Bacterial and NonBacterial CNS Infections EMERGENCY NEUROLOGY LECTURE

Bacterial and Non-Bacterial CNS Infections EMERGENCY NEUROLOGY LECTURE SERIES JULY 7, 2010 Dr. Abdullah Al-Salti R 3

CNS INFECTIONS Overview n n Life-threatening problems with high associated mortality and morbidity. Presentation may be acute, subacute, or chronic. Clinical findings determined by anatomic site(s) of involvement, infecting pathogen, and host response. Vulnerability of CNS to the effects of inflammation & edema mandates prompt diagnosis with appropriate therapy if consequences to be minimized.

CNS INFECTIONS OUT LINE 1. 2. 3. 4. Bacterial meningitis Aseptic Meningitis Viral encephalitis

CNS Infections n Meningitis • Bacterial, viral, fungal, chemical, carcinomatous n Encephalitis • Bacterial, viral n n Meningoencephalitis Abscess • Parenchymal, subdural, epidural

INFECTIONS 4 routes which infectious agents can enter the CNS a) hematogenous spread i) most common - usually via arterial route - can enter retrogradely (veins) b) direct implantation i) most often is traumatic ii) iatrogenic (rare) via lumbar puncture iii) congenital (meningomyelocele) c) local extension (secondary to established infections) i) most often from mastoid, frontal sinuses, infected tooth, etc. d) PNS into CNS i) viruses - rabies - herpes zoster

BACTERIAL MENINGITIS Meningitis refers to an inflammatory process of leptomeninges and CSF. Meningoencephalitis refers to inflammation to meninges and brain parenchyma. n n Meningitis classified: a) acute pyogenic i) usually bacterial meningitis b) aseptic i) usually acute viral meningitis c) chronic i) usually TB, spirochetes, cryptococcus. Incidence of 3 cases/100, 000 population/yr (~25, 000 total cases).

COMMON BACTERIAL PATHOGENS BASED ON PREDISPOSING FACTOR IN PATIENTS WITH MENINGITIS Predisposing Factor Age 0 -4 wk 4 -12 wk 3 mo to 18 yr Common Bacterial Pathogens Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes, Klebsiella pneumoniae, Enterococcus spp. , Salmonella spp. S. agalactiae, E. coli, L. monocytogenes, Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis H. influenzae, N. meningitidis, S. pneumoniae 18 -50 yr S. pneumoniae, N. meningitidis >50 yr S. pneumoniae, N. meningitidis, L. monocytogenes, aerobic gram-negative bacilli

Clinical Features Signs and symptoms: n rapid onset of fever n headache n photophobia n nuchal rigidity n lethargy, malaise n altered mentation n seizure n vomiting. van de Beek D, de Gans J, Tunkel AR, et al. Community-acquired bacterial meningitis in adults. N Engl J Med 2006; 354(1): 44– 53.

Clinical Features n n Study of 493 adult patients with bacterial meningitis, the presence of the ‘‘classic triad’’ of fever, neck stiffness, and altered mental status was present in two-thirds of patients. fever WAS the most common element, in 95%. (N Engl J Med 1993; 328(1): 21– 8. ) n Older patients with S. pneumoniae meningitis are more likely to have the classic triad. Weisfelt M, van de Beek D, Spanjaard L, et al. Community-acquired bacterial meningitis in older people. J Am Geriatr Soc 2006; 54(10): 1500– 7. n n Other studies have shown the classic triad to be less common, with estimates ranging from 21% to 51%. All cases studied had at least one of the three signs; the absence of the all components of the classic triad excludes the diagnosis in immunocompetent individuals.

Physical examination n A careful neurological examination is important to evaluate for : • focal deficits • increased intracranial pressure (ICP). n n Examination should include assessment for meningeal irritation • Brudzinski’s sign • Kernig’s sign findings include purpura or petechia of the skin, which may occur with meningococcemia.

