Bacterial meningitis (paediatrics)

thumb|right|300px|Pneumokoková meningitida Bacterial meningitis is a life-threatening disease. Its main cause is inflammation of meninges that cover brain or spinal cord, that very often affects the adjacent brain tissue. The most important bacteria that cause meningitis, from infancy onwards, are Neisseria meningitidis, Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae. Following the introduction of vaccination against Hib and meningococcal, the number of cases with this condition purulent meningitis dropped sharply. The most common bacteria that causes this disease is currently Str. pneumoniae. Str. pneumoniae typically affects children between 1 and 23 months of age.

Predisposing factors:
 * respiratory infection
 * otitis media - Middle ear inflammation
 * mastoiditis
 * head injury
 * immunodeficiency
 * haemoglobinopathy

Pathophysiology
Bacteria enter the subarachnoid space most often haematogeneous pathway (through the blood). They can enter directly into the subarachnoid space during the rupture of the intracranial abscess or more frequently through the dura mater during trauma, instrumental procedure or through the proliferation of extradural inflammatory focus (otitis, sinusitis). Among pathogens affecting CNS via non-haematogenic pathways (other than blood) we include Streptococcus spp., anaerobic bacteria and Gram-negative rods. Bacteria are transferred intravascularly from the nasopharynx via tight junctions between mucous epithelial cells, but transport through the mucosal barrier via the endocytose is also possible (seen in N. meningitidis infection). After the entry of bacteria via the intravascular route, the main element of virulence is encapsulation, i.e. capsule formation. We can see this phenomenon in S. pneumoniae, H. influenzae, N. meningitidis, Streptococcus agalactiae and E. Coli. After bacteria transfer to the CNS, bacteria replicate rapidly as there are insufficient immune mechanisms in the CNS to significantly block replication. In particular, immunoglobulin-mediated opsonisation is inefficient. As soon as the bacteria enters the subarachnoid space, the individual parts of the bacterial wall of the pathogen trigger a rather strong host inflammatory response. Released cellular components such as teichoic acid, peptidoglycans and lipopolysaccharides after treatment with bactericidal antibiotics are also involved. Bacteria and their components activate complement that is important for leukocyte chemotaxis (neutrophils = microphages and macrophages). This will lead to further progress of endothelial damage or new flare-up of the disease. Cytokines, which are then released, initiate a lot of processes and ultimately lead to neuronal damage and apoptosis. The main role in triggering the inflammatory response and in neurological damage have Interleukin 1 (IL-1), tumour necrosis factor alpha (TNF-α), and increased NO production. The bacterial action of neutrophils leads to the release of oxygen radicals, which also causes deepening of CNS damage.

The infection process moves and continues in the cortical vessels. The result is oedema and proliferation of endothelial arterioles cells. A similar process that affects the venous circulation leads to life-threatening thrombosis and obstruction of blood flow in the blood vessel. This increases intracellular sodium and consequently water. The subsequent development of brain swelling further impairs cerebral blood flow and leads to an increase in intracranial pressure (pressure in the skull) with possible uncal herniation. The oedema (swelling) of the brain thus becomes a combination of cytotoxic swelling with the combined cytotoxic action of bacteria and mediators of inflammation and vasogenic oedema in increasing capillary permeability. Due to the fact that the cerebral autoregulation of the circulation is impaired, there is also an increase in blood volume in the CNS and so the intracranial pressure continues to increase, leading to severe intracranial hypertension. Later obstruction of the arachnoid villi leads to a violation of the drainage of the liquor. Hydrocephalus or subdural effusions occur.

A number of patients with purulent meningitis experience increased secretion of the antidiuretic hormone ,which causes SIADH and leads to additional retention of free water. All of these factors contribute to the development of focal or generalised convulsions. In severe cerebral oedema, the central line structures of the CNS are causally displaced with their "trapping" in the region of the tentorium or foramen magnum. Caudal displacement causes herniation of parahippocampal gyres and/or cerebellum. These intracranial disabilities become clinically apparent as disturbances of consciousness and postural reflexes. The displacement of the brain-stem in a caudal direction leads to a disturbance of the III and VI cranial nerves. If these changes do not start to be treated, decortication and decerebration occur and consequently respiratory and cardiac arrest.

