Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression.

The aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases, such as tuberculosis or sarcoidosis, and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. We found that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of the gene encoding tuberous sclerosis 2 (Tsc2) was sufficient to induce hypertrophy and proliferation, resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation that was mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 toward increased glycolysis while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients, mTORC1 activation, macrophage proliferation and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.

The host-directed therapeutic imatinib mesylate accelerates immune responses to Mycobacterium marinum infection and limits pathology associated with granulomas.

Infections caused by members of the mycobacterium tuberculosis complex [MTC] and nontuberculous mycobacteria [NTM] can induce widespread morbidity and mortality in people. Mycobacterial infections cause both a delayed immune response, which limits rate of bacterial clearance, and formation of granulomas, which contain bacterial spread, but also contribute to lung damage, fibrosis, and morbidity. Granulomas also limit access of antibiotics to bacteria, which may facilitate development of resistance. Bacteria resistant to some or all antibiotics cause significant morbidity and mortality, and newly developed antibiotics readily engender resistance, highlighting the need for new therapeutic approaches. Imatinib mesylate, a cancer drug used to treat chronic myelogenous leukemia [CML] that targets Abl and related tyrosine kinases, is a possible host-directed therapeutic [HDT] for mycobacterial infections, including those causing TB. Here, we use the murine Mycobacterium marinum [Mm] infection model, which induces granulomatous tail lesions. Based on histological measurements, imatinib reduces both lesion size and inflammation of surrounding tissue. Transcriptomic analysis of tail lesions indicates that imatinib induces gene signatures indicative of immune activation and regulation at early time points post infection that resemble those seen at later ones, suggesting that imatinib accelerates but does not substantially alter anti-mycobacterial immune responses. Imatinib likewise induces signatures associated with cell death and promotes survival of bone marrow-derived macrophages [BMDMs] in culture following infection with Mm. Notably, the capacity of imatinib to limit formation and growth of granulomas in vivo and to promote survival of BMDMs in vitro depends upon caspase 8, a key regulator of cell survival and death. These data provide evidence for the utility of imatinib as an HDT for mycobacterial infections in accelerating and regulating immune responses, and limiting pathology associated with granulomas, which may mitigate post-treatment morbidity.

The Renin-Angiotensin-Aldosterone System Regulates Sarcoidosis Granulomatous Inflammation.

Rationale: Sarcoidosis is a granulomatous disorder of unclear cause notable for abnormal elevation of blood and tissue ACE1 (angiotensin converting enzyme 1) levels and activity. ACE1 regulates the renin-angiotensin-aldosterone system (RAAS), the terminal product of which is aldosterone, which selectively engages mineralocorticoid receptors to promote inflammation. Objectives: We sought to determine whether the RAAS promotes sarcoidosis granuloma formation and related inflammatory responses. Methods: Using an established ex vivo model, we first determined whether aldosterone was produced by sarcoidosis granulomas and verified the presence of CYP11B2, the enzyme required for its production. We then evaluated the effects of selective inhibitors of ACE1 (captopril), angiotensin type 1 receptor (losartan), and mineralocorticoid receptors (spironolactone, eplerenone) on granuloma formation, reflected by computer image analysis-generated granuloma area, and selected cytokines incriminated in sarcoidosis pathogenesis. Measurements and Main Results: Aldosterone was spontaneously produced by sarcoidosis peripheral blood mononuclear cells, and both intra- and extracellular levels steadily increased during granuloma formation. In parallel, peripheral blood mononuclear cells were shown to express more CYP11B2 during granuloma formation. Significant inhibition of sarcoidosis granulomas and related cytokines (TNFα, IL-1ß, IFNγ, IL-10) was observed in response to pretreatments with captopril, losartan, spironolactone, or eplerenone, comparable to that of prednisone. Conclusions: The RAAS is intact in sarcoidosis granulomas and contributes significantly to early granuloma formation and to related inflammatory mediator responses, with important implications for clinical management.

Idiopathic aseptic facial granuloma: A retrospective study of 43 cases.

