Powerpoint on HIV associated CNS infections. Ref Lancet Neurology

1. HIV-associated opportunistic infections of the CNS

2. Introduction
 About 7000 new HIV infections occur daily, 95% of which are in low-
income and middle-income countries, where only about a third of patients
who require antiretroviral drugs have access to them.
 In high-income countries, the combination antiretroviral therapy
(cART)since 1996 reduced the incidence of neurological opportunistic
infections, from 13.1 per 1000 patient-years in 1996–97 to 1.0 per 1000 in
2006–07
 The annual incidence of new infections has declined by 19% since the peak
of the worldwide HIV epidemic in 1999,
 In 2009 about 2.6 million individuals were newly infected.

3. CNS opportunistic infections in HIV
Many of the opportunistic infections that affect the CNS are
AIDS defining conditions.
o Progressive multifocal leukoencephalopathy (PML)
o CNS cytomegalovirus infection
o CNS tuberculosis.
o Cryptococcal meningitis.
o Cerebral toxoplasmosis, including toxoplasmic encephalitis.
Associated with high associated mortality.

4. AIDS
HIV infection is characterized by three stages:
o acute primary infection,
o an asymptomatic (latent) stage, and
o symptomatic chronic illness.
Disease progression is highly variable: from 6 months
after seroconversion to more than 20–30 years,
Mean survival after AIDS develops is 1.3 –3.7 years
Most CNS opportunistic infections result from
reactivation of latent pathogens which occur when
there is depletion of the CD4-cell count

5. General Principles of Diagnosis and Management
CNS opportunistic infections typically occur when the CD4-cell
count is less than 200 cells per μL
Diagnosis should be based on clinical presentation, temporal
evolution, CSF, and radiographic features
Multiple infections are present in 15% of cases and some
infections might be revealed only after combination
antiretroviral therapy is started
Combination antiretroviral therapy should be started, modified,
or continued with appropriate antimicrobial therapy
Antimicrobial treatment is generally required until immune
recovery (CD4-cell count more than 200 cells per μL) is achieved
with antiretroviral therapy

6. Clinical presentation
Infections such as toxoplasmic encephalitis and cryptococcal
meningitis evolve over hours.
PML and CNS lymphoma have a more indolent course often
taking weeks to months
Most often non-specific symptoms, such as fever and lethargy
The combination of new pattern of headache or headache
lasting longer than 3 days, new-onset seizures, or altered
mental function strongly suggest an acute focal brain lesion

8. Diagnostic work-up

9. CSF characteristics of HIV-associated CNS
opportunistic infections

10. CSF – Special tests

11. Tuberculous meningitis and brain
abscesses
Detection of acid-fast bacilli or the causative organism
by positive culture or PCR is often difficult
Sensitivities for these tests have been poor at about
50%, but pts with HIV have higher yield rates of up to
80% possibly owing to incomplete immune responses
and increased bacterial loads.
Repeated, large-volume lumbar punctures might
improve the yield

12. Treatment of Tb
Treatment for tuberculosis does not differ
significantly between patients with and without HIV
infection
Isoniazid, pyrazinamide, ethambutol, and rifampicin
for 2 months.
Rifabutin is an alternative for rifampicin which lowers
levels of protease inhibitors.
After this initial phase, isoniazid and rifampicin or
rifabutin are continued for at least 9–12 months.

13. Treatment of Tb
The role of corticosteroids and the optimum timing of
the initiation of cART in conjunction with
antituberculosis therapy remain controversial issues
Delayed initiation of cART is recommended for
patients with HIV-associated tuberculous meningitis.
Mortality from HIV-associated tuberculous meningitis
is more than 50%, no improvement with addition of
cART.
Mortality is extremely high in multidrug-resistant
tuberculosis and extensively drug-resistant disease

14. Toxoplasmic encephalitis
Toxoplasmic encephalitis is the most commonly reported
neurological opportunistic infection.
The incidence is declining.
In HIV patients toxoplasma serology may be negative.
Definitive diagnosis of CNS toxoplasmosis requires the following
1. Compatible clinical findings
2. Identification of one or more mass lesions by CT, MRI, or other
radiographic testing
3. Detection of T gondii in a clinical sample (CSF) by PCR

