Late-­onset mitochondrial encephalopathy with lactic
acidosis and stroke-­like episodes and the role of
serial imaging
Robert Ambrogetti,1 Ethan Kavanagh,2 Khalid ElTayeb3
1

Internal Medicine, University
Hospitals of Leicester NHS Trust,
Leicester, UK
2
University Hospitals of Leicester
NHS Trust, Leicester, UK
3
Neurology, University Hospitals
of Leicester NHS Trust, Leicester,
UK
Correspondence to
Dr Robert Ambrogetti;
​robert.​ambrogetti1@​nhs.​net
Accepted 16 February 2024

SUMMARY
Mitochondria are essential for human metabolic
function. Over 350 genetic mutations are associated
with mitochondrial diseases, which are inherited in a
matrilineal fashion. In mitochondrial encephalomyopathy,
lactic acidosis and stroke-­like episodes (MELAS),
defective mitochondrial function and resultant impaired
cellular energy production compromise vascular
perfusion in affected tissues. Early diagnostic criteria
suggested the diagnosis should be considered in those
under 40. However, a broader range of phenotypes are
now recognised, including those that present for the
first time later in life. The primary presenting feature
in MELAS is a stroke-­like episode invariably resulting
in patients undergoing neuroradiological imaging. We
present a case of a woman with a first presentation of
a stroke-­like episode and seizures in her 40s who was
eventually diagnosed with MELAS. We detail her clinical
presentation, treatment and diagnosis, emphasising the
role of serial imaging in her diagnosis.

BACKGROUND

© BMJ Publishing Group
Limited 2024. No commercial
re-­use. See rights and
permissions. Published by BMJ.
To cite: Ambrogetti R,
Kavanagh E, ElTayeb K. BMJ
Case Rep 2024;17:e259102.
doi:10.1136/bcr-2023259102

Mitochondria are vital to human life, producing
roughly 90% of the body’s energy on a cellular
level via oxidative phosphorylation (OXPHOS).1
The prevalence of known mitochondrial disease
in adults has been estimated to be around 12
per 100 000.2 However, the prevalence may be
higher in the general population as around 1 in
250 healthy adults have been found to carry
pathogenic mitochondrial DNA at low levels.3
There are over 350 gene mutations known to
cause mitochondrial disease.4 The m.3243A>G
was first identified in a case of mitochondrial
encephalomyopathy, lactic acidosis and stroke-­like
episodes (MELAS) in 1990.5 The m.3243A>G
MT-­TL1 variant has since been found to be one
of the most common pathological mitochondrial
mutations and accounts for up to 80% of cases of
MELAS.6 M.3243A>G MT-­
TL1 prevalence has
been reported to be between 0.017% and 0.236%
in adults.7 8 The transition of adenine to guanine
at nucleotide 3243 in mitochondrial tRNA results
in impaired protein formation and ultimately leads
to defective formation of complexes 1, 3, 4 and 5
of the OXPHOS system.9 10 The resultant impairment in cellular energy production causes vascular
lesions and compromised microvascular perfusion
in affected tissues.10 11 We present a case of late-­
onset MELAS caused by the m.3243A>G MT-­TL1
variant.

CASE PRESENTATION
A woman in her 40s presented to hospital with a
history of gradual decline in her cognitive function and nocturnal seizure activity over the last
2 weeks. She was an independent non-­smoker with
no alcohol consumption who worked in childcare and as a nanny. There is no family history of
mitochondrial disease. Her only other significant
medical history was of intermittent migraines and
long-­
standing sensorineural hearing loss previously attributed to a childhood measles infection,
compounded by 18 years of playing in a band
with minimal ear protection. CT scan of the head
was performed in the emergency department for
suspected stroke and showed bilateral basal ganglia
calcification with no other intracranial findings. As
a result, an MRI of the brain was performed by the
stroke team. This MRI brain showed widespread
cortical restricted diffusion in the right parieto-­
occipital region, suggested to be in keeping with
postictal changes, as seen in figure 1.
Given her symptoms and a raised white cell
count with neutrophilia on presentation she was
initially treated for bacterial and viral meningoencephalitis with ceftriaxone and aciclovir. However,
her cerebrospinal fluid (CSF) biochemistry, viral
panel, microscopy and culture were not in keeping
with an infectious aetiology. Other than a raised
lactate of 4.1 mmol/L on admission, her blood
tests, autoimmune screen, infection screen and
lumbar puncture results were unremarkable (CSF
results: glucose=4.6, protein=0.42 (0.10–0.45),
cultures=no growth, CSF PCR panel HSV1, HSV2,
varicella-­zoster, Enterovirus and Parechovirus=not
detected by PCR, cytology=no significant inflammation and no malignant cell conclusion CSF—
within normal limits). HIV1 and HIV2 tests were
normal, and blood cultures did not grow any organisms. Her autoimmune encephalitis serum screen
via indirect immunofluorescence was negative for
antibodies to CASPR2, LGI1, AMPA1, AMPA2,
GABAb, GABA A and NMDA antigens. Antinuclear
antibodies and extractable nuclear antigens (Ro, La,
U1RNP, RNP70, CENP, Jo-­1, Scl-­70) were negative.
Antineutrophil cytoplasmic antibodies (ANCA)
(immunofluorescence) were weakly positive at a
lower titre (P-­ANCA 1:40) with PR3 (<0.6 IU/mL)
and Myeloperoxidase (<1.0 IU/mL) negative. A
baseline electroencephalogram (EEG) showed no
epileptiform activity with intermittent widespread
slow waves in keeping with mild cerebral dysfunction. During this admission, a CT thorax, abdomen

