Meningitis in Children - I.V. Bohadelnikov 2005

Serous meningitis in children. General overview
Serous meningitis of viral etiology
Meningitis caused by Coxsackie and ECHO enteroviruses

Enteroviral meningitis is an acute infectious disease caused by Coxsackie and ECHO Viruses, characterized by The Development of meningeal, hypertensive-hydrocephalic, and infectious-toxic syndromes, with the latter usually predominating.

Etiology. Coxsackie and ECHO viruses belong to the genus Enterovirus within the family Picornaviridae. Coxsackie viruses were first isolated in 1948 by G. Dalldorf and G. Sickles from the stool of children treated at a neurological hospital in Coxsackie, New York, USA. Despite striking morphological similarities to polioviruses, enteroviruses differ in their antigenic Structure and never exhibit cross-reactions with Antibodies against the poliomyelitis pathogen. Based on their characteristic effects on suckling mice, Coxsackie viruses are divided into two groups: Group A viruses, which cause diffuse myositis with inflammation and focal necrosis of skeletal Muscles; and Group B viruses, which cause not only Central Nervous system involvement (focal degeneration, paralysis) but also necrosis of skeletal muscles, occasionally the myocardium, and inflammatory lesions of the Spleen and other Organs.

Each group comprises specific serotypes: 24 in Group A and 6 in Group B, which differ in their specific antigenic properties. While these serotypes lack a group-specific antigen, they do exhibit some degree of cross-reactivity.

ECHO viruses were discovered in 1951 by D. Enders. They were classified into a distinct group of enteric viruses due to their complete lack of pathogenicity in laboratory animals. Initially designated as unclassified «orphan» viruses (hence the acronym ECHO: Enteric Cytopathogenic Human Orphan viruses), 34 serotypes of ECHO viruses are currently recognized. This Classification is based on The properties of the specific viral capsid antigen, which is neutralized by type-specific antibodies. They lack group Antigens, and some type-specific antibodies show cross-reactivity.

Enteroviruses are relatively small, non-enveloped («naked») viruses with a mean particle diameter of 22–30 nm, and they are resistant to lipid Solvents. Their genome consists of a single-stranded, non-segmented RNA molecule. Viral Replication occurs in the host Cell Cytoplasm within a few hours and culminates in cell lysis. All enteroviruses are acid-stable and relatively stable at low pH (3.0), enabling them to survive the acidic environment of The Stomach, while their lack of a lipid envelope renders them resistant to Bile acids.

Serous meningitis is most frequently caused by Coxsackie A serotypes 1, 2, 4, 7, 9, 10, 16, 18, 22, and 24; Coxsackie B serotypes 1–6; and ECHO serotypes 2, 4, 6, 7, 9, 11, 14, 18, 25, 27, 30, and 31.

Key characteristics of Coxsackie and ECHO viruses include widespread Circulation among the population, environmental resilience, The ability to survive for prolonged periods on foodstuffs (milk, bread, vegetables), and resistance to Antibiotics. However, these viruses are rapidly inactivated by boiling and standard disinfectants. Neurotropism is a hallmark of most enteroviruses.

Epidemiology. The reservoir and source of enteroviral infection are individuals with manifest or subclinical (inapparent) forms of the disease, as well as healthy virus carriers. The primary route of transmission is fecal-oral (with enteroviruses typically persisting in the intestine for 3–5 months), and less commonly, airborne droplet transmission. Transplacental transmission is also possible. Transmission pathways include alimentary, waterborne, and contact routes. Individuals of all age groups are susceptible, but children aged 3 to 10 years are most frequently affected, with a higher incidence observed in boys than in girls.

The incidence peaks during the summer and autumn months, though sporadic cases occur year-round. Recovery from the infection confers lifelong type-specific Immunity.

Pathogenesis. The portal of entry for the infection is the mucous membranes of the digestive tract or nasopharynx. Over the course of 1–3 days, the virus multiplies at the primary site of invasion. Subsequent replication continues in lymphoid Tissues (Tonsils, Peyer's patches, regional Lymph Nodes), from which the viruses enter the bloodstream, resulting in primary («minor») viremia. By days 3–6, secondary («major») viremia occurs, which temporally coincides with the onset of clinical symptoms. During this phase, the pathogen is hematogenously disseminated to various organs and tissues, where its tropism is determined by the presence of specific viral receptors. The polymorphism of clinical manifestations is attributed to the existence of numerous enteroviral serotypes that possess receptors for various human tissues.

Viruses cross the Blood-Brain barrier (BBB) primarily to invade the central nervous system, causing inflammation of the Meninges, choroid plexuses, and brain parenchyma. Depending on the localization of the lesion within the central nervous system, meningitis or meningoencephalitis predominantly develops.

Central nervous system involvement in enteroviral infection is heavily influenced by factors such as the patient's immune status, the permeability of vascular and cellular membranes, the integrity of the blood-brain barrier, and the level of Organism sensitization.

Pathomorphology. The pathomorphological Changes in the central nervous system during enteroviral infection are characterized by edema, inflammatory infiltration, and hyperemia of the meninges, along with degenerative, inflammatory, and dystrophic alterations in Nerve Cells within the Cerebral Cortex, subcortical regions, Brainstem, and Midbrain, accompanied by diffuse perivascular and pericellular edema. The specific clinical picture depends on which region of the central nervous system exhibits the most prominent pathological changes.

