Common constitutional signs and symptoms of the HFMD include fever, nausea, vomiting, feeling tired, generalized discomfort, loss of appetite, and irritability in infants and toddlers. Skin lesions frequently develop in the form of a rash of flat discolored spots and bumps which may be followed by vesicular sores with blisters on palms of the hands, soles of the feet, buttocks, and sometimes on the lips. The rash is rarely itchy for children, but can be extremely itchy for adults. Painful facial ulcers, blisters, or lesions may also develop in or around the nose or mouth. HFMD usually resolves on its own after 7–10 days. Most cases of the disease are relatively harmless, but complications including encephalitis, meningitis, and paralysis that mimics the neurological symptoms of polio can occur.

Hand, foot, and mouth disease (HFMD) is a common infection caused by a group of viruses. It typically begins with a fever and feeling generally unwell. This is followed a day or two later by flat discolored spots or bumps that may blister, on the hands, feet, and mouth, and occasionally buttocks and groin. Signs and symptoms normally appear 3–6 days after exposure to the virus. The rash generally goes away on its own in about a week. Fingernail and toenail loss may occur a few weeks later, but will regrow with time.

The viruses that cause HFMD are spread through close personal contact, through the air from coughing, and the feces of an infected person. Contaminated objects can also spread the disease. Coxsackievirus A16 is the most common cause and Enterovirus 71 is the second-most common cause. Other strains of coxsackievirus and enterovirus can also be responsible. Some people may carry and pass on the virus despite having no symptoms of disease. Other animals are not involved. Diagnosis can often be made based on symptoms. Occasionally a throat or stool sample may be tested for the virus.

Handwashing may prevent spread and those infected should not go to work, daycare, or school. No antiviral medication or vaccine is available, but development efforts are underway. Most cases require no specific treatment. Simple pain medication such as ibuprofen or numbing mouth gel may be used. Occasionally intravenous fluids are given to children who are unable to drink enough. Rarely viral meningitis or encephalitis may complicate the disease.

HFMD occurs in all areas of the world. It often occurs in small outbreaks in nursery schools or kindergartens. Large outbreaks have been occurring in Asia since 1997. It usually occurs during the spring, summer, and fall months. Typically it occurs in children less than five years old, but can occasionally occur in adults. HFMD should not be confused with foot-and-mouth disease (also known as hoof-and-mouth disease) which mostly affects livestock.

Signs and symptoms may vary and some individuals may not experience any symptoms at all. The most common reported symptom of polioencephalitis is fatigue. Fatigue is associated with difficulty in attention, cognition, and maintaining wakefulness Some individuals experience psychiatric symptoms that include anxious mood, pain, insomnia, and depressed mood. Confusion and disorientation of time and space have also been reported. Motor symptoms vary more from patient to patient, but can include incoordination and tremors, nystagmus, loss of conjugate eye movements, rigidity and hemiparesis.

Viral encephalitis is a type of encephalitis caused by a virus.

It is unclear if anticonvulsants used in people with viral encephalitis would prevent seizures.

The incubation period for WNV—the amount of time from infection to symptom onset—is typically from between 2 and 15 days. Headache can be a prominent symptom of WNV fever, meningitis, encephalitis, meningoencephalitis, and it may or may not be present in poliomyelitis-like syndrome. Thus, headache is not a useful indicator of neuroinvasive disease.

- West Nile fever (WNF), which occurs in 20 percent of cases, is a febrile syndrome that causes flu-like symptoms. Most characterizations of WNF generally describe it as a mild, acute syndrome lasting 3 to 6 days after symptom onset. Systematic follow-up studies of patients with WNF have not been done, so this information is largely anecdotal. In addition to a high fever, headache, chills, excessive sweating, weakness, fatigue, swollen lymph nodes, drowsiness, pain in the joints and flu-like symptoms. Gastrointestinal symptoms that may occur include nausea, vomiting, loss of appetite, and diarrhea. Fewer than one-third of patients develop a rash.

