Oyama et al. BMC Neurology
(2020) 20:167
https://doi.org/10.1186/s12883-020-01748-7

CASE REPORT

Open Access

Neuroimaging pattern and
pathophysiology of cerebellar stroke-like
lesions in MELAS with m.3243A>G
mutation: a case report
Munenori Oyama1, Takahiro Iizuka2, Jin Nakahara1 and Yoshikane Izawa1*

Abstract
Background: Stroke-like episodes (SLEs) in mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like
episodes (MELAS) with m.3243A > G mutation usually develop in the cerebral cortex. Few reports have documented
SLEs in the cerebellum. The clinical neuroimaging features of cerebellar SLEs have not been fully investigated. We
report distinctive features of cerebellar stroke-like lesions (SLLs) in a case of MELAS with m.3243A > G mutation.
Case presentation: A 47-year-old Japanese man with type-2 diabetes presented to our hospital with acute onset of
aphasia. A brain MRI obtained on admission (day 1) showed increased diffusion-weighted imaging (DWI)/fluidattenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe, which subsequently spread along
the cortex posteriorly accompanied by a new lesion in the right anterior temporal lobe. The patient was initially treated
with acyclovir and subsequently with immunotherapy. However, on day 45, cerebellar ataxia developed. The brain MRI
showed extensive increased DWI/FLAIR signals in the cerebellum along the folia without involvement of deep
cerebellar nucleus or cerebellar peduncle; SLLs were incongruent with a vascular territory, similarly to classic cerebral
SLLs. Apparent diffusion coefficient (ADC) map did not show reduction in ADC values in the affected folia. Genomic
analysis revealed m.3243A > G mutation (heteroplasmy in leukocytes, 17%), confirming the diagnosis of MELAS. After
the treatment with taurine (12,000 mg/day), L-arginine (12,000 mg/day), vitamin B1 (100 mg/day), and carnitine (3000
mg/day), the patient became able to follow simple commands, and he was transferred to a rehabilitation center on
day 146. The follow-up MRI showed diffuse brain atrophy, including the cerebellum.
Conclusions: SLLs develop in the cerebellum in MELAS with m.3243A > G mutation. The neuroimaging similarities to
cerebral SLLs suggest the presence of the common pathophysiological mechanisms underlying both SLEs, which
include microangiopathy and increased susceptibility of the cortex to metabolic derangements.
Keywords: MELAS, Stroke-like episodes, Cerebellum, Angiopathy, MRI

* Correspondence: y-izawa@a3.keio.jp
1
Department of Neurology, Keio University School of Medicine, 35
Shinanomachi, Shinjuku, Tokyo 160-8582, Japan
Full list of author information is available at the end of the article
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Oyama et al. BMC Neurology

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Background
Stroke-like episodes (SLEs) in mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes
(MELAS) are episodic events mimicking ischemic stroke
[1], and a new definition of SLEs as “epileptic encephalopathy” has recently been proposed [2]. Although the
pathogenesis of SLEs remains largely unknown, vascular,
metabolic, and neuronal hyperexcitability hypothesis
have been proposed [3, 4]. Mitochondrial microangiopathy and neuronal vulnerability to increased energy demand are both presumed to play an important role in the
pathogenesis of SLEs [3].
Classic SLEs are usually attributed to a single, continuous lobular edematous lesion that gradually spreads to
adjacent cortex beyond the major vascular territory often
associated with focal epileptic seizure activity [5, 6].
Stroke-like lesions (SLLs) preferentially involve the cerebral cortex requiring high energy demand and usually
spare the basal ganglia. In contrast to classic SLEs, those
attributed to sparse or disseminated SLLs confined to
the cerebral cortex have recently been described as
“non-classic SLEs” [7], suggesting the presence of phenotypical diversity of SLEs associated with m.3243A < G
mutation in the mitochondrial tRNALeu(UUR) gene (MTTL1). Cerebellar SLLs have been regarded as “non-classic SLLs” [7]; however, few studies have documented
cerebellar SLLs [5, 7–10]. Accordingly, the clinical neuroimaging features of cerebellar SLEs have not been fully
investigated.
We herein report a case of MELAS with m.3243A < G
mutation, in which SLLs developed in the cerebellum
during the course of classic cerebral SLEs.
Case presentation
A 47-year-old right-handed Japanese man was admitted
to Keio University Hospital with acute onset of sensory
aphasia.
Fourteen days before his admission the patient began
to have difficulties in operating computers and document processing software. The symptoms worsened over
the next 10 days, without headache, fever, or seizure.
Three days before his admission, at evening, he suddenly
became incoherent and agitated in association with impaired auditory comprehension. He underwent a brain
MRI at another hospital; he was suspected of having a
herpes simplex encephalitis (HSE), and then he was
referred and admitted to the department of neurology at
our hospital for further evaluation and treatment. Prior
to admission he had no hypoglycemic episodes, preceding viral infection, recent medication changes, or other
precipitating events leading to seizure.
He had a past medical history of type-2 diabetes since the
age of 41 years, for which he had been treated with acarbose,
but he had no other history including cardiomyopathy, atrial

