CNS INFECTIONS II Reid Heffner, M.D. Department of Pathology and Anatomical Sciences December 13, 2018

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1 CNS INFECTIONS II Reid Heffner, M.D. Department of Pathology and Anatomical Sciences December 13, 2018 Robbins Basic Pathology. 10 th ed. Chap. 23, pp

2 I HAVE NO CONFLICTS OF INTEREST OR DISCLOSURES TO DECLARE. I HAVE NO FINANCIAL INTEREST IN, I RECEIVE NO FINANCIAL SUPPORT FROM AND I HAVE NO CONTRACTS WITH OR GRANTS FROM ANY PHARMACEUTICAL COMPANY OR ANY INDUSTRY

3 Meningitis Focal parenchymal lesions Viral encephalitis Parasitic disease CNS INFECTIONS Contents Unconventional (slow) agents

4 WEST NILE FEVER

5 West Nile Fever Was confined to Middle East for centuries First US case in summer of 1999 That year were 59 cases, 7 deaths Thousands of crows also died=first clue Probably came from imported bird Now has spread throughout US Reservoir in birds, mosquito transmission

6 West Nile Fever Reservoir in crows and other birds Culex mosquito

7 West Nile Fever Diagnosis based on IgM antibodies in CSF Plasma cell pleocytosis Sudden onset, fever, headache Rash, muscle weakness, myalgia, lymphadenopathy Most cases are mild 15-20% mortality with development of encephalitis Risk greater after age 50

8 West Nile morbilliform rash Red, maculopapular, pruritic, trunk and extremities

9 West Nile Fever J Neuropathology 68:1053,2009 Brainstem encephalitis Severe axonal neuropathy Anterior horn cell neuronophagia and loss Looks like poliomyelitis

10 West Nile Fever Lymphocytic cuffing, glial nodules, demyelination More prominent in the brainstem but affects other areas

11 CNS INFECTIONS Case Summary Healthy 70 year old man suddenly becomes ill Confusion, fever, fatigue, headache Diffuse weakness, DTRs, rash EMG shows axonal neuropathy Requires intubation Dies after 10 days

12 CASE DISCUSSION Questions to be answered Any additional information needed? What is the diagnosis? What is the cause? What is the prognosis? What is the treatment/prevention?

13 CASE DISCUSSION Questions to be answered Any additional information needed? Season, other cases, appearance of rash, viral studies What is the diagnosis? West Nile fever What is the cause? What is the prognosis? 15-20% mortality if there is encephalitis What is the treatment/prevention?

14 RABIES Rabies is worldwide

15 RABIES or ([Fr] RAGE) Usually due to an animal bite Rabid animal is aggressive Dogs, cats, wild carnivores Contact with bats less common Spread in aerosol Find the rabid animal and test it Long incubation period Shorter when bite is closer to head Human diagnosis can be made with corneal smear Show rabies antigen with immunofluorescence

16 RABIES-CLINICAL FACTS Headache, fever, paresthesias or pain at wound site Patients then become restless, develop seizures Have laryngeal muscle spasm with hydrophobia Nearly 100% mortality without therapy Vaccine is available Can be given after a bite along with human rabies immune globulin

17 RABIES PATHOLOGY Lymphocytic perivascular cuffing Especially brainstem Negri bodies=cytoplasmic viral inclusions Especially in hippocampus and Purkinje cells EM showing rhabdovirus

18 LATENT VIRUS INFECTIONS Herpes Simplex Encephalitis Most common sporadic encephalitis in US Usually due to HSV-1 HSV-2 causes meningitis 90% adult population has HSV-1 antibodies Primary infection occurs in childhood Often subclinical Encephalitis represents recurrent infection

19 Herpes Simplex Encephalitis Only 15% pts. have history of oral lesions Sudden onset of headache, fever, chills, lethargy May present as a mass (space- occupying) lesion CSF contains polys and red cells early Xanthochromia later (old hemorrhage) PCR has largely replaced brain biopsy for diagnosis Rapidly progressive; 20% mortality Rx with antivirals such as acyclovir Inhibits viral DNA polymerase

20 Herpes Simplex Encephalitis Herpes labialis (cold sore) Clusters of vesicles Virus latent in V nerve ganglia Reactivated travels out nerve

21 Herpes Simplex Encephalitis Area of increased density on CT which looks like hemorrhage Hemorrhagic lesions tend to be located in temporal lobe or inferior frontal lobe

22 Herpes Simplex Encephalitis Encephalitis tends to produce marked brain edema Patients in danger of dying from tonsillar herniation

