ARTICLE
Auteur(s) : Ashalatha Radhakrishnan1, Pasiri Sithinamsuwan1, A Simon Harvey2, Danny
Flanagan3, Gregory Fitt4, Sam
Berlangieri5, Graeme D Jackson3,6, Samuel F
Berkovic1,3,6, Ingrid E
Scheffer1,2,6,7
1Epilepsy Research Centre and Department of Medicine,
The University of Melbourne
2Department of Neurology, Royal Children’s Hospital
3Brain Research Institute, Melbourne
4Department of Radiology
5Department of Nuclear Medicine
6Department of Neurology, Austin Health
7Department of Paediatrics, The University of Melbourne,
Royal Children’s Hospital, Melbourne, Australia
Article reçu le 7 Juillet 2008, accepté le 15 Septembre 2008
Patients with refractory multifocal epilepsy are not usually
considered as surgical candidates. Detailed evaluation may show
that specific seizures have a greater impact on the quality of life
than others. In such cases, targeted surgery may hold benefits for
the patient even when full control of seizures is not anticipated.
An example of such an approach is corpus callosotomy to treat
disabling drop attacks in an individual with symptomatic,
generalised epilepsy with multiple seizure types.
Here, we describe a patient with multifocal epilepsy comprising
discrete occipital and frontal lobe seizures. The recent
development of frontal lobe seizures had markedly affected the
patient’s functioning. The frontal lobe seizures were due to a CCM
that developed following irradiation for acute lymphoblastic
leukaemia (ALL). The patient also had occipital lobe seizures
associated with MRI abnormalities thought to be delayed sequelae of
chemotherapy or radiotherapy. Surgery for the CCM produced marked
improvement in the patient’s quality of life, although it was
expected that he would not be rendered seizure-free due to the
ongoing occipital seizures.
Case report
An 18-year-old, right-handed boy, presented with an antalgic gait,
thigh pain, malaise and refusal to walk at 18 months of age
following an illness with coryza and mild fever. He had had a
normal birth and unremarkable developmental history. He was
diagnosed with ALL of the L1 type (Bennett et al. 1976), with 88%
blasts at 20 months. Tumour markers showed a pre-β lineage, and the
bone marrow karyotype showed one normal cell line and another
abnormal cell line containing a chromosome 1/19 translocation,
known to be associated with pre-β ALL (Carroll et al. 1984). His
white cell count was 28,000/cmm, with haemoglobin of 9.7 gm% with
normal platelets. He received cranial irradiation at a dose of 18
Gray in 15 fractions over eight months. His chemotherapy regimen
included an induction phase with vincristine, cytosine arabinoside,
followed by maintenance treatment with E-asparaginase, oral and
intrathecal methotrexate, 6-mercaptopurine, cyclophosphamide,
cytosine arabinoside, and prednisolone over two years. His
leukocyte count and bone marrow normalized by four years. He had
normal developmental milestones. Fine motor concerns with writing
became apparent when he started school at age six years. An MRI
brain scan showed increased signal involving the white matter
bilaterally, both in the periventricular regions and peripherally
with confluent, increased signal within the occipital lobes and was
consistent with leukoencephalopathy due to radiotherapy and
chemotherapy. Brain CT did not show calcification.
His epilepsy began at eight years with visual auras
characterised by flashing or flickering images moving across his
vision such as images of clouds (seizure type 1). He reported
macropsia, for example “a tap appearing large or distorted”. He had
a feeling of falling forward as though his head was forced forward,
or his head and eyes would deviate to either side with loss of
awareness for 30-60 seconds. Postictally, he vomited and was
confused for a few minutes. Seizures typically occurred daily on
becoming drowsy or awakening. Triggers included changes in
lighting, splashing in the shower or swimming. No photosensitivity
was noted on EEG; however, discharges appeared on eye closure. At
the age of 10 years, brain MRI showed bilateral, periventricular
white matter hyper-intensities in the parieto-occipital regions
(figure 1A). He
was refractory to the following anti-epileptic drugs:
carbamazepine, topiramate, lamotrigine, valproate, gabapentin and
clobazam. The visual seizures did not impact markedly on his daily
life as they were limited to periods around sleep, and they did not
affect his schoolwork.
At 15 years, he developed a new type of focal seizure (type 2).
These began with an aura of nausea and vomiting, and he felt a
tightness in his chest and abdomen “as if my stomach is pushed
together” accompanied by a feeling of anxiety and palpitations.
