CEREBRAL TOXOPLASMOSIS:

DIAGNOSIS & MANAGEMENT

Kiking Ritarwan
Departemen Neurologi FK USU
RSUP Haji Adam Malik Medan
Email:kikingritarwan@gmail.com

di presentasikan pada PIN SOLO Neuroemergensi,

Neuroinfeksi 7-9 November 2014
 Curriculum Vitae
• Nama : dr. Kiking Ritarwan SpS(K), MKT
• NIP : 19681117 1997 02 1 002
• Tempat/ tgl lahir : Medan/ 17 November 1968
• Agama : Islam
• Status Perkawinan : Kawin
• Alamat : Jl. Brigjen Katamso No 455 Medan # 20215.
Organisasi:
Riwayat Pendidikan
- Kepala subdivisi neuroinfeksi PERDOSSI-
Tamat SD Bhayangkari 1981
Sumut
Tamat SMP Negeri I Medan 1984
- Wakil Ketua International Pain Society (IPS) cab
Tamat SMA Negeri VI Medan 1987
Sumut
Tamat Dokter FK-USU 1993
- Anggota seksi Penelitian dan pengembangan
Tamat Dokter Spesialis Neurologi 2002
Ilmiah Perhimpunan Dokter Peduli AIDS
Magister Ilmu Kesehatan Tropik, 2007
Indonesia (PDPAI) cab Sumut
Study S3 FK-USU- 2014
-Anggota pengurus wilayah IDI Sumut
- Anggota PTHI Sumut

Riwayat Pekerjaan
Staff Pengajar Bagian Neurologi FK-USU 1997 sampai dengan sekarang.
Staff Pengajar FKG- USU 1997 sampai dengan 2011
Staff Pengajar S2-Magister Pasca Sarjana USU.
Lecture Alianz College Medical School, Penang, Malaysia
Is Neurological Disease is a problem
in HIV infection ??
Advanced HIV disease
30% neurological
illnesses (Pre-HAART era)
10% AIDS Dementia
Complex
10% Cerebral toxoplasmosis
10% Lymphoma
7% Cryptococcal meningitis
10-20% Peripheral
neuropathy
( Asia-Pacific region)
 Introduction
• Toxoplasmosis is the infection of humans
by the protozoan organism Toxoplasmosis
gondii.
• Obligate intracellular parasite
• Definitive Host: Cat (feline)
• Secondary Host :human, mamalia, bird
• The most common cause of intracranial
mass lesion in AIDS, typically chronic
progressive focal signs and seizure.
 Introduction ….
• HIV  Toxoplasma Encephalitis
• Most common as a reactivation of
previous infection.
• Most common in HIV patient with CD4 <
200/cmm.
• Cerebral toxoplasmosis has typically
findings on brain imaging, such as a
multiple ring-enhancing lesions.
 EPIDEMIOLOGY
• Incidence : variable, depend on :
– Definitive host.
– Sanitation.
– The presence of parasit.
• Prevalence : ↑ with age.
– US : 10 - 19 yrs : 5-30%.
> 50 yrs : 10-67%.
• Case Fatality Rate : 1-25%
203 cases of HIV-related CNS opportunistic infection
in RSCM Hospital, Jakarta in 2004 – 2006

Undetermined
24% Cerebral
CMV Toxoplasmosis
0% 31%

Bacterial
5%
Krypto TBC
13% 27%

HIV Infection and the Central Nervous System

April 14-16, 2007, Venice - Italy
Toxoplasma Life Cycle
 PATOGENESIS
Transmission : via oral route & placenta.
Digestive enzym phagocytosis
Cyst Sporozoit †

