Acta Neuropathol (1999) 97 : 520–524

© Springer-Verlag 1999

C A S E R E P O RT

K. Tsuchiya · H. Miyazaki · H. Akabane · M. Yamamoto ·
H. Kondo · H. Mizusawa · K. Ikeda

MELAS with prominent white matter gliosis and atrophy
of the cerebellar granular layer:
a clinical, genetic, and pathological study
Received: 28 July 1998 / Revised, accepted: 27 October 1998

Abstract This report concerns an autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes (MELAS) with unusual neuropathological findings. The patient was a Japanese woman who
was 21 years old at the time of death. Her mother is a patient with genetically confirmed MELAS. Her clinical
manifestations included convulsions and lactic acidosis in
the latter half of the first decade of life, followed by deafness, dementia, muscle weakness in the lower extremities,
slight ataxia in the upper and lower extremities, and diabetes mellitus. Muscle biopsy revealed ragged-red fibers,
and genetic study showed a point mutation at nucleotide
pair 3243 in mitochondrial DNA. She died of lactic acidosis. In the clinical course, she did not develop strokelike episodes. The neuropathological examination revealed
not only minute to small necrotic foci in the cerebral cortex, amygdala, hippocampus, and cerebellum, but also
prominent white matter gliosis in the central nervous system and cerebellar cortical degeneration of granular cell
type. Our neuropathological findings, including prominent white matter gliosis of the central nervous system
and cerebellar cortical degeneration of granular cell type,

K. Tsuchiya (쾷)
Department of Laboratory Medicine and Pathology,
Tokyo Metropolitan Matsuzawa Hospital, 2-1-1 Kamikitazawa,
Setagaya-ku, Tokyo, 156-0057, Japan
Tel.: +81-3-3303-7211, Fax: +81-3-3304-5109
K. Tsuchiya · H. Kondo · K. Ikeda
Department of Neuropathology, Tokyo Institute of Psychiatry,
Tokyo, Japan
H. Miyazaki
Department of Internal Medicine, Yokosuka Kyosai Hospital,
Kanagawa, Japan
H. Akabane
Department of Pathology, Yokosuka Kyosai Hospital,
Kanagawa, Japan
M. Yamamoto · H. Mizusawa
Department of Neurology, Tokyo Medical and Dental University,
Tokyo, Japan

may indicate morphologically widespread cellular dysfunction, not restricted to either neuronal or vascular derangement, in the brain pathology of MELAS.
Key words Atrophy of cerebellar granular layer ·
MELAS · Neuropathology · White matter gliosis

Introduction
Mitochondrial myopathy, encephalopathy, lactic acidosis
and stroke-like episodes (MELAS) was first proposed by
Pavlakis et al. [22]. They believed that MELAS represented a distinctive clinical syndrome and that it could be
differentiated from two other clinical disorders that were
also associated with mitochondrial myopathy and cerebral
disease: Kearns-Sayre syndrome and myoclonus epilepsy
with ragged-red fiber syndrome (MERRF) [4]. Recently,
analysis of mitochondrial DNA (mtDNA) has proven that
the point mutation at nucleotide pair 3243 is responsible
for about 80% of MELAS cases [6, 7]. Neuropathological
findings reported in patients with MELAS generally include necrotic lesions in the cerebral cortex without correlation to vascular supply, calcification in the basal ganglia, and peculiar vascular changes called “mitochondrial
angiopathy”. Prominent white matter gliosis in the central
nervous system and cerebellar cortical degeneration of
granular cell type have not been previously noted in the
neuropathology of MELAS.
We report here unusual neuropathological findings in a
patient with MELAS who did not develop stroke-like
episodes in the total clinical course.

Case report
The patient was a Japanese woman who was 21 years old at the
time of death. Her mother is a patient with genetically confirmed
MELAS. Her mother developed deafness at age 26, followed by
convulsion at age 55. Genetic analysis of her mother revealed a
point mutation at nucleotide pair 3243 in mtDNA. Her mother is

