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Chapter 70 Infective Syndromes of...

Chapter 70 Infective Syndromes of Central Nervous System Chapter Preview „„Meningitis „„Encephalitis and Encephalopathy „„Space-occupying Lesions Infections of the central nervous system (CNS) account ™™ Viral agents: They predominantly cause either meningitis for significant morbidity and mortality. Most of these (Chapter 73) or encephalitis (Chapter 74) infections present as a medical emergency; need prompt ™™ Parasitic agents: Neuroparasites most often cause space- treatment. occupying lesions, encephalitis or rarely meningitis; The CNS consists of the brain and spinal cord; covered discussed in Chapter 75 https://t.me/docinmayking by three layers of meninges—dura mater (outermost), ™™ Fungal agents of CNS: They cause mainly meningitis, arachnoid and pia mater (the latter two are collectively discussed in Chapter 75. called as leptomeninges). Between and around the meninges are spaces that include the epidural, subdural, Routes of Infection and subarachnoid spaces (Fig. 70.1). The organisms may gain access to the CNS by several routes. Infective syndromes of cns ™™ Hematogenous spread: This is the most common route, where entry into the subarachnoid space is gained The various infective syndromes of CNS are meningitis, through the choroid plexus or through other blood encephalitis and encephalopathy, space occupying lesions vessels of the brain and others (Table 70.1). ™™ Direct spread from an infected site present close to ™™ Bacterial agents: The bacterial agents of CNS mainly meninges—otitis media, mastoiditis, sinusitis, etc. cause meningitis (Chapter 71), also cause other CNS infections such as brain abscess or shunt infections (discussed in this chapter) and neurotoxin mediated Table 70.1: Infective syndromes of CNS. disease, tetanus (Chapter 72) Meningitis: It can be classified into— Acute bacterial meningitis: Caused by pneumococcus, meningococcus, H. influenzae, Listeria, Streptococcus agalactiae, gram-negative bacilli such as E. coli Acute viral meningitis: Mainly caused by enteroviruses, herpesviruses and others Chronic meningitis: Caused by bacterial agents (e.g. M. tuberculosis), viral, parasitic and fungal agents (e.g. Cryptococcus) Encephalitis and encephalopathy Encephalitis: Viral agents like herpes, rabies, arboviruses (e.g. Japanese encephalitis), parasites such as Toxoplasma Encephalopathy of infectious etiology such as slow virus infections, cerebral malaria, etc. Space-occupying lesions: Include Focal CNS lesions: such as brain abscess, subdural empyema, and epidural abscess Cystic parasitic diseases: such as neurocysticercosis, cystic echinococcosis, etc. Other infective syndromes of CNS Suppurative intracranial thrombophlebitis CSF shunt infections Myelitis (inflammation of spinal cord): e.g. poliomyelitis Fig. 70.1: Anatomy of central nervous system. Neurotoxin mediated: Tetanus and botulism 688 Section 9  Central Nervous System Infections ™™ Anatomical defect in CNS: It may occur as a result of inflammatory response in CSF (white blood cell count surgery, trauma, congenital defects which can allow >5/μL) organisms for ready and easy access to CNS ™™ Etiology: Although infections (bacterial, viral, parasitic ™™ Direct intraneural spread along the nerve: This is the or fungal) account for a significant proportion of cases least common route, occurs in cases of rabies virus or (Table 70.2), chronic meningitis may also be caused by herpes simplex virus (HSV) infection. non-infectious causes such as malignancy, autoimmune diseases, and chemical meningitis Meningitis ™™ Clinical forms: Chronic meningitis occurs in two clinical Meningitis is an inflammation of the leptomeninges forms (arachnoid and pia mater) surrounding the brain and „„ Chronic persistent meningitis: In most of the cases, spinal cord, with involvement of the subarachnoid space. the symptoms are chronic and persistent „„ Chronic recurrent meningitis: Characterized by Types of Meningitis discrete episodes of illness along with the absence Based on the onset, meningitis can be classified into: of symptoms with normal CSF parameters between ™™ Acute meningitis: Presents as an acute fulminant illness episodes. It is particularly seen in Mollaret’s that progresses rapidly in a few hours. It can be further meningitis, caused by HSV type 2. grouped into acute bacterial (or pyogenic) and acute viral ™™ CSF findings: In chronic meningitis, the CSF is pre- meningitis dominantly lymphocytic; although elevated neutrophil ™™ Chronic meningitis: Progressively worsens over weeks in CSF is observed in some of these infections. (>4 weeks). This includes bacterial, parasitic, fungal Note: Aseptic meningitis: The term ‘aseptic meningitis’ https://t.me/docinmayking agents and viral agents (Table 70.2). Some of the agents was traditionally used to describe those meningitis, where of chronic meningitis have a subacute course that the infectious etiology is unidentified (aseptic meaning progressively worsens over several days. The host inflammatory response in meningitis may vary—acute bacterial meningitis is characterized by elevated Table 70.2: Agents of