Clinical commentary
Epileptic Disord 2010; 12 (4): 330-4

Regression of stroke-like
lesions in MELAS-syndrome
after seizure control
Josef Finsterer1, Peter Barton2
1
2

Krankenanstalt Rudolfstiftung
Institute of Radiology Urania, Vienna, Austria

Received February 3, 2010; Accepted September 22, 2010

ABSTRACT – There are some indications that seizure activity promotes the
development of stroke-like episodes, or vice versa, in patients with mitochondrial
encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome or
other syndromic mitochondrial disorders. A 41-year-old Caucasian female with
MELAS syndrome, presenting with short stature, microcytic anaemia, increased
blood-sedimentation rate, myopathy, hyper-gammaglobulinaemia, an ironmetabolism defect, migraine-like headaches, and stroke-like episodes, developed complex partial and generalised seizures at age 32 years. Valproic acid
was ineffective but after switching to lamotrigine and lorazepam, she became
seizure-free for five years and stroke-like episodes did not recur. Cerebral MRI
initially showed enhanced gyral thickening and a non-enhanced T2hyperintensity over the left parieto-temporo-occipital white matter and cortex
and enhanced caudate heads. After two years without seizures, the nonenhanced hyperintense parieto-temporo-occipital lesion had disappeared,
being attributed to consequent seizure control. The caudate heads, however,
remained hyperintense throughout the observational period. This case indicates
that adequate seizure control in a patient with MELAS syndrome may prevent the
recurrence of stroke-like episodes and may result in the disappearance of strokelike lesions on MRI.
Key words: epilepsy, seizures, mitochondrial disorders, metabolic disease,
antiepileptics, MELAS

330

dichloracetic acid may have a beneficial effect. There are also some indications that seizure activity promotes the
development of SLEs (Iizuka et al.,
2002) and that effective seizure
control may prevent the development
and recurrence of SLEs and even
resolve stroke-like lesions, as in the
following case.

Case report
The patient was a 41-year-old
Caucasian female, height 160 cm,

Epileptic Disord Vol. 12, No. 4, December 2010

doi: 10.1684/epd.2010.0338

Correspondence:
J. Finsterer
Postfach 20,
1180 Vienna, Austria
<fifigs1@yahoo.de>

Stroke-like episodes (SLEs) and concomitant stroke-like lesions (SLLs) on
MRI are dominant features in patients
with mitochondrial encephalopathy,
lactacidosis and stroke-like episodes
(MELAS) syndrome (Testai and
Gorelick, 2010). Additionally, SLEs
occur in a number of other syndromic
and non-syndromic mitochondrial
disorders (Finsterer, 2007). Although
there is no consensus on the treatment
of SLEs, there is some evidence that
antioxidants, cofactors, L-arginine,
steroids, glycerol, edaravone, or

Stroke-like lesions in MELAS regress under antiepileptics

weight 55 kg, with a normal developmental history.
She was diagnosed at 32 years with MELAS syndrome
based on: the family history, clinical manifestations
such as growth retardation, short stature, increased bloodsedimentation rate, microcytic anaemia, migraine-like
headaches, SLEs, epilepsy, myopathy, hyper-gammaglobulinaemia, an iron-metabolism defect, and increased lactatepeaks on cerebral H-MR-spectroscopy. Muscle biopsy at
age 32 showed fibre atrophy and some ragged-red muscles
fibres. Screening for tRNA(Leu), tRNA(Ser), and tRNA(Lys)
mtDNA gene mutations by single-strand conformational
polymorphism (SSCP), for the m.3243A>G and the
m.8344A>G mutations by restriction fragment length polymorphism (RFLP), and further sequencing of the tRNA(Seer)
gene, failed to confirm the presence of a pathogenic mutation, thus MELAS syndrome was assumed to have been
caused by other mtDNA or nDNA mutations. Her sister,
who had a history of migraine, aseptic pleocytosis, encephalopathy, slight anaemia, and bilateral temporal calcifications and had died from cerebral oedema and intractable
epileptic seizures at age 19, was assumed to have also
suffered from MELAS syndrome. Her mother had died
from colon cancer.
At 32 years old, the index patient experienced a first
tonic-clonic seizure with aura. The EEG showed focal
slowing and sporadic sharp waves and spikes over the
left and right fronto-temporal projections with left-sided
predominance (figure 1). The MRI showed slight focal
atrophy (figure 2), bilateral hyperintense lesions in the
temporo-occipital region with gyral thickening, and
enhancement of the temporo-occipital cortex and the
caudate heads. Valproic acid treatment (600 mg/d) was
started. One month later, she experienced a similar aura
without cloni. One year after the first tonic-clonic seizure

