Cryptococcal meningitis in an immunocompetent patient.

Cryptococcal meningitis is a fungal infection that is most commonly thought of as an opportunistic infection affecting immunocompromised patients, classically patients with Human Immunodeficiency (HIV) infection. It is associated with a variety of complications including disseminated disease as well as neurologic complications including intracranial hypertension, cerebral infarcts, vision loss and other neurologic deficits. It is diagnosed by lumbar puncture with CSF studies, including fungal culture and cryptococcal antigen testing. We present a case of cryptococcal meningitis and fungemia in a previously healthy male patient who presented after multiple emergency department visits with persistent headache. After multiple visits, he underwent a lumbar puncture consistent with cryptococcal infection, and he was admitted to the hospital for initiation of antifungal therapy. His workup revealed no known underlying condition leading to immune compromise.

A correlation analysis between clinical manifestations, therapeutic strategies, and the prognosis of children with cryptococcal meningitis in China.

OBJECTIVE: This aim of this study was to analyze the correlations between clinical manifestations, treatment strategies, and the prognosis in cryptococcal meningitis (CM) in China. METHODS: This was a retrospective analysis of the clinical data of CM patients treated during the years 2002-2019. The clinical features and supplementary examinations, treatment strategies, and prognosis were summarized and then a correlation analysis was performed. RESULTS: Fifty patients were enrolled. The most common symptoms were fever, headache, and vomiting. Five of these patients died and five had visual impairment sequelae; nine of these patients were treated before 2010. Correlation analysis suggested that cerebral hernia, consciousness disorder, visual impairment, hydrocephalus, and an intracranial pressure >300mmH2O in cerebrospinal fluid (CSF) were associated with a poor prognosis. Whether or not the application of intrathecal administration had little effect on prognosis. Early surgical intervention with internal drainage helped to reduce the mortality and incidence of visual impairment sequelae, whether or not Cryptococcus was present in the CSF before surgery. CONCLUSIONS: Clinically, the presence of a cerebral hernia, consciousness disorder, hydrocephalus, visual impairment, or intracranial pressure >300mmH2O often indicates a poor prognosis in patients with CM. The prognosis improved significantly after 2010, following an adjustment of the treatment strategy. Early internal drainage is the key factor, and CSF positive for Cryptococcus before surgery is not a contraindication.

Epidemiological, clinical and biological profile of neuromeningeal cryptococcosis among people living with HIV in Kinshasa, Democratic Republic of Congo.

Neuromeningeal cryptococcosis (NMC) is one of the most frequent opportunistic infections (OI) in Human Immunodeficiency Virus (HIV) infection. In Kinshasa, the latest data on cryptococcosis were published in 1996. The objective was to describe the epidemiological, clinical and biological profiles of NMC in HIV-infected people living in Kinshasa. This is a descriptive study based on the medical records of patients who attended three clinics in Kinshasa between January 1 s t 2011 and December 31st 2014. Only the medical records of HIV-infected people presenting the NMC were reviewed. During the 4 year-period of the study, 261 HIV-positive patients presented to the clinics for neuromeningeal syndrome, including 23 with NMC. The global prevalence of NMC was 8.8% for the three clinics. The mean age was 42.8 ± 9.5 years, with male predominance (65.2%). The main symptoms were headache (73.9%), neck stiffness (60.9%), fever (47.8%), and coma (47.8%). Biological records were as follows: median CD4 cell count was 79 cells/mm3; cerebrospinal fluid (CSF) was clear for 56.5% of the cases with predominance of neutrophils in 73.9%. The outcome was fatal in 34.8% of cases. The prevalence and therapeutic outcome of NMC show that it constitutes a non-negligible OI in Kinshasa, especially in HIV-infected people at the AIDS stage. As HIV-infected people with severe immunosuppression are the most affected by NMC, active preventive measures should benefit this vulnerable category of people.

Cryptococcal meningitis in patients with lupus nephritis.

