MENENGITIS-ENCEPHALITIS

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MENENGITIS AND ENCEPHALITIS : 

MENENGITIS AND ENCEPHALITIS Dr.David Majinge July 2008 Mwanza -Tanzania

Definitions: : 

Definitions: Meningitis: inflammation of the leptomeninges and underlying subarachnoid cerebrospinal fluid (CSF) Encephalitis: an inflammation of the brain parenchyma, presents as diffuse and/or focal neuropsychological dysfunction

Definitions…. : 

Definitions…. Meningoencephalitis: inflammation of the meninges and brain parenchyma Cerebritis: describes the stage preceding abscess formation and implies a highly destructive bacterial infection of brain tissue, whereas acute encephalitis is most commonly a viral infection with parenchymal damage varying from mild to profound

Meninges of the cns : 

Meninges of the cns

Temporal Categorization : 

Temporal Categorization symptom onset divided into acute, subacute, and chronic categories. acute meningitis (<24 h) is almost always a bacterial infection subacute (1-7 d) myriad infectious and noninfectious etiologies chronic (>7 d) meningitis, viruses as well as tuberculosis, syphilis, fungi (especially cryptococci), and carcinomatous meningitis Presentation in acute meningitis signs and symptoms of meningeal inflammation and systemic infection of less than 1 day's duration may decompensate quickly and require emergency care, including antimicrobial therapy, within 30 minutes of presentation

Causes : 

Causes Bacterial S. pneumoniae N. meningitis H. influenzae Staphylococcus aureus Treponema pallidum Enterobacteriaceae

Bacterial causes….. : 

Bacterial causes….. Pseudomonas sp. Klebsiella sp. Listeria monocytogenes Borrelia burgdorferi Neisseria gonorrhoeae Clostridium sp. Mycobacterium tuberculosis Proteus sp. Ehrlichia bruella

Viral causes : 

Viral causes -Enterovirus (polio, coxsackie, echo) -Herpes simplex types 1 and 2 -Varicella-zoster virus -Adenoviruses -Epstein-Barr virus -Lymphocytic choriomeningitis virus -HIV -Influenza virus types A and B

Causes : 

Causes Fungal Cryptococcus neoformans Histoplasma capsulatum Coccidioides immitis Blastomyces dermatitidis

Causes : 

Causes Parasites Toxoplasma gondii Taenia solium (cysticercosis) Neigleria fouleria Entamoeba coli

Other Causes : 

Other Causes Aseptic: Lymphoma Carcinomatosis Sarcoidosis Chemical Inflammatory: Especially Vasculitides

ACUTE/SUBACUTE MENENGITIS : 

ACUTE/SUBACUTE MENENGITIS urgently 1) identify and treat patients with acute bacterial meningitis, (2) assess whether a central nervous system (CNS) infection is present in those with suspected subacute or chronic meningitis, and (3) identify the causative organism. Bacterial meningitis must be excluded.

PATHOPHYSIOLOGY : 

PATHOPHYSIOLOGY factors influence the development of bacterial meningitis, including virulence of the strain, host defenses, bacteria-host interactions

Pathophysiology…... : 

Pathophysiology…... -seeding usually occurs by hematogenous spread -local tissue and bloodstream invasion by bacteria colonized in the nasopharynx -infected contiguous structures invaded via septic thrombi or osteomyelitic erosion -meningeal seeding also may occur with a direct bacterial inoculate during trauma, sugrery or instrumentation -In the newborn is transmitted vertically from colonizing pathogens in the maternal intestinal or genital tract or horizontally from nursery personnel or caregivers at home

Pathophysiology….. : 

Pathophysiology….. the organism invades the submucosa by circumventing host defenses (eg, physical barriers, local immunity, phagocytes/macrophages) and gains access to the CNS by (1) invasion of the bloodstream (ie, bacteremia, viremia, fungemia, parasitemia) and subsequent hematogenous seeding of the CNS, which is the most common mode of spread for most agents (eg, meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis);

Pathophysiology….. : 

