Long-term MR imaging course of neurodegenerative Langerhans cell histiocytosis.

BACKGROUND AND PURPOSE: MR imaging signal intensity abnormalities in the cerebellum, the pons, and the basal ganglia, compatible with a neurodegenerative process (ND) were reported in up to 10% of patients with Langerhans cell histiocytosis (LCH). Although the imaging features of ND-LCH have been extensively described, the temporal course of ND-LCH has not been assessed as of yet. The purpose of this study was to describe the long-term course of MR imaging signal intensity abnormalities in ND-LCH on T1- and T2-weighted images. MATERIALS AND METHODS: In this retrospective study, 9 patients with ND-LCH with an observation time of at least 5 years were included. Three or more MR imaging studies per patient, performed in 3-year intervals (+/-11 months), were reviewed. Signal intensity abnormalities on T1- and T2-weighted images in the cerebellum, the pons, and basal ganglia were scored for their signal intensity quality and their extension. In addition, the severity of cerebellar atrophy was scored. RESULTS: The signal intensity alterations were not resolved in any of the patients. Instead, a progression of the signal intensity alterations either in the cerebellum or basal ganglia was observed in all of the patients but did not correlate with a clinical deterioration. Overt and severe neurologic symptoms were reported in only 2 patients in whom some form of atrophy was noted. CONCLUSIONS: ND-LCH appears to be a slowly progressive process. The increase of signal intensity abnormalities in the cerebellum and basal ganglia does not correlate with neurologic deterioration. MR imaging appears to be a sensitive technique to detect and monitor radiologic ND-LCH.

Risk factors for diabetes insipidus in langerhans cell histiocytosis.

BACKGROUND: Diabetes insipidus (DI) is the most frequent central nervous system (CNS)-related permanent consequence in Langerhans cell histiocytosis (LCH), which mostly requires life-long hormone replacement therapy. In an attempt to define the population at risk for DI, 1,741 patients with LCH registered on the trials DALHX 83 and DALHX 90, LCH I and LCH II were studied. RESULTS: Overall 212 of 1,741 patients (12%) was reported to have DI. In 102 of 1,741 patients (6%) DI was present at diagnosis of LCH. One thousand one hundred eighty three of 1,539 patients without DI at diagnosis had follow up information. One hundred ten of these (9%) later developed DI. The risk of developing DI was 20% at 15 years after diagnosis. Multisystem disease patients at diagnosis carried a 4.6-fold risk for DI compared to single system patients. Craniofacial lesions, in particular in the "ear," "eye," and oral region were associated with a significantly increased risk for DI (relative hazard rate, RHR 1.7), independent of the extent of disease. No influence of the duration of therapy could be determined, but the duration of initial disease activity (RHR 1.5) and the occurrence of reactivations (RHR 3.5) significantly increased the risk for DI. CONCLUSIONS: Patients with multisystem disease and craniofacial involvement at diagnosis, in particular of the "ear," "eye," and the oral region carry a significantly increased risk to develop DI during their course. This risk is augmented when the disease remains active for a longer period or reactivates.

Improved outcome of treatment-resistant high-risk Langerhans cell histiocytosis after allogeneic stem cell transplantation with reduced-intensity conditioning.

Children with multisystem Langerhans cell histiocytosis (LCH) and risk organ involvement who fail to respond to conventional chemotherapy have an extremely poor prognosis. Myeloablative stem cell transplantation (SCT) as a possible salvage approach for these patients has been associated with a high risk of transplant-related mortality. Therefore, allogeneic stem cell transplantation following a reduced-intensity conditioning regimen (RIC-SCT) has recently been performed as an alternative salvage approach. We report on the experience with allogeneic RIC-SCT in nine pediatric high-risk LCH patients. Conditioning regimen included fludarabine in all patients, melphalan in eight patients, total lymphoid irradiation in six patients, total body irradiation in two, antithymocyte globulin in five, and Campath in four patients. RIC-SCT was well tolerated with regard to common procedure-related complications. Two patients died 50 and 69 days after RIC-SCT, respectively. Seven out of the nine patients survived and showed no signs of disease activity (including one with nonengraftment and full autologous hematopoietic recovery) after median follow-up of 390 days post-SCT. Based on this observation, we conclude that RIC-SCT is a feasible procedure with low transplant-related morbidity and mortality and a promising new salvage approach for high-risk LCH patients with resistant risk organ involvement.

