1. Systemic Infections with Neurologic Manifestations Arlene S. Dy-Co, MD, FPPS, FPIDSP

2. SYSTEMIC INFECTIONS Infections in the bloodstreamAffecting the entire bodyDiverse

3. Systemic infections with Neurologic Manifestations Part of CNS syndromesSystemic manifestations dominate clinical pictureSyndromic approach to diagnosis less effective

4. Systemic VIRAL infectionsSystemic BACTERIAL infectionsSystemic PROTOZOAL infections

5. Systemic viral infections with neurologic manifestations MeaslesVaricellaDengue

6. Measles Rash disease of childhood Neurologic disease- community- acquired infection Fever, cough, diarrhea, rash

7. Significance ? Low incidence Long-term neurologic disabilities

8. Pathology Direct viral invasion Induction of autoimmune response

9. Neurologic manifestations Acute disseminated encephalomyelitis Measles inclusion body encephalitisSubacute sclerosing panencephalitis

10. ADEM Incidence Worldwide Common after measles 1 in 1,000 Common in children >2 years old normal immune system

11. fever 2-7days after onset of rash Neurologic manifestations Seizures Altered mental status Multifocal neurologic signs Monophasic course 10-20 days Improvement few days after onset

12. Pathology Autoimmune demyelinating disease triggered by measles perivenular demyelination No evidence of measles virus swelling of cerebral vessels Mononuclear cell infiltration autoimmune response to myelin - unexplained

13. Diagnosis clinical MRI –multiple foci of demyelination CSF –normal or slight increase in protein EEF non-specific diffuse slowing

14. Treatment Treatment not well established Corticosteroid widely used Higher mortality in steroid-treated IVIG, plasma exchange some success Ziegra SR. Corticosteroid treatment for measles encephalitis. J Pediatrics. 1961; 59:322

15. Prognosis Fatality rate- 10-40%Neurologic residua substantial Almost always present Johnson RT, et al. Measles encephalomyelitis –clinical and Immunologic studies. N Engl J med. 1984; 310:137-141

16. Prevention To decrease the incidence Vaccination highly effective and safe

17. Varicella Primary infection with varicella zoster virus Common, extremely contagiousGeneralized vesicular rash

18. Neurologic manifestations 1-3 per 10,000 Cerebellar ataxia 31% Encephalitis 20% Transverse myelitis, aseptic meningitis, stroke www.jwatch.orgwww.jwatch.org aug 11,2014

19. Cerebellar ataxia 1 per 4,000 days before to 2 weeks after the rash Vomiting Headache Lethargy ataxia Fever Nuchal rigidity Nystagmus seizures

20. Pathology unknown Lack of necropsy studies Proposed mechanisms Direct viral involvement of the cerebellum Immunologically mediated

21. Antibodies to VZV in the CSF of patients with neurologic abnormalities VZV specific DNA in the CSF of 3 children with varicella cerebellitis detected by PCR Echevarria JM et al. Subclass distribution of the serum and intrathecal IgG antibody response in varicella-zoster virus infection. J Infect Dis 1990 Puchammer E, et al. Detection of VZVDNA by PCR in the CSF of patients Suffering from neurological complications associated with chickenpox. J Clin Microbiol. 1991; 29:1513.

22. Diagnosis Uncomplicated Clinical presentation No further evaluation Complicated CSF –normal or slight increase in protein EEG-diffuse slow wave

23. Prognosis Cerebellar ataxia self-limited Resolves in 1-3 weeks Mortality -zero

24. Encephalitis Less common More severe 1-2 per 10,000 Most occur in children Highest in infants less than 1 y

25. Occurs 2 weeks before up to weeks after the rash Abrupt or gradual Headache Fever Vomiting Altered sensorium seizures Ataxia Hypertonia/hypotonia Hemiparesis Sensory changes

26. Pathology Role of active viral replication- uncertainWide range of histopathologic findingsDiffuse cerebral edema

27. Diagnosis CSF Frequently abnormal EEG Slow wave activity CT scan Cerebral edema Demyelination

28. Prognosis Mortality 5-35%Long-term sequela in 10-20% of survivors59 cases of varicella with encephalitis -5% mortality Lehman MD. J Pediatri 2014, Jul 22

