MENINGITIS - by DR K DELE

Meningitis is a severe CNS pathology and early and appropriate intervention is needed to prevent adverse outcome including mortality and long term complications. This presentation focuses on the different types of meningitis and the appropriate management options

1. MENINGITIS PRESENTED BY: DR KD DELE DEPT. OF FAMILY MEDICINE DORA NGINZA HOSPITAL

2. INTRODUCTION Meningitis is the inflammation of the protective membranes covering the brain and spinal cord known as the meninges. The inflammation is usually caused by an infection of the fluid surrounding the brain and spinal cord. Meningitis may also be non-infective in origin, e.g. in malignancy and toxic drugs

3. INTRODUCTION Microorganism can reach meninges by direct extension (e.g. ears, nasopharynx, cranial defect) or via blood stream Immunocompromised patients (e.g. HIV, cytotoxic drugs) are at increased risk of meningitis by unusual organisms Meningitis can be life-threatening because of the inflammation's proximity to the brain and spinal cord; therefore it is classified as a medical emergency.

4. MENINGES The meninges is the system of membranes which envelops the central nervous system.

5. MENINGES It has 3 layers: 1. Dura mater 2. Arachnoid mater 3 . Pia mater Subarachnoid space - is the space which exists between the arachnoid and the pia mater, which is filled with cerebrospinal fluid.

6. EPIDEMIOLOGY Estimated annual incidence of bacterial meningitis in the South African general population is 4/100 000. highest in < 1 year-olds (40/100 000). Followed by 1-4 year-olds (7/100 000). This is likely to be an underestimate of true incidence as it excludes those with culture-negative cerebrospinal fluid (CSF) and those with nonbacterial aetiologies.

7. EPIDEMIOLOGY Because of the high prevalence of human immunodeficiency virus (HIV) and tuberculosis in South Africa, the incidence of meningitis caused by Cryptococcus neoformans and Mycobacterium tuberculosis has increased in recent years Although either of these can present acutely, they more commonly present with chronic symptoms

8. RISK FACTORS Age- children younger than 5 years Use of immunosuppressive drugs Chronic malnutrition AIDS CSF Shunt Chronic alcoholism Diabetes Pneumonia

9. PATHOPHYSIOLOGY Causative organism enters the blood stream Cross the blood barriers Inflammatory reaction in meninges Inflammation of subarachnoid space and pia meter occur Inflammation may cause ICP CSF flows in subarachnoid space CSF cloudiness or infected CSF cell count increase Clinical symptoms and signs

10. PATHOPHYSIOLOGY

11. PATHOPHYSIOLOGY Most paediatric bacterial meningitis follows bacteraemia. The source of bacteraemia is seldom evident. Always look for multiple sites of infection. Rarely, infection may spread to the meninges directly from the sinuses, middle ear, mastoids, osteomyelitis of the skull or vertebral column, or through a connection to the outside world (skull fracture, dermoid sinus tract, meningocele ).

12. AETIOLOGY Bacterial Viral Fungal Parasitic/ protozoal Physical injury Cancer Certain drugs ( mainly, NSAID’S) Head injury Cerebral abscess Middle ear infection

13. AETIOLOGY: Bacteria Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae Escherichia coli Rickettsia species Leptospira species Staphylococcus aureus Salmonella non-typhi Listeria monocytogenes Streptococcus agalactiae (Group B) Treponema pallidum Mycobacterium tuberculosis

14. AETIOLOGY: Viruses Enteroviruses : Echo, Coxsackie Mumps Herpes simplex HIV Epstein-Barr virus Measles

15. AETIOLOGY: Fungal Cryptococcus neoformans Candida Coccidiodes Histoplasma Mucormycosis Aspergillus

16. AETIOLOGY: Parasitic/ protozoal Angiostrongylus Toxoplama Hydatid Amoeba Plasmodium Cysticercosis

17. AETIOLOGY Strep. pneumoniae has become the most common cause in all age groups The rate of N meningitidis has remained constant at 14-25%. This however may increase depending on epidemics of meningitis, particularly in the meningitis belt of Africa. There is now a widespread use of HIB vaccine; Hence, incidence of H influenzae meningitis which was once the most common cause of meningitis in all age groups, has dramatically decreased from 48% to 7% of all cases.