Bacterial meningitis Investigations

LP n n n Single most impt diagnostic test. Mandatory, esp if bacterial meningitis suspected. Tube #1 – glucose and protein Tube #2 – cell count and differential Tube #3 – gram stain and rountine culture, cyrptococcal antigen, AFB stain and culture Tube #4 – VDRL, or viral studies (PCR)

CSF Characteristics Bacterial Viral Opening Pressure Fungal TB Elevated Slight Normal Usually elevated or High high Glc Low Normal Low Pro Very high Few >200 Normal High None <200 None <50 None 20 -30 PMNs Mono Rbcs Wbcs (c/mm 3) Diff

CT Before LP in Patients with Suspected Meningitis n n n 301 pts with suspected meningitis; 235 (78%) had CT prior to LP CT abnormal in 56/235 (24%); 11 pts (5%) had evidence of mass effect Features associated with abnl. CT were: • • • age >60, immunocompromise, H/O CNS dz, H/O seizure w/in 7 d, & selected neuro abnls Hasbun, NEJM 2001; 345: 1727

CT head Before LP(Cont. ) n n Neuro abnls included altered MS, inability to answer 2 consecutive questions or follow 2 consecutive commands, gaze palsy, abnl visual fields, facial palsy, arm or leg drift, & abnl language 96/235 pts (41%) who underwent CT had none of features present at baseline CT normal in 93 of these 96 pts (NPV 97%). Of the 3 remaining patients, only 1 had mild mass effect on CT, and all 3 underwent lumbar puncture with no evidence of brain herniation Hasbun, NEJM 2001; 345: 1727

Consideration for lumbar puncture without neuroimaging David Somand, MDa, William. Meurer, MD Department of Emergency Medicine, University of Michigan, Taubman Center B 1354 SPC #5303, 1500 East Medical Center Drive, Ann Arbor, MI 48109 -5303, USA Department of Neurology, University of Michigan, Taubman Center 1914 SPC #5316, 1500 E. Medical Center Drive, Ann Arbor, MI 48109 -5316, USA n n n n Age less than 60 Immunocompetent No history of CNS disease No recent seizure (less than 1 week) Normal sensorium and cognition No papilledema No focal neurologic defecits

Acute bacterail meninigits MRI n n Not generally useful in acute diagnosis (Pt cooperation; logistics). Very helpful in investigating potential complications developing later in clinical course such as venous sinus thrombosis or subdural empyema.

Laboratory Testing Helpful in Distinguishing Bacterial from Viral Meningitis. CSF lactate. n Elevated CSF lactate concentrations may be useful in differentiating bacterial from nonbacterial meningitis in patients who have not received prior antimicrobial therapy. n study of 78 patients with acute meningitis in which CSF lactate concentrations of >4. 2 mmol/L were considered to be a positive discriminative factor for bacterial meningitis. Sens Spec PPV NPV n n 96%, 100%, 97%. Furthermore, other factors (e. g. , cerebralhypoxia/ischemia, anaerobic glycolysis, vascular compromise, and metabolism of CSF leukocytes) also may elevate. CSF lactate concentrations. Therefore, measurement of CSF lactate concentrations is not recommended for patients with suspected communityacquired bacterial meningitis. Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel, 1 Barry J. Hartman, 2 Sheldon L. Kaplan, 3 Bruce A. Kaufman, 4 Karen L. Roos, 5 W. Michael Scheld, 6 and Richard J. Whitley 7

Laboratory Testing Helpful in Distinguishing Bacterial from Viral Meningitis. C-reactive protein (CRP). n Serum CRP concentrations were capable of distinguishing Gram stain–negative bacterial meningitis, with a sensitivity of 96%, a specificity of 93%, and a negative predictive value of 99%. n Measurement of serum CRP concentration may be helpful in considering withholding antimicrobial therapy, on the basis of the data showing that a normal CRP has a high negative predictive value in the diagnosis of bacterial meningitis. Provided the CSF Gram stain result is negative. Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel, 1 Barry J. Hartman, 2 Sheldon L. Kaplan, 3 Bruce A. Kaufman, 4 Karen L. Roos, 5 W. Michael Scheld, 6 and Richard J. Whitley 7

Laboratory Testing Helpful in Distinguishing Bacterial from Viral Meningitis. procalcitonin concentration. n Elevated serum concentrations of the polypeptide procalcitonin, which are observed in patients with severe bacterial infection, were shown to be useful in differentiating between bacterial and viral meningitis. n n n In a study of 59 consecutive children hospitalized for meningitis , the sensitivity of measurements of the serum procalcitonin concentration (using a cutoff of 15. 0 mg/L) for the diagnosis of bacterial meningitis was 94%, and the specificity was 100%. In adults, serum concentrations 10. 2 ng/m. L had a sensitivity and specificity of up to 100% for the diagnosis of bacterial meningitis. At present, because measurement of serum procalcitonin concentrations is not readily available in clinical laboratories, recommendations on its use cannot be made at this time. Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel, 1 Barry J. Hartman, 2 Sheldon L. Kaplan, 3 Bruce A. Kaufman, 4 Karen L. Roos, 5 W. Michael Scheld, 6 and Richard J. Whitley 7