chronic meningitis. neutrophil count in CSF, whereas both acute viral meningitis Bacterial agents (Chapter 71) and chronic meningitis are predominantly lymphocytic; Common bacterial agents although exceptions to this general rule do exist. Partially treated suppurative meningitis Parameningeal infections (e.g. otitis media) Acute Bacterial (or Pyogenic) Meningitis (Chapter 71) Mycobacterium tuberculosis Borrelia burgdorferi (Lyme disease) Acute bacterial meningitis is characterized by elevated Treponema pallidum (secondary, tertiary syphilis) polymorphonuclear cells (i.e. neutrophils) in CSF (hence Rare bacterial agents: Nocardia, Actinomyces, Tropheryma whipplei, called as pyogenic meningitis); except for Listeria, where Leptospira, Brucella CSF is predominantly lymphocytic. According to the age, Viral agents the agents involved may vary. Some of the agents of acute viral meningitis may also present as ™™ Overall Streptococcus pneumoniae is the most common chronic meningitis Examples: Mumps, echoviruses, herpesviruses, HIV and cause of pyogenic meningitis lymphocytic choriomeningitis virus ™™ Others agents include meningococcus, Group B Parasitic agents Streptococcus, Haemophilus influenzae, Listeria Toxoplasma gondii monocytogenes and occasionally gram-negative bacilli Free-living amoebae such as Escherichia coli. Trypanosoma brucei (African sleeping sickness) Angiostrongylus cantonensis (Eosinophilic meningitis) Acute Viral Meningitis (Chapter 73) Gnathostoma spinigerum Baylisascaris procyonis Acute viral meningitis is caused by a number of viruses, Cysticercosis, schistosomiasis, echinococcal disease among which enteroviruses account for the majority of Toxocara canis and Trichinella cases (>85%). Others include herpesviruses, arboviruses Fungal agents (encephalitis group), HIV and rarely lymphocytic Cryptococcus neoformans choriomeningitis (LCM) virus, mumps virus. Candida albicans ™™ The CSF is predominantly lymphocytic Blastomyces dermatitidis ™™ Although they usually develop meningitis in few days Histoplasma capsulatum Coccidioides immitis after the infection; many of these viruses progress slower Aspergillus species and can also occasionally cause chronic meningitis. Sporothrix schenckii Pseudallescheria boydii Chronic Meningitis Cladophialophora bantiana Chronic meningitis is defined as persistence of men- Note: Some of these agents may present as a subacute form of meningitis, that ingitis exists for >4 weeks; associated with a persistent progresses over several days to 180) Moderately elevated Slightly elevated/normal Total leukocyte count (per mm3) 0–5 100–10,000 10–500 25–500 Predominant cell type Lymphocytes Neutrophils Lymphocytes Lymphocytes Glucose (mg%) 40–70 45 mg/dL (usually >250; 100–500 mg/dL (moderate 20–80 mg/dL (normal or markedly increased) to markedly increased) slightly elevated) 694 Section 9  Central Nervous System Infections Table 71.2: Preliminary clue about the etiological agents of Culture pyogenic meningitis based on CSF Gram stain. Ideal media for bacteriological culture of CSF are enriched Appearance in CSF Gram stain Suggestive of media like chocolate agar and blood agar, and differential Gram-positive diplococci, flame or Streptococcus media like MacConkey agar lanceolate-shaped with clear halo pneumoniae ™™ Enriching: As the bacterial load is very low, a part of the (capsulated) (Fig. 61.1) CSF can be inoculated into enriched media such as blood Gram-negative diplococci, capsulated, Neisseria meningitidis culture bottles at the bed side (preferred) or brain heart with adjacent sides flattened (lens or infusion (BHI) broth in the laboratory half-moon shaped) (Fig. 71.2) ™™ Blood culture can be collected in conventional blood Pleomorphic gram-negative coccobacilli, Haemophilus influenzae culture bottles such as BHI broth/agar or preferably in capsulated (Fig. 61.4A) automated blood cultures (e.g. BacT/ALERT) Gram-negative bacilli, arranged singly Escherichia coli or others ™™ Culture plates (blood agar and chocolate agar) are Gram-positive cocci in short chain Streptococcus agalactiae incubated at 37°C, preferably in candle jar (provides 5% CO2) for 48 hours Gram-positive short bacilli, often Listeria monocytogenes confused with diphtheroids Table 71.3: Culture and identification properties of common bacterial agents of pyogenic meningitis. In acute bacterial (pyogenic) meningitis: Streptococcus pneumoniae (Chapter 61) ™™ CSF usually contains >1000 leukocytes/µL and Culture: It produces α-hemolytic colonies on blood agar, https://t.me/docinmayking predominantly neutrophils (90–95%). However in described as draughtsman-shaped or carrom coin appearance Listeria meningitis, there is increased lymphocyte count Biochemical identification: It shows bile soluble, ferments in CSF inulin and sensitive to optochin ™™ The total protein content is elevated and the glucose level Neisseria meningitidis (discussed in this chapter) is markedly diminished or even absent It produces non- hemolytic colonies on blood agar, which on smear shows gram-negative diplococci (Fig. 71.2) ™™ CSF pressure is highly elevated. Biochemical identification: Meningococci are catalase and oxidase positive. They ferment