18. PREVAILING CAUSES ACCORDING TO AGE Age Bacterial Pathogen 0-4 weeks S agalactiae (group B streptococci); E coli K1; L monocytogenes 4-12 weeks S agalactiae ; E coli ; H influenza ; S pneumonia ; N meningitidis 3 months to 18 years N meningitides ; S pneumonia ; H influenzae Age 18-50 years S pneumonia; N meningitides ; H influenzae Age older than 50 years S pneumonia ; N meningitides ; L monocytogenes ; Aerobic gram-negative bacilli Immunocompromised state S pneumonia ; N meningitides ; L monocytogenes ; Aerobic gram-negative bacilli Very important: Mycobacterium and Cryptococcus

19. PREVAILING CAUSES: SPECIAL CONSIDERATION Special Consideration Bacterial Pathogen Intracranial manipulation, including neurosurgery Staph. Aureus ; Coagulase-negative staphylococci Aerobic gram-negative bacilli, including Pseudomonas aeruginosa Basilar skull fracture S pneumoniae H influenzae Group A streptococci CSF shunts Coagulase-negative staphylococci Staph. aureus Aerobic gram-negative bacilli Propionibacterium acnes

20. CLINICAL PRESENTATION

21. DURATION OF SYMPTOMS There is no absolute cut-off that differentiates acute from chronic meningitis. South African guidelines defined the duration of symptoms of acute meningitis as < 7 days. Longer duration of symptoms suggests meningitis with different aetiologies. Chronic meningitis in this environment are mostly Tuberculous and Cryptococcal meningitis

22. SIGNS AND SYMPTOMS Meningitis should be suspected in an adult with any two of the following: headaches, fever > 37.5oC, neck stiffness or Altered mental status (Clinical triad: headache, neck stiffness and fever)

23. SIGNS AND SYMPTOMS Severe headache • Irritability • Restlessness • Stiffness of neck • Malaise • Nausea/vomiting • High grade fever • Tachypnea • Seizures Disorientation Tachycardia Coma Sleeplessness Phonophopia Photophobia Altered mental status (confusion)

24. CLINICAL FEATURES FOR SOME MENINGEAL PATHOGENS Pathogen Suggestive clinical features Neisseria meningitidis Nonblanching petechial rash (some have a maculopapular rash). Conjunctival lesions. Varicella-zoster virus Chickenpox vesicular rash Mumps virus Parotid swelling (unilateral or bilateral) Herpes simplex virus Cutaneous or mucosal herpes simplex lesions Rickettsia species Eschar , ± regional lymphadenopathy, maculopapular rash involving palms and soles in some patients Treponema pallidum (syphilis) Maculopapular rash involving palms and soles, any HIV-positive patient or recent genital ulcer disease Leptospira species Jaundice and conjunctival suffusion Rabies virus Hallucinations, hypersalivation hydrophobia and spasms HIV Generalised lymphadenopathy. Other features suggestive of AIDS

25. EXAMINATION General: Non-specific to meningitis Wasting Lymphadenopathy Petechial rash Vitals Pyrexia Tachycardia

26. EXAMINATION: CNS Neck stiffness /nuchal rigidity: resistance to passive flexion) Lateralising signs Cranial nerve lesions Kerning’s sign Brudzinski’s sign GCS Witnessed Seizures

27. MENINGITIS: MANAGEMENT

28. Diagnostic evaluation History collection Physical examination CSF evaluation for pressure, proteins, glucose and leukocytes. Blood test e.g. CBC; Blood culture Imaging e.g. MRI; CT scan

29. INVESTIGATIONS Bloods – FBC, UEC,LFT, glucose, blood cultures. LP – chemistry, cells, MC&S, proteins, ADA, Cryptococcal antigen, Indian ink and glucose. CXR ± Neuroimaging – CT/MRI

30. PERFORMING A LUMBAR PUNCTURE An LP is considered an essential part of the examination of the patient with suspected meningitis.

31. ALGORITHM FOR LUMBAR PUNCTURE

32. NEUROLOGICAL CONTRAINDICATIONS TO LUMBAR PUNCTURE Neurological contraindications to lumbar puncture in the setting of suspected acute meningitis include: Coma or markedly decreased level of consciousness (Glasgow Coma Scale < 10). Papilloedema . Unexplained new focal neurological deficit, such as a hemiparesis or dysphasia. Isolated cranial nerve palsies (caution is advised). Unexplained seizures. Presence of a ventriculoperitoneal shunt .

33. Non-neurological Contraindications To Lumbar Puncture Non-neurological contraindications to lumbar puncture are: Severe cardiorespiratory compromise. Severe coagulopathy. Local sepsis overlying the LP site.

