Neurological Infectious Disease

[ONE]

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Neurological Infectious Disease

Meningitis

Bacterial Meningitis

• Epidemiology (see charts)
o H. influenze incidence dropped 99% with vaccination
o S.. pneumonia & N. meningitidis penicillin & cephalosporin resistance increasing
o Highest risk group (in North America) – infants (7.1 / 100000 vs 1/100000 in adults)
o The causative organism can be predicted by age, predisposing factor, underlying disease
o >50% adults with meningitis have RFs – sinus infection, brain abscess, neuroSx, head trauma, chronic disease (EtoH, cancer, DM, immunosupression, renal failure), pneumonia etc…





*Vancomycin is added empirically to the initial regimen if the presence of penicillin-resistant S pneumoniae is suspected or if a high incidence of resistance is reported in the community



• Pathophysiology
o Bacteria survive in CSF due to low immunoglobulin and complement levels
o Bacterial factors released are VERY potent inflammatory agents
o Massive leukocyte influx into CSF which release a brew of toxic stuff
o Endothelial cells are damaged and die leading to increased B-B permeability
• Clinical
o Stiff neck, H/A, fever, photophobia, N/V, lethargy, altered mental status
o Evolves to stupor and coma over HOURS (rarely over 1-2 days)
o Petchial-purpuric rash suggests N. meningitides (rarely S. aureus)
o Waterhouse-Friderichen syndrome - 10% fulminating meningococcal septicemia
• Complications
o Brain edema with herniation (10-15%)
o Focal neurological signs (15-20%) – both arterial and venous thrombosis
 Arteritis, vasospasm, disturbed cerebral autoregulation
o Seizures (20-40%)
o CN palsies (10%)
o Hearing impairment (purulent labyrinthitis) – 30%
o Cerebritis (10%)
o Systemic – ARDS, DIC, Septic shock, SIADH
• Diagnosis
o GIVE ABx prior to ANYTHING (get Blood C&S at same time)
o CT Scan if decreased LOC, seizures, focal signs PRIOR to LP
 NO LP if CT demonstrates signs increased ICP
o CSF – cloudy, polymorphs, low glucose, very high protein
o CSF C&S, gram stain – 70-90% sensitive; Blood C&S 50% sens
o PCR for meningococcus if suspicion exists but C&S and gram stain negative
o SEARCH for initial nidus of infection
• Treatment (Dr Roo’s Recipe)
o Blood C&S
o Empiric Antibiotics IV usually with adjuvant Corticosteroids
 Dexamethasone 10mg q6hr x 4 days (stop if NOT S. pneumoniae on culture)
o CT Scan (usually indicated prior to LP)
o LP
o Switch Antibiotics based on C&S
o Meningococcus? – isolation; chemoprophylaxis for all close contacts
• Other things to consider
o Venous thrombosis – heparin anticoagulation
o Seizures – duh – treat
o Sepsis – activated protein C
o ICP elevated – head elevation, hyperosmolar agents, hyperventilation, ICP monitor
o Worsening > Abx? Consider:
 Worsening cerebral edema, arteritis, infarction, venous thrombosis
 Inadequate or ineffective antibiotics
• Prognosis
o Mortality – 20-30% for pneumococcal and Listeria
o Morbidity – 20-40%


*Use ceftriaxone if penicillin-resistant N meningitidis occurs in the community.
†Ceftriaxone is preferred. Ceftazidime is used when Pseudomonas infection is likely (eg, neurosurgical procedures).


Whipple’s Disease
• Epidemiology
o Rural inhabitants, farmers, Europe and North America; M>>F; mean age 50 years
• The Bug – Tropheryma Whipplei (gram negative) – BUT PAS-positive is characteristic
• Clinical (Triad = Arthralgia, Weight Loss, Diarrhea)
o Onset – polyarthralgia most common – chronic migratory seronegative non-destructive
o Other – weight loss, diarrhea, low grade fever, lymphadenopathy, cardiac (culture neg SBE)
o CNS involvement 10-50%; CNS Whipple’s may be the only feature of infection
o Commonest CNS: Dementia, supranuclear ophthalmoplegia, myoclonus
o Pathognomonic (present in 20% of CNS Whipple’s):
 Oculomasticatory myorhythmia (OMM) is a unique finding in Whipple’s disease, characterised by a slow, smooth convergent–divergent pendular nystagmus associated with synchronous contractions of the jaw.
 Oculofacial-skeletal myorhythmia has also been described: a slow smooth convergent–divergent pendular nystagmus associated with synchronous contractions of other body parts.
• Diagnosis
o Duodenal Biopsy – granular foamy macrophages with PAS-positive inclusions
o CSF – PCR
• Treatment – IV Ceftriaxone x 2wks THEN Septra x 1year or more




Viral meningitis
• Clinical:
o Fever, H/A, stiff neck, photophobia
o N/V, anorexia, rash, diarrhea, myalgias may accompany or precede meningitis
o Signs – Meningismus only (NO focal signs)
• DDx:
o Nonpolio enteroviruses (coxsackievirus A & B, echovirus, other enteroviruses) COMMON
o Anthropod borne viruses (arbovirus including West Niles, Eastern & Western Equine, etc…)
o Herpes Viruses (HSV-2, EBV, VZV)
o HIV
o Lymphocytic choriomeningitis virus
• Epidemiology:
o Summer months, rash on face then spread = likely enterovirus meningitis
o Arbovirus infections transmitted by mosquito and tic bite in late summer and fall
o HSV-2 may cause recurrent meningitis (Mollaret’s meningitis) with or without genital lesions
o EBV – infectious mono may be complicated by meningitis; VZV with chicken pox or zoster
o HIV – meningitis typically complicates intial serocoversion; chronic recurrent during disease
• Differential Diagnosis of Aseptic Meningitis (i.e. negative bacterial cultures & CSF lyphocytosis)
o Infectious
 Fungal meningitis
• Immunocompetent – Cryptococcus, Coccidioides, Histoplasma, Blasto
• Immunosuppressed only – Candida, Aspergillus, Mucor
 TB
 Lyme
 Syphilis
 Bartonela henselae
o Neoplastic
 Lymphomatous meningitis
 Carcinomatous meningitis
o Inflammatory
 Sarcoidosis
 Behcet’s Disease
 Wegener’s Granulomatosis
o Medications
 NSAIDs
 Sulfa-containing antibiotics
 IVIg
 Isoniazid
• All possible Investigations (obviously dependent on presentation)
o CSF studies:
 Routine – Cell count + diff; Protein; Glucose;
 Bacteria – Gram stain and C&S
 Viruses – Serology (HSV, WNV, VZV); PCR (Herpes, WNV, HIV)
 Fungal – Culture, India Ink; Cryptococcal antigen, Histo antigen
 Lyme – B. burgdorferi antibodies
 Syphylis – VDRL & FTA-ABS
 TB – AMTD, culture, acid-fast smear
 Neoplastic – cytology, flow cytometry
 Sarcoid – ACE level, IgG Index and OCB
o Other:
 Throat and Stool cultures for Enteroviruses
 Acute and convalescent serologies for enteroviruses and arboviruses
 HIV serology
 VDRL, FTA-ABS
 EBV and other virus specific antibodies
 Behcets, Wegener’s Sarcoid investigations as needed
o Imaging – not necessary unless to rule out other suspected things
• Treatment – none in viral meningitis!! Acyclovir-gancyclo>>
o NSAIDS and antipyretics for symptomatic relief

CSF Studies in Various Disorder Causing Meningitis
•
•
• Exceptions to the CSF rules for viral meningitis:
o Decreased glucose may be seen in (but must repeat LP to follow closely if seen):
 Enteroviruses, HSV-2, VZV, LCM
o Decreased glucose more common in:
 Fungal, Listeria, TB, Carcinomatous meningitis, Sarcoid sometimes
o Polymorphonuclear leukocystosis (in 1st 48hrs only) may be seen in:
 WNV, eastern equine virus, Mumps
• BUT if seen – treat with antibiotics, repeat tap, confirm absence of bacteria