Langerhans cell histiocytosis in neonates.

BACKGROUND: To study the incidence, clinical patterns, course, and outcome of neonatal Langerhans cell histiocytosis (LCH). PROCEDURE: Retrospective analysis of the data of the Austrian/German/Swiss/Netherlands LCH Study Group. The incidence of neonatal LCH was estimated with the data from the population-based German Childhood Cancer Registry. RESULTS: The estimated incidence of neonatal LCH (LCH diagnosed within 28 days after birth) in the population-based registry was 1-2/1,000,000. In 61/1,069 trial patients (6%), the first disease manifestations were observed in the neonatal period. However, in only 20 of them, the diagnosis was established within this period. There was a preponderance of multisystem (MS)-LCH 36/61 (59%). Cutaneous changes were the most common initial manifestation in both, single-system (SS)-LCH (92%), and MS-LCH (86%). In 72% of the MS-LCH patients, risk organs (ROs) were involved at diagnosis as well. The probability of survival at 5 years was 94% in SS-LCH and 57% in MS-LCH, which is significantly lower than in older age groups. CONCLUSIONS: In contrast to the available literature, neonatal LCH is characterized by a clear predominance of MS-LCH. Cutaneous changes are the most common initial manifestation in neonates with both SS-LCH and MS-LCH. Prompt evaluation of disease extent upon diagnosis is mandatory for risk-adapted treatment. The disease course is unpredictable upon diagnosis. Close monitoring for disease progression is mandatory if isolated cutaneous LCH is managed by the "wait and see" approach. Neonates with MS-LCH, especially those with RO involvement at diagnosis, have less favorable prognosis compared to infants and older children, and need systemic therapy.

Pineal gland abnormalities in Langerhans cell histiocytosis.

BACKGROUND: The most common types of central nervous system (CNS) disease in Langerhans cell histiocytosis (LCH) comprise involvement of the hypothalamic-pituitary region (HPR) and neurodegenerative changes in the cerebellum, basal ganglia or pons. In the review process of magnetic resonance images (MRI) from 129 LCH patients a high frequency of cysts within or large pineal glands was noted by chance. PROCEDURE: To prove whether this observation was specific for LCH or not, we compared MRI findings of the HPR in LCH patients with a control group of 55 non-LCH patients with the same age and sex distribution. RESULTS: In LCH patients, the pineal gland was significantly larger and also the number of pineal cysts was significantly higher as compared to the control group. No difference was found regarding the size or frequency of cystic changes between patients who had received chemotherapy prior to the MRI and untreated patients. In the LCH patients, we further found a significant correlation of pineal gland enlargement with involvement of the HPR, but not with neurodegenerative changes. Analysis of melatonin (the principal hormone of the pineal gland) levels in 24 hr urine in 14 LCH patients did not reveal a melatonin deficiency or overproduction in the LCH group as compared to 6 normal controls. CONCLUSIONS: The pineal gland is another site of possible CNS involvement in LCH. LCH CNS patients did not show an overt disturbance in melatonin levels. The role of the pineal gland in CNS LCH remains to be defined.

Langerhans cell histiocytosis in adults. Report from the International Registry of the Histiocyte Society.