- West Nile neuroinvasive disease (WNND), which occurs in less than 1 percent of cases, is when the virus infects the central nervous system resulting in meningitis, encephalitis, meningoencephalitis or a poliomyelitis-like syndrome. Many patients with WNND have normal neuroimaging studies, although abnormalities may be present in various cerebral areas including the basal ganglia, thalamus, cerebellum, and brainstem.

- West Nile virus encephalitis (WNE) is the most common neuroinvasive manifestation of WNND. WNE presents with similar symptoms to other viral encephalitis with fever, headaches, and altered mental status. A prominent finding in WNE is muscular weakness (30 to 50 percent of patients with encephalitis), often with lower motor neuron symptoms, flaccid paralysis, and hyporeflexia with no sensory abnormalities.

- West Nile meningitis (WNM) usually involves fever, headache, and stiff neck. Pleocytosis, an increase of white blood cells in cerebrospinal fluid, is also present. Changes in consciousness are not usually seen and are mild when present.

- West Nile meningoencephalitis is inflammation of both the brain (encephalitis) and meninges (meningitis).

- West Nile poliomyelitis (WNP), an acute flaccid paralysis syndrome associated with WNV infection, is less common than WNM or WNE. This syndrome is generally characterized by the acute onset of asymmetric limb weakness or paralysis in the absence of sensory loss. Pain sometimes precedes the paralysis. The paralysis can occur in the absence of fever, headache, or other common symptoms associated with WNV infection. Involvement of respiratory muscles, leading to acute respiratory failure, can sometimes occur.

- West-Nile reversible paralysis, Like WNP, the weakness or paralysis is asymmetric. Reported cases have been noted to have an initial preservation of deep tendon reflexes, which is not expected for a pure anterior horn involvement. Disconnect of upper motor neuron influences on the anterior horn cells possibly by myelitis or glutamate excitotoxicity have been suggested as mechanisms. The prognosis for recovery is excellent.

- Nonneurologic complications of WNV infection that may rarely occur include fulminant hepatitis, pancreatitis, myocarditis, rhabdomyolysis, orchitis, nephritis, optic neuritis and cardiac dysrhythmias and hemorrhagic fever with coagulopathy. Chorioretinitis may also be more common than previously thought.

- Cutaneous manifestations specifically rashes, are not uncommon in WNV-infected patients; however, there is a paucity of detailed descriptions in case reports and there are few clinical images widely available. Punctate erythematous, macular, and papular eruptions, most pronounced on the extremities have been observed in WNV cases and in some cases histopathologic findings have shown a sparse superficial perivascular lymphocytic infiltrate, a manifestation commonly seen in viral exanthems. A literature review provides support that this punctate rash is a common cutaneous presentation of WNV infection.

Polioencephalitis is a viral infection of the brain, causing inflammation within the grey matter of the brain stem. The virus has an affinity for neuronal cell bodies and has been found to affect mostly the midbrain, pons, medulla and cerebellum of most infected patients. The infection can reach up through the thalamus and hypothalamus and possibly reach the cerebral hemispheres. The infection is caused by the poliomyelitis virus which is a single-stranded RNA virus surrounded by a non-enveloped capsid. Humans are the only known natural hosts of this virus. The disease has been eliminated from the U.S. since the mid-twentieth century, but is still found in certain areas of the world such as Africa.

An emerging infectious disease (EID) is an infectious disease whose incidence has increased in the past 20 years and could increase in the near future. Emerging infections account for at least 12% of all human pathogens. EIDs are caused by newly identified species or strains (e.g. Severe acute respiratory syndrome, HIV/AIDS) that may have evolved from a known infection (e.g. influenza) or spread to a new population (e.g. West Nile fever) or to an area undergoing ecologic transformation (e.g. Lyme disease), or be "reemerging" infections, like drug resistant tuberculosis. Nosocomial (hospital-acquired) infections, such as methicillin-resistant Staphylococcus aureus are emerging in hospitals, and extremely problematic in that they are resistant to many antibiotics. Of growing concern are adverse synergistic interactions between emerging diseases and other infectious and non-infectious conditions leading to the development of novel syndemics. Many emerging diseases are zoonotic - an animal reservoir incubates the organism, with only occasional transmission into human populations.

