Meningitis

Meningitis is an inflammation of the membranes of the brain or spinal cord. The disease is often infectious in nature and is one of the most common infectious diseases of the central nervous system.

Along with the membranes, the brain matter may also be involved in the process (meningoencephalitis). The full clinical picture of meningitis may develop rapidly - within a few hours or days (acute meningitis) or over a longer period of time (subacute or chronic meningitis).

Acute aseptic meningitis syndrome is a moderately severe, self-limiting viral infection that causes inflammation of the meninges. Encephalitis is inflammation of brain tissue, usually accompanied by impaired consciousness, cognitive impairment, or focal neurological symptoms.

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Epidemiology of meningitis

Viruses are the most common pathogens of acute aseptic meningitis. In large countries (USA), 8-12 thousand cases are registered annually. The introduction of modern diagnostic systems based on molecular typing methods has made it possible to identify the pathogen in 50-86% of cases.

Enteroviruses are considered to be the cause of 80-85% of all cases of meningitis of viral etiology. Newborns and children are most often affected due to the lack of specific antibodies. In Europe (Finland), the incidence of children in the first year of life reaches 219 per 100 thousand people per year, while for children over one year old - 19 per 100 thousand.

Arboviruses are the cause of meningitis transmitted by insects, accounting for about 15% of all cases of the disease. It is this group of pathogens that is responsible for the occurrence of cases of tick-borne encephalitis.

Herpes viruses are considered to be the cause of 0.5-3.0% of all aseptic meningitis, which often occur as a complication of primary genital herpes (HSV 1 - herpes simplex virus type 2) and very rarely - with recurrent. In patients with immune disorders, meningitis can be caused by cytomegalovirus, Epstein-Barr virus, HSV types 1 and 6. The most severe course of viral meningoencephalitis in patients without immunological disorders is associated with HSV type 2 infection; in patients with immune disorders, any viral neuroinfection becomes life-threatening.

Bacteria are a pressing issue due to the high mortality rate of meningitis caused by bacteria. The incidence rate in the world varies widely from 3 to 46 per 100 thousand people, the mortality rate varies significantly depending on the pathogen from 3-6% (Haemophilus influenzae) to 19-26% (Streptococcus pneumoniae) and 22-29% (Listeria monocytogenes). Aerobic gram-negative bacteria (Klebsiella spp, Escherichia coli, Serratia marcescens, Pseudomonas aeruginosa) and staphylococci (S. aureus, S. epidermidis) are becoming increasingly important pathogens of meningitis in patients with TBI, neurosurgery, and immunosuppression. The mortality rate for meningitis caused by staphylococci ranges from 14 to 77%.

Fungi. Meningitis caused by Candida occurs most frequently; about 15% of febrile patients with disseminated candidiasis have CNS damage. Risk factors include oncological diseases, neutropenia, chronic granulomatous diseases, diabetes mellitus, and obesity. Meningitis caused by cryptococci (Cryptococcus neoformans) also develops against the background of immunological disorders. About 6-13% of AIDS patients develop meningitis caused by this microflora.

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What causes meningitis?

Meningitis can be caused by viruses, bacteria, spirochetes, fungi, some protozoa and helminths.

Viruses

Enteroviruses, arboviruses, mumps virus, lymphocytic choriomeningitis virus, herpes viruses.

Bacteria

Haemophilus influenzae, Neisseria meningitidis, Streptococcus pneumoniae, Listeria monocytogenes, Streptococcus agalactiae, aerobic gram-negative bacteria - Klebsiella spp, E. coli, Serratia marcescens, Pseudomonas aeruginosa, Salmonella spp., staphylococci - S. aureus, S. epidermidis, other bacteria - Nocardia meningitis, Enterococcus spp., anaerobes, diphtheroids, Mycobacterium tuberculosis.

Spirochetes

Treponema pallidum, Borrelia burgdorferi.

Mushrooms

Cryptococcus neoformans, Candida spp, Coccidioides immitis.

Pathogenesis of meningitis

Pathogens can penetrate the subarachnoid space in various ways, each with its own pathogenetic features. In most cases, it is impossible to establish the exact mechanism of bacterial penetration into the central nervous system. Bacterial meningitis is conventionally divided into primary (bacteria enter the subarachnoid space from the mucous membranes) and secondary (spread by contact from nearby infection sites, such as ENT organs, or hematogenously, such as from the lungs or other distant infection sites). After pathogens penetrate the submucosal layer, they enter the subarachnoid space with the flow of lymph or blood, which is an ideal environment for their development due to stable temperature, humidity, the presence of nutrients, and the absence of humoral and cellular anti-infection defense systems due to the presence of the BBB. There is no limit to the proliferation of bacteria in the subarachnoid space until they are phagocytized by microglial cells, which act as tissue macrophages in the CNS and trigger an inflammatory response. As a result of inflammation, the permeability of the CNS capillaries increases sharply, and exudation of proteins and cells occurs, the presence of which in the CSF, together with clinical signs, confirms the presence of meningitis.

