study groups
I
18
0
9 Study II, 15 Study III, 4 Study IV
II
13
15
9 Study I, 8 Study III, 5 Study IV
III
17
17
15 Study I, 8 Study II, 3 Study IV
IV
20
24
4 Study I, 5 Study II, 3 Study III
29
Table 2. RE children and their participation in Study I–IV.
Case
Sex
Age of
seizure
onset
Study I
Study II
(years)
MRI
1
*
+
+
+
+
+
+
+
+
+
+
+
+
*
+
+
*
+
+
+
+
1
2
3
4
5
6
7
8
9
10
F
F
F
M
M
M
M
F
F
F
4
5
7
9
6
9
7
5
3
8
+
+
+
+
+
+
+
+
+
+
11
12
13
14
15
16
17
18
19
20
M
F
M
F
M
M
M
F
M
M
8
4
10
7
4
5
7
6
7
3
+
+
+
+
+
+
+
+
21
22
23
24
25
26
27
28
29
30
F
F
F
M
M
M
F
M
M
M
8
7
7
11
8
7
8
8
5
3
31
32
33
34
35
36
37
38
F
F
F
M
M
F
F
M
8
7
6
9
9
8
7
10
Total RE
Controls
H-MRS
Study III
MRI Neuropsychology
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
Study IV
Oromotor
+
+
+
+
+
+
+
+
+
+
*
18
0
13
15
+
+
+
+
13
13
2 (3*)
3
4
2
3
3
2
4
2
3
2 (3*)
4
3
2 (3*)
2
2
1
2
1
1
+
+
+
+
+
+
+
1
2
1
2
1 (2*)
1
1
1
1
1
+
+
+
+
+
+
+
+
1
1
1
1
1
1
1
1
+
17
17
Participation #
20
24
M: male; F: female; MRI: magnetic resonance imaging; 1H-MRS: proton magnetic
resonance spectroscopy.
*Subjects participated in Study II although their results were rejected owing to
suboptimal quality of the spectra.
# Number of studies in which the individual case participated.
30
Study I
The origin for this study was a girl with typical RE with recurrent typical
seizures resistant to common AED (case 1). A MRI examination disclosed
obvious hippocampal asymmetry. This finding encouraged us to MRI examine a consecutive series of children with RE as part of the clinical evaluation.
Eighteen children with electro-clinically characteristic RE, 9 girls and 9
boys, with an age range of 6–12 years (mean 9.2, median 10) were included.
The age at seizure onset was between 3 and 10 years (median 6 years), and
the mean duration of RE was 2.3 years. All children had been seizure-free
more than one month prior to the examination and all but one child were
treated with AED (carbamazepine or valproate). One girl had suffered from
one typical febrile seizure episode in infancy (case 8). They were all neurologically and mentally normal. Two children were initially considered as
left-handed (case 1 and 14), one of them were re-evaluated as being ambidextrous (case 14).
There were no controls included in the study.
Study II
The results of Study I justified further studies of hippocampus in children
with RE. Seventeen children were recruited mainly from the Study I population, 11 girls and 6 boys with an age range of 8–14 years (mean 11.3, median
11). High spectral quality bilaterally was obtained in 13 children. In the remaining four children this was not achieved due to movement artifacts, and so
they were excluded. Consequently the study group comprised 9 girls and 4
boys, aged 8–14 years (mean 11.7, median 12). The onset of RE was between 4 and 11 years (median 7) and duration of epilepsy was between 2 and
8 years (mean 4.4). All children were neurologically and mentally normal
and all were right-handed. One girl had had one typical febrile seizure in
infancy (case 8). Six of the children were treated with AED (valproate, carbamazepine or sulthiame), four children had been without treatment for at
least one year, and three children had never been treated. Three children had
inactive epilepsy, i.e. they had been seizure-free for up to five months beyond the five years (cases 2, 6 and 10). In the other patients, the interval
between the 1H-MRS and the latest seizure episode was at least one month.
The control group consisted of 22 children. Due to suboptimal spectral
quality, seven were excluded. Of the remaining 15 children, there were 8
girls and 7 boys, aged 8–14 years (mean 11.1, median 11). Two children
declined to participate in a MRI examination. Twelve of the 22 children had
participated as controls in Study III, where they had been matched for age,
sex and school performance. The additional ten had been matched for age
and sex. All were healthy and with normal psychomotor development, and
there was no history of febrile or any other seizures.
31
Study III
The study was initiated after Study I. Seventeen children, 7 girls and 10
boys, aged 7–14 years (mean 9.9, median 10.5) were included consecutively
in the study. Seizure onset was between 3 and 10 years of age (mean 6.3,
median 7) and the mean duration of RE was 3.9 years (median 3). All children were neurologically and mentally normal. One girl had suffered from
one typical febrile seizure episode in infancy (case 8). Twelve children were
treated with AED (valproate or carbamazepine) at the time of investigation.
All children had Swedish as their native language.
A control group of 17 children mainly classmates to the RE children were
enrolled in the study. They were matched with respect of sex, age and estimated intelligence according to evaluations of their teachers and parents.
Twelve of these children did also participate in Study II and nine participated in Study IV.
Study IV
Twenty children with typical RE, 11 girls and 9 boys, age range 8.2–14.6
years (mean 10.5, median 10.2) were included. The seizure onset ranged
from 3 to 11 years (mean 7.1, median 7) and the duration of RE at the time
of assessment between 1 to 9 years (mean 3.5, median 2.7). Twelve children
were treated with AED (carbamazepine, valproate or sulthiame) at the time
of investigation and two children had previously been treated with AEDs.
All were neurologically and mentally normal. One boy had slight speech
problems, otherwise no speech, language or swallowing problems were
known. One girl was left-handed (case 1) and four children had a history of
one to three typical febrile seizures (case 8, 27, 29 and 35).
The control group consisted of 24 children, 14 girls and 10 boys, with an
age range of 8.2–14.4 years (mean 11.0). They were mainly age- and gender
matched schoolmates to the RE children and without known speech, language, hearing or learning problems. Two children were left-handed. Nine
control children were the same as in Study III. All children had Swedish as
their native language.
32
Methods
Study I
MRI was performed with a 1.5 Tesla imager (Gyroscan NT, Philips, Best,
The Netherlands) at the Neuroradiological department, University Hospital,
Uppsala. Sedation or general anesthesia was not used. The sequences used
were according to the established ‘epilepsy program’:
x Sagittal T1-weighted spin echo images, 5-mm sections, 0.5-mm interslice gaps.
x Oblique axial images in the plane of the long axis of the hippocampus. Proton density- and T2-weighted spin echo images 4-mm
thick, 0.4-mm interslice gaps. Turbo inversion recovery images
2.0-3.5 mm thick, no interslice gaps.
x Oblique coronal images in a plane perpendicular to the long axis of
the hippocampus, no interslice gaps. T2-weighted turbo spin echo
images 2.5 mm thick, turbo inversion recovery images 2.0-3.5 mm
thick.
x The field of view varied according to head sizes, and the matrix
was most often 205 x 256.
One experienced neuroradiologist (R. Raininko), who neither had knowledge of the clinical histories, nor the EEG results, reviewed the images visually.
A follow-up MRI was performed in six children after one to three years
and reviewed by the same observer.
Study II
The study was performed on the same 1.5 Tesla MR system as in Study I,
applying the standard quadrature transmitter-receiver birdcage head coil. No
sedation or general anesthesia was used.
