HIV-associated opportunistic

infections of the CNS: the

neurosurgeon's vision
CLAUDIO ALEXANDER RIVAS PALACIOS
Postgraduate Student Third Year
Specialization in Neurosurgery
Faculty of Medicine
University of Cartagena
2021

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HIV-associated
opportunistic infections of
the CNS: overview

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 Magnitude of the problem

Incidence: 13.1 per

1000 patient-years in
1996–97

1. McArthur J.C, Tan I.L, et al. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012; 11: 605–17
2. Garvey L, et al. HIV-associated central nervous system diseases in the recent combination antiretroviral therapy era. Eur J Neurol 2011; 18: 527–34. 3
3. Nath A, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nature reviews, Neurology vol 12. 2016: 662-674
 Common CNS opportunistic
infections

1. McArthur J.C, Tan I.L, et al. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012; 11: 605–17
4. Lopera M.M, Lemos Y. Factores socioeconómicos y clínicos asociados con infecciones oportunistas en pacientes con HIV afiliados al sistema de salud. 4
Biomédica 2019;39:186-204
Opportunistic infections of the CNS
in pre-HAART and HAART era

5. Matinella A, et al. Neurological complications of HIV infection in pre-HAART and HAART era: a retrospective study. J Neurol (2015) 262:1317–1327 5
Level of immunosuppression and risk
of opportunistic infections

3. Nath A, Bowen L.N, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nature reviews, Neurology volu 12.
2016: 662-674 6
 Cellular tropism of organisms causing
opportunistic infections in the CNS

3. Nath A, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nature reviews, Neurology vol 12. 2016: 662-674 7
 Clinical characteristics

1. McArthur J.C, Tan I.L, et al. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012; 11: 605–17
3. Nath A, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nature reviews, Neurology vol 12. 2016: 662-674 8
 Cerebrospinal fluid characteristics

1. McArthur J.C, Tan I.L, et al. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012; 11: 605–17
3. Nath A, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nature reviews, Neurology vol 12. 2016: 662-674 9
 Radiographic characteristics

1. McArthur J.C, Tan I.L, et al. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012; 11: 605–17
3. Nath A, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nature reviews, Neurology vol 12. 2016: 662-674 10
 Immune reconstitution inflammatory
syndrome (IRIS)

1. McArthur J.C, Tan I.L, et al. HIV-associated opportunistic infections of the CNS. Lancet Neurol 2012; 11: 605–17
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3. Nath A, et al. HIV-associated opportunistic CNS infections: pathophysiology, diagnosis and treatment. Nature reviews, Neurology vol 12. 2016: 662-674
Tuberculous meningitis and
brain abscesses

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 Overview
• Mycobacterium tuberculosis
• Forms of CNS infection due to:
meningitis, tuberculoma and
• HIV infection: ↑ 5 fold in the
spinal arachnoiditis. likelihood of having CNS
involvement ⁶˒¹⁰
• 1-5% are complicated by CNS TB • CD4 count <100 cells/microL
⁶⁻⁸ • Related to IRIS ¹²
• Regions where the prevalence of • Pathogenesis  subarachnoid
TB is high: all three forms ⁶⁻⁸ rupture of cortical Rich foci ¹¹
• In regions where the prevalence
of TB is low: meningitis ⁹
9. United States CDC. Reported Tuberculosis in the United States, 2018.
6. Leonard JM, et al. Microbiol Spectr 2017; 5. 10. Rajasingham R, Rhein J, et al. Am J Trop Med Hyg 2015; 92:274.
7. WHO 2019 consolidated guidelines on drug-resistant tuberculosis treatment. 11. Rich AR, McCordock HA. Johns Hopkins Hosp 1933;52:5 13
8. Donovan J, Thwaites GE, Huynh J. Curr Opin Infect Dis2020; 33:259. 12. Pepper D.J, et al. Clin Infect Dis. 2009 Jun 1;48(11):e96-107
 Pathogenesis