Pathophysiology….. (2) a retrograde neuronal (ie, olfactory and peripheral nerves) pathway (eg, Naegleria fowleri, Gnathostoma spinigerum, viruses-rabies,HSV, VSV); or (3) direct contiguous spread (ie, sinusitis, otitis media, congenital malformations, trauma, direct inoculation during intracranial manipulation). Once inside the bloodstream, the infectious agent must escape immune surveillance (eg, antibodies, complement-mediated bacterial killing, neutrophil phagocytosis)

Explanations : 

Explanations In the csf, the paucity of antibodies, complement components, and white blood cells (WBCs) allows the bacterial infection to flourish Bacterial cell wall components initiate a cascade of complement- and cytokine-mediated events -: increased permeability of the blood-brain barrier

explanations : 

explanations -cerebral edema -presence of toxic mediators in the CSF -increasing numbers of inflammatory cells -cytokine-induced disruptions in membrane transport -increased vascular and membrane permeability

Slide 19: 

Key advances in the pathophysiology of meningitis include the pivotal role of cytokines (eg, tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]–1), chemokines (IL-8), and other proinflammatory molecules in the pathogenesis of pleocytosis and neuronal damage during bacterial meningitis. Increased CSF concentrations of TNF-alpha, IL-1, IL-6, and IL-8 are characteristic findings in patients with bacterial meningitis The proposed interplay among these mediators of inflammation is as follows: .

Slide 20: 

The exposure of cells (eg, endothelium, leukocytes, microglia, astrocytes, meningeal macrophages) to bacterial products released during replication and death incites the synthesis of cytokines and proinflammatory mediators. Recent data indicate that this process is likely initiated by the ligation of the bacterial components (eg, peptidoglycan, lipopolysaccharide) to pattern-recognition receptors such as the Toll-like receptors

Slide 21: 

TNF-alpha and IL-1 are the most prominent among the cytokines that mediate this inflammatory cascade. TNF-alpha is a glycoprotein derived from activated monocyte-macrophages, lymphocytes, astrocytes, and microglial cells. IL-1, previously known as endogenous pyrogen, is also produced primarily by activated mononuclear phagocytes and is responsible for the induction of fever during bacterial infections. Both molecules have been detected in the CSF of individuals with bacterial meningitis. In experimental models of meningitis, they appear early during the course of disease and have been detected within 30-45 minutes of intracisternal endotoxin inoculation.

Slide 22: 

Many secondary mediators, such as IL-6, IL-8, nitric oxide, prostaglandins (PGE2), and platelet activation factor (PAF), are presumed to amplify this inflammatory event, either synergistically or independently. IL-6 induces acute-phase reactants in response to bacterial infection. The chemokine IL-8 mediates neutrophil chemoattractant responses induced by TNF-alpha and IL-1. Nitric oxide is a free radical molecule that can induce cytotoxicity when produced in high amounts.

Slide 23: 

PGE2, a product of cyclooxygenase, appears to participate in the induction of increased blood-brain barrier (BBB) permeability. PAF, with its myriad of biologic activities, is believed to mediate the formation of thrombi and the activation of clotting factors within the vasculature. However, the precise roles of all these secondary mediators in meningeal inflammation remain unclear and should be investigated further.

Pathophysiology cont : 

Pathophysiology cont the net result is vascular endothelial injury and increased BBB permeability leading to the entry of many blood components into the subarachnoid space., to vasogenic edema and elevated CSF protein levels.

Slide 25: 

In response to the cytokines and chemotactic molecules, neutrophils migrate from the bloodstream and penetrate the damaged BBB, producing the profound neutrophilic pleocytosis characteristic of bacterial meningitis. The increased CSF viscosity resulting from the influx of plasma components into the subarachnoid space and diminished venous outflow lead to interstitial edema, and the products of bacterial degradation, neutrophils, and other cellular activation lead to cytotoxic edema.

Slide 26: 

The ensuing cerebral edema (ie, vasogenic, cytotoxic, interstitial) significantly contributes to intracranial hypertension and a consequent decrease in cerebral blood flow. Anaerobic metabolism ensues, which contributes to increased lactate concentration and hypoglycorrhachia. In addition, hypoglycorrhachia results from decreased glucose transport into the spinal fluid compartment. Eventually, if this uncontrolled process is not modulated by effective treatment, transient neuronal dysfunction or permanent neuronal injury results.