T1-weighted transverse, sagittal and coronal spin echo images were used
to position the volume of interest (VOI). The VOI, or single voxel, was a
rectangular box of dimensions 40 x 20 x 20 mm3 (16 ml), which was individually adjusted to cover most of the hippocampus, and to minimize partial
volume effects with other tissues. The resulting VOI consisted mainly of the
hippocampus and small portions of the perihippocampal brain tissue and
33
cerebrospinal fluid. Proton spectra of both hippocampal areas were recorded
with use of a PRESS sequence (TR/TE = 2000/32 ms, 256 accumulations,
1024 points, spectral bandwidth 1000 Hz), which also included unsuppressed
water reference scans for neurochemical quantitations. The acquisition time
for each hippocampus was 8 minutes and 40 seconds. The total time required
for the 1H-MRS measurements was around 45 minutes.
Data processing
Automated quantification of absolute metabolite concentrations was accomplished by LCModel (linear combination of model spectra of metabolite
solutions in vitro) (134), a user-independent frequency domain fitting program. The method uses the experimentally determined spectral pattern of
each metabolite without further analysis.
Concentrations are calculated as mmol/liter (mM) VOI, and are not corrected for residual T1, T2 relaxation effects and CSF contributions.
The identified metabolites were:
x Total N-acetyl aspartate (tNAA), i.e. the sum of N-acetyl aspartylglutamate and NAA.
x Total creatine (tCr), i.e. the sum of creatine and phosphocreatine.
x Choline-containing compounds (tCho).
x Glutamine/glutamate complex (Glx).
The concentration ratio (R) tNAA/tCr was calculated for the left (RL) and
right (RR) hippocampal region. Glx and tCho in relation to tCr were calculated in
the same way.
For the assessment of asymmetries in the metabolism of tNAA, Glx and
tCho respectively, we used an asymmetry index (AI):
AI = 2(_RL – RR _ / RL + RR )
The physicist performing the analyses did not know whether the children
were patients or controls.
The MRI examinations of RE children presented in Study I were reevaluated blinded by the author and R. Raininko simultaneously with additional MRI examinations of RE and controls in this study, and consensus
after evaluating each examination was achieved.
Study III
A neuropsychological test battery mostly consisting of well-known neuropsychological tests of memory and executive functions was administered.
The test battery was administered and evaluated according to a manual from
the Department of Psychology at the University of Melbourne (135) translated and adapted for use in Sweden by Croona, Hulterström and Kihlgren
and validated for Swedish school children (136). The tests evaluate information processing, executive functions and immediate and short-term memory.
34
The following neuropsychological tests are included in the battery:
Visuo-spatial skills
x Block Span Test (137)
x Complex Figure of Rey * (138)
x Spatial Learning test * (139)
Auditory-verbal skills
x Digits Forward (140)
x Rey Auditory-Verbal Learning test * (RAVLT) (141)
x Story Recall A+B* (142)
Executive functions
x Tower of London (143)
x Verbal Fluency (144)
x Trailmaking A & B (145)
The tests indicated with * comprise subtests of memory; new learning and
recall of new learning after 30 minutes.
Intellectual ability was measured by Ravens Coloured Progressive Matrices (146). Neurobehavioral questionnaires were administered to the children’s parents and their teachers. The questionnaire consisted of statements
regarding attentiveness, hyperactivity, impulsivity, emotional control, aggressive behavior and so on. It was evaluated on 70 Swedish school children
(136) and considered as a valid tool.
Study IV
A set of tests was chosen measuring oral, lingual and facial movements,
sensibility of lips and tongue and of word retrieving. Additionally, tests of reading
techniques and dichotic listening were performed.
Three experienced speech- and language therapists performed the assessments in the afternoon after school for the day, and most often pair wise, i.e.
a patient together with his/her control. The procedure took less than one hour
per child. Selected parts of the examinations were video or audio recorded.
General observations concerning concentration, pragmatic competence and
tonus were performed, and deviations in the anatomy of the oral cavity, face,
head and neck were registered by visual examination.
The quality of the motor performance was evaluated by scoring from 0 to
3 (no problems 0, slight 1, moderate 2 and severe 3).
35
Oral and facial motor assessments
x Lip and tongue movement (quality).
x Facial expressions (quality).
x Repeated consonant-vowel (CV) syllables (quality and speed).
x Articulation of a series of nonsense words and tongue-twisting
words (quality and speed).
Sensibility tests
x Two-point discrimination (10, 5 and 3 mm distance, respectively)
was tested on the lips and at the tip of the tongue. Each distance
was tested ten times consecutively and the percentage of correct
judgment was calculated.
Oral and written language tests
x Rapid Confrontation Naming test: 80 pictures of ordinary items are
presented to the child who is requested to name these correctly as
quickly as possible (147).
x Orthographic decoding test*: the child was asked to choose words
that appeared real and were correctly spelled (148).
x Phonologic decoding test*: the child should choose words sounding
as real words (148).
Each test was time-limited to two minutes, and the results transformed into
stanine-scores.
The child’s own estimation of its reading comprehension was documented.
Dichotic listening test *
The test was performed according to the routine practiced at the Department
of Speech and Language Therapy at the University Hospital, Uppsala. Pairs
of different nonsense CV syllables were presented in both ears simultaneously by a headset from a computerized program (CADDIC DC 1-324 VC,
Consonant Int. Ltd, Uppsala, Sweden) in a soundproof studio. The syllables
were combinations of six consonants /p/, /t/ , /k/ , /b/ , /d/ , and /g/ , with the
vowels /i/ , /a/ or /u/.
The test was administered in a non-forced condition, i.e. no specific attention instruction was given. The child was asked to repeat both CV syllables
immediately without being requested to lateralize, and the number of correct
syllables for each ear and of correct pairs were registered. During fifteen
minutes the child was exposed to 108 pairs of CV syllables.
The tests indicated with * were later added to the study and therefore performed on a subgroup consisting of 13 children with RE and 14 controls.
36
Statistics
A Mann-Whitney U test was used for analyzing continuous non-parametric
variables or small samples, and independent t test with Bonferroni correction
for comparing normally distributed continuous variables. Pearson’s twotailed correlation coefficient was applied for calculating agreements between
parameters. A p value of <0.05 was considered statistically significant.
The SPSS 10.0 software package (SPSS Inc. Chicago, IL) was used for
calculations.
37
Results
Study I
Using visual evaluation MRI showed an obvious hippocampal volume
asymmetry in five children (28%); in three the left hippocampus was smaller
than the right and in two the right was smaller than the left (Fig 4). High
signal intensities on T2-weighted images were detected in two of the smaller
hippocampi, focal in one and diffuse in the other (Fig 5). Additionally, in
one child without hippocampal asymmetry a high signal focus was detected
in the right hippocampus. In all six cases, the affected hippocampus was
ipsilateral to the side of the RD predominance.
Five children (28%) showed focal high signal intensities on T2-weighted
images subcortically in the frontal and temporal lobes bilaterally (Fig 6).
One of these cases also showed a hippocampal asymmetry (case 14).
Other abnormalities found were a heterotopic nodule above the right frontal
horn with a thin extension towards the convexity (case 2), and an asymptomatic Arnold Chiari type I malformation (case 3). In both cases a hippocampal asymmetry was evident.
A follow-up MRI examination was performed after one to three years in
six children with abnormalities and these findings remained unchanged.
The results of the neuroimaging Study I is presented in Table 3.