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now alive at the age of 56. The patient presented with convulsions
and lactic acidosis in the latter half of the first decade of life. She
also developed deafness and dementia in the first half of the second decade of life. At age 19, she began to exhibit dysphagia and
had difficulty with pronunciation. A neurological examination at
the age of 20 showed severe dementia, deafness, muscle weakness
and hyperreflexia in the lower extremities, and slight ataxia of the
upper and lower extremities. The electroencephalogram revealed
spikes and slow waves. Computerized tomography (CT) of the
brain showed brain atrophy and calcification of the bilateral basal
ganglia. Muscle biopsy revealed ragged-red fibers. We also detected a mtDNA point mutation at nucleotide pair 3243 causing an
A to G transition, which is a common mutation in MELAS in various tissues including the muscles and white blood cells. This mutation was heteroplasmic in all examined tissues. At age 21, she
fell into diabetic coma. Her diabetes mellitus was controlled by insulin therapy. At this time, her height was 137 cm, with a body
weight of 30 kg. She died of lactic acidosis at the age of 21. In the
total clinical course she did not develop stroke-like episodes. The
total duration of her disease was 13 years. The main pathological
findings outside the central nervous system were degeneration
with fibrosis of the skeletal muscles and a decreased number of the
islets of Langerhans with fibriosis in the pancreas.

Neuropathological findings
The weight of the brain before fixation was 830 g. Only the right
side of the brain was available for neuropathological examination.
A macroscopic examination revealed not only atrophy of the
frontal and temporal lobes, but also scattered small necrotic foci in
the cerebral cortex (Fig. 1A, B). The cerebellum showed slight atrophy, prominently in the dorsal part of the vermis. A histological
examination revealed minute to small, recent and old, necrotic foci
with relative preservation of the neurons and proliferation of the
capillaries in the cerebral cortex, amygdala, hippocampus, and
cerebellar cortex. Necrotic foci of the cerebral cortex were more
pronounced in the posterior portion of the cerebrum than in the anterior portion. Necrotic foci of the cerebral cortex were not corre-

Fig. 1 A–D Prominent white
matter gliosis. A, B Right cerebrum through the anterior part
of the striatum showing relative preservation of the myelin,
with the exception of a
necrotic focus (arrow), and
prominent fibrillary gliosis.
C–H Right cingulate gyrus
through the anterior part of the
striatum. C Relative preservation of the myelin. D, E Prominent gliosis in the cingulate
gyrus (D), particularly in the
white matter (E). F–H Immunocytochemistry using antibodies against GFAP. Positive
immunoreactivity for GFAP in
the cingulate gyrus (F), particularly in the white matter (G,
H) (GFAP glial fibrillary acidic
protein) A, C Klüver-Barrerra
stain; B, D, E Holzer stain. A,
B × 1.1, C, D, F × 7.8,
E, H × 360, G × 48

lated to the vascular supply of the cerebrum. In the cerebral white
matter, fibrillary gliosis was evident in spite of the absence of
myelin loss (prominent white matter gliosis) (Fig. 1). Immunocytochemistry using antibodies against glial fibrillary acid protein
(GFAP) also showed prominent gliosis, prominently in the cerebral white matter (Fig. 1). Slight astrocytosis without neuronal loss
was evident in the caudate nucleus, putamen, pallidum, thalamus,
subthalamic nucleus, red nucleus, substantia nigra, locus coruleus,
oculomotor nuclei, trochlear nuclei and hypoglossal nuclei. There
was pseudocalcification and a minute infarct in the globus pallidus. There was cerebellar cortical degeneration of granular cell
type in the cerebellar cortex, which was more apparent in the vermis than in the hemisphere. Cerebellar cortical degeneration of
granular cell type with prominent cactus-like expansions and stellate bodies in the dendrites of Purkinje cells was more pronounced
in the crest than in the depth of the cerebellar folia (Fig. 2). The
dentate nucleus showed slight neuronal loss, proliferation of the
glia, and pseudocalcification. There was degeneration of the pyramidal tracts, which was more obvious in the medulla oblongata
than in the midbrain.

Discussion
We think that our case belongs to the category of MELAS
because the case showed not only the typical clinical manifestations of MELAS, except the absence of stroke-like
episodes, but also genetical evidence compatible with
MELAS.
The outstanding clinical feature of our patient was the
absence of stroke-like episodes. Pavlakis et al. [22], who
proposed MELAS as a distinctive clinical syndrome, reported that stroke-like episodes, including cortical blindness, hemiparesis, and hemianopsia, were evident in 10 of
11 patients. Goto et al. [7], who studied 40 MELAS patients to characterize the clinical features, as well as the