23 Herpes Simplex Encephalitis Neutrophils predominate early Cowdry inclusion body Large, fills nucleus, red EM shows herpes virus

24 VARICELLA-ZOSTER INFECTIONS Varicella Worldwide Highly contagious Usually in children Ages 2-8 Rash begins on trunk Spreads to mouth, face, limbs Usually benign course

25 VARICELLA-ZOSTER INFECTIONS Herpes zoster Latent infection Trigeminal ganglion, posterior root ganglia especially Reactivation with lower immunity, HIV, aging, cancer Worldwide, sporadic, nonseasonal Usually in adults Neuropathy Very painful with fever Permanent nerve damage common Vesicular rash follows the path of involved nerve

26 SHINGLES-HERPES ZOSTER Vesicular rash following intercostal nerves Rash often unilateral

27 SHINGLES-HERPES ZOSTER IHC showing virus in neurons Inflammation in nerve root and ganglia Inclusions (nuclear) in neurons (like simplex) May be necrosis or hemorrhage in ganglia

28 Is Zika getting on your nerves? Association with microcephaly Now linked to Guillain-Barré syndrome 68 Columbian patients with G-B syndrome 66 patients had Zika virus infection NEJM 2016; 375:

29 Progressive multifocal leukoencephalopathy (PML) Cause is polyomavirus, DNA virus, 40nm Three known strains; JC is major strain 80% population has antibodies No clinical disease in vast majority Virus latent in lymphoid organs, bone marrow PML is an opportunistic infection AIDS, lymphoma, immunosuppression After MS treatment with natalizumab (vs α4-integrin) Poor cell-mediated immunity

30 Onset years Progressive multifocal leukoencephalopathy Younger patients who have AIDS Gradual development of symptoms Dementia and focal findings, especially loss of visual acuity CSF exam often normal or noncontributory Subacute course with 3-6 mo. survival

31 PML is a demyelinating disease Multiple small foci of demyelination Many lesions located in occipital white matter

32 PML Demyelination with many gitter cells Bizarre atypical astrocytes

33 PML Intranuclear inclusions in oligodendroglia Composed of numerous viral particles Infected oligos die leading to demyelination

34 AIDS neuropathology HAART therapy has reduced incidence Opportunistic infections CNS lymphoma Effects of the virus-cognitive dysfunction Diffuse white matter lesions Microglial nodules Giant cells near capillaries associed with hemosiderin deposits

35 AIDS neuropathology Multinucleated giant cells (infected microglia) near capillaries

36 Poliovirus infection Enterovirus infection Children more susceptible Adults more susceptible to paralytic disease Rapid paralysis, legs>arms Affects ventral horns of spinal cord Variant may be acute flaccid paralysis CDC.gov.acute flaccid myelitis/2018

37 Acute poliomyelitis Normal anterior horn cells Lymphocytic inflammation Microglial nodules Neuronophagia

38 UNCONVENTIONAL (SLOW) INFECTIONS Long latent period and course Spongiform change in CNS Agents have unconventional properties Lack DNA/RNA; contain protein (prions) Scrapie, kuru, C-J, mad cow disease NINDS.NIH.GOV/Creutzfeldt-Jacob disease

39 Creutzfeldt-Jakob Disease Subacute spongiform encephalopathy Disease both genetic and infectious Agent is an abnormal protein or prion PrP sc derived from normal protein PrP c Results from a conformational change Carlton Gajdusek, M.D.

40 Creutzfeldt-Jakob Disease About 10% cases are inherited PRNP gene on short arm of chromosome 20 Point mutations in gene coding for PrP c C-J disease (SSE) is also infectious (transmissible) Prions replicate PrP sc somehow recruits and transforms PrP c

41 Creutzfeldt-Jakob Disease Transmission unknown Onset in middle aged patients Severe dementia with memory loss Myoclonus Ataxia CSF contains excessive amt protein family of normal proteins Fatal in 6-24 months

42 Creutzfeldt-Jakob Disease Early spongiform stage SPONGE Spongiform change with marked cellular edema in neurons and neuropil

43 Creutzfeldt-Jakob Disease Late Stage Cerebral atrophy Striking gliosis (PTAH) and marked neuronal loss

44 Creutzfeldt-Jakob Disease Amyloid formation Prion protein undergoes a conformation change into a β- pleated sheet Becomes insoluble amyloid Amyloid (congophilic) plaque

45 Creutzfeldt-Jakob Disease Amyloid formation Amyloid plaque (silver stain) EM shows amyloid as masses of filaments

46 THE END