Summary: MRI in children with RE revealed some abnormalities in 10/18
(56%) of the children. Thus, eight (44%) MRIs were normal. Hippocampal
volume asymmetry and/or high signal intensities in T2-weighted images in
hippocampus are demonstrated. MRI also shows high signal intensities in
T2-weighted images in the junction between grey and white matter in temporal and frontal lobes bilaterally, irrespectively of hippocampal abnormalities.
38
Figure 4. Reduced size of the right hippocampus (arrow) (case 1; T1-weighted inversion recovery image).
39
Table 3. The results of MRI and 1H-MRS (Study I and II, respectively) and EEG.
Study I includes cases 1-18.
Study I
Case
/sex
Age at
seizure
onset
EEG
RD lateralization
(years)
1/F
2/F
3/F
4/M
5/M
6/M
7/M
8/F
9/F
10/F
11/M
12/F
13/M
14/F
15/M
16/M
17/M
18/F
19/F
20/F
21/F
22/M
4
5
7
9
6
9
7
5
3
8
8
4
10
7
4
5
7
6
8
7
7
11
R
L>R
L>R
R
L
L>R
R>L
R>L
L>R
R
R
L
R
L
L
R
R
R
L
R>L
L>R
L>R
Age
MRI
HC A
(years)
smallest
6
8
11
12
10
11
10
11
10
10
9
7
11
8
7
8
10
6
6
8
11
12
R
L
L
NA
NA
NA
NA
NA
NA
NA
R
NA
NA
L
NA
NA
NA
NA
Other
findings
HS L HC, Het.
AC I
SHSI
SHSI
SHSI
HSF R HC
SHSI
SHSI
HSF R HC
F: female; M: male; RE: rolandic epilepsy; RD: rolandic discharges; R: right; L: left;
NA: no asymmetry; HC: hippocampus; HC A: hippocampal asymmetry; HCR: hippocampal region; HS: high signal and; HSF: high signal focus in hippocampus (T2weighted images); SHSI: subcortical high signal intensity (T2-weighted images);
Het.: nodular heterotopia; AC I: Arnold Chiari I malformation; excl.: 1H-MRS performed but excluded due to suboptimal spectral quality; tNAA: total N-acetyl aspartate; tCr: total creatine; Glx: glutamine/glutamate; AI: asymmetry index.
The AIs > 95th percentile of those in controls are indicated in bold.
The ages of cases 19-22 in italics refers to the age of the child when MRI was performed included in study II.
40
Table 3. Continued.
Study II
MRI
Case
/sex
Case
No. in
H-MRS
tNAA/tCr
Glx/tCr
HC A
Age
smallest
(years)
L
HCR
R HCR
AI
L
HCR
R
HCR
AI
excl.
6
13
L
L
11
14
1.25
1.66
1.46
1.99
0.16
0.18
1.47
1.77
1.49
2.12
0.02
0.18
8
12
NA
NA
13
14
1.54
1.34
2.06
1.60
0.29
0.18
1.64
1.74
3.90
0.70
0.81
0.85
9
NA
13
1.88
1.18
0.46
2.48
1.05
0.81
10
excl.
2
11
excl.
NA
13
1.74
1.40
0.22
2.09
0.63
1.07
NA
NA
10
14
1.54
1.82
2.43
1.50
0.45
0.19
1.47
1.38
2.70
1.85
0.59
0.29
L
NA
L
NA
NA
8
10
10
10
12
1.62
2.06
1.55
1.26
1.57
2.01
1.40
1.39
1.62
1.27
0.22
0.38
0.11
0.25
0.21
2.92
1.24
1.55
1.41
1.91
2.73
1.23
4.33
1.50
1.58
0.07
0.01
0.94
0.06
0.19
Study
II
1/F
2/F
3/F
4/M
5/M
6/M
7/M
8/F
9/F
10/F
11/M
12/F
13/M
14/F
15/M
16/M
17/M
18/F
19/F
20/F
21/F
22/M
1
1
5
3
4
7
41
Figure 5. Diffuse increased signal intensity of the left hippocampus (arrow), which
is brighter than the adjacent cortex, whereas the normal right hippocampus and the
adjacent cortex show the same signal intensity (case 2; T2-weighted spin echo image).
Figure 6. High signal intensities in the superior frontal gyrus in three consecutive
2.5mm thick slices (case 7; T2-weighted spin echo image).
42
Study II
1
H-MRS (Table 3 and 4)
1
H-MRS examinations with high spectral quality of the HC region bilaterally
were obtained in 13 RE children and 15 controls.
AIs were not age dependent in neither children with RE nor in controls.
Thus, they are handled as one entity in the statistical calculations.
The AI of the tNAA/tCr ratios was significantly higher in the patients
than in the controls (z=4.49; p<0.001). In seven patients, the tNAA/tCr ratio
was lower in the left, and in six in the right hippocampal region. The AI of
the Glx/tCr ratios in the patients was not significantly different compared to
controls (z=1.54; p=0.123). In five patients the AIs of Glx/tCr were above
the 95th percentile of those of the controls. There was no significant correlation between the lateralization of the tNAA/tCr and Glx/tCr ratios. The AI of
tCho/tCr ratios was similar in both groups.
Representative spectra of a normal and an abnormal hippocampal region
are shown in Fig. 7 and results presented as box plot diagrams in Fig 8 and 9.
Figure 7. LCModel analysis of a 1H-MRS spectra of case 19. The dotted curves
display the spectra as measured. The solid curves show the fitted spectra. LCModel
spline baseline was subtracted from all spectra. The left hippocampal region (a)
shows a normal spectrum (tNAA/tCr, 2.06) and the right (b) an abnormal spectrum
(tNAA/tCr, 1.40).
NAA, N-acetyl aspartate, Cr, creatine, Cho, choline; Ins, myo-inositol; ppm, parts
per million.
43
Figure 8. Boxplots showing the asymmetry index of tNAA/tCr in the hippocampal
region in RE children and controls. The ends of the boxes fall at the upper and lower
quartiles, the solid line in the middle of the boxes is the median; and the whiskers
represent the range of the data.
Figure 9. Boxplots showing the asymmetry index of Glx/tCr in the hippocampal
region in RE children and controls. The ends of the boxes fall at the upper and lower
quartiles, the solid line in the middle of the boxes is the median; and the whiskers
represent the range of the data.
44
Table 4. The result of 1H-MRS of hippocampal region in RE children and controls.
Hippocampal region
Metabolite ratio
Left
Right
Asymmetry
Index
tNAA/tCr
RE, median (range)
1.57 (1.25-2.06) 1.50 (1.18-2.43) 0.22 (0.11-0.46)
Controls, median (range) 1.43 (1.16-1.76) 1.44 (1.22-1.78) 0.045
95th percentile of controls
0.086
p value RE vs. controls
<0.001
Glx/tCr
RE, median (range)
1.64 (1.24-2.92) 1.58 (0.70-4.33) 0.29 (0.01-1.07)
Controls, median (range) 1.38 (0.99-2.80) 1.28 (0.77-2.36) 0.16
95th percentile of controls
0.71
p value RE vs. controls
0.123
tCho/tCr
RE, median (range)
Controls, median
0.28 (0.19-0.33) 0.29 (0.16-0.39) 0.098 (0.0110.58)
0.25
0.35
0.097
tNAA: total N-acetyl aspartate; tCr: total creatine; Glx: glutamine/glutamate;
tCho: choline compound.
MRI (Table 3)
Four of 13 MRIs in the RE group showed a distinct asymmetry, and in all
cases the left hippocampus was smaller than right. In one case (case 18) the
result deviated from Study I. In the first study it was evaluated as normal,
while in this study the left hippocampus was evaluated smaller. The lateralization of a smaller hippocampus corresponds with lateralization of the lower
tNAA/tCr ratio in three of four cases.
