Primary cutaneous cryptococcosis due to Cryptococcus neoformans var. gattii serotype B,in an immunocompetent patient

The authors report a male patient, a seller with no detected immunosuppression, with an extensive ulcerated skin lesion localized on the left forearm, caused by Cryptococcus neoformans var. gattii serotype B. Oral treatment with fluconazole was successful. A review of the literature showed the rarity of this localization in HIV-negative patients. In contrast, skin lesions frequently occurs in HIV-positive patients, with Cryptococcus neoformans var. neoformans serotype A predominating as the etiological agent. In this paper, the pathogenicity of C. neoformans to skin lesions in patients immunocompromised or not, is discussed, showing the efficacy of fluconazole for the treatment of these processes.     

Pancoast's syndrome due to pulmonary infection with Cryptococcus neoformans variety gattii.

Immunocompetent hosts usually do not require antifungal therapy for pulmonary cryptococcosis. We present a case of right lung mass and Pancoast's syndrome due to locally invasive Cryptococcus neoformans variety gattii in a normal host. Lobectomy followed by therapy with amphotericin B and flucytosine was curative.     

Primary central nervous system (CNS) lymphoma in immunocompetent patients

Primary CNS lymphoma (PCNSL) has been increasing in incidence among both immunocompetent and immunocompromised patients. Today there is no uniform approach to the treatment of this disease. Whole brain irradiation (WBI) has been standard treatment, resulting in complete remission in the majority of patients, but with most patients relapsing and dying of their disease within 2 years after treatment. The addition of chemotherapy to WBI appears to prolong survival for patients younger than 60 years with median survival reaching a plateau at approximately 40 months. The issue of the best treatment for older patients remains controversial. Prospective studies will be needed, as it is impossible to draw conclusions from the nonrandomized small series published so far. This is because the prognostic variables of age and performance status to date have affected outcome more than therapy. In this review, some of the questions regarding the management of PCNSL are addressed. Since the role of radiotherapy remains unclear, we designed a new randomized multicenter study (G-PCNSL-SG-1 trial) to investigate the optimal timing of WBI after high-dose methotrexate (HD-MTX) chemotherapy.     

Immunohistochemical diagnosis of Cryptococcus neoformans var. gattii infection in chronic meningoencephalitis: the first case in Japan

Cryptococcus neoformans (C. neoformans) var. gattii infection usually occurs in tropical and subtropical areas, and rarely in the northern hemisphere. We report the first Japanese with cryptococcal meningoencephalitis caused by C. neoformans var. gattii infection that occurred during a trip to Australia. This agent was identified in a cerebellar biopsy specimen by immunohistochemical technique with serotype-specific anti-sera. Because the meningitis caused by it did not respond well to conventional therapy, we used an aggressive therapeutic regimen to successfully treat the patient. Even in areas where C. neoformans var. gattii does not exist, this infection should be considered possible as a travel-related infection.     

Lyme borreliosis of central nervous system (CNS) in children: A diagnostic challenge

Summary Within 24 months in a consecutive series of 84 children with neurological symptoms indicative of Lyme borreliosis of the central nervous system (CNS) 45 seronegative children (group III), 17 seropositive (group II), and 22 children with specificBorrelia burgdorferi results in cerebrospinal fluid (CSF) — i.e.B. burgdorferi antibodies and/or intrathecally producedB. burgdorferi antibodies and/or positiveB. burgdorferi culture in CSF were observed. The results show that intrathecally producedB. burgdorferi antibodies are the most important marker for the diagnosis of neuroborreliosis (with 71.4% positives) andB. burgdorferi cultivation directly from CSF may be successful in the earliest phase of the disease. Since each of the specific CSF parameters may be false negative in some cases, a careful synopsis of laboratory parameters was done. It shows that CSF protein and CSF cell values are higher in group I than in II or III. Neither can seronegativity exclude nor can seropositivity confirm the diagnosis of neuroborreliosis as in only 71% of group I serumB. burgdorferi antibodies were detected. In view of these aspects clinical and laboratory results are discussed.