Ambrogetti R, et al. BMJ Case Rep 2024;17:e259102. doi:10.1136/bcr-2023-259102

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Case report

Figure 1 Initial MRI brain diffusion-­weighted imaging (DWI) on first
admission shows widespread cortical restricted diffusion in the right
parieto-­occipital region.
and pelvis showed a right adnexal cyst. Provisional diagnoses
of posterior reversible encephalopathy syndrome (PRES) and
autoimmune encephalitis were given. The patient was started on
lacosamide and levetiracetam and completed a 5-­day course of
methylprednisolone. Although the patient showed some clinical
improvement during a course of intravenous methylprednisolone, a normal CSF and negative autoimmune screen protein
made autoimmune encephalitis less likely. Owing to the clinical improvement, absence of seizures and the patient’s good
functional independence, she was discharged with neurology
up. The patient remained seizure free and
outpatient follow-­
asymptomatic as an outpatient. A repeated MRI of the brain as
an outpatient 5 months later showed the right-­sided changes had
now developed into encephalomalacia and gliosis with atrophic
effect and moderate enlargement of the occipital horn of the
lateral ventricle, as seen in figure 2. Both the unilateral lesion
and the incomplete reversibility were considered not in keeping
with typical PRES.
Approximately 1 year later, the patient re-­presented to the
hospital with a 4-­day history of intermittent self-­resolving right
upper limb focal motor seizures, a reduction in vision bilaterally
and further cognitive decline. On examination, she was noted to
be of short stature and slim build. She had left-­sided homonymous hemianopia, reduced hearing in both ears, weakness in the
right upper and lower limbs (Medical Research Council grading
4/5) and more than five beats of clonus bilaterally in the lower
limbs. She did not have muscle pain or global muscle weakness.
Ophthalmology review and visualisation of her retina excluded

Figure 3 MRI brain diffusion-­weighted imaging (DWI) taken on the
second admission, approximately 1 year after the initial MRI brain,
showing new regions of left parietal cortical diffusion restriction.
retinitis pigmentosa. Her routine blood tests, creatine kinase
and CSF viral and bacterial studies on this admission were again
unremarkable other than a slightly elevated serum lactate of 2.1
mmol/L (CSF glucose 7.5 mmol/L, CSF protein 0.36 g/L (0.10–
0.45), CSF red blood cells=233, white blood cells=0, Gram
stain=no organism seen, cultures=no growth). CSF cytology
on this occasion was also reported as normal (CSF cytology—
normal, no inflammatory cells and no malignant cells). Baseline
EEG on this admission showed excess slow wave activity in a
widespread distribution, which was at times more pronounced
over the right temporal and parietal regions. No epileptiform
activity was seen. MRI brain on this admission showed mature
juxtacortical damage in the right parieto-­occipital and posterior
temporal lobes with gliosis, encephalomalacia with new gyriform
diffusion restriction and T2/fluid-­attenuated inversion recovery
(FLAIR) hyperintensity in the left parietal and occipital cortex,
as seen in figure 3.
A repeated MRI brain during this second admission showed
new lesions on the left parietal diffusion restriction with T2/
FLAIR hyperintensity, resolution of left occipital and parietal
changes with mature posterior cerebral volume loss on the right
occipital region. The migratory changes in a parietal/temporal/
occipital fashion were more in keeping with an atypical MELAS
in the context of gyriform-­restricted diffusion. Given the serial
MRI findings, history and exclusion of other more common
differentials, a diagnosis of late-­onset MELAS was suspected.
MELAS was subsequently confirmed by genetic testing, which
revealed an m.3243A>G MT-­
TL1 pathogenic variant with a
27% level of heteroplasmy in the blood-­derived DNA sample.
With the diagnosis confirmed with genetic tests from serum
samples, further testing with muscle biopsy was not necessary.
The patient showed clinical improvement with uptitration of
antiepileptic medications and was discharged with follow-­up.

