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\begin{document}

\title{Patent foramen ovale leading to mismanagement in a mitochondrial
myopathy, encephalopathy, lactic acidosis, and stroke-like episodes
(MELAS) patient}



\author[1]{Mehri  Salari}%
\author[2]{Masoud Etemadifar}%
\author[3]{Ronak Rashedi}%
\author[3]{Romina Rashedi}%
\affil[1]{Shahid Beheshti University of Medical Sciences}%
\affil[2]{Isfahan University of Medical Sciences}%
\affil[3]{Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of medical Sciences}%


\vspace{-1em}



  
  \date{May 17, 2024}


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\selectlanguage{english}
\begin{abstract}
We report the clinical, imaging, echocardiography and muscle biopsy
findings of a patient presenting by characteristics which have not been
reported in previous Melas cases. This is the first reported case of
MELAS accompanying with PFO, and the first case of MELAS with the
progressive pattern of ischemic lesions.%
\end{abstract}%



\sloppy


\textbf{Title page}

\textbf{Article Title:} Patent foramen ovale leading to mismanagement in
a mitochondrial myopathy, encephalopathy, lactic acidosis, and
stroke-like episodes (MELAS) patient

\textbf{Authors:}

\emph{Mehri Salari, MD}

Clinical Reasearch Development Unit of Shohada-e Tajrish Hospital,
Shahid Beheshti University of Medical Sciences, Tehran, Iran

Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical
Center of Excellence, Shahid Beheshti University of medical Sciences

\emph{Masoud Etemadifar, MD}

Department of Functional Neurosurgery, Medical School, Isfahan
University of Medical Sciences, Isfahan, Iran

\emph{\textsuperscript{*}Ronak Rashedi}

Clinical Reasearch Development Unit of Shohada-e Tajrish Hospital,
Shahid Beheshti University of Medical Sciences, Tehran, Iran

Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical
Center of Excellence, Shahid Beheshti University of medical Sciences

\emph{Romina Rashedi, MD}

Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical
Center of Excellence, Shahid Beheshti University of medical Sciences

\textbf{Corresponding author:}

\emph{1.} Ronak Rashedi

Department of Neurology, Shohada Tajrish Hospital, Tehran, Iran

Email: ronak.rashedi@gmail.com ronakrash

ORCID: 0000-0003-2123-9419

\textbf{Patent foramen ovale leading to mismanagement in a mitochondrial
myopathy, encephalopathy, lactic acidosis, and stroke-like episodes
(MELAS) patient}

\textbf{Abstract}

\textbf{Introduction:} Mitochondrial myopathy, encephalopathy, lactic
acidosis, and stroke-like episodes (MELAS) is the most common
maternally-inherited mitochondrial disorder presenting by stroke-like
episodes, seizures, encephalopathy and muscle weakness.

\textbf{Methods:} We report the clinical, imaging, echocardiography and
muscle biopsy findings of a patient presenting by unique characteristics
which have not been reported in previous cases of MELAS.

\textbf{Results:} The reported case is a 34 year old man with the
history of three times hospitalization due to muscle weakness,
encephalopathy, progressive cognitive decline and gradual visual loss.
Muscle biopsy revealed Ragged Red Fibers concomitant with mitochondrial
disorders. PFO was found in echocardiography leading to mismanagement of
this patient and MR imaging showed ischemic lesions with a progressive
pattern.

\textbf{Discussion:} This is the first reported case of MELAS
accompanying with PFO. All previous reported cases of MELAS have
mentioned a fluctuating characteristic for the ischemic lesions; hence
this is the first case of MELAS with the progressive pattern of ischemic
lesions.

\textbf{Key Words:} MELAS, mitochondrial disease, muscle biopsy,
clinical features

\textbf{Declarations}

\textbf{Funding:} This study has not received any financial support from
any organization

\textbf{Conflicts of interest/ Competing interests:} The authors declare
that they have no conflict of interest

\textbf{Ethics approval:} This study has been approved by Shahid
Beheshti Medical University research ethics committee and informed
consent was obtained from the subject in this study. This study was
performed in accordance with the ethical standards as laid down in the
1964 Declaration of Helsinki and its later amendments.

