Central Nervous System Immune Reconstitution Disease

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Central Nervous System Immune Reconstitution
Disease

• Françoise GRAY
• AP-HP Hôpital Lariboisière Université Paris
  VII, France

2

• Introduction of HAART, which is available for all
  patients in France since 1996, has dramatically
  modified the course and prognosis of HIV disease
• This benefit is mainly due to
• a decrease of the viral load
• a restored functional immune system

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Immune Reconstitution Inflammatory Syndrome
(IRIS)

• (Shelburne et al. Medicine 200281 213-27)
• Patient with AIDS
• HAART induced CD4 Viral Load
• Symptoms consistent with an infectious/inflammator
  y condition appeared while on antiretroviral
  therapy
• Symptoms could not be explained by
• - a newly acquired infection
• - the expected course of a previously
  recognized infection
• - side effects of therapy

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Systemic IRIS

• (Shelburne et al. Medicine 200281 213-27)
• Mycobacterial infections
• - M. Avium Complex lymphadenitis
• - Pulmonary tuberculosis
• Herpes zoster infections
• Pneumocystis Carinii pneumonia
• Hepatitis B and C

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IRIS and the CNS

• Paradoxical exacerbation
• - CNS M. Tuberculosis infection
• - Cryptococcus Neoformans meningitis
• - CMV retinitis
• (Shelburne et al. Medicine 200281
  213-27)
• PML
• HIV encephalitis

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7 AIDS patients who failed HAART
Intense perivascular infiltration by HIV-gp41
positive monocytes/macrophages
Severe leukoencephalopathy
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Acute hyperimmune leukoencephalopathy (Miller
et al. Acta Neuropathologica 2004108 17-23)

• 2 AIDS patients with low CD4 and high VL
• HAART CD4 VL
• Development (or worsening) of acute
  encephalopathy
• MRI leukoencephalopathy (X?)
• Rapid neurological deterioration and death

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Acute hyperimmune leukoencephalopathy (Miller
et al. Acta Neuropathologica 2004108 17-23)
Case 1
Case 2
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Acute hyperimmune leukoencephalopathy (Miller
et al. Acta Neuropathologica 2004108 17-23)
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Acute hyperimmune leukoencephalopathy (Miller
et al. Acta Neuropathologica 2004108 17-23)
p24
In situ PCR CD68
Case 1
Case 2
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Acute hyperimmune leukoencephalopathy (Miller
et al. Acta Neuropathologica 2004108 17-23)
CD8
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• 37 y-o homosexual male
• March 2003
• HIV (), CD4 10, VL 19 000 copies/ml
• HAART
• June 2003
• CD4 93
• Seizures, Aphasia, facial paresis
• MRI Arteriography
• Cerebral Biopsy

13
T2
Van de Ven et al. Cerebral vasculitis after
initiation antiretroviral therapy. AIDS 2002
162362-2364.
T1 Gd
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(No Transcript)
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HLA-DR
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HLA-DR
p24
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CD8
CD4
CD68
CD20
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Favorable outcome Steroids clinical
improvement HAART continued Normal
neurological status CD4 and CD8 normal
No new MRI
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• 42 y-o homosexual male
• October 1993 HIV ()
• January 2000 CD4 195
• HAART
• February 2001
• CD4 400 VL 0
• Confusion
• Memory disturbances
• Depression
• Gait disturbances

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February 2001
FLAIR
T2
T1 gado
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(No Transcript)
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HLA-DR
p24
HIVE
GFAP
NF
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CD20
CD3
CD8
CD4
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Fatal outcome HAART continued steroids April
2001 Improvement of neurological
status October 2001 Neurological,
biological radiological
worsening November 2001 Death
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IRIS PML
Contrast enhacement of lesions following
HAART resulting from inflammation and involvement
of the BBB, confirmed by cerebral biopsy
Favourable Collazos et al. Contrast enhancing
PML as an immune reconstitution event in AIDS
patients. AIDS 1999131426-8 Kotecha et al.
Enhancing PML An indicator of improved immune
status? Am J Med 1998 105541-3 Fatal Miralles
et al. Inflammatory reaction in PML after HAART.
AIDS 2001 151900-2 Safdar et al. Fatal immune
restoration disease in HIV 1-infected patients
with PML impact of antiretroviral
therapy-associated immune reconstitution. Clin
Infect Dis 35 1250-7
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• 37 y-o homosexual male
• July 1999
• HIV (), CD4 50
• HAART
• November 1999
• CD4 200
• Left Hemiparesis
• MRI contrast enhancing lesion of the white
  matter of right motor area
• Cerebral Biopsy