After an incubation period of up to seven days, the signs associated with swine vesicular disease occur. The first sign is a transient mild fever. Other signs include:

- Vesicles in the mouth and on the snout and feet

- Lameness and an unsteady gait, shivering and jerking–type leg movements

- Ruptured vesicles can cause ulcers on limbs and feet, and foot pads may be loosened.

Young animals are more severely affected. Recovery often occurs within a week. There is no mortality.

Swine vesicular disease has the same clinical signs as foot-and-mouth disease, and can only be diagnosed by laboratory testing.

The conjunctiva provides lining for the inside of the eyelid as well as a coating for the sclera, the white portion of the eyeball. It typically serves to provide lubrication for the eye through the production of mucus and tears. When infected with AHC, patients will experience painful, red eyes, swelling of the conjunctival tissue, and frequent mucus discharge from the eyes accompanied by excessive tearing and subconjunctival hemorrhaging. This hemorrhaging is caused by the rupture of blood vessels beneath the conjunctiva giving the eyes a bright red appearance. Some patients also experience blurry vision and fever in addition to the common symptoms and one in every ten thousand cases exhibits paralysis similar to that of polio.

West Nile fever is a viral infection typically spread by mosquitoes. In about 75% of infections people have few or no symptoms. About 20% of people develop a fever, headache, vomiting, or a rash. In less than 1% of people, encephalitis or meningitis occurs, with associated neck stiffness, confusion, or seizures. Recovery may take weeks to months. The risk of death among those in whom the nervous system is affected is about 10%.

West Nile virus is typically spread by infected mosquitoes. Mosquitoes become infected when they feed on infected birds. Rarely the virus is spread through blood transfusions, organ transplants, or from mother to baby during pregnancy, delivery, or breastfeeding. It otherwise does not spread directly between people. Risks for severe disease include age over 60 and other health problems. Diagnosis is typically based on symptoms and blood tests.

There is no human vaccine. The best method to reduce the risk of infections is avoiding mosquito bites. This may be done by eliminating standing pools of water, such as in old tires, buckets, gutters, and swimming pools. Mosquito repellent, window screens, mosquito nets, and avoiding areas where mosquitoes occur may also be useful. While there is no specific treatment, pain medications may be useful.

WNV occurs in Europe, the Middle East, Africa, India, Asia, Australia, and North America. In the United States thousands of cases are reported a year, with most occurring in August and September. It can occur in outbreaks of disease. The virus was discovered in Uganda in 1937 and was first detected in North America in 1999. Severe disease may also occur in horses and a vaccine for these animals is available. A surveillance system in birds is useful for early detection of a potential human outbreak.

Zika virus infections have been strongly associated with Guillain–Barré syndrome (GBS), which is a rapid onset of muscle weakness caused by the immune system damaging the peripheral nervous system, and which can progress to paralysis. While both GBS and Zika infection can simultaneously occur in the same individual, it is difficult to definitively identify Zika virus as the cause of GBS. Several countries affected by Zika outbreaks have reported increases in the rate of new cases of GBS. During the 2013–2014 outbreak in French Polynesia there were 42 reported cases of GBS over a 3-month period, compared to between 3 and 10 annually prior to the outbreak.

Most people who are infected have no or few symptoms. Otherwise the most common signs and symptoms of Zika fever are fever, rash, conjunctivitis (red eyes), muscle and joint pain, and headache, which are similar to signs and symptoms of dengue and chikungunya fever. The time from a mosquito bite to developing symptoms is not yet known, but is probably a few days to a week. The disease lasts for several days to a week and is usually mild enough that people do not have to go to a hospital.

