cpr on cerebral toxoplasmosis

1. Dated 25th March 2014

2. Age/sex- 32/M
Residence- triloki nath-kelonag-lahaul spiti
Date Of Admission- 22nd January 2014
Date Of Discharge- 11th February 2014

3. K/C/O immunocompromised state (HIV+) since last 1 year
Chief complaints - fever * 15 days
headache * 15 days
altered sensorium * 7 days
HOPI- fever-documented(till 102 F), a/w chills/rigors &
sweating episodes, no diurnal variation, relieved with
antipyretics, no h/o cough/burning micturition/altered bowel
habits
headache- generalised, moderate intensity, no
nausea/vomiting
altered sensorium- not recognising family members,
irrelevant talks

4. H/O drooping of both eyelids rt.> lt.
H/O diplopia
No H/O abnormal body movements/tongue bite/ bladder
or bowel incontinence/frothing from mouth
No H/O deviation of face/difficulty swallowing/nasal
regurgitation/nasal twang/ weakness of any body part
No H/O any abrupt change in weight/mouth
infections/prolonged diarrhea

5. PAST HISTORY-
• K/C/O immunocompromised state for last 1 yr
• No h/o DM/HTN/ATT/ART intake
• No h/o blood transfusions in past
PERSONAL HISTORY-
• ex smoker, ex alcoholic, vegetarian
• literate till 12th standard
• works in a private factory
• married since last 1.5 years without any child
• no h/o any illicit drug abuse
FAMILY HISTORY-
• non contributory
• wife is not a K/C/O immunocompromised state

6. GPE-o
conscious,
o not oriented to time/place/person,
o extremely agitated,
o GCS E4V4M4 (12/15)
o BP- 130/90 mm Hg, PR- 84/min
o no P/I/Cy/Cl/LAP
o Pupils b/l normal size symmetrical and
non reactive to light

7. CNS EXAMINATION–
o HMF- CNBA
o Meningeal signs- negative
o Speech- normal
o Cranial nerves- b/l ptosis with only abduction
movement in right eye & restricted upward gaze in left
eye s/o rt. nuclear third nerve palsy
o Sensory- CNBA
o Motor- moving all four limbs
o DTR- all present and symmetrical
o Plantars- b/l flexor response

8. Immunocompromised state (HIV+) with pyrexia with
headache with altered sensorium with right nuclear
third nerve palsy
etiology- meningoencephalitis with midbrain
involvement ?Tb ?fungal ?protozoal ?? bacterial

9. o RBS-81mg%
o S.Na- 132
o S.K- 4.0 meq/l
o S.Cl- 97
o Urea – 37
o Creat -1.1 mg%
o Proteins- T 7.8 A4.6
o Bilirubin- T0.6 C0.1 mg%
o ALP 110
o SGOT 45 IU/l
o SGPT 55

10. o Hb- 14 gm%
o TLC-7670/mm3(N74.5% L 24.8% M0.7%)
o ESR- 8mm/1st hr
o Platelets 156000/mm3

12. Multiple round lesions in b/l frontal lobes, grey-white
matter junction, right thalamus, right caudate nucleus
and midbrain with extensive perilesional edema

14.  CSF examination cytology RBC 90, WBC 1
sugar 56 (concomitant RBS 78 mg%)
proteins 60 mg%
ADA 5 IU/l (normal <10)
staining gram/ZN/india ink- NAD
cl/s- growth of contaminants
 CD4 count 21/microl

15. Multiple peripheral ring like and nodular enhancing
lesions with perilesional edema in b/l frontal lobes,
caudate, thalamus, midbrain, cerebellum, 1st
possibility- cerebral toxoplasmosis

19. Toxoplasma antibodies panel:
IgM 3.40 AU/ml (<6.00)
IgG 87.00IU/ml (<7.20)

20. HIV-AIDS with cerebral
toxoplasmosis

21. ON admission
o RT insertion and feed 200ml/4 hrly
o Foley’s catheterisation
o Tab. Cotrimoxazole DS 1 tab stat and then OD
o Inj. Dexamethasone 8 mg stat I/V f/b 4 mg I/V TDS
After 24-36 hrs after treatment initiation :
conscious and well oriented
Within one week-b/
l ptosis improved

24. Goldman’s CECIL MEDICINE 24TH EDN

25. MANSON’S TROPICAL DISEASES

26. Tachyzoite form causes a strong inflammatory
response and tissue destruction and is therefore
responsible for clinical manifestations . Under
pressure of the immune system, tachyzoites are
transformed into bradyzoites that form cysts
Both the cellular and humoral immune systems
control primary infection but the cellular arm
especially Th1 prevent reactivation