INVESTIGATIONS
Stated above.

DIFFERENTIAL DIAGNOSIS

Figure 2 Outpatient MRI brain T2 turbo-­spin-­echo dark fluid sequence
5 months after initial MRI, showing previous areas of right temporo-­
occipital and parietal regions restricted diffusion and hyperintensity to
have evolved into encephalomalacia and gliosis with atrophic effect and
moderate enlargement of the occipital horn of the lateral ventricle.

The clinical history, examination and imaging suggested an
encephalopathic process. The initial differential included infective, autoimmune, metabolic, medication or drug toxicity, postictal state and hereditary causes. Metabolic and toxic aetiology
was considered less likely from the outset as there was no obvious
source of metabolic derangement or causative medication.
The patient initially appeared to show some improvement
during a course of methylprednisolone, which suggested that
there may have been an underlying inflammatory or autoimmune condition. However, with a weakly positive P-­
ANCA
(1:40) of uncertain significance and an otherwise normal autoimmune screen, CSF protein, negative CSF cultures and viral

2

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Case report

We have reported a case of late-­onset MELAS caused by the
m.3243A>G MT-­
TL1 mutation. This mutation has been
shown to manifest clinically in multiple organs including the
eyes, ears, brain, endocrine organs, myocardium, intestines,
kidneys, muscles and nervous system.10 12 Organ involvement,
clinical manifestation, the timing of disease onset and severity
are determined by the proportion of mutated mitochondria

within cells and specific distribution of tissues affected.10 The
fluctuating levels of abnormal mitochondrial DNA in specific
cells and tissue distribution are accounted for by heteroplasmy
and random segregation of mitochondrial DNA during cell
division.4 12 13 Varying degrees of loss and gain of function in
mitochondrial proteins in cells of different tissues may also play
a role in disease severity.14 The most typical feature is stroke-­
like episodes. Other common features are headaches, cognitive
decline, seizures, lactic acidosis, short stature, motor weakness
and cortical vision loss.12 15 The m.3243A>G mutation can be
associated with various clinical phenotypes ranging from early
death to late-­onset disease and individuals who are asymptomatic carriers.10 This mutation is known to cause other mitochondrial syndromes, including myoclonus epilepsy with ragged red
fibres, maternally inherited diabetes and deafness and chronic
progressive external ophthalmoplegia.16 Various overlaps
between syndromes have also been observed.12 15 16 A significant proportion of patients with the m.3243A.G mutation have
a phenotype that does not meet the accepted criteria for these
classical mitochondrial syndromes. These can include asymptomatic carriers, non-­syndromic multisystem subtypes, isolated
sensorineural hearing loss, isolated myopathy, retinopathy or
nephropathy.10 13 16–20 As a result, the disease course, diagnosis
and prognosis can be challenging to navigate. After neurological
disease, cardiac pathology has the most impact on prognosis in
patients with MELAS.21 Multisystem involvement and specifically the significance of cardiac involvement can be overlooked
in clinical practice.
Early diagnostic criteria suggest that MELAS should be
suspected if there are stroke-­like episodes before the age of 40
years, encephalopathy with seizures and dementia or both with
lactic acidosis and/or ragged red fibres on muscle biopsy. The
diagnosis is considered confirmed if there are also two of the
following: normal early development, recurrent headaches or
recurrent vomiting.22 A broader range of phenotypes are now
recognised, including those with onset after the age of 40 years,
such as in our case.23 24 In the UK, best practice guidelines recommend genetic testing of serum for mitochondrial diseases such as
MELAS as a confirmatory test.4 However, diagnosis of MELAS
caused by the 3243A-­G mutation with blood samples has been
shown to be difficult, as mutational load decreases over time in
the serum and in some cases is undetectable.25 26 The amount
of heteroplasmy in blood samples has been shown to decrease
by ~1% per year and up to 29% over time with ageing.25–29
Hence, genetic testing of serum samples in older patients can be
associated with higher false negative rates.28 29 It has been noted
that mutant mitochondrial DNA remains at higher levels in
non-­dividing tissues such as skeletal muscle, urinary epithelium
and hair.25 26 Hence, in cases where the suspicion of MELAS
remains high despite indeterminant serum results, further
genetic testing of such tissues should be considered, especially in
older patients.4 25 26 Some authors suggest that urinary epithelial
cell sampling replaces muscle biopsy as the gold standard as it is
less invasive, and the associated mutational load has the highest
correlation with disease severity.25 26
Given the challenging nature of clinical diagnosis and the
need for molecular diagnosis, many patients with stroke-­like
episodes are initially diagnosed with ischaemic stroke, infectious
encephalitis, autoimmune encephalitis and vasculitis.30 This
can lead to a delay in the diagnosis. As the primary presenting
feature is a stroke-­like episode, invariably, patients with MELAS
undergo neuroradiological imaging.31 The radiological features
of MELAS syndrome can vary significantly. However, the most
common findings are stroke-­like lesions which do not conform

