Management of Meningitis

5th-year medical student seminar presentation under the supervision of Dr. Sudzilla, a specialist.

1. MENINGITIS PRESENTED BY NURUL HIDAYU BINTI IBRAHIM NIK NOR LIYANA

2. OUTLINE Introduction to meningitis Risk factor Anatomy and prognosis Aetiology History and physical examination Clinical features Complications Differential diagnosis Investigations Management

3. INTRODUCTION Meningitis is a disease caused by the inflammation of the meninges . The inflammation is usually caused by an infection of the fluid surrounding the brain and spinal cord . It can be life-threatening because of the inflammation’s proximity to the brain and spinal cord; therefore the condition is classified as a medical emergency . If not treated, meningitis can lead to brain swelling and cause permanent disability, coma, and even death . Broadly classified as : Acute meningitis Chronic meningitis WHAT IS MENINGITIS?

4. TERMS Set of symptoms similar to those of meningitis but not caused by meningitis. Meningism is caused by non- meningitic irritation of the meninges, usually associated with acute febrile illness, especially in children and adolescents . It therefore requires differentiating from other CNS problems with similar symptoms, including meningitis and some types of intracranial hemorrhage . The severity of clinical features varies with the causative organism. MENINGISM

5. RISK FACTORS Risk factors that place people at higher risk for bacterial meningitis include the following : Adults older than 60 years of age Children younger than 5 years of age People with alcoholism People with sickle cell anemia People with cancer, especially those receiving chemotherapy People who have received transplants and are taking drugs that suppress the immune system People with diabetes Those recently exposed to meningitis at home People living in close quarters (military barracks, dormitories) IV drug users People with shunts in place for hydrocephalus

6. ANATOMY OF MENINGES The meninges is the system of the membranes which envelops the CNS. It has 3 layers : Dura mater Arachnoid mater Pia mater Subarachnoid space – is the space which is filled with CSF

7. ANATOMY OF MENINGES

8. ANATOMY OF MENINGES

9. ANATOMY OF MENINGES

10. TRANSMISSION HOW DOES MENINGITIS SPREAD? An infectious agent can gain access to the CNS and cause meningeal disease via any of the 3 following major pathways : Direct contiguous spread (e.g. sinusitis , otitis media, congenital malformations, trauma, or direct inoculation during intracranial manipulation) 1. INVASION OF THE BLOODSTREAM Invasion of the bloodstream (i.e., bacteremia, viremia , fungemia , or parasitemia ) and subsequent hematogenous seeding of the CNS 2. RETROGRADE NEURONAL PATHWAY A retrograde neuronal ( eg , olfactory and peripheral nerves) pathway ( eg , Naegleria fowleri or Gnathostoma spinigerum ) 3. DIRECT CONTIGUOUS SPREAD

11. TRANSMISSION HOW DOES MENINGITIS SPREAD? 3. DIRECT CONTIGUOUS SPREAD Local extension from contiguous extracerebral infection ( eg , otitis media, mastoiditis , or sinusitis) is a common cause. Possible pathways for the migration of pathogens from the middle ear to the meninges include the following : The bloodstream Preformed tissue planes ( eg , posterior fossa) Temporal bone fractures The oval or round window membranes of the labyrinths

12. PATHOGENESIS

13. PATHOGENESIS

14. PROGNOSIS Patients with meningitis who present with an impaired level of consciousness are at increased risk for neurologic sequelae or death . A seizure during an episode of meningitis also is a risk factor for mortality or neurologic sequelae , particularly if the seizure is prolonged or difficult to control. In bacterial meningitis, several risk factors are associated with death and with neurologic disability. A risk score has been derived and validated in adults with bacterial meningitis. This score includes the following variables, which are associated with an adverse clinical outcome   : Older age Increased heart rate Lower Glasgow Coma Scale score Cranial nerve palsies CSF leukocyte count lower than 1000/ μL Gram-positive cocci on CSF Gram stain

15. PROGNOSIS Advanced bacterial meningitis can lead to brain damage, coma, and death. In 50% of patients, several complications may develop in the days to weeks following infection. Long-term sequelae are seen in as many as 30% of survivors and vary with etiologic agent, patient age, presenting features, and hospital course. Patients usually have subtle CNS changes.

