CNS Infections

1. CNS Infections

2. Path

3. Four principal routes via which infections may enter the nervous system • Hematogenous spread – arterial circulation, retrograde venous circulation • Direct implantation – traumatic, possibly iatrogenic • Local extension – secondary to an established infection in an air sinus – mastoid or frontal, infected tooth, surgical site • Peripheral nervous system – certain viruses – rabies, herpes zoster

4. Meningitis – definition and classification • Inflammatory process of the leptomeninges and CSF within the subarachnoid space • Classified into • Acute pyogenic • Aspetic (usually acute viral) • Chronic (TB, spirochetal, cryptococcal)

5. Acute pyogenic meningitis – causative agents, clinical • Causative agent vary with age of patient • Neonates – E coli, group B streptococci • Adolescents/young adults – neisseriameningitidis • Elderly – strep pneumonia, listeriamonocytogenes • Immunisation has drastically reduced haemophilusinfluenza • Immunosuppressed patient – klebsiella, anaerobic organisms • Clinical – systemic signs, headache, photophobia, irritability, clouding of consciousness, neck stiffness

6. Acute pyogenic meningitis – LP, associated syndromes • Lumbar puncture – frankly purulent CSF, under increased pressure, many as 90,000 neutrophils/mm^3, raised protein level, markedly reduced glucose content • Waterhouse-Friderichsensyndrome – results from meningitis associated septicaemia with hemorrhagic infarction of the adrenal glands and cutaneouspetechiae

7. Acute pyogenic meningitis – morphology • Acute – exudates evident within the leptopmeninges over the surface of the brain • Vessels are engorged and stand out prominently • Location of exudates varies • H.influenazae – basal • Pneumococcal meningitis – densest over cerebral convexities near the sagittal sinus • Fulminant meningitis – inflammation may extend to the ventricles – ventriculitis • Micro • Neutrophils fill the subarachnoid space in severely affected areas, predominantly around leptomeningeal blood vessels in less severe cases • Focal cerebritis – infiltration of inflammatory cells into the substance of the brain (go through the leptomeningeal veins) • Leptomeningeal fibrosis and hydrocephalus follow pyogenic meningitis • Chronic adhesive arachnoiditis – large quantities of capsular polysaccharide of the organism produce a particularly gelatinous exudates that encourages arachnoid fibrosis

9. Acute aseptic meningitis – clinical, LP, causative agents • Clinical - meingealirritation, fever, alterations of consciousness of relatively acute onset • Usually viral • Clinical course less fulminant, usually self limiting, treated symptomatically • CSF – lymphocytic pleocytosis, protein elevation is only moderate, sugar content is nearly always normal • 70% pathogen can be identified – commonly enterovirus • Echovirus, coxsackievirus, nonparalytic poliomyelitis – up to 80% of cases

10. Brain abscesses – path, predisposing conditions, organisms • Arise from • Direct implantation of organisms • Local extension from adjacent foci – mastoiditis, paranasal sinusitis • Hematogenous spread – primary site in heart, lungs, distal bones or after tooth extraction • Predisposing conditions • Acute bacterial endocarditis (multiple abscesses), cyanotic congenital heart disease (R to F shunt), chronic pulmonary sepsis (bronchiectasis) • Streptococci, staphylococci most common organisms in non-immunosuppressed

11. Brain abscesses – morphology • Macro – discrete lesions with central liquefactive necrosis, surrounding fibrous capsule, oedema • Most common brain regions in descending order – frontal lobe, parietal lobe, cerebellum • Micro – exuberant granulation tissue, neovascularisation around the necoriss that is responsible for marked vasogenic oedema • Collagen produced by fibroblasts from walls of vessels, outside fibrous capsule zone of reactive gliosis with numerous gemistocyticastrocytes

12. Brain abscesses – clinical, CSF, prognosis • Destructive lesions – patients present progressive focal deficits, signs of raised intracrnail pressure • CSF – under increased pressure, white cell count raised, protein raised, sugar content is normal • Source of infection may be apparent • Increased intracranial pressure and herniation may be fatal • Abscess rupture lead to ventriculitis, meiningitis, venous sinus thrombosis • Surgery, antibiotics, otherwise high mortality reduced to 10%