glucose and maltose but not CSF Microscopy (Gram Staining) sucrose Microscopic examination of gram-stained smear may give Serogrouping: Slide agglutination serogrouping (SASG) test a preliminary clue about the etiological agent of pyogenic is done to identify the serogroups of meningococci isolates by using appropriate antisera meningitis based on the morphology of the bacteria (Table Haemophilus influenzae (Chapter 61) 71.2). Culture: Blood agar with S. aureus streak line shows satellitism. ™™ This helps in early initiation of appropriate empirical Biochemical identification: Disk test for X and V factor antimicrobial therapy requirement shows growth surrounding combined XV disk ™™ Heaped smear: As the bacterial load in CSF may be Streptococcus agalactiae (Chapter 52) very low, to increase the sensitivity, several drops of CSF Culture: It produces β-hemolytic colonies on blood agar, which should be placed at the same spot on the slide, each drop on smear shows gram-positive cocci in short chain being allowed to air dry before the next is added Biochemical identification: It shows CAMP test positive and resistance to bacitracin ™™ Centrifugation: Alternatively, CSF can be centrifuged (by Serogrouping with group specific antisera shows Lancefield cytospin) and the deposit is examined for Gram staining. group B Gram-negative bacilli meningitis Direct Antigen Detection Escherichia coli and Klebsiella produce lactose-fermenting From CSF: After centrifugation of CSF, the supernatant colonies on MacConkey agar; identified by ICUT tests can be used for antigen detection. Latex agglutination test Non-fermenters: Pseudomonas is oxidase positive, whereas is performed using latex beads coated with anti-capsular Acinetobacter is oxidase negative. They produce non-lactose fermenting colonies; identified by ICUT tests (Chapter 65) antibodies. Listeria monocytogenes (discussed in this chapter) ™™ It is available for detection of capsular antigens of Motility: It shows tumbling type of motility at 25°C but non- common agents of meningitis such as S. pneumoniae, motile at 37°C (called differential motility, which is due to S. agalactiae, N. meningitidis, H. influenzae or E. coli temperature dependent flagella expression) ™™ Detection of capsular antigens in CSF is more sensitive Culture: It grows on blood agar (β-hemolytic colonies), and than CSF microscopy. chocolate agar. Note: Selective media such as PALCAM agar (containing mixture of From urine: Antigen detection in urine is useful for antibiotics) may be useful for isolation of Listeria from specimens pneumococcal meningitis. Immunochromatographic test such as food and environmental samples. (ICT) is available to detect the C-polysaccharide antigen of Abbreviations: ICUT tests, indole, citrate, urease and triple sugar iron agar test; S. pneumoniae in urine. CAMP, Christie, Atkins, and Munch-Peterson test.  Chapter 71  Bacterial Meningitis 695 „„ For pneumococcus: lytA (autolysin gene), ply (pneumolysin) and psaA (pneumococcus surface antigen A) „„ For H. influenzae: Conserved capsular gene bexA. T Reatment Pyogenic meningitis The mortality of pyogenic meningitis is very high (~20% for pneumococci) and among the survivors, up to 50% develop complications. Therefore, treatment should be initiated as early as possible. The choice of antimicrobial agent is based on the type of or- ganism suspected and good CSF penetration ability of the agent. Empirical therapy comprises of: ‰‰ Adult: IV cefotaxime or ceftriaxone and vancomycin is the recommended regimen. If Listeria is suspected, IV ampicillin Fig. 71.2: Meningococci in CSF smear (gram-negative diplococci, can be added to the regimen lens-shaped) (arrows showing). ‰‰ For neonates: IV ampicillin plus gentamicin is the Source: Centers for Disease Control and Prevention (CDC), Atlanta (with permission). recommended regimen ‰‰ IV dexamethasone is added to the regimen to reduce intra­ cranial pressure. ™™ Identification: Colonies grown on solid media are Definitive therapy: After the culture report is available, the https://t.me/docinmayking processed for identification of the organism either by empirical therapy is modified based on the organism isolated automated identification system such as MALDI-TOF or and its antimicrobial susceptibility pattern. VITEK, or by conventional biochemical tests (Table 71.3) ™™ Antimicrobial susceptibility test should be done to Agents of pyogenic meningitis initiate definitive antimicrobial therapy. It is carried out by disk diffusion test or preferably by automated MIC- Pneumococcal Meningitis based methods such as VITEK Streptococcus pneumoniae (or pneumococcus) is the ™™ Sensitivity: CSF and blood cultures may take >48 hours leading cause of meningitis in adults (>20 years of age), for organism identification and are positive in 70-85% of accounting for 50% of all cases. It is also the most common patients with bacterial meningitis. However, sensitivity agent of pneumonia, discussed in detail Chapter 61. drops rapidly in case of prior antimicrobial therapy or ™™ They may present as commensals in human nasopharynx, delay in processing from where the bacteria spread locally to cause otitis media ™™ Therefore, rapid diagnostic tests such as antigen or pneumonia and subsequently via the bloodstream detection or molecular test should be considered to to distant sites to cause invasive pneumococcal disease determine the bacterial etiology of pyogenic meningitis. such as bacteremia and meningitis ™™ The principle virulence factors include capsular Serology polysaccharide, C-carbohydrate antigen, pneumolysin Antibodies to capsular antigens of meningococci can be and autolysin detected in patient’s serum by ELISA. This is useful to study ™™ Risk factors: The predisposing factors that increase the seroprevalence and to know the response to vaccination; risk of pneumococcal meningitis include underlying not for diagnosis. pneumococcal pneumonia (most important) or otitis media, alcoholism, diabetes, splenectomy, Molecular Methods complement deficiency, hypogammaglobulinemia, Molecular tests are highly sensitive, detect even few and head trauma bacteria in CSF with less turnaround time than culture and ™™ The mortality rate remains high (~20%), despite antibiotic also help in serogroup identification. therapy. ™™ Formats: Multiplex PCR and multiplex real-time PCR Laboratory diagnosis and treatment of pneumococcal can be used for simultaneous detection of common infections have been discussed in detail in Chapter 61. agents of pyogenic meningitis ™™ BioFire FilmArray is an automated nested multiplex Meningococcal Meningitis PCR commercially available, which can simultaneously Meningococcal meningitis is of particular importance due detect 14 common agents of meningitis (both pyogenic to its potential to cause large outbreaks and epidemics. and viral) in CSF, with a turnaround time of 1 hour ™™ It is caused by Neisseria meningitidis (or meningococcus); ™™ Common genes targeted include: which appears capsulated gram-negative diplococci „„ For meningococcus: ctrA (capsule transport gene) with adjacent sides flattened (lens-shaped/half-moon and sodC (Cu-Zn superoxide dismutase gene) shaped) (Fig. 71.2) 696 Section 9  Central Nervous System Infections Table 71.4: Differences between Neisseria meningitidis and Epidemiology Neisseria gonorrhoeae. Worldwide, nearly 5 lakh cases of meningococcal disease N. meningitidis N. gonorrhoeae occur each year, and 5-16% of those die. Capsulated Noncapsulated ™™ Patterns of disease: Meningococcus causes several pat- Lens-shaped/half moon-shaped Kidney-shaped (diplococci with terns of invasive disease ranging from sporadic infection, (diplococci with adjacent sides adjacent sides concave) (Chapter to endemic, hyperendemic and explosive epidemics flattened) (Fig. 71.2) 77, Fig. 77.7) ™™ High prevalence area: The sub-Saharan belt of Africa Ferments glucose and maltose Ferments only glucose (from Ethiopia to Senegal) is the most prevalent area for Rarely have plasmids Usually possess plasmids, coding meningococcal infections. Around 30,000 cases are still for drug-resistant genes reported each year from this area Exist in both intra- and Predominantly exist in ™™ World: The serogroups distribution vary among various extracellular forms intracellular form regions of the world Habitat—nasopharynx Habitat—genital tract (urethra, „„ Group A: It was the leading cause of epidemic men- cervix), rarely pharynx ingitis worldwide. With the advent of vaccination, the occurrence of group A has been reduced consider- ™™ Neisseria has another pathogenic species, N. gonorrhoeae ably (causes gonorrhoea, Chapter 77), both differ from each „„ Group B and C are currently the major serogroups other in various aspects (Table 71.4) causing invasive disease worldwide ™™ Other species are commensals of the genital tract or oral  Group B can cause hyperendemic disease (>10 cases per 100,000 population) https://t.me/docinmayking cavity, such as N. lactamica, N. flavescens, N. mucosa, N. sicca, N. subflava, etc.; although they can be occasionally  Group C continues to cause outbreaks in Nigeria pathogenic to humans. (>4000 cases in 2018). ™™ Group X, Y and W are less commonly reported worldwide. Virulence Factors Group W (formerly W 135) can cause outbreaks in mass Capsular Polysaccharide gatherings; has caused the global outbreak in 2000 in It is the principal virulence factor of meningococci; protects Hajj pilgrimage the bacteria from complement-mediated phagocytosis. ™™ India: Sporadic cases have been occurring every year, ™™ Based on the antigenic nature of the capsule, mainly from North India with occasional outbreaks meningococci can be typed into 13 serogroups [A–D, X–Z, „„ Serogroup A has been reported from few places, though 29E, W, H-J and L], among which only 6 serogroups—A, accurate data on serogroup distribution is lacking B, C, X, Y, and W (formerly W135)—account for the „„ In 2015, >12,000 cases were reported, maximum from majority of cases of invasive disease Bihar (>8,000 cases). ™™ Other capsular serogroups and noncapsulated ™™ Seasonality: Meningococcal infections are common in meningococci (16% of isolates are noncapsulated) winter and spring (cold and dry climate) commonly colonize the nasopharynx of asymptomatic ™™ Age: Meningitis is common in early childhood (3 months carriers and are rarely