16. AETIOLOGY BACTERIAL VIRAL FUNGAL PHYSICAL INJURY DRUGS REACTION Severity/ treatment of illness differ depending on the cause. Thus, it is important to know the specific cause of meningitis.

17. AETIOLOGY BACTERIAL MENINGITIS VIRAL MENINGITIS The most serious form of meningitis is bacterial. Even with treatment, bacterial meningitis can be fatal some of the time. If bacterial meningitis progresses rapidly, in 24 hours or less, death may occur in more than half of those who develop it, even with proper medical treatment. Determining how many people get viral meningitis is difficult because it often remains undiagnosed and is easily confused with the flu. The prognosis for viral meningitis is much better than that for bacterial meningitis, with most people recovering completely with simple treatment of the symptoms.

18. AETIOLOGY FUNGAL MENINGITIS ASEPTIC MENINGITIS Fungal meningitis is a serious form of meningitis that is normally limited to people with impaired immune systems. Aseptic meningitis is a term referring to the broad category of meningitis that is not caused by bacteria. Approximately 50% of aseptic meningitis is due to viral infections . Other less common causes include drug reactions or allergies, and inflammatory diseases like lupus. It occurs in individuals of all ages but is more common in children

19. BACTERIAL CAUSES Listeria monocytogenes ( >50 years old) Group A β-hemolytic streptococcus Group B β- hemolytic streptococcus Mycoplasma pneumoniae Gram – ve rods COMMON ORGANISMS: Streptococcus pneumoniae (α-hemolytic streptococcus) Neisseria meningitidis Haemophilus influenzae OTHER ORGANISMS: VIRAL CAUSES Enteroviruses Herpes simplex virus

20. ORGANISMS RISK OR PREDISPOSING FACTORS BACTERIAL PATHOGEN Age 3 months – 18 years Neisseria meningitidis Streptococcus penumoniae Haemophilus influenza Age 18 – 50 years Streptococcus penumoniae Neisseria meningitidis Haemophilus influenza Age > 50 years Streptococcus penumoniae Neisseria meningitidis Listeria monocytogenes Aerobic gram-negative bacilli Immunocompromised state Streptococcus penumoniae Neisseria meningitidis Listeria monocytogenes Aerobic gram-negative bacilli Intracranial manipulation, including neurosurgery Staphylococcus aureus Coagulase negative staphylococci Aerobic gram-negative bacilli, including Pseudomonas aeruginosa Basilar skull fracture Streptococcus penumoniae Haemophilus influenza Group A streptococci

21. NEISSERIA MENINGITIDIS Also known as meningococcal meningitis Gram negative aerobic cocci , capsule 10% of healthy people are healthy nasopharyngeal carriers Begin as throat infection, rash Vaccination is recommended

22. NEISSERIA MENINGITIDIS STREPTOCOCCUS PNEUMONIAE Gram positive diplococci 70% of people are healthy nasopharyngeal carriers Most common in children (1 month to 4 years) Mortality: 30% in children, 80% in elderly Prevented by vaccination

23. NEISSERIA MENINGITIDIS HISTORY TAKING ~25% of those who develop meningitis have symptoms that develop over 24 hours. The remainder generally become ill over one to seven days . ~25% of patients have concomitant sinusitis or otitis that could predispose to  S pneumoniae  meningitis . Occasionally, if someone has been on antibiotics for another infection, the symptoms can take longer to develop or may be less intense. If someone is developing fungal meningitis (most commonly someone who is HIV positive), the symptoms may take weeks to develop. DURATION

24. NEISSERIA MENINGITIDIS HISTORY TAKING In contrast, patients with subacute bacterial meningitis and most patients with viral meningitis present with neurologic symptoms developing over 1 – 7 days . Chronic symptoms lasting longer than 1 week suggest the presence of meningitis caused by certain viruses or by tuberculosis, syphilis, fungi (especially cryptococci ), or carcinomatosis . DURATION