Langerhans cell histiocytosis (LCH), characterised by the infiltration of one or more organs by large mononuclear cells, can develop in persons of any age. Although the features of this disease are well described in children, they remain poorly defined in adults. From January 2000 to June 2001, 274 adults from 13 countries, with biopsy-proven adult LCH, were registered with the International Histiocyte Society Registry. Information was collected about clinical presentation, family history, associated conditions, cigarette smoking and treatment, to assist in future management decisions in patients aged 18 years and older. There were slightly more males than females (143:126), and the mean ages at the onset and diagnosis of disease were 33 years (standard deviation (S.D.) 15 years) and 35 years (S.D. 14 years), respectively. 2 patients had consanguineous parents, and 1 had a family history of LCH; 129 reported smoking (47.1%); 17 (6.2%) had been diagnosed with different types of cancer. Single-system LCH, found in 86 patients (31.4%), included isolated pulmonary involvement in 44 cases; 188 patients (68.6%) had multisystem disease; 81 (29.6%) had diabetes insipidus. Initial treatment consisted of vinblastine administered with or without steroids, to 82 patients (29.9%), including 9 who had received it with etoposide, which was the sole agent given to 19 patients. 236 patients were considered evaluable for survival. At a median follow-up of 28 months from diagnosis, 15 patients (6.4%) had died (death rate, 1.5/100 person years, 95% Confidence Interval (95% CI) 0.9-2.4). The probability of survival at 5 years postdiagnosis was 92.3% (95% CI 85.6-95.9) overall, 100% for patients with single-system disease (n=37), 87.8% (95% CI 54.9-97.2) for isolated pulmonary disease (n=34), and 91.7% (95% CI 83.6-95.9) for multisystem disease (n=163). Survival did not differ significantly among patients with multisystem disease, with or without liver or lung involvement) 5-year survival 93.6% (95% CI 84.7-97.4) versus 87.5% (95% CI 65.5-95.9), respectively; P value 0.1). LCH in adults is most often a multisystem disease with the highest mortality seen in patients with isolated pulmonary involvement. It should be included in the differential diagnosis of disseminated or localised disease of the bone, skin and mucosa, as well as the lung and the endocrine and central nervous system, regardless of the age of the patient. A prospective international therapeutic study is warranted.

Pattern and course of single-system disease in Langerhans cell histiocytosis data from the DAL-HX 83- and 90-study.

BACKGROUND: Single-system (SS) disease is the most common presentation in Langerhans cell histiocytosis (LCH) with a heterogenous clinical picture and course. Mostly bone and rarely skin or lymph nodes are involved. PROCEDURE: One hundred and seventy patients with SS-LCH were registered in the DAL-HX 83/90 studies. They were diagnosed according to uniform diagnostic criteria and followed by a standardised schedule. RESULTS: Single bone lesions were most common (68%), followed by multiple bone lesions (19%), isolated skin disease (11%), and isolated lymph node involvement (4 patients). In the detection of bone lesions radiographic skeletal survey proved to be superior to bone scan (97% vs. 82%). Treatment comprised surgery, irradiation and local instillation of steroids, and standardised chemotherapy for multifocal bone disease. After initial therapy 81% of the patients remained disease free. Reactivations restricted to the skeleton occurred in 18% of both unifocal and multifocal bone disease. Two skin patients had a chronic course. Fatality occurred only in one infant with skin disease who progressed to multi-system disease. Twenty-five percent of all patients developed permanent consequences, which were already present at diagnosis in about half of these patients and comprised mainly orthopedic problems related to lesional sites. Diabetes insipidus occurred in 3% and anterior pituitary dysfunction in 2% of the patients. CONCLUSIONS: The course in SS%LCH was benign. In bone disease reactivations remained restricted to the skeleton and did not influence survival. However, reactivations had an impact on morbidity, as permanent consequences were mostly related to the site of disease activity. Med Pediatr Oncol 2001;37:108-114.

A randomized trial of treatment for multisystem Langerhans' cell histiocytosis.