Encephalitis
• Differential
o Infectious
 HSV-1 (most common cause)
 Arboviruses (West Nile, St. Louis, Eastern & Western Equine, Japanese etc)
 Rocky mountain spotted fever & ehrlichioses
 Dengue in places that have it
 Immunocompromised – CMV, EBV, VZV, HHV-6, JC virus (all reactivation)
o Inflammatory – ADEM, Hashimoto’s Encephalopathy
o Paraneoplastic – Anti-Hu, Ma2, CRMP5
• Clinical
o Triad – FEVER, H/A, Altered LOC
o Seizures, Focal deficits
• The complete CSF work-up can include the following
o Herpes (HSV, VZV, EBV CMV)– CSF PCR
o Arbovirus – PCR WN, CSF IgM, Paired acute and convalescent sera
o HHV-6 – viral culture, paired sera
o Rocky Mountain Spotted Fever– PCR, paired sera
• HSV-1 Encephalitis
o Transmitted by close personal contact
o Primary infection in oral mucosal surface – typically asymptomatic
o Latent infection in trigeminal ganglion (via retrograde transport in trigeminal nerve)
o Reactivation usually leads to a cold sore unless you’re unlucky & it goes the other way
o May travel TWO routes to the brain:
 Trigeminal ganglion – affect anterior temporal lobe and limbic structues
 Via nasal mucosa and olfactory bulbs – affect orbitofrontal cortex
o Clinical
 Subacute course
 FEVER, HEADACHE, behavioral changes, seizures, focal deficits (aphasia, hemipa)
o Diagnosis
 Imaging – orbitofrontal & ant temp T2 hyperintense +/- hemorrhage – never normal
 CSF – typical viral profile (↑OP lyphocytic pleocytosis, ↑protein, ↓or norm glucose)
 HSV PCR – may be negative in first day – TREAT and REPEAT if suspicion high
 HSV antibodies > 8 days. If ratio serum:CSF antibodies < 20:1 = HSV in CSF
 EEG – PLEDS very characteristic (but we already now the diagnosis I hope)
o Treatment
 IV acyclovir 10mg/kg q8hr x 3wks (start STAT if clinical and MR are typical)
• S/E renal primarily – must give with lots of fluid to prevent ARF
 Acyclovir also used for VZV, EBV or unknown encephalitis just in case
 CMV – gets Gancyclovir + Foscarnet
 HHV-6 gets Foscarnet
• Arbovirus Encephalitis
o Inoculated into host by mosquitoes and tics with local replication then viremia
o Neurons infected after virus enters through cerebral capillary endothelial cells
o Virus spreads from cell to cells along dendrites and axons
o Basal Ganglia targeted by West Nile, Japanese, and Eastern Equine – cf HSV enceph
o NO treatments specific for these – just supportive
• West Nile Infections
o Clincal:
 Predilection for older, immunosuppressed individuals
 Incubation is 2-14 days (longer in immunocompromised)
 Most get mild influenza-like illness (h/a, sore throat, malaise, myalgia, fever, N/V)
 Maculopapular or morbiliform rash on entire body occasionally
o Less than 1 in 150 develop neurological disease which include:
 Aseptic Meningitis
 Encephalitis: predilection for basal ganglia, thalamus and SN
• Tremor common, other movement disorders typical
 Acute flaccid paralysis – Poliomyelitis like syndrome
 Other neurological disorders described – Cranial neuropathies
• Other Characteristic North American Artboviruses that you may never see (summer months)
o La Crosse virus
 Wooded areas of Midwestern states; Via mosquito
 Affects children primarily
 Prodrome followed by mild to severe typical encephalitis
o St. Louis virus
 Central and southwestern USA, western and central Canada, Mexico
 Adults>50 years; young develop mild aseptic meningitis
 Typical course of prodrome then encephalitis; 10-20% mort; sequelae in 10%
 SIADH and hyponatremia is Unique feature
o Eastern Equine encephalitis virus
 East coast from Maine to Florida
 Affects horses and pheasants 2-3 wks prior to humans
 Most severe encephalitis with typical prodrome – abrupt onset of high fever, seizures, progression to stupor and coma
o Western Equine encephalitis virus
 Western North America
 Severe in children under 6 months; mild or asymptomatic in adults
• Diagnosis of Arboviral Encephalitis
o Typical CSF – lymphocytic pleocytosis, ↑protein, normal glucose; PMNs may occur early
o CDC definition of confirmed case of arbovirus encephalitis:
 Febrile illness with encephalitis during a time when transmission likely to occur
 PLUS one of:
• Fourfold increase antibody titre between acute and convalescent sera
• Viral isolation from tissue, blood or CSF
• Specific IgM in CSF
o NOTE – detecting WN virus in serum is NOT sufficient to make diagnosis; you need:
 WN virus IgM in CSF (ELISA) – confirm with more specific test
 WN PCR in CSF positive
 Fourfold increase in MN specific IgG b/w acute and convalescent sera
 Virus isolation from brain or spinal cord
o Imaging – look for SN, basal ganglia and thalamus T2 and FLAIR hyperintensities
o


Subacute Sclerosing Panencephalitis
• Late manifestation in adolescents and young adults, developing nations, poorly immunized
• Average latency of 8 years after primary infection
• Main RF: Measles prior to age 2
• Clinical:
o Behaviour, personality and cognitive changes first signs
o Visual: Papilledema, chorioretinitis, homonomous field deficits, cortical blindness
o Motor: Limb and axial Myoclonus, time locked to periodic large amplitude sharp and slow waves (very long periods). Other movement disorders at myoclonus stage include chorea and ataxia. The hyperkinetic stage followed by rigid phase then akinetc mutism, and death
o Course may be stuttering or staged fashion, death in months to years
• Pathology:
o Mutations in measles M protein allows for persistent latent measles infection
o Spread through axonal pathways throughout brain
o Demyelination, neuronal loss, perivascular inflammation, gliosis, intranuclear and intracytoplasmic inclusions seen
o Most marked in Occipital Lobe, Thalamus and Putamen
• Dx:
o EEG – periodic, synchronous, symmetric, high amplitude complexes with slow periodicity time locked to myoclonic bursts
o CSF – Anti-measles Ab titres, increased IgG
o MRI – Periventricular and subcortical WM abnormalities