25. NEISSERIA MENINGITIDIS HISTORY TAKING

26. NEISSERIA MENINGITIDIS HISTORY TAKING SYMPTOM SIGN MECHANISM Chills, rigors Fever  (T>38°) Endogenous cytokines (released during the immune response to the invading pathogens) affect the thermoregulatory neurons of the hypothalamus, changing the central regulation of body temperature.   Invading viruses or bacteria produce exogenous substances ( pyrogens ) that can also re-set the hypothalamic thermal set point. Nuchal rigidity  (neck stiffness) Brudzinski sign and Kernig sign Flexion of the spine leads to stretching of the meninges.   In meningitis, traction on the inflamed meninges is painful, resulting in limited range of motion through the spine (especially in the cervical spine). Altered mental status Decreased  Glasgow Coma Scale (GCS) ↑ ICP → brain herniation → damage to the reticular formation (structure in the brainstem that governs consciousness)

27. NEISSERIA MENINGITIDIS HISTORY TAKING SYMPTOM SIGN MECHANISM Focal neurological deficits, e.g. vision loss Examples: cranial nerve palsies, hemiparesis, hypertonia, nystagmus Cytotoxic edema and ↑ ICP lead to neuronal damage.   Signs or symptoms depend on the affected area (cerebrum, cerebellum, brainstem, etc.) Seizures   Inflammation in the brain alters membrane permeability, lowering the  seizure threshold . Exact seizure pathophysiology is unknown. Headache Jolt accentuation of headache: headache worse when patient vigorously shakes head Bacterial exotoxins, cytokines, and ↑ ICP stimulate nociceptors in the meninges (cerebral tissue itself lacks nerve endings that generate pain sensation). Photophobia   Due to meningeal irritation. Mechanisms unclear; pathways are thought to involve the trigeminal nerve. Nausea and vomiting   ↑ ICP stimulates the  area postrema   (vomiting centre ), causing nausea and vomiting.   Petechial rash Meningococcemia (due to  N. meningitidis )

28. NEISSERIA MENINGITIDIS HISTORY TAKING OTHER IMPORTANT HISTORY Contact with TB patient (TB meningitis) Infection of middle ear, sinuses, lung or tooth and gum (brain abscess) Contact with infected bodily secretions (meningitis, herpes encephalitis) Sexual contact with a person infected with HIV (HIV encephalopathy) Penetrating head trauma (brain abscess) Neurosurgical complications (meningitis, brain abscess) A chronic illness, such as cancer A weakened immune system, such those with alcoholism, diabetes, HIV or people who have had organ transplant. A history of recent antibiotic use should be elicited. 40% of patients who present with acute or subacute bacterial meningitis have previously been treated with oral antibiotics (presumably because of misdiagnosis at the time of initial presentation).

29. NEISSERIA MENINGITIDIS PHYSICAL EXAMINATION GENERAL EXAMINATION Non -toxic looking might suggestive of viral origin. Sick, toxic looking might suggest bacterial origin. Glasgow-coma scale Kernig’s sign Brudzinki’s sign Look for other source of infections: Cutaneous petachie / purpura rash  meningococcus Middle ear, sinus infection Pneumonia  pneumococcus Papilledema (increase ICP) Cranial nerves examination ( III, IV, V, VI, and VII) SPECIFIC EXAMINATION

30. NEISSERIA MENINGITIDIS PHYSICAL EXAMINATION KERNIG’S SIGN (MENINGEAL STRETCH TEST)

31. NEISSERIA MENINGITIDIS PHYSICAL EXAMINATION BRUDZINSKI’S SIGN (MENINGEAL STRETCH TEST)

32. NEISSERIA MENINGITIDIS CLINICAL FEATURES CHRONIC MENINGITIS Lymphadenopathy Papilledema and tuberculomas during funduscopy Meningismus Cranial nerve palsies Occurs most common shortly after primary infection in childhood or as part of military TB . The presentation of chronic tuberculous meningitis may be acute, but the classic presentation is subacute and spans weeks. Patients generally have a prodrome consisting of fever of varying degrees, malaise, and intermittent headaches. TUBERCULOUS MENINGITIS

