(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 µmol/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
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Table 1. Clinical Characteristics of Two Young Patients
Presenting with LVO Stroke .