Due to being in the same family as dengue, there has been concern that it could cause similar bleeding disorders. However that has only been documented in one case, with blood seen in semen, also known as hematospermia.

Acute hemorrhagic conjunctivitis (AHC) (also spelled acute haemorrhagic conjunctivitis) is a derivative of the highly contagious conjunctivitis virus, otherwise known as pink eye. Symptoms include excessively red, swollen eyes as well as subconjuntival hemorrhaging. Currently, there is no known treatment and patients are required to merely endure the symptoms while the virus runs its five- to seven-day course. While it was first identified in Ghana, the virus has now been seen in China, India, Egypt, Cuba, Singapore, Taiwan, Japan, Pakistan, Thailand, and the United States.

Diagnosis is based on a circular "bull's-eye" rash at the site of infection called erythema chronicum migrans, which is very similar to that seen in Lyme disease. However, the symptoms of STARI are mild, and resemble influenza, with fatigue, muscle pains, and headache. Fever is sometimes seen, but is not characteristic.

Swine vesicular disease is most commonly brought into a herd by the introduction of a subclinically infected pig.

The disease can be transmitted in feed containing infected meat scraps, or by direct contact with infected feces (such as in an improperly cleaned truck).

ADEM has an abrupt onset and a monophasic course. Symptoms usually begin 1–3 weeks after infection. Major symptoms include fever, headache, nausea and vomiting, confusion, vision impairment, drowsiness, seizures and coma. Although initially the symptoms are usually mild, they worsen rapidly over the course of hours to days, with the average time to maximum severity being about four and a half days. Additional symptoms include hemiparesis, paraparesis, and cranial nerve palsies.

Residual motor deficits are estimated to remain in about 8 to 30% of cases, the range in severity from mild clumsiness to ataxia and hemiparesis.

Symptoms may include fever and headache, but the distinguishing characteristic of this disease is attacks of severe pain in the lower chest, often on one side. The slightest movement of the rib cage causes a sharp increase of pain, which makes it very difficult to breathe, and an attack is therefore quite a frightening experience, although it generally passes off before any actual harm occurs. The attacks are unpredictable and strike "out of the blue" with a feeling like an iron grip around the rib cage. The colloquial names for the disease, such as 'The Devil's grip' (see also "other names" below) reflect this symptom.

Southern tick-associated rash illness (STARI) or Masters' disease is an emerging infectious disease related to Lyme disease that occurs in southeastern and south-central United States. It is spread by tick bites, but the organism that causes the infection is unknown.

Zoonoses are infectious diseases of animals (usually vertebrates) that can naturally be transmitted to humans.

Major modern diseases such as Ebola virus disease and salmonellosis are zoonoses. HIV was a zoonotic disease transmitted to humans in the early part of the 20th century, though it has now evolved to a separate human-only disease. Most strains of influenza that infect humans are human diseases, although many strains of swine and bird flu are zoonoses; these viruses occasionally recombine with human strains of the flu and can cause pandemics such as the 1918 Spanish flu or the 2009 swine flu. "Taenia solium" infection is one of the neglected tropical diseases with public health and veterinary concern in endemic regions. Zoonoses can be caused by a range of disease pathogens such as viruses, bacteria, fungi and parasites; of 1,415 pathogens known to infect humans, 61% were zoonotic. Most human diseases originated in animals; however, only diseases that routinely involve animal to human transmission, like rabies, are considered direct zoonosis.

Zoonoses have different modes of transmission. In direct zoonosis the disease is directly transmitted from animals to humans through media such as air (influenza) or through bites and saliva (rabies). In contrast, transmission can also occur via an intermediate species (referred to as a vector), which carry the disease pathogen without getting infected. When humans infect animals, it is called reverse zoonosis or anthroponosis. The term is from Greek: ζῷον "zoon" "animal" and νόσος "nosos" "sickness".

