CENTRAL NERVOUS SYSTEM DISEASE IN LANGERHANS CELL HISTIOCYTOSIS

https://doi.org/10.1016/S0889-8588(05)70511-6Get rights and content

From its very beginnings, the history of Langerhans cell histiocytosis (LCH) has been inseparable from its central nervous system (CNS) manifestations. Hand36 in 1893 reported on a patient with “polyuria and tuberculosis,” which is now recognized as a typical case of diabetes insipidus and multisystem disease with exophthalmos. Other early reports14, 28, 44, 71 described characteristic cases with skull lesions and diabetes insipidus (DI). A comprehensive treatise on LCH and the nervous system has been provided by Kepes,45 who illustrated the wide range of clinical and histopathologic presentations of the disease. Apart from the common manifestations in the hypothalamic-pituitary axis, virtually all other parts of the CNS can be affected by LCH. The plethora of symptoms depends on the type and site of involvement. Clinically, four groups of patients can be distinguished: (1) those with a disorder of the hypothalamic-pituitary system; (2) patients presenting with site-dependent symptoms from space-occupying lesions, such as headaches or seizures; (3) those who exhibit a neurologic dysfunction mostly following a cerebellar-pontine pathway, including reflex abnormalities, ataxia, intellectual impairment, tremor, or dysarthria with variable progression to severe CNS deterioration; and (4) patients who present with an overlap of the symptoms mentioned previously.

During the last few years, a number of anecdotal case reports and small series of patients have appeared describing patients with variable CNS findings that were evaluated by modern imaging techniques.1, 27, 62, 65 In particular, MR imaging has provided an appropriate tool to facilitate the diagnosis and follow-up of CNS changes, even in patients with no or minimal neurologic symptoms.7, 26, 29, 35, 57, 64, 66, 75

There are still a number of unanswered questions regarding LCH-CNS disease. The actual incidence is unknown and the natural history still remains poorly understood. In this article, the wide spectrum of clinical manifestations of LCH-CNS are presented and correlated with the morphologic changes seen on imaging studies together with the histopathologic findings. Finally, the authors speculate on the pathogenesis, suggest guidelines for management of such patients, and discuss the therapeutic options.

Section snippets

LCH-CNS STUDY

Information provided in this article is based on both a comprehensive review of the literature and on data from the LCH-CNS Study. The latter was a retrospective collection of clinical data and information on imaging and histopathology of LCH in patients who presented with signs and symptoms of CNS involvement. The goal was to gather information on the variety of clinical and morphologic patterns of this disease.

Between 1991 and 1996, material on 38 patients was compiled from 27 institutions in

MAGNETIC RESONANCE IMAGING CHANGES AND DIFFERENTIAL DIAGNOSES (Table 2)

The increased availability of MR imaging has improved the diagnosis of CNS abnormalities. Most LCH patients now undergo MR imaging for the evaluation of DI. In one exceptional case in the LCH-CNS Study, profound abnormalities in the cerebellum and pons were found on such an occasion in the absence of any CNS symptoms apart from DI, which was associated with skull and temporal bone lesions. This case underscores the sensitivity of MR imaging and provides evidence for the importance of evaluating

HISTOPATHOLOGY

Four stages of LCH-CNS were described by Norman61: a hyperplastic-proliferative stage, a granulomatous stage, a xanthomatous stage, and a stage of fibrosis. Based on hematoxylin and eosin morphology of autopsy material, Kepes45 provided a comprehensive overview of the disorder in 1979. He proposed that the LCH cells arose from adventitial cells of blood vessels, causing perivascular histiocytic aggregates that evolved into larger granulomatous masses that contained variable portions of foamy

HYPOTHALAMIC-PITUITARY INVOLVEMENT

There is an outstanding but unexplained predilection of LCH for the hypothalamic-pituitary system, occurring mostly in the setting of systemic disease. It is also observed as an isolated entity described as Ayala's disease or Gagel's granuloma in early reports.4, 25

The signs and symptoms range from disturbances in social behavior, appetite, and temperature regulation or sleep pattern in case of hypothalamic involvement; to polyuria and polydipsia as manifestations of posterior pituitary

SPACE-OCCUPYING CNS LESIONS

Lesions exerting a mass effect may arise from neighboring bone lesions, from the meninges, or from the choroid plexus. The symptoms depend on the size and site of the lesions, and they are related largely to raised intracranial pressure or focal damage. They include headaches, vomiting, papilledema and optic atrophy, seizures, and other focal symptoms. These lesions may occur with or without other evidence of LCH.12, 59 They appear localized or multifocal,27 with some tendency to symmetry in