Clinical Features. The incubation period for enteroviral infection ranges from 2 to 14 days. The disease has an acute onset, marked by a rapid rise in body Temperature to high levels (38°C–39°C) with daily fluctuations of up to 1°C, and less frequently to subfebrile levels. In children, the fever often exhibits a biphasic (saddle-back) pattern: the first wave lasts 1–3 days, followed by a brief afebrile interval, and a second temperature elevation lasting 1 to 4 days. From the very first hours of the illness, hypertensive-hydrocephalic syndrome develops due to irritation of the ventricular choroid plexuses, increased CEREBROSPINAL FLUID (CSF) production, and meningeal edema. This leads to stretching of the meninges and triggers severe headaches. The headache is typically localized in the frontotemporal regions, less commonly in the occipital region, and may be diffuse or paroxysmal in nature. It is usually intense and bursting in character, frequently accompanied by pain upon eye movement and dizziness. Irritation of the vomiting center results in vomiting starting within the first hours of the disease. The vomiting is typically repetitive and projectile, occurring without preceding nausea, and sometimes relentless, bringing no relief to the child.

At the peak of intracranial Hypertension, focal microsymptoms may appear, such as extraocular Muscle weakness, pyramidal signs, and intention tremor. However, these neurological signs are transient and rapidly resolve as intracranial pressure decreases.

Meningeal signs may not appear immediately, often emerging on the 2nd or 3rd day; they are usually moderately expressed, short-lived, and frequently dissociated. Nuchal rigidity, along with Brudzinski's and Kernig's signs, are the most commonly observed manifestations. Abdominal Reflexes are diminished. Dissociation of the meningeal syndrome is manifested by the absence of some of its classic signs (e.g., presenting solely with nuchal rigidity or a positive Kernig's sign).

Some patients with enteroviral meningitis exhibit mild pyramidal, cerebellar, and vestibular disorders, as well as cranial nerve palsies. However, these symptoms are typically transient and subside alongside the reduction of intracranial pressure. Intracranial hypertension is manifested by hyperactive superficial and deep tendon reflexes, transient dizziness, and fundoscopic abnormalities such as dilated, tortuous retinal Veins with mild edema. Occasionally, classic meningeal signs may be entirely absent despite pronounced inflammatory changes in the cerebrospinal fluid («CSF-positive» meningitis).

In infants, meningitis may present with generalized seizures, whereas in older children, it may begin with altered consciousness or delirium. Drowsiness, lethargy, or conversely, agitation are frequently noted.

Patients with enteroviral infection often present with a characteristic clinical appearance that AIDS in Diagnosis, featuring facial flushing, a pale nasolabial triangle, dry Lips, and scleral injection. Oropharyngeal examination reveals hyperemia of the tonsillar mucosa and posterior pharyngeal wall. Catarrhal symptoms and cervical lymphadenopathy may also be present. Among other manifestations of enteroviral infection, a transient rash—which can be morbilliform, rubelliform, or scarlatiniform—is most frequently observed. Occasionally, epidemic pleurodynia occurs, characterized by severe pain in the Muscles of the back, legs, chest, and abdomen.

Enteroviral meningitis generally has a moderate clinical course. By the 2nd or 3rd day of illness, the headache diminishes, and vomiting ceases. Meningeal signs typically resolve by days 8–10. However, the normalization of cerebrospinal fluid parameters usually lags behind Clinical Recovery, occurring only by days 15–18 of the illness. Some patients exhibit a wave-like (relapsing) course characterized by 2–3 secondary temperature spikes and an exacerbation of meningeal signs. True relapses of the disease with a maximum interval of up to 30 days are rare.

Key diagnostic criteria for enteroviral meningitis:

1. Epidemiological history: predominantly summer-autumn seasonality, sporadic or clustered outbreaks, high contagiousness, with preschool and early school-age children being most frequently affected.

2. Acute onset characterized by a prominent general Intoxication syndrome and moderately pronounced meningeal signs.

3. Characteristic appearance of the patient: facial flushing, a pale nasolabial triangle, and conjunctival/scleral vascular injection.

4. Frequently, serous meningitis is combined with other Clinical forms of enteroviral infection (herpangina, exanthem, epidemic pleurodynia, etc.).

5. Meningeal syndrome is characterized by short duration, instability, frequent dissociation, and rapid resolution.

6. Other neurological manifestations may occur, such as pyramidal, cerebellar, and vestibular symptoms, which quickly disappear as intracranial pressure decreases.

7. A tendency toward a wave-like course with recurrent fever spikes, exacerbation of meningeal signs, and a potential for relapse.

8. Uninformativeness of CSF smear Microscopy.

9. Isolation of the virus from blood, CSF, feces, or nasopharyngeal swabs, alongside a 4-fold or greater rise in the titer of virus-neutralizing and hemagglutination-inhibiting antibodies in paired sera, confirms the etiological diagnosis.

Laboratory Diagnostics. Complete blood count. Mild leukocytosis or, more commonly, leukopenia, neutrophilia, a shift to the left, and a moderate increase in ESR are observed.

Virological examination. Materials for virological study include nasopharyngeal washes, feces, and cerebrospinal fluid. Pathogen isolation is performed using primary tissue cultures or cell lines. Pathogen identification is based on the cytopathic effect and its neutralization by type-specific antisera.

Serological examination. Characterized by a rising antibody titer in indirect hemagglutination assays (IHA), Complement fixation tests (CFT), and neutralization assays (NA) using paired blood sera collected at a 10–12 day interval, as well as in CSF. A 4-fold or greater increase in antibody titer, particularly against the isolated virus, is considered positive.

CSF analysis. The fluid is consistently clear and colorless, flowing in rapid drops or a steady stream. Its pressure reaches 300–400 mm H₂O or higher. Cytosis ranges from 100 to 1,000 cells per 1 µL. Notably, on the first day of illness, pleocytosis may be mixed or even neutrophilic in nature (up to 90%), but typically shifts to lymphocytic by the 2nd to 3rd day of the disease. Protein levels are either normal or moderately elevated, though they may also be decreased. Pandy's test is weakly positive.