Ambrogetti R, et al. BMJ Case Rep 2024;17:e259102. doi:10.1136/bcr-2023-259102

3

panels all indicated that infective and autoimmune processes
were less likely.
Based on initial MRI brain imaging and history, a working
diagnosis of PRES was considered. However, with no risk factors
for PRES, the unilateral nature of lesions on imaging and the
lack of reversibility over time, PRES became less likely.
Serial MRI brain imaging showed the development of new
lesions bilaterally of differing ages. Her case was reviewed in the
neurology and neuroradiology multidisciplinary team meeting,
where differential diagnoses, including MELAS, postictal
changes, limbic encephalitis and infectious causes such as prion
disease and herpes, were discussed. With no myoclonus or EEG
features consistent with prion disease, this diagnosis was considered less likely. The migratory changes on MRI in the distribution of the temporal, parietal and occipital lobes with gyriform
restricted diffusion in the context of a now prolonged relapsing
remitting temporal nature of symptoms and examination findings were thought to be more in keeping with MELAS than other
previously mentioned differentials.
Previous basal ganglia calcification on CT was noted. However,
in this case, the basal ganglia and cerebellum (areas often affected
in MELAS) were not acutely affected on repeat MRI imaging.
Muscle biopsies were initially requested. However, the diagnosis was confirmed with serum genetic testing, which revealed
TL1 mutation consistent with MELAS.
an m.3243A>G MT-­
Family history is usually important in the diagnosis of hereditary conditions. However, the patient’s parents and siblings are
healthy and not known to have any significant medical history or
features convincing of mitochondrial disease. No genetic testing
has been performed on her family members to date. However,
the patients’ parents were not known to have any medical significant medical history other than epilepsy that was attributed to
head injury. Hence, the investigatory process and serial imaging
became more important in reaching the diagnosis.

TREATMENT

The patient was initially treated for meningoencephalitis with
ceftriaxone and aciclovir. Further to this, she completed a 5-­day
course of intravenous methylprednisolone in light of a suspected
autoimmune aetiology. Her seizures were initially controlled
with an antiepileptic regimen of lacosamide (150 mg two
times per day) and levetiracetam (500 mg two times per day).
Clobazam (750 mcg once a day) was added with good effect for
further seizure control on her second admission. The treatment
options of MELAS are limited. Once the diagnosis of MELAS
was established, the focus of treatment was supportive in nature
with an emphasis on good seizure control and optimising quality
of life. Our patient did not have children and was not planning
to start a family.

OUTCOME AND FOLLOW-UP

The patient has not had any further hospital admissions, has
remained clinically stable and has been followed up as an
outpatient.