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fibrillation, migraine, sensorineural hearing loss, seizures, or
psychiatric illness. His growth and development were normal. His mother suffered from type-1 diabetes and deafness,
which had begun in her 40s, and suddenly died of unknown
cause at the age of 68 years. He had no habit of smoking,
drinking, or the use of illicit drugs.
On admission (day 1), the temperature was 36.6 °C,
the blood pressure 110/65 mmHg, the pulse 84 beat per
minute, and the oxygen saturation 97% while he was
breathing ambient air. The height was 154 cm, and the
weight was 42 kg; the body mass index was 17.7, but
physical examination was otherwise unremarkable. On
neurologic examination the patient was awake but agitated and uncooperative. He was able to speak fluently
but he had paraphasia and preservation; naming, repetition, and auditory and reading comprehension were
severely impaired, implying sensory predominant aphasia. Motor and sensory examination was grossly intact.
The neck was supple.
All results of the blood tests on admission were unremarkable, including serum CK level (71 U/L), except an
elevated level of HbA1c (7.3%). Cerebrospinal fluid
(CSF) examination revealed 1 white blood cell/μL, and a
protein level of 46 mg/dl. Oligoclonal bands were negative. A polymerase chain reaction testing was negative
for herpes simplex virus. CSF levels of pyruvic and lactic
acid were not examined. A brain MRI obtained on admission showed increased diffusion-weighted imaging
(DWI)/fluid-attenuated inversion recovery (FLAIR) signal in the left anterolateral temporal lobe mainly affecting the cerebral cortex with underlying subcortical
edema (Fig. 1, arrows). Apparent diffusion coefficient
(ADC) maps showed mild reduction in ADC values in
the left anterior temporal cortex (Fig. 1, arrowheads)
suggesting cytotoxic edema, but increase in ADC values
in the underlying subcortical white matter suggested
vasogenic edema. A MRA did not show vasospasm or
vascular occlusion. An electroencephalogram (EEG) recorded on day 4 showed sporadic sharp waves at the left
fronto-parietal region.
After admission the patient was empirically treated
with intravenous administration of acyclovir and oral levetiracetam (1000 mg/day) for possible HSE. He underwent a whole-body CT and a random skin biopsy but
the results were both unremarkable. For possible autoimmune encephalitis, he was also treated with intravenous high-dose methylprednisolone (IVMP: 1000 mg/day,
3 days) on day 10; however, the follow-up brain MRIs
obtained on day 7 and day 14 showed a continuous
spread of the lesion posteriorly along the cerebral cortex.
The follow-up EEG recorded on day 27 showed focal
periodic epileptiform discharges (FPEDs) at the left temporal region. The dosage of levetiracetam was increased
to 3000 mg/day. However, the brain MRI obtained on

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Fig. 1 Brain MRIs obtained 14 days after the onset of initial symptom. A brain MRI obtained on admission (day 1) shows increased DWI/FLAIR
signal in the left anterolateral temporal lobe, mainly along the cortex with edema (a, b, arrows). The follow-up brain MRI obtained on day 28
shows a newly appearing increased DWI/FLAIR signal in the right anterior temporal lobe, and posterior spread of the initial left temporal lesion
along the cerebral cortex (compatible with classic stroke-like lesion). Note mild reduction in ADC values in the left anterior temporal cortex (c,
arrowhead), suggesting ongoing regional metabolic derangements. ADC values in the left anterior temporal subcortical white matter is rather
increased, suggesting the presence of vasogenic edema. A: DWI; B: FLAIR; C: ADC map