In the control group, a subtle hippocampal asymmetry were revealed in four
of 13 MRI examinations, in all cases left being smaller than right. These
findings can be attributed to normal variation of left being smaller than right.
Summary: 1H-MRS of hippocampal region in children with RE demonstrates
an asymmetry of neuronal function evaluated by tNAA/tCr ratio compared
to matched controls. MRI reveals hippocampal volume asymmetries in both
patients and in matched controls, though more distinct in the epilepsy group.
The sample size is too small for estimating correlations regarding volume
and metabolic results.
45
Study III
Results presented as mean and standard deviations (SD) of the neuropsychological tests are presented in Table 5.
Table 5. Mean (SD) neuropsychological test results for children with RE and
matched controls.
Domain
Test
RE
Controls
p
Immediate
memory /speed
of processing
Block Span
Digit Span
Trail Making A
4.4 (0.9)
3.7 (1.4)
5.5 (2.6)
5.2 (0.8)
4.6 (1.5)
6.8 (2.0)
ns
ns
ns
New learning
Spatial learning test, recall
RAVLT, five trials
RAVLT, recall
Story recall A+B
Complex Figure of Rey,
recall
7.6 (2.6)
3.4 (1.3)
3.6 (2.0)
5.7 (2.3)
3.6 (1.8)
8.6 (0.8)
6.1 (2.1)
5.8 (1.8)
8.0 (1.3)
4.9 (1.9)
ns
<0.001
<0.01
<0.01
ns
Recall of
new learning
after 30 min
RAVLT, delayed recall
Story recall II
Spatial learning test II
Complex Figure of Rey II
3.4 (1.9)
5.1 (2.5)
6.7 (2.9)
4.1 (2.2)
5.9 (2.1)
7.8 (2.3)
7.5 (1.9)
4.6 (2.3)
<0.01
<0.01
ns
ns
Executive
functions
Verbal fluency FAS
Trail making B
Complex Figure of Rey,
organization
Tower of London
3.4 (1.6)
5.0 (2.0)
4.7 (2.4)
5.6 (1.7)
6.5 (0.8)
5.4 (2.0)
<0.01
ns
ns
5.0 (2.1)
6.8 (1.6)
<0.05
RAVLT: Rey Auditory-Verbal Learning test; FAS: initial letters for generating words; ns: non significant (t-test).
Intellectual measurement (IQ)
RE group 96.8 (65-115) and control group 95.3 (75.110), i.e. no difference.
Neurobehavioral variables (questionnaire)
Parents evaluation: greater difficulties in RE group compared to controls
regarding distractibility (t[32]=2.04, p<0.05), concentration (t[32]=3.20,
p<0.01), temper (t[32]=3.98, p<0.001), impulsiveness (t[32]=2.08, p<0.05)
and ability to understand instructions (t[32]=2.06, p<0.05).
Teacher’s evaluation: no differences were seen between the groups.
46
Academic achievement
According to the teacher’s evaluation, the RE group had difficulties in reading comprehension compared with controls (t[32]=2.16, p<0.05).
Summary: Neuropsychological assessments disclose auditory-verbal and
executive dysfunctions in children with RE compared to matched controls.
Visuo-spatial tests did not show differences between the groups. The RE
children had more behavioral problems compared to controls according to
questionnaires answered by their parents. The non-verbal IQ was normal in
both groups.
47
Study IV
The results of oromotor and sensibility tests are presented in Table 6.
Table 6. Results of oromotor and facial performance, sensibility and language tests
in children with rolandic epilepsy and controls.
Modality
Method
Facial movements
Facial expression
(forehead, nose, eyes)
a) Lip movements, quality
b) Tongue movements, quality
c) CV syllable, quality
Total score (a-c)
CV syllable, speed
Nonsense words, quality
Tongue-twisting words, quality
speed
Two-point discrimination
Tongue and lips
Rapid Confrontation Naming
(149) Speed and quality
Reading technique tests (148)
Orthographic decoding
Phonologic decoding
Reading comprehension
Oral movements
Articulation
Sensibility
Language
ns: not significant (Mann Whitney U test).
48
No. examined
RE / controls
20 / 24
20 / 24
20 / 24
20 / 24
20 / 24
20 / 24
13 / 14
13 / 14
p
ns
20 / 24
ns
< 0.05
ns
< 0.05
ns
< 0.01
< 0.01
ns
ns
20 / 24
ns
13 / 14
13 / 14
13 / 14
ns
ns
ns
Dichotic listening test (Table 7)
In the RE group all children showed a right ear advantage (REA). In the
control group twelve children showed REA, the two left-handed children
included, and two had a left ear advantage. There was a significantly lower
performance of correct CV syllables in the RE group compared with controls.
Table 7. Results of dichotic listening test in 13 children with rolandic epilepsy (RE)
and 14 controls.
Correct right ear
Correct left ear
Correct right + left
RE
(%)
Controls
(%)
p
60.6
40.8
15.9
68.8
56.7
33.4
<0.05
<0.05
<0.05
Mann-Whitney U Test was used.
Significant correlation was found in the RE group between correct right ear
performance and a lower score of tongue movements (r=-0.65; p<0.05) as
well as to the total score of oromotor score (lip and tongue movements and
CV syllable quality) (r=-0.57; p<0.05). These correlations were not found in
the control group. Performance on phonological reading test showed a positive correlation to correct left ear performance in the controls (r=0.75;
p<0.01), which was not found in the RE group. There was no correlation
concerning a better DLT performance and age or duration of epilepsy in the
RE group, or of age in the control group.
Summary: Children with RE show oromotor dysfunctions compared to controls concerning tongue movements, repeated CV syllables and articulation
of tongue-twisting and nonsense words. They also show a poorer performance in dichotic listening than matched controls.
49
Paper V
The delineation of ‘classical’ RE and related conditions in the literature is
sometimes imprecise and confusing. A simple classification is proposed until
genetic studies may clarify the issue:
1. RE ‘pure’ according to the original definition.
2. RE ‘plus’ including entities as benign partial epilepsy with affective
symptoms and autosomal dominant rolandic epilepsy with speech
dyspraxia. Also RE with some abnormal EEG patterns can be included here.
3. RE-related disorders as ABPE, epilepsy with CSWS and LKS.
4. Structural brain lesions with signs and symptoms as in RE.
50
Discussion
Classification and diagnosis of RE, inclusion and
exclusion criteria (Study V)
There is a never ending discussion among epileptologists about classification
of seizures and epileptic syndromes. This is perhaps more obvious among
neuropediatricians because of the dynamics of childhood epilepsies and the
fast developing genetic knowledge about epileptic syndromes over the last
decade. There is a general agreement that it is essential to have uniform criteria for each epileptic syndrome in order to communicate the different clinical aspects of these syndromes. Ever since the latest proposal for classification of epilepsies and epileptic syndromes by the Commission on Classification and Terminology of ILAE in 1989 (2), a discussion concerning classification has taken place, but so far there has not been any consensus for a new
one.