OBJECTIVE: To compare 2 active agents, vinblastine and etoposide, in the treatment of multisystem Langerhans' cell histiocytosis (LCH) in an international randomized study. STUDY DESIGN: One hundred forty-three untreated patients were randomly assigned to receive 24 weeks of vinblastine (6 mg/m(2), given intravenously every week) or etoposide (150 mg/m(2)/d, given intravenously for 3 days every 3 weeks), and a single initial dose of corticosteroids. RESULTS: Vinblastine and etoposide were equivalent (P > or = .2) in all respects: response at week 6 (57% and 49%); response at the last evaluation (58% and 69%); toxicity (47% and 58%); and probability of survival (76% and 83%) [corrected], of disease reactivation (61% and 55%), and of developing permanent consequences (39% and 51%) including diabetes insipidus (22% and 23%). LCH reactivations were usually mild, as was toxicity. All children > or = 2 years old without risk organ involvement (liver, lungs, hematopoietic system, or spleen) survived. With such involvement, lack of rapid (within 6 weeks) response was identified as a new prognostic indicator, predicting a high (66%) mortality rate. CONCLUSIONS: Vinblastine and etoposide, with one dose of corticosteroids, are equally effective treatments for multisystem LCH, but patients who do not respond within 6 weeks are at increased risk for treatment failure and may require different therapy.

Treatment of multisystem Langerhans cell histiocytosis. Results of the DAL-HX 83 and DAL-HX 90 studies. DAL-HX Study Group.

BACKGROUND: The prognosis of children with multisystem Langerhans cell histiocytosis (LCH) has improved with the application of chemotherapy. However, treatment strategies used varied from conservative approach with treatment only during disease exacerbation to intensive chemotherapy starting immediately after diagnosis. No single drug or regimen has been proven to be superior to the others. Thus, optimal treatment of multisystem LCH remains still an unsolved problem. PATIENTS: Three hundred and twenty-four patients enrolled in the DAL-HX 83 and DAL-HX 90 studies were retrospectively re-evaluated by using the current definition for disease extent. Sixty-three patients fulfilling the criteria for multisystem LCH (involvement of > or = 2 organ systems) were object of the present study. These were 33 males and 30 females, median age at diagnosis 11.5 months (range, birth-13 years 2 months). The median observation time was 7 years 6 months (4 years-11 years 8 months). METHODS: All patients had morphologically confirmed diagnosis, which was additionally verified through demonstration of CD1a antigen, presence of Birbeck granules or central pathologic review. Uniform evaluation including a complete medical history and physical examination, laboratory tests (complete blood count, liver function tests, coagulation profile) and radiographic survey (skeletal survey and/or radionuclide bone scan) was performed in all patients. Additional investigations (bone marrow tap, CT, MRI etc.) were performed upon specific indications. The 63 patients with multisystem LCH were evaluated with respect to response to therapy, clinical course, outcome and development of permanent disabilities. The results of the DAL-HX studies were compared with the results of the first randomized international clinical trial on multisystem LCH (LCH-I). RESULTS: Response to 6 weeks of initial therapy showed a clear discrimination between responders and non-responders, with only 6% of the patients having intermediate response. When correlated to survival response to initial therapy appears to be a powerful prognosticator in multisystem LCH. There were some typical patterns of clinical course. Complete disease resolution at some point of the clinical course was documented in 50 (79%) patients. Thirty-five of them remained disease free, while 15 experienced one or more episodes of disease reactivation. Chronic reactivating course without complete disease resolution was observed in one patient. Deteriorating disease with fatal outcome was shown in 12 (19%) patients. The overall survival after 5 years of observation was 81%. One or more disease-related permanent disabilities were documented in 24 patients, in 4 of them these were shown at diagnosis and in 20 patients these developed after therapy had been commenced. Despite more intensive chemotherapy, the overall survival in DAL-HX 83/90 cohort was comparable with that in LCH-I studies. However, LCH-I compares unfavorably to DAL-HX 83/90 in some very important aspects. With respect to reactivation rate, reactivation free interval and development of permanent disabilities better results were achieved with the more intensive initial and prolonged continuation therapy concept of the DAL-HX studies. Even after extended analysis it remains unclear whether the superiority of the DAL-HX studies has to be attributed to the administration of continuous steroids, to the combination of vinblastine and etoposide, or to the prolonged continuation therapy including mercaptopurine. Answers to these questions are expected from the ongoing international clinical trial LCH-II.