she presented with an episode of hemianopsia to the right
and simple and complex optic hallucinations. The EEG
showed high-amplitude spikes, sharp waves, polyspikes,
and spike-wave complexes over the left occipital projections with paroxysmal tendency to generalise. Valproic
acid treatment was increased. Six months later, a similar
episode occurred. The MRI showed, in addition to the
previous one, a more pronounced thickening of the gyri
in the temporo-occipital region (figure 2). Since valproic
acid is mitochondrion-toxic, the antiepileptic drug (AED)
treatment was changed to lamotrigine (slowly increasing
to 400 mg/d). At age 35 years, she experienced the next
stroke-like episode manifesting as a visual field defect,
with visual hallucinations, kakosmia, disturbed taste,
headache, and speech disturbance. The MRI disclosed a
left-sided occipito-temporal hyperintense lesion with
cortical enhancement and enhanced caudate heads.
The EEG showed spikes and sharp waves over the left
temporal projections shortly after onset of hyperventilation. Lorazepam (1 mg/d) was added. One month later, a
similar episode occurred. A further SLE with vertigo, dysosmia, and seizures occurred at age 36 years. Since then,
no further SLE occurred except for a tonic-clonic seizures
at 40 years, triggered by a bronchial infection. After the
last seizure, lamotrigine was increased to 600 mg/d but
levetiracetam was refused by the patient because of
tiredness.
After switching to lamotrigine and lorazepam, she became
seizure-free at age 36 years. Repeated cerebral MRI studies
between age 32 and 37 years showed enhanced, gyral
thickening and initially a non-enhanced T2-hyperintensity
over the left and right parieto-temporo-occipital white
matter and cortex and enhanced lesions over the caudate
heads (figure 3). At the age of 35 years, the right-sided

FP2 -G
FP1 -G
F8 -G
F4 -G
F2 -G
F3 -G
F7 -G
T4 -G
C4 -G
CZ -G
C3 -G
T3 -G
T6 -G
P4 -G
PZ -G
P3 -G
T5 -G
C2 -G
C1 -G

Figure 1. EEG recordings showing intermittent sharp waves over the left fronto-temporal projections.

Epileptic Disord Vol. 12, No. 4, December 2010

331

J. Finsterer, P. Barton

Figure 2. Coronary TIRM-sequence, showing slight inner atrophy of the left temporo-parietal region at age 33 years (left). An axial
T1-sequence of the same investigation shows gyral enhancement in the left temporo-occipital region (right).

Figure 3. TIRM-sequences, showing normal basal ganglia (left) and hyperintense heads of the caudate nucleus (right).

parieto-temporo-occipital white matter lesion had disappeared (figure 4). After a two-year seizure-free period, at
the age of 38 years, the MRI surprisingly showed further
improvement with complete disappearance of the left
occipito-temporo-parietal lesion without any volume loss,
but with the remaining caudate lesions (figure 4). Larginine, which has been also shown to have a beneficial
effect on SLLs in single cases (Kubota et al., 2004), was not
administered. Screening for mutated genes other than the
tRNA genes, such as ND1, ND4, ND5, COX2, COX3, or
POLG1, which may also cause MELAS (Deschauer et al.,
2007), was not performed due to a lack of funding.