DISCUSSION

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Case report

to typical vascular territories.31 These lesions are typically seen
in the occipital and parietal lobes. On MRI brain the lesions typically appear hyperintense on T2 weight and FLAIR sequences
and can show restricted diffusion in the acute phase.31 Over time,
these lesions can lead to atrophy and gliosis, as seen in this case.
Other common findings on neurological imaging are generalised
or focal brain atrophy and basal ganglia calcifications.31 Unfortunately, the neuroradiological features are variable, often non-­
specific and can be seen in many neurological conditions.31 Our
patient had repeated MRI brain scans over a period of approximately 1 year. The aforementioned neuroradiological features
were observed to be acute, chronic, bilateral and migratory with
fluctuating course, which, with the clinical history, aided the
diagnosis of a late-­onset/atypical MELAS. Our case highlights
the utility of serial MRI brain scans as a non-­invasive, yet effective method of aiding the diagnosis of atypical or late-­onset cases
of MELAS or neurological mitochondrial disease.
There is no curative or definitive treatment for MELAS. As
a result, management is centred around symptom control and
maintaining quality of life.32 Management often involves a multidisciplinary team approach to address the various clinical manifestations of the disease.32 The systems affected and the degree
of impairment will dictate the type of multidisciplinary team
involvement. Input from respiratory, cardiac, ophthalmological, endocrine, and genetic subspecialties and nutritional, audiological and rehabilitative services are often required.33 Many
patients with MELAS suffer from epilepsy. There are no specific
guidelines for seizure control in MELAS. Choice of antiepileptic regimen is usually selected based on the type of seizures,
patient gender, age, comorbidities, potential side effects, drug
interactions and patient preference.11 34 35 The first choice of
monotherapy for seizures in MELAS is usually lamotrigine or
levetiracetam.34 35 In our case, an antiepileptic drug regimen
of lacosamide and levetiracetam was initially effective. Later,
the addition of slow titration of low-­dose clobazam for seizure
control also proved effective. In female patients such as ours it is
important to consider the teratogenicity of antiepileptic medication. Lamotrigine and levetiracetam are considered to have the
least teratogenic effect.36 Sodium valproate has previously been
reported to cause worsening of symptoms and precipitate attacks
of seizures in patients with MELAS.37 The deleterious effects of
sodium valproate in patients with MELAS are mediated through
its inhibitory effects on the mitochondrial OXPHOS.38 Hence,
sodium valproate and other antiepileptic drugs with inhibitory
effects on mitochondrial function like phenobarbital, carbamazepine, oxcarbazepine, phenytoin, ethosuximide, topiramate,
gabapentin and vigabatrin should be avoided in patients with
MELAS.38
Mitochondrial disorders result in more oxidative stress and
can be associated with reduced levels of certain micronutrients
and amino acids (eg, creatine, folate and carnitine). Hence,
supplementation with combinations of antioxidants and vitamins (including multivitamins, coenzyme Q10, creatinine,
L-­carnitine, folate and B complex vitamins) can be considered.
However, their effectiveness has not been established.11 39
Mitochondrial DNA is inherited in a matrilineal fashion.
Hence, males affected with MELAS cannot pass on the condition.40 For young female patients with MELAS family planning
is particularly important. There are several reproductive options
available for patients with MELAS, including prenatal diagnosis
(PD), preimplantation genetic diagnosis (PGD) and mitochondrial replacement therapy (MRT).4 40 PD via villous sampling or
amniocentesis allows for the diagnosis of pathological mitochondrial DNA in the fetus. Similarly, PGD allows for the selection of

embryos with low variant load. However, for both PD and PGD,
determining the significance of mitochondrial variant loads at
such early stages requires specialist interpretation on a case-­by-­
case basis.40 MRT can prevent or reduce the transmission of
mitochondrial disease by replacing variant mitochondrial DNA
from a healthy donor.4 41

4

Ambrogetti R, et al. BMJ Case Rep 2024;17:e259102. doi:10.1136/bcr-2023-259102

Learning points
► Mitochondrial encephalomyopathy, lactic acidosis and stroke-­

like episodes (MELAS) can present for the first time in older
age. MELAS and mitochondrial disease should be kept in the
differential diagnosis in patients with typical symptoms and
radiological findings regardless of age.
► In atypical presentations of MELAS, serial MRI brain imaging
can play an important role in the diagnosis.
► Serum m.3243A>G MT-­TL1 variant load does not correlate
with disease severity and is more prone to give false negative
results, especially in older patients.
Contributors RA, EK and KE were responsible for drafting of the text, sourcing
and editing of clinical images, investigation results, drawing original diagrams and
algorithms, and critical revision for important intellectual content. RA, EK and KE
gave final approval of the manuscript.

Funding The authors have not declared a specific grant for this research from any
funding agency in the public, commercial or not-­for-­profit sectors.
Competing interests None declared.
Patient consent for publication Consent obtained from next of kin.
Provenance and peer review Not commissioned; externally peer reviewed.
Case reports provide a valuable learning resource for the scientific community and
can indicate areas of interest for future research. They should not be used in isolation
to guide treatment choices or public health policy.

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Ambrogetti R, et al. BMJ Case Rep 2024;17:e259102. doi:10.1136/bcr-2023-259102

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