Neuro OI Flashcards
Differentials for SOL on imaging
Toxoplasmosis, primary CNS lymphoma, TB, cryptococcus, non-Hodgkin lymphoma, syphillitis gummae
Possible causes of encephalitis
HIV, VZV, HSV, syphilis
Causes of meningitis
HIV seroconversion, cryptococcus, TB, syphilis, bacterial (eg strep pneumoniae)
Different causes of spastic paraparesis
HIV-vacuolar myelopathy, transverse myelitis from VZV, HSV, HTLV-1, toxoplasmosis, syphilis
Causes of polyradiculitis
CMV, NHL
What organism is most commonly associated with HIV related cryptococcal disease in the UK?
Cryptococcus neoformans var grubii (serotype A)
2nd most is cryptococcus neoformans bar neoformans (serotype D)
Where is c. neoformans var neoformans found?
Bird (primarily pigeon) droppings
(Non avian sources are also found)
Where is c. Neoformans var gatii found?
Eucalyptus trees
Therefore infections mainly in tropical and subtropical regions
What does cryptococcal skin disease look like?
Molluscum
Pathway of cryptococcus through the body
Inhaled into lungs.
May then cause localised disease.
Spreads to blood and diseminates.
Prostate can be a sanctuary site.
Symptoms of cryptococcal meningitis
Headache, fever
Meningism variable
Raised ICP may cause nausea, vomitting, confusion, coma
What might you see on CXR in pulmonary cryptococcal disease
Variable but include -
Widespread infiltration, nodular disease, isolated abscess formation, pleural effision
Rarer presentations of cryptococcal disease
Ocular palsy, papilloedema, chorioretinitis, osteolytic bone lesions
How to diagnose cryptococcal disease
Serum CrAg - generally if negative this excludes disseminated disease
If CrAg positive needs LP with manometry (after CT/MRI)
Fungal culture
Possible causes of false positive serum CrAg
Rheumatoid factor, heterophile antibodies
What should CSF be sent for if suspecting cryptococcal disease?
CrAg
Microscopy - India ink stain
Culture
What would you expect to see on India ink stain?
Clear around the wall of the yeast as the carbon grains cannot penetrate the capsule
(Cryptococcus)
What role do fungal sensitivities play in tx of cryptococcal disease?
ONLY if not responding to treatment can be used to guide a switch
Factors indicating poor prognosis in cryptococcal disease
Blood culture positive
Low white cells in CSF
High CSF CrAg
Confusion
Raised ICP
What is the induction treatment for neuro cryptococcal disease?
Liposomal Amphotericin B (ambisome) 4mg/kg/day IV (preferred)
Plus flucytosine 100mg/kg/day
Historically amphotericin B deoxycholate 0.7-1mg/kg/day used
Role of flucytosine in cryptococcal meningitis treatment
Speeds rate of sterilisation of CSF
Reduces incidence of relapse in patients not on HAART
Associated with enhanced toxicity in some studies, no impact on mortality
Why do we use ambisome rather than standard amphotericin B?
At least equivalent efficacy
Less nephrotoxicity
What would be an alternative therapy for cryptococcal meningitis if ambisome not tolerated?
Fluconazole 400mg/day +/- flucytosine
May be used as first line if good prognostic factors as easier to administer
Treatment of refractory cryptococcal meningitis
If all normal meds not tolerated can try newer Azoles voriconazole and posaconazole - expensive.
Management of raised ICP in cryptococcal meningitis
If opening pressure >25 reduce to below 20 or to 50% initial pressure
Repeat daily until stable
If resistant may require shunt
What is the maintenance therapy for cryptococcal meningitis?
Oral fluconazole 400mg OD 10/52 started after 2 weeks if patient is well
After 10 weeks drop to 200mg OD
Alternative weekly ambisome (fluconazole superior and less toxicity)
When would you not want to switch to maintenance therapy for cryptococcal meningitis at 2 weeks?
If poor prognostic factors and poor response to treatment repeat LP and consider prolonging induction therapy
How does LP impact options of tx for cryptococcal meningitis??
Historically would wait until CSF sterile to move to maintenance therapy
Not all doctors do this - if HAART is going to be started after 2 weeks risk of relapse and mortality likely to be less than seen in older studies
Treatment for isolated pulmonary cryptococcal disease
LP TO CHECK FOR OCCULT CNS DISEASE
If this is negative - treat pulmonary disease with fluconazole if moderate symptoms
If severe treat with ambisome until symptoms are controlled
Follow with prophylaxis
Do we give primary prophylaxis for cryptococcal disease?