associated with invasive disease. to 5 years) with a second peak occurring in adolescents (15–25 years of age) Other Virulence Factors ™™ Risk factors that promote colonization include: ™™ Outer membrane proteins: They are the porin proteins „„ Overcrowding and semiclosed communities, such as present beneath the capsule, embedded in the outer schools, military and refugee camps membrane „„ Travelers (e.g. Hajj pilgrims) ™™ LPS and endotoxin: Like other gram-negative bacteria, „„ Smoking meningococci possess LPS (lipopolysaccharide) and „„ Recent upper respiratory tract infection. endotoxins in their cell wall. Endotoxin induces the release ™™ Risk factors that promote disease include: of various inflammatory mediators, which in turn damage „„ Deficiency of terminal complement components the vascular endothelium. Endothelial injury is central (C5–C9) to many clinical features of meningococcemia, such as: „„ Eculizumab or ravulizumab therapy—a terminal „„ Increased vascular permeability leading to loss of complement inhibitor fluid and shock „„ Hypogammaglobulinemia and hyposplenism. „„ Intravascular thrombosis (due to activation of pro­ ™™ Carriers: 5-10% of populations are asymptomatic coagulants) leading to disseminated intravascular nasopharyngeal carriers at any given time. coagulation (DIC) „„ Myocardial dysfunction. Pathogenesis ™™ Others include IgA proteases, transferrin binding Humans are the only natural host for meningococci. Most proteins and adhesins. common source of infection is nasopharyngeal carriers.  Chapter 71  Bacterial Meningitis 697 ™™ Mode of transmission: It is by droplet inhalation and the Vaccine Prophylaxis portal of entry is through the nasopharynx Meningococcal polysaccharide vaccines are currently ™™ Spread of infection: From nasopharynx, meningococci formulated as either bivalent (serogroups A and C) or reach the meninges either by (1) hematogenous route quadrivalent (serogroups A, C, Y, and W135). causing septicemia (most common); or (2) by direct ™™ Schedule: Administered as two doses, 2–3 months apart spread along olfactory nerve through cribriform plate; to children of 3–18 months of age or as a single dose to or (3) rarely through conjunctiva. older children or adults ™™ Efficacy: It has a protective efficacy rate of >95%. The Clinical Manifestations duration of protection lasts for 3–5 years The majority of infected individuals become carriers. The ™™ Indication: It is recommended for high-risk people remainders develop the following manifestations: such as (i) contacts of patients during outbreaks, ™™ Rashes: A non-blanching rash (petechial or purpuric) (ii) splenic dysfunction, (iii) terminal complement develops in more than 80% of the cases (Chapter 55) component deficiency, (iv) taking eculizumab therapy, ™™ Septicemia: It is attributed to endotoxin induced (v) laboratory staff at risk, (vi) international travellers, endothelial injury leading to increased vascular including students going to study abroad permeability and intravascular thrombosis ™™ Capsular vaccine is not available for serogroup B as: ™™ Waterhouse–Friderichsen syndrome: It is a severe „„ Capsule of serogroup B (made up of sialic acid) is less form of fulminant meningococcemia, characterized immunogenic by large purpuric rashes (purpura fulminans), shock, „„ It is also encephalitogenic due to expression of similar disseminated intravascular coagulation (DIC), bilateral https://t.me/docinmayking cross reactive antigens on neural cells. adrenal hemorrhage and multiorgan failure (Fig. 55.6). ™™ Not given below 3 years: Similar to pneumococcal ™™ Pyogenic meningitis: It commonly affects young vaccine, meningococcal capsular vaccine is also an children (3–5 years of age). Presentation includes fever, example of T cell-independent antigen and is poorly vomiting, headache, neck stiffness—similar to any other immunogenic to children; hence not given to children bacterial meningitis, except for the presence of rashes of less than 2–3 years of age ™™ Chronic meningococcemia: It occurs rarely and is ™™ Conjugated vaccine: However, conjugated meningo­ characterized by repeated episodes of petechial rashes, coccal capsular vaccine is available which can be given to fever, arthritis, and splenomegaly young children. Addition of a protein carrier (adjuvant) ™™ Postmeningococcal reactive disease: Immune com­ increases the immunogenicity of the capsular vaccine. plexes (made up of capsular antigens and their antibodies) develop 4–10 days later, lead to manifestations like Vaccine for Group B (MenB Vaccine) arthritis, rash, iritis, pericarditis, polyserositis, and fever. Recently, recombinant vaccine for Group B meningococcus has Laboratory diagnosis is discussed in Table 71.3. been licensed. ‰‰ Vaccine contains four recombinant proteins: Adhesin A, T Reatment Meningococcal meningitis heparin binding antigen, factor H binding protein and outer Meningococcal meningitis is associated with high fatality (up membrane vesicles (OMV) to 50% when untreated) and high frequency (>10%) of severe ‰‰ Schedule: Two doses, given IM route 1 month apart sequelae. Early antibiotic treatment may reduce fatality to 50 years, transmission (mother to