Spiral CT of the lung in children with malignant extra-thoracic tumors: distribution of benign vs malignant pulmonary nodules.

The purpose of this paper is to clarify the distribution of benign vs malignant pulmonary nodules which are seen on spiral CT in children with malignant extra-thoracic solid tumors. Seventy-four children with known solid, extra-thoracic tumors underwent spiral CT of the chest. According to the initial and follow-up (interval 9.2+/-4.7 months) findings, the children were graded into four groups: I = normal; II = solitary nodule unchanged at follow-up; III = multiple nodules with one or more than one unchanged at follow-up; and IV = solitary or multiple nodules all changed at follow-up. Nodules without change at follow-up were regarded as benign. Forty-nine children did present with normal pulmonary CT exams. In 7 cases solitary pulmonary nodules were found unchanged (group II) at follow-up and in 2 cases (group III) some of the nodules were stationary. Thus, 12% (9 of 74) presented with at least one pulmonary nodule that did not change at follow-up. Solitary nodules (in groups II and IV) with a diameter <5 mm were in 70 % (7 of 10) unchanged at follow-up and regarded as benign. In children with known solid extra-thoracic tumors at initial presentation, 70% of solitary nodules ( <5 mm) may be benign. To avoid overstaging, smaller solitary nodules must not automatically be regarded as metastases.

Cyclosporine A therapy for multisystem langerhans cell histiocytosis.

BACKGROUND: Treatment of multisystem Langerhans cell histiocytosis (LCH) remains difficult. Various regimens of single and multiagent chemotherapy have been used, but a significant proportion of patients fail to respond to treatment. PROCEDURE: We have evaluated the use of cyclosporine A (CSA) in a controlled group of patients, who had received a systematic primary therapy (LCH-I). Patients received CSA either as a single agent (10 patients) or in combination with vinblastine, etoposide, prednisolone, and/or antithymocyte globulin (16 patients). RESULTS: Among the total of 26 patients treated, a single patient developed a complete response and three a partial response, whereas 85% (22 patients) had no response to CSA. CONCLUSIONS: CSA is at best of limited value in the treatment of patients with multisystem LCH, particularly those who had progressive disease while receiving chemotherapy.

Central nervous system disease in Langerhans cell histiocytosis.

Central nervous system (CNS) disease in Langerhans cell histiocytosis (LCH) is a poorly understood complication of yet unknown frequency. By far the most common manifestation is in the hypothalamic-pituitary system with diabetes insipidus as the leading sign, followed by other endocrinopathies and hypothalamic dysfunction. However, essentially all other parts of the CNS may be involved. On the one hand, space-occupying histiocytic infiltrates may lead to size- and site-depending symptoms, extending from adjacent bone lesions or arising from the meninges or choroid plexus. On the other hand, a progressive neurological deterioration can occur with mainly cerebellar-pontine symptoms. In this article, these clinical patterns are described in correlation with the morphology on MR imaging and histopathology. Further, the therapeutic strategies are reviewed critically, and guidelines for the management of patients with LCH-related CNS disease are presented.

Diabetes insipidus in Langerhans cell histiocytosis: results from the DAL-HX 83 study.