OBJECTIVE: Cryptococcal meningitis (CM) is a rare condition in patients with lupus nephritis (LN). Here, we describe the clinical characteristics, possible risk factors, and outcomes of LN patients with CM. METHODS: A systematic review of medical records from16 LN patients with CM admitted to our hospital was performed. A total of 32 cases were randomly selected as controls from LN patients without infection during the same period. RESULTS: The mean age of patients with CM at presentation was 35.1 years, and the female-to-male ratio was 15:1.The most common clinical manifestation was headache (93.7%); patients with CM had a significantly higher prednisone dose at the time of hospitalization, a higher SLE Disease Activity Index (SLEDAI), a higher urine protein/creatinine ratio, and a lower CD4+ T cells count than those without infection (p < 0.05). Patients with CM also had significantly higher activity index and more moderate and severe mesangial proliferation than those without infections (p < 0.001 and p = 0.025, respectively). CONCLUSION: Serious renal pathological changes, mass proteinuria, higher SLEDAI, higher prednisone dose, and a decline in CD4+ T cells could be risk factors for CM in patients with LN. Key Points ⦁ LN patients with CM had more serious renal pathological changes than those without infections; serious renal pathological changes could be a major risk factor for CM in patients with LN.

HIV-Negative Cryptococcal Meningoencephalitis Results in a Persistent Frontal-Subcortical Syndrome.

Twenty-seven previously healthy (of 36 consecutive eligible patients), HIV-negative cryptococcal meningoencephalitis (CM) patients underwent comprehensive neuropsychological evaluation during the late post-treatment period (1.3-4 years post diagnosis), assessing attention, language, learning, memory, visuospatial, executive function, information processing, psychomotor functioning, as well as mood symptoms. Seven of eight domains (all except attention) showed increased percentages of CM patients scoring in the less than 16th percentile range compared to standardized normative test averages, adjusted for education level and age. Comparison with a matched archival dataset of mild cognitive impairment/Alzheimer's disease patients showed that CM patients exhibited relative deficits in psychomotor and executive function with fewer deficits in memory and learning, consistent with a frontal-subcortical syndrome. MRI evaluation at the time of testing demonstrated an association of lower neuropsychological functioning with ventriculomegaly. These studies suggest that CM should be included in the list of treatable causes of dementia in neurological work ups. Future studies are needed to identify diagnostic and treatment regimens that may enhance neurological function after therapy.

Efficacy of ventriculoperitoneal shunting in patients with cryptococcal meningitis with intracranial hypertension.

BACKGROUND: Ventriculoperitoneal (VP) shunting in cryptococcal meningitis (CM) patients with high intracranial pressure (ICP) has been studied extensively. METHODS: A total of 74 CM patients with ICP were identified, including 27 patients with or without ventriculomegaly receiving VP shunting. RESULTS: Through retrospective analysis, there was an obvious decline in ICP as well as Cryptococcus count after VP shunting. Damage to the cranial nerves was improved after the surgery. For those patients receiving VP shunting, there was an obvious decline in ICP as well as Cryptococcus count, with less usage of mannitol. Hydrocephalus or ventriculomegaly was improved, and both the clearance time of Cryptococcus and the hospitalization time were shortened (p<0.05). The complications of VP shunting were not common. CONCLUSIONS: For patients diagnosed with CM and with apparent ICP, VP shunting can be considered regardless of whether there is damage to the cranial nerves or hydrocephaly.

Lumbar drainage for the treatment of refractory intracranial hypertension in HIV-negative cryptococcal meningitis.

Aim: This study aims to evaluate lumbar drainage (LD) for controlling refractory intracranial hypertension among non-HIV cryptococcal meningitis patients. Patients & methods: A case-control study was designed to compare LD (case) with repeated lumbar puncture (control). Results: Both LD and repeated lumbar puncture can efficiently control refractory intracranial hypertension. LD group showed better clinical symptom remission, such as lower rate of headache, vision disorders, signs of meningeal irritation and conscious disturbance, than control group. LD group was reported with higher intracranial pressure reduction (173.75 ± 17.72 mmH2O) than those among control group (113.50 ± 14.94 mmH2O; p < 0.05). Conclusion: LD is an effective and safe alternative to control refractory intracranial hypertension in HIV-negative cryptococcal meningitis patients.

Cryptococcal meningitis initially presenting with ST elevations and elevated cardiac biomarkers.

Acute neurological events are a common cause of ECG abnormalities and transient elevations in cardiac biomarkers. This case describes an uncommon presentation of cryptococcal meningitis in a non-immunosuppressed patient, presenting with altered sensorium and derangements in cardiac profile. Delay in diagnosing meningitis was avoided by paying close attention to the patient's presenting symptoms and by pursuing non-cardiac causes of ECG changes and elevations in cardiac troponin. Expeditious treatment and involvement of the infectious disease consultant resulted in excellent clinical response without permanent neurological sequelae.