The main mechanisms of invasion of pathogens into the central nervous system

• Colonization of the mucous membranes of the upper respiratory tract by pathogenic or opportunistic flora. The choice of the moment of invasion is associated with unfavorable conditions for the microorganism (hypothermia, overexertion, maladaptation), when pathogens use an unknown mechanism to enter the submucosal layer. With the flow of lymph and blood, pathogens enter the subarachnoid space.
• Defects in tissue integrity and liquorrhea as a result of congenital (dural fistula) or acquired (basal skull fracture) disorders (mainly Streptococcus pneumoniae). As a rule, the disease is preceded by increased nasal or ear liquorrhea.
• Hematogenous dissemination Usually occurs after the formation of a primary focus of infection in various organs and tissues. Most often occurs against the background of pneumonia caused by pneumococci, which have a genetic affinity for the structures of the meninges. In addition, with massive hematogenous dissemination, ischemic foci may arise as a result of embolism with the formation of microabscesses in the terminal sections of arterioles and capillaries, which carry the risk of involving brain tissue in the inflammatory process and the formation of encephalitic foci.
• Contact dissemination. Usually occurs as a result of the spread of ENT infections, after neurosurgical operations, as a result of tissue infection in open TBI.
• Neuronal dissemination. Characteristic of some viruses HSV (herpes simplex virus) types 1 and 6, VZV (shingles virus).

Mechanism of CNS damage in viral infections

Viruses penetrate the CNS hematogenously (viremia) and neuronally. The virus must overcome the epithelium to enter the blood; the virus also enters through bites of blood-sucking insects. From the blood, it enters the regional lymph nodes and other organs, including the CNS. In most cases, the virus actively replicates in the liver and spleen, creating conditions for massive secondary viremia, which usually leads to CNS infection. CNS damage is accompanied by dysfunction of the cortical and stem structures as a result of a combination of the direct cytopathic action of viruses and the body's immune response. However, viral invasion is considered the most important trigger for the disease. Neurophagia, the presence of viral antigens and nucleic acids can be detected in the brain parenchyma. After encephalitis, some symptoms may remain forever, although there is no viral invasion. Microscopic examination reveals demyelination and perivascular aggregation of immune cells, while viruses and viral antigens are absent. Meningitis and encephalitis are different infectious diseases, but sometimes it is very difficult to separate them. All neurotropic viruses, with the exception of the rabies virus, can cause meningitis, encephalitis and their combination - meningoencephalitis. Changes in the clinical picture of the disease reflect the involvement of various parts of the brain in the infectious process. That is why in many cases it is initially very difficult to determine the form, course, volume of damage to the central nervous system and to predict the outcome of the disease.

Mechanism of CNS damage in bacterial infections

When bacteria enter the subarachnoid space, they rapidly multiply, causing inflammation. Lymphogenous spread usually leads to inflammation, mainly affecting the subarachnoid space and ventricular system. With hematogenous spread, bacteria also enter the cavities of the brain, but are also capable of forming small diffusely located foci of inflammation in the brain, sometimes in the form of large foci, which soon manifest as encephalitic. In almost all cases of bacterial meningitis, intracranial hypertension of varying degrees of severity is observed, associated with hyperproduction of CSF and disruption of its rheological properties (increased viscosity), edema of the interstitium of the brain substance and vascular plethora. A high degree of intracranial hypertension and compaction of the brain substance create conditions for herniation and dislocation of the brain in the form of anteroposterior, lateral and helical displacements, significantly disrupting its blood circulation. Thus, microorganisms become a trigger for the development of inflammation, which is complicated by intracranial hypertension and vascular disorders that determine the outcome of the disease.

Symptoms of Meningitis

In most cases, infectious meningitis begins with vague warning signs of a viral infection. The classic triad of meningitis—fever, headache, and stiff neck—develops over hours to days. Passive flexion of the neck is limited and painful, but rotation and extension are not. In severe cases, rapid flexion of the neck in a supine patient causes involuntary flexion of the hips and knees (Brudzinski's sign), and an attempt to extend the knee with the hips flexed may encounter strong resistance (Kernig's sign). Neck stiffness, Brudzinski's sign, and Kernig's sign are called meningeal signs; they occur because tension irritates the motor nerve roots that pass through the inflamed meningeal membrane.

Although in the early stages of the disease the brain tissue is not yet involved in the inflammatory process, the patient may develop lethargy, confusion, seizures and focal neurological deficits, especially if left untreated.