\textbf{Consent to participate:} not applicable

\textbf{Consent for publication:} informed consent was obtained from the
subject in this study

\textbf{Introduction}

Mitochondrial disorders consist of a number of diseases, which are
mostly due to gene mutations of mitochondrial DNA (mtDNA) or nuclear DNA
(nDNA). Clinical traits usually demonstrate as symptoms in high
energy-consuming organs such as brain, skeletal muscles, myocardium and
endocrine systems\textsuperscript{1}. Mitochondrial myopathy,
encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is
presumably the most common mitochondrial disorder, which is inherited
maternally\textsuperscript{2}.

MELAS was first introduced in 1984\textsuperscript{3}, which typically
presents with stroke-like episodes, seizures, short stature,
encephalopathy, muscle weakness, nausea, vomiting, headaches, diabetes
mellitus, exercise intolerance, sensorineural hearing loss, myopathy and
lactic acidosis\textsuperscript{3,4,5,6}. Magnetic Resonance Imaging
(MRI) in company with muscle biopsy and genetic studies is now the
foundation of diagnosis in MELAS cases\textsuperscript{7}.

In this case report, we will review the presentation of symptoms,
diagnosis challenges and follow-ups in a patient affected with MELAS.
This study has been approved by Shahid Beheshti Medical University
research ethics committee and informed consent was obtained from the
subject in this study.

\textbf{Case Report}

A34- year old right-handed man was brought to the emergency department
with left upper extremity weakness and severe encephalopathy. In his
past medical history, multiple hospitalizations were found due to
similar symptoms. The patient's first admission dates back to 7 years
ago when he was admitted with bilateral visual loss, which had gradually
become worsen during 20 days. He also gave history of new onset seizure
and was admitted to rule out cerebral venous thrombosis (CVT).

Physical Examination revealed left homonymous hemianopia. Brain Magnetic
Resonance Imaging (MRI), Magnetic Resonance Venography (MRV), and
Magnetic Resonance Angiography (MRA) were done and although MRV and MRA
study were normal, Brain compound tomography (CT) and MRI findings were
suggestive of right temporal lobe ischemia. (Figure1) Laboratory tests
which were conducted for the patient were all within normal ranges,
including screening for vasculitis. Echocardiography was performed and
showed Patent Foramen Ovale (PFO).

Visual field was improved, but his seizure like movements persisted and
were misdiagnosed as pseudo-seizures.

6 years ago, he was admitted again because of sudden onset visual loss,
which was accompanied with nausea and vomiting. Neuro-ophthalmological
examinations disclosed homonymous hemianopia of right side. His vision
was gradually enhanced during the one month. Other neurological
examinations were unremarkable. Complete paraclinical and laboratory
studies were performed including cerebrospinal fluid analysis,
electrocardiogram (ECG), brain CT scan and brain MRI. All came back
negative except brain MRI which demonstrated signal changes in occipital
lobe. (Figure1)

Complete laboratory tests including autoimmune encephalopathy panel was
done which was negative in the patient. CSF analysis revealed high
lactate levels, which along with the high serum lactate level suggested
the diagnosis of mitochondrial encephalopathy, lactic acidosis and
stroke-like episodes (MELAS) syndrome. Other laboratory tests were
normal which are summarized in Table 1.

In his last admission, the neurological physical examination revealed
left side hemiplegia, significant cognitive decline (mini mental status
examination: 17).

Echocardiography was performed and showed that left atrial appendage
(LAA) was filled with clot, ejection fraction (EF) of 60 percent and
PFO, and he received warfarin.

To confirm the diagnosis of mitochondrial disorders muscle biopsy was
performed and it revealed ragged red fibers (RRF). (Figure2)

\textbf{Discussion and Conclusion}

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like
episodes (MELAS) is the most common maternally-inherited mitochondrial
disorder, which usually becomes symptomatic before the age of 40
years\textsuperscript{8}. MELAS is characterized by stroke-like
episodes, seizures, dementia, encephalopathy, lactic acidosis and also
RRFs on muscle biopsy\textsuperscript{9}.

Previous studies reporting cases of MELAS have shown specific
characteristics on brain MRI imaging of these patients. Transient
stroke-like lesions have been reported in these patients, typically
affecting gray matter without being restricted to vascular areas.
Involvement of white matter has also been observed in MELAS, being more
distinguished in periventricular white matter and centrum semiovale. All
the previously reported cases of MELAS have reported a fluctuating
characteristic for the lesions observed in the brain
MRI\textsuperscript{10}.