15. Toxoplasmic encephalitis - diagnosis
Lumbar puncture may be usually contraindicated.
So empiric treatment is usually initiated.
Primary CNS lymphoma is often the principal differential
diagnosis.
o MRI, 18-fluorodeoxyglucose PET, or thallium-201 SPECT
Brain biopsy could be necessary if equivocal or worsened
response to empirical treatment.
(The presence of Epstein-Barr virus DNA in the CSF favors the
diagnosis of lymphoma. )

16. Toxoplasmic encephalitis - treatment
Combined pyrimethamine, folinic acid, and sulfadiazine
has traditionally been used, although trimethoprim-
sulfamethoxazole equally effective.
91% respond within 14 days
Failure to improve within 10–14 days of starting treatment
should, therefore, prompt reassessment of the diagnosis,
with either thallium SPECT or brain biopsy
Corticosteroids are indicated only if substantial mass effect
is present and should be discontinued as soon as possible

17. Toxoplasmic encephalitis - treatment
Induction treatment should be continued for at least 6
weeks till radiographic improvement is recorded
Maintenance therapy should be continued in all patients
until immune reconstitution is achieved (persistent CD4-
cell count of more than 200 cells per μL
Mortality for toxoplasmic encephalitis remains high at 20–
60% within 1 year of diagnosis

18. Cryptococcal meningitis
Cryptococcal meningitis is thought to be the result of
reactivation of latent infection in the immunocompromised
The CSF opening pressure is typically raised during LP
The CSF profile can be normal in about 30% of patients
Microscopic detection with India ink staining and fungal culture
of the CSF
Immunoassays of cryptococcal antigens are rapid, sensitive, and
specific
Urinary antigen detection has high sensitivity (Resource poor)

19.  High propensity to cause communicating hydrocephalus with
increased intracranial pressure (15%)
 Guidelines recommend serial daily lumbar punctures if the
opening pressure is persistently greater than 25 cm H2O
 Recommended treatment is intravenous amphotericin B in
combination with oral flucytosine for a minimum of 2 weeks,
followed by oral fluconazole for at least 8 weeks.
 Prophylaxis with fluconazole is required until a durable immune
reconstitution with a CD4-cell count higher than 200 cells per μL is
achieved.
Cryptococcal meningitis
-treatment

20. Cryptococcal meningitis
-treatment
Recommended treatment is intravenous amphotericin B in
combination with oral flucytosine for a minimum of 2 weeks,
followed by oral fluconazole for at least 8 weeks.
Prophylaxis with fluconazole is required until immune
reconstitution with a CD4-cell count higher than 200 cells per μL
is achieved.
IRIS affects 10–40% of patients with cryptococcal meningitis and
has mortality 33–66%.
Appropriate management of IRIS includes continuation of cART,
antifungal therapy, and a course of corticosteroids.

21. Cytomegalovirus encephalitis
 Cytomegalovirus usually causes asymptomatic or clinically
benign infections and most people have been infected by the
time they reach adulthood
 In HIV, neurological diseases caused by cytomegalovirus are
rare but very serious.
 Encephalitis, retinitis, radiculomyelitis, or mononeuritis multiplex.
 MRI : meningeal enhancement or periventricular inflammation -
but not specific
 CSF neutrophil predominant pleocytosis
 PCR of CSF is highly sensitive and specific

22.  A combination of ganciclovir and foscarnet was generally used
before the introduction of cART but has severe side effects.
 The use of cART plus one anticytomegalovirus (usually
Ganciclovir) is favoured
 Foscarnet is used when patients develop leucopenia while
taking ganciclovir or in ganciclovir-resistant cases
 Secondary prophylaxis with long-term oral anticytomegalovirus
therapy should be continued till sustained immune recovery is
achieved with cART
Cytomegalovirus encephalitis - treatment