27. CD8+ T cells capable of lysing infected host
cells play a major role as effector lymphocytes
wheareas CD4+T cells are important to regulate
immune response to T.gondii
Within 2 weeks of infection, IgG, IgM, IgA,
IgE against parasite can be detected
In immunocompromised patients bradyzoites
are released from cysts, transform back into
tachyzoites and cause reactivation of the
infection

28. Transmission routes:
Oral
Blood & organs
Transplacental

29. Clinical manifestations
Clinical features
(host immune status)
Signs and sympotoms Pathology
Lymphadenitis
(immunocompetent)
Absent(90% cases), rarely
malaise, fever, night
sweats,Hp+Spl+, LAP
Follicular hyperplasia,
irregular clusters of
epithelial histiocytes
invading germinal centre
Toxoplasma
encephalitis
(immunocompromised)
Hemiparesis, personality
changes,
aphasia,seizures,
weakness, sensory
abnormalities
Multiple brain abscesses,
foci of enlarging necrosis,
microglial nodules
Retinochoroiditis
(immunocompetent
and
immunocompromised)
Ocular pain, loss of VA,
scotoma, photophobia
Necrotising retinitis
posterior pole and inner
layer(frequently U/L)
Congenital
Toxoplasmosis
(immunocompetent
mothers)
Microcephaly, blindness,
epilepsy, psychomotor or
mental retardation
Necrosis of cortex and
basal ganglia,
hydrocephalus,
periaqueductal and
periventricular vasculitis

30.  In immunocompetent- cervical LAP (MC), headache,
malaise, fatigue, fever, myalgia, sore throat, abdominal
pain, maculopapular rash, confusion,
RARELY-pneumonia, myocarditis, encephalopathy,
pericarditis, polymyositis
lab diagnosis- USUALLY UNREMARKABLE
(minimal lymphocytosis, raised ESR, nominal increase
in aminotransferases, CSF analysis- raised
pressure/mononuclear pleocytosis 10-50/slightly raised
protein/increased gamma globin/PCR Toxoplasma
DNA)
note- CSF of chronically infected individuals is normal

31. AIDS associated toxoplasma encephalitis results from
reactivation of chronic latent infection in more than
95% of patients. In patients with AIDS seropositive for
T.gondii, the risk for cerebral toxoplasmosis
approaches 30%.
 In pts. with TE resulting from reactivation of latent
infection in the CNS , affected organs include grey
and white matter of brain, retina, lungs, heart and
skeletal muscles

32. Incidence of TE correlates directly with
prevalence of T.gondii antibodies, the degree of
immunosuppression, the immunological
response to ART and the use of effective
prophylaxis against TE
>95% cases of TE is due to reactivation of
latent infection and occurs mostly when CD4
count <100/microlitre

33. Cl/m: encephalopathy, meningoencephalitis,
mass lesions
Cl/f: altered mental status(75%),fever(10-
72%),seizures(33%), headaches(56%),focal
neurological findings(60%) incl. motor deficits,
cranial nerve palsies, movement disorders,
dysmetria, visual field loss and aphasia

34. Without treatment, pts. may progress to coma
in days-weeks
Most often involved areas- brainstem, basal
ganglia, pituitary and corticomedullary
junction
Diffuse toxoplasmic encephalitis may develop
acutely and can be rapidly fatal; generalized
cerebral dysfunction without focal signs is the
most common manifestation, and CT scan
findings are normal or reveal cerebral atrophy.

35. Spinal cord involvement manifests as motor or sensory
disturbances of single or multiple limbs, bladder or
bowel dysfunctions, or both and local pain. Patients
may present with clinical findings similar to those of a
spinal cord tumor. Cervical myelopathy, thoracic
myelopathy, and conus medullaris syndrome have been
reported.
Pulmonary toxoplasmosis (pneumonitis) due to
toxoplasmosis is increasingly recognized in patients
with AIDS who are not receiving appropriate anti-HIV
drugs or primary prophylaxis for toxoplasmosis. The
diagnosis may be confirmed by demonstrating T
gondii in bronchoalveolar lavage fluid.

36. Pulmonary toxoplasmosis occurs mainly in patients
with advanced AIDS (mean CD4+count of 40 cells/μL
±75 standard deviation) and primarily manifests as a
prolonged febrile illness with cough and dyspnea.
Pulmonary toxoplasmosis may be clinically
indistinguishable from P.carinii pneumonia, and the
mortality rate, even when treated appropriately, may
be as high as 35%.
Ocular toxoplasmosis, ie, toxoplasmic
retinochoroiditis, is relatively uncommon in patients
with AIDS; it commonly manifests as ocular pain and
loss of visual acuity. Funduscopic examination usually
demonstrates necrotizing lesions, which may be
multifocal or bilateral. Overlying vitreal inflammation
is often present and may be extensive. The optic nerve
is involved in as many as 10% of cases.