No.
No effect on survival, risk of resistance, high cost
When to start ARVs in cryptococcal meningitis?
After 2 weeks
Why is ARV delayed for 2 weeks if being treated for cryptococcal meningitis?
Risk of IRIS
When can secondary prophylaxis for cryptococcal meningitis be stopped?
Once CD4 >100 in presence of undetectable VL for at least 3 months
What is the most common cause of mass lesions in immunocompromised HIV+ individuals?
Toxoplasma abscesses
How is toxoplasma infection acquired?
From cats
Either eating animals with disseminated infection or injection of oocytes from cat faeces contaminating soil, fruit, veg, water.
What is the lifetime risk of an untreated HIV+ person with toxo IgG positive developing toxoplasma encephalitis?
25%
Is toxoplasma infection in immunodeficiency patient usually due to primary infection or reactivation?
Reactivation
What is the clinical presentation of toxoplasmosis cerebral abscess?
Develops over days to weeks
Focal neurological signs, symptoms, sometimes seizures
If raised ICP - headaches and vomitting
Hemiparesis, visual field deficits, dysphasia, cerebellar syndrome and movement disorders - abscesses have predilection for basal ganglia
How might toxoplasmosis present outside the nervous system?
Chorioretinitis
Pneumonia
Differential diagnosis of toxoplasma abscesses
PCNSL, tuberculous abscesses, PML
What imaging would you request for ?toxoplasma abscesses?
MRI preferable to CT
SPECT may be helpful to exclude PCNSL
What are typical MRI findings with toxoplasmosis?
Multiple ring enhancing lesions at grey-white matter interface and in deep grey matter of basal ganglia or thalamus with cerebral oedema and mass effect
How might a low CD4 count impact MRI appearance of toxoplasma abscesses?
Absence of ring enhancement
Should you do an LP if you suspect toxoplasma abscesses?
May be helpful if diagnostic uncertainty but often contraindicated due to raised ICP.
CSF toxo PCR sensitivity 50% specificity >94%
When should a brain biopsy be performed in someone being treated for toxoplasmosis?
Lack of response after 2 weeks of treatment, clinical deterioration or atypical features
What is the sensitivity and specificity of PCR for toxo on CSF?
Sensitivity 50%
Specificity >94%
What is the first line treatment of toxoplasma encephalitis?
Loading dose 200mg pyrimethimine followed by 50mg/day (<60kg) to 75mg/day (>60kg)
Plus folinic acid 15mg/day
Plus either sulphadiazine 1-2g QDS or 15mg/kg QDS or clindamycin 600mg qds
For 6 weeks
Why is folinic acid given in treatment of toxo encephalitis?
Counteracts myelosupressive effect of pyrimethamine
What route should sulphadiazine be given in tx of toxo encephalitis?
Not available IV in UK.
Good oral bioavailability so give orally or via NG if unconscious.
If IV a necessity use clindamycin instead.
What is the likely cause of a rash while on treatment for toxoplasma encephalitis?
Generalised maculopapular rash most likely to be caused by sulphadiazine or clindamycin component.
Stop and switch to the other is possible.
Sulpha desensitisation possible but slow.
In the treatment of toxoplasma encephalitis why is sulphadiazine preferred over clindamycin?
Study showing less response to clindamycin in acute phase and two fold risk of progression in maintenance phase in clindamycin group
What is the maintenance therapy for toxoplasma encephalitis?
Same drugs lower doses
Pyremethimine 25mg/day
Sulphadiazine 500mg qds or 1-2g BD
Folinic acid 15mg/day
How should you treat toxoplasma encephalitis if recommended regime not tolerated?
P and FA plus atovaquone 1500mgBD
Sulphadiazine plus atovaquone 1500mg bd
P and FA plus either azithro/Clari/doxy/dapsone AND trimethoprim and sulphamethoxazole
Who should have primary prophylaxis for toxoplasma encephalitis?
Hiv patients with CD4 < 200 and positive toxoplasma serology
What is the primary prophylaxis for toxoplasma encephalitis?