34. CONTRAINDICATIONS TO LP ON CT SCAN Contraindications to lumbar puncture after computed tomography head scan: CT features of gross generalised brain swelling or significant hemispheral shift related to a mass lesion. However, it is important to note, that a normal CT brain does not exclude the presence of raised intracranial pressure

35. LP: CSF CHANGES Agent Opening Pressure WBC count per µL Glucose (mg/dL) Protein (mg/dL) Microbiology Bacterial meningitis 200-300 100-5000; >80% PMNs* <40 >100 Specific pathogen demonstrated in 60% of Gram stains and 80% of cultures Viral meningitis 90-200 10-300; lymphocytes Normal, reduced in mumps Normal but may be slightly elevated Viral isolation, PCR † assays Tuberculous meningitis 180-300 100-500; lymphocytes Reduced, <40 Elevated, >100 Acid-fast bacillus stain, culture, PCR Cryptococcal meningitis 180-300 10-200; lymphocytes Reduced 50-200 India ink, cryptococcal antigen, culture Aseptic meningitis 90-200 10-300; lymphocytes Normal Normal but may be slightly elevated Negative findings on workup Normal values 80-200 0-5; lymphocytes 50-75 15-40 Negative findings on workup

36. CSF CHANGES Normal Viral Bacterial TB Appearance Crystal-clear Clear/turbid Turbid/purulent Turbid viscous Mononuclear cells <5mm 3 10-100mm 3 <50mm 3 100-300mm 3 Polymorph cells Nil Nil 200-300/mm 3 0-200/mm 3 Protein 0.2-0.4 g/L 0.4-0.8 g/L 0.5-2.0 g/L 0.5-3.0 g/L Glucose 2 / 3 > 1 / 2 blood glucose > 1 / 2 blood glucose < 1 / 2 blood glucose < 1 / 2 blood glucose

37. CAUSES OF STERILE CSF Partially treated bacterial meningitis Viral meningitis Tuberculosis or fungal infection Neoplastic meningitis Syphilis Intracranial abscess Cerebral infarction Encephalitis OTHER

38. TREATMENT

39. IMMEDIATE INTERVENTION Acute meningitis is a medical emergency. All suspects should receive their first dose of antibiotics immediately blood culture and/or lumbar puncture (LP) should be performed before administration of the first dose of antibiotics (if possible) Administer ceftriaxone 80-100 mg/kg, maximum 2 g intravenously. Penicillin allergy is not a contraindication to ceftriaxone in acute meningitis Omit ceftriaxone only in documented ceftriaxone anaphylaxis. Note: Blood Culture + LP + IV ceftriaxone. Duration: Average of 10-14 days IV Antibiotics

40. INDICATION FOR AMPICILLIN Listeria monocytogenes , recent epidemics/cause of bacterial meningitis in South Africa, is resistant to cephalosporin. Empiric treatment for Listeria: Ampicillin 3 g (IVI 6hourly) in addition to ceftriaxone. Ampicillin may also be indicated in: patients > 50 years old, immunocompromised because of immunosuppressive drugs, alcoholism, liver cirrhosis, asplenia , end-stage renal failure diabetes mellitus

41. DOSES OF ANTIBIOTICS BY AGE GROUP Antibiotic Infants and children Adults Ampicillin 50 mg/kg/dose 6 hourly 3 g/dose given 6 hourly Benzyl penicillin 100!000 u/kg/dose 6 hourly 5 MU/dose given 6 hourly Cefotaxime 50 mg/kg/dose 6 hourly 2 g/dose given 6 hourly Ceftriaxone 50 mg/kg/dose twice daily 2 g/dose given 12 hourly Meropenem 40 mg/kg/dose 8 hourly 2 g/dose given 8 hourly Moxifloxacin Not recommended 400 mg given daily Vancomycin 15 mg/kg/dose 8 hourly 15 mg/kg/dose 8 hourly Gentamicin 5 mg/kg/dose given daily 1-2 mg/kg given 8 hourly Co- trimoxazole 8-12 mg TMP/kg/day given as divided doses 6-12 hourly 20 mg TMP/kg/day given as divided doses 6-12 hourly Chloramphenicol 100 mg/kg/day 6 hourly* 1 g/dose given 6 hourly