BACKGROUND: Idiopathic aseptic facial granuloma (IAFG) is an underrecognized pediatric skin disease, currently considered within the spectrum of rosacea. It usually manifests as a solitary, reddish, asymptomatic nodule on the cheek that resolves spontaneously. METHODS: Retrospective and descriptive observational study of 43 pediatric patients with a clinical diagnosis of IAFG, followed between 2004 and 2022, at two general hospitals in Argentina. RESULTS: IAFG predominated in girls (65%) and the average age of onset was about 6 years. A single asymptomatic nodule was seen in 79% of patients. The most common localization was the cheek (58%) followed by lower eyelids (41%). Family history of rosacea was present in 16% of patients. A concomitant diagnosis of rosacea and periorificial dermatitis was made in 14% and 9% of our population, respectively. Past or present history of chalazia was detected in 42% of the children. IAFG diagnosis was mainly clinical (88% of cases). Oral antibiotics were the most common indicated treatment (84%). Complete healing was achieved by the majority, but 18% of those with eyelid compromise healed with scars. CONCLUSIONS: IAFG is a benign pediatric condition that physicians should recognize in order to manage correctly. We herein refer to a particular morphologic aspect of IAFG lesions affecting the lower eyelids, where nodules adopt a linear distribution and have a higher probability of involute leaving a scar. Also, we consider that the concomitant findings of rosacea, periorificial dermatitis and chalazia in our patients, reinforce the consideration of IAFG within the spectrum of rosacea.

Extensive and deep granulomatous ulcers as an atypical manifestation of cartilage-hair hypoplasia syndrome: A diagnostic and therapeutic challenge.

Cartilage hypoplasia syndrome is a primary immunodeficiency disease characterized by short stature, hypoplastic hair and a variable degree of immunodeficiency. Noninfectious cutaneous granulomas represent an uncommon yet well-recognized manifestation within the spectrum of primary immunodeficiency diseases. However, cutaneous granulomas as a manifestation of cartilage-hair hypoplasia syndrome, are extremely rare. We present a case of a middle-aged man with cartilage hypoplasia syndrome featuring cutaneous granulomas, manifesting as chronic, extensive and deep cutaneous ulcers. The patient was treated with anti-TNF-alpha adalimumab with partial improvement. Our case underscores the broad spectrum of clinical manifestations associated with cartilage hypoplasia syndrome and adds new evidence to the potential therapeutic efficacy of anti-TNF-alpha drugs in its treatment.

Isolated Cutaneous Granuloma Caused by Candida Parapsilosis: Case Report and Literature Review.

Candidal granuloma is an uncommon type of deep chronic cutaneous candidiasis. Candida albican is the most common causative pathogen for candidal granuloma. We report herein the original case of a 69-year-old Chinese woman presented with a 3-year of painful cutaneous lesion on the back of left hand. Physical examination revealed a 4 × 5 cm large infiltrative reddish plaque with unclear boundaries. The yellow-white crusts were observed on the uneven surface of plaque. Histopathological examination of biopsy tissue revealed that yeast cells and the horizontal section of hyphae in the dermis by hematoxylin eosin staining and periodic acid-Schiff staining. Finally, the pathogen was identified as Candida parapsilosis by mycological examination and molecular identification. The patient was treated with itraconazole oral 200 mg twice daily combined with topical terbinafine hydrochloride cream for 2 months. The lesions were fully resolved and no recurrence was observed. Since the cutaneous infection caused by C. parasilosis were rarely reported, we also reviewed all 11 cases of cutaneous infection caused by C. parapsilosis in the PubMed. Our study highlighted that chronic unilateral infiltrated plaques or ulcers should be aware of the occurrence of fungal granuloma including candidal granuloma especially in immunocompromised patients.

Evaluation of the antiparasitic and antifibrotic effects of gallic acid on experimental hepatic schistosomiasis mansoni.