11. Rich AR, McCordock HA. Johns Hopkins Hosp 1933;52:5

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12. Be N, Kim K, et al. Curr Mol Med. 2009 March ; 9(2): 94–99.
 Disease forms
Tuberculous meningitis
• Progress through three phase ¹³˒¹⁴:
• Early prodromal
• Meningitic
• Paralytic
• Typical presentation: subacude
meningeal sings + fever
• Neurologic symptoms: altered
consciousness, personality changes and
coma; involving cranial nerve II and VI
• Hydrocephalus, vision loss
13. Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979; 241:264. 1. McArthur J.C, Tan I.L, et al. Lancet Neurol 2012; 11: 605–17
14. Farinha NJ, Razali KA, Holzel H, et al. J Infect 2000;41:61.
Tuberculoma
• Conglomerate granulomatous
focus
• Evident mass lesion of the brain
in the absence of TB meningitis
• Clinically silent - headache,
seizure, progressive hemiplegia,
and/or signs of ↑ PIC
• Later-stage tuberculomas are well
encapsulated
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3. Nath A, et al. Nature reviews, Neurology vol 12. 2016: 662-674
Imagen

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 Diagnosis
Tuberculous meningitis Tuberculoma
• Presumptive diagnosis  relevant • Presumptive diagnosis  clinical
clinical and epidemiologic factors and epidemiologic factors and
and typical CSF findings typical radiographic findings
• Definitively established  CSF • Definitive diagnosis  biopsy of the
with positive smear for AFB, CSF CNS lesion for histopathology and
culture positive, or CSF with acid-fast bacilli stain and culture
positive nucleic acid amplification surgical intervention should
test (NAAT) ¹⁷ beavoided as it may precipitate
meningitis ¹˒³

15. Bourgi K, Fiske C, Sterling TR. Curr Infect Dis Rep 2017; 19:39.
16. Lewinsohn DM, Leonard MK, LoBue PA, et al. Clin Infect Dis 2017; 64:e1. 1. McArthur J.C, Tan I.L, et al. Lancet Neurol 2012; 11: 605–17
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17. Marais S, Thwaites G, Schoeman JF, et al. Lancet Infect Dis 2010; 10:803. 3. Nath A, et al. Nature reviews, Neurology vol 12. 2016: 662-674
Treatment
• Antituberculous therapy 9 to 12 months
• Glucocorticoides:
• Neurosurgery intervention  Hydrocephalus
• Serial lumbar punctures in conjunction with clinical monitoring
• Surgical decompression of the ventricular system

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Cerebral toxoplasmosis

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 Overview
• Toxoplasma gondii
• Most common CNS infection in • 30% among AIDS patients with a
patients with AIDS who are not CD4 count <100 cells/microL ¹⁸
receiving appropriate • Related to IRIS ²⁰
prophylaxis ¹⁸
• Pathogenesis  Reactivation of
• Prevalence: 11% in US, > 80%
encysted bradyzoites rather than
European, LA, and African ¹⁹. ↑
primary infection
age, ≥ 50 y.

19. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents.

3. Nath A, et al. Nature reviews, Neurology vol 12. 2016: 662-674 (Accessed on May 16, 2019)
18. Abgrall S, et al. Clin Infect Dis 2001; 33:1747. 20
20. Tremont-Lukats IW, Garciarena P, et al. Ann Intern Med 2009;150:656.
 Pathogenesis

21. Randall L. M. and Hunter C. A. European Journal of Microbiology and Immunology 1 (2011) 1, pp. 3–9
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 Disease forms
Toxoplasmic encephalitis (cerebral
abscess)
• Most common manifestation of
toxoplasmosis in patients with HIV
infection
• Multiple cerebral abscesses are
common
• Localize in the basal ganglia
• Symptoms: headache, confusion,
fever and focal neurologic deficits or
seizures
22. Porter SB, Sande MA. N Engl J Med 1992; 327:1643.
3. Nath A, et al. Nature reviews, Neurology vol 12. 2016: 662-674.
Diffuse encephalitis
• Generalized nonfocal: altered state
of consciousness, cognitive deficits,
or seizures ³
Extracerebral toxoplasmosis
• Chorioretinitis:
• Posterior uveitis with eye pain and
↓VA, predominantly unilateral ²³
• Roth spots
• 30% of individuals will have
concomitant cerebral toxoplasmosis ²⁴
23. Moshfeghi DM, Dodds EM, Couto CA, et al. Ophthalmology 2004; 111:716.
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24. de‑la‑Torre, A. et al. Clin. Exp. Ophthalmol. 37, 458–466 (2009).
Imagen

