Ar

Neuropatholog:ca

Acta Neuropathol (Berl) (1987)74:287 - 293

9 Springer-Verlag1987

Mitochondrial encephalomyopathy*
A variant with heart failure and liver steatosis
A. Oldfors 1, M. Tulinius 2, E. Holme a, H. Kalimo 1, B. Kristiansson 2, and B.O. Eriksson 2
Division of Neuropathology, Department of Pathology I, Gothenburg University, Sahlgren Hospital, S-413 45 Gothenburg, Sweden
: Departments of Pediatrics I and II, Gothenburg University, East Hospital, S-416 85 Gothenburg, Sweden
3 Department of Clinical Chemistry, Gothenburg University, Sahlgren Hospital, S-413 45 Gothenburg, Sweden

Summary. We report the clinical and autopsy findings
in a young man o f 18 with a chronic progressive disorder comprised of lactic acidosis, mental deterioration, and epileptic seizures which were sometimes accompanied by stroke-like episodes with transient
hemiparesis and cortical blindness. He died of congestive heart failure. The autopsy showed lesions of
the gray matter of the brain. Both the putamen and
parieto-occipital cortex showed loss o f neurons and
proliferation of macrophages, astrocytes and vessels.
There was marked loss of neurons in the inferior
olives, and slight reduction of the number of Purkinje
cells. Skeletal muscle studies revealed ragged-red
fibers and structurally abnormal mitochondria. The
heart was enlarged: accumulations of mitochondria
occurred in the muscle fibers. The liver exhibited
marked fatty degeneration. Biochemical analyses
showed normal activities of pyruvate dehydrogenase
in thrombocytes, pyruvate carboxylase in lymphocytes, biotinidase in serum as well as succinate dehydrogenase and cytochrome c oxidase. The features of
this disorder differ in many respects from cases of
mitochondrial encephalomyopathy previously reported and cannot be assigned to any specific disease
entity.
Key words: Mitochondrial encephalomyopathy Lactic acidosis - Stroke-like episodes

Mitochondrial encephalomyopathies constitute a hererogenous group o f disorders [12, 31, 44]. Elevated
levels o f lactic acid in the blood is a c o m m o n sign of
disturbed mitochondrial function in these disorders.
* Supported by grants from the First of May Flower Annual
Campaign for Childrens Health and the Swedish Medical Research Council (proj no 07122)
Offprint requests to: A. Oldfors (address see above)

Because of difficulties in defining the underlying biochemical defects, attempts have been made to classify
these diseases into different groups according to their
clinical and morphological expression. These groups
include the Kearns-Sayre syndl}ome [23, 34, 41], which
usually does not include lactic acidosis, myoclonus
epilepsy and ragged red fibers ( M E R R F ) [13], and
mitochondrial myopathy, encephalopathy, lactic
acidosis and stroke-like episodes (MELAS) [35]. In
addition several cases which cannot be classified into
these groups have been reported (cf. [35]). We report
the clinical and autopsy findings of a case with
clinical and morphological features consistent with
mitochondrial encephalomyopathy, which does not fit
completely into any of these entities demonstrating
the heterogenety of this group of diseases as well as
the difficulty in their classification.

Case report
Clinical data

The patient was the second son of healthy non-consanguineous
parents: his older brother is healthy. On the mother's side, some
antecedents have a hereditary hand tremor, which has not been
associated with a shortened life-span. On the father's side, a
second cousin had a severe form of epilepsy and 30 years ago,
while in a fit, she died at the age of 22.
Pregnancy and delivery were both uneventful. The birth
weight was 3,400 g. The early psychomotor development was
normal: he was able to walk at 12 months, although he was
somewhat clumsy and had a tendency of stumble. Aged 6 years,
he was admitted to hospital because of transient coordination
difficulties following an upper respiratory tract infection. Aged
10 years, he showed learning difficulties and mild ataxia and
aged 11 his electrocardiogram (ECG) displayed pre-excitation.
At the age of 14, he had an episode of grand real seizures. The
electroencephalogram (EEG) showed fronto-temporal paroxysomal abnormalities. X ray of the cranium and echoencephalography were normal. During the following years his
learning difficulties increased because of mental deterioration
and his ataxia became more prominent. His height at 17 years
was 174 cm: his growth throughout puberty was unaffected.