Schistosomiasis afflicts approximately 120 million individuals globally. The hepatic pathology that occurs due to egg-induced granuloma and fibrosis is commonly attributed to this condition. However, there is currently no efficacious treatment available for either of these conditions.Our study aimed to investigate the potential antifibrotic and antiparasitic properties of different doses of gallic acid (GA) in experimental schistosomiasis mansoni. In addition, we investigated the outcomes of co-administering it with the standard anti-schistosomiasis treatment, praziquantel (PZQ).In experiment I, Schistosoma mansoni-infected mice were administered GA at doses of 10, 20, or 40 mg/kg. Their effectiveness was evaluated through parasitological (worm and egg loads, granuloma number and diameter), pathological (fibrosis percentage and H-score of hepatic stellate cells (HSCs)), and functional (liver enzymes) tests. In experiment II, we investigated the optimal dosage that yielded the best outcomes. This dosage was administered in conjunction with PZQ and was evaluated regarding the parasitological, pathological, functional, and immunological (fibrosis-regulating cytokines) activities.Our findings indicate that the administration of 40 mg/kg GA exhibited the highest level of effectiveness in experiment I. In experiment II, it exhibited lower antiparasitic efficacy in comparison to PZQ. However, it surpassed PZQ in other tests. It showed enhanced outcomes when combined with PZQ.In conclusion, our findings reveal that GA only slightly increased the antischistosomal activity of PZQ. However, it was linked to decreased fibrosis, particularly when administrated with PZQ. Our pilot study identifies GA as a natural antifibrotic agent, which could be administered with PZQ to mitigate the development of fibrosis.

Antemortem Diagnosis and Successful Long-term Management of Disseminated Intracoelomic Xanthogranulomatous Disease in an Eclectus Parrot (Eclectus roratus).

A 12-year-old male eclectus parrot (Eclectus roratus) was referred for evaluation of coelomic distention. Computed tomography and blood work revealed coelomic effusion with free coelomic mineral-attenuating material and elevations in the bile acids and aspartate aminotransferase activity, respectively. Coelomic effusion was consistent with macrophagic inflammation with abundant intracellular lipids. Initial treatment with meloxicam resulted in minimal patient improvement. Disseminated xanthogranulomatous inflammation was suspected based on imaging and diagnostic laboratory results, which were consistent with those previously reported. Biopsy samples of liver tissue and intracoelomic masses confirmed this diagnosis. Treatment was initiated with prednisolone 1 mg/kg/d for 6 months, followed by 0.5 mg/kg/d for 3 months. Clinical improvement was assessed based on owner evaluation, plasma bile acid concentrations, and repeated computed tomographic scans. After 2 months of treatment, the owner reported improved behavior and appetite; this persisted throughout treatment and when the bird was reexamined 17 months following the cessation of steroid therapy. Bile acid concentrations were normal 10 months after the prednisolone therapy was discontinued. Diagnostic imaging showed minimal coelomic effusion 10 months after the last prednisolone dose was administered, with improved ventilation of the air sacs and static to improved dystrophic mineral foci. This report describes the antemortem diagnosis and treatment of disseminated coelomic xanthogranulomatous disease in a psittacine species, with an observed measurable therapeutic response.

Rubella virus-associated necrotizing granulomatous inflammation with extensive eyelid, ocular, and orbital involvement.

We present a case of cutaneous granulomatous disease associated with rubella virus in a 4-year-old girl without an identifiable immunodeficiency. In this case, a combination of anti-inflammatory, anti-viral, and anti-neutrophil therapies successfully treated vision-threatening eyelid, conjunctival, scleral, and orbital inflammation.

Treatment of aseptic facial granuloma as a manifestation of pediatric rosacea with oral macrolides.

Aseptic facial granuloma is a rare pediatric disease, presenting with asymptomatic facial nodules on the cheeks or the eyelids and may represent a form of granulomatous rosacea in children. In this retrospective case series, 12 children with aseptic facial granuloma were treated with oral macrolides (erythromycin or roxithromycin) resulting in a healing of the lesions within a mean treatment time of 5.25 months with no recurrences. The treatment was mainly well tolerated. Oral macrolides may be effective in the treatment of patients with aseptic facial granuloma.

Antiedematogenic and Analgesic Activities of Abietic Acid in Mice.

