Professor and Acting Chair of Neurology Director, MS Comprehensive Care Center Stony Brook University Medical Center,

2. Learning Points To become familiar with abnormal CSF patterns associated with distinct acute and chronic CNS infection syndromes To be aware of the typical clinical syndrome for meningitis, encephalitis, and brain abscess To know the major causes of community acquired bacterial meningitis To become familiar with diagnosis and treatment of herpes simplex encephalitis To recognize major causes of the chronic meningitis syndrome

3. Learning Points To understand the clinical presentation, epidemiology, and pathophysiology of Lyme Disease To understand the importance of PCR in the diagnosis of CNS infections. To understand which disorders use PCR to make a diagnosis To understand the significance of Intrathecal Antibody production To understand and be able to explain the concept of Antigens in CSF. To understand which Antigens can be assessed and for which diseases

4. CSF: CNS Infection Document abnormalities consistent with infection syndrome Provide pattern based approach to differential diagnosis Suggest/identify specific agent

5. CSF Pattern Analysis Press Cells Glu Prot Syndrome ?? ?? ?? ?? septic meningitis (polys) (bacterial) ?or- ? - ? aseptic meningitis (<100 or encephalitis monos) (viral) ??,?or- ? ? ?or ?? chronic meningitis (monos) (mycobacterial, fungal)

6. Polymerase Chain Reaction Major molecular diagnostic technique Can detect organism-specific nucleic acid (DNA, RNA) qualitative and quantitative single pathogen or families can be automated (fluorescent fragment analysis) direct detection (branched DNA with multiple binding sites) can avoid target amplification

7. Polymerase Chain Reaction Positive very early into infection Extremely sensitive Diagnostic test of choice for many viral CNS infections (esp herpes viruses)

8. CSF PCR In Neurologic Infections Disorder Agent Sensitivity HSV encephalitis HSV �1 98% CMV encephalitis, CMV 80- 95% polyradiculitis TSP/ HAM HTLV �1 93% PML JC ?76% papovavirus TB meningitis M. tuberculosis 90% Whipple�s disease T. Whippelii NA

9. PCR: Cautions Does not necessarily indicate active infection May represent incidental finding Subject to false positives and negatives; requires rigid controls/ safeguards Low yield with tissue tropic/ low organism infections

10. Intrathecal Organism Specific Antibody Production Indirect evidence for CNS infection (may also reflect local activation) Requires paired CSF/ serum sample Multiple assays: serial dilutions, indirect/ direct ELISA, reference ratio Always occurs in setting of a polyspecific response

11. Intrathecal Organism Specific Antibody Production May persist months to years Antibody index: CSF/ serum antibody quotient: CSF/ serum Ig quotient (> 1.4 is abnormal) Specific OCB antibodies: antigen-based immunoblot

12. CSF Antigen Assays LA cryptococcal antigen test most useful (83%-98% sensitivity) Bacterial antigens should be used selectively not as sensitive as culture; gram stain just as sensitive proposed when gram stain negative, initial tests negative, partially treated, immunocompromised hosts not useful with normal CSF parameters, hospital acquired infections Remain + 1-10 days into therapy

13. CSF Antigen Assays ? Other antigens (histoplasma polysaccharide,cysticercus, CMV)

14. Inflammation of the meninges Clinical features: headache, fever, stiff neck (and altered mental status especially in septic meningitis) Infectious and noninfectious causes Meningitis

15. Acute meningitis septic (bacterial) aseptic (largely viral) Recurrent meningitis Chronic meningitis infectious noninfectious Meningitis

16. Bacterial Meningitis Life threatening illness 5-10 cases per 100,000 25,000 cases annually in the US up to 10x higher in less developed countries

17. Bacterial Meningitis Demographics in the US have changed marked ? in H. influenzae cases occurs in young adults vs. children ? in S. pneumoniae resistant (p�lln, cephalosporin) strains ? p�lln resistant N. meningitidis in specific regions (Spain, South Africa)