Septrin 480-960mg/day
Dapsone 50mg/day and pyrimethamine 50mg/week reserved for those allergic to septrin
When should you start ARVs in patient being treated for toxoplasma encephalitis?
As soon as clinically stable - approx 2 weeks - to lessen likelihood of IRIS
When can primary prophylaxis for toxoplasma encephalitis be stopped?
VL suppressed and CD4 >200 for 3/12
When should toxoplasma encephalitis maintainable therapy be stopped?
After 6 months of successful VL suppression and cd4 >200
How does the JC virus affect people?
JC virus
Asymptomatic seroconversion in childhood
Disseminates and sets up reservoirs in spleen, kidneys, bone marrow, b lymphocytes
Replicates in immunosuppression and b lymphocytes transport to brain and infect oligodendrocytes via serotonin receptor
Classic symptoms of PML
Subacute illness without constitutional symptoms
Focal neurology
Mainly motor deficit
Altered mental/mood status
Ataxia
Cortical visual symptoms
Over weeks to months
How can PML be distinguished from HIV encephalopathy?
Presence of focal neurology
What are typical MRI findings for PML?
Lesions - Bilateral, asymmetric, non enhancing t2 hyperintense t1 hypointense, restricted to white matter, no oedema
How to diagnose PML?
MRI
CSF for JC virus
Sufficient in most cases so avoid need for brain biopsy (gold standard)
What is affect of ART on CSF JC DNA testing?
Reduced viral replication and increased clearance - reduces sensitivity of test to 50% from 72-90%
What are poor prognostic factors in PML?
Clinical - older age, brainstem involved, decreased GCS
Viral - high CSF JC VL with delayed clearance
Radiological - early brainstem involvement
Immunological - cd4<100
Improved prognostic factors in PML?
Higher CD4 counts, contrast enhancement on in imagine, perivascular mononuclear infiltrated, JC specific cytotoxic t lymphocytes
Treatment for PML
ARVs only therapeutic option
One study showed better outcome with drugs based on higher CNS penetration score
Prognosis in PML
50% survival at one year if on ARVs
Some enter true remission of disease
Symptoms of CMV nervous system disease
Progressive disorientation, withdrawl, apathy, cranial nerve palsies
Insensitive and difficult to distinguish from aids dementia complex
Depression and mental slowing more evident in aids dementia complex
How does CMV lumbosacral polyradiculitis present?
Rapidly progressive, painful, bilateral ascending flaccid paralysis with saddle anaesthesia, areflexia, sphincter dysfunction
What percentage of those with CMV nervous system involvement have cerebellar or brainstem involvement?
30%
Diagnosis of neuro CMV
MRI and CSF CMV PCR
Radiological findings if CMV
Ct - diffuse white matter hypodensities with effacement, ventricular enlargement, meningeal enhancement, focal or nodular ring enhancing lesions
MRI far more sensitive for these features on GAD enhanced scan
Imaging lacks sensitivity
Treatment for neurological CMV disease?
No prospective controlled trials for this
Gancyclovir plus/minus foscarnet
ARVs critical
Prophylaxis against CMV encephalitis/polyradiculitis
Not required but ARVs likely to to decrease incidence of conditions
When can maintainence therapy for CMV encephalitis/polyradiculitis be stopped?
For reitinitis stop when sustained cd4>100 - evidence not there to do that in neuro cmv. Cautious approach based on clinical, CSF and blood cmv dna levels, imaging improvement
Treatment of cryptococcal infection during pregnancy?
Ambisome as per non pregnant
However flucytosine teratogenic so should be avoided in first trimester wherever possible and only used in rest of
Pregnancy if benefits outweigh risks
High Fluconazole doses should be avoided and switched for ambisome in early pregnancy - can be used in later stages of pregnancy as secondary prophylaxis
Treatment of toxoplasma in pregnancy?
Sulphadiazine and pyrimethamine - should be given with folinic acid
No clear evidence of teratogenicity in humans
If sulphadiazine is continues in 3rd trimester can cause neonatal haemolysis and methaemaglobinaemia
How is CMV treated in pregnancy?
Systemic therapy for systemic disease - all available agents associated with congenital anomalies in rats and rabbits - iv ganciclovir used most and considered first line
If foscarnet used due to potential for renal toxicity amniotic fluid needs monitoring for oligohydramnios
Isolated CMV retinitis should be treated with local Intravitreal therapy or implants
