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Table of Contents
CASE REPORT
Year : 2020  |  Volume : 14  |  Issue : 1  |  Page : 79-81

Obstructive hydrocephalus in a renal transplant recipient: An avertable diagnostic delay in unraveling cryptococcal meningitis!


1 Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Medical Microbiology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Submission29-Sep-2019
Date of Acceptance23-Dec-2019
Date of Web Publication31-Mar-2020

Correspondence Address:
Dr. Krishan Lal Gupta
Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_54_19

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  Abstract 


Cryptococcal infection constitutes 2.8% of opportunistic infections in solid-organ transplant recipients. The most common organ affected in renal transplant recipients (RTRs) is central nervous system and usually presents with chronic meningoencephalitis. Rapid neurological deterioration in RTR with chronic meningitis despite antimicrobial therapy should alert towards the possibility of either alternative/polymicrobial etiology or complications including hydrocephalus. In this context, we report a RTR with chronic meningitis initiated on empirical antitubercular therapy in the absence of conclusive microbiological diagnosis despite serial cerebrospinal fluid analysis and later admitted with complication in form of obstructive hydrocephalus requiring external ventricular drainage which proved to be therapeutic (decreasing raised intracranial hypertension) as well as diagnostic (yielding Cryptococcus), thereby confirming alternative etiology of chronic meningitis.

Keywords: Cryptococcal meningitis, obstructive hydrocephalus, renal transplant recipient


How to cite this article:
Sood V, Ramachandran R, Gupta S, Inamdar N, Prabhahar A, Gupta KL. Obstructive hydrocephalus in a renal transplant recipient: An avertable diagnostic delay in unraveling cryptococcal meningitis!. Indian J Transplant 2020;14:79-81

How to cite this URL:
Sood V, Ramachandran R, Gupta S, Inamdar N, Prabhahar A, Gupta KL. Obstructive hydrocephalus in a renal transplant recipient: An avertable diagnostic delay in unraveling cryptococcal meningitis!. Indian J Transplant [serial online] 2020 [cited 2020 Jul 6];14:79-81. Available from: http://www.ijtonline.in/text.asp?2020/14/1/79/281771




  Introduction Top


Central nervous system (CNS) infections complicate posttransplant course in 5%–10% of renal transplant recipients (RTRs).[1] Cryptococcal infections constitute up to 8% of invasive fungal infections (IFIs) in solid-organ transplant recipients and stands 3rd in frequency[2] after Aspergillus and Candida. It usually occurs in late (after 1 year) posttransplant period, unlike other IFIs, with overall incidence[3] of around 3% (range: 0.3%–5%). In an immunocompromised host, CNS is the most common site, and mortality rates[4] range between 33% and 42% unlike an immunocompetent host, where the lungs are the primary site and infection is usually subclinical and self-limiting.