In newborns, the role is played by the attack of the mother by pathogens, which are resettled in the newborn after the rupture of the amniotic membranes. Certain bacteria such as Streptococcus group B (Streptococcus agalactiae, GBS), enterogenic bacteria and Listeria monocytogenes can also infect newborns through the placenta (transplacental transmission). Newborns can also acquire meningitis via the nosocomial route. Bacteria enter subarachnoid spaces haematogenously. After they reach the CNS, the bacteria spread from the sinuses to the meningeal sheats, the choroidal plexus and the ventricles.IL-1 and TNF-α mediate a local inflammatory response due to the induction of phospholipase A2 activity, leading to the production of platelet activating factor (PAF) and arachidonic acid. The result is the re-production of prostaglandins, thromboxane and leukotrienes. Due to the activation of endothelial cells, leukocytes are attracted and proteolytic enzymes are released. These processes cause a disorder of the blood-brain barrier, the coagulation cascade is activated, brain oedema and tissue damage occur. Inflammation of the meningeal sheaths and ventricles will result in a polymorphonuclear response, an increase in proteinorachia, and cerebrospinal fluid consumption. Gram-negative bacteria more often cause the formation of empyema or abscesses in the CNS. Severe inflammatory exsudation can lead to obstruction of the aqueductus Sylvii and other areas. This will develop in an obstructive hydrocephalus.

Epidemiology
Mortality is highest in the first year of life and in Streptococcus pneumoniae infection. Neonatal mortality is high and survivors have significantly higher long-term sequelae. The gender predilection for individual pathogens is interesting - boys have a higher incidence of gram-negative meningitis, while girls have a higher incidence of listeria infection. GBS affects both sexes equally often. In terms of prognosis, prolonged or refractory convulsions are unfavourable, especially if they last longer than after the 4th day of hospitalisation. On the other hand, if convulsions occur within the first 3 days of hospitalization, they are not prognostically significant. Only 6% of patients show signs of DIC or endotoxin shock. These patients are also prognostically worse off.

Etiology
Neonatal meningitis usually enters the body through the vaginal flora. Gram-negative Enterobacteriaceae and Streptococcus agalactiae are the most common pathogens, Listeria monocytogenes infection is rare. Meningitis in children > 4 weeks is most commonly caused by Streptococcus pneumoniae and Neisseria meningitidis. Haemophilus influenzae is now rare thanks to vaccination against Hib.
 * Early-onset meningitis is caused by GBS and occurs within the first 7 days of life. The pathogen attacks the newborn prenatally or intrapartally. Infection is caused by maternal colonization and subsequent transmission and lack of protective antibodies in the newborn. It is often associated with gynaecological complications. The disease often occurs in the group of premature and low birth weight newborns.
 * Late-onset meningitis also caused by GBS occurs after the 7th day of life. The pathogen infects newborns intrapartally or by nosocomial transmission.

Clinical picture
In newborns the clinic is often rather bland and almost always non-specific. The set of clinical signs includes poor food intake, lethargy, apathy or irritability, apnoea, fever or hypothermia, convulsions, icterus, bulging fontanelle, pallor, shock, hypotonia, high-pitched crying, screeching cries, hypoglycaemia, resistant metabolic acidosis.