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A. Oldfors et al. : Mitochondrial encephalomyopathy

During the terminal 8 months of life, the disease became more
rapidly progressive. He had recurrent periods beginning with
headache, photophobia, vomiting and somnolence and ending
with generalized grand real seizures. After each attack, he
became more disabled with increasing dysarthria, tiredness and
clumsiness~ During two of his terminal attacks he had episodes
of left-sided hemiparesis and cortical blindness. Three months
before death he had severe cerebellar ataxia, dysarthria, bilateral
peroneal foot drop, decreased tendon reflexes and hypotonicity.
The echo-cardiogram showed a dilated, poorly contracting left
ventricle, while there was no dilatation of the left atrium. The
wall of the left ventricle was normal in thickness. Ophthalmological examination revealed macular changes with signs of
atrophy of the optic nerve but visual acuity was normal. He had
no ptosis but signs of discrete ophthalmoplegia with decreased
range of horizontal and upward movements of both eyes. Computerized tomography of the brain showed lucencies in the left
putamen and right parieto-occipital cortex. No signs of neurosensory hearing loss could be established. During his final
months, he developed signs of congestive heart failure.
Treatment with large doses of B-vitamins was not effective.
Because of increasing lactic acidosis ( 9 - 1 0 mmol/1) dichloroacetate was tried [49]. This reduced the levels of lactic acid to
normal but there was only temporary clinical improvement.
Aged 18 years he died of untreatable left heart failure with
pulmonary oedema.

Biochemistry
A biochemical investigation was started about 4 months before
the patient's death. Serum-transaminase activities were at the
upper reference limit, creatine kinase activity was 6.7 gkat/1
(reference interval < 3.3 lakat/1)and lactate dehydrogenase activity was 17 ~tkat/1 (reference interval < 8.0 ~tkat/1). All other
routine laboratory tests were normal. Serum-lactate concentrations were constantly elevated (4.2-9.6 mmol/1) with a lactate
to pyruvate ratio around 20. Lactate in the cerebrospinaI fluid
was also increased (2.9-3.2 mmol/1), as was the excretion of
lactate in the urine (50-360 mmot/mol creatinine). Plasmaalanine concentrations were at the upper reference limit or
slightly increased. Other plasma-amino acid abnormalities were
not found. Except for increased lactate excretion, the urinary
organic acids, determined by gas chromatography - mass
spectrometry, were essentially normal. Pyruvate dehydrogenase
deficiency was excluded by analysis of this enzyme in the
thrombocytes according to Blass et al. [4]. Pyruvate carboxylase
activity in the lymphocytes analyzed as described by Atkin et al.
[2] was normal. Serum biotinidase activity determined by the
method of Knappe et al. [24] was also normal.
Biochemical analysis of a muscle biopsy obtained 2 months
before death showed normal tevels of carnitine by the method
described by Cederblad and Lindstedt [9] and normal levels
of the mitochondrial enzymes, succinate dehydrogenase and
cytochrome c oxidase, which were determined by the methods
described by Karlsson [22].

Morphology
An autopsy was performed 2 days after death. The heart weighed
440 g: it was dilated. The coronary arteries were normal: focal
lesions were not found in the myocardium. Little evidence of
atheroma was seen in the large vessels. The lungs were markedly
congested and contained an abundance of clear oedematous
fluid. The digestive tract did not present naked eye changes. The
liver weighed 3,030 g: its cut surface was yellow and greasy.
The spleen, lymph nodes, adrenal and thyroid glands appeared
normal. The kidneys and urinary tracts were normal. The brain