Viral Meningitis: Symptoms

The patient's age and immune status, combined with the characteristics of the virus, determine the clinical manifestations of the infection. In enteroviral meningitis, the disease begins acutely, with fever (38-40 °C) for 3-5 days, weakness, and headache. Half of the patients experience nausea and vomiting. The leading signs of the disease are stiff neck muscles and photophobia. Children may experience seizures and electrolyte disturbances. In meningitis caused by HSV type 2, in addition to the symptoms of meningitis (neck muscle tension, headache, photophobia), urinary retention, sensory and motor disturbances, muscle weakness, and repeated tonic-clonic seizures are observed. In addition, pharyngitis, lymphadenopathy, and splenomegaly may occur in infections caused by the Epstein-Barr virus.

Bacterial Meningitis: Symptoms

Characteristic signs are acute onset, fever, headache, meningeal syndrome, signs of impaired brain function (decreased level of consciousness). It should be noted that meningeal syndrome (rigidity of the occipital muscles, positive Kernig and Brudzinski symptoms) may not occur in all patients with meningitis. Paresis of the cranial nerves (III, IV, VI and VII) is observed in 10-20% of patients, convulsions - in more than 30%. Edema of the optic disc at the onset of the disease is noted only in 1% of patients, this indicates chronic intracranial hypertension and is not important for the diagnosis of meningitis. Coma, hypertension, bradycardia and paresis of the third pair of cranial nerves indicate a high degree of intracranial hypertension.

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Fungal Meningitis: Symptoms

The most acute clinical symptoms develop in meningitis caused by Candida, in meningitis of other etiologies (cryptococci, coccidia) - gradually. As a rule, patients develop fever, headache, meningeal syndrome, the ability to contact the patient worsens, sometimes cranial nerve paresis and focal neurological symptoms are noted. In cryptococcal meningitis, invasion of the optic nerve is observed with a characteristic picture on the fundus. Meningitis caused by coccidia is characterized by a subacute or chronic course, meningeal syndrome is usually absent.

Classification of meningitis

The following types are distinguished:

• Viral infections of the central nervous system
• Acute aseptic meningitis syndrome
• Encephalitis
  • acute (resolves within a short period of time - several days),
  • chronic (the disease lasts for several weeks or months)
• Meningoencephalitis
• Bacterial and fungal infections of the central nervous system

The most common forms of meningitis are bacterial and aseptic. Acute bacterial meningitis is a severe disease characterized by the presence of pus in the cerebrospinal fluid. Bacterial meningitis progresses very quickly and without treatment is fatal. Aseptic meningitis is characterized by a milder course, the disease usually resolves on its own; aseptic meningitis is usually caused by viruses, but can be caused by bacteria, fungi, parasites, and a number of non-infectious factors.

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Diagnosis of meningitis

Acute meningitis is a serious disease that requires urgent diagnosis and treatment. The first emergency diagnostic measures are blood culture for sterility, as well as lumbar puncture followed by bacteriological examination of the cerebrospinal fluid (Gram staining and culture), biochemical analysis, including determination of protein and glucose levels, and cytological examination with differential cell count. If the patient has symptoms of an intracranial space-occupying process (focal neurological deficit, congestive optic nerve head, impaired consciousness, epileptic seizures), before performing a lumbar puncture, it is necessary to do a CT scan to exclude the possibility of wedging in the presence of an abscess or other space-occupying formation.

The results of the CSF analysis can help in the diagnosis of meningitis. The presence of bacteria in the stained smear or the growth of bacteria in the culture is the basis for formulating the diagnosis of "bacterial meningitis". In approximately 80% of cases, bacteria are found in a Gram-stained CSF smear, which are often identified already at this stage of the study. Lymphocytosis and the absence of pathogens in the CSF indicate aseptic meningitis, although they can also occur in treated bacterial meningitis.

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Cerebrospinal fluid analysis in meningitis

To diagnose meningitis of any etiology, a lumbar puncture with microscopy of a CSF smear, a study of protein and sugar concentration, culture and other diagnostic methods are mandatory.

Viral meningitis

The CSF pressure usually does not exceed 400 mm H2O. Viral meningitis is characterized by lymphocytic pleocytosis within 10-500 cells, in some cases the number of cells can reach several thousand. Neutrophils at the onset of the disease (6-48 hours) can make up more than 50% of the cells, in which case some experts recommend repeating the lumbar puncture after 5-8 hours to ensure a change in the nature of the cytosis. The protein concentration is moderately elevated (less than 100 mmol/l). The glucose level is usually about 40% of the blood level.