In infants and children we observe nuchal rigidity, opisthotonus, bulging fontanelle, convulsions, photophobia, headache, lethargy or irritability, inappetence, nausea, vomiting, fever or hypothermia, and again the characteristic high-pitched, squeaky cry. Bacterial meningitis is often preceded by a viral infection of the upper respiratory tract; a peracute course is also common. Patients may also have a different infectious focus and the diagnosis of meningitis may be significantly delayed. The so-called meningeal syndrome is characteristic for the age group of children > 1 year. It is atypically found in infants. It is characterized by cephalea, vomiting, disturbances of consciousness, symptoms from irritation of the anterior and posterior spinal roots:


 * Neck opposition (meninigism) = the child cannot touch the chest with the chin when lying down
 * Brudzinski = passive head tilt causes spontaneous flexion in the hip joints
 * Kernig = right-angle hip flexion followed by passive knee extension causes pain
 * Lasségue = painful elevation of the stretched lower limbs when we do not reach 90 degrees
 * Amoss (tripod symptom) = when sitting on the bed, the child cannot hold himself in a sitting position, he has to help himself by supporting his upper limbs
 * spine sign = soreness when trying to touch the forehead of the bent knees

In addition to neuroinfections, the differential diagnosis of neck opposition (meningismus) includes subarachnoid haemorrhage, abscesses or tumours in the posterior cranial fossa, and rarely deep neck infections or pneumonia. Sometimes patients come in serious condition with impaired consciousness, pathological reaction of the pupils and breathing pattern (Cheyne-Stokes pattern). Physical findings characterizing intracranial hypertension in bacterial meningitis include bulging and/or pulsatile fontanelle, altered mental status, hyperreflexia with positive Babinski's sign. There are also disturbances in the functions of the cranial nerves. Some patients may also show signs of circulatory failure.

Focal neurological findings can be observed in 20% of patients with purulent meningitis. Irritation of the n. vagus results in vomiting and bradycardia. Irritation of the sensitive roots of the spinal cord can cause cutaneous hyperesthesia, hyperacusis and also photophobia. Due to increased vasomotor activity, we also observe skin dermographism. Inflammation periodically extends to the adjacent cortical layer, which ultimately causes thrombosis and the development of infarction. Up to 80% of patients with meningitis develop SIADH in the first 48-72 hours. Patients who develop focal neurological symptoms are at higher risk of permanent neurological sequelae. In 33% of patients we can diagnose generalized or focal convulsions. Convulsions lasting during the first three days after the onset of the disease are not essential to prognostic significance. Conversely, convulsions that continue after the fourth day after the onset of the disease or convulsions that are difficult to control with treatment present a high risk of complications, as well as permanent neurological consequences. Meningococcal meningitis is characterised by petechiae and sufusions on the skin, but can also occur in H. influenzae infection. Changes on the skin may often not be specific, include blanching or maculopapular erythema. In neuroinfections in the acute stage of the disease with cerebral oedema, the surrounding tissues of the VI cranial nerve are relatively often oppressed during its course at the base of the skull. Its clinical correlate is diplopia, which disappears with the retreat of cerebral edema. Subacute or chronic course is typical for mycotic and mycobacterial meningitis.

The development of pericardial or joint effusions can be observed at the beginning and during the course of purulent meningitis. During the development of these symptoms in the initial phase of meningitis, we can cultivate pathogens causing purulent meningitis from exudates. Effusions that form more than a week after the onset of the disease are usually sterile.

Any deterioration in neurological status during purulent meningitis must be promptly explained. The method of choice is the CT scan, as most CNS complications (brain abscess, heart attack, cerebral edema, vasculitis, subdural effusion) are anatomically correlated. In infants with a sufficiently open fontanelle, we can also use head ultrasound.

Diagnostics
Diagnosis of purulent meningitis must be rapid and accurate. Treatment should be started within 30 minutes after the patient is suspected of having the disease. The diagnosis is based on the clinical picture (which can sometimes be very typical, sometimes atypical, often mitigated by already started p.o. treatment with antibiotics from another cause) and on the finding in cerebrospinal fluid. Cytology and biochemistry suggest a purulent finding. Diagnosis is confirmed by the detection of a pathogen in the cerebrospinal fluid and / or blood.

