A Case of Concomitant Cryptococcal Meningitis and Anti-NMDA Receptor Encephalitis in a Patient with Myelofibrosis on Ruxolitinib Therapy

A Case of Concomitant Cryptococcal Meningitis and Anti-NMDA Receptor Encephalitis in a Patient with Myelofibrosis on Ruxolitinib Therapy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A Case of Concomitant Cryptococcal Meningitis and Anti-NMDA Receptor Encephalitis in a Patient with Myelofibrosis on Ruxolitinib Therapy Benjamin Neale, Alexandra Yeoh This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6519535/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The following case presentation describes a rare association between two concomitant neurological diseases (cryptococcal meningitis and anti-NMDA receptor encephalitis) and ruxolitinib-treated myelofibrosis. The case also delves into the potential role immune reconstitution inflammatory syndrome (from ruxolitinib withdrawal) may have played in exacerbating the neurological conditions. Case Presentation A 66-year-old man, Mr. Evans (pseudonym), with a background of myelofibrosis on ruxolitinib therapy, presented to a rural emergency department, with one month of constitutional symptoms, and an associated mild headache. Mr. Evans appeared very fit and well, with no focal neurological signs or symptoms. He was discharged without a lumbar puncture, with his symptoms attributed to progression of his myelofibrosis. He re-presented nine days later with altered mental status and was diagnosed with cryptococcal meningitis, along with anti-NMDA receptor encephalitis. Conclusions This case will focus predominantly on that first presentation, and how Mr. Evan's care and risk stratification could have been optimised, to avoid progression to the second presentation. The case will highlight a lack of general awareness for the immunosuppressive potency of myelofibrosis and ruxolitinib and will push for change to current clinical guidelines to incorporate more infective screening, specifically for cryptococcus, to help avoid putting the next patient through what Mr. Evan's and his family endured. Myelofibrosis Ruxolitinib Cryptococcal meningitis Anti-NMDA receptor encephalitis Immune Reconstitution Inflammatory Syndrome Background Primary myelofibrosis (PMF) is, for the most part, caused by a genetic mutation in either Januk Kinase 2 (JAK2), Calreticulin (CALR) or the myeloproliferative leukemia virus oncogene (MPL), which results in an unwarranted release of inflammatory cytokines and excessive haematopoiesis 1 . Clinically, this leads to persistent vague infective symptoms without an obvious cause 1 . Physiologically, the overproduction of blood cells leads to bone marrow fibrosis and hepatosplenomegaly 1 . While not curative, a very useful medication for patients suffering from PMF is ruxolitinib, an inhibitor of both the JAK 1 and JAK 2 proteins 2 . Blocking JAK1/2 proteins puts a dampener on the aforementioned haematopoietic pathway overstimulated by genetic mutations 1 . This means fewer constitutional symptoms, decreased splenomegaly, and even decreased mortality rates. Unfortunately, it can also mean thrombocytopenia, anaemia and immunosuppression 1 . It also does not reverse bone marrow fibrosis; it just helps to halt its progression 2 . Cryptococcus is a fungal infection, particularly prevalent amongst patients with human immunodeficiency virus (HIV), but which can be found amongst any immunocompromised individual, especially with T-cell deficiencies 3 . While typically causing respiratory infections, cryptococcus is also one of the most common central nervous system (CNS) infections for this patient population 3 . It presents similarly to bacterial meningitis with headache, neck stiffness, fever and altered mental status, though develops more insidiously 3 . Amongst HIV patients, it presents over 1–2 weeks, though can last up to 12 weeks in non-HIV patients 3 . Anti-NMDA receptor (NMDAR) encephalitis is only a recently discovered disease as of 2007, when antibodies to the NMDA receptor were detected in the CNS fluid of 12 acutely psychiatric patients 4 . It is typically associated with ovarian teratomas, which produce NMDA antigens that inappropriately bind to NMDA receptors in the brain, but its aetiology is still a developing field of research 5 . It classically presents with psychiatric manifestations first (such as psychosis and personality changes), then neurological features (such as dyskinesias and seizures), then autonomic features (such as cardiac arrhythmias and hypotension 5 ). Here, we present a case linking these three uncommon pathologies and highlight the challenges of appropriate risk evaluation and diagnosis of a patient like this in a rural context. In particular, we aim to emphasise the importance of escalating to a lumbar puncture early for immunocompromised patients and aim to highlight the risks of reducing ruxolitinib doses too abruptly. We will particularly focus on the early stages of clinical evaluation, rather than later stages of management, and as such, will be focussing less on anti-NMDAR encephalitis, and more on the relationship between ruxolitinib-treated myelofibrosis and cryptococcal meningitis. Case Presentation Mr. Chris Evans (pseudonym), a fit and well-appearing 66-year-old man, presented to the emergency department of a rural hospital with a one-month history of subjective fevers, sweats and lethargy on a background of primary myelofibrosis, for which he took ruxolitinib 20mg twice daily. The rigors and night-sweats reportedly lasted 30–45 minutes per episode. On further questioning, he also reported one month of episodic mild headaches. He was afebrile. His vitals were within normal limits. He had no neck stiffness and his Kernig's sign was negative. There were no focal neurological symptoms. The only abnormal examination finding was a known splenomegaly due to his myelofibrosis. Investigation Mr. Evans' Result Baseline for Mr. Evans Normal range Hb 127 g/L At baseline 130–180 g/L Leukocytes 30.2 * 10 9 /L Above baseline, Mr. Evans leukocyte count is normally in the twenties 4.0–11.0 * 10 9 /L Neutrophils 13.9 * 10 9 /L At baseline, Mr. Evans neutrophil count is normally between 10.0–15.0*10 9 /L 2.0–8.0 * 10 9 /L Platelets 117 * 10 9 /L At baseline 150–450 * 10 9 /L CRP 4 mg/L At baseline 90 mL/min/1.73m 2 Haematology advised not to start antibiotics, given there were no documented fevers. Blood cultures, urine culture and chest X-ray all returned with no abnormality detected (NAD). During his three-day admission, only one fever was recorded (38.9 o C). His night sweats were visualised, soaking through a whole bed sheet. By the third day, his leukocytes spontaneously dropped markedly to 16.7* 10 9 /L and his neutrophils to 8.2* 10 9 /L. His platelets were also rapidly declining to 68* 10 9 /L. It was noticed on this day that Mr. Evan's ruxolitinib had not been charted. It was restarted on advice from the haematologist, at 5mg twice daily, in consideration of his rapidly declining platelet count. His ongoing symptoms and worsening headaches were attributed to his myelofibrosis, and he was discharged with paracetamol. Nine days later, he re-presented to the emergency department with three days of confusion, along with continuing headaches, fevers, sweats and lethargy. He was oriented to place and person, but not time. He demonstrated word-finding difficulty. His temperature was 38.1 o C, but once again, he demonstrated no symptoms or signs of meningism or focal neurology. His leukocytes remained around 18* 10 9 /L. This time, a full septic screen with lumbar puncture and neuroimaging