Laboratory Testing Helpful in Distinguishing Bacterial from Viral Meningitis. PCR. n In patients who present with acute meningitis, an important diagnostic consideration is whether the patient has enteroviral meningitis. n Enteroviral RT-PCR has been tested in clinical settings by numerous investigators and has been found to be more sensitive than viral culture for the detection of enterovirus, with a sensitivity and specificity of 86%– 100% and 92%– 100%, respectively. n lead to shortened patient hospitalization, decreased use of antimicrobial therapy for treatment of bacterial meningitis, and reduced need for ancillary diagnostic tests. Practice Guidelines for the Management of Bacterial Meningitis Allan R. Tunkel, 1 Barry J. Hartman, 2 Sheldon L. Kaplan, 3 Bruce A. Kaufman, 4 Karen L. Roos, 5 W. Michael Scheld, 6 and Richard J. Whitley 7

BACTERIAL MENINGITIS Managements

APPROACH TO THE PATIENT WITH SUSPECTED MENINGITIS Decision-Making Within the First 30 Minutes § Clinical Assessment § Mode of presentation Ø Acute (< 24 hrs) Ø Subacute (< 7 days) Ø Chronic (> 4 wks) § Historical/physical exam clues § Clinical status of the patient (ABCD) § Integrity of host defenses

Management algorithm for adults with suspected bacterial meningitis. Practice Guidelines for the Management of Bacterial Meningitis

Overall Goals in Management 1. To promptly recognize the patient with an acute CNS infection syndrome 2. To rapidly initiate appropriate empiric therapy 3. To rapidly and specifically identify the etiologic agent, adjusting therapies as indicated 4. To optimize management of complicating features

BACTERIAL MENINGITIS Antimicrobial Rx n n n Therapy is generally IV, high dose, & bolus. Dosing intervals should be appropriate for drug being administered. Utilize “cidal” therapy whenever possible. n Initiate therapy promptly (ie, within 30 mins)

THE THERAPY OF MENINGITIS CNS Penetration Good Diffusion • • • Penicillins 3 rd & 4 th Gen Cephs Chloramphenicol Rifampin TSX Poor Diffusion • • • Early Gen Cephs Clindamycin AMGs Tetracyclines Macrolides

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT Clinical Setting Likely Pathogens Community-acquired S. pneumoniae Ceftriaxone N. meningitidis 2 gm q 12 h [Listeria] + [H. influenzae] Vancomycin 1 -2 gm 12 h +/ Ampicillin 2 gm q 4 h Closed head trauma S. pneumoniae Pen G 3 -4 mu q 4 h Streptococci + Vancomycin 1 -2 gm q 12 h Therapy

EMPIRIC THERAPY OF MENINGITIS IN THE ADULT Clinical Setting High risk patients Compromised hosts Neurosurgical or Open head injury Nosocomial Elderly Likely Pathogens S. aureus Gram negative bacilli Listeria Therapy Vancomycin 2 -3 gm/d + Ceftazidime 2 gm q 8 h Cefepime 2 gm q 8 h [Ceftriaxone 2 gm q 12 h] [Cefotaxime 2 gm q 4 h] +/ Ampicillin 2 gm q 4 h

SPECIFIC THERAPY FOR KNOWN PATHOGENS Pathogen Recommended Therapy S. pneumoniae* N. meningitidis Streptococci Pen G 18 -24 mu/d or Ampicillin 12 gm/d [Chloro 75 -100 mg/kg/d] [Ceftriaxone 2 -4 gm/d] H. influenzae Cefotaxime 12 gm/d [Ceftriaxone 2 -4 gm/d] Group B strep Pen G 18 -24 mu/d or Ampicillin 12 gm/d [plus aminoglycoside]

SPECIFIC THERAPY FOR KNOWN PATHOGENS (continued) S. aureus Nafcillin 12 gm/d [Vancomycin 2 -3 gm/d] Listeria Ampicillin 12 gm/d or Pen G 18 -24 mu/d [plus aminoglycoside] Gram negative bacilli Cefotaxime 12 gm/d [Ceftriaxone 2 -4 gm/d] Pseudomonas Ceftazidime 6 -8 gm/d or Cefepime 6 gm/d [plus aminoglycoside]

BACTERIAL MENINGITIS Duration of ATB Rx Pathogen Duration of Rx (d) H. influenzae 7 N. meningitidis 7 S. pneumoniae 10 -14 L. monocytogenes 14 -21 Group B strep 14 -21 GNRs 21 NEJ 1997; 336 : 708

CORTICOSTEROIDS AND MENINGITIS n n Role of steroids still somewhat uncertain. Recent European study in adults suggested that Rx with dexa associated with ↓ in risk of unfavorable outcome (25%→ 15%, RR 0. 59) & in mortality (15%→ 7%, RR for death 0. 48). Benefit primarily pts w/S. pneumo. Dose of dex was 10 mg IV q 6 h X 4 d; per protocol, dex given concurrent with or 15 -20 mins before 1 st dose of ATBs.