Abscesses

Brain Abscess
• Epidemiology
o RFs – chronic sinusitis, otitis media, penetrating brain trauma, dental infections, IV drugs, immunosuppression, pulmonary AVMs (HHT), cyanotic heart disease (R-L shunts), SBE
• The Bugs:
o Immunosuppressed – Nocardia, Toxo, Entamoeba histolitica, fungi etc..
o Immunocompetant – anaerobes (streptococci, Bacteroides), staph aureus, Clostridium, Pseudomonas, Hemophilis; enteric gram negatives; 20% polymicrobial
o 20-40% have NO identified organism
• Pathophysiology and Pathology
o Develop by (1)Direct spread (2)Cranial trauma (surgery or violent) (3) Hematogenous
o Nocardia – acquired by inhalation or airborne spores – spreads hematogenously from lungs to CNS – leads to abscess in organ transplant recipients and in chronic steroid users
o Otitis and mastoiditis – abscess in inferior temporal lobe or cerebellum
o Frontal or ethmoid sinus, dental infections – abscess in frontal lobes
o Hematogenous spread – abscess at corticomedullary junction
o Four stages of evolution – occur in dead brain – healthy brain very resistant to abscess:
 Early cerebritis (days 1-3)
• Perivascular inflammation surrounding central necrotic core
• No ring on imaging – lots of edema
 Late cerebritis (4-9 days)
• Necrotic core is max in size; border of inflammatory cells, active fibroblasts, new vessels
• Imaging now shows early abscess – maybe ring
 Early capsule formation (10-13 days)
• Capsule develops; decrease in necrotic core size; macrophages
• Imagining shows typical homogenous ring enhancing lesion with lot of surrounding edema; may see bright ring on T1 and dark ring on T2 (due to free radical formation); DWI bright and ADC dark (like stroke but unlike tumor); T2 bright core; T1 dark core
 Late capsule formation (> 14 days)
• Dense well formed collagen capsule; necrotic core; periphery of inflam cells
• Same as early capsule
o Clinical
 Triad – fever, headache, focal neuron deficit – fever may resolve with encapsulation
 Seizures; raised ICP; herniation typically causes death
o Diagnosis – Imaging and Biopsy
 LP Contraindicated
 W/U – Echo, CXR, dental views, blood cultures, stereotactic biopsy
 DDx – brain tumor (1 or 2nd); granuloma; lymphoma; infarct; resolving hematoma; radiation necrosis; MS; thrombosed aneurysm
o Treatment
 Surgical drainage + Antibiotics
 Antibiotic only – multiple abscesses, abscess in eloquent brain, early cerebritis stage
 Empiric Abx (prior to biopsy) = Ceftriaxone + Vancomycin + Metronidazole
 Steroids – used if mass effect and potential herniation but taper quickly because reduce penetration of ABx into abscess (e.g. DEX 10mg q6hr x 3-7d)
 AEDs – 50-70% ultimately have seizures – use prophylactic AEDs in ALL x 2yrs

Epidural Abscess and Subdural Empyema
o Direct spread from sinuses or iatrogenic
o H/A; fever; MRI demonstrates abscess; focal signs; decreased LOC
o Rx – Surgical drainage urgently; ABx 1st empiric (see above) then specific pathogen

Epidural Spinal Abscess –



http://www.emedicine.com/neuro/topic349.htm


HIV
• Enters brain after initial infection where it resides in perivascular macrophages, microglia, astrocytes
• The brain is consider possible sanctuary site for HIV even with HAART therapy (limited drug access)

Opportunistic Infections of the CNS in HIV Patients
• Toxoplasmosis encephalitis
o See below

• Progressive Multifocal Leukoencephalopathy
o Epidemiology
 HIV (CD4<100), lymphoproliferative malignancy, other immunosuppressed
o The bug
 Polyomavirus; ubiquitous DNA virus that infects 80-90% of population
 JC virus thus named by the initials of patient 1st described with disease
o Pathophysiology
 Likely transmitted via respiratory droplets; takes up latent infection in lymph, brain
 Reactivation in immunosuppressed;
 HIV and PML synergistic effect to increase JC virus virulence
 JC virus infects oligodendrocytes (& astrocytes) leading to lysis leading to demyelination in WM of frontal, parietal, occipital lobes, cerebellum, brainstem
o Pathology
 Multifocal demyelination with some necrosis
 Bizarre, large, pleomorphic astrocytes
 Oligodendrocyte intranuclear inclusions (see path slides)
o Clinical
 Subacute progressive course evolving over weeks or months to death
 Altered mental status; cognitive deficits progress to dementia in 30-60%
 focal neurological deficits; generalized weakness
 visual disturbances (20-50%) – hemianopsia, cortical blindness
 Gait disturbance; incoordination
o Diagnosis
 Imaging – NON-enhancing multifocal WM abnormalities; especially parieto-occipital; minimal to no mass effect; (enhancement may be seen during immune reconstitution)
 CSF – normal or nonspecific elevations in protein and pleocytosis;
• JC virus DNA by PCR – 70-80% sensitive increases with progression; 90% specific; PPV & NPV >90% - Presence in correct clinical context confirms PML but absence of DNA by PCR DOES NOT rule out PML
 Biopsy – typical finding of nuclear inclusions confirms diagnosis (rarely needed)
o Treatment – NONE proven
 HAART therapy to restore immunity – improves survival
 Cidofovir – antiviral that has in vitro activity against polomavirus – only for severe
o Outcome – With HARRT – 1/3 dead by 12 weeks from onset; worse without HAART

• Cryptococcal meningitis
o See below

• Primary Central Nervous System Lymphoma
o

• CMV infections
o Epidemiology:
 Ubiquitous viral infection; most adults show serological evidence of latent infect
 Initial infection usually asymptomatic or occasionally mild febrile illness
 Afflicts very advanced HIV patients (CD4<50)
o The bug – CMV is a herpes virus (ds DNA enveloped virus)
o Pathophysiology and Pathology (Various Types)
 Encephalitis (most common)
• Microglial nodular encephalitis with typical micronodules composed of aggregates of glial cells and macrophages
• Typical intranuclear Cowdry B inclusions (“owl eyes”) in cytomegalic cells
• Found mainly in gray matter widely distributed
 Ventriculoencephalitis (second most common)
• Infection of ependymal cells lining ventricles
• Periventricular focal necrosis
 Polyradiculitis or Polyradiculomyelitis
o Clinical
 Usually previous history of CMV disease (retinitis, adrenalitis, esophagitis, colitis)
 Cooexistence of other pathogens very common (Toxo, PML, etc)
 Encephalitis – acute to subacute progressive encephalopathy +/- focal signs
 Ventriculitis – acute progressive encephalopathy; cranial neuropathies; ataxia; nystagmus; less cognitive disturbance than encephalitis
 CMV polyradiculitis – subacute onset of bilateral lower motor neuron leg weakness, which may progress to flaccid paraparesis, often accompanied by pain and paraesthesiae of the legs and perineum, areflexia, and sphincter dysfunction



o Diagnosis
 Look for other CMV infection
• Labs – adrenal insufficiency (hyponatremia, hyperkalemia – adrenilitis)
• Fundus – CMV retinitis
 Encephalitis/Ventriculitis
• CSF – monocytic pleocytosis; ↑protein; ↓glucose (sometimes normal)
• CMV PCR >90% sensitive and negative results excludes dx
• Imaging – NORMAL or nonspecific; ventriculitis shows subependymal enhancement which is characteristic
 Polyradiculitis
• CSF – POLYmorphonuclear pleocytosis; ↑protein; ↓glucose (sometimes normal)
• MRI – may have enhancement of roots
• CSF PCR positive in most cases
o Treatment (inhibition of viral DNA polymerase)
 Ganciclovir – S/E bone marrow suppression
 Foscarnet – nephrotoxicity
 Cidofovir – nephrotoxicity
 Induction phase (ganciclovir + foscarnet) then Maintenance phase with either
 HARRT therapy – immune reconstitution improves survival
o Median survival = 3 months (even with polyradic – usually from other infections)

HIV Associated Neuropathy and Myelopathy
• HIV-Associated Distal Sensory Polyneuropathy
o Epidemiology
• Most common neurological complication of HIV (30% of patients)
o Pathophysiology & Pathology
• Unknown – possible activated macrophage invasion of PNS (dysregulated immunity)
• Path – Distal pathology with loss of unmyelinated > myelinated fibres; axonal loss; not demyelinating; Skin biopsy shows loss of nociceptive C fibres from epidermis; some loss of cells in DRG
o Clinical
• Insidious onset, distal; feet 1st
• Symmetric, painful numbness, paresthesias, dysethesias, burning, lightening pains, stimulus evoked (allodynia, hyperalgesia)
• NO weakness (if present must consider myopathy, CMV radic, vasculitis)
• O/E – stocking & glove all modality sensory loss; absent ankle jerks in 66%
• Criteria for Probable DSPN:
• Pain, burning, dysethesia, paresthesia in feet>hands
• O/E – distal sensory Polyneuropathy (depressed ankle jerks, stocking-glove)
• No other etiology (exposure to ddC, ddI, d4T)
o Diagnosis:
• Clinical mainly – DDx acute toxic neuropathy related to ddI, ddC, d4T (see below)
• NCS/EMG – normal in 50%; other show sensory>motor distal axonal polyneurop
• Skin biopsy (NOT needed) – axonal swellings and reduced epidermal fibre density
• Rule out other causes of sensory neuropathy
• Impaired glucose tolerance (2hr OGTT), B12 level, TSH
o Treatment
• NO effective disease modifying therapy currently available
• HAART – may improve prognosis with virologic control
• Change antiviral to regimen without ddI, ddC, d4T
• Manage impaired glucose tolerance for those on PI
• Symptomatic Therapy is primary means of treatment (stuff for neuropathic pain)
• Amitriptyline, Gabapentin, Lidocaine Patch, Narcotics (morphine, fentanyl)
o DDx of peripheral neuropathy in HIV patients
• DSPN
• Antiretroviral therapy (ddI, ddC, d4T)
• Subacute onset painful distal sensory polyneuropathy
• Onset within months of starting antiretroviral
• Symptoms typically resolve on discontinuation of antiretroviral
• Impaired glucose tolerance – associated with PIs
• Alcohol neuropathy and Thiamine deficiency – typically painful sensory neuropathy
• Hepatitis C – painful sensory neuropathy or may be assoc with cryoglobulinemia
• CMV – acute polyradiculopathy