14. Subdural empyema – Path, clinical, symptoms, CSF, treatment • Bacterial/fungal infection of skull bones or air sinuses can spread to subdural space – empyema • Arachnoid, subarachnoid is unaffected, subdural empyema can produce a mass effect • Thrombophlebitis may develop in the bridging veins that cross the subdural space • Venous occlusions and infarction • Symptoms – source of infection related, febrile, headache, neck stiffness, focal neurologic signs, lethargy, coma • CSF similar to abscess • Treatment – surgical drainage, resolution occurs from the dural side, if complete -> thickened dura may be the only residual finding

15. Chronic bacterial meningoencepahlitis – TB – CSF, symptoms, complications, related infecitons • CSF – moderate pleocytosis (mononuclear cells), protein level is elevated strikingly so, glucose moderately reduced or normal • Symptoms – headache, malaise, mental confusion, vomiting • Most serious complication – arachnoid fibrosis – hydrocephalus • Obliterative endarteritis – arterial occlusion, infarction of underlying brain • Spinal roots may also be affected • AIDS patients also at risk of infection with M. avium-intracellulare – setting of disseminated infection • Lesion – confluent sheets of macrophages filled with organisms, minimal granulomatous reaction

16. Chronic bacterial meningoencepahlitis – TB – morphology • Morphology • Macro • Subarachnoid space contains a gelatinous or fibrinous exudates, most often at the base of the brain -> oliterateing the cisterns and encasing cranial nerves • Meningoencephalitis – most common pattern of involvement • Micro – mixture of lymphocytes, plasma cells, macrophages • Florid cases – well formed granulomas, caseous necrosis, giant cells • Arteries in subarachnoid space • Obliterative endarteritis • Inflammatory infiltrates in their walls, marked intimal thickening • Organisms often seen with acid-fast stains • Infection can spread to the choroid plexus and ependymal surface- through CSF • Long standing duration – dense, fibrous adhesive arachnoiditis • Tuberculoma – single or multiple well circumscribed intraparenchymal mass • May be several cm in diameter – mass effect • Micro – central core caseous necrosis surrounded by typical tuberculousgranulomatous reaction, calcification may occur in inactive lesions

18. Neurosyphillis – major forms –path/morphology • Meningovascularneurosyphilis • Chronic meningitis involving the base of the brain, cerebral convexities, spinal leptomeninges • Obliterative endarteritis (Huebner arteritis) • Perivascular inflammation, plasma cells, lypmhocytes • Paretic neurosyphilis • Insidious but progressive loss of mental and physical functions with mood laterations terminating in severe dementia • Micro – lesions associated with parenchymal damage in the cerebral cortex • Loss of neurons, proliferations of microglia, gliosis, riondepositsi -> Prussian blue stain • Granular ependymitis – proliferation of subependymalglia • Tabesdoraslis • Result of damage by the spirochete to the sensory nerves in the dorsal roots • Impaired joint position sense and resultant ataxia, loss of pain sensation, skin and joint damage (Charcot joints), lightning pains – sensory disturbances • Micro – loss of both axons and myelin in the dorsal roots, pallor and atrophy in the dorsal columns of the spinal cord

19. Neuroborreliosis– symptoms • Lyme disease • Caused by spirochete Boreeliaburgdorferi – transmitted by ticks (Ixodes) • Symptoms highly variable – aseptic meningitis, facial nerve palsies, mild encephalopathy, polyneuropathies

20. Viral meningoencephalitis – defn, characteristic histo, complications • Viral encephalitis – parenchymal infection of the brain – associated with meningeal inflammation, sometimes involvement of the spinal cord • Characteristic histo: perivascularcuffs and parenchymal mononuclear cell infiltrates, glial cell reactions (microglial nodules), neuronophagia • Complications – congential malformations (intrauterine – rubella), postenecepahlitic parkinsonism, immune mediated disease – perivenousdemyelination

