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Case Report

Received: 05.03.2021
Accepted: 21.04.2021

DOI: 10.5137/1019-5149.JTN.34196-21.4

Published Online: 18.10.2021

First Case of MELAS Syndrome Presenting with Local Brain
Edema Requiring Decompressive Craniectomy
Osman YESILBAS1, Esma SENGENC2, Melike ERSOY OLBAK3, Derya BAKO4, Oznur Gokce NIZAM5,
Mehmet Hakan SEYITHANOGLU6, Davut PEHLIVAN7, Serdar CEYLANER8, Dilara ICAGASIOGLU2,
Kursad AYDIN9
Karadeniz Technical University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Critical Care Medicine, Trabzon, Turkey
Bezmialem Vakif University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Istanbul, Turkey
3
Health Sciences University, Bakirkoy Dr. Sadi Konuk Research and Education Hospital, Department of Pediatrics, Division of Pediatric
Metabolism, Istanbul, Turkey
4
Health Sciences University, Van Training and Research Hospital, Departments of Radiology, Division of Pediatric Radiology, Van, Turkey
5
Bezmialem Vakif University, Faculty of Medicine, Department of Pediatrics, Istanbul, Turkey
6
Bezmialem Vakif University, Faculty of Medicine, Department of Neurosurgery, Istanbul, Turkey
7
Baylor College of Medicine, Department of Pediatrics, Division of Pediatric Neurology and Developmental Neuroscience, Houston, USA
8
Intergen Genetics Center, Division of Clinical Genetics, Ankara, Turkey
9
Medipol University, Faculty of Medicine, Department of Pediatrics, Division of Pediatric Neurology, Istanbul, Turkey
1
2

Corresponding author: Osman YESILBAS  drosmanyesilbas@gmail.com

ABSTRACT
Mitochondrial encephalomyopathy, lactic acidosis, and recurrent stroke-like episodes (MELAS) syndrome is a rare but one of the
most common maternally inherited multisystem disorder. Although patients with MELAS present a variable clinical profile, strokelike lesions have been detected in 90% of cases, with stroke being the first presenting symptom in 25% of cases. However, cases
of local brain edema requiring decompressive craniectomy has not been reported.

A 12-year-old male patient was admitted to our pediatric intensive care unit with altered mental status, seizures, and vision loss.
The patient was stuporous and presented neck stiffness. Complete blood count, serum electrolytes, biochemistry (including lactate
level), acute phase reactants, and repeated blood gas analysis were unremarkable. Brain magnetic resonance imaging (MRI) revealed
an edematous stroke-like lesion in the right occipital lobe accompanied by brain swelling. Intravenous ceftriaxone, acyclovir,
intravenous immunoglobulin (IVIG), and pulse steroid therapy were started for possible diagnosis of viral/bacterial/autoimmune
encephalitis; levetiracetam, phenytoin, and an infusion of sodium thiopental were started for refractory status epilepticus; and a
3% NaCl infusion was started for local brain edema. The results of serum autoimmune encephalitis panel were negative. Further
investigations for rheumatic, vascular, and metabolic disorders were unremarkable. Despite these supportive treatments, the patient
was clinically decompensated due to brain swelling that progressed to the left midline shift, and he underwent decompressive
craniectomy. Histologic examination of brain biopsy specimen revealed non-specific encephalitis findings. A pathogenic variant of
the MT-TL1 gene (m.3243A>T), responsible for MELAS, was detected. The patient’s condition dramatically improved after specific
treatment for MELAS.
If the diagnosis and treatment are delayed, MELAS syndrome can cause serious brain edema, which may ultimately require
decompressive craniectomy.
KEYWORDS: Child, Brain edema, Decompressive craniectomy, MELAS syndrome

ABBREVIATIONS: MELAS: Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, MRI: Magnetic resonance
imaging, DWI: Diffusion-weighted imaging, PICU: Pediatric intensive care unit, CSF: Cerebrospinal fluid, EEG: Electroencephalogram,
HSV: Herpes simplex virus, PCR: Polymerase chain reaction, ADC: Apparent diffusion coefficient
Osman YESILBAS
Esma SENGENC
Melike ERSOY OLBAK
Derya BAKO