33. NEISSERIA MENINGITIDIS CLINICAL FEATURES Cranial nerve palsies (III, IV, V, VI, and VII) often develop, suggesting basilar meningeal involvement . Clinical staging of tuberculous meningitis is based on neurologic status, as follows : Stage 1 - No change in mental function, with no deficits and no hydrocephalus Stage 2 - Confusion and evidence of neurologic deficit Stage 3 - Stupor and lethargy TUBERCULOUS MENINGITIS CLINICAL STAGING OF TUBERCULOUS MENINGITIS

34. NEISSERIA MENINGITIDIS CLINICAL FEATURES

35. NEISSERIA MENINGITIDIS COMPLICATIONS 1. HEARING LOSS 2. CEREBRAL OEDEMA AND INCREASED ICP 4 . BRAIN ABSCESS 4. STROKE Infections / inflammation from subarachnoid space  via cochlear aqueduct  inner ear  Inflammatory response – damages cochlear (hair cells) Cerebral edema may be vasogenic , from increased vascular permeability, cytotoxic from cerebral hypoxia, interstitial , from increased CSF volume, or a combination of all. Increased intracranial pressure, in turn, causes decreased cerebral perfusion, hypoxia/ischemia, and neuronal necrosis. 3. DISSEMINATED INTRAVASCULAR COAGULOPATHY (DIC) Bacterial products can damage the brain and blood vessels directly. Bacterial toxins cause neuronal apoptosis , and cell wall lipopolysaccharide (endotoxin), released from bacteria, activates clotting causing disseminated intravascular coagulation (DIC) .

36. NEISSERIA MENINGITIDIS DIFFERENTIAL DIAGNOSIS 1. Subarachnoid hemorrhage 2. TB meningitis 3. Space-occupying lesion 4. Meningoencaphalitis 5 . Epilepsy

37. NEISSERIA MENINGITIDIS INVESTIGATIONS BLOOD TESTS Full blood count (  white cell count) C-reactive protein Blood culture and sensitivity LUMBAR PUNCTURE AND CSF ANALYSIS For definitive diagnosis of meningitis, CSF needs to be collected for analysis. CONTRAINDICATIONS Infected skin over needle entry site Suspicion of increase ICP Coagulopathy Significant cardiorespiratory compromise Immunocompromised

38. NEISSERIA MENINGITIDIS INVESTIGATIONS LUMBAR PUNCTURE AND CSF ANALYSIS TEST BACTERIAL VIRAL FUNGAL TUBERCULAR Opening pressure Elevated Normal Variable Variable WBC count >1,000 / mm 3 <100/mm 3 Variable Variable Cell differential Neutrophils Lymphocytes Lymphocytes Lymphocytes Protein Mild to marked elevation Normal or mildly elevated Elevated Very high CSF-to -serum glucose ratio Markedly decreased normal Low Low IMAGING If a patient has the following: F ocal neurologic findings (excluding cranial nerve palsies), new-onset seizures, severely immunocompromised state, papilledema or presents with coma, perform a head computed tomography scan prior to doing a lumbar puncture to rule out the presence of intracranial mass lesions because of the potential risk for herniation

39. NEISSERIA MENINGITIDIS MANAGEMENT SUPPORTIVE TREATMENT Airway, breathing and circulation Mechanical ventilation – level of consciousness is very low / evidence of respiratory failure Intravenous fluid therapy – if hypotension or shock are present Monitor vital signs and neurologic status regularly Maintain adequate hydration and nutrition – tube feeding may be necessary DEFINITIVE TREATMENT (PHARMACOTHERPAPY) Antibiotic therapy Anti-inflammatory therapy Agents to decrease intracranial pressure (ICP) Anti- convulsant s