21. Anthropod-borne viral encephalitis – epi, clinical, CSF, morphology • Arboviruses – epidemic – tropical regions • In Australia – Murray Valley, in US – west nile virus • All animal hosts, mosquito vectors • Clinically – generalised neuro deficits – seizures, confusion, delirium, stupor, coma, focal signs, reflex asymmetry, ocular palsies • CSF – colourless, slightly elevated pressure, initially neutrophilpleocytosis converts to lymphocytes, protein level elevated, glucose normal • Morphology • Lymphocytic meiningoencephalitis – tendency for inflammatory cells perivascularly • Multiple foci of necrosis of gray and white matter • Neuronophagia – single cell neuronal necrosis with phagocytosis of the debris • Some cases prominent cortical involvement, others basal ganglia bear the brunt

22. HSV-1- epi, symptoms, morphology • Encephalitis – most common in children and young adults – 10% of patients had a history of prior herpes • Symptom – alterations in mood, memory, behaviour • Diagnosed with PCR • Morphology • Inferior and medial regions of the temporal lobes, orbital gyri of the frontal lobes • Necrotising, often hemorrhagic • Perivascular inflammatory infiltrate present • Cowdry type A intranuclear viral inclusion bodies – neurons and glia • Antiviral agents provide effective treatment • Some times – subacute course – weakness, lethargy, ataxia, seizures

24. Other viral encephalitis – HSV-2, herpes zoster, CMV • HSV-2 - Encephalitis – 50% of neonates delievered by vaginal birth to women with active primary HSV genital infection • AIDS – acute- hemorrhagic, necrotizing encephalitis • Herpes zoster (varicella) - Reactivation in adults – painful vesicular eruption – limited dermatomaldistribution, usually self-limited • Granulomatousarteritis • Immunosuppressed – acute necephalities – demyelination followed by necrosis • CMV • Foetuses and immunosuppressed • Utero – periventricular necrosis – serfver brain destruction – microcepahly – calcification • Most common pathogen in AIDS affecting CNS – 15-20% • Morphology • CMV inclusion bearing cells • Tendency for subependymal regions of the brain • Severe hemorrhagic necrotizing ventriculoencepahlitis and a choroid plexitis

25. Poliomyelitis – morphology, clinical • Still regions where it remains a problem • Causes subclinical or mild-gastritis – in a small fraction it invades the CNS • Morphology • Mononuclear cell perivascular cuffs and neuronophagia of the anterior horn motor neurons of the spinal cord • Cranial motor nuclei sometimes involved • Clinical • Initially meningeal irritation, may progress to involve the spinal cord • Flaccid paralysis – muscle wasting, hyporeflexia • Death can occur from paralysis • Myocarditis may also occur • Post-polio syndrome – may develop 25-35 years after resolution – progressive weakness associated with decreased muscle mass and pain, unclear pathogenesis.

26. Rabies – morphology, clinical • Severe encephalitis transmitted to humans by the bite of a rabid animal – dogs, bats etc • Morphology • Brain – oedema, vascular congestion • Micro – widespread neuronal degeneration, inflammatory reaction – most severe in the brainstem • Negri bodies – cytoplasmic, round to oval, eosinophilic inclusions that can be found in pyramidal neurons of the the hippocampus and Purkinje cells of the cerebellum – areas devoid of inflammation • Clinical • Virus enters CNS by ascending along peripheral nerves from wound site -> incubation period depends on distance between wound and brain -> typically 1-3 months • Early symptoms – malaise, headache, fever, local parathesias around the wound • As infection advances – extraordinary CNS excitability – slightest touch is painful, violent motor responses progressing to convulsions • Foaming – contracture of the pharyngel musculature on swallowing -> aversion to swallowing -> hydrophobia • Periods of alternating mania and stupor progress to coma and death

27. HIV - morphology • Neuropathologic changes demonstrated at post-mortem in 80-90% of AIDs • HIV aspetic meningitis occurs within 1-2 weeks of seroconversion in 10% of patients • Morphology • Chronic inflammatory reaction • Microglial nodules – multinucleated giant cell • Especially in the subcortical white matter, diencephalon, brainstem • Disorder of white matter – multifocal or diffuse areas of myelin pallor, axonal swelling, gliosis • HIV related dementia – related to the extent of activated microglia in the brain