This evolved to loss of awareness with facial grimacing, bilateral
upper limb automatisms and left hand dystonia. If standing, he
would walk away. If he was sitting, he had axial rocking and
bipedal automatisms, more marked on the right. Type 2 seizures were
triggered by exercise such as running around, and occurred whenever
he played sport. These seizures gradually escalated over eight
months, eventually occurring every two hours throughout the day by
16 years. These seizures compromised his daily life such that he
showed a dramatic decline in academic performance from being an A
grade student to struggling with schoolwork, in part due to
difficulty concentrating. He experienced increasing isolation from
his peers, low mood and self-esteem. His frequent attacks meant
that he required constant supervision and could not do any
activities alone such as walking to the shops.
In 2006, at 16 years, he underwent detailed epilepsy
characterization. An MRI brain scan showed a right frontal CCM
(figure 1C,D)
that had not been present on the most recent, previous MRI in 2003
(figure 1B). The
posterior periventricular abnormalities had resolved when repeat
imaging was performed at 13 years. Neuropsychological assessment
showed a focal visuo-perceptual deficit on a background of normal
cognitive function.
The patient underwent two periods of video-EEG monitoring, and
48 seizures were captured. Interictal EEG showed active, right
posterior temporo-occipital epileptiform discharges, and
intermittent theta and rare left occipital discharges (figure 2A). No interictal
frontal discharges were seen. Two type 1 seizures and 46 type 2
seizures were captured (see video sequences). The type 1 seizures
had no observable clinical features, changes in heart rate or EEG
changes (see video sequences). The type 2 seizure started with the
patient experiencing an aura and tachycardia (resting heart rate
70-80, ictal heart rate 140-160 beats/minute). He then lost
awareness, with bipedal and left hand automatisms, and head
deviation to the left. He clutched his abdomen with both hands,
leant forward bending his head, coughed, retched, and rubbed his
right eye with his right hand (see video sequences). The EEG of the
type 2 seizures showed right frontal onset of diffuse,
non-lateralized attenuation followed by rhythmic, low voltage
bifrontal fast activity (figure 2B, C).
The interictal, single photon emission computed tomography
(SPECT) study showed subtle, focal hypoperfusion of the right
mesial frontal region (figure 3A). An ictal SPECT
study was performed during a type 2 seizure (injected 44 seconds
from seizure-onset during a seizure lasting 84 seconds). This
showed hyperperfusion of the right mesial frontal cortex (figure 3B). An
interictal FDG-PET scan showed hypometabolism of the right mesial
temporal and posterior temporo-occipital regions (figure 4A) and subtle
hypometabolism in the right mesial frontal region (figure 4B).
Co-registration of interictal EEG-functional MRI (EEG-fMRI)
studies showed blood oxygen-level-dependent (BOLD) signal changes
in the right parieto-occipital region, which correlated with the
frequent, right parieto-occipital interictal discharges (figure 5A). A type
2-seizure ictal EEG-fMRI study showed a diffuse bilateral network
of increased BOLD signal with a right-sided emphasis. There was
involvement of the right frontal, central, parietal and temporal
regions and the motor strips bilaterally (figure 5B).
The patient underwent right mesial frontal lesionectomy in
August 2006. Histopathology showed a partially thrombosed cavernous
angioma with evidence of previous haemorrhage.
In the 22 months following surgery, the frontal seizures ceased
although with ongoing, daily, visual auras due to occipital lobe
seizures. His quality of life significantly improved after surgery.
He became more alert and interactive, his mood improved and he was
able to return to normal school life. He became independent, wrote
poetry and short stories. Life for the whole family improved in the
context of his improved seizure control as he was able to carry out
activities independently.
Discussion
Late sequelae of radiotherapy and chemotherapy
Cerebral cavernous malformations (CCMs) are angiographically occult
vascular lesions that are found in 0.5% of the general population.
CCMs occur either as isolated lesions in sporadic individuals or as
multiple lesions with a genetic basis. Acquired causes of CCMs are
recognised. For example, CCMs may develop as late sequelae after
irradiation of the brain. Post-irradiation CCMs are more frequently
reported in children with ALL as this is the most common group to
receive radiotherapy (Larson et al. 1998, Heckl et al. 2002, Maeder
et al. 1998). More than 3% of children receiving radiotherapy for
brain tumours develop CCM (Burn et al. 2007); this complication is
much rarer in the adult population (Furuse et al. 2005). The
average time interval between irradiation and the detection of a
CCM in children varies from 3 to 22 years after exposure to
radiation doses of 24 to 60 Gray (Megdiche Bazarbacha et al. 2004,
Duhem et al. 2005, Baumgartner et al. 2003).