The case we report here suffered from progressive cognitive decline,
encephalopathy, seizures and stroke-like episodes, being compatible with
the previously reported cases of MELAS. Nevertheless, this patient had
some unique features, never reported in cases of MELAS so far, leading
to mismanagement. Since structural heart diseases are more common in
young adults with stroke\textsuperscript{11}; to rule out the presence
of any heart diseases, echocardiography was performed in our patient and
patent foramen ovale (PFO) was discovered and confirmed with
trans-esophageal echocardiography (TEE). This finding was first
misdiagnosed as the reason for the patient's symptoms, medication was
prescribed according to this finding and further investigations were
postponed to his next admissions. Despite treatment with anticoagulant,
the patient had had another stroke, so investigation was done again to
find a cause and led to diagnosis of MELAS.

Our literature review revealed no evidence of existing PFO in MELAS
cases. Johnson et al. described a MELAS patient in their case report who
was once diagnosed with PFO in echocardiography which was later ruled
out with TEE. The only reason they could find for the incidence of
stroke in their patient was MELAS syndrome\textsuperscript{13}.

Another unique presentation in our patient was the pattern of ischemia
lesions being different from the previously reported fluctuating
characteristic of the lesions on MRI, lesions had a progressive pattern
in this patient and every time he was admitted, new lesions were added
to the old ones, without disappearing of previous lesions.

In conclusion, this is the first reported case of MELAS syndrome with
PFO and progressive pattern of ischemic lesions on brain MR imaging. The
presence of PFO has led to mismanagement and late diagnosis in this
patient. For this reason further investigations are recommended to rule
out PFO in MELAS cases presenting by stroke-like symptoms.

All procedures performed in this study were in accordance with the
ethical standards of Shahid Beheshti Medical University research ethics
committee and with the 1964 Helsinki Declarations and its later
amendments. The study was approved by the Bioethics Committee of the
Medical University of the Medical University of Shahid Beheshti.

\textbf{Abbreviations:}

\textbf{MELAS:} Mitochondrial myopathy, encephalopathy, lactic acidosis,
and stroke-like episodes

\textbf{MRV:} Magnetic Resonance Venography

\textbf{MRA:} Magnetic Resonance Angiography

\textbf{CT:} Compound Tomography

\textbf{PFO:} patent foramen ovale

\textbf{TEE:} trans-esophageal echocardiography

\textbf{CSF:} Cerebrovascular Fluid

\textbf{RRF:} revealed ragged red fibers

\textbf{EF:} Eejection Fraction

\textbf{ECG:} Electrocardiogram

\textbf{RBC:} Red Blood Cell

\textbf{WBC:} White Blood Cell

\textbf{Hb:} Hemoglobin

\textbf{MCV:} Mean Corpuscular Volume

\textbf{ESR:} Erythrocyte Sedimentation Rate

\textbf{PT:} Prothrombin Time

\textbf{INR:} International Normalized Ratio

\textbf{PTT:} Partial Thromboplastin Time

\textbf{BUN:} Blood Urea Nitrogen

\textbf{Cr:} Creatinine

\textbf{Na:} Sodium (from Latin natrium)

\textbf{K:} Potassium (from Latin kalium)

\textbf{CPK:} Creatine phosphokinase

\textbf{Alk.p:} Alkaline Phosphatase

\textbf{AST (SGOT):} Aspartate Aminotransferase (serum glutamic
oxaloacetic transaminase)

\textbf{ALT (SGPT):} Alanine Transaminase (serum glutamic-pyruvic
transaminase)

\textbf{PCO2:} partial pressure of carbon dioxide

\textbf{HCO3:} Bicarbonate

\textbf{References:}

1. Wang, Y.-X. \& Le, W.-D. Progress in Diagnosing Mitochondrial
Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like
Episodes.\emph{Chin. Med. J. (Engl).} \textbf{128} , 1820--1825 (2015).

2. Thambisetty, M. \& Newman, N. J. Diagnosis and management of
MELAS.\emph{Expert Rev. Mol. Diagn.} \textbf{4} , 631--644 (2004).

3. Pavlakis, S. G., Phillips, P. C., DiMauro, S., De Vivo, D. C. \&
Rowland, L. P. Mitochondrial myopathy, encephalopathy, lactic acidosis,
and strokelike episodes: a distinctive clinical syndrome. \emph{Ann.
Neurol.} \textbf{16} , 481--488 (1984).