Bacterial meningitis

CSF pressure usually exceeds 400-600 mm H2O. Neutrophil predominance with cytosis of 1000-5000 cells per 1 μl, sometimes over 10,000, is typical. In approximately 10% of patients, cytosis may be predominantly lymphocytic at the onset of the disease, most often this occurs in neonates with meningitis caused by L monocytogenes (up to 30% of cases), with low cytosis and a large number of bacteria in the CSF. CSF cytosis may be absent in approximately 4% of patients with bacterial meningitis, usually these are neonates (up to 15% of cases) or children under 4 weeks of age (17% of cases). Therefore, all CSF samples should be Gram stained, even in the absence of cytosis. Approximately 60% of patients have a decrease in CSF glucose concentration (<2.2 mmol/l) and a blood to CSF glucose ratio below 31 (70% of patients). The concentration of protein in the CSF increases in almost all patients (>0.33 mmol/l), which is considered a differential diagnostic sign with non-bacterial meningitis in patients who have not previously received antibiotics.

Gram staining of CSF smears is considered a rapid and accurate method for detecting pathogens in 60-90% of cases of bacterial meningitis, the specificity of the method reaches 100%, correlates with the concentration of specific bacterial antigens and bacteria. At a bacterial concentration of 103 CFU/ml, the probability of detecting bacteria using Gram staining is 25%, at a concentration of 105 and above - 97%. The concentration of bacteria can decrease in patients who have already received antibiotics (up to 40-60% when detected using staining and below 50% using culture). It has been shown that in newborns and children with bacterial meningitis and the isolation of bacteria from a CSF sample obtained during a diagnostic lumbar puncture, restoration of CSF sterility in 90-100% occurred within 24-36 hours after the start of adequate antibacterial therapy.

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Fungal meningitis

In meningitis caused by Candida, pleocytosis averages 600 cells per 1 μl, the nature of pleocytosis can be both lymphocytic and neutrophilic. Microscopy reveals fungal cells in approximately 50% of cases. In most cases, it is possible to obtain fungal growth from the CSF. In meningitis caused by cryptococci, the CSF usually has low pleocytosis (20-500 cells), neutrophilic pleocytosis is noted in 50%, the protein concentration is increased to 1000 mg% or more, which may indicate a block of the subarachnoid space. To identify fungi, special staining is used, which allows obtaining positive results in 50-75%. In meningitis caused by coccidia, eosinophilic pleocytosis is noted, the pathogen is isolated in 25-50% of cases.

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Etiological diagnosis of meningitis

Viral meningitis

With the development of molecular diagnostic methods (PCR), the efficiency of diagnosing viral infections of the central nervous system has increased significantly. This method identifies conservative (characteristic for a given virus) sections of DNA or RNA, has high sensitivity and specificity when studying normally sterile environments. This method has practically replaced virological and serological diagnostic methods due to its high efficiency and speed (the study lasts <24 hours).

Bacterial meningitis

There are several methods to confirm the etiology of meningitis:

• Counter immunophoresis (the duration of the study is about 24 hours) allows to detect antigens of N. meningitidis, H. influenzae, S. pneumoniae, group B streptococci, E coli. The sensitivity of the method is 50-95%, the specificity is more than 75% - allows to detect antigens of N. meningitidis, H. influenzae, S. pneumoniae, group B streptococci, E. coli.
• Latex agglutination (test duration less than 15 minutes) allows detection of antigens of N. meningitidis, H. influenzae, S. pneumoniae, group B streptococci, E coli.
• PCR diagnostics (test duration less than 24 hours) allows detection of DNA of N. meningitidis and L. monocytogenes, the sensitivity of the method is 97%, specificity is about 100%.

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Radiological diagnostics of meningitis

CT and MRI examination of the skull are not used to diagnose meningitis. However, these methods are widely used to diagnose complications of this disease. Indications for use include an unusually long period of fever, clinical signs of high ICP, the appearance of persistent local neurological symptoms or seizures, an increase in head size (newborns), the presence of neurological disorders, and an unusual duration of the CSF sanitation process. These studies are most effective in diagnosing liquorrhea in patients with meningitis due to a basal skull fracture, and in detecting fluid accumulations in the skull and paranasal sinuses.

Treatment of meningitis

If symptoms of meningitis are present, antibacterial treatment of meningitis is started immediately after blood culture. If there is doubt about the diagnosis and the course of the disease is not severe, the prescription of antibiotics can be postponed until the results of the cerebrospinal fluid culture are received.

CSF protein levels <100 mg/dL at the first lumbar puncture are found in approximately 14% of patients.

NOTE: Blood pressure, cytosis, and protein levels are approximate values; exceptions are common. PML may also predominate in diseases characterized by lymphocytosis, especially in the early stages of viral infections or tuberculous meningitis. Glucose changes are less variable.