37.  Other, uncommon manifestations of toxoplasmosis in
patients with AIDS include the following:
• Panhypopituitarism and diabetes insipidus
• Multiple organ involvement, with the disease manifesting
as acute respiratory failure and hemodynamic abnormalities
similar to septic shock
• Syndrome of inappropriate antidiuretic hormone secretion
and possibly orchitis
• Gastrointestinal system invasion of T gondii may result in
abdominal pain, diarrhea, and/or ascites (due to
involvement of the stomach, peritoneum, or pancreas)
• Acute hepatic failure
• Musculoskeletal involvement
• Parkinsonism
• Focal dystonia
• Hemichorea-hemiballismus

39. Tissue and body fluids- subinoculation into peritoneal
cavity of mice; tissue biopsy
Serology- routine method of diagnosis
 IgG- Sabin feldman dye test, IFA test, ELISA
 IgM-ELISA; ISAGA
 IgA- double sandwich technique
molecular diagnostics- PCR; RT-PCR

40. Typically acute phase IgM appears first about 1-2
weeks after infection f/b by IgA and IgE. Generally
IgM peaks at about 2 months. The time by which these
Igs can no longer be detected is highly variable
depending on the test employed usually about 6-9
months. IgG levels reach maximum at about 4 months
then decline to a lower level over next 12-24 months
but persist for decades.
The utility of the avidity test is based on the
observation that Toxoplasma IgG Abs from pts with
recently aquired T.gondii infection bind antigens
weakly(low avidity) compared from chronically
infected pts. with high avidity

41. Note- in IC pts. with TE indirect serologic methods
widely used in immunocompetent pts. are unrelible
because they fail to produce sufficient titres of
antibodies.
Although incidence of TE among IC pts. directly
correlates with the prevalence of anti-T.gondii
antibodies, the absence of IgG antibody makes
diagnosis of toxoplasmosis unlikely but not
impossible. Anti-toxoplasma IgM antibodies are
usually absent

42. Goldman CECIL MEDICINE

43. Presumptive clinical diagnosis of TE in AIDS
patients is based on clinical presentation, history
of exposure(as evidenced by positive serology),
and radiological evaluation. {PV 80%}
Definitive diagnosis of CNS Toxoplasmosis
requires
o Compatible clinical findings
o Identification of one or more mass lesions by
CT, MRI or other radiographic technique
o Detection of T.gondii in sample
.

44. Detection of T gondii DNA on polymerase chain
reaction (PCR) testing of cerebrospinal fluid (CSF)
samples may facilitate the diagnosis and follow-up of
toxoplasmosis in patients with AIDS. A positive PCR
in brain tissue does not necessarily indicate active
infection because tissue cysts persist in the brain long
after acute infection. PCR in blood samples has a low
sensitivity for diagnosis of toxoplasmic encephalitis in
AIDS patients.
CSF findings may also include elevated protein and
variable glucose and WBC counts (lymphocytic
pleocytosis). The presence of Epstein-Barr virus DNA
in the CSF favors the diagnosis of lymphoma.

45. Lumbar puncture may be contraindicated
because of increased intracranial pressure,
however.
For many clinicians, therefore, CNS toxoplasmosis is an empiric
diagnosis that relies on clinical and radiographic improvement
in response to specific anti-T gondii therapy .
In patients who fail to respond to specific
therapy, brain biopsy can be used to secure a
clinical sample for testing.

46. Indications for brain biopsy include either of the
following:
• Single mass lesion and negative serologic results
• No response to 14 days of empiric therapy
Diagnostic yield of stereotactic biopsies increases
with the number of specimens obtained.
Histologic findings include the following
Lymphocytic meningitis, individual cyst-containing
lesions
Astroglial and microglial nodules
Associated lymphocytic vasculitis
 Diffuse encephalitis

47. High-magnification photomicrograph shows a tissue cyst and tachyzoites in
the brain parenchyma.

48. Radiographic
features
When toxoplasmosis invades brain it causes acute encephalitis.
Focal mass lesions of variable size are seen with central area of
necrosis. Although grossly similar to an abscess , the lesion is
unencapsulated and therefore is histologically classified as
encephalitis rather than an abscess or granuloma. The imaging
findings in toxoplasmosis are a reflection of these
histopathological features
Typically cerebral toxoplasmosis manifest as multiple lesions,
with a predilection for the basal ganglia and corticomedullary
junction .