  Case Report Top


A 33-year-old male, who underwent a live emotionally related renal transplant 2 years back (wife as a blood group compatible donor), with stable graft function (serum creatinine of 1.2 mg/dL) on triple immunosuppression therapy (mycophenolate mofetil, tacrolimus, and prednisolone) presented now with holocranial headache of 2 months duration. He denied history of fever, vomiting, seizures, loss of consciousness, ear discharge, head injury, or altered sensorium. Clinical evaluation was unremarkable, and contrast imaging of the brain did not reveal any basal exudates, meningeal enhancement, or space-occupying lesion; however, there was mild hydrocephalus. Laboratory evaluation revealed normal hematological and biochemical profile with blood tacrolimus trough level of 6 ng/mL. Initial cerebrospinal fluid (CSF) analysis on an outpatient basis suggested chronic meningitis with raised protein (174 mg/dL), low sugar (48 mg/dL with corresponding blood sugar of 116 mg/dL), and raised cell count of 120 cells/mm3 (lymphocyte 80%). CSF microbiological evaluation (Gram stain, acid-fast bacilli stain, Adenosine deaminase (ADA), Mycobacterium tuberculosis-polymerase chain reaction [PCR], and India ink) was negative. Cryptococcal antigen and PCR for herpes simplex and cytomegalovirus (CMV) (serum as well as CSF) were also negative. Cultures including blood and CSF for bacteria as well as fungus, were sterile. Microbiological diagnosis of chronic meningitis remained elusive as repeated serial CSF evaluation (four times over a month, including cytology for malignant cells and PCR for Herpes simplex, varicella-zoster, CMV, HIV, and toxoplasma) was unyielding. Furthermore, absence of history of potential risk of exposure to tick bite, noncontributory history of travel or high-risk sexual behavior, absence of localizing focal neurological deficits, and lack of response to empirical cephalosporins made spirochetal infection less likely. Tacrolimus was consequently withheld on the outpatient basis considering possible culprit drug, however, symptoms persisted requiring hospitalization. In the absence of any fresh focal neurological deficit, the patient was empirically initiated on nonrifampicin-based anti-tubercular treatment (ATT) besides curtailed immunosuppression. The course remained status quo for almost 2 months when he was admitted with history of multiple episodes of generalized tonic–clonic seizures for the last 1 day followed by loss of consciousness. On evaluation, patient was drowsy with Glasgow Coma Score of 13/15. He was hemodynamically stable and had bilateral papilledema with terminal neck stiffness. Contrast imaging of the brain showed an increase in hydrocephalus [Figure 1]a and b] and subsequently ventriculoperitoneal shunt was placed. The ventricular fluid aspirated during surgery showed positivity for cryptococcal antigen. The patient was initiated on liposomal amphotericin and flucytosine and ATT was withheld. He recovered significantly with 3 weeks of amphotericin (4.5 g cumulative) and repeat tap from the shunt after 3 weeks postsurgery was negative for cryptococcal antigen assay. Thereafter, the patient received a consolidation phase with oral fluconazole (6 mg/kg/day for 8 weeks) and currently maintains stable graft function on dual immunosuppression and secondary suppressive fluconazole prophylaxis (4 mg/kg/day).
Figure 1:(a) Computed tomography of the brain showing hydrocephalus with no evidence of basal exudates, meningeal enhancement, or space-occupying lesion.(b) Computed tomography of the brain following extraventricular drainage with external ventricular drainage in situ. (300 × 300 Dots Per Inch (DPI))

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The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names, initials would not be published, and all standard protocols will be followed to conceal their identity.


  Discussion Top


Both tuberculous meningitis (TBM) and cryptococcal meningitis (CM), the two most common etiologies of chronic meningitis, are clinically indistinguishable and to an extent share similar CSF findings,[5] and sometimes, as in index case may result in diagnostic dilemma; however, extracranial involvement (particularly pulmonary and spinal) probably hints toward tubercular etiology. Our patient did not improve following empirical ATT and rather developed features suggesting obstructive hydrocephalus, requiring external ventricular drainage which proved not only therapeutic but also diagnostic (quantum of ventricular CSF yielded Cryptococcus), thereby confirming alternative etiology of CM.

Virulence of Cryptococcus neoformans is consequent to polysaccharide capsule,[6] which besides providing a physical barrier that interferes with phagocytosis by macrophages and clearance by the immune system and also inhibits production of proinflammatory cytokines and reduces leukocyte migration to sites of inflammation. Capsule also constitutes the major diagnostic feature of CM, as it can be visualized with light microscopy using India ink, mucicarmine, or Periodic acid–Schiff stain with high specificity (97%) but poor sensitivity (73%).[7] Confirmation requires culture on Saboraud's medium with specific biochemical reactions (urease and phenoloxidase) and detection of capsular antigen in CSF by latex agglutination test with capsular polysaccharide antigen titer >1:8 in serum or CSF, which has high sensitivity and specificity of over 90%.

As capsule appears to be the main virulence factor of this organism, meningeal infection with nonencapsulated form although rare,[8] nevertheless requires deliberation, as predisposing factors remain similar to those of encapsulated form. Capsule-deficient Cryptococcus poses a diagnostic challenge, with false-negative tests possibly explained by the fact that capsule deficiency makes it susceptible to phagocytosis by macrophages before it could reach the CSF.[9] Similarly, the latex agglutination test is also not useful as this test detects capsular polysaccharide antigens with the antibody affixed to latex particles.

Several other reasons for false-negative cryptococcal antigen testing include either a low level of antigen production by the organism (as presumed in index case) or a very high antigen level, whereby a prozone effect results in masking of the presence of a particular antigen because of a larger aggregate of nonbinding antibodies, which can be averted by performing very high dilutions to determine the presence of specific antigen. Besides antigen titer, other proposed reasons are either small-colony variants of C. neoformans (also seems plausible in index case) or capsule mutants,[10] which makes it less susceptible to antibiotics and more prone to relapse.

