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\begin{document}

\title{Hyperhomocysteinemia is related to large vessel occlusion in young
patients with COVID-19, two case reports}



\author[1]{SeyedehNarges  Tabatabaee}%
\author[2]{Fatemeh Rezania}%
\author[3]{Sevim Soleimani}%
\author[1]{Zahra Mirzaasgari}%
\affil[1]{Iran University of Medical Sciences}%
\affil[2]{St Vincent's Hospital Melbourne Pty Ltd}%
\affil[3]{Shahid Beheshti University of Medical Sciences}%


\vspace{-1em}



  
  \date{May 20, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
We report two cases of previously healthy young men with COVID-19
infection who developed acute ischemic stroke due to large vessel
occlusion followed by secondary events concerning for a further
thromboembolic event. We hypothesize that the hypercoagulable state
related to COVID-19 exacerbated the underlying hereditary thrombophilia
due to MTHFR-gene mutation.%
\end{abstract}%



\sloppy


\textbf{Hyperhomocysteinemia is related to large vessel occlusion in
young patients with COVID-19, two case reports}

Seyedehnarges Tabatabaee\textsuperscript{a} , MD, Fatemeh
Rezania\textsuperscript{b} , MD, Sevim Soleimani\textsuperscript{c} ,
Zahra Mirzaasgari\textsuperscript{a} *, MD

\textsuperscript{a} Division of Neurology, Firoozgar hospital, Iran
University of Medical Sciences, Tehran, Iran

\textsuperscript{b} Neurosciences Department, St Vincent's hospital,
Melbourne, Victoria, Australia

c School of Medicine, Shahid Beheshti Medical University, Tehran, Iran

\textbf{Corresponding author:} Zahra Mirzaasgari, MD, Division of
Neurology, Firoozgar hospital, Iran University of Medical Sciences,
Tehran, Iran

E-mail: Mirzaasgari@gmail.com

Written informed consent was obtained from the patient to publish this
report in accordance with the journal's patient consent policy.

Abstract:

Here, we report two cases of previously healthy young men with COVID-19
infection who developed acute ischemic stroke due to large vessel
occlusion followed by secondary events concerning for a further
thromboembolic event. We hypothesize that the hypercoagulable state
related to COVID-19 exacerbated the underlying hereditary thrombophilia.

Background:

Numerous neurological complications of COVID-19 have been identified.
Severe infection with corona virus could result in headache, epilepsy,
myasthenia gravis, cerebrovascular events and encephalitis (1-5).
Coagulopathy is a common feature of the disease and it is associated
with poor prognosis (6). The association between hyperhomocysteinemia
and cerebrovascular disorders have been studied (7). Elevated plasma
homocysteine levels could take place secondary to insufficient intake of
vitamin B12, vitamin B6, and folic acid as well as a genetic
predisposition. Mutations in the gene encoding the protein MTHFR are the
most commonly known genetic risk factor for hyperhomocysteinemia. The
most common MTHFR mutations are two single nucleotide polymorphisms
(SNP), C677T and A1298C. Both SNPs result in a decreased MTHFR activity,
which may cause hyperhomocysteinemia (8-9). Here we present two young
Asian men with a potential --previously silent- hereditary thrombophilia
who presented with COVID-19 pneumonia and two consecutive thromboembolic
events; i.e. ischemic stroke and NAION.