Awaiting this, the ILAE Task Force on Classification and Terminology in
2001 suggested a proposed diagnostic scheme for people with epileptic seizures and with epilepsy (150). This scheme consists of five ‘axes’: 1) ictal
phenomenology, 2) seizure type, 3) syndrome, 4) etiology and 5) impairment. The scheme is intended to provide the basis for a standardized description of individual patients rather than a fixed classification, and the development of a specific classification should be regarded as a continuing progressive work. Some changes of vocabulary are proposed, e.g. ‘focal’ replaces both ‘partial’ and ‘localization-related’ and ‘febrile seizures’ should
be used instead of ‘febrile convulsions’. Consequently, RE in this description is an example of an idiopathic focal epilepsy and remains denominated
as ‘benign childhood epilepsy with centrotemporal spikes’. In the third axis
‘benign epilepsy syndrome’ is defined as ‘a syndrome characterized by epileptic seizures that are easily treated, or require no treatment, and remit
without sequelae’. In RE, there are sometimes seizures that are intractable or
difficult to treat for a period, including some of our cases (see below). However, in general and in the long run the RS can be considered as easy to treat.
The first axis, ‘ictal phenomenology’, is probably useful in describing or
defining RS and in the second axis, ‘seizure type’, the focal elementary clonic motor signs and focal elementary sensory symptoms should be the appropriate seizure components of RS including sialorrhea.
51
It is important to have representative children included in studies of particular epileptic syndromes and avoiding selection bias has to be emphasized.
The delineation of RE is discussed in Study V where the typical electroclinical syndrome of RE according to the ILAE definition of 1989 (2) is
proposed to be called RE ‘pure’ in order to stress the boundary to other conditions with RD, which often have been confused with RE. As a consequence of this, reliable comparisons of study results are doubtful. An example is the neuropsychological study of Weglage et al. (94) on a group of
children with RD but including individuals both with and without RS, which
were considered as one group. Moreover, some studies of ‘atypical RE’
should have been assigned to conditions other than RE ‘pure’ (32, 57).
Wirell et al. (32), after having done a retrospective evaluation of 42 children
diagnosed as RE, suggested that the occurrence of atypical electro-clinical
features is the rule rather than the exception. By classifying clinical features
like Todd’s paresis, diurnal-only seizures, concomitant attention deficit disorder and SE as atypical, they found that 50% were clinically atypical. However, this is a too narrow delineation of RE according to many authors (18,
31), an opinion to which I agree. Furthermore, of most importance is that the
ILAE definition of RE and of idiopathic epilepsies do not expressly reject
these features. In our material one boy with postictal Todd’s paresis was
included. Concerning EEG, Wirell et al. (32) found atypical features as abnormal background activity and atypical spike morphology in 31%, which
definitely disqualifies the RE diagnosis according to the ILAE definition.
In cases with obvious brain lesions (e.g. widespread cortical malformations,
porencephalic cysts, post infectious and traumatic lesions, tumors (58-61, 65,
66, 151)) and concomitant RD, one must be very cautious to classify these
into RE (our RE ‘pure’) even if the seizure semiology and seizure outcome
happen to be in accordance. The reported studies are interesting as they
demonstrate the variability of phenotypes in focal idiopathic epilepsy but are
proposed to be separated from RE ‘pure’ into the group ‘structural brain
lesions with signs and symptoms as in RE’. On the other hand, when lesions
are distant from the rolandic area, they may be included as RE ‘pure’.
In Study I we presented one girl with Arnold Chiari malformation type I
and another girl with an isolated heterotopia above the frontal horn contralateral to the RD. In neither of these cases, there was a relation between the
electro-clinical symptomatology and the abnormalities. However, children
with cerebral palsy have been included in previous studies (17, 21). It has to
be admitted, that the distinction between what should be regarded as casual
findings, and findings which may have an impact on the epileptogenesis, is a
difficult issue in some cases.
52
Is it justified to classify an individual as having RE after only one seizure
provided that both EEG and semiology are those of typical RE? Some investigators agree to this (11, 18), but this is against the established definition of
epilepsy. In the present studies we demanded two or more seizures as mandatory for inclusion. In several cases, the first few seizures were presented as
nocturnal GTCS without preceding observation of focal signs, which is a
common course in RE. Appropriate age, normal neurologic examination, no
history of brain lesions and awake and/or sleep EEGs showing RD, qualifies
for the RE diagnosis.
Repeated normal EEG examinations with sleep recordings are very rare
and the diagnosis of RE in such patients should be accepted only with great
reservation (127). In order to follow the RE criteria strictly, a girl with several typical RS was excluded from Study IV after initial inclusion due to
absence of RD in three consecutive EEG recordings including sleep.
Two pairs of siblings were included in the study group, two in Study I and
III and one of these also in Study II. The families of those children were also
included in a genetic multicenter study, which provided evidence for linkage
of the electrographic pattern (RD) to chromosome 15q14 (109). However,
the genetics of RE is still to be clarified, and when this is achieved, it will
bring about an improved diagnosis of RE and related conditions.
It may be indicated to perform EEG on siblings and controls if an investigation mainly concerns EEG studies. However, one must bear in mind that
population studies have shown an RD incidence of approximately 3% in
children aged 3–14 years (40) which can confuse the results.
The localization of RD in our subjects is mainly in the rolandic and perirolandic area, i.e. corresponding to the centrotemporal or midtemporal, but
also parieto-occipital and fronto-temporal leads in EEG in accordance with
RE (45, 152). The discharges seem to ‘migrate’ in a posterior- anterior direction with increasing age. Drury and Beydoun (45) stated that posterior or
occipital RD may be related to RE as well and most important is the monomorphic sharp wave and not the location. This has also been confirmed in
studies using magnetic encephalography (MEG) (153, 154).
The course and prognosis of all included subjects in this study is in accordance with RE. A few children, including the index case, have had frequent
and medically resistant seizures periodically for some days or a few weeks
until the change of treatment had been accomplished. None had SE, nor
signs of oromotor difficulties interictally. Three children (8%) have had recurring sporadic RS for more than 3 years, where such recurrences can occur
in 7% of children with RE (11).
53
Magnetic resonance imaging (Study I)
In Study I a series of children with typical RE, examined by MRI, was presented and by visual evaluation a hippocampal volume asymmetry was
found in five cases.
Few MRI studies have been performed on children with RE using modern
techniques. Kohrogi et al. (155) (in Japanese) reported hippocampal volumetric measurements in 27 patients with BCECT, age 6–19 years, in 22 patients with TLE, age 5–22 years, and in 17 normal control subjects, age 6–15
years. The hippocampal volumes and the right minus left-side volumes were
not significantly different in the three groups, but the values in the TLE
group were more scattered. Moreover, there was no abnormal signal intensity in the hippocampus and no specific abnormality in the surrounding
structures. Thus, these normal results in the children with RE deviate from
our study and also from other reports of normative data, which will be discussed in the following. However, the normal findings, even in the TLE
group, raise doubts as to whether a comparison can be made because of the
different techniques.
Gelisse et al. (61) retrospectively evaluated 98 consecutively referred
children with RE during a 15-year period in which 28 had undergone MRI.
Five of the examinations revealed pathology consisting of a slight ventricle
dilatation and ‘hypersignals’ in white matter, moderate enlargement of the
right temporal horn, cavum septum pellucidum, bi-opercular polymicrogyria,
and marked right hippocampal atrophy, respectively. The latter findings was
reported separately (64), and the authors concluded that there was no causal
connection between the RE and this finding. To our knowledge there are no
prospective or longitudinal MRI studies in RE.
Is volumetry of the hippocampus a more reliable method than visual evaluation? Are the asymmetries found beyond the normal variation in children,
and are our results reproducible?