Although no structural lesion was identified on serial contrast imaging scans, it seems plausible that the circulating organisms in the CSF caused dysfunction of the arachnoid villi and impaired CSF absorption, resulting in obstructive hydrocephalus, which is a known complication of chronic meningitis and requires a high index of suspicion. In addition, while the indications for shunting in cryptococcal infection are not well understood, most groups suggest early shunt placement for better clinical outcomes.[11]

Finally, neurotoxicity[12] of drugs used in a RTR should also be borne in mind and remains one of the differentials for aseptic meningitis, especially in the absence of localizing/progressive focal neurological deficits. Tacrolimus was consequently withheld in the index patient on outpatient basis considering possible culprit drug; however, progression of symptoms with new-onset focal neurological deficit steered us to unravel CM.


  Conclusion Top


Failure to recognize either the nonencapsulated or small-colony variants may not only delay the diagnosis of CM and subsequent appropriate antifungal therapy but can also result in complications like hydrocephalus which could be life-threatening in the absence of urgent CSF diversion.

Learning objectives

  1. Although both TBM and CM are clinically indistinguishable and to an extent share similar CSF findings, nevertheless, extracranial involvement, particularly pulmonary and spinal hints toward possible tubercular etiology.
  2. When CM is suspected, particularly in transplant recipients, false-negative tests require deliberation toward infection by either small-colony variants, capsule deficient variants, and capsule mutants or prozone phenomenon.
  3. It is crucial that the management of patients with chronic meningitis includes careful observation for neurological symptoms that may indicate hydrocephalus which requires urgent CSF diversion to avoid permanent neurological damage.


Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors would like to thank Departments of Neurosurgery and Medical Microbiology.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Piotrowski PC, Lutkowska A, Tsibulski A, Karczewski M, Jagodziński PP. Neurologic complications in kidney transplant recipients. Folia Neuropathol 2017;55:86-109.  Back to cited text no. 1
    
2.
Pappas PG, Alexander BD, Andes DR, Hadley S, Kauffman CA, Freifeld A, et al. Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis 2010;50:1101-11.  Back to cited text no. 2
    
3.
Singh N, Forrest G; AST Infectious Diseases Community of Practice. Cryptococcosis in solid organ transplant recipients. Am J Transplant 2009;9 Suppl 4:S192-8.  Back to cited text no. 3
    
4.
Abhilash KP, Mitra S, Arul JJ, Raj PM, Balaji V, Kannangai R, et al. Changing paradigm of cryptococcal meningitis: An eight-year experience from a tertiary hospital in South India. Indian J Med Microbiol 2015;33:25-9.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Lan SH, Chang WN, Lu CH, Lui CC, Chang HW. Cerebral infarction in chronic meningitis: A comparison of tuberculous meningitis and cryptococcal meningitis. QJM 2001;94:247-53.  Back to cited text no. 5
    
6.
Buchanan KL, Murphy JW. What makes Cryptococcus neoformans a pathogen? Emerg Infect Dis 1998;4:71-83.  Back to cited text no. 6
    
7.
Saha DC, Xess I, Biswas A, Bhowmik DM, Padma MV. Detection of Cryptococcus by conventional, serological and molecular methods. J Med Microbiol 2009;58:1098-105.  Back to cited text no. 7
    
8.
Garber ST, Penar PL. Treatment of indolent, non-encapsulated cryptococcal meningitis associated with hydrocephalus. Clin Pract 2012;2:e22.  Back to cited text no. 8
    
9.
Sugiura Y, Homma M, Yamamoto T. Difficulty in diagnosing chronic meningitis caused by capsule-deficient Cryptococcus neoformans. J Neurol Neurosurg Psychiatry 2005;76:1460-1.  Back to cited text no. 9
    
10.
To KK, Cheng VC, Tang BS, Fan YW, Yuen KY. False-negative cerebrospinal fluid cryptococcal antigen test due to small-colony variants of Cryptococcus neoformans meningitis in a patient with cysto-pleural shunt. Scand J Infect Dis 2006;12:1110-4.  Back to cited text no. 10
    
11.
Liliang PC, Liang CL, Chang WN, Chen HJ, Su TM, Lu K, et al. Shunt surgery for hydrocephalus complicating cryptococcal meningitis in human immunodeficiency virus-negative patients. Clin Infect Dis 2003;37:673-8.  Back to cited text no. 11
    
12.
Anghel D, Tanasescu R, Campeanu A, Lupescu I, Podda G, Bajenaru O. Neurotoxicity of immunosuppressive therapies in organ transplantation. Maedica (Buchar) 2013;8:170-5.  Back to cited text no. 12
    


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