18. Bacterial Meningitis Etiology changes based on age neonatal (S. agalactiae group B strep, E. coli, Listeria monocytogenes) infants/ children (N. meningitidis, S. pneumoniae) adults aged 15-50 (S. pneumoniae 45-50%, N. meningitidis 30 to 40%, L. monocytogenes 8%, staphylococci, gram neg enteric bacilli, H. influenzae) adults aged >50 (S. pneumoniae, enteric gram neg; L. monocytogenes, H. influenzae)

19. Bacterial Meningitis Etiology based on other factors traumatic head injury (S. pneumoniae) neurosurgery (gram neg bacilli, staphylococci) Shunt (coag neg staph, Staph aureus)

20. Nationwide survey of Netherlands (696 episodes) S. pneumoniae (51%), N. meningitidis (37%) 95% of patients had at least 2 of 4 clinical features 14% comatose, 33% focal deficits Mortality 21% ? in pneumococcus vs. meningococcus *NEJM 2004; 351:1849 Adult Bacterial Meningitis*

21. Nationwide survey of France (n=1,084) Over one month of age: N. meningitidis 55.3%, S. pneumoniae 33.4% About 50% of pneumococcus isolates ? susceptibility to penicillin Mortality rate 10.8% meningococcus, 7.6% pneumococcus *Clin Infect Dis 2005; 41:1059 Pediatric Bacterial Meningitis*

22. Clinical Presentation Fever, headache, stiff neck Other features: nausea, vomiting, photophobia, lethargy Progressive deterioration in level of consciousness

23. Clinical Presentation Complications: cerebral edema, hydrocephalus, arteritis, septic venous sinus thrombosis, intracerebral hemorrhage, seizures, cranial nerve palsies (VIII), septic shock, DIC, renal failure, SIADH, central DI, adult RDS Purpuric/ petechial rash on trunk, legs suggests meningococcemia

24. Management Blood cultures ? Neuroimaging CSF analysis Adjunctive (dexamethasone) and antimicrobial therapy

25. Neuroimaging Focal neurologic deficit New onset seizure Papilledema Abnormal LOC Immunocompromised state

26. CSF Analysis Opening pressure > 180 mm H2o ? ? ? WBCs (neutrophil predominance) ? ? ? glucose < 40 mg/dl (58%) < 0.31 CSF to serum glucose ratio (70%) ? ? protein

27. CSF Analysis Gram stain (+ 60-90%) > 105 CFU/ ml +; ? 103 CFU/ ml 25%+ Bacterial antigens partial therapy immunocompromise nondiagnostic workup

28. CSF Analysis PCR broad range screen specific primers (S. pneumoniae, N. meningitidis, E. coli, L. monocytogenes, H. influenzae, S. agalactiae ) Lactate reserved for postop neurosurgical patients (? 4 mmol/l should be treated empirically)

29. CSF Predictors Of Bacterial Meningitis Glucose < 34 mg/dl (esp <20 mg/dl) CSF to blood glucose < 0.3 (esp <0. 23 mg/dl) Protein > 220 mg/dl WBC > 2,000/mm3 Polys > 1,180/mm3

30. CSF In Treated Bacterial Meningitis With IV antibiotics > 24 hrs culture, gram stain 3 days: glucose close to normal in 80% 7-10 days: abnormal but ? WBC in 50%; 50% normal CSF

31. Aseptic Meningitis 11 to 27 cases per 100,000 Benign, self-limited Inflammation of meninges,  ependyma, choroid plexus headache, fever, meningismus Enteroviruses are major pathogens No pathogen established in ? 33%

32. Viral Meningitis Pathogens Enteroviruses Mumps HSV-2 LCM HIV Adenovirus Influenza Arboviruses Other herpes viruses

33. Enteroviruses Nonenveloped RNA viruses; over 70  human pathogens; worldwide  distribution 40% to 60% of all viral meningitis cases,  most paralytic poliomyelitis cases, a  small number of encephalitis cases Children predominate for aseptic  meningitis, but meningitis as a  complication is higher in adults