fetus, during birth) particularly those with underlying diseases. ™™ Common food sources include contaminated coleslaw, https://t.me/docinmayking milk, soft cheeses, and several types of “ready-to-eat” T Reatment Group B Streptococcal meningitis foods, including delicatessen meat and uncooked hotdogs Meningitis should be treated with penicillin for a duration of 14 ™™ Age: Listeriosis is common among extremes of age days, as shorter courses may lead to relapse. (neonate and old age) Group B Streptococcus is discussed in detail in Chapter 52. ™™ Use of proton pump inhibitors increases the risk by reducing the gastric acid mediated killing of Listeria Gram-negative bacilli Meningitis ™™ Other risk factors: Pregnant women and immuno­ Gram-negative bacilli cause meningitis in individuals compromised individuals are at higher risk with chronic and debilitating diseases such as diabetes, ™™ Due to its ability to survive refrigeration (4°C), it is cirrhosis, or alcoholism and in those with chronic UTI. commonly found in stored foods especially aged soft Gram-negative meningitis can also occur secondary to cheeses, packaged meats, milk and cold salads neurosurgical procedures, particularly craniotomy, and ™™ Listeriosis is most often sporadic, although outbreaks head trauma with CSF rhinorrhea or otorrhea. do occur. ™™ Escherichia coli and Klebsiella are one of the common cause of pyogenic meningitis in neonates Pathogenesis ™™ Intracellular survival: After entry into the intestinal epithelium, it survives inside the host cell, mainly due Table 71.5: Early and late-onset group B Streptococcus disease in to lysis of phagosome by forming pores (mediated by neonates. listeriolysin O) Characteristics Early-onset disease Late-onset disease ™™ Then it causes host cell actin polymerization, which Age of onset 0–6 days of birth 7–90 days of birth helps the bacterium to reach near the cell membrane Increased risk Prematurity and Not associated ™™ Finally, it migrates to the adjacent epithelial cells/ following obstetric prolonged labor macrophages by direct cell-to-cell spread, mediated complications by listeriopods. Mode of During or before Contact with a transmission to the birth from the colonized mother and Clinical Manifestations baby colonized maternal nursing personnel genital tract Clinical manifestation depends on the age of the patient Common clinical Pneumonia and/ Meningitis (most com- and other risk factors, such as immunosuppression. Most manifestations or respiratory mon) and bacteremia of the human infections are caused due to serotypes 1/2a, distress syndrome 1/2b, and 4. (most common), ™™ Neonatal listeriosis: Two clinical presentations are bacteremia and recognized—early-onset and late-onset neonatal disease meningitis (Table 71.6) Common serotypes Ia, III, V, II, Ib Type III ™™ In pregnant women: It affects both mother and the Case fatality rate 4.7% 2.8% fetus. (1) Fetal complications, such as abortion, preterm  Chapter 71  Bacterial Meningitis 699 Table 71.6: Differences between early- and late-onset neonatal ™™ Mycobacterium tuberculosis listeriosis. ™™ Borrelia burgdorferi (Lyme disease) Early-onset neonatal disease Late-onset neonatal disease ™™ Treponema pallidum (tertiary syphilis) Occurs 5 days of birth (Mean ™™ Rare bacterial agents such as Nocardia, Actinomyces, (Mean age 1.5 days) age 14.2 days) Tropheryma whipplei, Leptospira and Brucella. Acquired from maternal genital flora Acquired from environment Clinical Manifestations Associated with obstetrical Not associated complications like premature Neurologic manifestations of chronic meningitis are delivery and low birth weight determined by the anatomic location of the inflammation Most common form is neonatal Most common form is and its consequences. Cardinal features include: sepsis neonatal meningitis ™™ Persistent headache and neck or back pain/stiffness Granulomatosis infantiseptica: Not seen (similar to pyogenic meningitis) Occurs rarely, characterized ™™ Hydrocephalus: Accumulation of CSF within the by miliary microabscesses and ventricles causes increased pressure inside the skull granulomas, mostly in skin, liver ™™ Cranial neuropathies: Leads to facial weakness, diminished and spleen vision, papilledema, optic atrophy, hearing loss Mortality rate is up to 50% Mortality rate is 60 years) Mycobacterium tuberculosis Infections of CNS „„ Common risk factor is immunosuppression (steroid Tuberculosis of the CNS accounts for ~5% of extrapulmonary therapy, HIV, diabetes, malignancy) cases. It is seen most often in young children but also „„ Listeria can cause meningitis in kidney transplanted develops in adults, especially those infected with HIV. It patients 1-month after the transplantation presents in two clinical forms: tuberculous meningitis and „„ It also causes gastroenteritis following consumption tuberculoma. of contaminated milk, meat and salads. Laboratory diagnosis of listeriosis is discussed in Table 71.3. Tuberculous Meningitis (TBM) T Reatment Listeriosis TBM results from the hematogenous spread of primary or post-primary pulmonary TB. Typically, the disease ‰‰ Meningitis: Ampicillin is the drug of choice, given for 2–3 evolves over 