Slide 27: 

The level of cytokines, including IL-6, TNF-alpha, and interferon-gamma, has been found to be elevated in patients with aseptic meningitis. The cell walls of both gram-positive and gram-negative bacteria contain potent triggers of the inflammatory response The mediators of the inflammatory response include cytokines (tumor necrosis factor, interleukin 1, 6, 8, 10), platelet activating factor, nitric oxide, prostaglandins, and leukotrienes

CSF NEUTROPHLIC MONOCYTIC PLEOCYTOSIS : 

CSF NEUTROPHLIC MONOCYTIC PLEOCYTOSIS -Occurs via plial vessels -Neutrophils adhere to Endothelial cell through Specific adhesion molecules modulated by inflammatory cytokines -families of adhesion Molecules *Ig superfamily (ICAM 1,2), *Integrin family (CD11, CD18) and the Selectin family- Elam1 -Specific transmembrane glycoproteins on Endothelia facilitate adhesion

EXUDATE IN SUBARACHNOID SPACE : 

EXUDATE IN SUBARACHNOID SPACE Results from the inflammation- Grey-yellow Abundant in Neutrophils, bacteria Days 2-3 of infxn, inflmn in subarachnoid blood vessels wt subintimal infiltration of arterial walls by lymphocytes and neutophils Meningeal veins distend→ Mural infxn→ Focal necrosis of vessel wall→Mural thrombus in lumen → Haemorrhaghic cortical infxn →blockage of N CSF pathways →hydrocephalas →Focal neurological deficit or Brain herniation →

AETIOLOGY- Age specific : 

AETIOLOGY- Age specific

Common Agents : 

Common Agents H. influ- B serotype Streptoc- Mostly Group B N. Menengitidis – Epidemics in A, C serotypes Prevalence of invasive Pneumococcal disease seen to rise with rising prevalence of HIV Greater risks of Invasive Pneumococcal disease among the HIV +ve population Streptococcus pneumoniae (1.1) in all except neonates

Common agents : 

Common agents Neisseria meningitidis (0.6), usually local outbreaks among young adults, epidemics internationally, and increased incidence in late winter or early spring Group B streptococci (0.3), in newborns Listeria monocytogenes (0.2) in newborns, elderly, and immunocompromised Haemophilus influenzae, type b (0.2) in unvaccinated children and adults

Agents By Age : 

Agents By Age Neonates - Group B or D streptococci, nongroup B streptococci, Escherichia coli, and L monocytogenes Infants and children - H influenzae (48%), S pneumoniae (13%), and N meningitidis Adults - S pneumoniae, (30-50%), H influenzae (1-3%), N meningitidis (10-35%), gram-negative bacilli (1-10%), staphylococci (5-15%), streptococci (5%), and Listeria species (5%)

MODES OF INFECTION/RISK FACTORS : 

MODES OF INFECTION/RISK FACTORS 1.Nasopharyngeal acquisition of Virulent org -Hib; concomittant RTI, HIV, DM, Alcohilism -N. menengitidis; deficiency in terminal complement components C5-C8, C9 (Membrane Attack Complex) Psuedomonal menengitis- assocn with distant foci; RTI, Endocarditis -Asplenic states, M.M, Hypogamma, alcoholism, Cirrhosis Group B Strep- Early onset sepsis in neonate; PROM, LBW

General Risk Factors : 

General Risk Factors Aged 60 years or older Aged 5 years or younger, especially children with diabetes mellitus, renal or adrenal insufficiency, hypoparathyroidism, or cystic fibrosis Immunosuppressed patients are at increased risk of opportunistic infections and acute bacterial meningitis. Immunosuppressed patients may not show dramatic signs of fever or meningeal inflammation.

