MIS-A and MIS-C are heterogeneous disorders with a variable clinical spectrum. Delayed diagnosis, increasing severity of illness, and severe neurological involvement increase mortality and morbidity. Neurological manifestations are often overshadowed by cardiac or multi-organ dysfunction, and are reported only in around 23% of MIS-C.21 Organ symptoms that are prominently involve the gastrointestinal and cardiac systems.
Our series demonstrates prominent and early neurological manifestations of MIS-A. 67.5% of patients experienced disabling strokes, however transverse myelitis COVID encephalitis, rhabdomyolysis, acute encephalopathy and critical illness myo-neuropathy (CIMN) were also encountered. Importantly 50% did not have a significant cardiac illness. When severe cardiac manifestations developed, they occurred later in the illness leading to a delayed consideration of MIS-A.1
The average time to recognition of MIS-A was longer in patients without early cardiac manifestations (4.1 days) as compared to patients with early cardiac manifestations (1.5 days). However, this discrepancy is also explained by the earlier consideration of MIS-A when cardiogenic manifestations supervened as well as increasing familiarity with MIS-A during the later part of the study.
D-dimer, CRP, ferritin were the most frequently elevated laboratory markers. Lymphopenia was frequently encountered and the median number of organ systems involved was 3.37 (range 1–5).
Anticipating that MIS-A may be reported as an adverse event following immunization (AEFI), three post-vaccination (PV-AEFI) scenarios have been postulated.6 [Figure 3] In our cohort, we encountered a fourth scenario: MIS-A in two partially vaccinated patients with concurrent COVID-19 re-infection in one and new COVID-19 infection in the other (10 days after the first dose). (Fig. 3). Whether the MIS-A was precipitated by SARS-CoV-2 infection or potentiated by immunization is unclear (as in antibody dependent enhancement). Nevertheless, the first case (Patient no 2) developed MIS-A within the expected timeline for a PV-MIS-A (> 4 weeks). It was also difficult to differentiate between COVID-19 associated encephalitis or a MISA-encephalitis.
COVID-19 induces both a thrombocytopathy (functional platelet disorders affecting either platelet activity and/or function) and an endotheliopathy (functional endothelial disorders affecting either endothelial activity and/or function). The combination of these two leads to a thrombo-inflammation.7 The SARS CoV-2 virus also impairs the immune system resulting in a Th2 response against the virus rather than the essential Th1 response. This excessive humoral response with a diminished cellular immune response can lead to severe disease manifestations as well as a Type 3 hypersensitivity with deposition of immune complexes in blood vessels, complement activation and recruitment of other immune cells such as, producing a COVID microvasculitis.8
Although strokes are uncommon in COVID-19 and account for < 1.3% of complications, they are more disabling and associated with higher mortality.9Multiple mechanisms are responsible for ischemic strokes in COVID-19. While the main mechanisms include hypercoagulability, vasculitis, thrombo-inflammation and cardiomyopathy. Secondary hemorrhagic transformation of ischemic strokes may be due to endothelial damage or a COVID-19 associated consumption coagulopathy.10
ACE 2 receptors have been found in the diaphragm of some patients with COVID-19. 11This may have a role in prolonged respiratory muscle weakness and longer duration of mechanical ventilation. Critical illness myopathy (CIM) and polyneuropathy (CIP) are found in patients with severe COVID-19 after prolonged ICU stay. Other factors such as medications, steroids, critical illness per se, muscle hypoperfusion and metabolic factors also contribute to CIM and CIP.12,13 Almost 60% of those who die during acute COVID-19 show muscle inflammation, ranging from mild to severe inflammatory myopathy. In fact, SARS-CoV-2 is thought to be associated with an immune-mediated myopathy.14
Whether similar mechanisms are at play in MIS-A are as yet unknown. Nevertheless, the para or post infectious hyperinflammatory host response is likely to injure the same structures as in acute COVID-19. Thus, the neurological manifestations of MIS-A mirror those seen in acute COVID-19, albeit with a lower frequency due to the rarity of this syndrome compared to the pandemic.
As MIS-A is still a rare condition and our sample size is comparatively small, we could have missed other neurological manifestations of MIS-A. Nevertheless, as our study was conducted in a quaternary care hospital, where complex cases are admitted, our study findings are likely to be generalisable to the population.
In conclusion, conspicuous neurological manifestations with MIS-A are rare (> 2.2%) and often overshadowed by multi-system organ dysfunction. However, neurological disorders can be the presenting manifestation of a MIS-A. Such patients also may be left with greater morbidity and mortality.