: 0000-0002-4290-0491 Oznur Gokce NIZAM
: 0000-0003-4002-785X M. Hakan SEYITHANOGLU
: 0000-0002-2316-0790 Davut PEHLIVAN
: 0000-0003-0642-6793 Serdar CEYLANER

: 0000-0003-2615-3307 Dilara ICAGASIOGLU
: 0000-0003-3571-0742 Kursad AYDIN
: 0000-0001-5788-0270
: 0000-0003-2786-1911

: 0000-0002-7728-2611
: 0000-0003-1513-6149

1

Yesilbas O. et al: Severe Brain Edema Secondary to MELAS Syndrome

█

INTRODUCTION

M

itochondrial encephalomyopathy, lactic acidosis,
and stroke-like episode (MELAS) syndrome is one
of the most frequent maternally inherited mitochondrial diseases. It is a multi-organ disorder with broad
manifestations, including stroke-like episodes, seizures, lactic
acidemia, recurrent headaches, myopathy, cortical vision loss,
hemiparesis, hearing impairment, recurrent vomiting, altered
consciousness, diabetes, developmental delay, peripheral
neuropathy, learning disabilities, memory impairment, myoclonus, ataxia, psychotic disorders, cardiomyopathy, cardiac
conduction abnormalities, and nephropathy. Most affected
individuals develop symptoms of MELAS between the ages
of two and 40 years (2,13). On conventional magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI),
stroke-like lesions are identified as essential imaging features
of MELAS. These lesions predominantly affect the posterior
lobes of the brain and are not confined to the vascular territories (12).
In this article, we report an extremely rare case of MELAS
syndrome that required urgent decompressive craniectomy
for severe brain edema. According to the available English
literature, this is the first reported case in which decompressive
craniectomy was performed to ameliorate MELAS syndromerelated severe brain edema. Written informed consent was
obtained from the patient’s parents.
█

CASE REPORT

A 12-year-old male patient was referred to our pediatric
intensive care unit (PICU) with altered mental status, seizures,
and vision loss. The patient’s medical history revealed that
approximately 2 years ago, he had been admitted to another
hospital with fever, altered mental status, and seizures. He
had been treated for seizures and meningoencephalitis based
on physical and cerebrospinal fluid (CSF) examinations and
brain MRI results (Figure 1A, B). His electroencephalogram
(EEG) findings were unremarkable. Results of polymerase
chain reaction (PCR) assay for herpes simplex virus (HSV),
CSF culture, and serum autoimmune encephalitis panel
were negative. He was discharged from the hospital with a
prescription of oral levetiracetam after completion of antibiotic
and antiviral treatment. For approximately two years since
discharge, he had been experiencing loss of consciousness
with accompanying visual symptoms lasting 15-20 minutes.
During this period, results of a repeat EEG, serum autoimmune
encephalitis panel, acyl-carnitine profile, serum lactate, plasma
amino acids, and urine organic acid levels were unremarkable.
Since significant regression was observed on the brain MRI
(Figure 1C), the condition had been attributed to encephalitis
sequelae, and he was treated with levetiracetam for epilepsy.
When he was referred to our institution in a comatose stage
(Glasgow Coma Scale score of 9), his pupils were isochoric,
and pupillary light reflex was present in both eyes. Blood
pressure, heart/respiratory rate, and body temperature were
all within the normal ranges for his age. Respiratory effort was
sufficient, lung auscultation was normal, and pulse oxygen