Risk factors….. : 

Risk factors….. Crowding (eg, military recruits and college dorm residents) increases risk of outbreaks of meningococcal meningitis. Splenectomy and sickle cell disease increase the risk of meningitis secondary to encapsulated organisms. Alcoholism and cirrhosis: Multiple etiologies of fever and seizures in these patients make meningitis challenging to diagnose. Diabetes Recent exposure to others with meningitis, with or without prophylaxis

Risk factors……. : 

Risk factors……. Contiguous infection (eg, sinusitis) Dural defect (eg, traumatic, surgical, congenital) Thalassemia major Intravenous (IV) drug abuse Bacterial endocarditis Ventriculoperitoneal shunt Malignancy (increased risk of Listeria species infection) Some cranial congenital deformities

Virulence Factor Mechanisms : 

Virulence Factor Mechanisms virulence factors involved; a) Nasopharyngeal Colonisation-evasion of Secretory Ig A; IgA Proteases b) Epithelial Cell invasion- after avoidance of ciliary clearance thro *Ciliostasis, *Injury to ciliated cells, *selective adherence to non-ciliated cells

Virulence factors….. : 

Virulence factors….. c) Endocytosis via Cell surface pilli in N. Meningitidis d) Transcellular Movementt in Membrane –bound vacuoles Eg -H. influenza; e) Between Apical tight junctions of columnar epithelial cells

Slide 40: 

-Blood stream invasion- Host’s Complement System evaded thro capsular polysacchride -Crossing BBB - Via Dural venous sinuses - Non-Specific Sterile focal inflammation above Cribriform plate - Choroid plexus-Hi Blood flow -Adhesion to Critical BBB components: E. coli -Phagocytosis and consequent intracellular transport Virulene mechanisms

Virulence Factors …. : 

Virulence Factors …. Colonization or mucosal nvasion Secretory IgA: Mucosal epitheliumIgA protease secretionCiliary activity: Ciliostasis by Adhesive pili2. Intravascular survival: ComplementEvasion of alternative pathway by polysaccharide capsule3. Crossing of blood-brain barrier: Cerebral endotheliumAdhesive pili4. Survival within CSF: Poor opsonic activity increases Bacterial replication

CLINICAL MANIFESTATIONS : 

CLINICAL MANIFESTATIONS Headache- inflam stimulation of nociceptive fibres Of the meninges Fever Meningismus- Kernigs, Brudzinskis signs Cerebral dysfxn signs- confusion, delirium, ↓ Loc N,V, Rigours, profuse sweating, weakness, Myalgia, Photophobia

Clinical manifestations… : 

Clinical manifestations… C. nrve Palsies iv, vi, vii 10-20% of cases esp wt Pseud. meningitis Siezures-40% Purpuric rash wt grey necrosis in Neis. meningitis Neonates- Listlessness, High pitched cry, refusal to feed, irritability Elderly- Obtundation, lethargy

DX : 

DX Lumbar Puncture for CSF-  opening pressure -Neutrophilic pleocytosis - High proteins -Hypoglycorrhachia CSF Analysis- WBC 103-106 wt Neutrophilia - Glc < 2.2 mmol/l - CSF Glc: Serum Glc < 0.31 -CRP 

DX….. : 

DX….. Counter-current Immunoelectrophoresis- specific Microbial antigen in CSF Limulus lysate test →LPS in CSF CSF TNF Microbial PCR CT & MRI- little role in acute phase

COMPLICATIONS& SEQUALAE : 

COMPLICATIONS& SEQUALAE Shock * H.L DIC * Language delay SIADH * M.R Subdural effusion * C.P Siezure disorder * Siezures Encephalopathy * Behavioural abn Brain herniation

Ddx : 

Ddx Brain abcess, Subdural empyema, Epidural abcess, Viral menengitis/encephalitis, CNS Syphillis, Neurologic Manifestations of Lyme dz, TBM, Fungal Menengitis, Rickettsial Infxn, Bacterial endocarditis, Chemical menengitis due to drugs, radiocontrast agents and anaesthetics

CHRONIC MENENGITIS : 

CHRONIC MENENGITIS Neurological syndrome for> 4/52 wt persistent inflammatory response in CSF i.e WBC >5µl Causes a) Meningeal infxn b) Malignancy c)Non-infectious inflammatory disorders d) Chemical menengitis e) Paramenengial infxn

PATHOPHYSIOLOGY : 