CEREBELLAR SYNDROME/NEUROLOGIC DEGENERATION

The second most common site of LCH-CNS involvement after the hypothalamus-hypophyseal axis is the cerebellum.1, 5, 13, 22, 37, 39, 46, 77, 86 The incidence of this finding is unknown. In the LCH-CNS Study, 23 of 38 patients (60%) presented with changes in the cerebellum. The frequency of signs of cerebellar dysfunction in recent studies varies from 1% to 12%, presumably depending on the different duration of the observation periods, which ranged from 13 to 25 years.24, 78, 85 Neurologic

COMBINATION OF DIFFERENT CNS MANIFESTATIONS

As already mentioned, the majority of patients display more than one type of lesion. Often DI with structural changes in the hypothalamic-pituitary region heralds the involvement of other parts of the brain, sometimes by years. In the infratentorial space, the bilateral symmetric changes in the cerebellar dentate nuclei and white matter are the most common finding. Supratentorially, extraparenchymal lesions deriving from the meninges and the choroid plexus are frequently seen. They range from

SPECULATIONS ON PATHOGENESIS

The etiology of LCH-CNS remains poorly understood. The crucial questions are the following: Where do LCH-CNS lesions come from, and what factors influence the development of the various types of lesions? Why are the hypothalamus-pituitary and the cerebellar-pontine regions preferential sites? Are any special local factors encouraging the development of infiltrates? Are there any specific host factors influencing the development of more tumorous infiltrates in some patients and of degenerative

GUIDELINES FOR THE MANAGEMENT OF

LCH-CNS PATIENTS

ACKNOWLEDGMENT

The authors are grateful to V. Broadbent, G. D'Angio, and A. J. Barkovich for their expert advice and also wish to thank E. Thiem, B. Holzinger, and M. Minkow for their help in the evaluation of the patient data and preparation of the manuscript.

References (86)

  • W.H. Breidahl et al.

    Cerebral and brain stem Langerhans cell histiocytosis

    Neuroradiology

    (1993)
  • V. Broadbent et al.

    Diabetes insipidus associated with Langerhans cell histiocytosis: Is it reversible?

    Med Pediatr Oncol

    (1997)
  • V. Broadbent et al.

    Anterior pituitary function and computed tomography/magnetic resonance imaging in patients with Langerhans cell histiocytosis and diabetes insipidus

    Med Pediatr Oncol

    (1993)
  • A. Ceci et al.

    Langerhans cell histiocytosis in childhood: Results from the Italian Cooperative AIEOP-CNR-H.X'83 Study

    Med Pediatr Oncol

    (1993)
  • A. Ceci et al.

    Etoposide in recurrent childhood Langerhans' cell histiocytosis: An Italian Cooperative Study

    Cancer

    (1988)
  • M. Cerda-Nicolas et al.

    Primary eosinophilic granuloma of the frontal lobe

    Virchows Arch A Path Anat Histol

    (1980)
  • H. Chiari

    Über Veränderungen im Zentralnervensystem bei generalisierter Xanthomatose von Typus Schüller-Christian

    Virchows Arch Path Anat

    (1933)
  • H.A. Christian

    Defects in membranous bones, expohthalmos and diabetes insipidus; an unusual syndrome of dyspituitarism: A clinical study

    Med Clin North Am

    (1920)
  • N. Colombo et al.

    Posterior pituitary gland: Appearance on MR images in normal and pathologic states

    Radiology

    (1987)
  • E.J. Czarnecki et al.

    MR demonstration of Wegener granulomatosis of the infundibulum, a cause of diabetes insipidus

    AJNR Am J Neuroradiol

    (1995)
  • R.D. Darnell et al.

    Antiserum from a patient with cerebellar degeneration identifies a novel protein in Purkinje cells, cortical neurons, and neuroectodermal tumors

    J Neuroscience

    (1991)
  • L.F. Drolshagen et al.

    Cervical meningeal histiocytosis demonstrated by magnetic resonance imaging

    Pediatr Radiol

    (1987)
  • R.L. Dubowsy et al.

    Severe cerebellar degeneration and delayed onset ataxia in histiocytosis X

    Pediatr Res

    (1985)
  • D.B. Dunger et al.

    The frequency and natural history of diabetes insipidus in children with Langerhans cell histiocytosis

    N Engl J Med

    (1989)
  • I. Feigin

    Xanthomatosis of the nervous system

    J Neuropathol

    (1956)
  • I. Fujisawa et al.

    Posterior lobe of the pituitary in diabetes insipidus: MR findings

    J Comput Assist Tomogr

    (1987)
  • H. Gadner et al.