28. Progressive multifocal leukoencephalopathy – clinical, morphology • Viral encephalitis – JC polyomarivurs – preferentially infects oligodendrocytes -> demyelination is the main effect • Exclusive to immunosuppressed individuals • Most people have serological exposure to JC virus by the age of 14 years • Clinically – focal, relentlessly progressive neurologic symptoms and signs • Imaging – extensive, often multifocal, lesions in the hemisphere or cerebellar white matter • Morphology • Patches of irregular, ill-defined destruction of the white matter – mm to entire lobes • Micro • Centre – lipid laiden macrophages, loss of axons • Edge – greatly enlarged oligodendrocytes nuclei – glassy amphophilic viral inclusions – viral antigen • May be bizarre giant astrocytes – one to several irregular, hyperchromatic nuclei

29. Subacute scleroingpanencephalitis • Rare progressive clinical syndrome – cognitive decline, spasticity of limbs, seizures • Occurs in children or young adults - after early-age acute infection of measles • Disease – altered measles virus in the CNS • Morph • Micro – widespread gliosis, myelin degeneration, viral inclusions -> nuclei of oligodendrocytes, neurons, also get neurofibrillary tangles

30. Fungal meningoencaphlitis – common agents, patterns of infection • Brain usually involved with widespread hematogenous dissemination • Most often – candidaalbicans, mucor species, aspergillus fumigates, Cryptococcus neoformans • Endemic areas – histoplasmacapsulatum, coccidiodiesimmitis, blastomycesdermatitidis • Three main patterns of fungal infection • Vasculitis – seen with mucromycosis and aspergillosis – direct fungal invasion of blood vessel walls, also seen in candidiasis • Vascular thrombosis produces infarction – usually hemorrhagic • Parenchymal invasion – granulomas or abscesses – often coexists with meningitis • Commonly – candida, Cryptococcus • Candida – multiple microabscesses • Mucormycosis – direct extension – common in DKA (?) • Chronic meningitis

31. Cryptococcal meningitis – CSF, morphology • Opportunistic infection – HIV/AIDs – may be fulminant and fatal • CSF – few cells, high protein – using India ink stain – yeasts can be visualised – in tissue use PAS or silver stains • Morphology • Chronic meningitis – basal leptomeninges – opaque, thickened by reactive tissue -> may obstruct outflow of CSF from the foramina of luschka and megendie -> hydrocephalus • Gelatinous material within subarachnoid space • Soap bubbles – small cysts in the parenchyma – prominent in basal ganglia • Parenchymal lesions – aggregates of organisms within perivascular (Virchow-Robin) spaces

32. Cerebral toxicoplasmosis – clinical, morphology • Opportunistic infection – HIV immunosuppression • Clinical symptoms – subacute –evolve over 1-2 wk period, focal or diffuse • Ring-enhancing lesion – not pathognomonic – also seen in lymphoma, TB, fungal • Non-immunosuppressed – pregnancy – cerebritis in the fetus -> multifocal cerebral necrotising lesions that may calcify -> severe damage to the developing brain • Morphology • Brain abscesses – gray-white junction, and deep gray nuclei • Acute lesions – central foci of necrosis, petechieal haemorrhages – chornic inflammation • Organisms seen on H&E, Giemsa stains • Blood vessels – fibrinoid necrosis, thrombosis • Treatment – coagulation necrosis surrounded by lipid-laiden macrophages • Chronic lesions – small cystic spaces, containing scattered lipid and hemosiderinlaiden macrophages

33. Cerebral amebiasis • Rapidly fatal necrotising encephalitis – naegleria species • Chronic granulomatousmeningoencepahlitis – acanthamoeba • Methenamine silver or PAS stains – visualise organisms

