Lymphocytes T8 infiltrative encephalitis: a new form of neurological complication

in HIV infection

François-Xavier Lescure, Françoise Gray, Julien Savatovsky,

Corinne Amiel, Jérome Pacanowski, Pierre-Marie Girard,

Jean-Michel Molina, Gilles Pialoux, Antoine Moulignier

Background• Improvement of severity in neuro-cognitive disorders

since HAART (Jellinger et al. 2000, Arminio Monforte et al. 2004)

• Persistance of overall neuro-cognitive disorders – Brain is a HIV sanctuary (Lambotte et al. 2005) with a complicated

pharmacology for ARV (Antinori et al. 2005, Letendre et al. 2008)

– Chronic neuro-inflammation hypothesis (Nath et al. 2006, Yilmaz et al. 2008)

• Improvement of survival in HIV-infected patients (Lhose et al. 2007, Leyden et al. 2007)

• Emergence of atypical neurological cases– Central discordant HIV diseases (Stingele et al. 2001, Canestri et al.

2009)– Severe demyelinating leukoencephalopathies (Langford et al. 2002,

Miller et al. 2004, Rackstraw et al. 2006)

Method

• Aim– Review of medical files– Historical, clinical, paraclinical and pathological

data

• Design– Retrospective– Descriptive– Study period: 1999-2008

Features of patients

• N=14• Sex ratio M/F: 8/6• Risk groups:

– 9 heterosexuals, 4 MSM, 1 transfusion• Ethnic origin:

– 7 American Africans, 2 Arabics, 5 Caucasians• Co infections:

– 2 HBV, 1 HCV• Other comorbidities:

– 1 lupus, 1 DILS, 1 diabetes, 1 HTA, 1 renal disease, 1 bullous pemphygoid

Features of HIV infections at BL

• Median duration of HIV infection = 10 years [1-18]• CD4 cells count nadir < 200 μL/mL: 78%• AIDS history: 71%• HAART: 86%• Median ART duration: 4 years [0-14]• Median ART Charter: 1.6 [1.5-2]• Median plasma VL (copies/mL) = 117 [<40-10,000]• Median CD4 cells count (μL/mL) = 493 [6-900]

Clinical characteristics• Clinical signs

– Epilepsy , n=6 (4 status epilepticus)

– Headhache , n=5– Coma, n=4– Dizziness, n=4– Confusion, n=4– Dementia, n=4– Mild memory disorders, n=3– Neurological deficit , n=3– Mood troubles, n=1

• Presentation– Acute, n=5– Subacute, n=6– Chronic, n=2

Paraclinical characteristics• Plasma VL (copies/μL)

– 692 [<40-65,800] – vs 117 before event

• CD4 cells count (μL/mL)– 182 [84-742]

– vs 493 before event

• CSF– Lymphocytes = 40 [1-220]– Protein = 0.9 [0.4-1.5]– Glucose = normal

• CSF VL (copies/μL)– 2236 [1,100-36,242]

– vs 692 in the plasma

• Clinical signs – Epilepsy , n=6 (4 status

epilepticus)– Headhache , n=5– Coma, n=4– Dizziness, n=4– Confusion, n=4– Dementia, n=4– Mild memory disorders, n=3– Neurological deficit , n=3– Mood troubles, n=1

• Presentation– Acute, n=5– Subacute, n=6– Chronic, n=2

WM T2 high signal

Areas with restricted diffusion

perivascular contrast

enhancement

Differential diagnosis

• JCV• CMV• HSV• VZV• EBV• HHV6• Enterovirus

• Syphilis• Lyme• Cryptococcosis• Toxoplasmosis• TB• Lymphoma• MS• …

Differential diagnosis

• JCV• CMV• HSV• VZV• EBV• HHV6• Enterovirus

• Syphilis• Lyme• Cryptococcosis• Toxoplasmosis• TB• Lymphoma• MS• …

NEGATIVE

Pathological data (N=9/14)