    Treatment strategy for disseminated Langerhans cell histiocytosis

    Med Pediatr Oncol

    (1994)
  • O. Gagel

    Eine Granulationsgeschwulst im Gebiete des Hypothalamus

    Zeitscrift fuer die gesamte Neurologie und Psychiatrie

    (1941)
  • J.C. George et al.

    MR of intracranial Langerhans cell histiocytosis

    J Comput Assist Tomogr

    (1994)
  • M. Goldzieher

    Über Sektionsbefunde bei Diabetes insipidus

    Verh Dtsch Ges Pathol

    (1913)
  • M. Graif et al.

    MR imaging of histicytosis X in the central nervous system

    AJNR Am J Neuroradiol

    (1986)
  • J.S. Greenberger et al.

    Results of treatment of 127 patients with systemic histiocytosis (Letterer-Siwe Syndrome, Schuller-Christian syndrome and multifocal eosinophilic granuloma)

    Medicine

    (1981)
  • J.E. Greenlee et al.

    Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degeneration and ovarian carcinoma

    Ann Neurol

    (1983)
  • S.M. Greenwood et al.

    Unifocal eosinophilic granuloma of the temporal lobe

    Surg Neurol

    (1981)
  • N. Grois et al.

    Report of the Histiocyte Society Workshop on “Central Nervous System (CNS) Disease in Langerhans Cell Histiocytosis (LCH).”

    Med Pediatr Oncol

    (1997)
  • N. Grois et al.

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

    Med Pediatr Oncol

    (1995)
  • N. Grois et al.

    Central nervous system disease in Langerhans cell histiocytosis

    Br J Cancer

    (1994)
  • A. Hand

    Polyuria and tuberculosis

    Arch Pediatr

    (1893)
  • R.H.A. Haslam et al.

    Progressive cerebellar ataxia associated with Hand-Schüller-Christian disease

    Dev Med Child Neurol

    (1971)
  • J. Hayward et al.

    Central nervous system and Langerhans' cell histiocytosis

    Med Pediatr Oncol

    (1990)
  • J. Heine

    Beitrag zur Schüller-Christian'schen Krankheit

    Beitraege zur pathologischen Anatomie und allgemeinen Pathologie

    (1934)
  • R.H. Hewlett et al.

    Histiocytosis of the cauda equina

    Neurology

    (1976)
  • Y. Ichikawa et al.

    Pituitary stalk thickening in central diabetes insipidus due to sarcoidosis [letter]

    Sarcoidosis

    (1995)

    • Cited by (174)

    • Socio-behavioral dysfunction in disorders of hypothalamic-pituitary involvement: The potential role of disease-induced oxytocin and vasopressin signaling deficits

      2022, Neuroscience and Biobehavioral Reviews
      Citation Excerpt :

      Estimates of CNS involvement in LCH patients vary widely and are reported to range from 3.4% to 57% (Yeh et al., 2018). CNS LCH most commonly affects the HPIT region (Grois et al., 1998; Fahrner et al., 2012). While a confirmatory biopsy is required to make a definitive diagnosis of LCH, tumor location may make performing a biopsy difficult and/or clinically contraindicated in some patients.

    • Histiocytic disorders

      2021, Lanzkowsky's Manual of Pediatric Hematology and Oncology

    • Endocrine and metabolic assessment in adults with Langerhans cell histiocytosis

      2018, European Journal of Internal Medicine
      Citation Excerpt :

      In more than a half of cases oncogenic mutations could be found, more frequently BRAFV600E [6,9,10] or rarely KRAS and TP53 but probably LCH is not a classical neoplastic disease but a neoplastic process with inflammatory manifestations [11]. About pituitary gland, autoptic series showed infiltrative Langerhans cells in about 5–50% of the LCH population [12–15] but really few studies have examined the real prevalence of endocrine diseases among adult LCH patients prospectively [16,17]. Diabetes Insipidus (DI) is the most frequent endocrine alteration described, its prevalence being among 15% and 50% of LCH patients [18,19], in particular about 40% considering only LCH MS-RO− patients, and at present it is considered the most common LCH permanent complication [15,20].

    • Histiocytosis Syndromes

      2016, Lanzkowsky's Manual of Pediatric Hematology and Oncology

    • Strategies for the Prevention of Central Nervous System Complications in Patients with Langerhans Cell Histiocytosis: The Problem of Neurodegenerative Syndrome

      2015, Hematology/Oncology Clinics of North America

    • Neurological Manifestations of Histiocytic Disorders

      2023, Current Neurology and Neuroscience Reports
    View all citing articles on Scopus

    Address reprint requests to Nicole G. Grois, MD, St. Anna Children's Hospital, Kinderspitalgasse 6, A-1090 Vienna, Austria

    View full text
    Copyright © 1998 W. B. Saunders Company. Published by Elsevier Inc. All rights reserved.