Chemokine and Cytokine Cascade Caused by Skewing of the Th1-Th2 Balance Is Associated with High Intracranial Pressure in HIV-Associated Cryptococcal Meningitis.

PURPOSE: Serum cytokines/chemokines play important roles in cryptococcal meningitis, but it is unclear whether cytokines/chemokines in cerebrospinal fluid (CSF) contribute to high intracranial pressure (HICP) in HIV-associated cryptococcal meningitis (HCM). METHODS: CSF cytokines/chemokines were assayed in 17 HIV-uninfected patients, 26 HIV-infected patients without CNS infection, and 39 HCM patients at admission. Principal component analysis and correlation and logistic regression analyses were used to assess the relationships between these parameters. RESULTS: The CSF Th1, Th2, and macrophage cytokines showed an obvious increase in HCM patients as compared to the HIV-uninfected patients and HIV-infected patients without CNS infection. CSF IL-6, GM-CSF, and IL-8 were positively correlated with CSF fungal burden. Serum CD4 count, CSF Th1 cytokines (TNF-α, TNF-ß, IL-12, IL-1ß, IL-12, IL-1α, TNF-α, TNF-ß, IL-12, IL-1γ, and IL-12) and Th2 cytokines (IL-4 and IL-10) contribute to HICP. CONCLUSION: Overall, the present findings indicated that both pro- and anti-inflammatory cytokines of Th1, Th2, and macrophage origin contributed to the development of HCM. Specifically, the chemokine and cytokine cascade caused by skewing of the Th1-Th2 balance and reduced CD4 count were found to be important contributors to HICP. Summary. Our research suggested that chemokine and cytokine cascade caused by skewing of the Th1-Th2 balance in HIV-infected patients played more important role than Cryptococcus numbers and size in CSF on the development of high intracranial pressure in HIV-associated cryptococcal meningitis, providing a new understanding of mechanisms of HCM.

Relationship between intracranial pressure and antifungal agents levels in the CSF of patients with cryptococcal meningitis.

The purpose of this study was to evaluate the influence of intracranial hypertension in the cerebrospinal fluid (CSF) levels of amphotericin B and fluconazole levels of patients with cryptococcal meningitis. CSF samples and intracranial pressure were obtained by means of routine punctures performed at days 1, 7, and 14 of therapy, respectively. Amphotericin B and fluconazole CSF levels were measured by HPLC method as previously described. The minimum inhibitory concentration for amphotericin B, fluconazole, 5΄flucytosine, and voriconazole of each Cryptococcus isolate was performed according to CLSI. The predominant Cryptococcus species found was C. neoformans, and the major underlying condition was AIDS. Only one CSF sample had a detectable level for amphotericin B during the 14 days of therapy. Fluconazole CSF levels progressively increased from day 1 to day 14 of therapy for most cases. Fluconazole levels in the CSF were above the minimum inhibitory concentrations (MICs) for Cryptococcus during the initial 14 days of antifungal therapy. Variations of intracranial pressure did not affect amphotericin B and fluconazole levels in the CSF. The generalized estimating correlation (GEE) and Spearman correlation test (SCT) showed no significant correlation between the amphotericin B or fluconazole concentrations in the CSF and intracranial pressure (P = .953 and P = .093, respectively for GEE test and P = .477 and P = .847, respectively, for SCT). Combination therapy of amphotericin B with fluconazole was effective in 60% of the patients considering CSF cultures were negative in 9 of 15 patients after 14 days of therapy. Further studies are necessary to evaluate the role of intracranial hypertension on the therapeutic efficacy of different antifungal agents in patients with cryptococcal meningitis.

Radiology Case of the Month: Idiopathic CD4 Lymphocytopenia.

A 39 year-old male with a history of diabetes, retinitis pigmentosa, and genital warts presented with intractable occipital headaches accompanied with nausea and vomiting. The patient had markedly depressed CD4 counts. Furthermore the patient tested negative for HIV and HTLV 1/2 and had normal immunoglobulin levels. During hospital course the patient underwent a lumbar puncture and multiple imaging exams, including both CT and MR. Except for occasional nausea and vomiting controlled by therapeutic lumbar punctures, phenergan, and dilaudid the patient's hospital course was uncomplicated.