The following conditions are contraindications to lumbar puncture:
 * moribund patient in severe condition, has hypotension, respiratory distress
 * brain abscess, CNS tumor and other cases of intracranial hypertension
 * focal neurological symptoms
 * prolonged seizures
 * anizokoria
 * infection at the expected injection site
 * haemorrhagic diathesis

We then perform the LP after stabilizing the overall condition of the patient. As soon as the intracranial pressure drops, we choose diagnostics via CT or MRI scan. CT can show cerebral edema (we find a loss of differentiation between white and gray matter) or obliteration of the ventricles and cisterns. A characteristic finding in cerebrospinal fluid that indicates purulent meningitis is:
 * opalescent to turbid fluid
 * proteinorrhachia > 1 gram
 * thousands to tens of thousands of polymorphonuclear cells with about 90% predominance over mononuclear cells
 * reduced glycorrhachia (significant is glycorrhachia < 1/3 of the glycaemic value, which is performed in parallel with the liquid collection)

If a strongly opalescent to turbid cerebrospinal fluid leaks during lumbar puncture, we do not wait for the results of biochemistry and cytology and start therapy immediately. In some cases, the cerebrospinal fluid is so hardened that it is not possible to take it with a standard needle and it is necessary to use a thicker needle (usually a 20 G needle). In the very early stage of purulent meningitis, the finding in cerebrospinal fluid may not be very convincing and it is necessary to repeat the puncture at least 24 hours apart. If there is blood in the cerebrospinal fluid, it is good to find out the ratio between the number of erythrocytes and leukocytes. At a ratio of <500: 1 and if the cerebrospinal fluid is also xantochromic after centrifugation, there is a likelihood of finding intracranial hemorrhage (subarachnoid hemorrhage). At a ratio of> 500: 1 and if the cerebrospinal fluid is not xantochromic after centrifugation, it is probably fresh, artificial bleeding due to puncture. If we have a large amount of blood in LP, then 1 leukocyte can be counted per 700 erythrocytes and 10 mg protein / liter can be counted per 1000 erythrocytes.

The diagnosis is confirmed by the identification of the pathogen that caused the disease. The cerebrospinal fluid and blood are mainly examined. We can use microscopic examination, culture, latex agglutinacin or detection of Streptococcus pneumoniae antigen in cerebrospinal fluid. Cross-reactivity between Streptococcus pneumoniae and Hemophilus influenzae and between GBS and E. Coli is possible in antigen detection. The modern method is then to detect the pathogen by PCR. In the tripple test, we detect the most common three main pathogens - meningococcus, pneumococcus and Haemophilus. However, we can also detect Staphylococcus aureus, Listeria monocytogenes and Mycobacterium tuberculosis by PCR. right|thumb|300px|Hemofilová meningitida

When suspected of meningitis or a septic condition of unclear etiology, lumbar puncture must be performed, unless contraindications are present ! („whenever you think of an LP, you should do it“)

Blood is also taken. In bloodcount+dif. we demonstrate leukocytosis with a left shift. Thrombocytopenia may be associated with DIC and thus represents a much worse prognosis. In biochemistry we can find elevation of CRP and procalcitonin, based on the development of the disease and other biochemical abnormalities.Lactic acidosis may be indicated by an astrup. A comprehensive examination of coagulation parameters is crucial. In particular, this comprehensive examination may indicate ongoing DIC, especially in meningococcal meningitis. We investigate APTT, INR and Quick, EGT, antithrombin III, D-dimers and fibrinogen, and of course platelet s.