49. CT
 Typically, cerebral toxoplasmosis appears as multiple
hypodense regions predominantly in the basal ganglia and
at the corticomedullary junction. However, they may be
seen in the posterior fossa. Size is variable, from less than 1
cm to more than 3 cm, and there may be associated mass
effect.
 enhancement - following administration of contrast there is
nodular or ring enhancement which is typically thin and
smooth
 double-dose delayed scan - may show a central filling on
delayed scans
 calcification - seen in treated cases; may be dot-like or
thick and 'chunky'

50. MRI
 T1 - may be difficult to identify, but are typically iso intense or hypo intense
 T2 -
intensity is variable, from hyper intense to iso intense
hyper intense - thought to represent necrotising encephalitis
iso intense - thought to represent organising abscess
lesions are surrounded by perilesional oedema
 T1 C+ (Gd) - lesions often demonstrate ring enhancement or nodular
enhancement. Eccentric target sign (small central foci of enhancement
within the necrotic cavity) is specific for toxoplasmosis
MR spectroscopy
◦ increased lactate
◦ increased lipids
◦ reduced Cho and NAA
◦ Increased lipid-lactate peak is characteristic, however choline peak also
may be seen in few cases.

51. Transaxial contrast-enhanced computed tomography scan in a
24-year-old man with human immunodeficiency virus infection
and central nervous system toxoplasmosis shows a low-attenuating
mass with minor peripheral ring enhancement.

52. T1-weighted axial gadolinium-enhanced magnetic resonance image at the level of the
basal ganglia in a 37-year-old patient with human immunodeficiency virus infection.
The image shows 2 complex, ring-enhancing lesions in the basal ganglia on the right,
surrounded by notable white matter edema. Additional lesions were noted elsewhere
in the brain. This appearance is typical of central nervous system toxoplasmosis,
which has the propensity to involve the basal ganglia

53. 95% specificity; 25%sensitivity

54. Typically see clinical improvement in 1-2 weeks and
radiological improvement in 2-3 weeks (MRI more
sensitive than CT)
If no improvement- consider for stereotactic CT
guided brain biopsy / PCR amplification of CSF for JC
or EBV
SPECT; PET

55. D/D-
PCNSL
cerebral Tb
cryptococcosis
aspergillosis
microsporidiosis
T.cruzi
metastasis
glioblastomas

58. Oxford american
handbook of
neurology

59. Neurological practice:an indian
perspective by wadia

60. Manson’s
tropical diseases

63. In patients in whom brain imaging shows multiple lesions,
whether serologic results are negative or positive,
antitoxoplasmosis therapy should be initiated.
In cases of impending herniation, an open biopsy with
decompression is indicated.
Corticosteroid treatment may be warranted in cases of
impending brain herniation. However, their use may complicate
the interpretation of a response to antitoxoplasmosis therapy.
Standard therapy consists of pyrimethamine, sulfadiazine, and
folinic acid in combination. Trimethoprim-
Sulfamethoxazole (TMP-SMZ) can be used as an alternative
regimen. A Cochrane data base review failed to find a
significant difference between standard therapy and TMP-SMZ.
Clindamycin/Atovaquone can be used in patients allergic
to sulfa drugs. Effective antiretroviral therapy is equally
important.

64. Anticonvulsants should be administered to pts. with
history of seizures but they should not be administered
prophylactically to all pts.
With antibiotic therapy, 74% of patients improve by
day 7, and 91% improve by day 14. Imaging studies
are performed every 4-6 weeks until complete
resolution of the lesion or stabilization after partial
resolution.
Primary therapy is given for 6 weeks, followed by
long-term suppressive therapy at reduced doses, with
the duration determined by response to highly active
antiretroviral therapy (HAART).

65. Individuals who have completed initial therapy for
TE should receive secondary prophylaxis
indefinitely unless immune reconstitution occurs and
CD4+T cell count >200/microlitre for at least 6
months occurs as a consequence of ART
Note (1)- most drugs used for the treatment of
toxoplasmosis are active only against tachyzoite
forms of the parasite and treatment does not eradicate
infection
Note (2) pts with TE should be monitored routinely
for ADR and clinical and radiological improvement

66. Patients who are seropositive for Toxoplasma should be started
on primary prophylaxis against CNS
toxoplasmosis if their CD4+ count drops below 100 cells/μL.
The preferred prophylactic regimen is one double-strength
tablet of trimethoprim-sulfamethoxazole (TMP-SMZ) daily,
which also provides prophylaxis against Pneumocystis
jiroveci pneumonia (PCP). The recommended alternative for
patients who cannot tolerate TMP-SMZ is dapsone-pyrimethamine
plus leucovorin, which is also effective against
PCP.
Primary prophylaxis can be discontinued in pts who have
responded to HAART with an increase in the CD4+ counts
>200 for more than 3 months

69. Thank you