CRYPTOCOCCAL MENINGITIS - Case presentation

1. Guide
Prof. Mohd Ashraf
Bhat
Professor & Head
Department of Nephrology
Moderator
Prof. Iftikar Bashir
Department of Endocinology
Senior
Resident
Dr. Hilal Azad
Senior Resident,
Deptt of Nephrology
Presented
by
Dr. Shami Kumar
PG Medicine (2Y - PG -1458)

2.  60 y/m, T2DM , post renal transplant on Tac/MMF/pred.
a/w h/o
 Low grade fever x 1 week
 Gait instability x 2days
 Slurring of speech
Associated history of
-- Headache – mild and global
-- Vomiting – 2 episodes
-- Generalised weakness
Case Profile

3. No history of :
•Altered mental status
•Abnormal body movements
•Urinary / faecal incontinence
•Trauma
•Difficulty in swallowing
•Blurring of vision
•Backache
•Drug intoxication
•Respiratory symptoms
•Altered bowel and bladder habits
• ATT intake

4. Past history:
T2DM x 20 yrs (complicated - triopathy).
Renal transplantation – 2 years back (donor - wife)
H/O rash in left naso-labial area (?herpetic) x 1 month back
Family history: not significant
Allergic history : not significant

5. Drug history :
Tab. Prednisolone – 10 mg x OD
Tab. Tacrolimus – 1 mg x BD
Tab. Mycophenolate mofetil- 360 mg x TID
Tab. Metoprolol– 25 mg x OD

6. Patient was conscious, cooperative and oriented in time, place and person
General Physical Examination
VITALS
Pulse - 104 b/m
B .P - 130/70 mmhg
R.R - 24 /min
Spo2 - 92 % on room air
Temp - 100.2 F

7. Pallor (+)
Icterus (-)
Cyanosis (-)
Oedema (-)
No clubbing / LAP Cushingoid facies (+)
Tongue - moist
Crusting over left naso-labial fold
No neck swelling
JVP normal

8. Systemic Examination
Chest - No deformity
- B/L NVBS (+)
CVS - S1 S2 (+)
- No rub/ murmur
P/A - Soft /NT/ND
- BS(+) , No organomegaly

9. NEUROLOGICAL EXAMINATION
- HMF (Normal)
- Neck - Free
- Speech – Dysarthic
- Pupils- B/L NSRTL
- FUNDUS No Papilledema
(b/l PDR)
MOTOR:
-Bulk (normal)
- Tone (decreased all over)
- Power – grade 5 all limbs
- DTR – absent both upper and
lower limbs
- Plantars – B/L down
SENSATIONS:
Impaired touch, pain &
Vibration (Symmetrically)
CEREBELLAR SIGNS:
Gait –Ataxic
No nystagmus

10. Differential Diagnosis
 Meningitis - ? viral
? Bacterial
? Fungal
? Tubercular
 Cerebrovascular event.
 Viral cerebellitis.

11. HB TLC DLC PLT MCV/MCH
13.1 5.7 63/23 80 91/29
12.9 5.0 83/7 82 90/29
12.4 6.8 85/5 130 88/29
urea creatinine
62 1.6
48 1.5
35 1.1
Bil ALT ALP TP Alb
0.74 48 75 5.6 3.5
0.89 34 57 6.0 3.4
0.67 44 56 6.1 3.2
Cal Po4 UA CPK LDH Amy BSR
8.7 3.3 7.6 91 124 34 153
INVESTIGATIONS

12. Na K pH pCO2 HCO3 Lac
134 4.6 7.36 42 21 1.8
136 4.8 7.38 35 20 0.7
VIRAL SEROLOGY
HBsAg NR
ANTI-HCV NR
HIV I&II NR
CMV IgM NR
HSV I & II NR
EBV IgM NR

13. ECG - NSR, Rate 60/min
Chest x-ray - WNL
Urine R/E - pus cells 1-2
Calcium oxalates few
Sugar +
protein nil
Blood culture- sterile
Urine culture- sterile

14. NCCT HEAD
Diffuse periventricular Small hypodensities S/o Small Vessel
disease.
MRI Brain:
Multifocal T2 hyperintense foci in B/L cerebellum with
suppression of signal on FLAIR on all MRI sequences, No
perilesional edema seen.