was ordered. Neither his CT brain, nor his MRI brain found any appreciable disease. He was placed on prophylactic intravenous antibiotics and antivirals. Cerebrospinal Fluid analysis from Mr. Evans’ lumbar puncture: Investigation Mr. Evans' Result Normal range Opening pressure 15.5cm H2O 7-18cm H2O Erythrocytes 469 * 10 6 /L < 0 Leukocytes 226 * 10 6 /L < 5 * 10 6 /L Polymorphs 23 * 10 6 /L Mononuclear 206 * 10 6 /L Glucose 0.4 mmol/L 2.0-3.9 mmol/L Protein 3.35 g/L 0.15–0.45 g/L Gram stain No bacteria seen Based on the Cerebrospinal Fluid (CSF) cytology, the infectious diseases consultant (ID) suggested adding on a cryptococcus antigen test to the already collected sample of CSF. This returned a positive result on the same day. The patient was therefore started on liposomal amphotericin B and flucytosine. A positive anti-NMDA antibody result came back six days later. While Mr. Evans did demonstrate profound confusion and disorientation, which even lead to some code greys (hospital alarms for threatening behaviour), he never demonstrated the classic psychiatric changes of anti-NMDAR encephalitis, nor any of the later neurological or autonomic signs. He had both receptive and expressive aphasias, which can be explained by both anti-NMDAR encephalitis and cryptococcal meningitis. His second MRI showed severe progression of his cryptococcal meningitis but no signs of anti-NMDAR encephalitis progression. The decision agreed upon by ID and neurology consultation was to withhold the immunosuppressive treatment required for anti-NMDAR encephalitis, to avoid worsening his already profound cryptococcal infection. The details and specific nuances of Mr. Evans' further care are unfortunately inaccessible to us, as he was transferred to a tertiary centre. What is known is that he developed an acute kidney injury to his high-intensity antifungal regime. As such, his therapy was switched to fluconazole, which then lead to liver failure. The patient also developed several complications including two cryptococcomas, a right basal ganglia infarct and aspiration pneumonia. Mr. Evans' and his family opted for palliative care, given the frequency of iatrogenic complications and his worsening prognosis. He was transferred back to our regional health service, closer to home, for ongoing palliative care and social work input. Discussion The predominant opportunity for improvement in this case lies within the patient's first presentation. There are two key events that we'd like to focus on: the first is the omission of a lumbar puncture, the second is the sudden reduction of Mr. Evans' ruxolitinib. Hesitation for doing a lumbar puncture is understandable here. Mr. Evans' presentation is very subtle, even in comparison with other immunosuppressed cases, which are known to present more insidiously. There was no altered mental status, there were no focal signs of neurology and there were no signs of meningism. There was just a mild headache. His constitutional symptoms could very reasonably be explained by his pre-existing myelofibrosis. His leukocytosis, while significant on presentation, self-resolved to his baseline rapidly the next day. As did his fever, spiking above 38 o C only once. Lumbar punctures are painful, invasive procedures, with associated risks like post-lumbar puncture headache, infection and nerve damage, that can be hard to justify to patients, especially when they appear so well. Of course, for a severely immunosuppressed patient, sepsis cannot be ruled out without a thorough septic screen, which is not complete without a lumbar puncture since, unfortunately, blood cultures have very little correlation to CSF cultures 6 . What makes this case difficult is that the degree of immunosuppression associated with myelofibrosis or ruxolitinib is not as well known or as thoroughly researched as other causes of immunocompromise. The largest randomized controlled trial on ruxolitinib's efficacy in myelofibrosis, the COMFORT trial, found very little difference in severe infections between ruxolitinib and placebo users 7 . In fact, the only significant difference in infectious profile was an increased incidence of herpes zoster virus (HZV) amongst the intervention arm 7 . However, it is important to note that all participants in this study had advanced (intermediate-2 or high risk) myelofibrosis, according to the Dynamic International Prognostic Scoring System (DIPSS) 7 . DIPSS, along with spleen size, are the two most significant factors determining infective risk 8 . Hence, patients in both arms of the study were already significantly immunosuppressed before therapy. Immunosuppression from myelofibrosis is often not as quickly recognised, but the disease carries a doubled risk of infection and a quintupled risk of infection-related mortality 8 . Mr. Evan's DIPSS was intermediate-2 because his peripheral blood blasts were > 1% and his karyotype from bone marrow cytogenetics had 14 abnormalities. His spleen length was 17.7cm (normal length < 12cm). This puts Mr. Evans at a high risk of infection even before ruxolitinib therapy. Despite the findings of the COMFORT trial, there is gathering evidence that the infective risk of ruxolitinib has been underestimated, as more cases are demonstrating associations with severe infections like tuberculosis, progressive multifocal leukoencephalopathy and cryptococcus 9 . This case suggests that in current clinical practice, the immunosuppressive risk of both myelofibrosis and ruxolitinib is acknowledged but not considered serious. We would like to use this case to raise awareness for the infective risk associated with myelofibrosis and highlight DIPSS and spleen size as important means of quantifying that risk. We would also like to add to the gathering evidence of severe infections associated with ruxolitinib, highlight that ruxolitinib research is still developing and should be approached with extreme caution in clinical practice. The second opportunity for improvement was the sudden reduction of Mr. Evans' ruxolitinib therapy. There was a two-day period in which his ruxolitinib was ceased entirely, as his regular medications went uncharted on admission. There is no documented reasoning for this omission. This put Mr. Evans at risk of two conditions: ruxolitinib discontinuation syndrome (RDS) and immune reconstitution inflammatory syndrome (IRIS). RDS is a more acute complication, occurring between two and twenty-one days post-ruxolitinib dose reduction 10 . It is essentially a rapid progression of myelofibrosis and can lead to life-threatening conditions such as systemic inflammatory response syndrome and disseminated intravascular coagulopathy 10 . The likely mechanism behind RDS is a hypersensitivity to suddenly increased levels of JAK1 after ruxolitinib is ceased, leading to cytokine storms, tumour lysis syndromes, splenomegaly and worsening cytopenias 10 . IRIS can occur to any immunocompromised patient, after a sudden boost to their immune system 11 . It is when a previously unknown, latent infection is suddenly recognised, and a large-scale immune response is mounted against it 11 . It features a counter-intuitive decline in clinical picture following improved immunity, with intensified fevers, rising inflammatory markers and localised damage at the area of infection and is at risk of occurring for up to six months post change to immune status 11 . Fortunately, across the two days, there were no acute changes to Mr. Evans’ clinical picture. However, there was a rapid reduction in his platelet count from 117*10 9 /L to 68*10 9 /L. Regardless of whether or not this decline was caused by