Reversible hearing loss following cryptococcal meningitis: case study.

BACKGROUND: Sensorineural hearing loss is a recognised complication of cryptococcal meningitis. The mechanism of hearing loss in patients with cryptococcal meningitis is different from that in bacterial meningitis. CASE REPORT: An immune-competent man with cryptococcal meningitis presented with sudden onset, bilateral, severe to profound sensorineural hearing loss and vestibular dysfunction. He was initially evaluated for cochlear implantation. However, he had a significant recovery; he no longer required surgery and was able to cope without a hearing aid. CONCLUSION: Typically, cochlear implantation is performed with some urgency in patients with hearing loss post-bacterial meningitis, because of the risk of labyrinthitis ossificans. However, this process has not been described in patients with cryptococcal meningitis. Furthermore, patients with hearing loss associated with cryptococcal meningitis have shown varying degrees of reversibility. In this case report, hearing loss from cryptococcal meningitis is compared with that from bacterial meningitis, and the need for cochlear implantation in patients with cryptococcal meningitis is discussed.

The immunopathogenesis of cryptococcal immune reconstitution inflammatory syndrome: understanding a conundrum.

PURPOSE OF REVIEW: Cryptococcal meningitis causes significant mortality among HIV-infected patients, despite antifungal therapy and use of antiretroviral therapy (ART). In patients with cryptococcal meningitis, ART is often complicated by immune reconstitution inflammatory syndrome (IRIS), manifesting as unmasking of previously unrecognized subclinical infection (unmasking CM-IRIS) or paradoxical worsening of symptoms in the central nervous system after prior improvement with antifungal therapy (paradoxical CM-IRIS). We review our current understanding of the pathogenesis of this phenomenon, focusing on unifying innate and adaptive immune mechanisms leading to the development of this often fatal syndrome. RECENT FINDINGS: We propose that HIV-associated CD4 T-cell depletion, chemokine-driven trafficking of monocytes into cerebrospinal fluid in response to cryptococcal meningitis, and poor localized innate cytokine responses lead to inadequate cryptococcal killing and clearance of the fungus. Subsequent ART-associated recovery of T-cell signaling and restored cytokine responses, characterized by IFN-γ production, triggers an inflammatory response. The inflammatory response triggered by ART is dysregulated because of impaired homeostatic and regulatory mechanisms, culminating in the development of CM-IRIS. SUMMARY: Despite our incomplete understanding of the immunopathogenesis of CM-IRIS, emerging data exploring innate and adaptive immune responses could be exploited to predict, prevent and manage CM-IRIS and associated morbid consequences.

Visual evoked potentials show strong positive association with intracranial pressure in patients with cryptococcal meningitis.

OBJECTIVE: To verify the relationship between intracranial pressure and flash visual evoked potentials (F-VEP) in patients with cryptococcal meningitis. Method The sample included adults diagnosed with cryptococcal meningitis admitted at a reference hospital for infectious diseases. The patients were subjected to F-VEP tests shortly before lumbar puncture. The Pearson’s linear correlation coefficient was calculated and the linear regression analysis was performed. RESULTS: Eighteen individuals were subjected to a total of 69 lumbar punctures preceded by F-VEP tests. At the first lumbar puncture performed in each patient, N2 latency exhibited a strong positive correlation with intracranial pressure (r = 0.83; CI = 0.60 - 0.94; p < 0.0001). The direction of this relationship was maintained in subsequent punctures. CONCLUSION: The intracranial pressure measured by spinal tap manometry showed strong positive association with the N2 latency F-VEP in patients with cryptococcal meningitis.

Visual evoked potentials show strong positive association with intracranial pressure in patients with cryptococcal meningitis / Potenciais evocados visuais mostram correlação positiva forte com a pressão intracraniana em pacientes com meningite criptocócica

Objective : To verify the relationship between intracranial pressure and flash visual evoked potentials (F-VEP) in patients with cryptococcal meningitis. Method The sample included adults diagnosed with cryptococcal meningitis admitted at a reference hospital for infectious diseases. The patients were subjected to F-VEP tests shortly before lumbar puncture. The Pearson’s linear correlation coefficient was calculated and the linear regression analysis was performed. Results : Eighteen individuals were subjected to a total of 69 lumbar punctures preceded by F-VEP tests. At the first lumbar puncture performed in each patient, N2 latency exhibited a strong positive correlation with intracranial pressure (r = 0.83; CI = 0.60 - 0.94; p < 0.0001). The direction of this relationship was maintained in subsequent punctures. Conclusion : The intracranial pressure measured by spinal tap manometry showed strong positive association with the N2 latency F-VEP in patients with cryptococcal meningitis. .