18. CSF ANALYSIS
TLC- 40 CELLS
DLC – N (55) , L (45)
GLUCOSE – 28 mg/dl (CSF/Serum Glucose – 0.18) ,
PROTEIN – 60 mg/dl

19. CSF for G/S & Culture and Cryptococcal antigen
Gram stain & Culture: Sterile
CSF for AFB stain : Neg
Fungal stain/ indian ink- Encapsulated yeast cells
seen , s/o cryptococcal infection
Fungal culture - growth of cryptococcus
neoformans
CSF for Cryptococcal antigen – positive
CSF for CMV /EBV/HSV : Neg

20. FINAL DIAGNOSIS
T2DM , POST-RENAL TRANSPLANT ADMITTED WITH
CRYPTOCOCCAL MENINGITIS

21. Treatment Initially Received in hospital
Inj TeIcoplanin 400mg iv BD
Inj Meropenem 500mg iv BD
Tab Acyclovir 800mg TID (1 day only)
Inj Thiamine 200mg IV BD
Tab . Ecosprin Av OD
After Final Diagnosis patient was started on
Inj Liposomal Amphotericin B 300mg iv OD x 4 weeks
Insulin and Immunosuppresants were continued

22. • .
Course during Hospital stay
Patient received 4 weeks therapy of injection liposomal
Amphotericin B.
Patient was discharged in stable condition on Tablet
Fluconazole 400mg OD
Immunosuppressant's were continued

24. Cryptococcosis in solid organ transplant recipients
•Third most commonly occurring invasive fungal infection.
•Accounts for approximately 8 % of invasive fungal infections.
•Overall incidence – 0.2 to 5 %.
•Higher incidence in heart and kidney transplant recipients.
•Late occurring infection (median time 16 to 21 months post-transplant).
• Time to onset is earlier for liver & lung as compared to renal transplant
recipients
American journal of transplantation 2013;13:242-249

25. •Estimated lifetime and 12 month cumulative incidence - 12 and 0.2 %
respectively.
•90 day and 12 month mortality rates - 15 and 27% respectively
Risk factors :
Male sex
Geographic environmental exposure
Corticosteroids
Liver disease(viral hepatitis ,liver failure & cirrhosis)
Alemtuzumab therapy (anti CD52 ab)
Calcineurin inhibitors(skin , soft tissue & bone involvement)

26. Last 2 forms (within first 30 days after transplant).
Cryptococcus can present as follows:
1. Primary infection after transplantation.
2. Reactivation in host secondary to transplant associated
immunosuppression.
3. Donor derived infection through transplanted organ ; or
4. Rarely unrecognised pretransplant cryptococcosis.

27. Pathogen Sero-
-type
Geographic
distribution
Environmental
distribution
Affected patient
groups
C. Neoformans
var grubii
A Worldwide Birds, particularly
pigeon excreta
HIV patients,
Immunocompromised
patients rarely
Immunocompetent
C. Neoformans
var gatti
B,C Tropics &
Subtropics
Flowering Eucalyptus
trees
Immunocompetent
patients
C. Neoformans
var neoformans
D Worldwide Birds, particularly
pigeon excreta
Immunocompromised
patients rarely
Immunocompetent
C. Neoformans
var grubii/var
neoformans
hybrid
AD Not Known Not Known Rare Clinical isolate;
Immunocompromised
patients
Occasional disease has been described with C. albidus & C. laurentii

28. PATHOGENESIS
•Yeast forms are generally inhaled to initiate exposure.
•Desiccated yeast cells (3 micro m) or basidiospores(1-2 um) are considered
infectious particles .
•Yeast cells – more resistant to innate immunity response than spores.
•Inside lungs - encounter alveolar macrophages & 3 possible scenarios;
1. Total clearance of pathogen .
2. Lung – lymph node complex (M.C. Outcome) and
3. Lung parenchyma and tissue invasiveness.
Immunocompromised host – complex may replicate and disseminate.