34. Enteroviral Meningitis Summertime Family unit illness Abrupt onset without prodrome Initial CSF neutrophil pleocytosis

35. Chronic Meningitis Varying combinations of headache, fever, stiff neck, ? confusion, disorientation, lethargy Associated with abnormal CSF pattern (? mononuclear WBCs, ? protein, ? glucose) Symptoms/ signs and CSF abnormalities persist ? 4 weeks

36. Chronic Meningitis Infectious M. tuberculosis Cryptococcus Other fungal pathogens (coccidioides, histoplasma, candida) Spirochetal Noninfectious Neoplastic Vasculitis Neurosarcoidosis

37. Inflammation of brain parenchyma Acute/subacute febrile illness with headache, altered level of consciousness, disorientation, behavior/language disturbance, focal/diffuse parenchymal signs May involve additional areas (meninges, spinal cord, nerve root) Acute Encephalitis: Definition

38. Accounts for 18-29% of acute neurologic infections 1,000 to 20,000 cases per year (esp. July-September) Incidence 0.07 to 12.6 cases per 100,000 per year Most common in children under age 10 (16.7 cases per 100,000 child years) Acute Encephalitis: Epidemiology

39. Most adult cases aged 15 to 30; unusual after 40 More common in males (60%) Most patients (> 60%) previously healthy Acute Encephalitis: Epidemiology

40. Causal agent identified in 15-73% of cases Infectious (80%) viral (90%) nonviral (10%) Noninfectious (20%)

41. Arboviruses Herpesviruses Enteroviruses Measles Mumps Lymphocytic Choriomeningitis virus (LCM) Rabies Human Immunodeficiency Virus (HIV) Adenovirus Acute Encephalitis: Viral Causes

42. Bacteria M. tuberculosis (TB) Spirochetes Brucella Listeria Subacute bacterial endocarditis Whipple disease Actinomycetes Nocardia Fungi Cryptococcus Histoplasma Parasites Malaria Toxoplasma Trypanosomiasis Amoeba Rickettsiae Rocky mountain spotted fever Ehrlichia Typhus Mycoplasma Acute Encephalitis: Nonviral Infectious Causes

43. Child or young adult Summertime History in terms of days Acute change in behavior or level of consciousness Recent/current febrile illness Specific features

44. Fever (almost 60%) Mental status changes (more than lethargy) Focal vs diffuse neurologic findings Meningeal features (at least 30%) Systemic findings Skin lesions

45. Blood studies routine serologic tests Cerebrospinal fluid Neuroimaging (especially contrast MRI) Electroencephalogram

46. Abnormal in up to 95% of patients Mild to moderate mononuclear pleocytosis, ? protein, normal glucose Culture possible for enteroviruses, mumps, LCM, listeria, Western, Eastern and Venezuelan equine encephalitis Acute Encephalitis: CSF

47. Direct inspection for amoebae, trypanosomes, stains for TB Useful special tests: intrathecal organism-specific antibody production antigen detection nucleic acid detection (PCR) Acute Encephalitis: CSF

48. HSV-1 Ubiquitous agent, 90%+ of adults seropositive Most common cause of non - epidemic fatal viral encephalitis Year round and all ages , but especially <20 and >40 2000 cases each year Responds to IV acyclovir for 14 to 21 days (30mg/kg/day � q8h)

49. HSV-1 Primary infection, reinfection, reactivation Characteristic focality orbitofrontal, temporal cortex, limbic structures localized inflammation, necrosis, inclusion bodies

50. HSV Encephalitis: Clinical Features Fever Early headache Temporal lobe involvement (90%) Early behavioral changes, seizures (40%), hemiparesis(33%), ? level of consciousness

51. HSV Encephalitis: CSF ? Pressure ? RBC (50%), ? WBC, ? protein PCR + 98-99% (remains + several days into Rx) Intrathecal antibody production (> 7days) ? Viral load has worse prognosis