Trophozoite

Transported throughout the body via

lymphatic system & blood steam

Trophozoites proliferation

Cell †
PATOGENESIS
-Overview of pro-inflammatory
responses generated by macrophages
during toxoplasmosis.
-Exposure to T. gondii initiates MAPK
and NF-κB signaling, leading to
synthesis of cytokines, including IL-12,
that stimulate production of IFN-γ from
NK and T cells.
- Macrophages become activated by a
combination of IFN-γ and TNF-α,
leading to upregulation of iNOS and the
p47 GTPases, which limits parasite
replication. Interactions with activated T
cells through CD40/CD40L ligation also
contributes to parasite control.
-In addition, activated macrophages
express MHC class I and II, and can
present parasite-derived antigen to
activated CD4+ and CD8+ T cells.
 Sign & Symptoms
• Depend on patient immunity.
• 80% asymptomatic.
• Incubation period : 1-2 weeks  chronic.
• Non specific.
• The most common : cervical lymphadenopathy.
• Others :
– slightly increase temperature.
– Myalgia, dysphagia, headache, urtica, rash, and
hepatosplenomegali.
• Asymptomatic : sign & symptoms disappear after several
months.
• Immunity   reactivation of the disease.
 Sign & symptoms
• Status mental disorder. • Movement disorder:
• Fever : persistent / up and Dystonia.
down. Chorea.
• Headache. Athetosis
• Focal neurologic deficit. Hemibalismus
• Decrease of
consciousness.
• Convulsion.
• Meningeal sign.
• Vision disorder.
 Sign & symptoms in HIV
• Subacute.
• Headache.
• Fever.
• Focal lesion  focal neurologic deficit.
• Convulsion (15-25%).
• Mental disorder.
• Movement disorders.
• Neuropsychiatric. : paranoid, psychosis,
dementia, agitation, anxiety.
• Brain stem : cranial nerve paresis.
 Geographical distribution of Toxoplasma gondii genotypes and
possible relationships with human disease

Geographical area Genotypes

Europe Type II (haplogroup 2),
highly predominant; type
III, more present in South
Europe; other genotypes
sporadically observed
America North America Type II
(haplogroup 2), haplogroup
12, type III (haplogroup 3), other genotypes
South and Central America High genotypic diversity; some
haplogroups share with Africa
(haplogroup 6); type II sporadically
Africa African1,2,3, (haplogroup 6)
Asia Less genotype diversity in South America

Clin. Microbiol. Rev. 2012, 25(2):264.

 Laboratory finding
• Confirmed case : Toxoplasma gondii
positif in blood, tissue and body fluid.
• IgM Toxoplasma.
• IgG avidity Toxoplasma : (+)
Lumbar Puncture
• Acute :
– Intracranial pressure ↑.
– Mononuclear pleiocytosis (10-50 cell/ml)
– Protein slightly ↑.
– Glucose : N.
– PCR toxoplasma gondii : (+)
• Chronic : not significant.
The relation was CD4 count and opportunistic infection

(McPhee & Papadakis 2010)

 Diagnosis
• Definitive : Brain Biopsy
• A presumptive diagnosis
can be made if the patient has a CD4 count
<100 and:
– Seropositive for T. gondii IgG antibody.
– Has focal neurological deficits.
- Has typical findings on brain imaging,
such as multiple ring-enhancing
lesions.
• If these criteria are met, there was a 90%
probability of the diagnosis.
 Diagnosis…..
• Brain biopsy:
– Definitive diagnosis is made by
pathologic examination of brain
tissue obtained by open or
stereotactic brain biopsy.
– Organisms are demonstrated on
hematoxylin and eosin stains.
– Some laboratories also use
immunoperoxidase staining which
can increase diagnostic sensitivity.
BRAIN BIOPSY
 Radiology
CT Scan + contrast.
Multiple hypodens area.
Predilection area :
Basal ganglia.
Corticomedullary junction.
MRI.
Multiple lesion : 1- >3 cm + ring enchancement.
Diagnosis....
IgG and IgM
• The majority with seropositive anti-
toxoplasmosis IgG antibodies, peaks
within 1-2 months after infection
• Anti-toxoplasmosis Ig M antibody
positive only in the early phase of
infection, decreased / disappeared
until the third month in the acute
phase.
 INTERPRETASI HASIL DIAGNOSIS