First case: A previously healthy 39-year-old Asian man was admitted to
hospital with 10 days prodromal symptoms of fever, chills, malaise and
cough (Table 1). There was a positive family history for recurrent deep
vein thrombosis in his mother and maternal aunt. The oropharyngeal swab
test for coronavirus disease 2019 (COVID-19) by qualitative RT-PCR was
positive. He was commenced on COVID-19 treatment with Remdicivir as well
as prophylactic anticoagulation. Despite this his respiratory symptoms
were not improving. Ten days into his admission, he developed a left
hemiparesis involving the face and limbs. He underwent emergent clot
retrieval with recombinant tissue plasminogen activator (rTPA). His
brain CT-scan showed hypodensity within right middle cerebral artery
(MCA) territory (Fig 1.a). He was commenced on dual antiplatelets with
Aspirin 100 mg daily and Clopidogrel 75 mg daily and atorvastatin 80 mg
daily. He was intubated shortly after this due to altered conscious
state together with severe respiratory involvement. Upon completion of
another 7 days of treatment for COVID19 pneumonia with Remdicivir and
Dexamethasone he was successfully extubated. Unfortunately, he declined
further evaluation and left the hospital against medical advice at this
point. He then represented few days later with a painless right eye
vision loss upon waking in the morning. This presentation was about one
month after his initial respiratory symptoms. He was transferred to our
center to undergo diagnostic work-ups. He underwent carotid Doppler
ultrasonography that showed right ICA complete occlusion. This was
confirmed by DSA that showed a complete occlusion of proximal right
carotid artery (fig 1.b). His trans-thoracic echocardiography revealed a
large aortic arch thrombus (fig 1.c). He was commenced on
anti-thrombotic regime, initially with Heparin infusion. This was
switched to Rivaroxaban 20mg daily after. Dual antiplatelet therapy was
ceased. A complete ophthalmic examination was performed by
ophthalmologist who found a relative afferent pupillary defect (RAPD), a
normal optic disc and impaired color vision (as examined by Ishihara
color test) in the right eye. His visual acuity was reduced to hand
motion in the right eye. Intraocular pressure, extraocular movements,
and slit-lamp examination were normal. His ophthalmic history was
unremarkable. The occurrence of consecutive thromboembolic events in the
absence of other risk factors except for COVID infection urged us to run
an extensive thrombophilia screen. Homocysteine level was found to be
elevated at 50\selectlanguage{greek}µ\selectlanguage{english}mol/L (normal lab reference less than 15). Vitamin B12
and folic acid level were normal. MTHFR activity examined by genetic
testing reveled a homozygous MTHFR A1298C variant. He continued on
stroke preventive therapy with Rivaroxaban 20mg daily and atorvastatin
80mg daily, patient was discharged and lost to follow up.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1. a. CT-scan, Hypodensity in MCA territory. B. DSA, Rt ICA
occlusion. C. Trans thoracic echocardiography, a large aortic arch
thrombus.

Second case presentation:

A previously healthy 34-year-old, non-smoker, Asian man was admitted to
hospital with sudden onset right hemiparesis along with Broca's aphasia
(Table 1). Twelve days prior, he had developed symptoms of anosmia,
malaise and cough. His oropharyngeal swab for COVID-19 by qualitative
RT-PCR was positive. At his arrival his brain CT-scan showed hypodensity
within Left ACA and MCA territory (fig 2.a), and there was no time for
clot retrieval treatment. His Magnetic Resonance Imaging of brain
demonstrated a true diffusion restriction within ACA and MCA territory
(fig 2.b, c). He was commenced on dual antiplatelet therapy, with
Aspirin 100 mg daily and Clopidogrel 75 mg daily and Atorvastatin 80 mg
daily. He then underwent carotid Doppler ultrasonography that showed an
acute left ICA complete occlusion due to an intraluminal thrombosis of
5.9x9.8-millimeter diameter (fig 2.d). His trans-thoracic and
transesophageal echocardiography were unremarkable. He was then
commenced on anti-thrombotic regime with Heparin infusion adjusted to
6-hourly PTT monitoring. This was however changed to Rivaroxaban 20mg
daily. An acute rise in his serum creatinine level from 0.9 mg/dL to 4.6
mg/dL was detected on day 8th. Although his acute kidney injury (AKI)
suggested to be secondary to an ATN due to Glomerulonephritis after
renal consultation, kidney biopsy was not performed due to ongoing
anticoagulation therapy to prove this. He received 1-gram intravenous
methylprednisolone daily for 3 days. Kidney function subsequently
improved. His Serum creatinine was 1.3 mg/dl at time of discharge.
Kidney injury secondary to thromboembolic events, is one of the major
complications of COVID-19 and is considered as a mortality factor. The
possibility of sequential thromboembolic events in the absence of other
known risk factors except for COVID infection urged us to run an
extensive thrombophilia screen. Homocysteine level was found to be
62\selectlanguage{greek}µ\selectlanguage{english}mol/L. Therefore, MTHFR activity was examined by genetic testing and
reveled a homozygous mutant for the MTHFR C677T polymorphism. Treatment
continued with Rivaroxaban 20mg daily and atorvastatin 80mg daily,
patient was discharged and lost to follow up.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2. a. CT. Scan, Hypodensity in MCA territory. b \& c. MRI, FLAIR,
hyperintense lesion in MCA territory. c. Carotid Doppler
ultrasonography, acute left ICA complete occlusion.

