**5. Pathogenesis of neurogenic pulmonary edema**

Patients with enterovirus encephalitis who suffer from pulmonary edema, pulmonary hem‐ orrhage and cardiopulmonary collapse usually have fairly normal premorbid cardiac func‐ tion with normal pulmonary artery pressures and vascular resistance [56]. Myocarditis is also not evident on autopsy reports [57].

Involvement of the medulla and hence, the vagal nucleus and medial reticular nuclei is postulated to cause pulmonary edema [58, 59]. Neurogenic pulmonary edema occurs when there is pulmonary edema and CNS disease in the absence of underlying cardio‐ pulmonary disease [58]. While the pathogenesis is not clear, it is believed that an insult to the medulla results in torrential release of catecholamine. This in turn, causes a rapid increase in total peripheral vasoconstriction and systemic hypertension, shifting blood from the systemic circulation to the pulmonary circulation. Since the pulmonary circula‐ tion is usually a low resistance system, it is unable to adapt to the sudden increase in hy‐ drostatic pressure. The results are protein rich pulmonary edema and pulmonary hemorrhages. The resulting ''catecholamine storm'' induces catecholamine cardiotoxicity as well including coagulative myocytolysis, myofibrillar degeneration, and cardiomyo‐ cytes apoptosis [60]. This neurogenic nature is validated by MRI findings of brainstem in‐ volvement [61] and postmortem examinations of mortality cases of enterovirus encephalitis in which pathological lesions were predominantly located in the brainstem and the spinal cord, rather than in the lung or heart [21, 27, 62].

#### **6. Pathogenesis in chronic infection**

Chronic infection by enterovirus has been reported [63] and it is postulated that the persis‐ tence of infection alters normal neural stem cell migration and or differentiation. Although viral latency has yet to be established, there is evidence for their persistence in infected cells for years [64-66]. Therefore, enteroviral RNA may be reactivated upon stimulation. In the case of hypogammaglobulinaemia, reactivated enterovirus is not inactivated and can spread freely. In the same degree, persistent meningoencephalitis has been reported in patients with agammaglobulinemia [67, 68]. In fact, the first case of enteroviral meningoencephalitis was reported in a patient with agammaglobulinemia [69].