Terapie
Léčbu zahájíme hned při podezření na meningitidu. Před nasazením ATB se ideálně odebere kultura z krve a z likvoru. Pokud je pacient v těžkém stavu, LP odložíme i o několik dnů, dokud nedojde ke stabilizaci celkového stavu. Zpravidla již nejde prokázat patogen, ale biochemické a cytologické změny jsou přítomny a potvrdí nám tak diagnosu purulentní meningitidy. Velmi pečlivě monitorujeme parenterální přívod tekutin, protože hlavně novorozenci jsou více náchylní k rozvoji hyponatremie a to v důsledku SIADH. Tyto změny mohou být spojeny i s křečemi, které lze pozorovat během prvních 72 hodin. Většina dětí s purulentní meningitidou však přichází pod obrazem těžké sepse a vyžaduje dostatečnou volumexpanzi. Zvýšený intrakraniální tlak způsobený edémem mozku je u novorozenců vzácnější a to především z důvodu větší compliance intrakrania. Taktéž je dobré denně zkontrolovat obvod hlavičky u dětí, které mají otevřenou fontanelu. Sledujeme krevní plyny a metabolickou stabilitu. Po prodělané meningitidě u všech dětí a to i u novorozenců je nutné vyšetřit sluchové evokované potenciálvy BAER. Purulentní meningitida se léčí pomocí antibiotik a zajistí se podpůrná opatření.

Antibiotická terapie
Průběh onemocnění a určitý patogen určuje, jak dlouho léčba potrvá. GBS meningitida se léčí cca 10 – 21 dní. U gramnegativních bakterií trvá déle, než je likvor sterilní a doporučuje se léčba spíše v délce 3–4 týdnů. K indikaci opakované lumbální punkce svědčí nelepšící se stav pacienta po zahájení léčby nebo po meningitidě, kterou vyvolaly gramnegativními bakterie. Kontrolní LP se provede s odstupem 48 - 72 hodin. Pokud je léčba správná, bude likvor sterilní. A pokud nedošlo k lepším výsledkům nálezu, je nutné sonografické vyšetření a změna antibiotik. Další LP provádíme podle klinické odpovědi nebo při selhání počáteční léčby a změně antibiotik. Sono může odhalit ventrikulitidu a jiné parenchymové změny, které svědčí pro komplikovaný průběh. Při zlepšení nálezu v likvoru a celkového stavu, stačí kontrola likvoru po 7 dnech. V poslední punkci před ukončením léčby nemusí být úplně normální počet leukocytů, jednoznačně ale musí být normální glykorrhachie, proteinorrhachie a negativní kultivace likvoru.
 * Věk < 6 týdnů: Pro novorozence a děti < 6 týdnů věku se při podezření na purulentní meningitidu doporučuje kombinace ampicilinu a cefalosporinu III. generace. Ampicilin je dobrý na pokrytí vůči GBS, Listeria monocytogenes, Enterokokům a některým kmenům enterobakterií. Výborně proniká do likvoru, proto ho preferujeme před Gentamycinem, který má sice taktéž dobré antimikrobní spektrum, ale nedosahuje takových hladin v likvoru jako právě ampicilin. Cefalosporin III. generace je dobrá na pokrytí GBS a enterobakterie. Mezi primárně rezistentní patří vždy Listeria monocytogenes a enterokok. Používá se ceftriaxon nebo cefotaxim. Cefotaxim se méně váže na albumin, proto lépe proniká a méně kompetuje s bilirubinem ve vazbě na albumin. Ceftriaxon rovněž způsobuje žlučový sludging.

V poslední punkci před ukončením léčby nemusí být úplně v normě počet leukocytů, jednoznačně ale musí být normální glykorrhachie, proteinorrhachie a negativní kultivace likvoru.


 * Věk > 6 týdnů: Bez ohledu na věk musí být antibiotická terapie započata co nejdříve. Nejčastěji však do 30 minut od vyslovení podezření na purulentní meningitidu. Volba antibiotika u dětí starších více jak 6 týdnů se určuje na základě 3 nejčastějších patogenů – Neisseria meningitidis, Streptococcus pneumoniae a Hemophilus influenzae typ b. Hlavní volbou zůstávají cefalosporiny III. generace. Podáváme ceftriaxon 50 mg/kg á 12 hod. i.v. nebo cefotaxim 50 mg/kg á 6 hod. i.v. Při průkazu pneumokoka nebo meningokoka můžeme léčbu při dobré citlivosti dokončit krystalickým penicilinem v dávce 50 mg/kg á 4 hod. i.v.