2 | Turk Neurosurg, 2021

saturation in room air was 96-98%. Results of complete
blood count with differential, serum electrolytes, biochemistry
(including lactate level), acute phase reactants, and blood gas
analysis were unremarkable. MRI revealed midline, subuncal,
and central herniation due to the mass effect of stroke-like
lesions involving the right parietal, temporal, and occipital
lobes (Figure 1D). Magnetic resonance angiography and
venography scans were unremarkable. Lumbar puncture was
deferred because of herniation risk. The background rhythm
in the patient’s electroencephalogram was irregular and slow.
Mechanical ventilatory support was initiated after the rapid
sequence intubation protocol. Intravenous (IV) ceftriaxone,
acyclovir, IV immunoglobulin (IVIG, 2 g/kg over 5 days), and
pulse steroid therapy (30 mg/kg for 5 days) were started for
possible diagnosis of viral/bacterial/autoimmune encephalitis;
levetiracetam, phenytoin, and an infusion of sodium thiopental
were started for refractory status epilepticus; a 3% NaCl
infusion was started for local brain edema (serum sodium level
was targeted between 160 and 165 meq/L); subcutaneous
enoxaparin was started to treat the stroke-like lesions found on
the brain MRI, and fentanyl infusion was started for analgesia.
Results of serum autoimmune encephalitis panel, plasma
acyl-carnitine profile, serum lactate, plasma amino acids,
urine organic acids, and further investigations for rheumatic
and vascular diseases were unremarkable.
On the fifth day of PICU admission, anisocoria, bradycardia,
and hypertension emerged when his serum sodium level was
163 meq/L. Intravenous mannitol (4x0.5 gr/kg) treatment was
promptly added to therapies and a repeat MRI (Figure 1E) was
performed immediately. Because of the progression of brain
herniation, decompressive hemicraniectomy was performed.
After decompressive hemicraniectomy, the herniation gradually regressed (Figure 1F). Histologic examination of brain
biopsy specimen revealed non-specific encephalitis findings.
A pathogenic mutation m.3243A>T was detected in the MTTL1 gene, and MELAS was diagnosed on the eighth day of
PICU hospitalization. A high (10g/m2) IV dose of L-arginine,
coenzyme Q10 (10 mg/kg per day), B vitamins cocktail, and
levocarnitine (100 mg/kg/day) were promptly administered for
the treatment of MELAS. He was extubated, and non-invasive
mechanical ventilatory support was initiated on the end of the
third day since the MELAS-specific therapies were initiated.
The patient’s condition gradually improved over the course
of his hospitalization and he was discharged without any
respiratory support on the thirty-sixth day of admission.
At discharge, he could understand and speak fluently, but
his vision was impaired. Subsequently, he was followed by
a pediatric metabolism and neurology specialist, with oral
arginine, coenzyme Q10, L-carnitine, vitamin B cocktail, and
levetiracetam. During a two-year follow-up, he started to walk
with support, but unfortunately, he still could not see clearly.
█

DISCUSSION

Although the underlying pathophysiology of MELAS syndrome
is not fully understood, impaired mitochondrial energy
production, microvasculature angiopathy, and nitric oxide

Yesilbas O. et al: Severe Brain Edema Secondary to MELAS Syndrome

A

B

C

D

E

F

Figure 1: First row (A-C): First hospitalization of the patient in another hospital. A) Axial FLAIR magnetic resonance imaging (MRI)
performed on the first day of admission shows mild swelling involving the cortex and subcortical areas and hyperintensity in the left
temporo-occipital lobe. B) Progression of in cortical and deep subcortical swelling with deep white matter involvement on the thirteenth
day. C) One month later (after hospital discharge): slight hyperintensity and atrophy in the left temporo-occipital lobe is noted, indicative
of previous stroke-like lesions. Second row: Second hospitalization of the patient in our pediatric intensive care unit. D) Axial T2weighted MRI was performed on the day of admission. Mild swelling involving the cortex and subcortical area and hyperintensity in the
right parieto-occipital lobe is seen. E) Axial FLAIR MRI was performed on the fifth day of admission. A midline shift is seen due to the
increasing mass effect of the stroke-like lesion involving the right parietal, temporal, and occipital lobes. Involvement of the cingulate
gyrus is seen, causing subfalcine herniation. F) T2-weighted MRI was performed after decompressive craniectomy. Slightly regressed
midline shift is noted-a finding indicative of the mass effect of a stroke-like lesion and persistence of subfalcine-midline herniation.