The late effect of irradiation-induced CCM occurs predominantly
in children; however, the mechanism is unknown. Heckl and
colleagues postulated that a small, pre-existing CCM not visible on
MRI could grow secondary to irradiation (Heckl et al. 2002).
Irradiation causes adventitial fibrosis and endothelial oedema,
resulting in narrowing of the vascular lumen.
Toxic leukoencephalopathy may occur secondary to radiotherapy or
chemotherapy, and may be clinically, radiologically and
pathologically indistinguishable between the two aetiologies
(Filley 1999). The severity may be more severe where chemotherapy
is administered intrathecally or intravenously in combination with
radiotherapy. Intrathecal methotrexate in particular may be
associated with leukoencephalopathy. Most commonly, radiation
exposure is associated with a late, delayed leukoencephalopathy
with neurobehavioural changes such as learning disabilities in
children. Milder neurobehavioural effects are associated with a
greater likelihood of reversibility as noted in our patient (Filley
1999).
Surgical decision-making
The decision to progress to epilepsy surgery in this young man
involved multiple admissions for video-EEG monitoring, a range of
investigations and many complex discussions.
Initially, we had to delineate whether there were actually two
types of seizures or simply different spread patterns emanating
from a single epileptogenic focus. The recent-onset attacks
differed from the long-standing seizures, most notably with a
different aura, evolution and triggers. The semiology of the
recent, disabling seizures began with an aura of fear,
palpitations, a sensation of tightness in the chest and abdomen,
and nausea, followed by pedal automatisms and hyperkinetic
behaviour. The clinical features were clearly those of frontal
seizures (Jobst et al. 2000), compared with his original occipital
(Taylor et al. 2003) seizures characterised by a visual aura. The
frontal lobe seizures had a characteristic ictal EEG onset pattern
and an associated lesion. The occipital seizures did not have an
EEG signature, but it is well known that simple partial seizures
can be silent on surface EEG. Also, there was no history of one
seizure type progressing to the other.
Multiple investigations were performed and closely scrutinised
to confirm the clinical impression of two discrete seizure types
rather than spread from the occipital focus to the frontal region.
Thus, the close attention to the video-EEG data was crucial to
determining suitability for epilepsy surgery. The EEG showed
frequent, right temporo-occipital interictal epileptiform
discharges (IED) and infrequent left occipital discharges;
interictal frontal discharges were not seen. The presence or
absence of IED in FLE indicative of an “irritative zone” does not
crucially influence surgical decision-making and outcome (Worrell
et al. 2002).
In comparison with the interictal recordings, ictal studies gave
evidence to support the case for epilepsy surgery. The frontal lobe
seizures showed high frequency, low amplitude beta discharge over
the right frontal electrodes (Fp2-F8-F4) within 2-3 seconds of
seizure-onset in all 46 of the type 2 seizures (figure 2B, C). In
contrast, there was no ictal rhythm seen in the two recordings of
the type 1 seizures. The focal beta discharge at the onset of the
frontal lobe seizures was highly indicative of seizure origin in
terms of spatial and temporal resolution. The focal beta discharge
served as a marker of the epileptogenic zone in frontal lobe
resections and was associated with excellent seizure-free outcome
following surgical resection (Worrell et al. 2002, Kazemi et al.
1997).
Our patient was referred from the northern part of Australia
with his MRI reported as showing posterior abnormalities only. With
the identification of frontal lobe seizures, we scrutinised his MRI
carefully and compared his serial studies over 10 years. We found a
right mesial frontal lesion that had only emerged in the preceding
three years. It is critical that MRI studies are reviewed in the
light of electro-clinical seizure semiology as subtle lesions may
be easily missed.
Functional imaging is helpful in localising seizure-onset.
Comparison of ictal to interictal SPECT in our patient added
considerable weight to seizure localization (figure 3A, B). In frontal
lobe seizures in children, ictal SPECT demonstrated unilateral
frontal hyperperfusion in 91%, which was concordant with
electroclinical lateralisation in 95% of cases (Harvey et al.