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MRI, November 1999
T1
T2
T1, Gado
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HE
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HE
HE
ISH JC
ISH JC
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HE
CD68
CD3
CD20
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CD8
CD4
IL1-b
HLA-DR
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CD4
CD4
CD8
CD8
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Since 2000 HAART continued
Improvement of the neurological status
(physiotherapy) May 2003 CD4 1036 CD8 2017
MRI lesions unchanged (regression?)
no contrast enhancement
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FLAIR
FLAIR
October 2001
July 2000
T1 gado
T1 gado
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Fulminant PML following HAARTVendrely et al.
Acta Neuropathol 2005109449-455

• 52 y.-o. Caribbean Male
• 1986 HIV
• December 2003 Progressive onset
• - Depression,
• - Psychomotor slowing
• - Speech disorders
• January 2004 -gt admitted to hospital
• - CD4 117, viral load 314 072 copies/ml
• - MRI suggestive of PML
• HAART

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Fulminant PML following HAARTVendrely et al.
Acta Neuropathol 2005 109449-455
MRI, January 2004
FLAIR
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Fulminant PML following HAARTVendrely et al.
Acta Neuropathol 2005 109449-455

• February 2004
• CD4 300, Viral loadlt3 log
• Aphasia
• Confusion, Coma
• MRI extension of the lesions,
• contrast enhancement
• Cerebral Biopsy

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Fulminant PML following HAARTVendrely et al.
Acta Neuropathol 2005 109449-455
FLAIR
MRI, February 2004
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HE
CD8
HE
CD68
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Fulminant PML following HAARTVendrely et al.
Acta Neuropathol 2005 109449-455
March 2004 High doses of steroids - Rapid
neurological deterioration - Death from septic
shock
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KB
KB
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KB
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HE
ISH JC
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KB
HE
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CD8
CD4
CD20
CD68
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CD8
KB
ISH JC
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Fulminant PML following HAARTVendrely et al.
Acta Neuropathol 2005109449-455

• In Summary
• Acute Progressive Multifocal
  Leukoencephalitis, with marked inflammation and
  abundant virus
• Acute perivenous leukoencephalitis (ADEM)

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Immune Reconstitution Inflammatory Syndrome (IRIS)

• Inflammatory reaction unmasking a smouldering
  active infection
• Symptomatic cryptococcal meningitis
• Woods et al. AIDS 1998 121491-4
• Breton et al. Am J Med 2002 113155-157
• CMV Retinitis
• Jacobson et al. Lancet 19973491443-5
• HIV Encephalitis
• Langford et al. AIDS 2002.161019-1029

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Immune Reconstitution Inflammatory Syndrome (IRIS)
2) Non specific immunopathologic reaction
Aseptic meningitis in patients with
Cryptococcus Neoformans infection Woods et al.
AIDS 1998 121491-4 Vitritis in patients
successfully treated for CMV retinitis
Karavellas et al. J Infect Dis 1999
179697-700 Infiltration by CD8 CTL in HIV
encephalitis Miller et al. Acta Neuropathol
2004 10817-23.
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Immune Reconstitution Inflammatory Syndrome (IRIS)
Pathophysiology Exaggerated  overzealous
response of a newly reconstituted immune system
to infectious antigens already present in the
patient when therapy started Restoration of
T-cell function allows an influx of memory
T-cells that recognized the infectious antigens
(HIV or JCV antigens)
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IRIS and HIVE or PML
Pathophysiology The influx of lymphocytes may
be beneficial Kotecha et al. Am J Med
1998 105541-3 Hoffmann et al. J Neurol
Neurosurg Psychiatry 2003 741142-44 It
also may be harmful Dysregulation of the
CD8/CD4 T cell balance?? Miralles et
al. AIDS 2001 151900-2 Safdar et al.
Clin Infect Dis 35 1250-7 Miller et al.
Acta Neuropathol 2004 10817-23
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In Conclusion
In AIDS patients with HIVE or PML, HAART-induced
restoration of a pathogen-specific immune
response may result in an unusually intense
inflammatory reaction Impairment of the BBB
(vasculitis?) and Contrast enhancement at
MRI Influx of CD8 lymphocytes -
Beneficial Macrophage activation Control of
viral infection - Harmful (dysregulation of
CD4/CD8 balance ?) Accentuation of viral
infection Perivenous leukoencephalitis
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F. Gray J. Mikol H. Adle-Biassette C. Bazille F.
Chrétien A. Vendrely
G. Corcket M.A. Bretel P. Castagnet K. Dossou I.
Levesque C. Poiron C. Sanchez
J.B. Thiebault F. Héran D. Fredy
B. Bienvenu J. Gasnault A. Moulignier
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Thank you for your attention