A summary of the condition was issued by the United States Centers for Disease Control as part of a September 26, 2014 health advisory:

The CDPHE, Children's Hospital Colorado, and CDC are investigating nine cases of acute neurologic illness among pediatric patients. The cases were identified during August 9–September 17, 2014 among children aged 1–18 years (median age 10 years). Most of the children were from the Denver metropolitan area. All were hospitalized. Common features included acute focal limb weakness and specific findings on magnetic resonance imaging (MRI) of the spinal cord consisting of non-enhancing lesions largely restricted to the gray matter. In most cases, these lesions spanned more than one level of the spinal cord. Some also had acute cranial nerve dysfunction with correlating non-enhancing brainstem lesions on MRI. None of the children experienced altered mental status or seizures. None had any cortical, subcortical, basal ganglia, or thalamic lesions on MRI. Most children reported a febrile respiratory illness in the two weeks preceding development of neurologic symptoms In most cases, cerebrospinal fluid (CSF) analyses demonstrated mild-moderate pleocytosis (increased cell count in the CSF) consistent with an inflammatory or infectious process

The CDC requested physicians provide information about cases meeting four criteria: patients diagnosed after August 1, 2014, who are no older than 21 years of age, showing acute onset of focal limb weakness, with a spinal cord lesion largely restricted to gray matter visualized by MRI.

A group in Texas reported having observed a pattern in 2013 of one to four cases per year with similar polio-like characteristics.

The CDC Morbidity and Mortality Weekly Report and a CDC Clinician Outreach and Communication Activity (COCA) conference call, noted that many cases had neck, back, or extremity pain, but otherwise those affected generally had normal sensation in their limbs. A few participants in the conference call discussed whether pain, later abating, might precede the onset of paralysis.

An October 21 report in "Neurology News" described outbreaks in California and Colorado, suggesting that the number of cases might be 100 or more nationwide. Diagnosis included a good medical history, MRI imaging, and the elimination of transverse myelitis or Guillain–Barré syndrome as potential causes. Physicians were using a listserv online mailing list to communicate about similar cases in Alabama and Kansas. The largest known cluster of cases was in Colorado, with 29 total, 12 of which were reported since August.

Three out of four cases treated in Alabama involved a complete inability to move one arm, reminiscent of peripheral nerve injury: The three cases since August really look like each other. They have severe arm flaccidity and no mental status changes. All of them have similar spine MRIs showing gray matter involvement. You could lay all three MRIs on top of each other and they look almost the same. It's pretty striking. ... It you lift the arm up, it literally drops. Sensation is usually intact. There might be slightly decreased sensation in the other arm, but these are younger kids, so they’re not always so cooperative in giving you a good sensory exam.

Children’s Mercy Hospital, where three or possibly four cases had occurred since August reports: The sudden onset of flaccid paralysis in single or multiple limbs with absolutely no sensory findings, the MRIs all showing uniformly a signal increase in the ventral horns of the spinal cord — this is exactly the same region of the spinal cord affected in polio ... Almost all of the patients have an increase in their white blood cells in the cerebrospinal fluid. Some of the patients have brainstem findings and cranial-nerve findings. This is all the same as what polio does. None of us has ever seen anything like this before, with few exceptions.

An October 23 special session at an annual meeting of the Child Neurology Society, where a show of hands suggested that the 250 participants had collectively treated more than 100 cases. Though a third of the participants raised their hands when asked if they had seen a recent case, only two hands were raised when they were asked if they had seen a complete recovery. A hospital in Philadelphia had seen at least 10 cases. At that time the nationwide CDC count was given as 51. The Stanford University School of Medicine suggested an even higher number: "I was on a conference call a few weeks ago with about 50 doctors from medical centers across North America. Every center had seen cases. That puts the numbers real high, real fast." The number affected was still far less than the tens of thousands affected in polio seasons. Fortunately, as with polio, the number of cases appeared to be decreasing with the onset of cold weather.

Of 64 patients meeting the CDC criteria before October 29, 80% had had a preceding respiratory illness and 75% reported fever in the days leading up to limb weakness, the onset of which was generally abrupt. By November 20 the number of confirmed cases stood at 88 from 29 states.

