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 association of cns cryptococcosis and tuberculosis meningitis remains extremely rare event , especially when a concurrent severe immunodeficiency state such as hiv disease is excluded ( 1 ) .
thus , limited anecdotal cases of concomitant cns cryptococcsis and tuberculosis were reported in international literatures .
of our knowledge this association has not been reported in sarcoidosis yet ( 2 - 3 ) .

 a 42-year - old iranian man , a known case of sarcoidosis , presented with fluctuating hearing loss , headache , confusion and impaired cognition .
the patient was in good health until july 2007 that was treated with prednisone and azathioprine for two years with impression of sarcoidosis .
he did not receive any medication from 2009 till 2011 . in may 2011 , he developed hearing loss , headache and perioral skin lesions .
the patient was admitted in a local hospital and after some clinical and laboratory evaluation , treated by a three days cyclophosphamide pulse with impression of sarcoidosis exacerbation .
he improved clinically to some extent ; but after one month developed progressive severe headache , fluctuating cognitive impairment , and decreased level of consciousness due to symptomatic communicating hydrocephalus ( fig .
findings of cerebrospinal fluid analysis showed protein , 1 gr / dl ; glucose , 27 mg / dl ; without cell .
the results of the gram stain , indian ink and staining for acid fast bacilli , mycobacterium tuberculosis ( mtb ) polymerase chain reaction ( pcr ) , and results of serum human immunosuppressive virus ( hiv ) and human t - cell leukemia virus tests all were negative .
antinuclear antibody , complement , vitamin b12 , and folate levels were normal . in july 2011 , prednisolone , 60 mg / day ,
repeated csf analyses were inconclusive . hence , a trial of infliximab and rituximab were tried with hypothesis of intractable neurosarcoidosis in september 2011 .
after 4 months ( jan 2012 ) , due to deterioration of neurological symptoms he was referred to our center .
a complete immunological - infectious - rheumatological work up was done on him and the csf analysis disclosed high protein ( about 1350 mg / dl ) , low glucose ; ( 27 mg / dl ) without any cell . 
 
although at presentation ( april 2011 ) , no radiological abnormalities were reported on brain mri ( a ) , in jun 2011 , because of deterioration of clinical symptoms ( diplopia , severe progressive headache , and decreased level of consciousness ) due to development of symptomatic communicating hydrocephalus , a ventriculoperitoneal shunt was inserted in right frontal horn of lateral ventricle which led to relative improvement of clinical symptoms ( b ) . 