• HIV-1-Associated Vacuolar Myelopathy
o Epidemiology – advanced HIV with low CD4 counts
o Pathology – like B12 def – vacuolation of spinal cord WM affecting primarily posterior and lateral columns; spongiform changes macroscopically; thoracic cord most affected
o Clinical
• Subacute progressive course
• Difficult walking, sexual dysfunction, urinary urgency, incontinence
• O/E – spastic tone, weakness in LE, hyperreflexia, babinski’s; sensory level often absent due to diffuse involvement of the cord
o Diagnosis –
• exclude other causes of HIV myelopathy - Toxo, TB, HTLV-1, CMV, syphilis, carcinomatous meningitis, lymphoma, compressive from usual stuff
• Other tests – B12, syphilis serology, HTLV-1
o Treatment – Nothing modifies course
• Symptomatic – antispasticity, bladder and bowel management

HIV Dementia
• Epidemiology
o Prevalence increasing as HIV patients surviving longer (same as DSPN) while the incidence rates have dropped (reflecting HAART therapy) – lifetime prevalence = 15%
o Still, dementia occurs in moderately advanced immunosuppression
• Pathophysiology and Pathology
o Factors released from infected cells induce cascades that are eventually neurotoxic
o Neurons themselves are not infected by HIV
o Potential factors that lead to neurotoxicity include:
• Tat & gp120 (and others) – viral protein is directly neurotoxic
• Inflammation – activated macrophages-microglial cells releasing cytokines, MMPs, leading to apoptosis, oxidative stress, excitotoxicity
• Astrocyte damage leads to impaired glutamate uptake - excitotoxicity
o Path – Global atrophy; multinucleated giant cells; Nodular encephalitis with microglial nodules; leukoencephalopathy with patchy demyelination; gliosis – NOT specific
• Clinical
o Insidious progressive course over months – usual course in untreated 6-9 months
o Subcortical dementia profile (cognitive, behavioral and motor dysfunction):
• Memory loss – selective for impaired retrieval
• Impaired ability to manipulate acquired knowledge (frontal dysfunction)
• Mental slowing
• Apathy, irritability, inertia
• Motor disturbance – gait disturbance, impaired eye movements, parkinsonism, hyperreflexia and frontal release signs
• Diagnosis – mainly clinical while ruling out DDx
o Imaging – symmetric leukoencephalopathy affects deep WM non-enhancing, global atrophy
o CSF to rule out other infections; etc…
• Treatment
o HAART – substantial number of patients improve with immune reconstitution
o If viral replication well controlled on HAART – may stabilize for long-term

Fungal Infections
• Immunosuppressed = AIDS, cancer patients on chemotherapy, transplant patients on anti-rejection medications, long-term steroid use, the very old and young, inherited immunodeficient states

Cryptococcus neoformans
• Epidemiology
o Worldwide (most common fungal meningitis)
o Found in soil; bird excreta;
o Risk group – immunosuppressed > immunocompetent
• Pathophysiology
o Inhaled as spores; may cause symptoms of pneumonia; hematogenous spread to CNS
• Clinical (varied presentation)
o Meningitis (most common)
 Fever, H/A, cranial neuropathies (basal meningitis), mental status changes
 Rapid progression in severely immune suppressed; subacute and chronic occur
o Encephalitis (with multiple small disseminated cryptococcomas) – seizures, encephalopathy
o Mass lesion – single large granulomatous lesion (looks like any abscess)
• Diagnosis (easiest fungus to diagnose):
o CSF India ink for direct visualization (50-80% sensitivity)
o ELISA for cryptococcal antigen (very sensitive and specific)
o Imaging – normal most common – enlarged enhancing Virchow Robins spaces in BG typical
• Treatment (3 stages)
o Induction – Amphotericin B + flucytosine
o Clearance – amphotericin B or fluconozole
o Maintenance – Fluconozole (indefinitely for all AIDS patients) – relapse occurs

Coccidioides immitis
• Epidemiology
o Desert regions of the southwester USA (San Joaquin Valley) & Central america
o Immunosuppressed > immunocompetent
• Pathophysiology
o Inhalation leads to primary pulmonary infection (usually asymptomatic)
o May develop disseminated disease (1%) with lytic bone and vertebral disease and CNS
• Clinical
o Meningitis (may be only manifestation of disseminated disease) – aggressive basal meningitis with cranial nerve palsies and possible vascular compromise with stroke
o Hydrocephalus and raised ICP
o Encephalitis and abscess less common
• Diagnosis
o Index of suspicion in endemic areas plus travelers to these regions
o CSF – eosinophilia in 70% (unique feature); culture and direct visual rarely positive (25%)
o Complement fixation and serologies in CSF more sensitive (70% sens 100% specific)
• Treatment
o Induction – Fluconozole high-dose
o Maintenance – Fluconozole low-dose indefinitively in immunocompromised
o Ventriculostomy for hydrocephalus

Histoplasma capsulatum
• Epidemiology
o Central United States (Mississippi/Ohio River Valley); common in areas infested by bats
• Pathophysiology
o Inhaled spores in soil containing bird or bat exceta; exposure occurs in caves and barnyards
o Risk group – immunocompromised > immunocompetent
• Clinical
o Pulmonary disease mostly (cause of calcified nodules in lung)
o 10-20% of those with disseminated disease develop CNS disease (rarely occur alone)
o Meningitis (mostly) – basal meningitis, chronic, headache, encephalopathy
o Mass lesion (abscess) or encephalitis rarely
• Diagnosis
o Blood and bone marrow culture in disseminated disease; bone marrow biopsy
o H. capsulatum antigen detection in serum and urine (sensitive and specific)
o CSF detection of H. capsulatum antigen and antibodies
o CSF cultures Insensitive – use large volumes and repeat
• Treatment
o Amphotericin B – follow with repeat LPs looking for neg cultures and normalization of CSF
o Recurrence in 50%

Blastomyces dermatitidis
• Epidemiology
o Ohio and Mississippi River basins; activity outdoors nears waterways risk
o Risk group – immunocompetent = immunosuppressed (NO increase risk)
• Pathophysiology
o Inhalation leads to primary pulmonary infection – may be asymptomatic or cause local dx
o Dissemination to skin, bones (vertebral osteomyelitis), GU tract – Rarely CNS disease
• Clinical
o In context of disseminated blastomycosis – fevers and weight loss
o Mass lesions (most common) – spinal or cerebral abscesses, focal signs, seizures, encephal
o Meningitis – chronic with headache, meningismus, lethargy
• Diagnosis
o CSF cultures and direct visualization very insensitive
o Biopsy of mass lesions best bet
o Look for systemic blasto – CXR, BAL, GU, Bone, Blood serologies
• Treatment – same as histoplasmosis