Volumetry has the advantage of being objective and sensitive. The
method provides quantitative data and detects bilateral atrophy. However,
the method requires normative data and high intra-rater reliability. Further, it
is labor-intensive and time-consuming. Volumetry can improve detection of
hippocampal volume loss but only by 5-8% over visual evaluation
(Kuzniecky, personal communication). In order to compare the diagnostic
accuracy between visual assessment and volumetry, Cheon et al. (156) studied 48 adults who underwent surgery for TLE and found that visual assessment was slightly superior in estimating unilateral hippocampal sclerosis.
Berkovic et al. (157) came to the same conclusion, whereas other authors
present an opposite opinion (158, 159).
There is some normative data reported in children. Giedd et al. (160), investigating 99 normal children age 4–18 years reported a ‘right-greater-than54
left’ asymmetry of the hippocampus with no proportion given. No age dependency was seen. Ho et al. (161) examining eight normal children age 3–
15 years, found that the left hippocampus was 8% smaller than right. Utsunomiya et al. (162) performed MRI in 42 children aged 3 weeks–14 years
with other neurological findings. Volumetry of hippocampal formation
showed a larger right than left side in 91%. In the older age group a difference of approximately 8-10% was found. This was not seen in the youngest
children. In adults, there are numerous reports of the left hippocampus being
smaller than the right in healthy individuals, but also absence of side-to-side
asymmetry (163).
The asymmetries found in Study I in the three ‘left-smaller-than right’ cases
by visual assessment are obviously outside of the normal range. The two
‘right-smaller-then-left’ cases are definitely abnormal. The high signal lesions seen in the hippocampus in three children were slight and we do not
consider these findings as signs of mesial temporal sclerosis.
The high signal intensities on T2-weighted images in the junction of
white and grey matter observed in five children were located in the temporal
poles and in the frontal lobes. This can be interpreted as a possible expression of delayed maturation. Similar findings have not been described earlier
in other idiopathic epilepsies. MRI performed on six children about three
years after the first examination showed these abnormalities to be stable.
This may be due to too short intervals between the examinations and the
young age of these children. As the high signal lesions were permanent, we
could also exclude the possibility that they were a result of recent seizures
which have been reported to cause this kind of lesions in grey matter (164,
165). The clinical significance of these findings remains unclear, but a
longer follow-up period will probably clarify the issue.
The other abnormal MRI findings, a heterotopia (case 2, Table 3) and an
Arnold Chiari type I malformation (case 3, Table 3), are considered as coincidental. An Arnold Chiari type I malformation has been described in one
child with RE in a report by Kramer et al. (63). Few cases of cortical malformations in RE have been reported, some incidental (61, 65), and one considered as causing RD and RS (66). Cendes at al. (166) stated that neuronal
migration disorders, including nodular heterotopia, are more likely associated with hippocampal atrophy (‘dual pathology’), independent of the distance of the lesion from the hippocampus. We consider our case 2 with a
heterotopia above the right frontal horn, similar to focal transmantle dysplasia and a smaller hippocampus contralaterally as coincidental.
A limitation of Study I is the lack of control subjects. The observer of the
MRIs was aware of the epilepsy diagnosis, but not of the electrographic fea55
tures. In Study II, we blindly re-evaluated the MRIs included in Study I as
well as additional MRIs. We consider the blinded evaluation in connection
with Study II as the most appropriate and reliable one.
1
H-MRS (Study II)
Is the asymmetry of tNAA/tCr ratios in the hippocampal region in RE children demonstrated in Study II valid and of any clinical significance?
Few reports on normative data of 1H-MRS in children are available. Choi
et al. (86) examined 17 healthy children age 3–14 years and found symmetric ratios of NAA/tCr in the allocortex which comprises the hippocampus
and a part of the parahippocampal gyrus included in a 5 ml voxel. In our
study, however, we found asymmetries. The difference may depend on the
fact that Choi et al. compared the mean ratios of each side, while in Study II
AI was calculated in the patients and compared with controls (median AI
0.22 in RE, 0.045 in controls). In our study, the median of the tNAA/tCr
ratios of the hippocampal region was principally the same (see Table 4).
Compared to Choi et al. we used a considerably larger voxel size (16 ml),
apparently covering more than solely the hippocampus (the volume estimated to approximately 3-5 ml by volumetry in adults), i.e. part of the parahippocampal gyrus and cerebrospinal fluid (CSF) are included. Thus, we
called the investigated volume the ‘hippocampal region’. This may influence
the spectral profile, however, by using ratios of the metabolites and calculating AI, the influence of CSF on the results can be regarded as minimal. An
advantage of the large voxel size is a better signal-to-noise ratio.
Evidently, 1H-MRS most appropriately reflects the neuronal function of
the hippocampus or hippocampal region, whereas MRI studies the morphology. 1H-MRS has especially been useful for lateralizing the epileptogenic
zone in MRI negative TLE (67, 167). NAA is confined to neurons and neuronal processes both in grey and white matter and a decreased concentration
indicates loss of neurons or a neuronal dysfunction (168, 169). Kuzniecky et
al. (170), in a study including MRI volumetry, 1H-MRS and histopathology
in adults with TLE, found that the neuronal-glial ratio in the resected hippocampus correlated with hippocampal volumetry but did not correlate with
the metabolic measurement obtained with 1H-MRS. The conclusion was that
the metabolic events measured by 1H-MRS reflect neuronal and glial dysfunction rather than neuronal cell loss.
As NAA can be regarded a marker of neuronal function, it is evident that
1
H-MRS has the potential for being a tool in cognitive assessment. A number
of studies in epilepsy populations have begun to elucidate this field of research. In a study of 22 children with intractable TLE, Gadian et al. (171)
found that verbal IQ correlated selectively and significantly with left mesial
temporal NAA/Cr+Cho ratios, whereas nonverbal IQ correlated selectively
56
and significantly with right mesial NAA/Cr+Cho. In an adult population
with TLE Martin et al. (172) found a significant negative correlation between Cr/NAA ratios of the left hippocampus and verbal memory. A few
other authors have examined various cognitive functions with hippocampal
1
H-MRS (173, 174) and this area of work is under development.
The rationale in performing the 1H-MRS study of the hippocampi was
firstly the asymmetrical hippocampal findings of the MRI study, and secondly, which is more important, the results of the neuropsychological Study
III showing cognitive deficits in RE children. Other groups have reported
similar results, which will be reviewed in the following. However, our sample of only eight of the RE children participating in both studies, is too small
for making any reliable correlations between the results of Study II and III.
Is it possible that AED treatment can influence the 1H-MRS results? All
our six children on medication were prescribed fairly moderate dosages and
no one showed signs of adverse effects. We consider such an influence as
unlikely, but there are few studies concerning this subject. Simister et al.
(72) in a 1H-MRS study of the frontal lobes (both grey and white matter) in
21 adults with idiopathic generalized epilepsy, showed a lower myo-inositol
in a subgroup taking valproate but otherwise no interaction with AED was
noted. Compared with controls, an elevation of Glx and a reduction of NAA
were observed.
Concerning Glx, glutamate is the chief excitatory neurotransmitter, thus
an indicator of hyperexcitability in the epileptogenic zone. In our study,
there was a tendency towards a higher AI of the Glx/tCr ratio in the RE
group compared to the controls, which may reflect an imbalance in the hippocampal region of this neurotransmitter. However, a higher resolution of
the spectra and a larger sample is needed to achieve more reliable results.