brain t2w imaging disclosed multiple periventricular hypersignal lesions and non - communicating hydrocephalus ( especially left side ) . likewise , extensive meningeal enhancement was in favor of chronic progressive inflammatory ventriculo - meningitis .
after 5 days , the search for the yeast - specific polysaccharide antigen by a commercial latex agglutination assay became positive for cryptococcus neoformans .
the conditions such as rheumatoid factor , sera with > 200 mg fe 3+/dl , improper cleaning of the ring slide , and non - specific reactivity in hiv - infected patients which can lead to false positive reactions to latex agglutination test were excluded ( 4 - 5 ) .
all tested samples of csf and serum of our patient were negative for indian ink staining .
this staining procedure usually is expected to be positive in 72.4% of patients with cryptococcal meningitis
( 6).amphotericin b plus flucytosine was started with a diagnosis of cryptococcal ventriculitis and anti - tuberculosis drugs were discontinued . due to of cystic changes of ventricles and
shunt malfunction , a new ventriculoperitoneal ( vp ) shunt was inserted in the frontal horn of left lateral ventricle .
repeated csf examinations pointed out persistent increased in albumin content , and low glucose levels without any cell .
microscopic , culture , and pcr for detection of mycobacterium tuberculosis in csf remained negative for the first two months .
after two months of systemic antifungal treatment , the patient deteriorated insidiously , with abnormal csf , protein above 1 gr / dl , glucose below 20 mg / dl , cell ; ( 2 lymphocyte ) , and adenosine deaminase ( ada ) ; ( 7
the mri findings of brain 
 showed severe meningeal enhancement and progressive white matter lesions ( figure 2 ) .
therefore , reevaluation was done with suspicion of amphotericin resistant fungal infection , shunt superinfection , reactivation of neurosarcoidosis , and co - infection of cryptococcosis and other infections such as tuberculosis .
because of decreased level of consciousness due to increased intracranial pressure , the patient emergently operated and right temporal horn cystic lesion was evacuated .
gross appearance of brain revealed congested and inflamed cortex with severe rise of intracranial pressure ( icp ) , accompanied with multiple patchy white exudates on the surface of cerebral cortex that was suggestive for fungal infection ( cryptococcosis ) . the csf sample ( from temporal cystic lesion ) showed spider web clot appearance which was suggestive for tuberculosis . at this time , pcr test for mycobacterium tuberculosis , acid fast bacilli ( afb ) smear , and culture were positive in csf and brain specimens .
cryptococcal latex agglutination test was positive . only at this time we had the first positive sign in pcr test and afb smear and culture for mycobacterium tuberculosis from csf .
repeated sputum , bronchoalveolar lavage fluid , and urine smear for afb and tuberculin skin test were all negative . unfortunately , despite combined therapy of amphotericin b ( systemic and intraventricular ) and antitubercular treatment with five drugs ( isoniazid , rifampin , etambuthol , pirazinamide and streptomycin ) , the patient deteriorated clinically and died after several weeks . 
 
imaging study : extensive periventricular lesions and multiple cystic changes , were detected on flair ( a ) and t2w ( b , c ) brain image .
mri with gadolinium ( d ) enclosed significant ventricular and basal cisterna enhancement despite of antifungal treatment .
 vancomycin and ceftriaxone were prescribed for seven days , but was discontinued because of negative culture and new gram stain tests . 
 
 
vps : ventriculoperitoneal shunt ; ada : adenosine deaminase ; afb : acid fast bacilli ; pcr : polymerase chain reaction 


 simultaneous association of cryptococcosis and tuberculosis is well recognized in immune - compromised states such as patients with hiv and gold - miners especially in a cases of silicosis ( 1 , 7 - 8 ) .
immunomodulative states such as innate immune system impairment , vitamin d deficiency , hiv , and drug induced immunosuppression due to rituximab and infliximab are risk factors for reactivation of latent infections such as tuberculosis and cryptococcosis ( 9 - 10 ) .
dea garcia - hermoso and et al . observed that latent cryptococcal infection may become reactivate even 9 to 13 years after dissemination ( 11 ) .
likewise , recently , joseph , and et al . postulated that tuberculosis infection is an independent risk factor for reactivation and dissemination of cryptococcal infection in hiv patients of south africa ( 9 ) .
this hypothesis is compatible with observations of murray and et al . in african hiv patients showing that cryptococcal infection is a main cause of late mortality and morbidity in patients with tuberculosis who were treated with antituberculosis drugs ( 12 ) . on the other side , ellerbroek and et al .
have shown that components of polysaccharide capsule of cryptococcus such as glucurono - xylo - mannan and galactoxylomannan can lead to induction of suppressor t cells and inhibition of leukocyte chemotaxis to inflammatory sites ( 13 - 14 ) .
these phenomena may explain immunosuppression that is accompanied with cryptococcosis and thereby rare but plausible association of cryptococcosis and tuberculosis even in an immunocompetent patient ( 15 ) .
our patient was a known case of cutaneous sarcoidosis that became complicated by simultaneous cryptococcosis and tuberculosis infection of cns . 
 