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Neuroborreliose im Kindesalter: eine diagnostische Herausforderung

Zusammenfassung Bei 84 Kindern mit Verdacht auf Neuroborreliose wurde der klinische Verlauf und eine Palette spezifischer und unspezifischer Laborparameter aus Liquor und Serum untersucht. Als spezifische, für eine Neuroborreliose beweisende Parameter wurdenB. burgdorferi-Antikörper im Liquor und/oder intrathekal produzierteB. burgdorferi-Antikörper und/oder eine positiveB. burgdorferi-Kultur im Liquor gewertet. Diesen Kindern mit definitiver Neuroborreliose (Gruppe I, n=22) wurden 17 nur im SerumB. burgdorferi-positive (Gruppe II) und 45B. burgdorferi seronegative Kinder (Gruppe III) gegenübergestellt und die unspezifischen Parameter im Gruppenvergleich auf ihre Borrelienrelevanz hin überprüft. Aus klinischer Sicht zeigt sich, daß die neurologische Erkrankung oftmals die Erstmanifestation der Lyme Borreliose im Kindesalter ist (seröse Meningitis und/oder Hirnnervenparese), die nach adäquater antibiotischer Therapie in der Regel auscheilt. Aus den serologischen Ergebnissen ist abzuleiten, daß (1) zur Diagnose einer Neuroborreliose die Bestimmung von intrathekalen Antikörpern die höchste diagnostische Trefferquote aufweist (71,4%), (2) die Liquor-Kultur in frühen Krankheitsstadien aussichtsreich erscheint, (3) in Einzelfällen jeder der drei spezifischen Liquor-Parameter falschnegativ sein kann, (4) daß ein erhöhtes Liquor-Protein bei gesicherter Neuroborreliose deutlich häufiger als in den Vergleichsgruppen (II, III) anzutreffen ist und (5) daß ein positiverB. burgdorferi-Titer im Serum ebensowenig ein deutlicher Hinweis auf eine Neuroborreliose sein kann wie ein negativer eine solche ausschließt (71% seropositive in Gruppe I).

     

Molecular diagnosis of the central nervous system (CNS) infections

Central nervous system (CNS) infections such as meningitis and encephalitis are medical emergencies that require rapid diagnosis of the causative pathogen to guide early and adequate treatment since a delay in implementing an adequate antimicrobial therapy can lead to death. The current microbiological diagnostic methods based on culture or antigen detection have important limitations in their capacity to accurately identify the different potential pathogens causing CNS and, in the time, to obtaining results. Rapid syndromic molecular arrays have been developed. The main advantage of using a meningoencephalitis panel based in a multiplex test is that includes bacteria, viruses and fungi, covering the most prevalent microorganisms causing meningitis and encephalitis and the turn-around time is circa 1 h. The use of these multiplex-PCR based tools is reviewed and the advantages and disadvantages of this technique are discussed.     

Dengue virus infection of the central nervous system (CNS): a case report from Brazil

Dengue infection that is accompanied by unusual complications has been described in Brazil. We report on the presence of dengue virus in the central nervous system (CNS) of a patient who died in 1998 in Rio Grande do Norte, northeast Brazil. DEN-2 viruses were isolated from the brain liver, and lymphnode tissue of a 67-year-old man whose signs and symptoms were those of dengue infection and a secondary immune response. A postmortem revealed nose bleeds a liver that was brownish with yellow areas, and pulmonary and cerebrae congestion. Immunoperoxidase staining showed a dengue antigen-specific positive reaction in the gray matter cells of the cerebrall cortex; a granular citoplasmatic reaction was seen in the neurons. Dengue infection should always be considered as a cause encephalitis in tropical countries, especially in those where the disease is endemic.     

Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis

Haemophagocytic lymphohistiocytosis (HLH) may cause meningoencephalitis and significant neurological sequelae. We examined the relationship between neurological symptoms and cerebrospinal fluid (CSF) at diagnosis, and long-term outcome, in all children enroled in the HLH-94-study prior to July 1, 2003, for whom information on CSF at diagnosis was available (n = 193). Patients were divided into four groups: (i) normal CSF (cells/protein) and no neurological symptoms (n = 71); (ii) normal CSF but neurological symptoms (n = 21); (iii) abnormal CSF but no symptoms (n = 50); and (iv) abnormal CSF with neurological symptoms (n = 51). At diagnosis, neurological symptoms were reported in 72/193 (37%) (seizures = 23); abnormal CSF in 101/193 (52%), and either or both in 122/193 (63%). Altogether 16/107 (15%) survivors had neurological sequelae at follow-up (median 5.3 years). Multivariate hazard ratios (HR) for mortality were 0.98 [95% confidence interval (CI) = 0.42-2.31], 1.52 (0.82-2.82) and 2.05 (1.13-3.72) for groups 2-4, compared with group 1. Moreover, sequelae were more frequent in group 4 (7/21, 33%) compared to groups 1-3 (9/86, 10%) (P = 0.015). Patients with abnormal CSF at diagnosis had significantly increased mortality [HR = 1.78 (95% CI = 1.08-2.92), P = 0.023]. Thus, a substantial proportion of HLH survivors suffer neurological sequelae, and children with abnormal CSF have increased risk of mortality and neurological sequelae. Prompt treatment of HLH at onset or relapse may reduce these complications.     