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 Diagnosis
Presumptive diagnosis  CD4
count <100 cells/microL, has not
been receiving effective prophylaxis
to prevent toxoplasmosis:
• Compatible clinical syndrome
• Positive T. gondii IgG antibody
• Brain imaging whit typical
radiographic appearance
90% probability that the diagnosis
is TE ²⁵
3. Nath A, et al. Nature reviews, Neurology vol 12. 2016: 662-674
25. Cohn JA, McMeeking A, Cohen W, et al. Am J Med 1989; 86:521.
• All of the above criteria are not
met
• not responded to initial therapy
• If a solitary CNS lesion is
detected: then evaluation for
CNS lymphoma should be
performed
 Brain biopsy ²⁵˒²⁶ definitive
diagnosis (S: 96% ²⁷)
26. Andrews BT, Kenefick TP. West J Med 1993; 158:249.
27. Antinori A, Ammassari A, De Luca A, et al. Neurology 1997; 48:687. 24
 Treatment
• Antimicrobial therapy
• Initial drug regimen (six weeks): sulfadiazine + pyrimethamine + leucovorin
• Maintenance therapy (CD4 count >200 cells/microL for at least six months ¹⁹):
sulfadiazine + pyrimethamine + leucovorin lower doses
• Antiretroviral therapy (ART)  2 weeks of starting treatment for TE
• Prevention
• Negative serology
• Positive serology  primary prophylaxis (CD4 counts<100 cells/microL who
are T. gondii IgG-positive): TMP-SMX (CD4 count is >200 cells/microL for at
least three months)

19. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. (Accessed on May 16, 2019)
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Cryptococcal
meningoencephalitis

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 Overview
• Cryptococcus neoformans (rarely,
Cryptococcus gattii)
• Ubiquitous environmental yeast • CD4 count <100 cells/microL
found in soil and bird droppings
• Related to IRIS 10-45% ²⁹
• Highest number of estimated cases:
sub-Saharan Africa (720,000) y • Pathogenesis  primary
South and Southeast Asia (120,000) pulmonary infection (latent
²⁷ infection) disseminated infection
• 15–20% of deaths attributed to HIV- with a predilection for the CNS
associated opportunistic infections
²⁸
27. Rhein, J. et al. Lancet Infect. Dis. 16, 809–818 (2016). 29. Katchanov, J. et al. Int. J. STD AIDS 26, 912–914 (2015).
28. Park BJ, Wannemuehler KA, Marston BJ, et al. AIDS 2009; 23:525. 27
 Pathogenesis

30. Cyptococcus. From Human Pathogen to Model Yeast. Washington, DC, ASM Press, 2011, fi gura 1, p. 238. ©2011 American Society for Microbiology.
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31. Kronstad J et al. Nat Rev Microbiol. 2011 March ; 9(3): 193–203.
 Clinical presentation
Symptoms
• Begin indolently over 1-2 weeks
Physical examination
• The most common symptoms are
fever, malaise and headache ³³ • Lethargy or confusion in
• Symptoms of meningeal irritation ¼ association with fever
patiens • Cranial neuropathies ³³
• Communicating hydrocephalus with • Tachypnea and skin lesions
increased intracranial pressure (15% resembling molluscum
of patiens) ³²
contagiosum ³⁴
• Dysfunction in multiple cranial nerves
• Diastolic hypertension
32. Chen YY, Lai CH. Neuroepidemiology 2011; 36: 79–84.
33. Cox GM, Perfect JR. Topley and Wilson's Microbiology and Microbial Infections, 9th Ed, Edward LA (Ed), Arnold Press, London 1997. 29
34. Murakawa GJ, Kerschmann R, Berger T. Arch Dermatol 1996; 132:545.
Imagen

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 Diagnosis
• High index of suspicion  patients • Cryptococcal culture CFS: 3 to 7
CD4 cell count <100 cells/microL + days definitive diagnosis
isolated fever and headache. • Cryptococcal antigen (CrAg)
• Initial evaluation  includes a • Spinal fluid: strongly supports the
careful history, neurologic exam, diagnosis (S:93-100%, E: 93-98%) ³⁵
and serum cryptococcal antigen • Serum/plasma 
(CrAg). • Symptomatic patients: cannot undergo
LP ³⁶
• Lumbar puncture (LP) • Asymptomatic patients: early infection
• ↑ ICP • PCR (S > 90%): distinguish
• CFS persistent culture-positive relapse
• Neuroimaging from IRIS ³⁷
35. Tanner DC, Weinstein MP, Fedorciw B, et al. J Clin Microbiol 1994; 32:1680.
36. Asawavichienjinda T, Sitthi-Amorn C, Tanyanont V. J Med Assoc Thai 1999;82:65. 31
36. Rhein J, Bahr NC, Hemmert AC, et al. Diagn Microbiol Infect Dis 2016;84:268.
 Treatment
• Antifungal therapy ¹⁹˒³⁸ • Control of ICP
• Induction (2 weeks): liposomal • Evacuatory LP
amphotericin B plus flucytosine • Lumbar or ventricular drains
(fluconazole)
• Consolidative (8 weeks):
• ART: 2 and 10 weeks after
fluconazole antifungal therapy has been
• Maintenance (≥ 1 y): fluconazole; initiated  reduce the risk of
(CD4 count is >200 cells/microL for developing IRIS
at least three months) • Not glucocorticoids ³⁹

19. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. (Accessed on May 16, 2019
38. Perfect JR, Dismukes WE, Dromer F, et al. Clin Infect Dis 2010; 50:291. 32
39. Beardsley J, Wolbers M, Kibengo FM, et al. N Engl J Med 2016; 374:542.
Progressive multifocal
leukoencephalopathy (PML)

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 Overview
• Polyomavirus JC (JCV): John • CD4 count <200 cells/microL ⁴⁴
Cunningham virus
• Normal CD4+ T cell counts ⁴⁵
• Asymptomatic primary infection
with JCV occurs in childhood; • Inflammatory PML (PML-IRIS)
antibodies 86% percent of adults ⁴⁰ • Pathogenesis: JCV remains latent
• PML are disease that occurs almost in kidneys and lymphoid organs
exclusively in immunosuppressed  reactivate, replication
individuals ⁴¹ (rearrangement of the viral
• Post ART: the incidence of PML in genome)  neurotropic variants
patients with HIV infection has that can replicate in glial cells 
decreased ⁴²˒⁴³ demyelination ⁴¹
40. Weber T, Trebst C, Frye S, et al. J Infect Dis 1997; 176:250. 43. Engsig FN, Hansen AB, Omland LH, et al. J Infect Dis 2009; 199:77.
41. Kartau M, Sipilä JO, et al. Degener Neurol Neuromuscul Dis 2019; 9:109. 44. Berger JR, Aksamit AJ, Clifford DB, et al. Neurology 2013; 80:1430. 34
42. Sacktor N. J Neurovirol 2002; 8 Suppl 2:115. 45. Aksamit AJ Jr. Continuum (Minneap Minn) 2012; 18:1374.
 Pathogenesis

.
46. Major E, Yousry T, Clifford D. Lancet Neurol 2018; 17: 467–80 35
 Disease forms
Classic PML
• Subacute neurologic déficits ⁴⁴ :
• Altered mental status JCV encephalopathy ⁵⁰
• Motor deficits, limb ataxia, gait ataxia
• Visual symptoms • Focal areas of cell loss in the
• Seizures (44%) ⁴⁷˒⁴⁸ cortex and limited demyelination
JCV granule cell neuronopathy (GCN) ⁴⁹
• Infection of cortical pyramidal
• Lytic infection of cerebellar granule cell
neurons neurons
• Ataxia, incoordination, dysarthria, and • Developed aphasia and
cerebellar atrophy progressive cognitive decline in
• Does not result in white matter lesions of the absence of focal neurologic
cerebellar.
deficits
44. Berger JR, Aksamit AJ, Clifford DB, et al. Neurology 2013; 80:1430
49. Du Pasquier RA, Corey S, Margolin DH, et al. Neurology 2003; 61:775.
47. Lima MA, Drislane FW, Koralnik IJ. Neurology 2006; 66:262.
48. Miskin DP, Herman ST, Ngo LH. J Neurovirol 2016; 22:464. • The
50. Wüthrich C, Dang X, Westmoreland S,course was
et al. Ann Neurol rapidly
2009; 65:742. fatal 36
Imagen

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 Diagnosis
• Suspect PML ⁴⁴ • PCR JVC (S >95%)
• Subacute neurologic deficits • Repeat the LP and PCR CSF for JCV
• MRI: focal or multifocal white • Negative PCR test does not rule
matter lesions (without mass out PML ⁵¹
effect, not vascular territories) • Possible PML ⁴⁴˒⁵²
• Diagnostic approach ⁴⁴ • Negative PCR test x 2
• LP: PCR JVC (DNA) in CSF
• Suspect another cause
• Brain biopsy
 Brain biopsy ⁵³˒⁵⁴ gold standar,
definitive diagnosis (S: 64-96%, E:
100%)
44. Berger JR, Aksamit AJ, Clifford DB, et al. Neurology 2013; 80:1430. 53. Koralnik IJ, Boden D, Mai VX, et al. Neurology 1999; 52:253.
51. Marzocchetti A, Di Giambenedetto S, et al. J Clin Microbiol 2005; 43:4175. 54. Skolasky RL, Dal Pan GJ, Olivi A, et al. J Neurol Sci 1999; 163:32. 38
52. Cinque P, Koralnik IJ, Clifford DB. J Neurovirol 2003; 9 Suppl 1:88.
 Treatment: neurosurgery intervention
• There is no specific treatment for PML  immune reconstitution
• Initiating or optimizing effective antiretroviral therapy (ART) 4  IRIS
can be treated with glucocorticoids
• One-year survival rate: 50% ART – 10% no ART 8-9

19. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. (Accessed on May 16, 2019)
55. Antinori A, Ammassari A, Giancola ML, et al. J Neurovirol 2001; 7:323.
56. Antinori A, Cingolani A, Lorenzini P, et al. J Neurovirol 2003; 9 Suppl 1:47. 39
Primary CNS
lymphoma (PCNSL)

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 Overview
• Epstein-Barr virus (EBV)
• HIV-related NHL  PCNSL
• 10-15% NHL in people living with
HIV 2, 5 ⁵⁷˒⁵⁸
• The incidence of PCNSL in HIV↓:
ART 7 ⁵⁹
• CD4 count <100 cells/mL
• Risk factors:
• High HIV viral load
• Chronic co-infection with hepatitis
B and hepatitis C virus in patients
receiving ART.
• Pathogenesis  oncosuppressor
deregulation leading to loss of
control of viruses, unregulated
expansion of these B cells ⁶⁰

57. Coté TR, Biggar RJ, Rosenberg PS, et al. Int J Cancer 1997; 73:645. 59. Uldrick TS, Pipkin S, Scheer S, Hessol NA. AIDS 2014; 28:397.
58. Gopal S, Patel MR, Yanik EL, et al. J Natl Cancer Inst 2013; 105:1221. 41
60. Cingolani A, De Luca A, Larocca LM, et al. J Natl Cancer Inst 1998; 90:364.
 Pathogenesis

Carbone A, Gloghini A, Caruso A, De Paoli P and Dolcetti R. Int. J. Cancer: 140, 1233–1245 (2017). 42
Clinical presentation
Signs and symptoms • Systemic "B" symptoms: 80%
• Acute to subacute  confusion, PCNSL
lethargy, memory loss,
hemiparesis, aphasia, and/or
seizures progressing over days to
weeks.

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 Diagnosis
Definitive diagnosis: Diagnosed based on the triad:
• Stereotactic biopsy or CSF flow • Compatible MRI with diffusion
cytometry and/or cytology and perfusion sequences and
Clinical certainty spectroscopy
• Typical clinical and radiographic • Positive EBV DNA (PCR) of CSF
findings for PCNSL, detection of • Unresponsiveness to 2-3 weeks
EBV DNA in the CSF of toxoplasmosis treatment
cannot undergo biopsy without glucocorticoids.

Moulignier A, Lamirel C, Picard H, et al. Neurology 2017; 89:796. 44

Imagen

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 Treatment
• First-line therapy
• Intravenous methotrexate (MTX) combination ART.
• Brain radiation therapy (WBRT) not first-line or consolidative therapy  poor
durability of responses
• Assessment of response  brain MRI with and without contrast
compared with baseline
• Options for recurrent/refractory disease
• WBRT: chemotherapy-refractory disease and those who cannot tolerate
systemic therapy. Focal irradiation followed by immunotherapy with

Moulignier A, Lamirel C, Picard H, et al. Neurology 2017; 89:796.

Rubenstein JL, Geng H, Fraser EJ, et al. Blood Adv 2018; 2:1595. 46
 Treatment
• First-line therapy
• Intravenous methotrexate (MTX) combination ART.
• Brain radiation therapy (WBRT) not first-line or consolidative therapy  poor
durability of responses
• Assessment of response  brain MRI with and without contrast
compared with baseline
• Options for recurrent/refractory disease
• WBRT: chemotherapy-refractory disease and those who cannot tolerate
systemic therapy. Focal irradiation followed by immunotherapy with

Moulignier A, Lamirel C, Picard H, et al. Neurology 2017; 89:796.

Rubenstein JL, Geng H, Fraser EJ, et al. Blood Adv 2018; 2:1595. 47
"Even the most difficult can be said in a simple
way, but it is difficult. Even the simplest can be
said in a difficult way and it is easy“

Carl Erik Soya

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