CORTICOSTEROIDS AND MENINGITIS (Cont) Only pts with cloudy CSF, + CSF Gm. S, or CSF WBC count >1000 were enrolled n Accompanying editorial raised concerns about use of steroids in pts with DRSP who are being Rx’ed with vanc b/o ↓ in CNS conc of vanc with concurrent steroid use. n Practically speaking, almost all pts with presumed bacterial meningitis are candidates for at least 1 dose of dexa n NEJM 2002; 347: 1549

Acute bacterial meningitis Antibiotic prophylaxis n n Is recommended for high-risk exposures to patients with Neisseria or Hib meningitis. (potentially share secretions). Regimens include : n single-dose ciprofloxacin or ceftriaxone. n rifampin 600 mg every 12 hours for five doses. There is no indication for prophylaxis for exposure to pneumococcal meningitis. Quinolone resistance has been reported to Neisseria, and this class of antibiotics is no longer recommended for prophylaxis in parts of the United States. David Somand, MDa, William. Meurer, MD Department of Emergency Medicine, University of Michigan, Taubman Center B 1354 SPC #5303, 1500 East Medical Center Drive, Ann Arbor, MI 48109 -5303, USA Department of Neurology, University of Michigan, Taubman Center 1914 SPC #5316, 1500 E. Medical Center Drive, Ann Arbor, MI 48109 -5316, USA

PREDICTORS OF ADVERSE CLINICAL OUTCOMES IN PTS WITH COMMUNITY-ACQUIRED BACTERIAL MENINGITIS n Retrospecitve study; 269 pts (84% culture +). n Adverse clinical outcome in 36% of pts(Death 27%, neuro deficit 9%). n ↓BP, altered MS, and seizures on presentation all independently associated with adverse clinical outcome. n n Adverse outcomes in 5% of low risk pts (0 features), 37% of intermediate risk pts (1 feature), and 63% of high risk pts (2 -3 features). Delay in administration of appropriate ATB Rx also associated with adverse clinical outcome. Aronin et al, AIM 1998; 129: 862

Aseptic Meningitis

Aseptic Meningitis n n n All non-bacterial causes of meningitis Typically less ill appearing than bacterial meningitis Most common cause is viral • HSV n n n Consider especially in infants presenting with seizure Usually HSV type II Treat with acyclovir • Enterovirus (coxsackie, echovirus) n n Typically occurs during late summer and fall Spread via respiratory secretions and fecal-oral Affects all ages Generally self-limited illness

Aseptic Meningitis n Other Viral • • • HIV Lymphocytic choriomeningitis virus Arbovirus Mumps CMV EBV VZV Adenovirus Measles Rubella Rotavirus Influenza and parainfluenza

Aseptic Meningitis n Other infectious • Borrelia burgdorferi • Mycobacterium tuberculosis • Treponema pallidum • Mycoplasma pneumoniae • Rickettsia, erlichia, brucella • Chlamydia

Aseptic Meningitis n Fungal • Cryptococcus • Coccidiodes • Histoplasmosis n Parasitic • Angiostrongylus • Toxoplasmosis

Aseptic Meningitis n Medication • NSAID’s • Bactrim • Pyridium n Malignancy • Lymphoma and leukemia • Metastatic carcinoma n Autoimmune • Sarcoid • Behcet’s • SLE

Viral Meningitis • Very common clinical course is less fulminant compared to bacterial n Often caused by enteroviruses n Polioviruses Coxsackieviruses Echoviruses n Treatment is supportive

VIRAL ENCEPHALITIS

Introduction n Encephalitis is an acute inflammatory process affecting the brain Viral infection is the most common and important cause, with over 100 viruses implicated worldwide Symptoms • • • n Fever Headache Behavioral changes Altered level of consciousness Focal neurologic deficits Seizures Incidence of 3. 5 -7. 4 per 100, 000 persons per year