Neuropsychological assessment (Study III)
The most evident findings in the neuropsychological study were deficits in
the performance of auditory-verbal memory and learning assessments in the
RE group compared to their matched controls. The RE children disclosed
problems concerning their capacity for both new learning and long-term
recall according to RAVLT and Story Recall tests. Metz-Lutz et al. (175)
found a significantly lower result of RAVLT in RE children with right-sided
RD. They also investigated the children within two weeks from the first seizure and a significant cognitive weakness mainly in subtests involving shorttime memory learning and attention was disclosed. The shortcoming in the
auditory-verbal domain has also been pointed out in other similar studies of
RE children (95, 96). The only subtest of auditory-verbal function measurement, which did not show any group difference, was the Digit Span test reflecting immediate memory function.
57
Test results showing the children’s executive abilities were significantly
poorer compared with controls. This has also been shown regarding Word
Fluency by Baglietto et al. (96).
The subtests of the visuospatial domain failed to detect any differences
between the groups. This result conflicts with the findings of other authors
(91, 93, 96, 176), but few studies on visuospatial functions are performed in
RE.
The outcome of the neurobehavioral variables evaluated by questionnaires, contradicts previous studies (89), but confirms some of the findings
in more recent studies (93, 97, 175, 177, 178). A problem of selection bias in
previous studies has been the exclusion of children with ‘neuropsychiatric
abnormalities’ (11). The close relation between RE and individuals with just
RD and neurobehavioral disorders has been pointed out by Doose (179).
Holtmann et al. (180) found RD without seizures in 5.6% of 483 children
diagnosed with ADHD, which is significantly higher than found in normal
children (27, 40). The association between two common childhood disorders
might be coincidental, or an expression of a common hereditary impairment
of brain maturation (108). In our study, it cannot be excluded that the neurobehavioral problems in the RE children maybe a confounding factor for the
results of the executive tests.
Concerning intelligence measurements by Raven’s coloured matrices, no
difference was seen between RE children and controls. This is in accordance
with most other studies. Beaussart (10) studied 221 children with RE and
found a normal prevalence of slight mental retardation, however, Beaumomoir et al. (49) found two of 26 children with RE who had low IQ scores.
It is now well established that a proportion of children with RE has some
degree of cognitive dysfunction. A follow-up study after approximately three
years of the children included in Study III and an additional 16 children with
RE has been performed by Lindgren et al. (personal communication). These
results show normalization of all variables compared to control children,
even though the RE children still scored lower in the Verbal Fluency test
than the controls.
Oromotor assessments (Study IV)
In Study IV the oromotor assessments disclosed differences in tongue mobility and articulation between RE children and controls. Normally, the child
with RE has no obvious speech problems, but there have been several case
studies reporting more prolonged or repeatedly occurring oromotor dysfunction combined with speech defects. This has been reported in patients having
partial SE (34, 35, 37, 38, 98), and in connection with the initial phase of the
epilepsy with marked epileptiform activity in the EEG (36, 87, 99-101, 181),
a phase which has also been entitled ‘acute’ (100).
58
There are few reports concerning oromotor assessments of RE children in
an ‘active’, but not ‘acute’ phase similar to the children participating in
Study IV. Staden et al. (95) revealed abnormalities in dyspraxia screening in
nine children, most frequently concerning lip and tongue movements and
difficulties in articulating a sequence of syllables. However, they rarely
found problems with articulation of ‘complex words’, which are similar to
tongue twisting words used in our tests, and caused marked problems in the
RE group in Study IV.
The brief assessments concerning language function included in Study IV
did not reveal any differences between the RE and control children, which is
in agreement with other reports (38, 95). Staden et al. (95) found some degree of language dysfunction in 13 out of 20 children with RE concerning
reading, spelling and expressive grammar. There may be a selection bias,
however, in that the parents of 11 of 20 children were concerned about their
children’s language and learning problems. An additional report of RE has
found some degree of language dysfunction or delay in RE children (97).
Dichotic listening (Study IV)
Dichotic listening test showed a significant poorer result in the children with
RE compared with controls. Normative data for our age group and for the
method used in the present study are lacking. Hugdahl (personal communication) reported data from ‘The Bergen dichotic listening database’ with
slightly different methods concerning children age 8-15 years. These data
show around 45% correct for the right ear and around 42% correct for the
left ear. According to these figures, the children with RE in Study IV performed almost normal, contradicting our results which were compared with
controls. Dichotic listening has been used in investigating RE children by
Metz-Lutz et al. (175) who found an ‘impaired divided attention’ in eight of
22 children with RE, which seems to be similar to our results. Moreover,
Hommet et al. (182) used dichotic listening in 23 adolescents and young
adults who were ‘in complete remission’ of RE, i.e. no seizure activity or
abnormal EEG tracing had been seen ‘for at least one year’. No difference in
performance between patients and controls was found, which may be an
illustration of maturation of the auditory system in this older age group compared to our children.
The theoretical background to the findings of deviating DLT performance
in our RE group may be the proximity of the rolandic and perirolandic areas
to Heschl’s gyrus, which mainly consists of Brodmann’s area 41 and 42.
This area contains the primary auditory receptive area, which is essential for
discriminations requiring a response to changes in the temporal patterning of
sounds and for recognition of the location or direction of sounds. Hypothetically, epileptic activity in an adjacent area, i.e. the lower rolandic cortex,
may disturb the optimal function of auditory perception.
59
Figure 10. Lateral view of the left cerebral hemisphere. The positions of the EEG
surface electrodes according to the International 10-20 system are indicated.
Figure 11. Coronal section of the right cerebral hemisphere.
60
Neurophysiology and summary
The ‘rolandic area’ or ‘rolandic cortex’ comprises the gyri on each side of
the rolandic fissure or central sulcus, i.e. the pre- and postcentral gyri responsible for the typical semiology of RS (see Fig10). The lower boundary is
the upper bank of the sylvian fissure. The upper boundary, however, is not
distinct.
In EEG terminology, RD are located ‘centrotemporal’ or ‘midtemporal’,
but the semiology of RS is rarely if ever referable to the temporal lobe. The
classification of focal (partial, localization-related) seizures as in RE may
give the false impression of the existence of an epileptic region comprising a
small and well-delineated focus of neuronal pathology. However, focal seizures and focal syndromes are almost always due to diffuse, and at times
widespread, areas of cerebral dysfunction (183). It is also a well-known fact
that the RD in EEG are quite widespread. Legarda et al. (152) found that RD
are exclusively suprasylvian in origin disclosing high central and low central
subgroups with different semiology according to the cortical representation.
Spike triggered functional MRI (fMRI) (184) performed in a girl with typical
RE demonstrated activation of the left facial region of the somatosensory
cortex, which was suggested to be consistent with the facial sensorimotor
involvement of RS.
MEG studies performed in patients with RE have localized the RD to
both the upper and lower rolandic area (153). Moreover, it has been suggested that the RD are generated in the rolandic region near the somatosensory cortex (185, 186) or in the precentral cortex, closer to the second than to
the primary somatosensory cortex (154). This may underlie the hyperexcitability of related sensorimotor cortices (187). In this context also maturation
in the thalamocortical development process has been mentioned (187).
Studies of RE children including Study III have revealed neurobehavioral
problems, which indicates dysfunctions in circuits distant from the rolandic
area, i.e. complex circuits in frontal lobes including interhemispheric interactions (175-177). These ‘anatomicofunctional’ circuits mature between childhood and adolescence, i.e. during the same age period as the presence of the
active RE. Thus, the course of RE is probably dependent on the maturation
of these circuits.
In summary, there are several observations indicating that the neurophysiological background of RE is not only restricted to the rolandic cortex.