Discussion
In this case study of MELAS syndrome, it remains inconclusive whether regression of the stroke-like lesions (SLLs)

332

occurred spontaneously or due to the AED treatment.
However, previous studies have shown that effective,
long-term seizure control with non-mitochondrion toxic
AEDs in MELAS syndrome may not only prevent the
development of new SLLs but may also result in their disappearance, suggesting a pathogenetic role for epileptic
activity in the development, maintenance, and recurrence
of SLLs (Kubota et al., 2004). According to this hypothesis,
epileptic activity results in metabolic dysfunction of
neurons with consecutive development of typical focal
lesions seen on MRI in MELAS patients (Iizuka et al.,
2003; Iizuka et al., 2002). On MRI, SLLs present with
variable appearance, particularly in the acute stage. Most
commonly, a SLL represents a vasogenic oedema, which
shows up on MRI as hyperintensity on T2 and an elevated
apparent diffusion coefficient (ADC) (Ohshita et al., 2000;
Ito et al., 2008). The hypersignal on DWI, in the case of

Epileptic Disord Vol. 12, No. 4, December 2010

Stroke-like lesions in MELAS regress under antiepileptics

Figure 4. Axial T2-weighted MRI at 35 years old in the described patient showing a left temporo-parieto-occipital hyperintensity, being interpreted as a stroke-like lesion (left). This lesion had disappeared within one year after having become seizure-free at 37 years (right).

elevation of ADC, corresponds to a T2 shine-through
effect. SLLs remain hyperintense on T2-weighted images
for months after onset but become hypointense or isointense in the chronic stage. On ADC maps, which reflect
the underlying pathophysiology better than DWI, SLLs
show up as elevation over months (Ohshita et al., 2000;
Ito et al., 2008) to become hypointense or alternatively
hyperintense in the chronic stage (Ohshita et al., 2000).
Only for a short period during the initial stages may a SLL
show up as hypointensity on T2-weighted images and
reduced on the ADC map (Ito et al., 2008). Although
classical SLLs may exclusively present as vasogenic,
reversible oedema, cytotoxic and vasogenic oedema
may coexist within the same lesion (Ishikawa et al.,
2009), particularly at onset of the SLE (Tzoulis and
Bindoff, 2009).
According to the epilepsy hypothesis, SLLs represent
regions of neuronal hyperactivity, resulting in increased
focal energy demand and a mismatch between impaired
energy production and increased energy requirement
(Kubota et al., 2004). An argument for a beneficial role
of AEDs in the presented patient is based on the observation that SLLs did not disappear on MRI as long as
the patient experienced seizures. Under valproic acid,
seizures were not only poorly controlled but SLLs also
remained unchanged on MRI since their first recognition.
Valproic acid inhibits oxidative phosphorylation, induces
apoptosis of microglia, and sequesters carnitine (Toth
et al., 2001), which explains why it is contraindicated in
mitochondrial disorders and may even worsen cerebral
manifestations of the disease (Lin and Thajeb, 2007).
In addition to valproic acid, other mitochondrion-toxic
AEDs include barbiturates and phenytoin (Finsterer and
Segall, 2010). To ultimately assess the role of AEDs on

Epileptic Disord Vol. 12, No. 4, December 2010

the dynamics of SLLs, however, larger series with similar
patients and the development of experimental studies are
mandatory.
This case indicates that prevention of seizures by effective
AED therapy in patients with MELAS syndrome may
prevent the recurrence of SLEs and may also result in the
disappearance of SLLs on cerebral MRI. AEDs, such as
lamotrigine or lorazepam, should be considered as a supportive therapy in patients with acute or chronic SLLs.

□

Disclosure.
None of the authors has any conflict of interest or financial support
to disclose.

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