**7. Clinical signs and symptoms**

fore, enhancing infectivity. *In vitro* experiments have shown that the addition of immune sera from patients increased EV71 infection of THP-1 cells, a leukemia cell line of macro‐ phage lineage with monocytic markers, whereas addition of Fc-RI (CD64) significantly in‐

Furthermore, patients who suffer from neurogenic pulmonary edema have been reported to have lower absolute monocyte counts, CD4, CD8 and NK cells counts as compared to pa‐ tients who had autonomic nerve system abnormalities and uncomplicated brainstem ence‐

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

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

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

**5. Pathogenesis of neurogenic pulmonary edema**

and the spinal cord, rather than in the lung or heart [21, 27, 62].

**6. Pathogenesis in chronic infection**

also not evident on autopsy reports [57].

hibited the infection [54].

phalitis [56].

268 Encephalitis

Enteroviruses can cause a wide spectrum of clinical diseases, including but not limited to the common cold, gastroenteritis, hand, foot and mouth disease (HFMD), herpangina, myo‐ carditis, severe neonatal sepsis-like disease, hepatoadrenal failure, aseptic meningitis, acute flaccid paralysis, meningoencephalitis, encephalitis, neurogenic pulmonary edema, pulmo‐ nary hemorrhage and shock induced sudden death especially in the young age group [13, 62, 70]. The neurological presentations include aseptic meningitis, benign intracranial hyper‐ tension, acute flaccid paralysis, opsoclonus-myoclonus syndrome, Guillain-Barre syndrome, transverse myelitis, encephalitis, cerebellitis, brainstem encephalitis, rhombencephalitis and encephalomyelitis [13, 25, 26, 71-76].

Clinical manifestations can be classified according to 5 grades. In grade I, patients demon‐ strate clinical signs of HFMD and/or herpangina with erythematous vesicles on palms, soles, elbows and trunk and oral ulcers on mucosa of lips as well as palate. The majority of pa‐ tients will display grade I symptoms as seen in the 1998 Taiwan epidemic where 5506 out of 5632 patients were classified to have grade I symptoms [61]. In grade II, patients suffer from fever, photophobia, vomiting, headache, and abdominal pain. Patients who initially exhibit grade II symptoms may subsequently progress onto grade III. The disease may take a fulmi‐ nant course in patients younger than 2 years of age, deteriorating directly to grade IV in a short period of time. In grade III, patients may demonstrate lethargy, apathy, drowsiness, tachycardia, cranial nerve involvement (VI-XII), myoclonic jerks, monoparesis or hemipare‐ sis, conjugate gaze disturbances, dyspnea and ataxia. Patients with grade III symptoms that are younger than 2 years of age usually progress to grade IV while older patients tend to recover completely after 1-2 weeks. In grade IV, patients experience hypothermia, pulmona‐ ry edema, respiratory failure, neurogenic shock and semicoma. In the last stage, grade V, there is pulmonary hemorrhage, respiratory distress syndrome, cardiorespiratory failure, coma and death. According to symptomatology, encephalitis is suspected in grade III-IV.

HFMD and herpangina are generally mild, self-limiting illnesses that occur in infants and young children. The culprit virus for HFMD and herpangina is usually coxsackie-virus A16 or EV71 [8, 14, 19]. Despite this, a small percentage of patients can rapidly decompensate and die within days. In cases where neurological complications occur, the culprit viruses isolated are usually EV71 and coxsackie-virus A16 [19] in some instances other echovirus 7 [77, 78].

Patients who had CNS complications were usually younger and more likely to have symp‐ toms of fever, vomiting, breathlessness and signs of shock that includes cold peripheries and poor urinary output [5]. The exact symptoms and signs depend on the extent of CNS in‐ volvement. For example, in EV71 encephalitis, clinical signs of lethargy and cranial nerve palsies such as conjugate gaze disturbance, dyspnea and tachycardia suggest involvement of the brain stem, [61] and this is further substantiated by the magnetic resonance imaging.