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biochemical and muscle biopsy findings relating to the
mtDNA mutation at nucleotide pair 3243, reported that
stroke-like episodes including episodic headaches with
vomiting, unconsciousness and convulsions were present
in more than 80% of MELAS cases, regardless of the
presence or absence of the point mutation at nucleotide
pair 3243. Hirano and Pavlakis [10], who reviewed
110 patients with MELAS to define the clinical spectrum
of this disease, reported that stroke-like episodes were evident in 99% of the patients. Recently, Kaido et al. [12] reported an unusual autopsy case of MELAS with a point
mutation at nucleotide pair 3243 in mtDNA, with no clin-

ical evidence of stroke-like episodes during the last 10 years
of the patient’s life.
From the literature concerning the clinical features of
MELAS, it is apparent that absence of stroke-like
episodes in MELAS is very rare. In this regard, our case is
noteworthy.
The pronounced neuropathological features of our patient were prominent white matter gliosis in the central
nervous system and cerebellar cortical degeneration of
granular cell type. Neuropathological findings which have
been reported so far in patients with MELAS are multiple
infarct-like lesions without correlation to vascular supply,

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Fig. 2 A–C Cerebellar cortical degeneration of
granule cell type. A Vermis of the right cerebellum
showing prominent rarefaction of granule cells in
the crest of the folia. H&E stain. B Cerebellar cortex showing relative preservation of Purkinje cells.
Klüver-Barrera stain. C Cactus-like expansion in the
molecular layer of the cerebellar cortex. Bodian
stain. A × 6.8, B × 68, C × 170

predominantly in the posterior cerebral cortex, calcification in the basal ganglia, and peculiar vascular changes
called “mitochondrial angiopathy” [1, 9, 18, 21]. According to Pavlakis et al. [22], who reviewed three previously
reported autopsy cases of MELAS, the fundamental neuropathological findings of MELAS were microcystic liquefaction or focal softening of the cerebral cortex and calcification in the basal ganglia. Neuropathological findings
in our case, which showed necrotic foci in the cerebral
cortex and pseudocalcification in the pallidum, fundamentally agree with the findings of Pavlakis et al. [22].
Prominent white matter gliosis, which is also termed
dissociation glio-myelinique, is a neuropathological entity: hyperactivity of the glia and/or degree of fibrillary
gliosis is more prominent than the degree of myelin loss.
Prominent white matter gliosis has been observed in various neurological diseases including subacute sclerosing
panencephalitis [26], Nasu-Hakola’s disease [14], a special form of senile dementia of Alzheimer’s type [17], and
progressive subcortical gliosis [19]. Mizukami et al. [16],
who described an autopsy case of MELAS, noted diffuse

moderately fibrillary gliosis in the cerebral and cerebellar
white matter. They speculated that widespread gliosis
might be due to metabolic disturbance including lactic
acidosis. The pathogenesis of prominent white matter
gliosis is not apparent, but the prominent white matter
gliosis observed in our case suggests an abnormality of
the glia in the brain pathology of MELAS.
Cerebellar cortical degeneration of granular cell type
has been observed in a variety of neurological disorders
including familial cerebellar degeneration [20], a sporadic
case of cerebellar hypoplasia [23], cerebral lipidosis [3],
organic mercury poisoning [11, 24], an ataxic form of
Creutzfeldt-Jakob disease [2, 25], and Menkes’ kinky hair
disease [15].
From the literature on the neuropathology of MELAS,
it is apparent that there have been no descriptions of cerebellar cortical degeneration of granular cell type as seen in
our case. In this regard, the autopsy case described by
Hart et al. [9] is of interest, as their study revealed that
profound neuronal alterations were present in the granular
layer of the cerebellum. They did not, however, notice

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cactus-like expansions in the dendrites of Purkinje cells.
Kishi et al. [13] reported a Japanese autopsy case of
MELAS, in which neuropathological findings revealed
severe loss of granule cells in almost all areas of the cerebellar cortex. However, they did not describe whether
cactus-like expansions in the dendrites of Purkinje cells
were present.
Various theories exist regarding the etiology of strokelike episodes in MELAS. One of the two most common
theories is that the cells become metabolically unstable
and cease to function normally, with subsequent failure of
energy production. This theory has been supported by
cerebral blood flow studies [8]. The other theory is that
blood vessels are involved, with resultant malfunction and
downstream ischemia. Evidence for this includes reported
abnormalities of cerebral pial arterioles and small arteries
[21]. Recently, Gilchrist et al. [5] reported a brain biopsy
done in a case of genetically confirmed MELAS, which
showed that 82% of the brain mitochondria carried the
disease mutation. They concluded that MELAS represents
widespread cellular dysfunction, not restricted to either
neuronal or vascular derangement. Our pathological findings, including prominent white matter gliosis of the central nervous system and cerebellar cortical degeneration
of granular cell type, provide morphological support for
the conclusions of Gilchrist et al. [5].

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