23. Progressive multifocal leukoencephalopathy
 The incidence of PML has declined with cART (7/1000 patient-
years to 0.7/1000)
 In the brain, JC virus infects mainly oligodendrocytes and
astrocytes, and, occasionally, cerebellar granular cells and
cortical pyramidal neurons
 PML typically causes multifocal demyelinating lesions
 JC-virus granule cell neuronopathy with cerebellar ataxia, JC-
virus encephalopathy, and JC-virus meningitis

24. PML - diagnosis
 MRI T2 & Flair hyperintense, T1 well demarcated hypo intense lesions.
The cortical ribbon is classically spared. Minimal tissue oedema or no
contrast enhancement is usual unless PML is complicated by IRIS
 Rarely, the only radiological finding is severe cerebellar atrophy
 Definitive diagnosis of PML is established by the detection of JC virus in
CSF by PCR
 Sensitivity varies across laboratories, but specificity is high
 Brain biopsy might occasionally be required to confirm the diagnosis.

25. PML - treatment
The mainstay of treatment for PML in patients
infected with HIV is immune reconstitution with cART
This improved survival from 10% before the
introduction of cART to 50–75%
No antiviral therapy with proven efficacy is available.
IRIS – treated with steroids

26. Herpes simplex virus encephalitis
 Infrequent cause of CNS opportunistic infections
 Herpes simplex virus type 1 typically causes encephalopathy
that might develop subacutely over several weeks
 Herpes simplex virus type 2 typically causes a diffuse
meningoencephalitis that can recur.
 PCR of the CSF is highly sensitive (100%) and specific (99.6%)
for herpes simplex virus DNA

27. HSV Encephalitis -management
 T2-hyperintensities in most cases and sometimes gadoliniumenhancing
lesions involving the inferomedial temporal
 Lesions may also involve the brainstem, cerebellum, diencephalon, and
periventricular zones
 The treatment of choice is 30 mg/kg aciclovir daily, given intravenously
for 14–21 days (Resistance reported)
 Progression can occur despite treatment, especially if CD4-cell counts
are low
 Ganciclovir and foscarnet have also been used with some success
 Rare relapses within 3 months of treatment
 Clinical trial of 90 days of valaciclovir after induction treatment – results
awaited.

28. ConclusionsConclusions
 Though CNS opportunistic infections in HIV pts are decreasing with cART,
still concern in those with delayed diagnosis or HIV treatment is inadequate.
 PML, primary CNS lymphoma, and multidrug-resistant tuberculosis have no
effective treatment and mortality still remain high.
 Early daignosis of HIV and access to cART remain most important for
prevention.
 Concurrent infection with more than one CNS opportunistic infection is
important. (Also possibility neurosyphilis, varicella zoster, cerebral malaria,
Chagas disease, and neurocysticercosis).
 Knowledge acquired is useful in the context of immunosuppression for
transplanted and in the testing of new immunomodulatory drugs for
autoimmune diseases.

29. thank
you

31. (A) Cryptococcal meningitis in a man aged 58 years who presented
with headache, weight loss, anorexia, and a generalised seizure,
with a CD4-cell count of 10 cells per μL. The arrow shows
gadolinium enhancement of the posterior meninges on T1-
weighted MRI. A cryptococcoma is present in the right basal
ganglion

32. (B) Cerebral toxoplasmosis in a man aged 39 years who presented with
generalised seizure and nadir in CD4-cell count of 2 cells per μL. Diagnosis was
confi rmed by brain biopsy. Multiple hyperintense lesions with surrounding
oedema (arrow), appearing as a hypointense rim, with mass eff ect can be seen
on T2-weighted, fl uid-attenuated inversion recovery MRI.

33. (C) Primary CNS lymphoma in a man aged 21 years who presented with acute-onset
left-sided weakness and a CD4-cell count of 0 cells per μL. Diagnosis was confi rmed
by brain biopsy. A rim-enhancing lesion (arrow) is visible in the right temporoparietal
lobe on gadolinium-enhanced MRI.

34. (D) Progressive multifocal leukoencephalopathy in a man aged 42 years who
presented with lethargy, left hemiparesis, dysphagia, seizures, and visual
hallucinations. T2-weighted, fl uid-attenuated inversion recovery MRI shows
asymmetric, confluent hyperintensities involving the cerebral white matter (arrow)
without mass effect.