VIRAL ENCEPHALITIS Herpesviruses Herpes simplex Varicella-zoster Epstein Barr Cytomegalovirus Enteroviruses Polioviruses Coxsackieviruses Echoviruses Myxo/paramyxoviruses Influenza/parainfluenzae Mumps Measles Miscellaneous Adenoviruses LCM Rabies HIV Togaviruses Eastern equine Western equine Venezuelan equine St. Louis Powasson California West Nile

Patient History n n n Detailed history critical to determine the likely cause of encephalitis. Prodromal illness, recent vaccination, development of few days → Acute Disseminated Encephalomyelitis (ADEM). Biphasic onset: systemic illness then CNS disease → Enterovirus encephalitis. Abrupt onset, rapid progression over few days → HSE. Recent travel and the geographical context: • Africa → Cerebral malaria • Asia → Japanese encephalitis • High risk regions of Europe and USA → Lyme disease n n Recent animal bites → Tick borne encephalitis or Rabies. Occupation • Forest worker, exposed to tick bites • Medical personnel, possible exposure to infectious diseases.

History cont. n Season • Japanese encephalitis is more common during the rainy season. • Arbovirus infections are more frequent during summer and fall. n Predisposing factors: • • Immunosuppression caused by disease and/or drug treatment. Organ transplant → Opportunistic infections HIV → CNS infections HSV-2 encephalitis and Cytomegalovirus infection (CMV) n Drug ingestion and/or abuse n Trauma

Initial Signs n n n Headache Malaise Anorexia Nausea and Vomiting Abdominal pain

Developing Signs n n n Altered LOC – mild lethargy to deep coma. AMS – confused, delirious, disoriented. Mental aberrations: • • • n n hallucinations agitation personality change behavioral disorders occasionally frank psychosis Focal or general seizures in >50% severe cases. Severe focused neurologic deficits.

Neurologic Signs n n Virtually every possible focal neurological disturbance has been reported. Most Common • Aphasia • Ataxia • Hemiparesis. • Involuntary movements • Cranial nerve deficits (ocular palsies, facial weakness)

Other Causes of Encephalopathy n n n Anoxic/Ischemic conditions Metabolic disorders Nutritional deficiency Toxic (Accidental & Intentional) Systemic infections Critical illness Malignant hypertension Mitochondrial cytopathy (Reye’s and MELAS syndromes) Hashimoto’s encephalopathy Traumatic brain injury Epileptic (non-convulsive status) CJD (Mad Cow)

Differential Diagnosis n Distinguish Etiology • (1) Bacterial infection and other infectious conditions • (2) Parameningeal infections or partially treated bacterial meningitis • (3) Nonviral infectious meningitides where cultures may be negative (e. g. , fungal, tuberculous, parasitic, or syphilitic disease) • (4) Meningitis secondary to noninfectious inflammatory diseases

VIRAL ENCEPHALITIS DIAGNOSIS. LP: n n CSF usually colorless - slightly pressure - initially a neutrophilic pleocytosis, which rapidly converts to lymphocytes - proteins are - glucose is normal PCR for HSE and other viral infection is diagnostic.

VIRAL ENCEPHALITIS DIAGNOSIS. MRI: n May show temporal or orbitofrontal cortex enhancement or edema in HSE. n In most other acute viral encephalities , neuroimaging finding are nonspecific. n Can exclude subdural bleeds, tumor, and sinus thrombosis. EEG: • • • Non specific Diffuse slowing. Focal abnormalities in the temporal region. HSV Brain biopsy : n Reserved for patients who are worsening, have an undiagnosed lesion after scan, or a poor response to acyclovir.

Treatment. Only HSV disease has specific therapy available. Acyclovir is capable of improving patient outcome. n • • dose : 10 mg/kg intravenously every 8 hours. Duration 14 -21 days. ganciclovir can be used in CMV infections. pleconaril has shown promise in enteroviral. Outcomes n Outcomes are variable depending on etiology. n EEE and St. Louis encephalitis generally have high mortality rates and Severe neurologic sequelae among survivors. n WNV is associated with significant morbidity and morality. n Mortality of HSV encephalitis before acyclovir was 60% to 70%, and with treatment approximately 30%. n Cognitive disability, seizures, and motor deficits are common sequelae seen among survivors

Bacterial and Non-Bacterial CNS Infections EMERGENCY NEUROLOGY LECTURE SERIES JULY 7, 2010 Dr. Abdullah Al-Salti R 3