PATHOPHYSIOLOGY Classification on anatomical site I, Intracranial Menengitis ii, Spinal Menengitis

INTRACRANIAL MENENGITIS : 

INTRACRANIAL MENENGITIS Acute Menengitis is attended by Inflm in cerebrospinsl space. This can spread to brain parenchyma thro arachnoid cuffs that surround B. vessels & penetrate brain tissue ( Virchow-robin spaces) Anatomical loc’n of the inflm& it’s consequences determine the features - Persistent headaches and stiffness -hydrocephalus

Intracranial meningitis : 

Intracranial meningitis -Cranial neuropathies; in basal menengitis - cognitive/Personality change -gait disturbances The bigger the constellation of signs the wider is the spread of the inflmn In HIV, Menengitis without headache or fever can occur

AETIOLOGY : 

AETIOLOGY MTB Norcardia asteroides Actinimyces israeli Neutrophil pleocytocis in CSF for these Brucella Whipples dz

Aetiology….. : 

Aetiology….. Fungi- Blastomyces dermtidis -candida albicans -Histoplasma capsulatum -Aspergillus Spp -Cryptococcus neoformans Non infectious causes -SLE - Exogenous Chemical Menengitis

Aetiology….. : 

Aetiology….. Viral- Mumps, Lymphocytic choriomenengitis,Echovirus, HIV ( Acute retroviral syndrome), herpes simplex Parasitic dz- T. Gondii, B.procyonis, Trypanosomiasis, Cystcercosis,A. Cantonensis, T. Spirila

DX : 

DX CSF Biochemistry, Culture - G. Stain - AFB - Fungal wet mount -Indian Ink Prepn & Culture - VDRL - P24 markers - assays for Crypt Antigen, oligoclonal Ig G - Cytology

Dx…. : 

Dx…. Contrast enhanced MRI, Ct scan- can preceed menengial biopsy Cerebral angiography- Cerbral arteritis Adjunctive tests

VIRAL MENENGITIS : 

VIRAL MENENGITIS Unique features- Headache is frontal, peri orbital - CSF findings; Lymphocytic pleocytosis,  Prot, N Glc -Etiology enteroviruses make up pathologic agent in 70% 0f culture –ve asepti menengitis - Org; Enteroviruses, arboviruses, LcMV, HSV 2, VZV CMV, EBV, MUMPS

Viral meningitis : 

Viral meningitis DX- CSF Exam total Cell count <1000 - CRP -Lactic acid - LDH -IL 6, Soluble IL2 receptor - TNF: has been proposed to distinguish btw viral and bacterial aetiologies

ENCEPHALITIS : 

ENCEPHALITIS Swelling throught the brain

Etiology : 

Etiology The etiology of encephalitis is usually infectious, but may be noninfectious, such as the demyelinating process in acute disseminated encephalitis. Infectious etiologies: Viral agents, such as HSV type 1 and 2 (almost exclusively in neonates), VZV, EBV, measles virus (PIE and SSPE), mumps, and rubella are spread through person-to-person contact.

aetiology : 

aetiology Important animal vectors include mosquitoes, ticks (arbovirus), and warm-blooded mammals (rabies, lymphocytic choriomeningitis). Bacterial pathogens, such as Mycoplasma species and those causing rickettsial or catscratch disease, are rare and invariably involve inflammation of the meninges out of proportion to their encephalitic components. Encephalitis due to parasites and fungi other than Toxoplasma gondii

Viral Encephalitis : 

Viral Encephalitis the virus replicates outside the CNS and gains entry either by hematogenous spread or by traveling along neural (rabies, HSV, VZV) and olfactory (HSV) pathways. The etiology of slow virus infections, such as those implicated in the measles-related subacute sclerosing panencephalitis (SSPE) and progressive multifocal leukoencephalopathy (PML), is poorly understood

Viral Encephalitis : 

Viral Encephalitis the virus enters neural cells, with resultant disruption in cell functioning, perivascular congestion, hemorrhage, and inflammatory response diffusely affecting gray matter disproportionately to white matter. Focal pathology is the result of neuron cell membrane receptors found only in specific portions of the brain and accounts for regional tropism found with some viruses. For example, HSV has a predilection for the inferior and medial temporal lobes.