RDS, the new thrombocytopenia presented a dosage problem when re-starting ruxolitinib. Ruxolitinib is recommended at 5mg twice daily for patients with platelet counts between 50–100*10 9 /L 12 , which is a large drop from his previous dose of 20mg twice daily. While necessary to avoid a ruxolitinib-induced thrombocytopenia, this dose reduction meant that the threat of RDS and IRIS occurring in Mr. Evans persisted. For this alone, Mr. Evan’s arguably should not have been discharged, and it was IRIS that likely exacerbated, if not instigated his second presentation. In current guidelines, infective screening is recommended only prior to initiation of JAK therapy, but not prior to dose changes or as IRIS prevention. The infective screening includes HIV, hepatitis B and hepatitis C, with consideration of HZV and mycobacterial risk 13 , but does not include cryptococcal screening, since there are only a handful of reported cases linking cryptococcus to ruxolitinib and direct research into the prevalence of their correlation is lacking 9 . By contrast, in HIV therapy, cryptococcus is screened routinely (in patients with CD4 counts < 100cells/microlitre) prior to initiating anti-retroviral therapy (ART) to avoid the risk of IRIS that ART will introduce, once the immune system is abruptly boosted 14 . This is because cryptococcus is one of the most common causes of CNS infection in HIV patients, and in fact, in any patient with T-cell immunodeficiency 15 . While ruxolitinib does not reduce CD4 count in the same way that HIV does, it is shown, both in vivo and in vitro, to significantly decrease dendritic cell's ability to produce interleukins and ability to migrate 16 . Since dendritic cells are one of the primary antigen presenting cells, presenting foreign antigens to CD4 and CD8 from which t-cell immunity is initiated, CD4 and CD8 activity has been showed to be significantly reduced in mouse models given ruxolitinib 16 . There is, therefore, a theoretical association between the immunocompromise imposed by ruxolitinib and HIV, which would suggest predispositions to a similar profile of infections. Interestingly, the sensitivities and specificities of serum versus CSF cryptococcal antigen (CrAG) testing, to diagnose cryptococcal meningitis, is comparable. The sensitivities of both are 99% 17 . The specificity of serum CrAG is slightly decreased at 95% as opposed to CSF CrAG which is 99% 17 . Another option is point-of-care testing, which can be performed very cheaply, where only 40 microlitres of serum is required to assess for cryptococcal antigens, with a recorded 100% sensitivity 18 . If a serum CrAG had been done on Mr. Evans in his first admission, it would have very likely been positive. We would like to use this case to add to the data linking ruxolitinib to cryptococcus and make a push for further research into the degree of its correlation, possibly justifying incorporating cryptococcal screening into routine screening for JAK therapy, especially given the accuracy and accessibility of the screening tests. We would also like to make a push for more frequent infective screening to be incorporated into clinical practice for any high-risk patient, as IRIS prophylaxis, not just prior to initiation of therapy. Finally, we'd like to use this opportunity to heighten awareness amongst healthcare professionals about RDS, and encourage increasing patient education, which could have drastically changed the outcome of this case. Strengths The main strength of this case is its unique associations between rare and emerging diseases. It is one of few cases linking cryptococcal meningitis to ruxolitinib treated myelofibrosis, and it is one of even fewer cases linking cryptococcal meningitis to anti-NMDAR encephalitis. The case therefore provides a platform for debate into current management trends, such as consideration for incorporating regular cryptococcal screening prior to ruxolitinib initiation or dose changes. The case highlights the immunosuppressive extent of myelofibrosis with ruxolitinib and provides an opportunity to discuss the risks of ruxolitinib weaning. The case's subtle, insidious clinical presentation also distinguishes it from others, emphasising just how low the threshold needs to be for lumbar puncture in immunosuppressed patients. The added diagnosis of anti-NMDAR encephalitis, while not a focus of our case discussion, provides new insight into the rapidly progressing understanding of this very recently discovered disease, particularly concerning aetiology. Some theories have proposed that infectious encephalitis (particularly herpes simplex virus encephalitis) can lead to anti-NMDAR encephalitis, by inducing excessive NMDA receptor antibody production 19 . Perhaps something similar occurred here with cryptococcal meningitis. The case also provides a novel association between anti-NMDAR encephalitis and the excessive rebound immune state from IRIS, the latter of which is known to cause auto-immune flare-ups 11 , although no literature exists to suggest causation. Finally, the case illustrates the challenges of managing anti-NMDAR encephalitis and cryptococcal meningitis concomitantly and presents how specialists chose to tailor management to Mr. Evans' unique clinical picture. Limitations There was an unavoidable reliance on clinical documentation, as we were not able to be part of Mr. Evan's entire hospital journey. The documentation, while often very thorough, sometimes neglected clinical reasoning, which made analysis of management challenging. We were also limited by inaccessibility to Mr. Evan's full management after he was transferred to a tertiary centre, although that meant we were forced to focus more on the clinical presentation and diagnosis, providing a unique area of focus to explore in the case's discussion. As with any case presentation, there was also an inevitable retrospective bias. This was more prevalent for aspects of the case which we were not personally present for, but we attempted to account for this by reading the documented clinical reasoning closely and through thorough analysis of updated literature of epidemiological associations and current management guidelines. Conclusion The two most important points from this case is to have a low threshold for lumbar puncture and to be very wary of the dangers of rapidly weaning ruxolitinib. In someone who is severely immunocompromised, such as someone with intermediate-2 grade myelofibrosis, splenomegaly and the added immunosuppressive risks of ruxolitinib, a full septic screen is required to rule out infectious causes before moving through to other differentials, and a full septic screen requires a lumbar puncture. Greater attention to the risks of ruxolitinib weaning is required from healthcare professionals, in order to avoid complications like RDS and IRIS. However, in the event of dose reduction, we would like to make the case for infective screening to be incorporated into regular clinical practice to account for the risk of IRIS, and for cryptococcus to be considered amongst routinely screened infections for ruxolitinib, given the theoretical association, accessibility of the screening tool and devastating consequences of a missed diagnosis. Abbreviations PMF Primary Myelofibrosis JAK Januk Kinase CALR Calreticulin MPL Myeloproliferative Leukemia Virus Oncogene HIV Human Immunodeficiency Virus CNS Central Nervous System NMDAR NMDA Receptor NAD No Abnormality Detected CSF Cerebrospinal Fluid ID Infectious Diseases HZV Herpes Zoster Virus DIPSS Dynamic International Prognostic Scoring System RDS Ruxolitinib Discontinuation Syndrome IRIS