Exacerbated inflammatory responses to harmful stimuli can lead to significant pain, edema, and other complications that require pharmacological intervention. Abietic acid (AA) is a diterpene found as a significant constituent in pine species, and evidence has identified its biological potential. The present study aimed to evaluate abietic acid's antiedematogenic and anti-inflammatory activity in mice. Swiss mice (Mus musculus) weighing 20-30 g were treated with AA at 50, 100, and 200 mg/kg. The central nervous system (CNS) effects were evaluated using open-field and rotarod assays. The antinociceptive and anti-inflammatory screening was assessed by the acetic acid and formalin tests. The antiedematogenic activity was investigated by measuring paw edema induced by carrageenan, dextran, histamine, arachidonic acid, and prostaglandin, in addition to using a granuloma model. The oral administration of abietic acid (200 mg/Kg) showed no evidence of CNS effects. The compound also exhibited significant antiedematogenic and anti-inflammatory activities in the carrageenan and dextran models, mostly related to the inhibition of myeloperoxidase (MOP) activity and histamine action and, to a lesser extent, the inhibition of eicosanoid-dependent pathways. In the granuloma model, abietic acid's effect was less expressive than in the acute models investigated in this study. In conclusion, abietic acid has analgesic and antiedematogenic activities related to anti-inflammatory mechanisms.

Symptomatic Intrathecal Catheter Tip Granuloma Formation With Ultralow-Dose and Low-Concentration Morphine Infusion: A Case Report and Review of Literature.

OBJECTIVES: This study aimed to describe catheter tip granuloma (CTG) formation in a patient on ultralow-dose, low-concentration morphine via intrathecal (IT) drug delivery system (IDDS) and to review literature for reports of IT granuloma formation and association with drug type, drug dose, and drug concentration. MATERIALS AND METHODS: This review describes diagnosis and management of a patient with CTG on ultralow-dose, low-concentration morphine. PubMed data base search was conducted from January 1990 to July 2021 for original articles on CTG formation in humans getting intrathecal analgesics. Data were extracted on indications for IDDS, time to detect CTG, and type of drug/s with drug doses and concentrations. Percentages and average with range for age, sex, duration of infusion, drug doses, and drug concentrations were calculated. RESULTS: We describe CTG formation and spinal cord compression with worsening of sensorimotor deficits in a patient receiving intrathecal morphine at ultralow dose (0.6 mg/d) and low concentration (1.2 mg/mL), which is the lowest reported morphine dose associated with CTG in the literature. Our literature review shows all IT drugs have the potential for granuloma formation, and there is no drug with granuloma-inhibiting effect. CONCLUSIONS: There is no drug, dose, or concentration that has granuloma-sparing effect. It is imperative to maintain vigilance for potential CTG in all patients with IDDS. Routine monitoring and prompt evaluation for any unexplained symptoms or change in neurologic status from baseline is critical in early detection and treatment of CTG.

Auranofin attenuates Schistosoma mansoni egg-induced liver granuloma and fibrosis in mice.

Schistosomiasis is a serious tropical disease. Despite extensive research into the etiology of liver fibrosis, effective therapeutic options remain limited. This study aims to assess the effectiveness of auranofin in treating hepatic granuloma and fibrogenesis produced by Schistosoma (S.) mansoni eggs. Auranofin is a gold complex that contains thioglucose tetraacetate and triethylphosphine. Eighty BALB/c male mice were divided into four groups (n=20/group): negative control (GI), positive control (GII), and early (GIII) and late (GIV) treatment groups with oral auranofin according to beginning of treatment 4th week and 6th week post-infection. Mice were infected subcutaneously in a dose of 60±10 cercariae/mouse. Worm counts, egg loads, and oogram patterns were determined. Biochemical, histological, and immunostaining of interleukin-1ß (IL-1ß), Sirtuin 3 (SIRT3), and smooth muscle actin (SMA) were assessed. GIII showed a significant decrease in the total S. mansoni worm burden and ova/gram in liver tissue (with reduction percent of 63.07% and 78.26%, respectively). Schistosomal oogram patterns, immature and mature ova, also showed a significant decrease. The reduction in granuloma number and size was 40.63% and 48.66%, respectively, in GIII, whereas in GIV, the reduction percent was 76.63% and 67.08%. In addition, the degree of fibrosis was significantly diminished in both treated groups. GIV showed significant reduction in IL-1ß and SMA expression and increase in SIRT3 expression. These findings reveal how auranofin suppresses the development of liver fibrosis. Therefore, it is crucial to take another look at auranofin as a prospective medication for the treatment of S. mansoni egg-induced hepatic granuloma and consequent fibrosis.