1993). EEG-fMRI provided supportive information about the right
posterior quadrant interictal epileptiform discharges, presumably
relevant to the occipital seizures (figure 5). The probable
type 2 seizure recorded during fMRI was supportive of perilesional
involvement, but was not considered for clinical decision-making
because it was performed purely for research.
The epilepsy surgery discussion centred around whether there
were sufficiently convincing data to show that the type 2 seizure
arose independently in the frontal lobe rather than representing
spread from a single focus in the occipital lobe, and whether the
patient would benefit from epilepsy surgery directed solely at the
frontal focus. To address the first question, it is clear that the
type 2 seizure was frontal in nature with frontal lobe semiology,
ictal EEG frontal lobe signature, SPECT localisation to the frontal
lobe and a MRI mesial frontal lesion. Rather than spread from the
occipital lobe, there was evidence of frontal onset as the aura was
different, the two seizure semiologies did not occur together and a
highly epileptogenic lesion was found in the frontal lobe. In
answer to the second question, the patient’s quality of life had
deteriorated since onset of the FLE in terms of school and social
functioning. He had coped well with daily, mild occipital seizures
for many years. Here we showed that the vast majority (46/48) of
seizures arose in the frontal lobe. The issue of surgery was
broached and it was carefully explained that occipital seizures
would continue at the same frequency but hopefully, the frontal
lobe seizures would cease or occur at a far reduced frequency with
resection of the frontal lesion, allowing resumption of previous
activities.
Considerable time was spent discussing the value of intracranial
monitoring. In a patient with multifocal or dual pathology, further
delineation of the exact ictal-onset zone with invasive strategies,
such as implantation of intracranial electrodes, is regarded as the
gold standard. This is essential when clinical,
electrophysiological and neuroimaging data are ambiguous or
discordant (Dubeau et McLachlan 2000, Worrell et al. 2002,
Romanelli et al. 2004, Cross et al. 2006). However, careful
analysis of non-invasive evaluation incorporating seizure
semiology, scalp EEG, neurophysiological and neuroimaging
techniques can localize epileptic foci accurately and determine
likely benefit of surgery (Koh et al. 2000, Karenfort et al. 2002,
Francione et al. 2005). Here, our patient had concordant clinical
semiology, EEG data and a congruent lesion on structural and
functional imaging, such that invasive studies were not essential
and carried risks of complication (Harvey et al. 1993, Cascino et
al. 1992, Pondal-Sordo et al. 2007, Shukla et al. 2003). Equally,
it was important that the clinical team made it clear to the
patient and his family not to expect seizure-freedom from the
surgical resection in view of his multifocal epilepsy.
Surgery for multifocal epilepsy
Multifocal epilepsy does not preclude successful epilepsy surgery.
Studies of patients with tuberous sclerosis show that benefit can
be gained from resection of one tuber in children with multiple
tubers or even multiple tuberectomies (Weiner et al. 2006).
Here, we were not attempting to resect multiple abnormal
regions. Rather, we focused on removing the epileptogenic lesion
responsible for the prominent and disabling frontal seizures of
recent onset. Surgery for the occipital seizures was not indicated
for several reasons: seizures were not disabling, seizure-onset was
not lateralized nor was a discrete lesion present, and surgery
would have produced an unacceptable visual defect. Detailed
analysis may show that a patient has seizures arising from
different cortical foci that occur at different frequencies. If one
seizure focus is more active and those seizures are more disruptive
to daily function, surgery may still prove beneficial. If surgery
is offered with appropriate counselling, the patient may elect to
undergo surgery despite the expectation of ongoing epilepsy. As
seen here, surgery may significantly improve the patient’s quality
of life even though seizures from the remaining foci continue to
occur.
Our case highlights the benefits derived from: (1) careful
evaluation of multiple seizure types, in terms of their origin and
impact, (2) the importance of patient auras, seizure semiology and
evolutions, (3) the search for an occult epileptogenic lesion that,
once found, obviated the need for intracranial EEG monitoring, and
(4) the application of surgery to one of multiple seizure foci,
resulting in striking improvement in the patient’s quality of life.
This case illustrates the importance of not dismissing patients
with multifocal epilepsy as unsuitable surgical candidates and
emphasizes that in some cases, seizure freedom is not always the
endpoint that is sought. Such surgery should be considered curative
for the disabling epilepsy, rather than “palliative”.
Acknowledgments
We thank the patient and his family for their support and
enthusiasm for the publication of this report. Our research is
supported by the National Health and Medical Council of Australia.
Grants.
National Health and Medical Research Council of Australia.
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