35. Transmissible spongiform encephalopathies - pathogenesis • Prions – abnormal forms of cellular protein that cause transmissible neurodegenerative disorders • Path/molecular genetics • PrP 30-kD cellular protein in neurons • Disease – PrP undergoes conformational change from PrPc to PrPsc (alpha helix to beta pleated sheet) • With this change – resistant to digestion with proteases • Acumulation of PrPsc in neural tissue -> unsure how this causes a problem _. Cytoplasmic vacuoles -> neuronal death • PrPsc may be created normally at a very low rate • PrPsc facilitates the conversion of PrPc to PrPsc – infectious nature • PRNP – encodes PrP • Variety of mutations – familial forms

36. CKD and vCKD • Creutzfedlt-Jakob disease • Most common prion disease • Clinically – rapidly progressing dementia, startle myoclonus • Onset – subtle memory and behaviour changes • Incidence 1/million • Peak incidence in the 7th decade • Familial forms due to mutation in PRNP (codon 129 met or val) • Average survival 7 months from onset of symptoms • Variant creutzfedlt-Jakob disease • Affects young adults • Behavioural disorders appeared at early stages, neuro symptoms progress slower • Characterised – extensive cortical plaques with surrounding halo of spongiform change • Linked with bovine spongiform encephalopathy

37. Morphology of CKD • Progression to dementia so rapid – little cortical atrophy • Spongiform transformation of the cerebral cortex - uneven formation of small, apparently empty, microscopic vacuoles of varying size • Advanced stage – severe neuronal loss, reactive gliosis, expansion of vascuolated areas into cystlike spaces – status spongiosus • Kuru plaques – extracellular deposits of aggregates of abnormal protein – Congo-red or PAS positive

38. Fatal familial insomnia • Named after the sleep disturbances it causes • Specific mutation in PRNP gene • Lasts fewer than 3 years – neuro signs – ataxia, autonomic disturbances, stupor, coma • Morphology – no spongiform pathology, but there is neuronal loss andreactivegliosis in anterior ventral and dorsomedial nuclei of the thalamus, also inferior olivary nuclei

40. Clinical

41. Viral meningitis – investigations, management • Investigations • Dx by LP -> glucose normal, protein normal or slightly elevated, excess of lymphocytes -> VERIFY THAT ANITBIOTICS HAVE NOT BEEN GIVEN PRIOR TO LP • Management • Condition usually benign and self limiting • Recovery usually in days • Complete recovery without therapy is the rule

42. Bacterial meningitis - management • Management • Take specimens – blood culture, PCR, throat swab • Start empirical antibiotics • If no clinical signs indicating mass lesion, hydrocephalus, cerebral oedema – then – LP, otherwise CT first

43. Bacterial meningitis- treatment • Benzylpenicillinimmediately if bacterial meningitis suspected • Adults 18-50, meningococcal rash • Ceftriaxone • Suspected penicillin resistant pneumococcal infection • Ceftriaxone, vancomycin (or rifampicin) • Adults over 50, listeria is suspected • Ceftriaxone + ampicillin (or co-trimoxazole) • When the bacteria is known • N. meningitidis – benzylpenicillin • Strep pneumoniae – ceftriaxone • If resistant – vancomycin • H influenza – ceftriaxone • Listeriamonocytogenes – ampicillin plus gentamicin • Strep suis – cefriaxone • If allergic to penicillins – chloramphenicol, vancomycin • Coricosteroids – dexamethasone – limit to 2 days

44. Viral encephalitis – investigations, management • Investigations • CT/MRI – low density lesions in temporal lobe • LP – exclude mass lesion • Excess lymphocytes – polymorphonuclear cells may dominate in early stages, glucose normal, protein may be elevated • EEG usually abnormal in early stages – periodic slow wave activity in temporal lobes • PCR – viral DNA • Management • Anticonvulsant treatment is often necessary • Raised ICP -> dexamethasone • HSV – acyclovir -> should be given to all patients suspected of viral encephalitis • Mortality – 10-30%, surviviros – residual epilepsy, cognitive impairments