Axonal transport of neuronal antigens characteristic of subpopulations of central nervous system (CNS) neurons

Monoclonal antibodies (MAbs) are useful for the identification of nervous system antigens localized to neuronal subpopulations. We have examined the transport of the corresponding antigens of four such MAbs in guinea pig retinal ganglion-cell axons. Determination of the axonal transport rate of radiolabeled antigens allowed their assignment to one of the three major anterograde axonal transport rate components, each of which is through to convey a subcellular structural system in the axon. Antigens identified by three of the MAbs were found to be transported in slow component b of axonal transport, the component thought to convey the cytoplasmic matrix, and an antigen identified by the fourth MAb was found in slow component a, similarly thought to contain the linear cytoskeletal elements. Assignment of these antigens to the different rate components suggests that they may be associated with a particular structural system in neurons. Additionally, in cases where more than one nervous system cell type may express a particular antigen, the identity of the neuronal form of the antigen has been confirmed by its axonal transport. The roles that these antigens may play in the nervous system during normal axonal function and during neuropathogenesis can now be further examined.     

Epidemiology and host- and variety-dependent characteristics of infection due to Cryptococcus neoformans in Australia and New Zealand. Australasian Cryptococcal Study Group.

A prospective population-based study was conducted in Australia and New Zealand during 1994-1997 to elucidate the epidemiology of cryptococcosis due to Cryptococcus neoformans var. neoformans (CNVN) and C. neoformans var. gattii (CNVG) and to relate clinical manifestations to host immune status and cryptococcal variety. The mean annual incidence per 10(6) population was 6.6 in Australia and 2.2 in New Zealand. Of 312 episodes, CNVN caused 265 (85%; 98% of the episodes in immunocompromised hosts) and CNVG caused 47 (15%; 44% of the episodes in immunocompetent hosts). The incidence of AIDS-associated cases in Australia declined annually (P<.001). Aborigines in rural or semirural locations (P<.001) and immunocompetent males (P<.001) were at increased risk of CNVG infection. Cryptococcomas in lung or brain were more common in immunocompetent hosts (P< or =.03) in whom there was an association only between lung cryptococcomas and CNVG. An AIDS-associated genetic profile of CNVN serotype A was confirmed by random amplification of polymorphic DNA analysis. Resistance to antifungal drugs was uncommon. The epidemiology of CNVN infection has changed substantially. Clinical manifestations of disease are influenced more strongly by host immune status than by cryptococcal variety.     

Pseudouveitis: a clue to the diagnosis of primary central nervous system lymphoma in immunocompetent patients

Primary oculocerebral non-Hodgkin lymphoma (NHL) of the immunocompetent patient is associated with significant morbidity and mortality, but early diagnosis and follow-up may improve prognosis. The eye, anatomically and embryologically part of the central nervous system (CNS), can be the primary site of the lymphomatous process. In patients with symptoms of atypical uveitis, vitrectomy can be of great help for early diagnosis of primary central nervous system lymphoma. We retrospectively reviewed the diagnostic features, treatment, and evolution of 10 patients with primary central nervous system lymphoma who presented with symptoms of pseudouveitis. The patients complained of chronic vitreal opacities, increasing with time. These symptoms contrasted with the absence of the usual signs of inflammation of the anterior segment or of the retina, which characterize true uveitis. Vitrectomy was proposed after lumbar puncture and cerebral magnetic resonance imaging. Six vitrectomies were carried out, 3 patients had a stereotaxic biopsy, and 1 patient had a cardiac biopsy. A pathologic diagnosis of large B-cell lymphoma was made on vitrectomy specimens in 100% of the patients who had this procedure. The mean time from onset of ocular symptoms to diagnosis was 24 months. This series was characterized by a rare systemic dissemination of the NHL (negative in 80%), a strong preponderance of B-cell NHL, and the absence of association with Epstein-Barr virus (EBV) among these immunocompetent patients. To our knowledge, this series includes the only reported case of oculocardiac lymphoma. Meningeal dissemination appeared to be associated with a poor prognosis. Neurologic complications of treatment combining radiotherapy and methotrexate were significant among patients older than 60 years of age. The current study suggests that primary central nervous system lymphoma should be suspected in patients with pseudouveitis, and that the diagnosis can be established quickly and without side effects by vitrectomy. These patients should be followed carefully in order to detect meningeal dissemination.     