Indisputably, the intrinsic epileptogenesis is located in this region, but it may
be hypothesized that there are other underlying and modifying factors of
importance for the syndrome. Our findings of an asymmetric distribution of
the marker of neuronal function in the hippocampal region in RE children
can be regarded as an additional contribution in this research.
61
The hippocampus is essential for learning, memory processing and storing and has numerous but mainly indirect connections with the cortex, the
so-called neocortical-hippocampal loop, as well as within the limbic system.
The hippocampal formation, the entohirnal cortex and parahippocampal
gyrus (see Fig 11) are all believed to participate actively in the memory processes (188). A hypothesis is that the cognitive deficits demonstrated in RE
children are at least partly determined by a maturational dependent defect in
these structures and in their neocortical connections.
Limitations of Study I–IV
Overall the sample size in the different studies is small, which is a limitation
in statistical calculations. However, non-parametric tests for small samples
(Mann Whitney U test) did clearly show differences between RE and control
children in Study II and IV, as well as the t-test used for normal distributed
material in Study III. The ideal situation had naturally been if the same children participated in all studies, which would have made possible an optimal
comparison between the results. It had been even better with longitudinal
studies. This age group, 8 to 14 years, is in general co-operative and curious
about participating in such investigations. Nevertheless, there are difficulties
in recruiting school children in particular for repeated examinations.
The EEG results in the present studies were mainly presented as supporting the RE diagnosis and for showing the lateralization of RD. More thorough investigations were not performed or intended in any of the studies,
even if this could have been desired in Study II–IV. Repeated and scheduled
EEGs for research purposes are often difficult to obtain because of practical
and psychological reasons, e.g. the older children are more sensitive concerning their history of epilepsy.
62
Conclusions
Investigations of children with typical electro-clinical RE according to the
ILAE definition have revealed:
x
Hippocampal volume asymmetry by visual evaluation in 5/18 children (28%) and high signal intensities in the hippocampus in 3/18
(17%) where two also showed volume asymmetry. High signal intensities on T2-weighted images in the junction between grey and
white matter in temporal and frontal lobes bilaterally in 5/18 children (28%). The clinical significance of these findings is unclear.
The last mentioned abnormality may be an expression of delayed
cerebral maturation.
x
Asymmetry of neuronal function in the hippocampal region assessed
by tNAA/tCr ratio in 1H-MRS examinations compared with matched
controls.
x
Dysfunctions in auditory-verbal skills, both regarding new learning
and recall of learning and in executive skills compared with matched
controls.
x
Behavioral problems assessed by parental questionnaires compared
with matched controls.
x
Oromotor dysfunctions concerning tongue movements, repeated
consonant-vowel syllables and articulation of tongue-twisting and
nonsense words compared with matched controls.
x
Lower performance in dichotic listening compared with matched
controls which may indicate slight problems with auditory discrimination.
The results indicate an abnormal neuronal function near or distant from the
rolandic and perirolandic area. It is proposed that the cognitive deficits and
the oromotor dysfunction demonstrated in children with RE are caused by a
defect, or more probably, a delayed myelination in terms of maturation,
which may normalize completely or partially. Further studies will clarify this
topic.
63
A classification of RE and related conditions is proposed until results of
ongoing genetics research may clarify the delineations:
1) RE ‘pure’, i.e. children included in the studies,
2) RE ‘plus’ (e.g. benign partial epilepsy with affective symptoms and
autosomal dominant rolandic epilepsy with speech dyspraxia),
3) RE-related disorders (e.g. atypical benign focal epilepsy, epilepsy
with CSWS and LKS)
4) Structural brain lesions with signs and symptoms as in RE.
64
Future directions
x
x
x
x
Follow-up studies of children with RE, both concerning morphology
by MRI, and neurometabolism by 1H-MRS are important. The spectroscopy technique is improving which increases the possibilities to
non-invasively explore the extremely complicated brain. Further
neuropsychological studies are also needed, and as mentioned, our
team has already performed this (Lindgren et al.,personal communication). Electrographic studies in connection with cognitive assessments are also demanded.
The mentioned studies may explain if maturation of the brain will
completely resolve the abnormalities demonstrated in RE children,
or if some will remain into adulthood.
Further genetic studies concerning the idiopathic childhood epilepsies including RE and RD are needed in order to clarify if they may
have a common underlying genetic etiology.
Appropriate delineation of RE and the idiopathic childhood epilepsies are also needed for communication and research. The results of
genetic studies will probably be constructive in this topic.
65
Acknowledgements
This thesis has been made possible by many supporting and generous people
and I would particularly like to thank:
First of all, I would like to express my gratitude to all the children and their
parents for their patience in participating in the studies.
Professor Orvar Eeg-Olofsson, my principal tutor, who with never failing
enthusiasm, scientific curiosity, encouragement, patience, humour and energy has guided me through this scientific work. Orvar, you will never retire!
Professor Raili Raininko, my second tutor, who with great skill and patience
have taught me everything I know about radiology and for always having
time for me!
My co-authors – Astrid Frylmark, Cecilia Croona, Margareta Kihlgren and
Jan Weis – for generously sharing your special knowledge. Without you this
thesis had not been possible!
Karin Edebol Eeg-Olofsson for your scientific and clinical assistance,
friendship and for sharing your husband’s time with me!
Monica Bergel and Lilian Stålhammar at the Department of Speech and Language Therapy for performing many of the assessments and sharing your
knowledge with me.
For support from the Department of Women’s and Children’s Health
through Professor Torsten Tuvemo and Professor Jan Gustafsson.
My colleagues at the Neuropediatric clinic for friendship and support – AnnKristin Ölund, Bosse Strömberg, Cissi Tjäder, Eva Kimber, Margareta Dahl,
Najah Khalifa and Ulrika Wester. A special gratitude to the Head of our
group, Gunnar Ahlsten, who gave me the opportunity to take a leave of absence from the clinical work and to David Henley who also helped me with
the English text!
66
All other colleagues at the Children’s hospital, old ones and new ones, for
your ongoing support and co-operation.
Katrin Larsson, a key-person in the care of children with epilepsy, for your
continual co-operation and for friendship.
The staff at ward 95B for always being kind and helpful and fun to work
with, in particular Birgit, Karin, Britt-Marie, Christine, Melva and Agneta –
we have struggled together since the early 1990s when I came to the Children’s hospital!
Hans Arinell for sharing your statistical knowledge with me.
Inga Andersson and Barbro Westerberg for assistance with practical aspects
of this work.
Håkan Pettersson at the ‘Photo Graphic Design’ unit at the Department of
Radiology, for excellent help in making the figures – at the last moment!
The wonderful music of Esbjörn Svensson, Bobo Stensson and Chic Corea
during the many late nights alone with my computer…
My dear friends and relatives, I hope I will see you more often!
My mother and late father, my brothers Magnus, Henrik, Fredrik and my late
brother Anders, my late grandparents, who always have been very supportive and encouraging in all my endeavours.
And most of all, my beloved Maria, for all your support, patience and love,
and my children Tove, old enough to understand and respect that her father
has had a busy time, Martin, so young he doesn’t care, he just wants to
chat, and little Johan, for smiling and growing! I love you Ɔ !
This work was supported by grants from Föreningen Margaretha hemmet, the Erik
Lysholm Memorial Foundation, the Family Norin Epilepsy Research Foundation,
the Birgit and Bengt Hedström Child Neurology Research Foundation, the Gillbergska Foundation, Glaxo-Smith-Kline (former Glaxo Wellcome) and Swedish Medical
Research Council K2001-73X-13158-03A.
67
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