Immune Reconstitution Inflammatory Syndrome ART Anti-Retroviral Therapy CrAG Cryptococcal Antigen Declarations Ethics Approval and Consent to Participate Not applicable Consent for Publication We, the co-authors of this case presentation, have received full consent from the patient and next of kin for their de-identified information to be published. Availability of Data and Materials The datasets generated and/or analysed during the current study are available at Ovid Medline (https://www.wolterskluwer.com/en/solutions/ovid/ovid-medline-901) and BMJ (https://www.bmj.com/) Competing Interests We declare no competing interests involved in the writing of this case presentation. Funding There was no funding. Author’s Contributions BN analysed the clinical documentation, analysed the areas for improvement, conducted literature reviews, and wrote up the bulk of the paper. AY was part of the treating team for Mr. Evan’s case, obtained consent from Mr. Evans and was heavily involved in editing the paper. All authors read and approved the final manuscript. Acknowledgements Not applicable References Verstovsek S, Mesa RA, Livingston RA, et al. Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. J Hematol Oncol. 2023;16:82. https://doi.org/10.1186/s13045-023-01471-z . Haq M, Adnan G. Ruxolitinib. 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Ash publications. 2013. 122 (7): 1192–1202. Available at: https://doi.org/10.1182/blood-2013-03-484642 Temfack E, Rim JJB, Spijker R, Loyse A, Chiller T, Pappas PG, Perfect J, Sorell TC, Harrison TS, Cohen JF, Lortholary O. Cryptococcal Antigen in Serum and Cerebrospinal Fluid for Detecting Cryptococcal Meningitis in Adults Living With Human Immunodeficiency Virus: Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies. Clin Infect Dis. 2021;72(7):1268–78. 10.1093/cid/ciaa1243 . PMID: 32829406; PMCID: PMC8522332. Kabanda T, Siedner MJ, Klausner JD, Muzoora C, Boulware DR. Point-of-care diagnosis and prognostication of cryptococcal meningitis with the cryptococcal antigen lateral flow assay on cerebrospinal fluid. Clin Infect Dis. 2014;58(1):113–6. 10.1093/cid/cit641 . Epub 2013 Sep 24. PMID: 24065327; PMCID: PMC3864499. Leypoldt F, Titulaer MJ, Aguilar E, Walther J, Bönstrup M, Havemeister S, Teegen B, Lütgehetmann M, Rosenkranz M, Magnus T, Dalmau J. Herpes simplex virus-1 encephalitis can trigger anti-NMDA receptor encephalitis: case report. Neurology. 2013;81(18):1637–9. 10.1212/WNL.0b013e3182a9f531 . Epub 2013 Oct 2. PMID: 24089390; PMCID: PMC3806918. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6519535","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":458220074,"identity":"02b59078-33ee-4864-95e6-1782e7020b37","order_by":0,"name":"Benjamin Neale","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAElEQVRIiWNgGAWjYBACAwiWgPAeMNjIwNhEaklgSOMhSgsCJDAcJqzFnL33QMHPHIs8Bunmgx8SKs7zmM9uYPzwMYdB3uAAdi2WPecSDHu3SRQzyBxLlkg4c5tH5s4BZsmZ2xgMN+DQYnAjx8CAd5tEYoNEjoFEYtttHgmJBDZm3m0MjDi13H9jYPgXrCX/84/Ef+fgWuxx28JjYAy1hQ1IHoBrScSlxbInx8BYFqilTSLNzCLhWDJQS2Iz0C8SyTNxaDFnP2Nm+HZbXWK/RPLjGx9q7OQkJJIPfvi4zca2D4cWIGADxw0bQoCxgYEBf+wwP8AnOwpGwSgYBaOAAQANZFYEaHUoKQAAAABJRU5ErkJggg==","orcid":"","institution":"Latrobe Regional Hospital","correspondingAuthor":true,"prefix":"","firstName":"Benjamin","middleName":"","lastName":"Neale","suffix":""},{"id":458220075,"identity":"6c18525e-23a9-48e3-ae0a-3b38bd7c2875","order_by":1,"name":"Alexandra Yeoh","email":"","orcid":"","institution":"Latrobe Regional Hospital","correspondingAuthor":false,"prefix":"","firstName":"Alexandra","middleName":"","lastName":"Yeoh","suffix":""}],"badges":[],"createdAt":"2025-04-24 09:53:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6519535/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6519535/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83563375,"identity":"9584a3a8-681b-4ae7-8008-5db006d798b4","added_by":"auto","created_at":"2025-05-28 14:09:07","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":494958,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6519535/v1/51970777-8fad-43a4-b0ce-c186084143d3.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A Case of Concomitant Cryptococcal Meningitis and Anti-NMDA Receptor Encephalitis in a Patient with Myelofibrosis on Ruxolitinib Therapy","fulltext":[{"header":"Background","content":"\u003cp\u003ePrimary myelofibrosis (PMF) is, for the most part, caused by a genetic mutation in either Januk Kinase 2 (JAK2), Calreticulin (CALR) or the myeloproliferative leukemia virus oncogene (MPL), which results in an unwarranted release of inflammatory cytokines and excessive haematopoiesis\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Clinically, this leads to persistent vague infective symptoms without an obvious cause\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Physiologically, the overproduction of blood cells leads to bone marrow fibrosis and hepatosplenomegaly\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. While not curative, a very useful medication for patients suffering from PMF is ruxolitinib, an inhibitor of both the JAK 1 and JAK 2 proteins\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Blocking JAK1/2 proteins puts a dampener on the aforementioned haematopoietic pathway overstimulated by genetic mutations\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. This means fewer constitutional symptoms, decreased splenomegaly, and even decreased mortality rates. Unfortunately, it can also mean thrombocytopenia, anaemia and immunosuppression\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. It also does not reverse bone marrow fibrosis; it just helps to halt its progression\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCryptococcus is a fungal infection, particularly prevalent amongst patients with human immunodeficiency virus (HIV), but which can be found amongst any immunocompromised individual, especially with T-cell deficiencies\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. While typically causing respiratory infections, cryptococcus is also one of the most common central nervous system (CNS) infections for this patient population\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. It presents similarly to bacterial meningitis with headache, neck stiffness, fever and altered mental status, though develops more insidiously\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Amongst HIV patients, it presents over 1\u0026ndash;2 weeks, though can last up to 12 weeks in non-HIV patients\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAnti-NMDA receptor (NMDAR) encephalitis is only a recently discovered disease as of 2007, when antibodies to the NMDA receptor were detected in the CNS fluid of 12 acutely psychiatric patients\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. It is typically associated with ovarian teratomas, which produce NMDA antigens that inappropriately bind to NMDA receptors in the brain, but its aetiology is still a developing field of research\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. It classically presents with psychiatric manifestations first (such as psychosis and personality changes), then neurological features (such as dyskinesias and seizures), then autonomic features (such as cardiac arrhythmias and hypotension\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e).