sarcoidosis is a multisystem noncaseating granulomatous disease with a propensity for lung , eye , and skin which in less than 5 percent of patients involves nervous system ( 16 - 17 ) .
recently , immunopathological similarities between sarcoidosis and mycobacterial diseases became an attractive subject for investigators .
both tuberculosis and sarcoidosis are granulomatous diseases that are accompanied with antigen - specific th1 response ( 18 ) .
hajizadeh and et al . have reported that antibodies against mycobacterial antigens such as recombinant mycobacterium tuberculosis catalase - peroxidase and early secreted antigenic target protein were elevated in the sera of patients with sarcoidosis ( 19 ) .
they found significant difference between sarcoidosis patients and ppd negative controls by evaluating immune response to mycobacterial antigens with x vivo enzyme - linked immunospot assay ( elispot ) on peripheral blood mononuclear cells ( pbmnc ) .
eishi and et al could isolate mycobacterial dna and rna from sarcoidal tissues by pcr techniques ( 20 ) . according to these evidences
, some investigators postulated that sarcoidosis may be an immune reaction to mycobacterium tuberculosis ( 21 ) .
nonetheless ; immunological reactions in sarcoidosis are complex and usually seem as a paradox . despite cd4 + lymphocytopenia , sarcoidosis by itself does not increase risk of opportunistic infections other than cryptococcosis ( 5 , 22).likewise , in spite of significant regional and systemic granulomatous inflammation in patients with sarcoidosis , the immune response to tuberculin is suppressed and lead to allergy ( 23 ) . given this , we think that probably after exposure to mycobacterial antigens , some genetic or epigenetic predisposing factors modulate immune system and lead to sarcoidal reactions , like immunological reactions to mycobacterium leprea . hence , it may be plausible to expect that sarcoidosis patients be susceptible to reactivation of latent mycobacterium in specific conditions which change aforementioned modulating factors . in our patient
, it seems that immunomodulation due to cryptococcosis and drug ( rituximab and infliximab ) induced immunosuppression may be important in reactivation of latent tuberculosis .
surely , more studies are required to explain correlation between tuberculosis and sarcoidosis and elucidate this hypothesis
. 
 
 introduced patient had unusual presentations that led to delayed diagnosis of tuberculosis . despite several diagnostic work ups , until late stages of disease
no evidence of mycobacterium bacilli was detected and all primary work ups were negative for acid fast bacilli .
meningitis due to tuberculosis usually is associated with mononuclear cell in csf pleocytosis , high albumin content and low glucose level . only in approximately 5 percent of immunocompetent patients and 11 percent of immunosuppressive patients ,
csf cell count would be less than 5 in microliter that it can be an indirect sign of severity of disease ( 24 ) .
repeated csf analysis of presented patient during several months disclosed no evidence of pleocytosis that is not typical for tuberculosis .
moreover , untreated tuberculosis infection of cns has a progressive course and almost always results in death in 3 to 6 weeks ( 25).our patient had a slowly progressive course for months without treatment .
probably , cryptococcosis or sarcoidosis - induced immunomodulation or unique strain of mycobacterium tuberculosis species may be shared in this problem . 


 although in immunocompetent state and sarcoidosis , co - infection of cns cryptococcosis and tuberculosis is very rare , clinical deterioration in patients who receive anti cryptococcal treatment should prompt an aggressive work up for identifying additional infectious agent especially tuberculosis ; and vice versa . since miss or delay in diagnosis of an unsuspected disorder can lead to irrecoverable sequels .
sarcoidosis is a multisystem noncaseating granulomatous disease with a propensity for lung , eye , and skin which recently have been proposed that mycobacterium tuberculosis may contribute in its pathogenesis , and rarely involves central nervous system ( cns ) . despite cd4 + lymphocytopenia , sarcoidosis by itself does not increase risk of opportunistic infections other than cryptococcosis . 
 nonetheless , simultaneous association of cns cryptococcosis and tuberculosis infection remains extremely rare event in immunocompetent states , and has not been reported in sarcoidosis yet . 
 we here presented such a case in a 42 years old man , a known case of sarcoidosis with diagnostic and therapeutic difficulties were encountered in a fourteen - month - long hospitalization period .