Candida
• Epidemiology
o Ubiquitous; normal commensals in human respiratory, GI and GU systems
o Risk groups – immunosuppressed only; neutropenia especially high risk; critically ill neonates, post-operative neurosurgical patients, pts receiving corticosteroids
• Pathophysiology
o Enters body via mucosal surfaces injured by wounds, mucositis
o Iatrogenic through indwelling catheters, direct inoculation with ventriculostomies
• Clinical
o Parenchymal (encephalitis), meningitis, and retinal disease often coexists
o Vascular pathology common – infarctions & hemorrhage
• Diagnosis
o Look for typical retinal cotton-wool spots on fundoscopy
o CSF cultures and direct visual very insensitive (use large volumes)
• Treatment – Amphotericin B

Aspergillus species
• Epidemiology
o Ubiquitous
o Risk groups – profoundly immunosuppressed; especially neutropenic
• Pathophysiology
o Direct extension from paranasal sinues leads to rhinocerebral syndrome and abscess
o Pulmonary disease with hematogenous dissemination
• Clinical
o Abscesses – from embolic source or direct extension
o Infarctions – stroke syndromes affecting posterior circulation commonly; usually occurs with rhinocerebral disease invading cavernous sinus and basal cisterns – hemorrhages seen as vessels walls is infected with aspergillus emboli
• Diagnosis – Biopsy showing typical hyphae
• Treatment – Surgery for abscess

Zygomycetes (Mucor)
• Epidemiology
o Ubiquitous
o Risk factors – poorly controlled diabetes; acidotic states (e.g. DKA), immunosuppressed
• Clinical
o Infarctions – Rhinocerebral syndrome – invasion through veins into cavernous sinus with thrombosis of ICA frequent; ophthalmic involvement; nasal discharge; black eschar
o Abscesses
• Treatment – Surgery

Tuberculosis
• Epidemiology
o Immigrants from endemic countries; homeless living in shelters; native reservations; HIV
o M. tuberculosis only natural reservoir is HUMANS (i.e. without us there could be no TB)
• Pathophysiology
o Transmitted by inhalation of aerosolized droplets
o Enter alveoli and multiply; silent hematogenous spread by 2-4 weeks to organs & CNS
o 10% immunocompetent develop pulmonary TB; extrapulmonary TB is AIDS defining
o Tubercles (caseating granulomas) form in lung; in meninges called Rich foci
o Rupture of expanding tubercle in meninges = TB meningitis
 Leads to infectious arteritis and stroke; hydrocephalus; adjacent encephalitis
o Expanding tubercles in the parenchyma = tuberculoma or abscess
• Clinical
o TB meningitis = basal meningitis
 Non-specific prodrome 2-4 weeks (fatigue, fever, malaise, myalgia)
 Then fever, H/A, N/V, mental status changes, memingismus
 CN palsies (¼) – VI>III, IV, VII, VIII
 Stroke – hemiparesis (10-15%); Seizures
 Fundoscopic – choroid tubercles (10%)
o Tuberculoma
 Solid caseation with few bacilli; 1/3 multiple; subacute to chronic course
 May coexist with meningitis; may be anywhere
 Clinical – h/a, seizures, papilledema with raised ICP
 CSF may be normal; CSF cultures usually normal
 Dx – PPD, CXR, neuroimaging findings and response to TB meds
o Abscess
 Rare; single; liquefaction with many bacilli; acute course
o Spinal Cord and TB Radiculomyelitis
 Granulomatous subarachnoid exudate leads to inflammation and ischemia in cord
 Clinical – transverse myelitis and radicular pain
 Thoracic cord most common
o TB Vertebral Osteomyelitis (Pots Disease)
 Thoracolumbar region; L1 most common
 Begins in vertebral body and spreads to disc then anterior and posterior ligaments
 May see vertebral collapse; psoas abscess
• Investigations:
o Abnormal CXR – 50% (60% HIV)
o Positive PPD – 50% (30% HIV)
o Hyponatremia – 50%
o CSF – may be neutrophylic initially then lymphocytic pleocytosis (200cell); elevated protein; decreased glucose (that goes lower in sequential taps); Acellular in 15% HIV pts
o CSF acid-fast staining – 5-25% sens; TB culture 60% sens (but long wait)
o PCR of CSF (AMDT) – 54-100% sens (i.e. nothings perfect to rule out TB)
o Imaging – MRI – basal meningitis; stroke; ring enhancing tuberculomas with edema
• Treatment
o Frequently treat based on suspicion; typical CSF & imaging; empirical therapy
 Isoniazid 300mg/d – peripheral neuropathy (use pyridoxine 25mg/d); liver toxicity
 Rifampin 600mg/d – S/E – liver toxicity, orange stained body fluids
 Ethambutol 15-25mg/kg/d – S/E – optic neuritis that may be reversible
 Pyrazinamide 20-35mg/kg
 Streptomycin 15mg/kg
 4 drugs x 2 months then 2 drugs (ISO + Rifampin) x 10 months
o Corticosteroids – add to regimen in most cases
 Rational – some patients experience WORSENING upon start of TB treatment with rapid deterioration and death due to massive release of antigenic TB proteins from dying mycobacterium – also see paradoxical tuberculoma in early TB treatment
• Prognosis (for meningitis) – 27% mortality
o Stage 1 – fully conscious; normal mental status; normal neuro exam
o Stage 2 – confused NOT comatose with focal signs (CN palsy, hemiparesis)
o Stage 3 – comatose, multiple signs – POOR prognosis
• HIV and TB presentation
o More neutrophilic pleocytosis; more with normal CSF; poor prognosis; less PPD +

Syphilis
• Epidemiology – Risk factors – HIV positive; black; male; lower socioeconomic strata
• The Bug – Treponema pallidum – small cork-screw shaped intracellular bacterium
• Pathophysiology & Pathology
o Transmitted by sexual contact with infected patient through mucosal surfaces or abrated skin
o Vertical transmission also occurs (mother to child)
o Hematogenous dissemination occurs at time of onset of secondary syphilis
o Meningovascular – due to chronic meningitis and multifocal arteritis
o Parenchymal – chronic meningoencephalitis – loss of neurons, gliosis, rod-shaped microglia
• Clinical:

Primary Syphilis
• Painless chancre at site of inoculation – spirochetes can be seen on microscopy
• NO neurological involvement during primary infection

Secondary Syphilis
• 2-12 weeks later
• Dissemination – fever, malaise, rash (characteristic erythematous scally papules on the hands and soles of feet), lymphadenopathy, condyloma lata, mucus patches
• Neurosyphilis seen during this stage:
o Asymptomatic neurosyphilis (50%) – manifested by CSF abnormalities (↑cells, ↑protein, serological tests in CSF positive) and no neuron findings – only 1-2% symptomatic:
o Syphilitic meningitis
• During 1st 2 years > primary – typical meningitis symptoms (like viral meningitis)
• Cranial neuropathies (especially VII, VIII, and optic nerve) – resolve with therapy
• DDx – aseptic meningitis including crypto and TB in HIV patients
• May resolve spontaneously without treatment
o Meningovascular syphilis – see below
• Once second stage resolves patients enter a latent, asymptomatic period with positive serology