day 28 showed a newly appearing lesion in the right anterior temporal lobe (Fig. 1). Because multifocal corticosubcortical MRI lesions are characteristic features of
anti-γ-aminobutyric acid A receptors (GABAaR) encephalitis [11], the patient was also treated with a total of 5
cycles of plasma exchange (PLEX) between day 33 and
day 42, without obvious beneficial effects.
In the evening on day 43 the patient began to complain of feeling dizzy. Two days later dysarthria and
cerebellar ataxia became clear. The brain MRI obtained
on day 45 showed extensive increased DWI/FLAIR signals in the cerebellum mainly along the folia, without
apparent reduction in ADC values (Fig. 2b). A few days
later, the patient became mute and somnolent. An EEG
revealed FPEDs mainly at the left frontal region. On day
48 CSF lactate and pyruvate levels were 10.2 mmol/L
and 0.33 mmol/L, respectively; CSF lactate/pyruvate (L/
P) ratios were markedly elevated (30.9). The follow-up
brain MRI obtained on day 52 showed expansion of
cerebellar lesions, which predominantly affected the folia
with edema. Tonsil and nodule were involved, but the
deep cerebellar nucleus or cerebellar peduncle were not
involved (Fig. 2d).
Based on possible maternal inheritance of diabetes,
short stature, elevated CSF L/P ratios, cerebral SLLs, and
the lack of evidence of cardiogenic embolism, the patient

underwent a genomic analysis, which demonstrated a
m.3243A > G mutation with 17% heteroplasmy in leukocytes, confirming the diagnosis of MELAS.
After the treatment with taurine (12,000 mg/day), Larginine (12,000 mg/day), vitamin B1 (100 mg/day), and
carnitine (3000 mg/day), the patient became able to follow
simple commands, and he was transferred to a rehabilitation center on day 146. These drugs were well tolerated
and there were no adverse events. The brain MRI obtained 4 months after admission showed diffuse brain atrophy including the cerebellum. The modified Rankin
Scale at the last follow-up (9 months after admission) was
scored 4, with residual cognitive deficits. Nerve conduction study, needle electromyography, and audiometry were
not performed during the course of the disease because
no consent was obtained for these studies.

Discussions and conclusions
This case highlights the following important features: (1)
autoimmune encephalitis must be diagnosed after exclusion of alternative causes including MELAS; (2) SLLs can
develop in the cerebellum in a MELAS patient with
m.3243A > G mutation; (3) the cerebellar folia are preferentially involved; (4) distribution of the cerebellar SLLs is
incongruent with a vascular territory; (5) deep cerebellar
nucleus and cerebellar peduncle are not affected by SLLs.

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Fig. 2 Brain MRIs obtained during the acute stage of cerebellar stroke-like episode. A brain MRI obtained on day 45 (2 days after the onset of
dizziness) shows extensive increased DWI/FLAIR signals in the cerebellum, without apparent reduction in ADC values (a-c). Note preferential
involvement of the cerebellar folia sparing deep cerebellar nuclei or cerebellar peduncles, and progressive expansion of edematous lesions along
the folia on day 52 (d). A: FLAIR: B: ADC map; C and D: DWI

Despite the absence of pleocytosis, oligoclonal bands,
or fever, the patient was initially suspected of having
autoimmune encephalitis, HSE, or tumor, based on the
initial MRI findings, psychiatric symptoms, and aphasia,
resulting in delayed diagnosis. In this case multifocal
cortico-subcortical lesions rapidly developed, associated
with epileptiform discharges. Similar MRI findings are
often seen in patients with anti-GABAaR encephalitis,
and SLE-mimicking lesions with focal lactate accumulation and hyperperfusion have recently been reported in a
case of anti-GABAaR encephalitis [12]. In MELAS, classic SLLs mainly involve the cortex and gradually spread
to the adjacent cortex with accompanying subcortical
edema, which is different from anti-GABAaR encephalitis. It should be kept in mind that autoimmune encephalitis must be diagnosed after the reasonable exclusion
of alternative causes, including MELAS [13].
It is interesting that the folium (cortex) was preferentially
involved in cerebellar SLEs, as was in classic cerebral SLEs.
It remains speculative why the cortex is preferentially

involved in SLEs of MELAS, but it has been shown that the
dendrite-rich cortex are particularly vulnerable to hypoxia
[14], thus the cerebral cortex with high metabolic demand
are presumed to be more susceptible to metabolic derangements when increase in energy demand (seizure) or decrease in energy supply develop due to ischemia, metabolic
breakdown, increased reactive oxygen species, or vasogenic
edema associated with blood-brain barrier (BBB) dysfunction, all of which are presumably attributed to respiratory
chain dysfunction in neurons, astrocytes, endothelial cells,
or smooth muscle cells of small blood vessels [3, 4].
Basal ganglia are often involved in Leigh encephalopathy or MELAS/Leigh overlapping syndrome, but rarely
involved by SLLs in MELAS. Interestingly, in this case,
the cerebellar cortex, including tonsil and nodule, was
extensively involved but deep cerebellar nuclei were not
involved on MRI. The reason why such deep structure
(basal ganglia or cerebellar nuclei) are being spared in
SLLs remains unknown; however, it has been shown that
there is a striking increase in number of mitochondria in