IgG4-related ophthalmic disease in association with adult-onset asthma and periocular xanthogranuloma: a case report.

A 54-year-old male presented with a three-year history of bilateral upper eyelid and peri-orbital swelling and adult-onset asthma. Histopathology of a left orbital biopsy showed lymphoid follicles with foamy macrophages and Touton giant cells. Clinical, histological and radiological features were consistent with adult-onset asthma and periocular xanthogranuloma. Treatment with rituximab led to a complete clinical and radiological remission. Nine years later, his condition relapsed with a biopsy of the left orbit and lacrimal gland demonstrating features of IgG4-related disease and adult-onset asthma and periocular xanthogranuloma. Immunohistochemistry showed increased numbers of IgG4+ plasma cells (290 per high power field) and an elevated IgG4+/IgG+ plasma cell ratio of 480%. Involvement by both disorders in the orbit and ocular adnexa of a single patient has not previously been reported in the literature, to the best of our knowledge, and suggests a possible aetiologic or pathophysiologic association.

Interleukin-13-Overexpressing Mice Represent an Advanced Preclinical Model for Detecting the Distribution of Antimycobacterial Drugs within Centrally Necrotizing Granulomas.

The Mycobacterium tuberculosis-harboring granuloma with a necrotic center surrounded by a fibrous capsule is the hallmark of tuberculosis (TB). For a successful treatment, antibiotics need to penetrate these complex structures to reach their bacterial targets. Hence, animal models reflecting the pulmonary pathology of TB patients are of particular importance to improve the preclinical validation of novel drug candidates. M. tuberculosis-infected interleukin-13-overexpressing (IL-13tg) mice develop a TB pathology very similar to patients and, in contrast to other mouse models, also share pathogenetic mechanisms. Accordingly, IL-13tg animals represent an ideal model for analyzing the penetration of novel anti-TB drugs into various compartments of necrotic granulomas by matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MS imaging). In the present study, we evaluated the suitability of BALB/c IL-13tg mice for determining the antibiotic distribution within necrotizing lesions. To this end, we established a workflow based on the inactivation of M. tuberculosis by gamma irradiation while preserving lung tissue integrity and drug distribution, which is essential for correlating drug penetration with lesion pathology. MALDI-MS imaging analysis of clofazimine, pyrazinamide, and rifampicin revealed a drug-specific distribution within different lesion types, including cellular granulomas, developing in BALB/c wild-type mice, and necrotic granulomas in BALB/c IL-13tg animals, emphasizing the necessity of preclinical models reflecting human pathology. Most importantly, our study demonstrates that BALB/c IL-13tg mice recapitulate the penetration of antibiotics into human lesions. Therefore, our workflow in combination with the IL-13tg mouse model provides an improved and accelerated evaluation of novel anti-TB drugs and new regimens in the preclinical stage.

Do Anti-tuberculosis Drugs Reach Their Target?─High-Resolution Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging Provides Information on Drug Penetration into Necrotic Granulomas.

Tuberculosis (TB) is characterized by mycobacteria-harboring centrally necrotizing granulomas. The efficacy of anti-TB drugs depends on their ability to reach the bacteria in the center of these lesions. Therefore, we developed a mass spectrometry (MS) imaging workflow to evaluate drug penetration in tissue. We employed a specific mouse model that─in contrast to regular inbred mice─strongly resembles human TB pathology. Mycobacterium tuberculosis was inactivated in lung sections of these mice by γ-irradiation using a protocol that was optimized to be compatible with high spatial resolution MS imaging. Different distributions in necrotic granulomas could be observed for the anti-TB drugs clofazimine, pyrazinamide, and rifampicin at a pixel size of 30 µm. Clofazimine, imaged here for the first time in necrotic granulomas of mice, showed higher intensities in the surrounding tissue than in necrotic granulomas, confirming data observed in TB patients. Using high spatial resolution drug and lipid imaging (5 µm pixel size) in combination with a newly developed data analysis tool, we found that clofazimine does penetrate to some extent into necrotic granulomas and accumulates in the macrophages inside the granulomas. These results demonstrate that our imaging platform improves the predictive power of preclinical animal models. Our workflow is currently being applied in preclinical studies for novel anti-TB drugs within the German Center for Infection Research (DZIF). It can also be extended to other applications in drug development and beyond. In particular, our data analysis approach can be used to investigate diffusion processes by MS imaging in general.