40. NEISSERIA MENINGITIDIS MANAGEMENT ANTIBIOTICS (ACUTE MENINGITIS) INFECTION SUGGESTED TREATMENT COMMENTS PREFERRED ALTERNATIVE Common organisms: Streptococcus pneumoniae Neisseria meningitidis Haemophilus influenzae Ceftriaxone 2gm IV q12h OR Cefotaxime 2 – 4gm IV q8h Dexamethasone 10mg IV q6h is recommended to be administered 15 to 20 minutes before or at the time of first dose of antibiotics, for up to 4 days or until there is no evidence of pneumococcal meningitis. Antibiotic treatment must be started immediately, regardless of any investigations undertaken. If no organism isolated and patient is responding, continue antibiotics for 14 days.

41. NEISSERIA MENINGITIDIS MANAGEMENT ANTIBIOTICS (ACUTE MENINGITIS) ISOLATED CAUSATIVE ORGANISM SUGGESTED TREATMENT COMMENTS PREFERRED ALTERNATIVE HAEMOPHILUS INFUENZAE (GRAM – VE BACILLI) Ceftriaxone 2gm IV q12h STREPTOCOCCUS PNEUMONIAE (GRAM +VE COCCI) Benzylpenicillin 4MU IV q4-6h for 10-14 days. For penicillin resistant strains Vancomycin 1gm IV q12h NEISSERIA MENINGITIDIS (GRAM – VE COCCI) Prophylaxis for household and close contact of meningococcal meningitis Ceftriaxone 2gm IV q12h Ciprofloxacin 500mg PO as single dose; Close contacts are defined as those individuals who have had contact with oropharyngeal secretions either through kissing or by sharing toys, beverages, or cigarettes.

42. NEISSERIA MENINGITIDIS MANAGEMENT ANTIBIOTICS (CHRONIC MENINGITIS) INFECTION SUGGESTED TREATMENT COMMENTS PREFERRED ALTERNATIVE TUBERCULOUS MENINGITIS Mycobacterium tuberculosis Intensive 2 months S/EHRZ and 10 months HR Pyridoxine 10- 50mg PO q24h needs to be prescribed together with Isoniazid. ( Streptomycin should replace Ethambutol in TB meningitis as it crosses BBB better than Ethambutol .) Treatment is continued for 12 months. CPG on management of Tuberculosis, 3rd edition, 2012; 16, 22, 40-42, 56) WHO Treatment of Tuberculosis Guidelines, 4th ed. 2009

43. NEISSERIA MENINGITIDIS MANAGEMENT ANTI-INFLAMMATORY THERAPY Dexamethasone 10 mg IV 6 hourly x 4 days Mannitol 1 – 1.5 g/kg IV given over 15 minutes ICP LOWERING AGENT ANTICONVULSANTS Diazepam, Lorazepam Administered if patient has seizure Action: Mannitol is a hyperosmolar agent that makes the intravascular space hyperosmolar to the brain and permits movement of water from brain tissue into the intravascular compartment

44. NEISSERIA MENINGITIDIS PREVENTION AND PROPHYLAXIS PRECAUTION Completion of recommended schedule of vaccination is an effective way of protecting individuals from certain types of bacterial  meningitis (E.g. meningococcus , pneumococcus and Hib ) FOLLOW UP R epeat cerebrospinal fluid exam in patients in whom there is doubt about the success of therapy or the accuracy of the initial diagnosis Patients who respond promptly to therapy may no longer need repeat cerebrospinal fluid exams Monitor for hydrocephalus and treat the condition appropriately - hydrocephalus usually manifests within the first few weeks of infection and is treated with ventriculoperitoneal shunting Monitor for neurologic sequelae and provide appropriate supportive therapy Sequelae include hearing impairment, cranial nerve palsies and motor deficits Supportive therapy should be individually tailored Use of mask, gloves, and gowns prevents spread of disease as meningitis is a droplet infection VACCINATION

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