Moyamoya Angiopathy is known to be a form of immune reactive Vasculitis resulting from vascular immune injury and inflammation response [11, 12]. Inflammation promotes onset or progression of MMA via two major mechanism: (I) anti-inflammatory mediators (IL-4, IL-10, IL-13, IFN-α and TGF-β) affecting vascular reactivity and auto-regulation leading to acceleration or acute aggravation of MMA, (II) pro-inflammatory mediators (IFN-β, IFN-γ, TNF-α, IL-1, IL-6) activating RNF dependent signal transducing pathway and influencing initiation and often fulminant progression of MMA. T-cell mediated autoimmune response can also accelerate the pathology. Thus, an acute systemic inflammatory state is anticipated to cause hyperplasia of the intimal vascular smooth muscle cells and neovascularization by proliferation of endothelial cells, leading to angiogenesis heralding luminal narrowing and collateral formation. In the same lines, SARS-CoV2 induced “cytokine storm” with increase in inflammatory cytokine may influence RNF-213 and caveolin-1 leading to onset and progression of MMA [4, 6].
Besides many factors including dehydration, systemic hypotension, recent infection, hot bath, vigorous exercise, emotional outburst, increased body temperature, crying or hyperventilation can potentiate precipitation of symptoms of MMA by causing transient cerebral hypoperfusion. Infection with SARS-CoV2 and associated hemodynamic stress with emotional disruption and cytokine storm could act as precipitating factors for MMA [5, 6].
The risk of ischemic CVA by itself is more with COVID-19 infection compared to influenza . The three important mechanisms implicated are hypercoagulability, vasculitis and cardiomyopathy. The viral invasion of the vascular endothelium leads to activation of contact and complement system which further initiates inflammatory cascades. The affinity of COVID-19 to the ACE2 receptors expressed abundantly on vascular endothelium, leads to both direct local as well as systemic immune response to pathogen (“cytokine storm”) leading to a widespread thrombosis, microangiopathy and angiogenesis, which disrupts the ACE2 mediated regulation of sympathoadrenal system, vascular autoregulation and cerebral blood flow [8, 14].
Among the 74 patients who could be contacted, 14 patients had features of COVID-19 symptoms, 9 of them suffered from aggravation or new onset neurological symptoms, 8 of them were of pediatric age group. Among the pediatric MMA, only one patient suffered from a new onset fixed motor paresis and later on died most likely by its complications. While the other 7 patients had aggravation of their previous neurological symptom, 5 of them had increase in frequency of TIA and 2 of them suffered from breakthrough seizure. The only adult patient with symptoms suggestive of COVID-19 and aggravation of neurological symptoms had worsening of headache frequency and severity.
The aggravation of TIA symptoms were clinically more significant than occurrence of breakthrough seizures, since focal motor seizure often are residual signs independent from the perfusion status, whereas TIA represents hemodynamic insufficiency which probably precipitated in the background of hemodynamic stress and SARS-CoV2 infection [5, 6, 15]. Moreover, in MMA, it may be extremely difficult to interpret ischemic events, since many MRI-evident ischemic lesions can be clinically silent, while clinical TIA often can be associated with cerebral infarction on brain imaging . Thus, patients with aggravation of TIA in our cohort following flu-like symptoms may have sustained permanent tissue damage of brain, which can be confirmed by brain imaging only after physical follow-up.
The worsening of headache during and immediately after COVID-19 infection can be related to the aggravated cerebral hypoperfusion or may be part of TIA symptom by itself. The already chronically hypoperfused cerebral circulation in patients of MMA leads to lowering of migraine threshold and the ischemic penumbra in states of aggravated hypoperfusion can result in increased risk of spreading cortical depression resulting in migrainous aura [6, 17].
Besides the 2 patients with COVID-19 infection, another 2 patients without any symptoms suggestive of COVID, also of pediatric age group, had suffered breakthrough seizure and non-compliance on anti-epileptic drugs was noted in 3 from these 4 patients. The prevailing COVID-19 pandemic had led to strict travel restrictions, and since majority of our patients were of rural residence, the formation of containment zone according to government policy and curtailment of public transport had greatly deterred the regular physical follow-up of those patients , leading to a protracted period of time since last follow-up of 9.2 ± 1.7 months. In addition, a decreased financial capacity to buy the medications on their own or unavailability for the previously prescribed drugs in their locality has led to non-compliance in 9.5% of our population, leading to the risks of breakthrough seizure.
The major limitation of our study included (1) inability to search out to a major fraction of MMA patients who were a regular follow-up of our stroke-clinic previously, (2) no physical follow-up was possible in the study period, and (3) brain imaging could not be done in our facility even in patients with aggravation of neurological symptoms. However, strength of the study remains in its very frequent verbal contact with a relatively large population of patients harboring a rare disease such as MMA during COVID-19 pandemic allowing the understanding the impact of later on the former.