52. HSV Encephalitis: Neuroimaging FLAIR enhances early detection Early : gyral edema with hypointense T1 and hperintense T2 lesions in temporal lobe, cingulate gyrus

53. HSV Encephalitis: Neuroimaging Involvement may be unilateral MRI may worsen despite clinical improvement Limbic involvement correlates with cognitive sequelae

54. HSV Encephalitis: EEG Diffuse slowing Unilateral or bilateral temporal periodic discharges Slow wave complexes (2-3/second)

55. Brain Abscess Focal intracerebral infection begins as cerebritis of injured tissue, develops into pus collection surrounded by vascularized capsule 0.3-1.3 per 100,000 annually

56. Brain Abscess Predisposing features parameningeal infection pulmonary or cardiac disease neurosurgery/ cranial trauma organ/ bone marrow, stem cell transplant HIV infection

57. Brain Abscess Clinical presentation involves headache (77%), fever (53%), focal neurologic deficit (36%) with ? LOC (53%), nausea/ vomiting (51%) Differential diagnosis: GBM, metastasis, encephalitis, subdural epyema, epidural abscess, infarction, sarcoidosis, tumefactive MS

58. Brain Abscess Evaluation Blood: CRP more helpful than ESR, WBC; blood cultures + ~10%, (up to 86% + with listeria) CSF nonspecific (LP generally not performed) Gd+ MRI stereotactic brain biopsy Management Antimicrobials ? surgery

59. Abscess Therapy Broad spectrum, high dose antibiotics for > 6-8 weeks 3rd generation cephalosporin + metronidazole (community acquired) meropenem + vancomycin (postop, trauma) Minimally invasive, closed-needle drainage (local anesthesia, CT guidance)

60. Abscess Therapy Medical therapy alone cerebritis stage small (<2-3cm) or surgically inaccessible (esp. brainstem) stable neurologically but poor medical condition Surgery for neurologic deterioration, or if abscess size does not ? within 1-4 weeks

61. Abscess Therapy May follow serum CRP in abscesses which have been excised/ aspirated CT may enhance for several months post Rx Glucocorticoids progressive deterioration/ impending herniation with edema/ mass effect

62. Abscess Therapy Complications seizures obstructive hydrocephalus ventricular rupture (mortality > 80%) brain edema meningitis hyponatremia hemorrhage

63. Abscess Therapy Mortality as low as 5% Morbidity seizures (12%) focal neurologic deficits (18%) Prophylaxis antibiotics up to 5 days postop for penetrating craniocerebral injuries prophylaxis for craniotomy

64. Lyme Disease Multisystem infection caused by bacterial spirochete (Borrelia burgdorferi) Bacteria present in infected ticks of Ixodes ricinus family Three species (B.burgdorferi sensu stricto, B.garinii, B.afzelii) Passed to humans, other mammals when tick attaches to skin and feeds Reinfection possible

65. Epidemiology Endemic in > 15 states (reported from 49 states), Europe and Asia; 50 countries Three US foci northeast (Maine-Maryland) midwest (Wisconsin, Minnesota) west (northern California, Oregon) 92% of cases from 9 states (CT, RI, NY, PA, DE, NJ, MD, MA, WI) Forested areas of Europe middle Europe (Germany, Austria, Slovenia) Scandinavia (Sweden)

66. Lyme Disease: Neurologic Involvement Approaches 40% of symptomatic infections Occurs at all disease stages I CSF + for spirochetes (pre-meningitis) II Meningitis (aseptic), Meningoencephalitis (cerebellar ataxia, myelitis) Cranial neuropathy (VII) Acute painful radiculoneuritis III Encephalopathy Chronic polyradiculoneuropathy Encephalomyelitis

67. Summary Neurologic infections involve a diverse array of acute and chronic syndromes There are special aspects to CNS infections that impact on diagnosis, management, prognosis and complications Accurate diagnosis and treatment minimize morbidity and mortality