\u003c/p\u003e \u003cp\u003eHere, we present a case linking these three uncommon pathologies and highlight the challenges of appropriate risk evaluation and diagnosis of a patient like this in a rural context. In particular, we aim to emphasise the importance of escalating to a lumbar puncture early for immunocompromised patients and aim to highlight the risks of reducing ruxolitinib doses too abruptly. We will particularly focus on the early stages of clinical evaluation, rather than later stages of management, and as such, will be focussing less on anti-NMDAR encephalitis, and more on the relationship between ruxolitinib-treated myelofibrosis and cryptococcal meningitis.\u003c/p\u003e"},{"header":"Case Presentation","content":"\u003cp\u003eMr. Chris Evans (pseudonym), a fit and well-appearing 66-year-old man, presented to the emergency department of a rural hospital with a one-month history of subjective fevers, sweats and lethargy on a background of primary myelofibrosis, for which he took ruxolitinib 20mg twice daily. The rigors and night-sweats reportedly lasted 30\u0026ndash;45 minutes per episode. On further questioning, he also reported one month of episodic mild headaches.\u003c/p\u003e \u003cp\u003eHe was afebrile. His vitals were within normal limits. He had no neck stiffness and his Kernig's sign was negative. There were no focal neurological symptoms. The only abnormal examination finding was a known splenomegaly due to his myelofibrosis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvestigation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMr. Evans' Result\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eBaseline for Mr. Evans\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eNormal range\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHb\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e127 g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt baseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e130\u0026ndash;180 g/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e30.2 * 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAbove baseline, Mr. Evans leukocyte count is normally in the twenties\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.0\u0026ndash;11.0 * 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophils\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13.9 * 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt baseline, Mr. Evans neutrophil count is normally between 10.0\u0026ndash;15.0*10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0\u0026ndash;8.0 * 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelets\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117 * 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt baseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e150\u0026ndash;450 * 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCRP\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt baseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;10 mg/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eeGFR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAt baseline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026gt;90 mL/min/1.73m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e\u003c/h2\u003e \u003cp\u003eHaematology advised not to start antibiotics, given there were no documented fevers. Blood cultures, urine culture and chest X-ray all returned with no abnormality detected (NAD). During his three-day admission, only one fever was recorded (38.9\u003csup\u003eo\u003c/sup\u003eC). His night sweats were visualised, soaking through a whole bed sheet.\u003c/p\u003e \u003cp\u003eBy the third day, his leukocytes spontaneously dropped markedly to 16.7* 10\u003csup\u003e9\u003c/sup\u003e/L and his neutrophils to 8.2* 10\u003csup\u003e9\u003c/sup\u003e/L. His platelets were also rapidly declining to 68* 10\u003csup\u003e9\u003c/sup\u003e/L. It was noticed on this day that Mr. Evan's ruxolitinib had not been charted. It was restarted on advice from the haematologist, at 5mg twice daily, in consideration of his rapidly declining platelet count. His ongoing symptoms and worsening headaches were attributed to his myelofibrosis, and he was discharged with paracetamol.\u003c/p\u003e \u003cp\u003eNine days later, he re-presented to the emergency department with three days of confusion, along with continuing headaches, fevers, sweats and lethargy. He was oriented to place and person, but not time. He demonstrated word-finding difficulty. His temperature was 38.1\u003csup\u003eo\u003c/sup\u003eC, but once again, he demonstrated no symptoms or signs of meningism or focal neurology. His leukocytes remained around 18* 10\u003csup\u003e9\u003c/sup\u003e/L. This time, a full septic screen with lumbar puncture and neuroimaging was ordered. Neither his CT brain, nor his MRI brain found any appreciable disease. He was placed on prophylactic intravenous antibiotics and antivirals.\u003c/p\u003e \u003cp\u003eCerebrospinal Fluid analysis from Mr. Evans\u0026rsquo; lumbar puncture:\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Tabb\" border=\"1\"\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInvestigation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMr. Evans' Result\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNormal range\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpening pressure\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.5cm H2O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7-18cm H2O\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eErythrocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e469 * 10\u003csup\u003e6\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLeukocytes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e226 * 10\u003csup\u003e6\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;5 * 10\u003csup\u003e6\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePolymorphs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23 * 10\u003csup\u003e6\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMononuclear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e206 * 10\u003csup\u003e6\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlucose\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.4 mmol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.0-3.9 mmol/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProtein\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.35 g/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.15\u0026ndash;0.45 g/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGram stain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo bacteria seen\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBased on the Cerebrospinal Fluid (CSF) cytology, the infectious diseases consultant (ID) suggested adding on a cryptococcus antigen test to the already collected sample of CSF. This returned a positive result on the same day. The patient was therefore started on liposomal amphotericin B and flucytosine.\u003c/p\u003e \u003cp\u003eA positive anti-NMDA antibody result came back six days later. While Mr. Evans did demonstrate profound confusion and disorientation, which even lead to some code greys (hospital alarms for threatening behaviour), he never demonstrated the classic psychiatric changes of anti-NMDAR encephalitis, nor any of the later neurological or autonomic signs. He had both receptive and expressive aphasias, which can be explained by both anti-NMDAR encephalitis and cryptococcal meningitis. His second MRI showed severe progression of his cryptococcal meningitis but no signs of anti-NMDAR encephalitis progression. The decision agreed upon by ID and neurology consultation was to withhold the immunosuppressive treatment required for anti-NMDAR encephalitis, to avoid worsening his already profound cryptococcal infection.