29. Treatment and Prevention Cerebellar ataxiaEncephalitis No evidence for antiviral therapy Antiviral therapy Live, attenuated vaccine –effective and safe

30. Dengue 4 serotypesViral hemorrhagic fever

32. Dengue Cause and existence of neurologic manifestations has been a controversy Neurologic manifestation reported from every country strong evidence to support neuroinvasion non-specific encephalopathy, encephalitis Soares CN et al. Dengue infection neurologic manifestations and CSF. J Neurol Sci 2006; 249; 19.

33. 150 CSF samples from fatal cases Evidence of DENV in 41 CSF out of 84 positive patients Araujo FMC, et al. CNS involvement in Dengue: a study of fatal cases from a dengue endemic area. Neurology2012,;78:736.

34. 4% with suspected CNS infections were infected with dengue virus 18% of children with encephalitis were confirmed with dengue infection Solomon, et al. Neurologic manifestations of dengue infection Lancet 2000 Kankirawatana et al. Dengue infection presenting with CNS manifestation J child Neurol 2000

35. 3 types of Neurologic manifestations Classic signs with acute infection Encephalitis with acute infection Post- infection disorder

36. Reduced level of consciousness Seizures Prolonged coma Other signs of severe dengue infection Shock Vascular leakage hemorrhage Metabolic disturbances

37. Diagnosis CSF Moderate lymphocytic pleocytosis CT/MRI Diffuse cerebral edema CSF Viral isolation

38. treatment No effective drugs Fluid managemen t prevention Vaccine not yet available Vector control

39. Systemic bacterial infections with neurologic manifestations Typhoid feverCat-scratch disease

40. Typhoid fever Caused by S. ser. typhiinsidious Incubation period 10-14 days Related to inoculum size

41. Fever malaise anorexia abdominal pain Dull, continuous frontal headache Drowsy Irritable delirious Relative bradycardia Toxic facies Coated tongue Doughy abdomen meningismus

42. Typhoid with CNS manifestations 27% Occurring 6 days after fever onset Lasts for 8 days Restlessness, confusion, disorientation Resolution in 4 days

43. Typhoid delirium state/toxemia Specific neurological complications

44. Pathogenesis Not knownMetabolic disturbances, toxemia, hyperpyrexiaCerebral edema, hemorrhage

45. Diagnosis Isolation of Salmonella from cultures Could not be isolated from CSF

46. Relapse rate is 5-10%Case fatality highest among childrenDelay in instituting effective antibiotic Bhandari et al.Typhoid encephalopahty in children. Indian Journal child health 1990

48. Severe typhoid fever Treatment Parenteral Ceftriaxone 100mkd OD x 5-7days ciprofloxacin 20mkd BID x 7 days Oral Cefixime 20mkd OD x 14 days Ciprofloxacin 20mkd BID x 7 days Azithromycin 20mkd OD x 7 days

49. Dexamethasone Reduces mortality rate from 35-55 % to 10%For severe typhoid3mg/kg then 1mg/kg q6 for 48 hours

50. Control seizureManage increased ICP

51. Prevention Hand washing Careful food processing Prevention Safe water Appropriate sewage disposal

52. 4 doses >6yo Single dose >2yo Oral live attenuated Parenteral Vi capsular polysaccharide Vaccination High-risk groups

53. Cat-scratch disease Typical 90% Cutaneous papule lymphadenopathy Atypical Extranodal Complicated CSD with NEUROLOGIC MANIFESTATIONS

54. Neurologic manifestations Encephalopathy Neuroretinitis

55. CSD with Encephalopathy 2-4% May be fulminant Often recover fully Easily overlooked Follows lymphadenopathy by days to months Persistent headache Fever Seizures Neurologic deficits