4. Hirano, M. \& Pavlakis, S. G. Topical Review: Mitochondrial Myopathy,
Encephalopathy, Lactic Acidosis, and Strokelike Episodes (MELAS):
Current Concepts. \emph{J. Child Neurol.} \textbf{9} , 4--13 (1994).

5. Ciafaloni, E. \emph{et al.} MELAS: clinical features, biochemistry,
and molecular genetics. \emph{Ann. Neurol.} \textbf{31} , 391--398
(1992).

6. Ito, H., Mori, K. \& Kagami, S. Neuroimaging of stroke-like episodes
in MELAS. \emph{Brain Dev.} \textbf{33} , 283--288 (2011).

7. Hirano, M. \& Pavlakis, S. G. Mitochondrial myopathy, encephalopathy,
lactic acidosis, and strokelike episodes (MELAS): current
concepts.\emph{J. Child Neurol.} \textbf{9} , 4--13 (1994).

8. Sinnecker, T. \emph{et al.} Diagnosis of adult-onset MELAS syndrome
in a 63-year-old patient with suspected recurrent strokes - a case
report. \emph{BMC Neurol.} \textbf{19} , 91 (2019).

9. Song, W. J. \emph{et al.} Twenty-one-year follow-up of variable onset
MELAS syndrome with heteroplasmic nt3243A\&gt;G mtDNA mutation: A case
report. \emph{J. Genet. Med.} \textbf{16} , 31--38 (2019).

10. Saneto, R. P., Friedman, S. D. \& Shaw, D. W. W. Neuroimaging of
mitochondrial disease. \emph{Mitochondrion} \textbf{8} , 396--413
(2008).

11. Williams, L. S., Garg, B. P., Cohen, M., Fleck, J. D. \& Biller, J.
Subtypes of ischemic stroke in children and young
adults.\emph{Neurology} \textbf{49} , 1541--1545 (1997).

12. Katsanos, A. H. \emph{et al.} Recurrent stroke and patent foramen
ovale: a systematic review and meta-analysis. \emph{Stroke} \textbf{45}
, 3352--3359 (2014).

13. Johnson, E. C. B., West, T. W., Ko, N. U. \& Strober, J. B. A
41-year-old man with new headache and altered mental status. \emph{The
Neurohospitalist} \textbf{1} , 48--54 (2011).

\textbf{Table 1: Summary of Patient's Laboratory results}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Laboratory Data} & \textbf{Results}\tabularnewline
\midrule
\endhead
\textbf{Blood Tests} & \textbf{Blood Tests}\tabularnewline
WBC & 9200 /uL\tabularnewline
Hb & 12.3 g/dl\tabularnewline
MCV & 87 fL\tabularnewline
Platelets & 271000 /uL\tabularnewline
ESR & 26 mm/hr\tabularnewline
PT & 13\tabularnewline
INR & 1.3\tabularnewline
PTT & 42\tabularnewline
BUN & 21 mg/dl\tabularnewline
Cr & 1.2 mg/dl\tabularnewline
Na & 136 mEq/L\tabularnewline
K & 4.7 mEq/L\tabularnewline
CPK & 184\tabularnewline
Alk.p & 273 U/L\tabularnewline
AST (SGOT) & 17 U/L\tabularnewline
ALT (SGPT) & 28 U/L\tabularnewline
PH & 7.31\tabularnewline
PCO2 & 57\tabularnewline
HCO3 & 28.5\tabularnewline
\textbf{CSF Analysis} & \textbf{CSF Analysis}\tabularnewline
RBC & 120\tabularnewline
Leukocyte & 10\tabularnewline
Neutrophil & 8\tabularnewline
Glucose & 103\tabularnewline
Protein & 45\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{FIGURE 1}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{FIGURE 2}

\textbf{Figure captions}

\textbf{Fig.1} Fluid attenuated inversion recovery (FLAIR) images 2013
showing ischemic lesions in the right occipital lobe and posterior
parietal regions. FLAIR images in 2014 showing left occipital and
posterior parietal lobe ischemia. In 2020 FLAIR imagines revealing
bilateral ischemic lesions on occipitoparietal regions and generalized
brain atrophy.

\textbf{Fig.2} Modified Gomori trichrome section of biopsy showed
increased mithochondrial staining in the subsarcolemmal and
intermyofibrillar region of muscle fibers responsible for Ragged Red
appearance.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

\selectlanguage{english}
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