\u003c/p\u003e \u003cp\u003eThe details and specific nuances of Mr. Evans' further care are unfortunately inaccessible to us, as he was transferred to a tertiary centre. What is known is that he developed an acute kidney injury to his high-intensity antifungal regime. As such, his therapy was switched to fluconazole, which then lead to liver failure. The patient also developed several complications including two cryptococcomas, a right basal ganglia infarct and aspiration pneumonia.\u003c/p\u003e \u003cp\u003eMr. Evans' and his family opted for palliative care, given the frequency of iatrogenic complications and his worsening prognosis. He was transferred back to our regional health service, closer to home, for ongoing palliative care and social work input.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe predominant opportunity for improvement in this case lies within the patient's first presentation. There are two key events that we'd like to focus on: the first is the omission of a lumbar puncture, the second is the sudden reduction of Mr. Evans' ruxolitinib.\u003c/p\u003e \u003cp\u003eHesitation for doing a lumbar puncture is understandable here. Mr. Evans' presentation is very subtle, even in comparison with other immunosuppressed cases, which are known to present more insidiously. There was no altered mental status, there were no focal signs of neurology and there were no signs of meningism. There was just a mild headache. His constitutional symptoms could very reasonably be explained by his pre-existing myelofibrosis. His leukocytosis, while significant on presentation, self-resolved to his baseline rapidly the next day. As did his fever, spiking above 38\u003csup\u003eo\u003c/sup\u003eC only once. Lumbar punctures are painful, invasive procedures, with associated risks like post-lumbar puncture headache, infection and nerve damage, that can be hard to justify to patients, especially when they appear so well. Of course, for a severely immunosuppressed patient, sepsis cannot be ruled out without a thorough septic screen, which is not complete without a lumbar puncture since, unfortunately, blood cultures have very little correlation to CSF cultures\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. What makes this case difficult is that the degree of immunosuppression associated with myelofibrosis or ruxolitinib is not as well known or as thoroughly researched as other causes of immunocompromise.\u003c/p\u003e \u003cp\u003eThe largest randomized controlled trial on ruxolitinib's efficacy in myelofibrosis, the COMFORT trial, found very little difference in severe infections between ruxolitinib and placebo users\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. In fact, the only significant difference in infectious profile was an increased incidence of herpes zoster virus (HZV) amongst the intervention arm\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. However, it is important to note that all participants in this study had advanced (intermediate-2 or high risk) myelofibrosis, according to the Dynamic International Prognostic Scoring System (DIPSS)\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. DIPSS, along with spleen size, are the two most significant factors determining infective risk\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Hence, patients in both arms of the study were already significantly immunosuppressed before therapy.\u003c/p\u003e \u003cp\u003eImmunosuppression from myelofibrosis is often not as quickly recognised, but the disease carries a doubled risk of infection and a quintupled risk of infection-related mortality\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Mr. Evan's DIPSS was intermediate-2 because his peripheral blood blasts were \u0026gt;\u0026thinsp;1% and his karyotype from bone marrow cytogenetics had 14 abnormalities. His spleen length was 17.7cm (normal length\u0026thinsp;\u0026lt;\u0026thinsp;12cm). This puts Mr. Evans at a high risk of infection even before ruxolitinib therapy.\u003c/p\u003e \u003cp\u003eDespite the findings of the COMFORT trial, there is gathering evidence that the infective risk of ruxolitinib has been underestimated, as more cases are demonstrating associations with severe infections like tuberculosis, progressive multifocal leukoencephalopathy and cryptococcus\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis case suggests that in current clinical practice, the immunosuppressive risk of both myelofibrosis and ruxolitinib is acknowledged but not considered serious. We would like to use this case to raise awareness for the infective risk associated with myelofibrosis and highlight DIPSS and spleen size as important means of quantifying that risk. We would also like to add to the gathering evidence of severe infections associated with ruxolitinib, highlight that ruxolitinib research is still developing and should be approached with extreme caution in clinical practice.\u003c/p\u003e \u003cp\u003eThe second opportunity for improvement was the sudden reduction of Mr. Evans' ruxolitinib therapy. There was a two-day period in which his ruxolitinib was ceased entirely, as his regular medications went uncharted on admission. There is no documented reasoning for this omission. This put Mr. Evans at risk of two conditions: ruxolitinib discontinuation syndrome (RDS) and immune reconstitution inflammatory syndrome (IRIS). RDS is a more acute complication, occurring between two and twenty-one days post-ruxolitinib dose reduction\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. It is essentially a rapid progression of myelofibrosis and can lead to life-threatening conditions such as systemic inflammatory response syndrome and disseminated intravascular coagulopathy\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The likely mechanism behind RDS is a hypersensitivity to suddenly increased levels of JAK1 after ruxolitinib is ceased, leading to cytokine storms, tumour lysis syndromes, splenomegaly and worsening cytopenias\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. IRIS can occur to any immunocompromised patient, after a sudden boost to their immune system\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. It is when a previously unknown, latent infection is suddenly recognised, and a large-scale immune response is mounted against it\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. It features a counter-intuitive decline in clinical picture following improved immunity, with intensified fevers, rising inflammatory markers and localised damage at the area of infection and is at risk of occurring for up to six months post change to immune status\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFortunately, across the two days, there were no acute changes to Mr. Evans\u0026rsquo; clinical picture. However, there was a rapid reduction in his platelet count from 117*10\u003csup\u003e9\u003c/sup\u003e/L to 68*10\u003csup\u003e9\u003c/sup\u003e/L. Regardless of whether or not this decline was caused by RDS, the new thrombocytopenia presented a dosage problem when re-starting ruxolitinib. Ruxolitinib is recommended at 5mg twice daily for patients with platelet counts between 50\u0026ndash;100*10\u003csup\u003e9\u003c/sup\u003e/L\u003csup\u003e12\u003c/sup\u003e, which is a large drop from his previous dose of 20mg twice daily. While necessary to avoid a ruxolitinib-induced thrombocytopenia, this dose reduction meant that the threat of RDS and IRIS occurring in Mr. Evans persisted. For this alone, Mr. Evan\u0026rsquo;s arguably should not have been discharged, and it was IRIS that likely exacerbated, if not instigated his second presentation.