29. • Factors allowing for invasiveness :
Pathogen virulent factors:
A. Capsule – antiphagocytic property.
B. Melanin – antiphagocytic and anti oxidative.
C. Urease - enhances CNS invasion.
 Reduced inflammation & neutrophil migration , formation of giant yeast cells &
variation on chromosome copy no may be other important fungal mediated
pathogenic mechanisms.

30. CLINICAL PRESENTATION
• Presents mainly with pulmonary or CNS involvement.
• Depends on type of transplant.
• Can infect any other body site –
skin , soft tissue , muscle , bone & joints ,head & neck , eye
genitourinary & gastrointestinal tracts, cardiovascular ,
thyroid & adrenal glands.

31. Clinical features and incidence of Cryptococcosis among different solid organ
transplant recipients
Type of solid organ
transplant
Incidence Clinical feature
Lung and
heart–lung
2% Common pulmonary involvement but dissemination can
occur.
Cryptococcus skin manifestations such as cellulitis and
Cryptococcus associated IRIS have been documented.
Cryptococcus can colonize the airways of lung transplant
recipients and can cause endobronchial fungal infection.
Heart 3% High mortality associated with fungemia by Cryptococcus
and can be manifested with sepsis. Cryptoccocal necrotizing
soft tissue infection and hepatic Cryptococcosis have been
described
Renal 2.8% Cryptoccocal necrotizing soft tissue infection, deafness,
blindness, part of a polymicrobial pneumonia, parathyroid
gland infection, prostatitis, pyelonephritis, skull
osteomyelitis, lymphadenitis and bilateral complete
ophthalmoplegia have been described
Liver 2.4% Liver failure in liver transplant recipients is independently
associated with Cryptoccocal meningitis
mortality . Hepatic Cryptococcosis, cellulitis and skin scalp
eruption have been described.

32. CENTRAL NERVOUS SYSTEM
 CNS involvement seen in total of 48 to 89 % of solid organ transplant patients with
cryptococcosis.
• 12 week mortality – 21.2%.
• Usual post transplant onset – 19 months.
• Present as
1. Meningitis (14%) / meningoencephalitis – M.C.
2. Cryptococcomas / parenchymal abscesses (12%).
3. Hydrocephalus (4%).

33. CRYPTOCOCCAL MENINGITIS
• Most common manifestation.
• Usually subacute or chronic.
• Invariably fatal without appropriate therapy.
• Death - from 2 weeks to several years.
• Clinical presentation and course vary – underlying medical
conditions(diabetes , sarcoidosis , glucocoticoid use) & immune
status of host.

34. • Most common symptoms;
• Headache – frontal / temporal.
• Altered mental status- personality changes, confusion ,lethargy
obtundation & coma.
• Nausea and vomiting are common.
• Fever & neck stiffness - less common.
• Seizures – (4%).
• Cranial neuropathies –(15%).
• Focal neurological deficit –(5-15%).
• Dizziness , cerebellar ataxia & syncope.

35. • Visual symptoms – (21%) & neuro-ophthalmic findings in upto 33%.
• Visual symptoms include;
1. Impaired visual acuity- increased ICP.
2. Necrotising optic neuropathy- cryptococcal infiltration
3. Compression of optic nerve
4. Diplopia – intermittent or persistent.
5. Papilledema (1.5 to 12%).
6. Field defects- homonymous , bitemporal or altitudinal.

36. Psychiatric symptoms – may also be presenting feature, include
1. Psychosis .
2. Behavioural changes.
3. Mania .
• Hearing defects , aphasia & choreoathetoid movements.
• Dementia is a potential sequelae – indicate presence of
hydrocephalus as a late complication.

37. DIAGNOSTIC WORKUP
• Lab. Diagnosis :
1. MICROSCOPY
Indian ink / gomori’s methanamine silver stains /Mucicarmine stain / fontana mason stain
2. CULTURE FROM TISSUE SAMPLES
• Sputum / BAL / blood / CSF.
• Blood culture – positive in 45% of patients with meningitis.
• Sabourad’s agar (3-12 days), staib’s birdseed, dopa, caffeic acid media.
3. ANTIGEN DETECTION
• Polysaccharide Ag testing by Latex agglutination test / ELISA / lateral flow assay.