Podpůrná terapie

 * Stabilizace oběhu
 * Kortikosteroidy
 * Antikonvulsivní léčba
 * Antiedematosní léčba
 * Léčba koagulopatie
 * Experimentální terapie

Komplikace
Mezi nejčastější komplikace purulentní meningitidy patří rozvoj křečí, které postihují až 1/3 pacientů. Prognosticky nepříznivé jsou perzistující křeče, rozvoj křečí v průběhu nemoci a fokální charakter křečí. V těchto případech může být vysoké riziko trvalého neurologického postižení. Komplikace purulentních meningitid dle věku

Prevence
Při podezření na invazivní pneumokokové onemocnění epidemiolog eviduje klinickou formu onemocnění a případné úmrtí jako případná epidemiologická opatření. Dále ověřuje, jak se provádí odběr biologického materiálu od nemocného pro laboratorní průkaz etiologie a kontroluje, jestli byl pacient v minulosti očkován proti invazivním pneumokokům. Preventivní opatření antibiotik lidem, co jsou s nemocným v kontaktu, není doporučeno. Epidemiologická opatření, která se týkají invazivního onemocnění Hib zahrnují čtyřdenní lékařský dozor u dětí mladších 6 let. Rodiče těchto dětí jsou poučeni, že je nutné kontaktovat lékaře při podezření na příznaky onemocnění, včetně zvýšené teploty. Preventivní podávání antibiotik blízkým osobám není doporučováno. U invazivních meningokokových onemocnění se doporučuje blízkým osobám lékařský dohled po dobu 1 týdne. U těchto osob lékař pátrá po příznacích suspektního meningokokového onemocnění. Při lékařském dohledu je nutné zvláště věnovat pozornost osobám v úzkém kontaktu s nemocným (v rodinách, v internátech) a tzv. rizikovým kontaktům: osoby do jednoho roku, adolescenti a osoby nad 65 roků věku, osoby u nichž je známa imunodeficience, osoby po předchozím respiračním onemocnění, osoby zeslabené jinou chorobou. Pouhý průkaz N. meningitidis nepodkládá léčbu antibiotiky. Protektivní chemoterapie je indikována u rizikových kontaktů nebo s prvními příznaky, které teoreticky nevylučují suspektní meningokokového onemocnění. Během lékařského dohledu po dobu jednoho týdne od posledního styku s nemocným lékař zjišťuje další eventuelní kontakty, u nichž vzniká indikace k okamžitému zahájení protektivní chemoterapie. V České republice je k cílené protektivní chemoterapii doporučen V - penicilin perorálně v terapeutických dávkách po dobu jednoho týdne. U malých dětí lze alternativně použít ampicilin v terapeutických dávkách. Vyšetření nasopharyngeálních a laryngeálních výtěrů u kontaktů zajišťuje epidemiolog nebo lékař provádějící lékařský dohled. U meningokoka používáme meningokokovou polysacharidovou vakcínu A+C. Indikována je podle epidemiologické situace v rizikových skupinách včetně asplenie po 2. roce života. U pneumokoka máme k dispozici polyvalentní polysacharidovou vakcínu. Doporučuje se u imunokompromitovaných pacientů (asplenie, nefrotický syndrom, imunosuprese, HIV). U Hemofila se používá konjugovaná vakcína proti H. influenzae typ b, která je součástí rutinního očkovacího kalendáře.
 * Chemoprofylaxe
 * Imunizace

Související články

 * Meningitida • Meningitida (pediatrie)
 * Virová meningitida • Serózní meningitidy a meningoencefalitidy • Herpetická meningoencefalitida
 * Hnisavá meningitida (infekce) • Hemofilová meningitida • Tuberkulózní meningitida
 * Infekční onemocnění mozku • Neuroinfekce, záněty CNS/PGS • Encefalitida