deficiency are possible interacting mechanisms secondary
to various mutations, especially in the MT-TL1 gene, similar
to that in our patient (2). The m.3243A>G pathogenic variant
in the mitochondrial gene MT-TL1 causes symptoms in
approximately 80% of individuals. Stroke-like episodes,
which occur in 84–99% of affected individuals, are the main
manifestation of MELAS (2,3). These episodes clinically emerge
with partially reversible aphasia, headaches, altered mental
status, seizures, cortical vision loss, and motor weakness
secondary to progressive neurological impairment, as in our
patient (2,11). MELAS syndrome usually present clinically in
adolescents and adults. Most patients are between 5 and 15
years of age similar to our patient (15). The diagnosis of MELAS
syndrome is challenging because the clinical manifestations,
which may be related to the functioning of many organ
systems, are often non-specific. At the first hospitalization,

our patient was misdiagnosed with encephalitis because of
his clinical manifestations (fever, neck stiffness, neurological
dysfunction, and seizures) and biochemical features of
CSF. Zhang et al. (15) reported a case of 13-year-old male
patient who was misdiagnosed with encephalitis, similar to
our patient. In our patient, the loss of consciousness with
accompanying visual symptoms for approximately two years
was attributed to epileptic attacks secondary to encephalitis
sequela because his brain MRI results improved during this
period. Although lactic acidosis, especially elevated lactate
levels in the CSF, are essential signs of this syndrome, such
levels can be normal in a minority of individuals with MELAS
syndrome (9). In our patient, no increase in serum lactate was
observed during hospitalization. Since lumbar puncture was
not performed in our PICU because of possible herniation risk,
CSF lactate levels could not be investigated.

Turk Neurosurg, 2021 | 3

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Yesilbas O. et al: Severe Brain Edema Secondary to MELAS Syndrome

Occasionally, conventional neuroimaging methods may
fail to distinguish this disease from ischemic stroke and
meningoencephalitis (6,15). Classical T2-weighted brain
MRI findings include increased signal intensity abnormalities
that simulate ischemic stroke predominate in the occipital,
parietal, and temporal lobes in patients with MELAS.
These brain lesions can be unilateral or bilateral, frequently
involving the cortex and mostly affecting the gray matter
more than white matter. The affected areas and their borders
do not correspond to a specific vascular distribution. Brain
magnetic resonance angiography usually yields no findings
of abnormalities (2,6,7,8,15). The lesions are not necessarily
permanent and may sometimes show contrast enhancement
due to the increased permeability resulting from reperfusion
and congestion secondary to blood-brain barrier damage.
Clinical and radiological improvements may be observed
with time (5,8). Initially, our patient was misdiagnosed with
meningoencephalitis, but his clinical and radiological findings
improved later, which is compatible with the data reported
in the literature. A characteristic hallmark of MELAS, which
was also seen in our patient, is that recurrence may occur in
different locations with each attack (5).
DWI mostly shows an increased apparent diffusion coefficient
(ADC) in stroke-like lesions of MELAS, in contrast to the
decreased ADC seen in ischemic strokes (5,8). This feature of
MELAS strongly suggests that vasogenic, but not cytotoxic,
edema is a predominant characteristic in the stroke-like lesion
of this syndrome. Breakdown and increased permeability
of the blood-brain barrier, secondary to mitochondrial
respiratory failure in the endothelial cells and smooth muscles
of the cerebral arterioles, are speculated to be the underlying
pathophysiology (1,14). Although there are a few reported
cases of brain edema secondary to MELAS syndrome in the
literature (10,14), to the best of our knowledge, our patient
is the first patient in whom decompressive craniectomy was
performed for severe brain edema.
Magnetic resonance spectroscopy (MRS) is another ancillary
non-invasive method for diagnosing stroke‐like episodes in
MELAS. These episodes are associated with elevated lactate
peaks and low N‐acetylaspartate/choline ratios. Additionally,
serial MRS imaging can be used to monitor clinical and
radiological improvement after MELAS-specific treatment,
such as IV L-arginine administration (4).
█

CONCLUSION

Diagnosis of MELAS syndrome is challenging because the
clinical manifestations are often non-specific. Important
radiological findings for the diagnosis of stroke-like episodes
include brain MRI findings of lesions that predominantly affect
the posterior lobes not confined to the vascular territories.
Although lactic acidosis, especially elevated lactate levels in
the CSF, are essential signs of this syndrome; however, lactate
levels can be normal in a minority of individuals. Clinicians
should be aware that if the diagnosis and treatment are
delayed, MELAS syndrome can cause serious brain edema,
requiring decompressive craniectomy.

4 | Turk Neurosurg, 2021

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