Systemic high-dose methotrexate plus ifosfamide is highly effective for central nervous system (CNS) involvement of lymphoma

Patients with malignant central nervous system (CNS) involvement of lymphoma have a poor prognosis with intrathecal chemotherapy and radiation. In this paper, we report the results we obtained in such patients by intravenous chemotherapy with high-dose methotrexate and ifosfamide (HDMTX/IFO). The study involved a review of all patients who received HDMTX/IFO for CNS involvement of malignant lymphoma at our hospital. Therapy consisted of 4 g/m² of MTX (4 h infusion on day 1) and 1.5–2 g/m²/day of IFO (3 h infusion on days 3–5). The study included 20 patients with a median age of 65 years (range, 30–83) and CNS relapse of a malignant lymphoma. Seventeen patients had been pretreated with up to two chemotherapy regimens. The objective response rate was 90% with 12 complete or unconfirmed complete (CR and CRu) and six partial remissions. All patients had at least stabilization of their neurological symptoms. Myelosuppression was the most common toxicity. The median follow-up time was 14.9 months. The median time to neurological progression was 8.9 months. Twelve patients received subsequent therapy, including high-dose chemotherapy with autologous stem cell transplantation in five cases. The median overall survival was not reached. Systemic chemotherapy with HDMTX/IFO is a feasible and promising treatment modality for CNS relapse of a malignant lymphoma.     

Ca2+ -mediated degradation of central nervous system (CNS) proteins: Topographic and species variation

Incubation of homogenates of rat, rabbit, and bovine spinal cord and of bovine brain white and gray matter in the presence of calcium (5 mM) produced an extensive degradation of the neurofilament triplet proteins (NFP; 200 K, 150K, and 69K). The breakdown products of the NFPs were identified by immunoblot. The glial fibrillary acidic protein (GFAP), microtubular proteins (MTP), and myelin proteins were also degraded. The 150 K NFP was more susceptible than the other NFPs. The extent of calcium-mediated degradation was slightly greater with rat spinal cord than the others. Bovine brain white matter had more activity than gray, which had no appreciable degradative activity. The breakdown was prevented by both EGTA and leupeptin but a similar concentration of MgCl₂ (5 mM) had no effect. These results suggest that NFPs are degraded by a Ca²⁺ -activated neutral proteinase in the central nervous system (CNS) of several species. The lesser activity in gray matter suggests that the enzyme is enriched in axons, myelin, and/or oligodendroglial cells.     

Secondary central nervous system (CNS) involvement in patients with diffuse large B-cell lymphoma: a therapeutic dilemma

Secondary central nervous system (CNS) involvement in diffuse large B-cell lymphoma (DLBCL) includes an isolated CNS relapse or CNS involvement with systemic disease progression. This rare but fatal clinical problem still remains a therapeutic dilemma in the management of DLBCL. However, there are limited data about its treatment outcome. In this study, we gathered 73 cases with secondary CNS involvement of DLBCL from 11 hospitals in Korea. The data were retrospectively compared according to the status of systemic disease (isolated vs. combined CNS involvement) and the use of high-dose methotrexate treatment (HD MTX). Twenty-nine patients showed isolated CNS involvement while 44 had combined CNS involvement with systemic relapse or progression. Thirty-three cases (45.2%) occurred within 6?months from the initial diagnosis, and the majority of these were associated with systemic disease relapse or progression (n?=?27). In isolated CNS involvement, HD MTX resulted in fewer treatment failures (3/11) than the other treatments such as other salvage chemotherapy and/or radiotherapy/intraventricular chemotherapy (14/15). However, neither HD MTX nor other treatments were effective at reducing the treatment failure rate in combined CNS involvement (8/10 and 23/30, respectively). Thus, isolated CNS involvement had a better survival than combined involvement (P?=?0.008), but systemic disease progression was the main cause of death in combined as well as isolated CNS involvement. In conclusion, the prognosis of secondary CNS involvement was dismal even after intensive chemotherapy using HD MTX. Further research focusing on the development of an optimal treatment strategy is warranted.