Tertiary Syphilis
• 1/3 of untreated patients will develop tertiary syphilis (many never had secondary manifestations)
• Cardiovascular (most common – cardiomyopathy, aortitis), granulomatous and neurologic forms exist
• Neurosyphilis at this stage include
o Meningovascular Syphilis
• Peak 7 years > primary
• Acute onset focal deficits (stroke duh) – hemiparesis in 83%; seizures; ataxia
• MCA (2/3) > basilar distribution strokes; may also effect spinal cord
o Parenchymatous Syphilis (general paresis of the insane and tabes dorsalis)
• 10-20 years > primary infection
• General paresis – Insidious onset of dementia, personality changes, irritability, sleep disturbance, psychiatric symptoms – Neuro Signs – tremors, seizures, Pupillary changes (including Argyl-Robertson) – course untreated months to years
• Tabes Dorsalis – recurrent lancinating pains in legs>arms, back; sensory ataxia; abnormal characteristic gait; bladder dysfunction; Signs – Rhomberg+, loss of vibration and position sense; arreflexia; Charcot joints – evolves over 20 years – pathology – atrophic posterior columns and posterior roots
• Ocular Syphilis – progressive optic neuropathy leading to blindness
• CSF may be normal
o Gummatous Neurosyphilis
• Least common; granulomatous disease that exerts mass effect
• Usually arise from meningeal surface; rarely parencymal
• Clinical – focal deficits and mass effect
• CSF may be normal
• Diagnosis
o Cultures NOT useful; combo of history, labs, serology
o CSF – lyphocytic pleocytosis ↑protein, normal glucose; may be normal in tertiary syphilis
o CSF VDRL – Specific but NOT sensitive (10-30%) therefore NO SNOUT, but does SPIN
o CSF FTA-ABS – very sensitive BUT not specific; therefore does SNOUT
• Diagnostic Algorithm
o Lumbar puncture in:
• Clinical neurosyphilis
• HIV with latent syphilis
• Any active tertiary symphilis
• Treatment failure
o Diagnosis of Neurosyphilis:
• CSF pleocytosis
• Reactive CSF VDRL
• Reactive CSF FTA-ABS
• Treatment – Penicillin G 18-24 million U/d x 10-14 days
• Follow-up – repeat LP qmonthly until CSF cell count is normal (if not at 6months – retreat)

Lyme
• Epidemiology
o Tic bite in the Northeast (Maine to Maryland) and Midwest (Wisconsin and Minnesota)
o Most commonly in late spring and summer months
• The Bug – Spirochete Borrelia burgdorferi acquired from Ixodes tic bites; >24hrs feeding
needed

ixodes tic


• Pathophysiology
o Not much known about this. Oligodendrocytes thought to be target (thus WM lesions that simulate MS). Also perivascular infiltrate and axonal loss on a vasculitic basis in PNS biopsies. CNS biopsies rare – demyelination, lymphoplasmacytic parenchymal infiltrates
o Mechanism of all PNS features (CN neuropathies, polyradic and MM) are all likely due to perivascular inflammation and axonal damage (i.e. they are vasculitic injuries)
• Three Clinical Stages:

Stage 1 – Erythema migrans +/- flu-like illness (80%)

Stage 2 – days to weeks later disseminated infection of the:
• Nervous system (15%) (Classic Triad in Bold = Garin-Bujadoux-Bannwarth syndrome)
o PNS
1. Bilateral Facial nerve palsy (commonest, 1 in 4)
• 1 in 4; associated meningitis in majority
• DDx – sarcoid & GBS
• Other cranial nerves can also be affected, including optic neuritis
2. Painful Polyradiculopathy
• Can mimic mechanical – dermatomal sensory, motor and reflex changes with NO prior trauma, no disc on MRI; summer in endemic
• CSF – inflammatory changes; segmental myelopathy may be present
3. Lumbosacral or Brachial Plexopathy
4. Mononeuropathy Multiplex
o CNS
1. Meningitis (associated with facial palsy usually)
• 10% untreated ultimately develop meningitis
• Viral-like CSF – lyphocytic pleocytosis, ↑prot, normal glucose
2. MS-like disease that resolves – 0.1% develop parenchymal involvement
• Cardiac – conduction defects and heart block
• Joints – oligoarthritis

Stage 3 – chronic stage (5%)
o CNS – Lyme encephalopathy – subtle cognitive disturbance – may not exist
o PNS – Axonal polyneuropathy, confluent mononeuropathy multi
o Joints – Treatment resistant arthritis in 10%
• Diagnosis (neuroborreliosis) –
o CSF – viral-like (lymph pleo, incr prot, norm gluc) – cultures of CSF useless
o CSF serology – more sensitive for acute infection than chronic
o Serum serology - ELISA not specific; Western Blot to increase specificity
o Hx – most important, especially classic EM lesion
• Treatment
o Early disease – Doxycycline
o Neuroborreliosis (including VII palsy) – IV Ceftriaxone 2g qd 2-4 wks

Protozoal Infections

Toxoplasmosis
• Obligate intracellular parasite
• Stages of development – feline species (essentially cats) are only definitive hosts
o Oocytes – ingested tissue cysts from cat prey (e.g. mice) mature in intestine of cat and form oocytes which are exceted in feces of cat. Sporozoites in oocytes are infective when ingested and form Tachyzoites
o Tachyzoites – enter cells, undergo repeated replication, leading to cell death and rupture and hematigenous spread of tachyzoites to all body tissues
o Cysts – immune response leads to formation of tissue cysts containing much less active bradyzoites that remain in tissue for life of animal. They are infective if eaten or if immune system becomes suppresses
o


• Methods of transmission
o Ingestion of Oocytes – cat feces on veggies (yum yum) or in water
o Ingestion of Cysts – from undercooked meat (usually lamb of pork)
o Iatrogenic – through organ transplantation of infected organ (esp heart, liver)
 More common is reactivation of latent disease in organ recipients
o Congenital – in pregnancy with primary infection via placental transmission
 15% prevalence seropositivity in USA women of childbearing age
 Risk of congenital transmission begins if 1 infection by 3 month pre-conception
 Risk of congen. Infection lowest in 1st trimester and highest in 3rd
 Severity of congenital infection worst in 1st and mildest (and asymptomatic) in 3rd
 Unrecognized asymptomatic congenital toxoplasmosis may show up later as:
• Chorioretinitis
• Delayed growth into the 2nd and 3rd decades
 Spiramycin used to reduce vertical transmission in woman at risk
 Immunosuppressed (e.g. HIV+) women can transmit previous infection
 NO transmission through breast milk



• Prevalence of infection:
o 22.5% overall seroprevalence in the USA; rises with age
• Pathology:
o Multifocal necrotic lesions with predilection for the basal ganglia
o May be hemorrhagic
o Tachyzoites on histology confirms diagnosis
• Clinical:
o Immunocompetent – 90% asymptomatic; 10% short lived lymphadenopathy +/- fever
o Chorioretinitis:
 Typically a late manifestation of congenital toxoplasmosis (may be new acquired)
 Visual loss
 Fundoscopy – “headlight in the fog” appearance typical
o Immunosuppresed – Toxoplasmosis Encephalitis
 AIDs; organ transplants; cancer
 Encephalitis:
• Mental status changes, seizures, focal deficits, cerebellar, movement d/o
• Presentation over days to weeks
• DDx:
o Lymphoma
o PML
o CMV ventriculitis and encephalitis
o Focal abscess (bacterial, Cryptococcus, aspergillus, TB, nocardia)
o Congenital Toxoplasmosis – see Peds notes
• Detection:
o Serologic tests:
 IgG – suggests previous infection – useful in pregnant women (risk congenital toxo if absent) and immunosuppressed (risk reactivation of Toxo if present)
 IgM – useful in diagnosis of congenital toxo in newborns – useful for ruling out recent acquired infection in 1st & 2nd trimesters of pregnancy – useless in immunosup
 IgG avidity – high avidity rules out recent (3months) infection – useful in pregnancy
o Direct Tests:
 PCR – useful in all forms of toxo – amniotic fluid, vitreous fluid, CSF – positive CSF PCR can represent latent toxo or active disease – so does NOT prove that CNS disease is toxo (might still be lymphoma etc…)
 Identify Tachyzoites – NOT easy – best chance in biopsy, but you can try in CSF
• Imaging:
o NOTHING pathognomonic – but some features are suggestive
 Basal ganglia involvement
 Does NOT affect periventricular region or demonstrate ependymal spread
 Has Low-intensity capsule with hyperintense core and surround on T2WI
• Differentiate from Lymphoma:
•