45. Cerebral abscess – investigations, management • Investigations • CT – single or multiple low density areas with ring enhancement (contrast), surrounding cerebral oedema • LP – if CT is ok • Elevated WCC and ESR • Consider cerebral toxicoplasmosis, or TB secondary to HIV • Management • Antimicrobial therapy once diagnosis is made • Site- source – organisms – treatment • Frontal lobe – paranasal sinuses, teeth – streptococci, anaerobes – cefuroxime, metronidazole • Temporal lobe – middle ear – streptococci, enterobaceteriaceae – ampicillin, metronidazole, ceftazidime (or gentamicin) • Cerebellum – sphenoid sinus, mastoid/middle ear – Pseudomonas, anaerobes - ampicillin, metronidazole, ceftazidime (or gentamicin) • Any site – penetrating trauama – staphylococci – flucloxacillin • Multiple – metastatic and cryptogenic – streptococci, anaerobes – benzylpencillin if endocarditis or cyanotic heart disease, otherwise cefuroxime plus metronidazole • Surgical treatment – burr-hole aspiriation, excision – esp if capsule • Anticonvulsants often necessary • Mortality 10-20% - may be related to delay in initiation of treatment

46. Gullian-barre’ syndrome - clinical • Develops in 70% of patients 1-4weeks after RTI or diarrhoea – particaulrly campylobacter • Predominantely cell mediated inflammatory response directed at the myelin protein of spinal roots, peripheral and extra-axial cranial nerves -> complemented mediated destruction of myelin sheath and associated axon • Clinical – distal paraesthesia and limb pains – precede rapidly ascending muscle weakness • Facial and bulbar weaknes commonly develops • Ventilar support in 20% • Widespread loss of reflexes • 80% recover in 4-6 months, 4% die, rest have neuro deficits

47. Gullian-barre’ syndrome – investigations, management • Investigations • CSF – protein elevated at some stage of the illness, no rise in cell number • Electrophysiological studies – conduction blokd and multifocal motor slowing – delayed F waves • Identify underlying cause – campylobacter, CMV, mycoplasma • Acute porphyria – exclude by urinary porphyrin estimation • Management • Regularly monitor respiratory function • Corticosteroid shown to be ineffective • Plasma exchange and IV immunoglobulin shorten duration of ventilation assistance

48. Myasthenia gravis - clinical • 15-50, F > M in younger, reverse in older • Cardinal symptom – fatigable weakness of the muscles – movement initially strong, rapid weakening occurs – worsening symptoms towards end of day or after exercise is characteristic • No sensory signs or involvement of CNS – but weakness of oculomotor muscles may mimick a central eye movement disorder • First symptoms – ptosis, diplopia • Also – weakness of chewing, swallowing, speaking or limb movement • Limb muscle- commonly shoulder girdle • Respiratory failure is not an uncommon cause of death • Prognosis variable, remission spontaneously sometimes • If confined to eye muslces – prognosis excellent • Young F higher remission rates if thymectomy • Rapid progression more than 5 years after its onset is uncommon

49. Myasthenia gravis - investigations • Tensilon test • Inject – short acting anti-cholinesterase (edroponoium bromide) – test drug with small amount - then bigger amount 8 minutes later – improvement in muscle power occurs within 30 seconds persists for 1-2 minutes • Ice pack test • Ice on eye to help extra ocular muscles • Serological testing • AChRA is found in 50% of cases • Anti-MuSK (muscle specific kinase) especially in negative AChRA patients • 6-12% of patients are seronegative • Electrophysiological confirmation • Repeptitive nerve sitmulation • Single fibre

50. Myasthenia gravis - treatment • Principles of treatment • Maximise the activity of AchR in the neuromuscular junction • Anticholinesterase • Pyridostigmine – 30-120 mg, 6hourly • Muscarinic side effects • Limit or abolish the immunological attack on motor end plates • Thymectomy – antibody + under 25, symptoms not confined to extraocular eye muscles, unless disease established for more than 7 years • Plasma exchange – removing antibody blood – marked improvement – brief – crisis management, pre-operative • Plasmapheresis – remove offending autoantibodies • Intravenous immunoglobulin – alternative to plasma exchange in the short term treatment of severe myasthenia, MOA of action uncertain • Corticosteroid treatment – improvement commonly preceded by marked exacerbation of symptoms – should be initiated in hospital • Usually to continue for months to years • Others – azathioprine – reducing dosage of steroids