56. Deficits usually self-limited Resolution-weeks to months Death due to CSD encephalitis in 2 healthy children

57. Neuroretinitis Seen in association with bacteremia Aseptic meningitis encephalopathy Painless sudden loss of visual acuity Papilledema Macular exudates in star formation Prognosis good Vitrectomy rarely indicated

58. Laboratory studies no specific positive findings CNS involvement Parenteral therapy Short-term anti- convulsant therapy

59. Role of antimicrobial controversial Neuro- retinitis Steroid use difficult to evaluate 2 reports of 4yo given steroid Encepha -lopathy

60. Systemic protozoal infection with neurologic manifestations Malaria

61. Most important parasitic diseaseIncidence and prevalence decreasing

62. Classic symptoms High fever, chills, sweats Plasmodium falciparum Febrile non-specific illness without localizing signs

63. Severe disease Without exposure young immunocompromised

64. P. falciparum Different clinical syndromesCerebral malaria

65. Cerebral Malaria Unexplained coma Patient with malaria parasitemia Clinical case definition High sensitivity, low specificity

66. Disease prodrome Fever Diaphoresis chills Rapidly progresses to coma Blantyre scale <2 Seizures Brainstem dysfunction

67. Neurologic manifestations Generalized seizuresSigns of increased ICPConfusion, stupor, coma

68. Sequestration of parasitized RBC in microvasculature Cytokine abnormalities Abnormalities of blood- brain barrier

69. Histologic hallmark Swollen discolored brain Cerebral vessels packed with parasitized rbc EEG Generalized symmetrical and asymmetrical slowing Focal slowing CSF Elevated opening pressure Little cellular response

70. Treatment Antimalarials Early detection and treatment of complications

71. Dosing Schedule of Quinine Dihydrochloride in the Treatment for Severe Plasmodium falciparum Malaria Infection Age Group Quinine dihydrochloride Loading DoseMaintenance Dose Children 8 years to 16 years 15 mg salt/kg IV drip for 4 hours in 10 ml/kg D 5 W or 0.9 NaCl (infusion rate must not exceed 5mg/kg per hour) 10 mg salt/kg IV drip for 4 hours every 8 hours in D 5 W or 0.9 NaCl Children 7 years and younger 10 mg salt/kg in IV drip for 4 hours 10 mg salt/kg IV drip every 12 hours Parenteral Quinine Dihydrocloride Infusion PLUS Tetracycline/Doxycycline/Clindamycin

72. Doxycycline 3 mg/kg BW once a day (QD) for 7 days Tetracycline 250 mg 4 times a day (QID) for 7 days Clindamycin 10 mg/kg BW twice a day (BID) for 7 days

73. ICU No adjunctive therapy decreased mortality and morbidity Parenteral therapy Until parasite density decreases Able to tolerate oral therapy

74. Therapy Glucose correctionfluidsantipyretics

75. benzodiazepinesphenobarbitalPhenytoin

76. fatal untreated Coma resolves rapidly Mortality 15-25% treated

77. Acute seizures increase mortality Long-term neurologic disability 60 -fold higher odds of adverse neurologic outcome

78. Prevention Bed netschemoprophylaxisVaccine development

79. chemoprophylaxis DrugsScheduleDose PregnantAdultPediatric A. For People Travelling To Endemic Areas Doxycycline Tablet (100 mg) Start two to three days prior to travel, daily while in the area and continue up to four weeks upon leaving the area contraindicated< 8 years: contraindicated > 8 years old: 2 mg/kg up to 100 mg daily Mefloquine Tablet (250 mg base) Start 1-2 weeks before travel; take weekly while in the area, and continue up to four weeks upon leaving the area contraindicated1 tablet weekly < 45 kg: 5 mg/kg bw 5-10 kg ⅛ tab 10-19 kg ¼ tab 20-30 kg ½ tab 31-45 kg ¾ tab CholoroquineStart 2 weeks before travel, take weekly while in the area and continue 4 weeks after leaving the area 2 tabletsNA < 8 years: 5 mg/kg b.w. > 8 years: 2 tablets

80. Summary Systemic infections with Neurologic manifestations bacterial protozoal viral