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the smooth muscle and endothelial cells, which were
most prominent in the pial arterioles and small arteries
but less frequent and severely sparse in the larger pial
arteries and intracerebral arterioles and small arteries
[15]. The difference in vascular changes in location may
in part contribute to difference in neuronal susceptibility
to metabolic derangements between the cortex and deep
structure.
Although classic SLLs often continuously spread to
the adjacent cerebral cortex [5, 6], cerebellar SLLs also
showed similar spreading pattern by preferentially involving the folia. Progressive spread of classic SLLs are
often accompanied by sustained epileptiform discharges
or non-convulsive status epilepticus. In this case, gradual
spread of the classic SLLs in the left temporal lobe was
accompanied by FPEDs, but it is difficult to assess electrophysiological changes in the cerebellar cortex.
Regarding cerebral perfusion changes, classic cerebral
SLLs are often accompanied by focal hyperperfusion
reflecting increased synaptic activity [5–7]. A previous
one study [9] demonstrated cerebellar hyperperfusion
during the acute stage of cerebellar SLEs, but unfortunately, we did not assess perfusion changes.
Cerebellar ataxia is one of the common symptoms in
m.3243A > G carriers (20–66%) [16, 17] and cerebellar
atrophy is also seen in 24% of patients with MELAS
[16]. However, in most cases ataxia is associated with
chronic neurodegenerative process of the cerebellum (atrophy), not due to acute onset of cerebellar SLEs. Accordingly, cerebellar SLEs have rarely been reported.
Although in this case we cannot exclude the possibility
that cerebellar SLEs were precipitated by a preceding
PLEX, the pathogenesis of cerebellar SLEs remain to be
fully elucidated. The lack of apparent reduction in ADC
values may suggest that the cerebellar SLLs mainly consist of vasogenic edema as reported in classic cerebral
SLEs [18]. BBB dysfunction has also been implicated in
the mechanism of cerebellar SLLs based on extravasation of plasma protein in the small blood vessels in the
cerebellum in patients with MELAS [9].
This study has limitations of being retrospective and
based on a single case report. We did not perform a perfusion study or histopathological examination of the affected cerebellum.
Despite these limitations, we could characterize several
distinctive features of cerebellar SLEs in a patient with
m.3243A < G mutation. Clinical neuroradiological similarities of cerebellar and cerebral SLEs may imply the presence of the common pathophysiological mechanisms
underlying both SLEs. We stress on a potential role of
microangiopathy and increased susceptibility of the cerebellar cortex to metabolic derangements, as previously
reported in classic cerebral SLEs [5, 6]. Further studies are
required to conclude the pathogenesis of cerebellar SLEs.

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Abbreviations
ADC: Apparent diffusion coefficient; BBB: Blood brain barrier;
CSF: Cerebrospinal fluid; DWI: Diffusion-weighted imaging;
EEG: Electroencephalogram; FLAIR: Fluid-attenuated inversion recovery;
FPEDs: Focal periodic epileptiform discharges; GABAAR: γ-aminobutyric acid A
receptors; IVMP: Intravenous high-dose methylprednisolone;
MELAS: Mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes; MRA: Magnetic resonance angiography; MRI: Magnetic
resonance imaging; PLEX: Plasma exchange; SLEs: Stroke-like episodes;
SLLs: Stroke-like lesions
Acknowledgements
The authors acknowledge the medical staff at Keio University Hospital for
their dedicated care of the patient and the cooperation.
Authors’ contributions
MO, JN, and YI played a major role in the acquisition of data. MO, YI, and TI
analyzed and interpreted the patient data regarding a series of MRI images.
MO and TI were major contributors in writing the manuscript. All authors
have read and approved the final manuscript.
Funding
n/a.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated
or analyzed during the current study.
Ethics approval and consent to participate
n/a.
Consent for publication
The written informed consent has been obtained from the patient for
publication of this case report and any accompanying images.
Competing interests
JN is an Editorial Board Member of BMC Neurology. MO reports no
disclosure. TI receives a grant from The Japan Epilepsy Research Foundation
and research support from Astellas Pharma Inc. JN receives research grants
from Daiichi-Sankyo, Eisai, Böehringer-Ingelheim, and Pfizer. YI receives grants
from Keio University Program for the Advancement of Next Generation Research Projects. The authors declare that this case report was not conducted
in the commercial or financial relationships that could be constructed as a
potential conflict of interest.
Author details
1
Department of Neurology, Keio University School of Medicine, 35
Shinanomachi, Shinjuku, Tokyo 160-8582, Japan. 2Department of Neurology,
Kitasato University School of Medicine, Sagamihara, Japan.
Received: 9 March 2020 Accepted: 26 April 2020

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