• Treatment: NOTE – Pyrimethamine/sulfadiazine + Folic acid = PS/F
o Congenital (i.e. mom diagnosed as new toxo infection during pregnancy):
 Not yet transmitted to fetus – Spiramycin throughout pregnancy
 Amniotic fluid PCR positive or 3rd trimester infection – PS/F – then treat newborn
 PS – teratogenic during 1st and early 2nd trimester
o Ocular – often self-limited – may watch – if vision threatened – PS/F
o Immunosuppressed (Encephalitis):
 Brain imaging in AT RISK individuals (AIDS, transplant) with clinical
 Typical imaging – PS/F – then monitor clinical and imaging:
• Clinical should improve 50% by 1 week
• Imaging – 2-4 wks should see improvement; 3-6 wks resolution
• If NOT – consider lymphoma
 After resolution – maintenance therapy for LIFE (lower dose PS/F) – in HIV can stop when CD4 count > 200 and viral load down
 Donor+/Recipient- - ALL should receive SEPTRA prophylaxis for life
 S/E – PS – folate antagonists that causes myelosuppression
 Clindamycin as alternative to sulfadiazine in sulfa alergic




Cerebral Malaria
o WHO Criteria for cerebral malaria: P. falciparum in a blood film in a patient with unarousable coma with other causes of encephalopathy excluded. May be only impaired consciousness and hyperparasitemia (>4%)
• Vector – bite of female Anopheles mosquito
• Epidemiology:
o P. falciparum only type to produce severe forms of malaria (including cerebral malaria)
o Present in Tropical Africa, Papua New Guinea, Haiti, East Asia
o P. vivax in South America and Indian Subcontinent – NO cerebral malaria
o MOST common fatal infectious disease – 1-2 million / yr (95% falciparum)
• At risk
o young children and pregnant women in highly endemic regions (subtropical africa)
o travelers to these regions (who are not immune)
o SS trait, thalasemia, G6PD deficiency confer partial protection against severe malaria
• Clinical:
o 10-16d incubation (range 9d to 3mon)
o 1st - Non-specific flu-like (fevers, malaise, chills, N/V etc)
o 2nd – high grade fever (104-5), shaking chills and rigors begin next (periodicity q3d)
o Cerebral malaria (mortality 20-50%; prognostic – LOC, presence of complications):
 Seizures common – 70% children, 20% adults
 Acute onset delirium and reduced LOC, coma
 Focal signs – any including oculomotor
 Papilledema is RARE;
 CSF is NORMAL usually (except increased ICP)
 Endemic area – febrile encephalopathy with normal CSF = malaria
o Systemic Effects
 Severe haemolytic anemia
 Hemoglobinuria with acute renal failure (Black Water fever)
 ARDs
 DIC
 Sepsis, SIRS, Acidosis, Hypoglycemia (also complication of Quinine)
o CSF is usually NORMAL with elevated OP and lactate as only abnormalities
• Pathogenesis of impairment of consciousness:
o Impaired microcirculation and sequestration of RBCs in the cerebral circulation due to
 1) upregulated adhesion molecules,
 2) knob like protrusions from parasitized erythrocytes make them sticky,
 3) platelet accumulation
 4) cytokines induce endothelial tight junction loosening and extravasation of plasma, edema. May see petechial hemorrhages
o Local synthesis of Nitric Oxide increased and inhibits neurotransmission
o Impaired blood-brain barrier leads to cerebral edema
o Systemic dysfunction (SIRS, renal failure, pulmonary edema, electrolytes, etc…)
• Pathology:
o Brain edematous
o Multiple petechial hemorrhages in white matter
o Small vessels engorged with parasitized erythrocytes
o Perivascular hemorrhages
o Durck granuloma – collection of monocytes surrounding hemorrhages
•


Diagnosis –
o Thin and Thick blood film to note parasitemia – may be negative due to sequestration in cerebal vessels or prior use of antimalarial drugs – REPEAT 3x before r/o malaria
o CSF may be NORMAL (or pleocytosis and elevated protein)
o Imaging – may be NORMAL or infarcts and hemorrhages; edema
• Tx:
o Quinine 10mg/kg IV over 2-8hrs daily x 7 days (Max 1800mg/d)
 S/E – Cinchonism (tinnitus, hearing loss, N/V); hypoglycaemia, prolonged QT risk or arrythmias
o Alternatives – Quinidine, Artemether, Artesunate, Mefloquine
o PS/F added as adjuvant to quinine therapy
o Treat complications:
 Hypoglycemia – common, multifactorial – bad prognosis – D50W
 Raised ICP – intracranial pressure transducer
 Anemia – often severe – transfusion
 Systemic – manage as they appear – ICU management



African Trypanosomiasis (Sleeping Sickness) – 3rd most important parasitic disease in world
• Epidemiology
o Equatorial Africa only
o Especially around rivers, water collection points, forests, near lakes
o End of dry season is worst time
• Bug
o T. brucei gambiense – evolves as chronic course – western Africa
o T. brucei rhodesiense – evolves as more acute course – eastern Africa
• Vector – Tse Tse fly (Glossina palpalis) – infects with each bite
• Clinical:
o Acute (Hemolymphatic Stage)
 Incubation < 3wks (1-2wks if rhodesiense)
 chancre at inoculation site
 Fever, rigors, N/V, diarrhea
o Meningoencephalitic Stage (CNS invasion by trypanosomes)
 Occurs months to years (gambiense) or wks to months (rhodesiense) later
 Death after months to years (gambiense) or 6-9 months (rhodesiense) untreated
 Symptoms:
• Headache
• Diurnal somnolence
• Nocturnal Insomina
• Movement disorder (tremor, ataxia)
• Weakness
• Neuropsychiatric changes and dementia
• FATAL in 100% untreated patients
• Diagnosis:
o Acute & Chronic –
 Thin and thick blood smears show trypanosome commonly in rhodesiense but uncommon in gambiense
 Serology if blood film is negative
 IF tryposomiasis is diagnosed by above two methods then
• Treat patient ASAP
• Stage patient with CSF analysis. CNS disease present if:
o Elevated WBC
o Trypanosoma identified
 CNS Disease requires different (and dangerous) treatment
• Treatment
o CNS Disease – Melarsoprol – is arsenic compound and can causes usual problems:
 Polyneuropathy & severe hemorrhagic leukoencephalopathy in 10%



Trypanosomal Chancre

American Trypanosomiasis (Chagas Disease)
• Epidemiology
o Americas only (South America to southern USA)
o 90 million prevalence – mainly lower socioeconomic classes exposed to vector
• Bug – Trypanosoma cruzi
• Vector – Reduviid bugs that mite other animals (e.g. Ridninus Prolixus)
• Pathophysiology
o Bug takes blood meal and poops out T.cruzi which enters the host through mucosal membranes (conjunctiva, nasal or oral mucosa) or broken skin (intact skin resistant)
• Clinical:
o Acute (children mainly > 1wk)
 Non-specific febrile illness with lymphadenopath
 Specific – Romana’s sign = conjunctivitis +periorbital edema (child in endemic area)
 Portal of entry shows chancre in 25% of cases
 Severe acute – myocarditis, meningoencephalitis – 10% fatal
o Chronic Chagas (30% of infected)
 Dilated Cardiomyopathy
• Cardiac arrhythmia & syncopal attacks
• CNS and systemic embolization from mural thrombi
 Autonomic destruction involving heart and GI tract:
• Hypotension, arrhythmia
• Megacolon, achalasia
• Diagnosis – typical course is diagnostic
o Acute disease – 90% find trypanosome in thick or thin blood smear
o Chronic disease – serology (many false positive)
• Treatment – Acute and Chronic – nifurtimox/ benzondazole

Helminthic Infections

• Classification of Helminths
o Flatworms
 Cestodes (tapeworms)
 Trematodes (flukes)
o Roundworms (nematodes)

