Clinical Brief

Indian J Pediatr 1999; 66 : 621-625
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i

Melas Syndrome
Saroj Kurnar Singh, Dinesh Sarin*, Jacob M. Puliyel, Rajeev Srivastav, Richa Gupta,
Nirmal Kumar and Ann Mathews

Departments of Pediatrics and Neurology* St. Stephen's Hospital, T@ Hazari, Delhi
Abstract. An 11 year old male presented with headache, vomiting and weakness of right side of
body. One day after admission he developed right focal seizures. He had 5 previous episodes of
stroke, the first at 1t months age. His milestones were normal upto the first episode but
subsequent mile stones were delayed. His serum and CSF lactic acids were raised. Muscle biopsy
showed ragged red fibres on modified Gomori-trichrome staining. His EEG, CT scan and MRI were
normal this time. The child improved spontaneously after 7 days. His recovery time progressively
became shorter with each episode of stroke. Maximum time for recovery was noted during first
episode and least in current episode. This is the first report of Melas syndrome in Indian literature.
(Indian J Pediatr 1999; 66 : 621-625)

Key words : Melas syndrome; Mitochondrial myopathy; Lactic acidosis.

The syndrome of mitochondrial myopathy,
encephalopathy, lactic acidosis and stroke
like episodes (Acronym as MELAS) is characterized by short stature, hemiparesis,.
hemianopsia, cortical blindness, lactic
acidemia and ragged red fibres in skeletal
muscle1. Other frequently encountered features of MELAS are sensorineural hearing
loss, headache, nausea, vomiting and basal
ganglia
calcification2.
Development
through infancy is usually normal in
MELAS1. Clinical features usually appear
between 5 to 15 years of age and manifestations below the age of one year are rare 3.
Infants present with symptoms of failure to
thrive, vomiting, lactic acidosis, cogrdtive
regression before developing stroke like
episodes *z,6. No case of MELAS has been
reported in Indian literature so far.

Reprint requests : Dr Saroj Kumar Singh, C-3, 4
Rajpur Road, St. Stephen's Hospital Staff
Quarters, Tis Hazari, Delhi - 110 054.

CASE REPORT
An 11 year old male was admitted with a 2
days history of hemiparesis of the right
side. He had headache on the day before
the onset of weakness. Previously, he had 4
episodes of transient hemiparesis, the first
at the age of 11 months and subsequently
at the age of 2 years, 4 years, and 9 years.
Recovery from the 1st episode took 8
months. Recovery from subsequent episodes took 2 months, 6 weeks, and 11 days
respectively. After the 1st episode CSF
analysis and EEG were normal. The CT
scar~ showed right hemispheric edema and
midline shift to the left with right lateral
ventricle compression (Fig 1). CT scan was
repeated after the 2nd episode and showed
a similar picture. Magnetic resonance imaging done a month later was normal. His
developmental milestones were apparently
normal upto the first episode at 11 months
of age. However, an IQ at the age of 41,4

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S.K. SINGH ET AL

Vol. 66, No. 4,1999

diagnosed for MELAS syndrome. He was
treated with intravenous fluid and phenobarbitone for convulsions. The recovery
was complete on d a y seven after admission.
DISCUSSION

Fig. 1. C.T. scan head showing right hemispheric edema and midline shift to left
with right lateral ventricle compression.
years was 45. He needed help from his parents for toilet activities and for dressing.
His speech consisted of monosyllables. His
hearing was not impaired.
On admission this time he had p o w e r of
grade 1 / 5 in right u p p e r and lower limbs
with exaggerated reflexes and an extensor
plantar. On the d a y after admission he developed right focal seizure without loss of
consciousness. His anthropometry showed
height just b e l o w the 5th centile and
weight just above the 5th centile. His head
size was normal. His grandmother, mother
and two siblings were noted to have short
stature with height below 5th centile. There
was no evidence of a similar affection in
any other family member.
His blood count, serum electrolyte sodium, p o t a s s i u m and calcium and cerebrospinal fluid examination were unremarkable. EEG, CT scan and MRI of the cranium
were normal. His plasma lactate and CSF
lactate were 116 m g / d l . (normal 3-12 rag/
dl) and 33.90 m g / d l (normal range 10.80 to
18.98 m g / d l ) respectively. Muscle b i o p s y
s h o w e d ragged red fibres consistent with
respiratory chain e n z y m e defect. He was

MELAS was first described by Pavlakis
S.G. et al in 19841. Lactic acidosis and ragged red fibres associated with stroke constitute the cardinal features of the syndrome. Lactic acidosis and ragged red fibres associated with intractable myoclonic
seizure and cerebellar signs occur with
(myoclonic epilepsy and ragged red fibres)
MERRF. In the Kearns-Sayre syndrome the
association is with ophthalmoplegia and
retinal pigmentary changes with one of the
following - heart block, raised CSF protein
or cerebellar signs 1.7.8. Our patient had all
the characteristic clinical features MELAS
of syndrome. He had no retinal pigment
changes, normal CSF and EEG and no cerebellar signs. His first episode occurred in
infancy. In most cases reported in infancy,
failure to thrive, developmental delay and
hypotonia is followed b y stroke like eposides 3. Our case was normal till the first episode of hemiparesis.
There are other supportive diagnostic
findings in MELAS. CT scan shows basal
ganglia calcification or lucent areas and infarction in cerebral and cerebellar hemispheres 1,2,9,~~ MRI at onset of symptoms
and even later has revealed migrated T2
weighted hyperintensities in temporal, parietal and occipital cortices followed by atrophy 9.11. MRI spectroscopy revealed increased lactate in both temporal and occipital lobe n. In MELAS syndrome EEG abnormalities such as focal, unilateral or diffuse slowing without paroxysmal discharg-