1–2 weeks or longer, which differentiates it weeks in combination with gentamicin for synergistic effect ‰‰ Cotrimoxazole is given for patients with penicillin allergy from bacterial meningitis. ‰‰ In febrile gastroenteritis, Amoxicillin is recommended in Clinical Features immunocompromised, elderly or pregnant patients ‰‰ Antibiotics to be avoided: Cephalosporins, chloramphenicol TBM often presents subtly as headache, slight mental are not active in vivo; vancomycin, linezolid, macrolides and changes, low-grade fever, malaise, night sweat, anorexia, tetracyclines are not recommended. and irritability. ™™ Subsequently, it may evolve acutely with severe Staphylococcal Meningitis headache, confusion, lethargy, altered sensorium, and S. aureus and coagulase-negative staphylococci can cause neck rigidity meningitis following invasive neurosurgical procedures, ™™ Cranial nerves paresis (ocular nerves in particular) is a particularly ventricular shunting (Chapter 51). frequent finding. Stroke may occur due to involvement of cerebral arteritis ™™ Ultimately, it progresses towards coma, with hydroceph- Chronic bacterial meningitis alus and intracranial hypertension. Several bacterial meningitis present as chronic stage, characterized by persistence of signs and symptoms as well Laboratory Diagnosis as the CSF abnormality for >4 weeks. The bacterial agents ™™ CSF analysis: Examination of CSF reveals— causing chronic meningitis include the following. „„ High leukocyte count (up to 1,000/μL), mostly ™™ Partially treated pyogenic meningitis lymphocytic. However, neutrophils may be elevated ™™ Parameningeal infections (e.g. otitis media) in the early stage 700 Section 9  Central Nervous System Infections „„ Protein content of 100–800 mg/dL signs, cranial neuritis (including bilateral facial palsy), „„ Low glucose concentration. and radiculoneuropathy However, it should be noted that any of these three ™™ CSF findings include elevated lymphocytes (~100 cells/ parameters can be within the normal range. μL), elevated protein levels and normal or slightly low ™™ Cobweb coagulum: When CSF is kept in a tube for 12 glucose level hours, a coagulum forms in the form of a cobweb due to ™™ Meningopolyneuritis: This is seen in cases from Europe higher fibrin content in the fluid and Asia, which presents as radicular pain with CSF ™™ Acid-fast staining of CSF: Direct smear of CSF sediment pleocytosis, without meningeal or encephalitic signs. may reveal long slender beaded acid-fast bacilli This is called as Bannwarth’s syndrome „„ However, the sensitivity of acid fast stain is very low ™™ These early neurologic abnormalities usually resolve (10-40%) and may require repeated lumbar punctures completely within a month, but rarely chronic to increase the yield neurologic disease may occur later „„ Acid-fast staining of cobweb may give better yield as ™™ Treatment: IV ceftriaxone for 14–28 days is recommended TB bacilli may be trapped in the cobweb. However, for neuroborreliosis. Alternatively IV cefotaxime or IV fibrin strands in the cobweb may be mistaken as fungi. penicillin G can be given. ™™ Culture of CSF is diagnostic in up to 80% of cases and remains as the gold standard test. However, culture is Neurosyphilis (Treponema pallidum) time consuming, takes 4–8 weeks by Lowenstein-Jensen Neurosyphilis is a type of tertiary form of syphilis, which medium and 2-3 weeks by automated liquid culture, such develops in about10% of untreated patients. as Mycobacteria Growth Indicator Tube (MGIT) ™™ Syphilis is a sexually transmitted disease, discussed in https://t.me/docinmayking ™™ GeneXpert assay: It is an automated real-time PCR, detail in Chapter 77 has a sensitivity of up to 80% and is the preferred ™™ Invasion of CNS occurs early within first few weeks of initial diagnostic option. In addition to detection of M. infection, which is followed by years of asymptomatic tuberculosis, it can also detect resistance to rifampicin period. ™™ Imaging studies (CT and MRI) may show hydrocephalus and abnormal enhancement of basal cisterns. In more Clinical Manifestations than half of cases, evidence of old pulmonary lesions or Neurological manifestations appear usually several a miliary pattern is found on chest X-ray. decades after the initial infection. Common manifestations include: T Reatment Tuberculous meningitis ™™ Asymptomatic neurosyphilis: This may be seen in up to 25-40% of cases; may present with CSF abnormalities If unrecognized, TBM is invariably fatal. ‰‰ Treatment should be initiated immediately upon a positive without any clinical manifestations. Very rarely, acute GeneXpert MTB/RIF result. A negative result does not exclude meningitis may be seen in 1–2% of cases of secondary a diagnosis of TB and requires further diagnostic workup syphilis ‰‰ It responds well to anti-tubercular therapy, if started early. ™™ Meningeal syphilis: Presents as features of chronic However, neurologic sequelae may occur in 25% of treated meningitis cases, if initiation of treatment is delayed ™™ Meningovascular syphilis: Presents with vasculitis of ‰‰ Adjunctive glucocorticoids may be used to reduce the CSF arteries leading to embolic stroke pressure, resulting