Diabetes insipidus (DI) in Langerhans cell histiocytosis (LCH) is a common complication of unclear etiology. The incidence varies among different publications from 15% to 50%. In the prospective DAL-HX 83 study, 19 out of 199 patients (9.5%) registered with newly diagnosed LCH were diagnosed to have DI. All patients were stratified according to uniform criteria. One hundred and six patients with disseminated disease were treated with standardized polychemotherapy promptly after diagnosis. At the time of diagnosis of LCH, DI was already established in 8 out of 199 patients (4%). After diagnosis, DI occurred in only one out of the remaining 91 patients with localized disease (1%) and in 10 out of 100 remaining patients with disseminated disease (10%). In 8 patients, the onset of DI was associated with other signs of active LCH. The cumulative risk to develop DI after a median observation time of 5 years 3 months was 11%. Retrospective analysis of clinical features revealed multisystem involvement, skull and orbital lesions, and in particular intracranial extension from osseous lesions to constitute risk factors for DI. Magnetic resonance imaging studies (MRI) were available in 12 patients and showed abnormalities of the pituitary region in 10 children. In none of the patients with established DI was it reversed or ameliorated by any treatment. However, the rapid institution of systemic chemotherapy for disseminated disease seems to prevent the occurrence of DI and may be responsible for the low frequency of DI in the DAL-HX83 study.

Central nervous system disease in Langerhans cell histiocytosis.

Diabetes insipidus and anterior pituitary dysfunction, are familiar central nervous system (CNS) complications of Langerhans cell histiocytosis (LCH) but the pathophysiology and biological behaviour of other forms of CNS involvement in LCH are poorly understood. In an attempt to improve our understanding of these rare complications, we studied 23 patients with LCH in whom neuroradiological abnormalities, with or without neurological dysfunction other than diabetes insipidus, developed during the course of disease. Neuroradiological abnormalities were of three basic types (a) poorly-defined changes in white matter, (b) well-defined changes in white and grey matter and (c) extra-parenchymal "tumoural" masses. There was a profusion of associated neurological signs and symptoms in most cases but some patients were asymptomatic. The neuropathological features were complex but infiltration of the CNS by histiocytes with xanthomatous change, particularly prominent in mass lesions, was common in the 13 cases in which biopsies were done. Patients with lytic lesions of the skull and diabetes insipidus are evidently most at risk of developing these rare manifestations of LCH. Therapeutic questions could not be answered from this study because no standard treatment had been given and outcome varied widely.

LCH-I: a randomized trial of etoposide vs. vinblastine in disseminated Langerhans cell histiocytosis. The Histiocyte Society.

An international randomized trial in Langerhans cell histiocytosis (LCH) has been initiated by the Histiocyte Society. This report reviews the rationale, design, and progress of LCH-I, which compares etoposide (VP-16) and vinblastine in the treatment of disseminated LCH. Data on the risk of etoposide-associated (therapy-induced) malignancy, in the setting of histiocytosis, are reviewed. The available evidence leads to the recommendation that the study of etoposide in LCH should be continued.

Treatment strategy for disseminated Langerhans cell histiocytosis. DAL HX-83 Study Group.

Treatment of Langerhans cell histiocytosis (LCH) remains problematic. To test the hypothesis that rapid initiation and long-term continuation of chemotherapy can improve survival and reduce recurrence and late consequences of disseminated LCH, we have completed a prospective clinical trial (DAL HX-83). One hundred six newly diagnosed patients were stratified into three risk groups (A: multifocal bone disease [n = 28]; B: soft tissue involvement without organ dysfunction [n = 57]; C: organ dysfunction [n = 21]). All patients received an identical initial 6-week treatment (etoposide [VP-16], prednisone, and vinblastine), and continuation treatment for 1 year, slightly adapted according to stratification at diagnosis. It included oral 6-mercaptopurine and eight pulses of vinblastine and prednisone for all patients, plus VP-16 in group B and VP-16 and methotrexate in group C. Eighty-nine percent and 91% of patients in groups A and B and 67% of the most severely affected group C, achieved complete resolution of disease. The speed of resolution was rapid (median 4 months) and independent of disease severity. The frequency of recurrence after initial resolution was low (12%, 23%, and 42% in groups A, B and C); overall fully 77% of patients have remained free of recurrence. Permanent consequences developed after diagnosis in 20% of the patients. Diabetes insipidus after initiation of treatment occurred in only 10% of patients. Mortality (9%) was limited to patients of groups B (two patients) and C (eight patients). Finally, among the 106 patients treated by DAL HX-83 none have developed a malignancy (median follow-up 6 years, 9 months). The shorter duration of active disease, low rate of recurrence and permanent consequences, and improved survival among patients with poor prognosis support the strategy of rapid initiation of a predefined prolonged treatment upon the diagnosis of disseminated LCH.