Slide 64: 

Although most histologic features are nonspecific, brain biopsies are the diagnostic criterion standard for rabies. Presence of Negri bodies in the hippocampus and cerebellum are pathognomonic of rabies, as are HSV Cowdry type A inclusions with hemorrhagic necrosis in the temporal and orbitofrontal lobes. In contrast to viruses that invade gray matter directly, acute disseminated encephalitis and postinfectious encephalomyelitis (PIE), secondary to measles (most common), Epstein-Barr virus (EBV), and CMV, are immune-mediated processes, which result in multifocal demyelination of perivenous white matter.

ENCEPHALITIS : 

ENCEPHALITIS CNS infxn where Infctve processs+ Inflammatory response involve both the meninges and the brain paenchyma Clinically; Febrile illness, signs of Meningeal irritation + Altered level of consciousness or abn Mental state. Evidence of focal or diffuse neurological signs S & S reflect the sites of infxn and inflmn

Slide 66: 

Etiology- Multiple viruses; most common Arboviruses, Enteroviruses, HSV 1, mumps DX – As for viral mengitis + Serologic studies CSF nucleic acid amplification, Brain biopsy, virus isolation from stool, urine blood, throar washings DDX – Paramenengial infxn, non viral infectious menengitides, neoplastic menengitis, SLE, Reye’s syndrome

Strptococcal Meningitis : 

Strptococcal Meningitis

TB Meningitis : 

TB Meningitis

Herpes Simplex Encephalitis : 

Herpes Simplex Encephalitis Prediliction for temporo-parietal regions

Cryptococcal Meningitis : 

Cryptococcal Meningitis Perivascular infiltrations

Cryptococcal neofomans : 

Cryptococcal neofomans

Table 1- CSF Findings : 

Table 1- CSF Findings

Treatment : 

Treatment Neisseria meningitidis (Meningococcus) can usually be treated with a 7-day course of IV antibiotics: Penicillin-sensitive -- penicillin G or ampicillin Penicillin-resistant -- ceftriaxone or cefotaxime Prophylaxis for close contacts (contact with oral secretions) -- rifampin 600 mg bid for 2 days (adults) or 10 mg/kg bid (children). Rifampin is not recommended in pregnancy and as such, these patients should be treated with single doses of ciprofloxacin, azithromycin, or ceftriaxone

Treatment…. : 

Treatment…. Streptococcus pneumoniae (Pneumococcus) can usually be treated with a 2-week course of IV antibiotics: Penicillin-sensitive -- penicillin G Penicillin-intermediate -- ceftriaxone or cefotaxime Penicillin-resistant -- ceftriaxone or cefotaxime + vancomycin

Treatment… : 

Treatment… Listeria monocytogenes is treated with a 3-week course of IV ampicillin + gentamicin. Gram negative bacilli -- ceftriaxone or cefotaxime Pseudomonas aeruginosa -- ceftazidime Staphylococcus aureus Methicillin-sensitive -- nafcillin Methicillin-resistant -- vancomycin Streptococcus agalactiae -- penicillin G or ampicillin Haemophilus influenzae -- ceftriaxone or cefotaxime

Preventions : 

Preventions Vaccination Vaccinations against Haemophilus influenzae (Hib) have decreased early childhood meningitis significantly Vaccines against type A and C Neisseria meningitidis, the kind that causes most disease in preschool children and teenagers There is also a risk of autoimmune response, and the porA and porB proteins on Type B resemble neuronal molecules Pneumococcal polysaccharide vaccine against Streptococcus pneumoniae is recommended for all people 65 years of age or older. Pneumococcal conjugate vaccine is recommended for all newborns starting at 6 weeks - 2 months

prevention : 

prevention Mumps vaccination has led to a sharp decline in mumps virus associated meningitis Prophylaxis In cases of meningococcal meningitis, prophylactic treatment of close relatives with antibiotics (e.g. rifampicin, ciprofloxacin or ceftriaxone) may reduce the risk of further cases

Prevention….. : 

Prevention….. Improvement in public health programmes, living standard, and health education

Slide 81: 

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