Fig. 1. Vertical section of the brain showing a lesion in the left
putamen (arrow)
weighed 1,280 g. No abnormalitieswere observed on the external
surface. Corona1 sections of the brain disclosed about 10-ramwide softenings in the outer part of the left putamen (Fig. 1) and
deep cortical layers of the right parieto-occipital region. The
ventricles were not dilated. Focal lesions were not seen in the
brain stem, cerebellurn or spinal cord.
Specimens from the various organs were fixed in a 4% solution of paraformaldehyde and embedded in paraffin for light
microscopical examination. Additional specimens from the
central nervous system (CNS), femoral nerve, heart, liver and
skeletal muscle were fixed in 2.5% glutaraldehyde in 0.1 M
sodium phosphate buffer and embedded in Epon 812 for electron
microscopy. Specimens from the deltoid and quadriceps muscles
were frozen in isopentane in liquid nitrogen for histochemical
studies.
A muscle biopsy from the quadriceps muscle obtained
2 months before death was examined histochemically and ultrastructurally. Pathological changes were found in the CNS, skeletal muscles, femoral nerve, liver, myocardium and lungs,

CNS. The lesions of the left putamen and the right parietooccipital cortex showed almost complete loss of nerve cells,
proliferation of macrophages and astrocytes, and also of
capillaries (Fig. 2). At the edge of the lesions occasional viable
neurons were observed between proliferating capillaries. The
lesions were indistinguishable from infarcts but no occluded
vessels or atheromatous lesions were observed. Elsewhere in the
cerebral cortex no obvious lessions were seen. Sommer's sector
and Ammon's horn did not present any histological abnormality.
The thalamus, caudate nucleus, mamillary bodies, mid brain,
pons and the optic nerves showed no light microscopical

A. Oldfors et al.: Mitochondrial encephalomyopathy

289

Fig. 3. Section of the inferior olive showing marked loss of nerve
cells. Luxol, x 32

Fig. 2. Section through part of the lesion of the right parietooccipital cortex. Note loss of nerve cells, gliosis and capillary
proliferation in the lower part of the picture. PAS, x 120
changes. The inferior olives showed marked loss of nerve cells
(Fig. 3). The nerve cells of the Purkinje cell layer and the dentate
nuclei were slightly reduced in number and the astrocytes were
increased in number. Electron microscopy of remainingPurkinje
cells revealed an abundance of mitochondria showing autolytic
changes but no unequivocal pathological change. The neurons
of the spinal cord did not show any degenerative changes,
although the number of motorneurons appeared to be reduced.
The ascending and descending tracts of the spinal cord appeared
normal.

Skeletal muscle. The muscle biopsy showed some variability of
fiber size and numerous "ragged-red" fibers, containing material
which stained intensely by the modified Gomori trichrome stain
and after incubation for succinate dehydrogenase (SDH)
(Fig. 4). Electron microscopy revealed many muscle fibers containing collections of abnormal mitochondria: many of these
presented paracrystalline inclusions (Fig. 5). Involvement of
lower motor neurons was evidenced by the occurrence of type
grouping of the muscle fibers (Fig. 6).
Peripheral nerve. Cross sections of the femoral nerve embedded
in resin were examined by light and electron microscopy. They
showed loss of large myelinated axons but evidence of actual
axonal degeneration was not seen.
Liver. The macroscopic appearance of severe steatosis of the
liver was verified by light microscopy (Fig. 7). Convincing
mitochondrial changes were not observed by electron microscopy.

Fig. 4. Cross section of the deltoid muscle after incubation for
succinic dehydrogenase (SDH). Note fiber size variation and
accumulation of positively stained material in several muscle
fibers (arrows). • 150

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A. Oldfors et al.: Mitochondrial encephalomyopathy

Fig. 7. Paraffin section of the liver showing severe vacuolation
of the parenchymal cells due to extraction of lipids. Van Gieson,
• 120
Fig. 5. Electron micrograph of abnormal skeletal muscle mitochondria. Some are enlarged with abnormal arrangements of
the cristae (large arrow) others contain paracrystalline inclusions
(small arrow). • 20,000

Fig. 8. Electron micrograph of the myocardium. The myofibrils
are separated by large collections ofmitochondria (M). x 10,000

Fig. 6. Cross section of the quadrieeps muscle incubated for
myofibrillar ATPase after pre-incubation at pH 4.3. Note grouping of type 1 (dark) and type 2 (unstained) muscle fibers. • 120

Myocardium. Paraffin sections of the myocardium appeared
normal. However, by electron microscopy, it was evident that
the muscle fibers presented increased numbers of enlarged
mitoehondria, which in addition to autolytic changes exhibited
irregularities of the eristae (Fig. 8).