Objetivo : Verificar a relação entre pressão intracraniana e potencial evocado visual por flash (PEV-F) em pacientes com meningite criptocócica. Método A amostra incluiu pacientes admitidos em um hospital de referência para doenças infecciosas. Realizou-se PEV-F antes de cada punção lombar. Calculou-se o coeficiente de correlação de Pearson e a equação de regressão linear entre as variáveis latência N2 e pressão intracraniana inferida através de raquimanometria. Resultados Dezoito pacientes foram submetidos a um total de 69 punções lombares. A latência N2 mostrou correlação positiva forte com a pressão de abertura verificada na primeira punção lombar a que cada paciente foi submetido (r = 0,83; IC = 0,60 – 0,94; p < 0,0001). A positividade da correlação foi mantida nas aferições subsequentes. Conclusão Houve associação positiva forte entre a latência N2 do PEV-F e pressão intracraniana em pacientes com meningite criptocócica. .

Diffusion tensor imaging study of white matter damage in chronic meningitis.

Tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are two of the most common types of chronic meningitis. This study aimed to assess whether chronic neuro-psychological sequelae are associated with micro-structure white matter (WM) damage in HIV-negative chronic meningitis. Nineteen HIV-negative TBM patients, 13 HIV-negative CM patients, and 32 sex- and age-matched healthy volunteers were evaluated and compared. The clinical relevance of WM integrity was studied using voxel-based diffusion tensor imaging (DTI) magnetic resonance imaging. All of the participants underwent complete medical and neurologic examinations, and neuro-psychological testing. Differences in DTI indices correlated with the presence of neuro-psychological rating scores and cerebrospinal fluid (CSF) analysis during the initial hospitalization. Patients with CM had more severe cognitive deficits than healthy subjects, especially in TBM. There were changes in WM integrity in several limbic regions, including the para-hippocampal gyrus and cingulate gyrus, and in the WM close to the globus pallidus. A decline in WM integrity close to the globus pallidus and anterior cingulate gyrus was associated with worse CSF analysis profiles. Poorer DTI parameters directly correlated with worse cognitive performance on follow-up. These correlations suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities. Abnormalities in the limbic system and globus pallidus, with their close relationship to the CSF space, may be specific biomarkers for disease evaluation.

Increased permeability of blood-brain barrier is mediated by serine protease during Cryptococcus meningitis.

OBJECTIVES: To determine the role of serine protease in the disruption of the blood-brain barrier (BBB) during Cryptococcus neoformans meningitis. METHODS: Reverse transcription-polymerase chain reaction and immunohistochemistry were used to determine the production of serine protease by different strains of C. neoformans. BBB permeability in immunosuppressed rats inoculated with C. neoformans or C. neoformans plus aprotinin was examined via Evans blue staining. In vitro BBB permeability (transwell passage of horseradish peroxidase) was determined in human brain microvascular endothelial cells (BMECs) cultured with serine protease or serine protease plus aprotinin. Electron microscopy of rat brain tissue was used to visualise C. neoformans infection. RESULTS: Serine protease mRNA and protein were detected in all C. neoformans serotypes. C. neoformans infection increased BBB permeability in vivo, but this effect was ameliorated by aprotinin. Treatment of BMECs with serine protease increased permeability in vitro. This effect was reversed by aprotinin. CONCLUSION: Serine protease secreted by C. neoformans leads to BBB disruption during Cryptococcus meningitis. Serine protease may be a novel treatment target for Cryptococcus meningitis.

Cryptococcal meningitis associated with tuberculosis in HIV infected patients.

Opportunistic infections are common complications of advanced immuno-deficiency in individuals with Human Immunodeficiency Virus (HIV) infection. Following involvement of the lung, the central nervous system (CNS) is the second most commonly affected organ. We report two cases of concurrent cryptococcal meningitis and tuberculosis (TB) in HIV infected persons. A high suspicion of multiple opportunistic infections should be kept in mind in HIV seropositive individuals.