Vol. 66, No. 4, 1999

MELAS SYNDROME

es have been recorded 1. A typical EEG pattern consisting of increase in slow activity
and a decrease in alpha frequency and epileptiform discharge has been reported 12.
PET studies in patients with MELAS have
demonstrated a m a r k e d decrease in cerebral metabolic ratio of oxygen (CMRO2)
with relatively preserved cerebral blood
flow and cerebral metabolic ratio of glucose supporting a disturbance of mitochondrial oxidative metabolism in the brain 13.
Xenon 13 planar regional cerebral blood
flow has shown diffuse hyperperfusion of
all cerebral regions. This h y p e r p e r f u s i o n
persisted even one m o n t h later. Cerebral
hyperperfusion is thought to represent a
sort of adaptation to the altered mitochondrial function leading to impaired intracellular utilization and mefabolism 14. In our
patient CT scan initially showed right hemispheric edema but basal ganglia calcification was not noted. EEG and MRI were
normal. PET study was not done.
Histopathology of brain under light microscopy m a y show a diffuse fibrillary gliosis with a b u n d a n t reactive gemistocytes,
focal evidence of ischemic neuronal injury
and e d e m a is. Muscle biopsy u n d e r light
microscopy usually shows ragged red fibres and increase in fat droplets. Electron
microscopy shows increase mitochondria
and atypical mitochondria in the subsarcolemal region, some with inclusion bodies 1~ This syndrome was found to be associated with respiratory chain disorder, particularly complex I (NAD, CoQ reductase) ~,I6. Multiple defects of respiratory
chain e n z y m e s including complex I+III,
II+III and complex IV were described in
m a n y cases of MELAS s y n d r o m e ~6. It is
conceivable that single defect in any one of
the several e n z y m e s of the respiratory
chain could p r o d u c e the same resultant

623

syndrome 2. Valproate therapy may precipitate an acute episode by further suppressing complex IV activity which occurs in
50% of MELAS patients 1~
Electron microscopy of blood vessels often shows increased numbers of abnormal
mitochondria within vascular smooth muscle and in endothelial cells. It is hypothesised that the stroke like episodes in
MELAS may be due to impaired autoregula~ion secondary to the impaired metabolic
activity of mitochondria in the endothelial
and smooth muscle cells of blood vesselslL
MRI changes cannot be explained on the
basis of vascular territory and involvement
of small arterioles and capillaries m a y be
considered as one of the explanations ~.
Pancreatic dysfunction in form of acute
and chronic pancreatitis, peripheral neuropathy and kidney damages is reported in
MELAS syndrome 3,11,17.
MELAS appears to be transmitted genetically and in most cases it is related to
mitochondrial inheritance from mother to
child 2. More than 80% cases show presence
of A to G point mutation at nucleotide pair
3243 in the mitochondrial DNA (mtDNA)
tRNAL,u (u~)and rarely at 32713,~7,~8. The proportion of mt-DNA n e e d e d to cause disease in muscle is usually b e t w e e n 50-96%
in MELAS cases*. The percentage of mutant mitochondrial g e n o m e s in muscle is
higher in patients as compared to relatives
and it is higher in symptomatic relatives as
compared to asymptomatic ones 2~ Pathogenesis of MELAS syndrome is not known.
It is postulated that secondary somatic mtDNA mutations can be initiated by 3243 AG mutation and accumulation of somatic
mutations in individuals with deleterious
mitochondrial genotype can contribute to
progressive mitochondrial dysfunction in
MELAS2L The course of MELAS is varia-

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S.K. S'INGH ET AL

ble. In c e r t a i n series cases w e r e a s y m p t o matic in b e t w e e n strokes. As m o r e patients
with M E L A S are s t u d i e d for a longer perio d of time, s t e p w i s e course, as o p p o s e d to
a g r a d u a l or p r o g r e s s i v e course, m a y bec o m e m o r e a p p a r e n t ~. O u r p a t i e n t h a d
five d i s c r e t e e p i s o d e s of h e m i p a r e s i s b u t
the t i m e t a k e n for r e c o v e r y p r o g r e s s i v e l y
got lesser with each episode.
Various t r e a t m e n t s i n c l u d i n g h i g h carb o h y d r a t e diet, c a m i t i n e , high dose of thiamine, Vit C, s t e r o i d s a n d Vit K h a v e b e e n
t r i e d w i t h little or n o success. C r e a t i n i n e
was tried in o n e child, w i t h b e n e f i c i a l effect. This effect s e e m s to b e d u e to b o t h a
h i g h e r initial c r e a t i n i n e p h o s p h a t e availability a n d a n i n c r e a s e d rate of resynthesis
d u r i n g r e c o v e r y p e r i o d 16. C O Q a n d indeb e n o n e h a s lead to i m p r o v e m e n t in
M E L A S cases 13,22. N i c o t i n a m i d e t r e a t m e n t
lead to d e c r e a s e in l a c t a t e a n d p y r u v a t e
concentration, h e n c e d e c r e a s e in lesion volu m e in MRI within first m o n t h 23.
Children with recurrent stroke who
have delayed milestones but normal early
d e v e l o p m e n t m u s t b e i n v e s t i g a t e d for
M E L A S . C l i n i c a l f e a t u r e s , lactic a c i d e m i a
and presence of r a g g e d red fibres in muscle
c o n f i r m diagnosis. CT scan, MRI findings
m a y help in diagnosis.
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