Treatment and outcome

• Treatment: – Steroids: 8/14– Change ART: 9/14– Cyclophosmamide: 3/14

• Prognosis– Initial efficacy of steroids– But, frequent relapses (35%)– And, very severe overall prognosis

• Death: 35%• Survival with Sequellae: 35%• Survival without sequellae: 30%

How to do the diagnosis

• Patients profile– Stable patients on an immunological point of view but not

perfectly virologicaly controled• Additional sensitive criteria

– Acute or subacute diffuse severe encephalitis– CD8+ lymphocytes meningitis– Imaging

• Diffuse leukoencephalopathy • Areas with restricted diffusion• Perivascular contrast enhancement (better depicted

using spin-echo T1 with magnetization transfer)

How to do the diagnosis

• Patients profile– Stable patients on an immunological point of view but not

perfectly virologicaly controled• Sensitive criteria

– Acute or subacute diffuse severe encephalitis– CD8+ lymphocytes meningitis– Imaging

• Diffuse leukoencephalopathy • Areas with restricted diffusion• Perivascular contrast enhancement (better depicted

using spin-echo T1 with magnetization transfer)« Central DILS »

« A crash of thunder

in an apparently serene sky »

How to entry in this disease?

T8 encephalitis

Stop ART Blip

How to entry in this disease?

T8 encephalitis

Virological escape

Stop ART Blip

Langford et al. 2002

How to entry in this disease?

T8 encephalitis

Virological escape

Stop ART Blip

IRISLangford et al. 2002 Miller et al. 2004

HIV

tatnef

GP120

TNFɑ

IL1ß

RANTES

M-T8

Pathogenesis hypothesis

• Asymptomatic patients = stable balance

- HIV neuro-pathogenicity vs central immunogenicity

HIV

tatnef

GP120

TNFɑ

IL1ß

RANTES

M-T8

Pathogenesis hypothesis

• Asymptomatic patients = stable balance

- HIV neuro-pathogenicity vs central immunogenicity• Patients with chronic NCD = mild unstable balance

- Persistent neuro-virulence or persistent neuro-inflammation

HIV

tatnef

GP120

TNFɑ

IL1ß

RANTES

M-T8

Pathogenesis hypothesis

Wang et al. 2006, Scaravilli et al. 2007, McCrossan et al. 2006, Price et al. 2000, Tsunoda et al. 2005, Shacklett et al. 2004

• Asymptomatic patients = stable balance

- HIV neuro-pathogenicity vs central immunogenicity• Patients with chronic NCD = mild unstable balance

- Persistent neuro-virulence or persistent neuro-inflammation

• Subacute phenomenon = acute unbalanced mecanism

- HIV central sanctuarisation or

- Directly or secondary HIV driven immunological burnt-out according to the domino or « hit and run » theory

In conclusion

• An emergent form of neurological complication in HIV population

• In well controlled but long term infected and not perfectly virological suppressed patients

• A peripheral increase of HIV replication and decrease of CD4

• An acute, severe and diffuse meningoencephalitis• Specific abnormalities in MRI• Good initial response to corticotherapy and ARV

intensification if necessary• Overall severe prognosis

Acknowlegments• Fondation Ophtalmologique Rothschild :

– Antoine Moulignier, Julien Savatovsky• Hôpital Bichat :

– Homa Adle-Biassette• Hôpital La Pitié Salpétrière :

– Brigitte Autran, Guislaine Carcelain• Hôpital Lariboisière :

– Françoise Gray, Jacqueline Mikol • Hôpital Saint Antoine :

– Jean-Luc Meynard, Jérôme Pacanowsky, Nadia Vallin, Pierre-Marie Girard

• Hôpital Saint Louis : – Jean Michel Molina

• Hôpital Tenon : – Corinne Amiel, Gilles Pialoux

Xavier.lescure@tnn.aphp.fr