\textbf{(Location of Table 1)}

Discussion:

Respiratory disorders have been reported as the main complication of
COVID-19. However, there are reports that documented many other symptoms
like cerebrovascular events especially secondary to an increase in risk
of coagulopathy (10). This study describes two previously healthy men
with COVID-19 that presented with ischemic stroke due to large vessel
occlusion due to MTFHR gene mutations. To our knowledge these are the
first two cases describing MTFHR gene mutations in the setting of
hypercoagulability and sequential thromboembolic events in COVID-19
infection. The relative ratio of strokes in the young with age under 45
years old has been increasing over the past few decades (11).
Hematologic and vasculopathic etiologies accounts for 44\% of strokes in
young patients (12). The most common causes in this age group are
nonatherosclerotic, more often as a consequence of cardio embolism or
arterial dissection (13). Inflammation-driven hypercoagulable and
vasculopathic state secondary to a recent infection is an independent
risk factor for stroke (odds ratio 3.4--14.5), mostly respiratory in
origin (14-15). It has been reported that higher incidence of ischemic
stroke is common with other respiratory viruses like Influenza and also
with other coronaviruses (16) and recent data suggests COVID-19 confers
a greater risk of stroke than influenza (17). Now it is well documented
that COVID-19 can lead to hypercoagulable state that results in venous
and arterial thromboembolism (10, 18). Our patients were found to have
elevated serum homocysteine, possibly contributing to their
hypercoagulable states. Typically, a level 60 \selectlanguage{greek}µ\selectlanguage{english}mol/L is considered
severely elevated (19). The elevated serum homocysteine which is the
result of MTHFR gene polymorphisms as in case of MTHFR C677T could lead
to decreased enzyme activity and therefore to an elevation of serum
homocysteine leve and in turn to thromboembolic events (9). It is
controversial whether ischemic stroke is directly related to MTFHR
mutation or not. In a recent study in Tunisian adults, it is confirmed
that C677T and A1298C MTFHR variants are important risk factors for
arterial ischemic strokes (20). In a meta-analysis by Shan Kang et al
MTHFR A1298C genetic polymorphism was associated with increased risk of
ischemic strokes (21). Acute cerebrovascular disease was reported to
occur 1.4\% of COVID-19 patients. The most common manifestation in
87.4\% of these patients was with acute ischemic stroke (22). Mao et al
reported 5.7\% of patients with severe COVID-19 infection developed
cerebrovascular disease later in the course of illness (23). More
recently, emergent large LVO has been reported in patients with
COVID-19. Shingo Kihira et al suggested that COVID-19 is related to LVO
rather than small vessel occlusion. In their study of 329 participants,
71 patients (21.6\%) developed LVO (24). Likewise, in our cases carotid
occlusion took place in previously healthy young adults. Several studies
have found an association between hyperhomocysteinemia and NAION
(25-26). Different mechanisms have been suggested to play role. In our
case, coagulation disorders could be in play (27). The high
coagulopathic complications in our cases could be related to high levels
of homocysteine along with MTHFR gene mutism that might have remained
silent in the absence of COVID-19. This highlights the importance of
thrombophilia assessment in COVID-19 patients with sequential events
concerning for recurrent thromboembolism.