38. CSF IN CRYPTOCOCCAL MENINGITIS
1. Positivity for CSF antigen titre.
2. Increased opening pressure (16 – 29 cm of H2O).
3. Pleocytosis (25- 330 wbc /mm3).
4. Increase in protein levels (60 – 190 mg/dl).
5. Positive CSF culture.
• CSF cryptococcal antigen testing – more sensitive and specific than indian ink
staining or fungal culture.
• Serum cryptococcal antigen testing is also a very sensitive test (90%) for initial
diagnosis of infection , but titres among transplant recipients are normally lower
than in HIV patients.

39. IMAGING
• Chest X ray : alveolar or interstitial infiltrates.
• CT scan : no pathognomic brain damage. May be normal or reveal – meningeal enhancement ,
single or multiple nodules (cryptococcomas) , cerebral edema or
hydrocephalus.
• MRI scan : more sensitive for detection of multiple enhancing nodules within brain parenchyma ,
, meninges , basal ganglia & midbrain. Cryptococcal gelatinous pseudocyst are
hypointense to brain on T1W1 & very hyperintense on T2W1, suppress on FLAIR.
Perilesional edema absent.
- Tuberculoma are hypointense on T2W1.
- Toxoplasmosis usually has multifocal ring like hyperintense lesions (T2) with
significant perilesional edema.
-Primary lymphoma in HIV/AIDS patients often show necrosis & ring enhancement.

40. Axial T2-weighted magnetic
resonance image shows
clustered hyperintensities in
the left caudate; these are
consistent with enlarged
Virchow-Robin spaces caused
by small cryptococcomas

41. PHASE THERAPY OF CHOICE DURATIO
N
Meningitis and disseminated disease or moderate to severe non-CNS disease
Induction Preferred: Liposomal AmB (3–4 mg/kg per
day IV) or ABLC (5 mg/kg per day
IV) Plus Flucytosine (100 mg/kg per day in
four divided doses)
Alternative (in the absence of Flucytosine):
lipid formulation of AmB (LF-AmB)
2 weeks
4-6 weeks
Consolidatio
n
Fluconazole PO 400–800 mg
(6–12 mg/kg) daily
Salvage therapy in relapses: Fluconazole
800–1200 mg PO daily or
Voriconazole 200–400 mg PO daily or
Posaconazole 200 mg PO QID
8 weeks
10-12 weeks
Maintainenc
e
Fluconazole PO 200–400 mg daily 6-12 mo
Mild to moderate non-CNS disease including pulmonary disease
Therapy Fluconazole PO 400 mg (6 mg/kg) daily 6-12 mo
Pretransplant asymptomatic pulmonary nodules
Therapy
Antifungal regimens for cryptococcal disease in ORGAN TRANSPLANT RECIPIENTS

42. • Immunosuppressive management should include sequential or step
Wise reduction of immunosuppressants ,with consideration of lowering the
corticosteroid dose first.
• Abrupt withdrawal or reversal of immunosuppression- leads to a shift towards a
proinflammatory state > poses risk of IRIS or organ rejection.
• Drug – drug interactions must be considered – especially with calcineurin inhibitors.
• AmBd – nephrotoxic > used with caution , not recommended as first line .

43. PREGNANT WOMEN:
1. For disseminated and CNS disease > use AmBd or LF-AmB with or without
fluocytosine {category C drug}.
2. Start fluconazole {category c} after delivery; avoid during 1st trimester & during
last 2 trimesters > judge the use with need for continuous antifungal drug exposure
during pregnancy.
3. Watch for IRIS (Immune reconstitution Inflammatory syndrome)in postpartum
period.

44. • CHILDREN:
1. Induction and consolidation therapy – AmBd(1 mg /kg/day IV) plus Flucytosine
(IOO mg/kg/day orally in 4 divided doses) for 2 weeks
followed by Fluconazole (10-12 mg/kg/day orally) x 8 weeks.
• For AmBd intolerant patients ,either liposomal AmB (5 mg/kg/day) or ABLC (5
mg/kg/day).
• Maintainance therapy is Fluconazole(6 mg/kg/day orally).

45. THANK YOU