CNS Infections

Path

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

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)

Acute pyogenic meningitis – causative agents, clinical

• Causative agent vary with age of patient– Neonates – E coli, group B streptococci– Adolescents/young adults – neisseria meningitidis– Elderly – strep pneumonia, listeria monocytogenes– Immunisation has drastically reduced haemophilus

influenza– Immunosuppressed patient – klebsiella, anaerobic

organisms• Clinical – systemic signs, headache, photophobia,

irritability, clouding of consciousness, neck stiffness

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-Friderichsen syndrome – results from meningitis associated septicaemia with hemorrhagic infarction of the adrenal glands and cutaneous petechiae

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

Acute aseptic meningitis – clinical, LP, causative agents

• Clinical - meingeal irritation, 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

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

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 gemistocytic astrocytes

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%

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

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

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 tuberculous granulomatous

reaction, calcification may occur in inactive lesions

Neurosyphillis – major forms –path/morphology

• Meningovascular neurosyphilis• 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, rion depositsi -> Prussian blue stain– Granular ependymitis – proliferation of subependymal glia

• Tabes doraslis• 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

Neuroborreliosis – symptoms

• Lyme disease• Caused by spirochete Boreelia burgdorferi –

transmitted by ticks (Ixodes)• Symptoms highly variable – aseptic meningitis,

facial nerve palsies, mild encephalopathy, polyneuropathies

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: perivascular cuffs and parenchymal mononuclear cell infiltrates, glial cell reactions (microglial nodules), neuronophagia

• Complications – congential malformations (intrauterine – rubella), postenecepahlitic parkinsonism, immune mediated disease – perivenous demyelination

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 neutrophil pleocytosis

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

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

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 dermatomal distribution, usually self-limited– Granulomatous arteritis– 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

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.

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

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

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

Subacute scleroing panencephalitis

• 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

Fungal meningoencaphlitis – common agents, patterns of infection

• Brain usually involved with widespread hematogenous dissemination• Most often – candida albicans, mucor species, aspergillus fumigates,

Cryptococcus neoformans• Endemic areas – histoplasma capsulatum, coccidiodies immitis,

blastomyces dermatitidis• 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

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

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 hemosiderin laiden

macrophages

Cerebral amebiasis

• Rapidly fatal necrotising encephalitis – naegleria species

• Chronic granulomatous meningoencepahlitis – acanthamoeba

• Methenamine silver or PAS stains – visualise organisms

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

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

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

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 andreactive gliosis in anterior ventral and dorsomedial nuclei of the thalamus, also inferior olivary nuclei

Clinical

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

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

Bacterial meningitis- treatment• Benzylpenicillin immediately 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– Listeria monocytogenes – ampicillin plus gentamicin– Strep suis – cefriaxone

• If allergic to penicillins – chloramphenicol, vancomycin• Coricosteroids – dexamethasone – limit to 2 days

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

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

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

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

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

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

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

Shigella – clinical, management• Clinical

– Burning discomfort in affected dermatome – discrete vesicles 3-4 days later– Severe disease suggests an underlying immunodeficiency– Thoracic dermatomes commonly involved– Ophthalmic division of trigeminal nerve is also involved– Ramsay Hunt syndrome – facial palsy, ipsilateral loss of taste and buccal

ulceration, rush in the external auditory canal – geniculate ganglion involvement

– Granulomatous cerebral angiitis – cerebrovascular compliation – stroke-like syndrome

• Management and prevention– Acyclovir – reduce early and late onset pain– Analgesia