TNF-α antagonists differentially induce TGF-ß1-dependent resuscitation of dormant-like Mycobacterium tuberculosis.

TNF-α- as well as non-TNF-α-targeting biologics are prescribed to treat a variety of immune-mediated inflammatory disorders. The well-documented risk of tuberculosis progression associated with anti-TNF-α treatment highlighted the central role of TNF-α for the maintenance of protective immunity, although the rate of tuberculosis detected among patients varies with the nature of the drug. Using a human, in-vitro granuloma model, we reproduce the increased reactivation rate of tuberculosis following exposure to Adalimumab compared to Etanercept, two TNF-α-neutralizing biologics. We show that Adalimumab, because of its bivalence, specifically induces TGF-ß1-dependent Mycobacterium tuberculosis (Mtb) resuscitation which can be prevented by concomitant TGF-ß1 neutralization. Moreover, our data suggest an additional role of lymphotoxin-α-neutralized by Etanercept but not Adalimumab-in the control of latent tuberculosis infection. Furthermore, we show that, while Secukinumab, an anti-IL-17A antibody, does not revert Mtb dormancy, the anti-IL-12-p40 antibody Ustekinumab and the recombinant IL-1RA Anakinra promote Mtb resuscitation, in line with the importance of these pathways in tuberculosis immunity.

Anti-inflammatory, antioxidant, anti-fibrotic and schistosomicidal properties of plumbagin in murine schistosomiasis.

Schistosomiasis is still a major health problem affecting nearly 250 million people worldwide and causes approximately 280,000 deaths per year. The disease causes a serious granulomatous inflammatory response that produces significant mortality. Plumbagin reportedly displays anti-inflammatory, anti-fibrotic, antioxidant and anthelmintic properties. This study further elucidates these properties. Mice were infected with schistosomes and divided into five groups: non-infected untreated (C); infected untreated (IU); non-infected treated with plumbagin (P); infected treated with plumbagin (PI) and infected treated with praziquantel (PZ). Mice treated with 20 mg plumbagin/kg body weight showed reduction of 64.28% and 59.88% in male and female animals, respectively. Also, the number of eggs/g tissue was reduced 69.39%, 68.79% and 69.11% in liver, intestine and liver/intestine combined, respectively. Plumbagin alleviated schistosome-induced hepatosplenomegaly and reduced hepatic granuloma and liver collagen content by 62.5% and 35.26%, respectively while PZQ reduced hepatic granuloma and liver collagen content by 41.11% and 11.21%, respectively. Further, plumbagin treatment significantly (p < .001) reduced IL-4, IL-13, IL-17, IL-37, IFN-γ, TGF-ß and TNF-α levels and significantly (p < .001) upregulated IL-10. Plumbagin treatment restored hepatic enzymes activity to nearly normal levels and induced an increase in catalase, SOD, GSH, total thiol and GST in liver tissue homogenate. NO and LPO content was, however, decreased. Moreover, serum IgG levels significantly increased. The present study is the first to report immunomodulatory and schistosomicidal activities of plumbagin in schistosomiasis.

Granulomatous Diseases of the Central Nervous System.

PURPOSE OF REVIEW: To discuss the pathophysiology, key clinical features, necessary diagnostic evaluation, and current treatment regimens for granulomatous diseases of the central nervous system. RECENT FINDINGS: The diagnosis and management of granulomatous disease of the central nervous system has been revolutionized by advances in diagnostic imaging. Nevertheless, tissue and/or cerebrospinal fluid (CSF) sampling remains necessary to establish the diagnosis in most cases. Establishing a specific diagnosis is critical because treatment selection needs to focus on the granulomatous process centering on either antibiotic or immunosuppressive agents. Particular for non-infectious granulomatous disease more aggressive immunotherapies may help in clinical outcome. There are multiple non-infectious and infectious etiologies for granulomatous disease of the central nervous system. Clinical manifestations result from local structural invasion of granulomas or granulomatous inflammation of the blood vessels and meninges. Rapid diagnosis and specific treatment is essential.