42. CEPHALOSPORIN AND PENICILLIN ALLERGY Patients with documented cephalosporin anaphylaxis should be treated with vancomycin and ciprofloxacin or moxifloxacin . Alternatives are chloramphenicol or meropenem Patients with penicillin allergy requiring empiric treatment for Listeria spp. should receive co- trimoxazole

43. STEROIDS Previously adjunctive corticosteroids were recommended in patients with bacterial meningitis Studies have shown sthat adjunctive dexamethasone, the most widely studied corticosteroid, does not significantly reduce death or neurological disability In South Africa therefore, the routine use of adjunctive corticosteroids is not recommend

44. TB MENINGITIS M tuberculosis is an acid-fast bacillus that causes a broad range of clinical illnesses that can affect virtually any organ of the body Patients generally have a prodrome of fever of varying degrees, malaise, and intermittent headaches. Patients often develop central nerve palsies (III, IV, V, VI, and VII), suggesting basilar meningeal involvement

45. TB MENINGITIS Duration of therapy: 9 months RHZE for first two months Then rifampicin and isoniazid for the remaining 7 months Steroids may be used. Prednisone. The recommended dose is 60-80 mg/d, which may be tapered gradually during a span of 6 weeks

46. TB MENINGITIS RMP 20mg/kg (max. 600mg) INH 20mg/kg (max 300mg) PZA 30-40mg/kg (max. 2g) Ethionamide 20mg/kg (max 300mg) Dexamethasone x 2 days Adults Rifafour (3-5) Dexamethasone 8mg 12hrly for 24hours / Prednisone 60-80 mg/d, tapered gradually x 6 weeks

47. FUNGAL: CRYPTOCOCCAL MENINGITIS Cryptococcal meningitis C neoformans is an encapsulated yeast like fungus It has been found in high concentrations in aged pigeon droppings The infection is characterized by the gradual onset of symptoms, the most common of which is headache

48. CRYPTOCOCCAL MENINGITIS

49. CRYPTOCOCCAL MENINGITIS The following is recommended as the preferred induction regimen: a short-course (one-week) amphotericin B deoxycholate and flucytosine, followed by fluconazole on days 8 to 14. Alternative recommended regimens include two weeks of fluconazole (1200 mg daily) and flucytosine, two weeks of Amphotericin B and fluconazole, or one week of Amphotericin B with two weeks of fluconazole Amphotericin B (0.8-1 mg/kg/d IV) – Alternate day CUE checks

50. CRYPTOCOCCAL MENINGITIS Consolidation phase – antifungal therapy : Fluconazole 400-800 mg daily for eight weeks. Maintenance therapy: Long-term antifungal therapy with fluconazole (200 mg/d) is most effective for life or until CD4 count > 200.

51. CRYPTOCOCCAL MENINGITIS Many cases of cryptococcal meningitis is complicated by increased ICP. Measuring the opening pressure during the lumbar puncture is strongly advised. Make an effort to reduce such pressure by repeated lumbar puncture, a lumbar drain, or a shunt

52. COMPLICATIONS: MENINGITIS Cranial nerve palsies Venous sinus thrombosis Subdural empyema Brain abscess Long term: hearing impairment, obstructive hydrocephalus, brain parenchymal damage

53. PREVENTION Haemophilus influenzae type b vaccine is given during childhood routine immuniz . Pneumococcal meningitis vaccine - called pneumococcal conjugate vaccine (PCV7) can be given. For Neisseria meningitides (meningococcal meningitis), a meningococcal vaccine can be used for high-risk groups

54. Prophylaxis in contacts Meningococcal Rifampacin 10mg/kg twice dly x 2 days <1month 5mg/kg twice dly x 2 days Cetriaxone 250mg IMI stat (adults) 125mg IMI stat ( children) Ciprofloxacin 500mg PO bd (adults) Influenza Rifampicin 20mg/kg twice dly for 4 days 10mg/kg twice dly for 4 days (child)

55. References Guidelines for the management of acute meningitis in children and adults in South Africa TH Boyles, C Bamford, K Bateman, L Blumberg, A Dramowski , A Karstaedt , S Korsman , DM le Roux, G Maartens , S Madhi , R Naidoo, J Nuttall, G Reubenson , J Taljaard , J Thomas, G van Zyl, A von Gottberg , A Whitelaw, M Mendelson. South Afr J Epidemiol Infect 2013;28(1) WHO 2018. Guidelines For The Diagnosis, Prevention And Management Of Cryptococcal Disease In HIV-Infected Adults, Adolescents And Children. WHO: Geneva.

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