Cysticercosis
• Epidemiology
o Ubiquitous pork tapeworm (Taenia solium)
o Endemic in Latin America, sub-Saharan Africa, India, Indonesia, China
o MOST common cause of epilepsy in developing countries
• The bug – Taenia solium
• How you get it:
o Ingestion of food contaminated with T. solium eggs (note – you cannot get cysticercosis by eating infected pork meat which does NOT contain ova – you get t. solium tape worm only – you must ingest the OVA to get invasion disease) BUT once you have the tapeworm – it produces eggs which you poop:
o Fecal-oral route – eat your own infected feces (auto-infection) – major route of inoculation
• Pathology
o Lodge in subcutaneous tissues, skeletal muscle, CNS and the eye
o Predilection for these sites (esp eye and brain) due to immunologically protected sites
o Types:
 Intraparenchymal cysts – vesicular stage (alive) lasts for years then bug dies and ultimately calcifies
 Extraparencymal neurocysticercosis – basal subarachnoid, ventricular, sylvian
 Spinal cord, eye, intracellar
• Clinical:
o Can produce almost any form of neurological presentations. Most common:
o Seizures (70%)– develop years after primary infection
o Raised ICP – usually due to hydrocephalus from arachnoiditis, ventricular cysts, giant cysts
o Focal signs – usually chronic progressive (acute if due to stroke)
o Cysticercotic encephalitis – rare; due to increased host immune response
o Dementia – secondary to raised ICP, etc…
• Diagnosis
o Imaging – see below
o Serologic tests – EITB has 100% specificity and 98% sensitivity in Blood samples
o Response to trial of Abx
o Direct visualization in fundus
o Biopsy proven surgical specimen
• Treatment
o Treatment is tailored to type of neurocysticercosis – see table for complex directions







Echinococcosis (Hydatidosis Disease)
• Epidemiology:
o Countries bordering Mediterranean Sea and Australia, Middle East
• The bug – larval forms of the canine tapeworm Echinococcus spp.
• Pathophysiology
o Humans (intermediate hosts) ingesting eggs in food and water contaminated by dog feces
o Eggs transform into cysts in various body organs (liver, lungs, heart, kidneys, CNS)
o CNS disease in only 5% - large fluid filled cysts that have little or no surrounding edema
o Sites: parenchyma, subarachnoid, ventricular, spinal cord, epidural (i.e. anywhere)
• Clinical
o Seizures
o Rasied ICP
o Focal deficits – depends on location
o Myelopathy
o Proptosis and ophthalmoplegia if ocular or orbital
• Diagnosis – Imaging pretty darn obvious (DDx – cystic neoplasm, neurocysticercosis, TB, toxo)
• Treatement –
o surgical removal – Don’t to rupture cyst wall – allergic reaction & recurrent hydatid dx
o Albendazole – used perioperatively generally as prophylaxis for recurrent disease

Schistosomiasis
• Epidemiology:
o Arab peninsula, Africa, Southeast Asia, South America, Caribbean
• The bug – flukes of the genus Schistosoma
• Pathophysiology
o Two hosts – Fresh water snails where the infectious type of schistoma is generated and released into the fresh water source where they come in contact with humans
o Humans – the schistosoma can penetrate skin quickly, enter the bloodstream and deposit themselves in – LIVER, bladder, CNS (especially spinal cord vessels)
o Induce an intense inflammatory reaction leading to CNS injury
• Clinical:
o Acute meningoencephalitis – fever, stiff neck, seizures, decreased LOC
o Acute transverse myelitis associated with granulomatous masses in the conus and cauda
• Diagnosis:
o CSF – lymphocytic pleocytosis, elevated protein, normal glucose
o Brain lesions enhance, usually multiple; enlarged, enhancing spinal cord lesions
o Positive ELISA for schistosomal antibodies in CSF (sensitive but NOT specific)

Rickettsial Infections

Rocky Mountain Spotted Fever
• Triad: Rash, fever, and history of tick bite
• Rickettsia Rickettsii transmitted from American dog or Rocky Mountain Wood Tick in southeastern and southcentral states in April to September (North Carolina and Oklahoma most cases)
• Clinical
o Incubation is 5-10 days, children at greatest risk
o Over 90% of patients are infected during April through September
o Onset non-specific with severe headache, fever, malaise, N/V, myalgias
o Later adbo pain, joint pain and diarrhea
o Rash is characteristic, occurs days after onset of fever, on wrists and ankles then spreads, initially maculopapular, then petechial (absent in 10-15%)
o Encephalitis – Delirium, seizures, coma, hyperreflexia
• Diagnosis – Hx most important, acute and convalescent sera, PCR available
• Treatment – Doxycycline 100mg q12hr – very effective



Infections in Organ Transplant Recipients
• Infections due to:
o Complication of transplant itself (nosocomial infections)
o Reactivation on CNS virus or parasite
o Dissemination of fungus in immunocompromised state (from lung usually)
o Acquired infection (virus, parasite) from donor
• Immediately Post-op
o Solid Organ – not yet immunosupressed
 Typical CNS infections secondary to hematogenous spread of common nososomial infections (gram neg and staph meningitis, abscesses, etc)
o Bone Marrow Transplant– immunosuppressed at time of surgery (to ablate bone marrow)
 Viral encephalitis presenting in typical fashion
 HSV-1, HHV-6 (common), EBV, VZV, CMV (very suppressed)
• 2 to 6 months Post-Tx
o Candida fungemia with dissemination to CNS – commonest in Liver Tx patients
o Aspergillus species – Aspergilloma; most common intrancerebral mass lesion, from lung, skin, ear, or operative wound (other causes of mass lesion include Crypto, Nocardia abscess, Toxo, Blasto, mucormycosis)
o Cryptococcus – second commonest invasive fungus – meningitis
o Mucormycosis – contiguous spread from sinuses intracranially
o Toxoplasmosis – multiple intracerebral lesions
o Viral encephalidities, CMV encephalitis, ventriculitis, myelitis, polyradiculitis
• >6 months Post-Tx
o Meningitis – Cryptococcus, Histoplasmosis, Coccidiosis
o Listeria encephalitis – was common until TMP-SPX Rx as prophyaxis for P. carinii
o PML
o EBV-related CNS lymphoma
• Most common and Labs:
o Cryptococcus – crypo antigen in CSF, fungal culture and stain (India ink)
o Toxoplasmosis – Imaging and response to treatment (CSF studies not sensitive)
o Histoplasmosis – CT Chest, Histo Ag in CSF and Urine, Fungal cultures
o Blastomyocosis – CSF culture (insensitive), biopsy, India Ink
o Coccidiosis – CSF eosinophilia (70%), fungal culture +25%, CSF Ag in CSF

Tetanus
• Germination of C. tetani spores in anaerobic environment of necrotic tissue
• Release of tetanus toxoid locally and hematogenously
• Endocytosed at the terminal Endplates of motor neurons, carried via retrograde transport to spinal cord.
• Moves transynaptically to dendrites of inhibitory interneurons, to presynaptic terminals
• Cleaves VAMP, a secretory machinery protein, to block neurotransmission
• Leads to classic clinical phenotype:
o 7-10 days after deep penetrating wound in unimmunised patient
o Trismus (LockJaw) – difficult opening mouth, neck stiffness and sore throat early
o Facial muscle spasms = risus sardonicus
o More generalized muscular spasms developed, become stimulus sensitive, painful
o Laryngeal and respiratory involvement may lead to resp compromise
o Axial involvement leads to opisthotonus
o Autonomic Instability – severe labile BP, pyrexia, sweating, gastric stasis and diarrhea
o Spasms and Autonomic peak at 2 weeks and subside by 1 month, rigidity lasts longer
• Dx – Hx and P/E, Tetanus cultured from wound
• Rx – 1st: Metronidazole 7-10d, 2nd: Doxy, Clinda; NOT Penicillin since it acts as GABA antagonist