A. Oldfors et al.: Mitochondrial encephalomyopathy
Lungs. The inter-alveolar capillaries were distended with red
blood cells and oedematous fluid filled the alveoli: there was no
leucocyticreaction in the lungs.

Discussion

In many patients with encephalomyopathy, a primary
defect of the mitochondria has been suspected on the
basis of lactic acidosis and morphological abnormalities of the mitochondria, although the biochemical
defect has not been established [46]. Since the
mitochondrial encephalomyopathies constitute a heterogenous group of disorders with regard to the
clinical and pathological findings, attempts have been
made to find common factors which would help to
make a provisional diagnosis until the metabolic defect is discovered. From case reports of mitochondrial
encephalomyopathies three syndromes, which all
show ragged red fibers, have emerged: Kearns-Sayre,
MELAS and M E R R F syndromes.
The Kearns-Sayre syndrome is defined by Rowland et al. [41] as a disorder in which mitochondrial
myopathy, ophthalmoplegia, atypical pigmentary degeneration of the retina and onset of illness before the
age of 20 are constant findings. In addition to these
features, heart block, increased levels of CSF protein,
growth failure, cerebellar ataxia and various other
signs of CNS involvement are most often found. Most
cases are sporadic. Cases examined post mortem have
shown spongy degeneration of the gray and white
matter of the CNS [7, 8, 10, 50]. Lactic acidosis and
liver steatosis do not occur in the Kearns-Sayre
syndrome.
M E R R F (myoclonus epilepsy and ragged red
fibers) is a syndrome whose features are mitochondrial
myopathy, myoclonic seizures and cerebellar ataxia
[14, 15]. However, other signs of involvement of the
nervous system are often encountered and include
dementia, optic atrophy, neuronal hearing loss and
involvement of the peripheral nerves with sensory loss.
Most of the patients are short of stature. They show
increased levels of blood lactate. Stroke-like episodes
were later added to the picture of M E R R F [14], which
brings this syndrome very close to MELAS. Ophthalmoplegia, pigmentary retinal degeneration and heart
block are not encountered in the M E R R F syndrome.
Maternal inheritance was reported by Rosing et al.
[40]. Few cases have been examined post mortem.
They presented diffuse spongy degeneration and
neuronal loss of the cerebral cortex, neuronal loss in
the dentate, gracile and cuneate nuclei and degeneration of the posterior white columns of the spinal cord
I13]. Changes of the liver have not been reported.
MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) is a

291
syndrome which was described by Pavlakis et al. [35]
and DiMauro et al. [12]. The cardinal features are
mitochondrial myopathy, seizures, stroke-like episodes and short stature. In addition dementia is often
seen. Ophthalmoplegia, pigmentary degeneration of
the retina, ataxia, myoclonus, and heart block are not
features of the MELAS syndrome. Only four reports
are available on the CNS changes in patients who have
been considered to have the MELAS syndrome. Post
mortem examinations have revealed focal zones of
cortical neuronal loss, gliosis and vascular proliferation in two siblings [46]. The case of Hart [16] showed
diffuse cortical neuronal loss and spongy degeneration and is consistent with progressive cerebral
poliodystrophy. Mukoyama et al. [32] reported the
autopsy findings of a case of MELAS with myoclonus.
The neuropathology revealed multiple both solitary
and continous lesions of softenings and spongy
alterations in the cerebral cortex. The distribution of
the lesions did not correspond to a vascular pattern.
In addition localized softenings of the thalamus and
basal ganglia were reported.
The case presented in this report cannot be included in any of the syndromes which are described
above, although the case shows similarities with each
of them. Lack of retinal pigmentary degeneration,
heart block and short stature excludes the KearnsSayre syndrome. Lack of myoclonic epilepsy excludes
the M E R R F syndrome. The presence of ataxia and
lack of short stature make it different from the
MELAS syndrome, although many other features
were common to MELAS and the case we describe.
MELAS is, according to the original article by
Plaitakis [38], a syndrome based on clinical findings
and pathological changes in the muscle. The few reports on the neuropathology of the MELAS syndrome
has not supported the view that it is accompanied by
consistent structural changes in the brain. The cases
of Shapira et al. [46] revealed focal cortical areas with
loss of neurons, microcyst formation, gliosis and
vascular proliferation, while other areas of the cortex
were normal. It thus showed some resemblance to the
case we describe. In addition to these syndromes, cases
of encephalopathy associated with mitochondrial
myopathy have been described in cases of Leigh's
disease [30], Alpers' disease [39] and the HacketTarlow syndrome [13]. The latter eponym is used in
the literature, to include a heterogenous group of disorders which lack distinctive features. The brain
lesions in our case are not compatible Leigh's disease,
i.e., relative sparing of neurons with necrosis of the
neuropil and proliferation of capillaries with fairly
characteristic topography [21, 26]. Neither was the
local character consistent with Alpers' disease, i.e.,
poliodystrophy with diffuse spongy degeneration of