in faster resolution. ™™ General paresis of insane: It is a late manifestation, presents with features of parenchymal damage such Tuberculoma (or Tuberculous Granulomas) as (mnemonic ‘paresis)—defects in personality, affect, It is an uncommon manifestation of tubercular infection reflexes (hyperactive), eye (e.g. Argyll Robertson pupils), of CNS; presents as space-occupying lesions (firm nodule sensorium (illusions, delusions, hallucinations), intellect with central caseous necrosis), and usually causes seizures (recent memory loss), and speech and focal signs. CT or MRI reveals contrast-enhanced ring ™™ Tabes dorsalis: It is also a late manifestation, presents lesions, but biopsy is necessary to establish the diagnosis with features of demyelination of the posterior and to differentiate it from malignancies. columns such as ataxia, foot drop, paresthesia, bladder disturbances and impotence. Neuroborreliosis (Lyme Disease) Lyme disease (Chapter 32) is caused by Borrelia burgdorferi, Laboratory Diagnosis transmitted by tick bite. Apart from cutaneous lesions and Neurosyphilis is diagnosed by the following tests. arthritis; Lyme disease may also present with various CNS ™™ CSF analysis: CSF examination reveals increased infections. lymphocytes (>5/μL), and increased protein level (>45 ™™ Manifestations: After several weeks or months, mg/dL) ~15% of untreated patients develop frank neurologic ™™ CSF VDRL test: Venereal disease research laboratory abnormalities, including meningitis, subtle encephalitic (VDRL) is a nontreponemal test, detects antibodies  Chapter 71  Bacterial Meningitis 701 against a nonspecific cardiolipin antigen derived from ™™ PCR-based tests have a high reliability; can amplify bovine heart T. pallidum specific genes, such as gene coding for „„ It is highly specific and, when reactive, is considered 47-kDa surface antigen (lipoprotein) and 39-kDa basic diagnostic of neurosyphilis. However, it has low membrane. sensitivity „„ Other nontreponemal test like RPR (rapid plasma T Reatment Neurosyphilis reagin) test cannot be performed on CSF, therefore Aqueous crystalline or procaine penicillin G is given for 10– should not be used in substitution of VDRL for 14 days for neurosyphilis or in cases of abnormal CSF in any neurosyphilis. stage. ™™ The FTA-ABS test (fluorescent treponemal antibody ‰‰ Consider re-treatment if non-treponemal titres in CSF do absorption) on CSF is reactive far more often than the not decrease by four-folds within 2 years of completion of CSF VDRL test in all stages of syphilis, but reactivity may treatment reflect passive transfer of serum antibody into the CSF. A ‰‰ In patients with penicillin allergy, desensitization to nonreactive FTA-ABS test on CSF however may be used penicillin has to be done, following which penicillin is to rule out asymptomatic neurosyphilis administered. EXPECTED QUESTIONS https://t.me/docinmayking I. Write essays on: III. Multiple Choice Questions (MCQs): 1. A 7-year-old girl was admitted to the hospital with 1. Neonatal meningitis acquired through infected complaints of high-grade fever, headache, vomiting, birth canal is due to: altered mental status, seizure and neck rigidity. a. S. pyogenes b. Viridans streptococci CSF sample was collected by lumbar puncture in c. S. agalactiae d. S. pneumoniae a sterile container and sent to the laboratory for 2. Carrom coin appearance of colonies is seen for: biochemical analysis, direct microscopic test, culture a. S. pyogenes b. Viridans streptococci and sensitivity testing. c. S. agalactiae d. S. pneumoniae Questions: 3. Which is not a property of S. pneumoniae? a. What is the probable clinical diagnosis? a. Bile solubility b. What are the etiological agents, pathogenesis b. Animal pathogenicity in mice and clinical manifestations of this disease? c. Growth in presence of 40% bile c. Describe the laboratory diagnosis in detail? d. Optochin sensitivity d. What are the treatment modalities according to 4. Serotyping and serosubtyping of meningococci the etiological agents? are based on: 2. Alisha, A 4-year-old girl from Bhubaneswar was a. Outer membrane proteins brought to the emergency room by her parents due b. Endotoxin to an acute onset of fever, neck rigidity and altered c. Capsular polysaccharide sensorium for the past 2 days. Physical examination d. Transferrin binding proteins showed that when her neck was passively flexed, her 5. Which of the following is not a common cause of legs also flexed (positive Brudzinski’s sign). Direct neonatal meningitis? examination of the CSF showed gram-positive, a. E. coli b. S. agalactiae lanceolate-shaped diplococci surrounded by a clear c. Listeria d. S. pneumoniae halo. 6. Biochemical analysis of pyogenic meningitis a. Identify the clinical diagnosis of this condition reveals all of the following, except: and the most likely etiologic agent? a. CSF pressure: highly elevated b. How will you confirm the etiological diagnosis in b. Total leukocyte count: Highly elevated, neutro- the laboratory? philic II. Write short notes on: c. Glucose: highly elevated 1. Listeriosis. d. Total proteins: markedly increased 2. Tubercular meningitis. Answers 1. c 2. d 3. c 4. c 5. d 6. c