\u003c/p\u003e \u003cp\u003eIn current guidelines, infective screening is recommended only prior to initiation of JAK therapy, but not prior to dose changes or as IRIS prevention. The infective screening includes HIV, hepatitis B and hepatitis C, with consideration of HZV and mycobacterial risk\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, but does not include cryptococcal screening, since there are only a handful of reported cases linking cryptococcus to ruxolitinib and direct research into the prevalence of their correlation is lacking\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eBy contrast, in HIV therapy, cryptococcus is screened routinely (in patients with CD4 counts\u0026thinsp;\u0026lt;\u0026thinsp;100cells/microlitre) prior to initiating anti-retroviral therapy (ART) to avoid the risk of IRIS that ART will introduce, once the immune system is abruptly boosted\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. This is because cryptococcus is one of the most common causes of CNS infection in HIV patients, and in fact, in any patient with T-cell immunodeficiency\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. While ruxolitinib does not reduce CD4 count in the same way that HIV does, it is shown, both in vivo and in vitro, to significantly decrease dendritic cell's ability to produce interleukins and ability to migrate\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. Since dendritic cells are one of the primary antigen presenting cells, presenting foreign antigens to CD4 and CD8 from which t-cell immunity is initiated, CD4 and CD8 activity has been showed to be significantly reduced in mouse models given ruxolitinib\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. There is, therefore, a theoretical association between the immunocompromise imposed by ruxolitinib and HIV, which would suggest predispositions to a similar profile of infections.\u003c/p\u003e \u003cp\u003eInterestingly, the sensitivities and specificities of serum versus CSF cryptococcal antigen (CrAG) testing, to diagnose cryptococcal meningitis, is comparable. The sensitivities of both are 99%\u003csup\u003e17\u003c/sup\u003e. The specificity of serum CrAG is slightly decreased at 95% as opposed to CSF CrAG which is 99%\u003csup\u003e17\u003c/sup\u003e. Another option is point-of-care testing, which can be performed very cheaply, where only 40 microlitres of serum is required to assess for cryptococcal antigens, with a recorded 100% sensitivity\u003csup\u003e18\u003c/sup\u003e. If a serum CrAG had been done on Mr. Evans in his first admission, it would have very likely been positive.\u003c/p\u003e \u003cp\u003eWe would like to use this case to add to the data linking ruxolitinib to cryptococcus and make a push for further research into the degree of its correlation, possibly justifying incorporating cryptococcal screening into routine screening for JAK therapy, especially given the accuracy and accessibility of the screening tests. We would also like to make a push for more frequent infective screening to be incorporated into clinical practice for any high-risk patient, as IRIS prophylaxis, not just prior to initiation of therapy. Finally, we'd like to use this opportunity to heighten awareness amongst healthcare professionals about RDS, and encourage increasing patient education, which could have drastically changed the outcome of this case.\u003c/p\u003e\n\u003ch3\u003eStrengths\u003c/h3\u003e\n\u003cp\u003eThe main strength of this case is its unique associations between rare and emerging diseases. It is one of few cases linking cryptococcal meningitis to ruxolitinib treated myelofibrosis, and it is one of even fewer cases linking cryptococcal meningitis to anti-NMDAR encephalitis. The case therefore provides a platform for debate into current management trends, such as consideration for incorporating regular cryptococcal screening prior to ruxolitinib initiation or dose changes. The case highlights the immunosuppressive extent of myelofibrosis with ruxolitinib and provides an opportunity to discuss the risks of ruxolitinib weaning. The case's subtle, insidious clinical presentation also distinguishes it from others, emphasising just how low the threshold needs to be for lumbar puncture in immunosuppressed patients.\u003c/p\u003e \u003cp\u003eThe added diagnosis of anti-NMDAR encephalitis, while not a focus of our case discussion, provides new insight into the rapidly progressing understanding of this very recently discovered disease, particularly concerning aetiology. Some theories have proposed that infectious encephalitis (particularly herpes simplex virus encephalitis) can lead to anti-NMDAR encephalitis, by inducing excessive NMDA receptor antibody production\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. Perhaps something similar occurred here with cryptococcal meningitis. The case also provides a novel association between anti-NMDAR encephalitis and the excessive rebound immune state from IRIS, the latter of which is known to cause auto-immune flare-ups\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, although no literature exists to suggest causation. Finally, the case illustrates the challenges of managing anti-NMDAR encephalitis and cryptococcal meningitis concomitantly and presents how specialists chose to tailor management to Mr. Evans' unique clinical picture.\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eThere was an unavoidable reliance on clinical documentation, as we were not able to be part of Mr. Evan's entire hospital journey. The documentation, while often very thorough, sometimes neglected clinical reasoning, which made analysis of management challenging. We were also limited by inaccessibility to Mr. Evan's full management after he was transferred to a tertiary centre, although that meant we were forced to focus more on the clinical presentation and diagnosis, providing a unique area of focus to explore in the case's discussion.\u003c/p\u003e \u003cp\u003eAs with any case presentation, there was also an inevitable retrospective bias. This was more prevalent for aspects of the case which we were not personally present for, but we attempted to account for this by reading the documented clinical reasoning closely and through thorough analysis of updated literature of epidemiological associations and current management guidelines.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe two most important points from this case is to have a low threshold for lumbar puncture and to be very wary of the dangers of rapidly weaning ruxolitinib. In someone who is severely immunocompromised, such as someone with intermediate-2 grade myelofibrosis, splenomegaly and the added immunosuppressive risks of ruxolitinib, a full septic screen is required to rule out infectious causes before moving through to other differentials, and a full septic screen requires a lumbar puncture. Greater attention to the risks of ruxolitinib weaning is required from healthcare professionals, in order to avoid complications like RDS and IRIS. However, in the event of dose reduction, we would like to make the case for infective screening to be incorporated into regular clinical practice to account for the risk of IRIS, and for cryptococcus to be considered amongst routinely screened infections for ruxolitinib, given the theoretical association, accessibility of the screening tool and devastating consequences of a missed diagnosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePMF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePrimary Myelofibrosis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eJAK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJanuk Kinase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCALR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCalreticulin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMPL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMyeloproliferative Leukemia Virus Oncogene\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHIV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHuman Immunodeficiency Virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCNS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCentral Nervous System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNMDAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNMDA Receptor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNAD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNo Abnormality Detected\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCSF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCerebrospinal Fluid\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eID\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInfectious Diseases\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHZV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHerpes Zoster Virus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDIPSS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDynamic International Prognostic Scoring System\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRDS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRuxolitinib Discontinuation Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIRIS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eImmune Reconstitution Inflammatory Syndrome\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eART\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAnti-Retroviral Therapy\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCrAG\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eCryptococcal Antigen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for Publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe, the co-authors of this case presentation, have received full consent from the patient and next of kin for their de-identified information to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of Data and Materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available at Ovid Medline (https://www.wolterskluwer.com/en/solutions/ovid/ovid-medline-901) and BMJ (https://www.bmj.com/) \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe declare no competing interests involved in the writing of this case presentation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere was no funding.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor\u0026rsquo;s Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBN analysed the clinical documentation, analysed the areas for improvement, conducted literature reviews, and wrote up the bulk of the paper.\u003c/p\u003e\n\u003cp\u003eAY was part of the treating team for Mr. Evan\u0026rsquo;s case, obtained consent from Mr. Evans and was heavily involved in editing the paper.\u003c/p\u003e\n\u003cp\u003eAll authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eVerstovsek S, Mesa RA, Livingston RA, et al. Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. J Hematol Oncol. 2023;16:82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s13045-023-01471-z\u003c/span\u003e\u003cspan address=\"10.1186/s13045-023-01471-z\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHaq M, Adnan G. Ruxolitinib. [Updated 2023 Jun 5]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK570600/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK570600/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePescador Ruschel MA, Thapa B, Cryptococcal Meningitis. 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Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ncbi.nlm.nih.gov/books/NBK567803/\u003c/span\u003e\u003cspan address=\"https://www.ncbi.nlm.nih.gov/books/NBK567803/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAustralian Medicines Handbook. Jan 2025. Available at: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://amhonline.amh.net.au.acs.hcn.com.au/chapters/anticancer-drugs/kinase-inhibitors/ruxolitinib\u003c/span\u003e\u003cspan address=\"https://amhonline.amh.net.au.acs.hcn.com.au/chapters/anticancer-drugs/kinase-inhibitors/ruxolitinib\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e accessed 14 April 2025.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcLornan D, Psaila B, Ewing J, Innes A, Arami S, Brady J et al. Dec. 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Neurology. 2013;81(18):1637\u0026ndash;9. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1212/WNL.0b013e3182a9f531\u003c/span\u003e\u003cspan address=\"10.1212/WNL.0b013e3182a9f531\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e. Epub 2013 Oct 2. PMID: 24089390; PMCID: PMC3806918.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Myelofibrosis, Ruxolitinib, Cryptococcal meningitis, Anti-NMDA receptor encephalitis, Immune Reconstitution Inflammatory Syndrome","lastPublishedDoi":"10.21203/rs.3.rs-6519535/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6519535/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe following case presentation describes a rare association between two concomitant neurological diseases (cryptococcal meningitis and anti-NMDA receptor encephalitis) and ruxolitinib-treated myelofibrosis. The case also delves into the potential role immune reconstitution inflammatory syndrome (from ruxolitinib withdrawal) may have played in exacerbating the neurological conditions.\u003c/p\u003e\u003cp\u003e\u003cb\u003eCase Presentation\u003c/b\u003e\u003c/p\u003e \u003cp\u003eA 66-year-old man, Mr. Evans (pseudonym), with a background of myelofibrosis on ruxolitinib therapy, presented to a rural emergency department, with one month of constitutional symptoms, and an associated mild headache. Mr. Evans appeared very fit and well, with no focal neurological signs or symptoms. He was discharged without a lumbar puncture, with his symptoms attributed to progression of his myelofibrosis. He re-presented nine days later with altered mental status and was diagnosed with cryptococcal meningitis, along with anti-NMDA receptor encephalitis.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis case will focus predominantly on that first presentation, and how Mr. Evan's care and risk stratification could have been optimised, to avoid progression to the second presentation. The case will highlight a lack of general awareness for the immunosuppressive potency of myelofibrosis and ruxolitinib and will push for change to current clinical guidelines to incorporate more infective screening, specifically for cryptococcus, to help avoid putting the next patient through what Mr. Evan's and his family endured.\u003c/p\u003e","manuscriptTitle":"A Case of Concomitant Cryptococcal Meningitis and Anti-NMDA Receptor Encephalitis in a Patient with Myelofibrosis on Ruxolitinib Therapy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-22 04:36:27","doi":"10.21203/rs.3.rs-6519535/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c2778793-a8e2-4dc1-a0ec-f67223c95685","owner":[],"postedDate":"May 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-28T14:08:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-22 04:36:27","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6519535","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6519535","identity":"rs-6519535","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}