The patients experience poor spirits, drowsiness, susceptibility to fears, headache, vomiting, delirium, and even coma. The patients may also experience trembling limbs, myoclonia, nystagmus, ataxia, eyeball movement disorder, weak or acute flaccid paralysis (AFP), and convulsions. By physical examinations, signs meningeal irritation can be found, with weakened or absent tendon reflex and Babinski sign positive.

The patients experience shortness of breath, dyspnea or change of respiratory rhythm, cyanosis of lips, and coughing with white, pinkish, or bloody foamy sputum. By auscultation, moist rales or phlegm wheezing can be heard.

The patients experience grayish pale face, skin disturbance, cold limbs, cyanosis of fingers (toes), cold sweating, and prolonged refilling period of the capillaries. The patients may also experience increased or decreased heart rate, superficial and rapid pulses, as well as increased or decreased blood pressure. In other cases, the pulse may be weakened or absent.

Some scholars believed that HFMD caused by EV71 can be hardly distinguished from HFMD caused by CoxA16 based on the clinical symptoms. However, EV71 infection is commonly accompanied by acute aseptic meningitis, brain stem encephalitis, acute flaccid paralysis, and neurogenic pulmonary edema, which is more dangerous than CoxA16 infection. However, CoxA16 infection is simply manifested as HFMD, with no other accompanying diseases. Studies also indicated that the size of herpes as well as the style of rash erupting are different between EV71-induced and CoxA16-induced HFMD.

The infant patients commonly experience myoclonia, trembling, ataxia, nystagmus, and cranial nerve paralysis, such as swallowing nerve, abduct nerve, and facial nerve paralysis. The clinical manifestations are categorized into three levels: Level I, only manifestations of myoclonus, trembling, and ataxia; Level II, concurrence of myoclonus and autonomic nerve dysfunction (including nausea, vomiting, systemic coldness, palpitation, shortness of breath, unstable blood pressure, and elevated blood sugar); and Level III, autonomic nerve dysfunction and pulmonary edema or pulmonary hemorrhage. Pulmonary edema or hemorrhage is manifested by sudden tachypnea, tachycardia, cyanosis, shock, rales at lung and foamy sputum, circulatory failure, coma, absent pupil reflex to light, and apnea. Studies have demonstrated that vomiting, tachycardia, high blood pressure, and dysphagia are the important signs indicating brain stem dysfunction.

The patients experience severe headache and accompanying fever, vomiting, and neck rigidity. In some cases, the patients experience simultaneous involvement of the meninges and brain parenchyma, which is known as the meningoencephalitis type. Accompanying various degrees of consciousness disturbance may be found.

The patients experience acute unilateral or bilateral limb weakness, decreased muscle strength, movement difficulty, and weakened or absent tendon reflex. Most patients can be completely cured, rarely with permanent neurological sequela such as limb paralysis.

EV71 infection might cause acute cerebellar ataxia, and the patients experience trunk ataxia, with/without accompanying nystagmus, most of which can be completely healed. Although brain function can be completely recovered, accompanying various degrees of cerebral cortex atrophy might occur.

Increased peripheral blood WBC count, blood sugar, and early hypersensitivity C-reactive protein (hs-CRP) have clinical significance. The peripheral blood WBC count and blood sugar can be used to assess the condition and predict the prognosis, while Hs-CRP is a sensitive indicator for the early diagnosis and clinical medication.

In some cases, the patients experience mild elevation of ALT, AST, blood sugar, and other myocardial enzymes. The degree of elevation is positively related to the severity of the condition. In addition, it is closely related to the prognosis. At the convalescence stage, these indicators gradually return to normal. Their high levels at the convalescence stage are possibly related to immune lesions.

The titer of the virus and antibody at the acute stage being at least four times above the convalescence stage or the titer ≥1:256 has diagnostic value.

The etiological examinations include viral isolation and culture, RT-PCR, fluorescent quantitative PCR, and serological test. Enterovirus isolation after tissue culture is the golden standard for the diagnosis. Specific nucleic acid test of the enterovirus, such as EV71 and CoxA16, is the main examination to define the pathogen of HFMD, which is efficient, convenient, highly sensitive, and specific. In addition, such a test is more sensitive than cell culture. As one of the diagnostic examinations for enterovirus infection, it can be applied to determine the neutralizing antibody titer of serum enterovirus. The serum collected at the acute stage is commonly compared to that collected at the convalescence stage, and an increase of at least four times of the antibody titer is defined as positive of viral infection.

X-ray and CT scanning are commonly applied to diagnose the respiratory complications of HFMD, whose demonstrations are related to the changes of the condition. The demonstrations show severity, changes, and prognosis of the condition, which are of clinical significance in assessing the condition, changing therapeutic plans, and predicting prognosis.

MR imaging is the most sensitive radiological examination for the diagnosis of HFMD complicated by encephalitis, especially brain stem encephalitis. It can be applied to detect the location, range, and severity of the lesions.

Plain MR imaging commonly demonstrates no abnormalities, and contrast imaging demonstrates no meningeal enhancement, which is different from bacterial meningitis. In cases complicated by viral encephalitis, MR imaging demonstrates necrosis and edema at bilateral temporal lobes and bilateral frontal lobes, with long T₁ long T₂ signals at the affected cerebral lobes.

EV71 can cause brain stem encephalitis, with lesions commonly found at the medulla oblongata, pons, midbrain, and commonly dorsal brain stem. At the acute stage, the lesions are demonstrated with high T₂WI signal and no obvious space-occupying effect but no T₁WI signal, suggesting acute inflammation of the brain tissue. Most of these lesions are reversible. Along with further development of the condition, the lesions are demonstrated with low T₁WI signal, high T₂WI signal, high FLAIR signal, and high DWI signal, with poorly defined boundaries and inapparent space-occupying signs. In some cases, the brain stem is subject to atrophy and shrinkage in the advanced stage, with central cavity at the brain stem (Figs. 17.5, 17.6, and 17.7).

The radiological demonstrations of encephalitis are nonspecific, with large range of lesions involving the cerebral lobes, basal ganglia, thalamus, brain stem, cerebellum, corona radiata, and corpus callosum. The lesions mainly involve the gray matter, possibly with concurrent involvement of the white matter. However, their space-occupying effect is relatively slight, only with local broadening of the gyrus, shallow sulcus, and no shift of the midline structures. The lesions are demonstrated as small patches with low density. MR imaging demonstrates long T1 long T2 signals, high T₂WI FLAIR signal, and high DWI signal, with poorly defined boundaries. CT scanning at the late stage (2 months after onset) demonstrates obvious shrinkage of the lesions and small spots of low-density lesions. MR imaging demonstrates small spots of long T1 long T2 signal, high T₂WI FLAIR signal, and low DWI signal. In cases with brain arterial endarteritis, which leads to cerebral infarction or hemorrhagic cerebral infarction, MR imaging demonstrates signs of cerebral infarction. During the hyperacute stage, T₁WI and T₂WI fail to demonstrate any significant signal change, but high DWI signal. During the acute stage, the lesions are demonstrated as low T₁WI signal, high T₂WI signal, and high FLAIR signal. The lesions eventually develop into encephalomalacia (Figs. 17.8, 17.9, and 17.10). In cases complicated by hemorrhagic cerebral infarction, the signal changes are complex. In the advanced stage, brain atrophy can be demonstrated.