IgG – ; IgM – IgG – ; IgM + Ig G +; Ig M- IgG + ; IgM +

Sehat Sedang terinfeksi Pernah terinfeksi Uji Aviditas

At least 1 wk before At least 1 year before

Kuat Lemah

Reaktivasi/Reinfeksi Reaktivasi/Reinfeksi
At least 12 wk before At least 3 wk before
 Differential Diagnosis
Toxoplasmosis P CNS L
Location Basal ganglia. Periventricular
Gray-white junction
Number of lesion Multiple Solitary>multiple
Enhancement pattern Ring Heterogeneous or
homogeneous.
Edema Moderate to marked Variable
T2-weighted image Hyperintense Isointense to
(lesion relative to hyperintense.
white matter)
Diffusion-weighted Usually hypointense Often hyperintense
image (positive)
 Differential Diagnosis
Toxoplasmosis P CNS L
MR perfusion Decreased Increased
MR spectroscopy Markedly elevated Markedly elevated
lactate. choline

SPECT thallium “Cold”-no thallium “Hot”-increased

(lesion relative to uptake thallium uptake.
white matter)
Other Toxoplasma IgG Ab EBV DNA amplified
(+) (90% of patients) by PCR in CSF
(most patients)
 Empiric anti toxoplasmic
treatment
2004
• Pyrimethamine-sulfadoxine bid po
– Drug allergy 34.2 %
• Clindamycin 600 mg qd po
2005 - present
• Pyrimethamine 200 mg load  75 mg/d
• Clindamycin 600 mg qd po
 Subacute onset of neurologic symptoms with focal lesion on MRI

Single lesion Multiple lesion

SPECT
SPECTscan
scan Enhancing Non-enhancing

Toxoplasma
uptake
uptake uptake
uptake
uptake Edema
Edema No
Noedema
edema
titer in serum

Likely tumor Abscess or Negative Positive Biopsy CSF for

necrotic JCV
lymphoma PCR
Biopsy Treat for
Biopsy toxoplasmosis
Biopsy edge
center of
of lesion Repeat MRI in Negative Positive
lesion
10 days
Aggressive
If PCNSL, No improvement Improvement ART
treat with
Radiotherapy Biopsy Continue maintenance therapy
 HIV patient with CD4 < 200 + Focal lesion in CT / MRI

Multiple lesion Single lesion

Mass effect/
Mass effect/ Homogen
herniation ?
herniation ? enhancement

Yes Brain biopsy

No No
Yes No Yes
Empirical Treatment :
o Pyrimethamin &
Steroid sulfadiazine or if
allergi with sulfa Thalliun
dapat menggunakan SPECT Scan
o Pyrimethamin &
Clindamycin atau Negative
Azythromycin
Positif

Brain biosy
A
 Prevention
• Avoid undercooked meat lamb, beef,
pork heated at 74-77OC.
• Rinse vegetable & fruits with running water
• Cat hygiene.
• Primary prevention : HIV patient with
CD4<100/cmm and toxoplasma gondii
seropositif.
 Prevention
• Primary prevention :
First line :
o Sulfadiazine + Pyrimethamine or
o Clindamycine + Pyrimethamine or

Second line :
o Trimethoprim sulfamethoxazole or
o Dapsone + Pyrimethamine.
● Stop : HAART (+) & CD4 > 200/cmm 3 months.
 Summary
• Obligate intracelllular parasite..
• Most common focal lesion in the brain in HIV patient.
• Most common as a reactivation of previous infection.
• Variabel in clinical sign & symptoms.
• Seropositive anti-toxoplasmosis IgG antibodies
• Brain imaging: multiple ring-enhancing lesions.
• Lumbal puncture :
– Acute : PCR toxoplasma gondii : (+)
– Chronic : not significant