Conclusion:

We presented two cases of previously healthy young men with COVID-19
infection who developed acute ischemic stroke due to large vessel
occlusion followed by secondary events concerning for a further
thromboembolic event. Both these patients were found to have
hyperhomocysteinemia along with a MTFHR gene mutation. Hypercoagulable
state as a result of COVID-19 could have exacerbated the underlying
silent coagulopathy in these patients. We suggest that performing an
extensive thrombophilia screen is indicated in COVID-19 patients without
conventional vascular risk factors who present with recurrent events
concerning for thromboembolism.

List of abbreviations:

NAION: Nonarthritic anterior ischemic optic neuropathy

ATN: Acute tubular necrosis

LVO: Large vessel occlusion

RT-PCR: Real-time reverse-transcriptase-- polymerase-chain-reaction

DSA: Digital subtraction angiography

ICA: Internal carotid artery

MTFHR: Methylenetetrahydrofolate reductase

rTPA: Recombinant tissue plasminogen activator

MCA: Middle cerebral artery

ACA: Anterior cerebral artery

RAPD: Relative afferent pupillary defect

AKI: Acute kidney injury

NIHSS: National Institutes of Health Stroke Scale

References:

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MTHFR (C677T, A1298C), FV Leiden polymorphisms, and the prothrombin
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24. Kihira S, Schefflein J, Mahmoudi K, Rigney B, N. Delman B, Mocco J,
et al. Association of coronavirus disease (COVID-19) with large vessel
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Evaluation of traditional and emerging cardiovascular risk factors in
patients with non-arteritic anterior ischemic optic neuropathy: a
case-control study. Graefe's Archive for Clinical and Experimental
Ophthalmology. 2009;247(5):693-7.

26. Kawasaki A, Purvin VA, Burgett RA. Hyperhomocysteinaemia in young
patients with non-arteritic anterior ischaemic optic neuropathy. British
journal of ophthalmology. 1999;83(11):1287-90.

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disease 2019: a systematic review. Inflammation and Regeneration.
2020;40(1):31.

\textbf{Table 1. Clinical Characteristics of Two Young Patients
Presenting with LVO Stroke} .\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
Variable & patient 1 & patient 2\tabularnewline
\midrule
\endhead
Age-yr & 39 & 34\tabularnewline
Sex & Male & Male\tabularnewline
Medical history and risk factor for stroke & None & None\tabularnewline
Medications & None & None\tabularnewline
NIHSS score & 11 & 12\tabularnewline
Outcome status & Discharged home & Discharged home\tabularnewline
Signs and symptoms of stroke & Left hemiparesis, Dysarthria & Broca
aphasia, Right hemiparesis\tabularnewline
Vascular territory & proximal right ICA & proximal Left
ICA\tabularnewline
Imaging for diagnosis & CT, DSA & CT, MRI, Cervical color doppler
sonography\tabularnewline
Treatment for stroke & Heparin, Rivaroxaban & Heparin,
Rivaroxaban\tabularnewline
COVID-19 symptoms & Malaise, Headache, Fever, Cough & Anosmia, Malaise,
Cough\tabularnewline
White-cell count-per mm3 & 9800 & 6800\tabularnewline
Platelet count-per mm3 & 183000 & 263000\tabularnewline
Prothrombin time-sec & 14 & 13.5\tabularnewline
Activated partial thromboplastin time-sec & 28 & 27\tabularnewline
Fibrinogen-mg/dl & 323 & 255\tabularnewline
D-dimer-ng/ml & Positive & Weakly positive\tabularnewline
\bottomrule
\end{longtable}

Reference ranges are as follows: platelet count, 150,000 to 450,000 per
cubic millimeter; prothrombin time, 12.3 to 14.9 seconds; activated
partial-thromboplastin time, 25.4 to 34.9 seconds; fibrinogen, 175 to
450 mg per deciliter.

Scores on the National Institutes of Health Stroke Scale (NIHSS) range
from 0 to 42, with higher numbers indicating more severe stroke.

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