Tetrasomy 8 in acute monoblastic leukemia (AML-M5a) with myelosarcomatosis of the skin.

We report a new case with isolated tetrasomy 8, an 82-year-old female patient in whom multiple disseminated nodular skin infiltrations up to 5 cm in diameter preceded acute monoblastic leukemia (AML-M5a). Despite an initial response to chemotherapy and radiotherapy, the patient died 1 year after diagnosis of relapsed leukemia. To assess the size of the tetrasomic clone, fluorescence in situ hybridization (FISH) analysis with a centromere-specific chromosome 8 probe was performed. Seventy percent of interphase cells showed four signals and 22% showed three signals. Because this trisomic clone was not detected by conventional cytogenetics, tetrasomic cells may have a proliferation advantage in vitro. Whether tetrasomy 8 arises from a simultaneous mitotic nondisjunction of both chromosomes 8 during one cell division or evolves secondarily from trisomy 8 through a second mitotic error is not known. Alternatively, trisomy 8 may originate from tetrasomy 8 by loss of one chromosome 8.

Central nervous system disease associated with Langerhans' cell histiocytosis.

PURPOSE: To study the pathogenesis of central nervous system (CNS) lesions in Langerhans' cell histiocytosis (LCH), discuss their differential diagnosis and suggest guidelines for their management. PATIENTS AND METHODS: Central nervous system (CNS) disease with Langerhans' cell histiocytosis (LCH) is a poorly understood disorder. Most commonly, the hypothalamic-pituitary region is involved, leading to diabetes insipidus (DI) or other endocrinopathies. We report four patients in whom lesions in the pons, cerebellum, basal ganglia, cerebral white matter, or optic nerve and tract were demonstrated by magnetic resonance imaging (MRI). RESULTS: Three developed a progressive neurological disorder with cerebellar and pontine symptoms leading to severe disability--in one patient to blindness and death--in spite of various treatment approaches. In the fourth patient, who had MRI examinations to evaluate long-standing DI, CNS lesions were detected in the absence of neurological symptoms. There was no correlation between activity of LCH, severity and course of the CNS disease, or morphology of the lesions on MRI. Brain biopsy was performed in the three symptomatic patients and revealed cerebellar atrophy in one. Normal brain tissue was obtained from two patients. In none of the patients could autoantibodies to nervous system tissue be detected in serum or cerebrospinal fluid. CONCLUSION: Based on clinical, pathological, and MRI findings in our four patients and on information in the literature, we conclude that the CNS disease associated with LCH, although insufficiently understood, is likely to be a manifestation of histiocytosis in the brain, and we propose guidelines for the management of patients with this disorder.

Conventional vs. liposomal amphotericin B in immunosuppressed children.

Invasive fungal infections, mostly caused by Candida and Aspergillus species, are a major cause of early morbidity and mortality in immunocompromised children. The treatment of choice for systemic fungal infections is still the early intravenous administration of amphotericin B. However, conventional AMB therapy is often limited by severe side effects such as fever, chills, bronchospasm, and nephrotoxicity. In recent reports liposomal AMB (AmBisome) was shown to be effective in the treatment of severe systemic fungal infections. So far, clinical experience with AmBisome in children is still anecdotal and no comparative study is yet available. In the following we report on 11 immunosuppressed children who were treated with conventional or liposomal AMB for longer than 3 weeks.