Zoonotic transmission can occur in any context in which there is companionistic (pets), economic (farming, etc.), predatory (hunting, butchering or consuming wild game) or research contact with or consumption of animals, animal products, or animal derivatives (vaccines, etc.).

Inoculation of throat washings taken from people with pleurodynia into the brains of newborn mice revealed that enteroviruses in the Coxsackie B virus group were likely to be the cause of pleurodynia, and those findings were supported by subsequent studies of IgM antibody responses measured in serum from people with pleurodynia. Other viruses in the enterovirus family, including echovirus and Coxsackie A virus, are infrequently associated with pleurodynia.

The September 26, 2014 CDC health advisory that described the cases continued with the identification of enterovirus 68, a member of the enterovirus D species, as a suspected cause:

CSF testing to date has been negative for West Nile virus and enteroviruses, including poliovirus. Nasopharyngeal specimens were positive for rhinovirus/enterovirus in six out of eight patients that were tested. Of the six positive specimens, four were typed as EV-D68, and the other two are pending typing results. Testing of other specimens is still in process. Eight out of nine children have been confirmed to be up to date on polio vaccinations. Epidemiologic and laboratory investigations of these cases are ongoing.

The United States is currently experiencing a nationwide outbreak of EV-D68 associated with severe respiratory disease. The possible linkage of this cluster of neurologic disease to this large EV-D68 outbreak is part of the current investigation. CDC is seeking information about other similar neurologic illnesses in all states, especially cases clustered in time and place. CDC has particular interest in characterizing the epidemiology and etiology of such cases.

One moderator of the October 3, 2014 CDC COCA conference call (Steve Oberste) described the then-current test for enterovirus D-68 as a generic polymerase chain reaction amplification of enterovirus sequence, followed by sequencing to determine the serotype, but said that a faster and less labor-intensive real-time PCR assay was in the process of validation. On October 14, 2014 the CDC began using the new test.

The MMWR report noted the difficulty of establishing causation by the virus:

This cluster of acute neurologic illnesses occurred against a backdrop of detection of EV-D68 causing severe respiratory disease in many parts of the United States, including Colorado (1,2). There are two case reports in the literature of EV-D68 causing neurologic illness (acute flaccid paralysis and encephalomyelitis) as evidenced by detection of EV-D68 in the CSF (3,4). However, given the current suspected widespread circulation of EV-D68 respiratory infections in Colorado, and the antecedent respiratory illness in most of these children, the detection of EV-D68 in nonsterile upper respiratory tract specimens in those with neurologic illness might be coincidental. Epidemiologic and laboratory investigations of these cases are ongoing.

Avindra Nath, clinical director of the National Institute of Neurological Disorders and Stroke and president of the International Society for NeuroVirology, compared the situation to the prolonged investigations that led to confirmation of HIV as the cause of AIDS. In response to the suggestion that the enterovirus might be taking over the role of polio, Nath said that enterovirus 68 was far less virulent and spread much more slowly than polio, and that, unlike in polio, only a few cases of paralysis were seen per thousand children infected. He also suggested that adults with respiratory diseases should also be evaluated for neurologic deficits, and that infectious disease should be considered as a cause when patients presented with neurologic symptoms.

Types of encephalitis in humans include:

- Arbovirus encephalitis

- La Crosse encephalitis

- Enterovirus

- California encephalitis virus

- Japanese encephalitis

- St. Louis encephalitis

- Eastern equine encephalitis virus

- Western equine encephalitis virus

- Venezuelan equine encephalitis virus

- Murray Valley encephalitis virus

- Tick-borne meningoencephalitis

- Powassan encephalitis

- West Nile virus

- Herpes simplex

- Human herpesvirus 6

- Varicella zoster virus

- Rabies

- HIV

- H5N1 encephalitis

- Nipah virus encephalitis

- Lymphocytic choriomeningitis, which also causes encephalitis