292
the cortex [1]. On the other hand, the above mentioned
eponymic diseases are not unequivocal entities. F o r
example in Leigh's disease at least four different
deficient enzymes have been reported [37, 45, 47, 49].
The ataxia in our case, which on the basis of post
mortem examination could probably be ascribed to
olivo-cerebellar atrophy, indicates the presence of
systemic degeneration which together with optic
atrophy and ophthalmoplegia bears some resemblance to olivo-ponto-cerebellar atrophy (OPCA) of
the sporadic type [38]. Olivo-cerebellar atrophy and
multiple focal lesions of the gray matter o f the brain
were also described in two brothers with myoclonic
epilepsy [27]. However, they had no lactic acidosis nor
did their muscle biopsies present ragged-red fibers.
The nature o f the cardiomyopathy with congestive
heart failure in this patient has not been determined.
The accumulation ofmitochondria in the myocardium
is an unspecific phenomenon seen in functional
overload and congestive heart failure [3, 29, 36]. N o
mitochondrial abnormalities o f the kind seen in the
patient's skeletal muscle were observed in the myocardium. Marked structural changes in mitochondria
have been described in the myocardium in cases of
mitochondrial cardiomyopathy [18, 33]. Cardiomyopathy has been associated with various forms of
myopathic diseases with mitochondrial abnormalities
[17, 20, 28, 42, 43]. However, none of these previous
descriptions shows much clinical resemblance to the
present case.
Bogousslavsky et al. [5] described a patient who
had lactic acidosis, mitochondrial myopathy, cardiomyopathy and neurodegenerative features including
multiple infarcts of the brain, thus exhibiting several
features in c o m m o n with the case we report, and was
considered to be a variant o f Kearns-Sayre syndrome.
Their patient had short stature, no steatosis of the
liver and no stroke-like episodes: it differed thus in
some respects from our case. Kuriyama et al. [25]
described a case ofmitochondrial encephalomyopathy
with multiple brain infarctions but without cardiomyopathy and liver disease. Biochemical studies indicated a defect in the respiratory chain.
Steatosis of the liver in the present case was not
accompanied by structural changes o f the mitochondria of the liver. It is, however, likely that the
fatty change of the liver is a result of the same biochemical defect that produced the lesions o f the other
organs. Fatty change of the liver has been described
in disorders with biochemically defined defects of the
mitochondria, such as cytochrome c oxidase
deficiency [11, 39]. The case o f Prick et al. [39] had
the neuropathological features o f Alpers' disease and
mitochondrial myopathy. Hepatic disease has also
been described in other cases of Alpers' disease [6,

A. Oldfors et al.: Mitochondrial encephalomyopathy
19]. The case we describe did not, however, show the
features of Alpers' disease and cytochrome c oxidase
deficiency was excluded biochemically.
The case presented in this report represents an
example of encephalopathy and myopathy of probable mitochondrial origin. It differs in several ways
from other cases previously reported and may thus
represent a separate disease entity. It also illustrates
the difficulties in the classification of these diseases,
which has to be based on clinical, pathological and
biochemical findings.

Acknowledgements. The technical assistance of Monica
Jacobsson and the linguistic revision of Dr. William G.P. Mair,
and the advice and suggestions of Prof. Salvatore DiMauro and
Dr. Darryl C. DeVivo, New York, are gratefully acknowledged.

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Received December 29, 1986/Accepted April 17, 1987