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Adult leukoencephalopathies with prominent infratentorial involvement can be caused by Erdheim–Chester disease

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Abstract

Background

Leukoencephalopathies with prominent involvement of cerebellum and brainstem, henceforward called prominent infratentorial leukoencephalopathies (PILs), encompass a variety of inherited and acquired white matter diseases. Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis likely under-diagnosed as cause of adult PIL.

Methods

We reviewed the clinical and laboratory information of ten consecutive sporadic adult patients with PIL of unknown origin, who were investigated for ECD.

Results

There were seven males and three females; mean age at clinical onset was 49.6 years (range 38–59); cerebellar ataxia with or without other neurological symptoms was the only or the main clinical manifestation; diabetes insipidus was present in three individuals. Eight patients had white matter focal supratentorial abnormalities, in addition to the infratentorial white matter changes. Six out of eight patients had spinal cord lesions. Thoraco-abdominal CT showed periaortic sheathing in two patients, whole-body FDG-PET revealed increased glucose uptake in the long bones of the legs in five patients, brain FDG-PET showed overt infratentorial hypermetabolism in one patient. In eight patients, ECD was confirmed by bone scintigraphy, pathological data, or both. Two ECD patients treated with vemurafenib showed a marked improvement of neurological symptoms and brain MRI abnormalities at 1 year follow-up.

Conclusions

Symptoms of PIL can be the only clinical manifestation of ECD. Adult patients with PIL of unknown origin should undergo investigations aimed at unveiling ECD, including bone scintigraphy and whole-body FDG-PET. The early diagnosis allows starting disease-modifying therapies of an otherwise life-threatening disease.

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References

  1. Schiffmann R, van der Knaap MS (2009) Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 72:750–759

    Article  PubMed  PubMed Central  Google Scholar 

  2. Gass A, Filippi M, Grossman RI (2000) The contribution of MRI in the differential diagnosis of posterior fossa damage. J NeurolSci 172(Suppl 1):S43–S49

    Google Scholar 

  3. Rovira À, Sastre-Garriga J, Auger C et al (2013) Idiopathic inflammatory demyelinating diseases of the brainstem. Semin Ultrasound CT MR 34:123–130

    Article  PubMed  Google Scholar 

  4. Akman-Demir G, Bahar S, Coban O et al (2003) Cranial MRI in Behçet’s disease: 134 examinations of 98 patients. Neuroradiology 45:851–859

    Article  CAS  PubMed  Google Scholar 

  5. Pittock SJ, Debruyne J, Krecke KN et al (2010) Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). Brain 133:2626–2634

    Article  PubMed  Google Scholar 

  6. Tateishi U, Terae S, Ogata A et al (2001) MR imaging of the brain in lymphomatoidgranulomatosis. AJNR Am J Neuroradiol 22:1283–1290

    CAS  PubMed  Google Scholar 

  7. Landolfi JC, Thaler HT, DeAngelis LM (1998) Adult brainstem gliomas. Neurology 51:1136–1139

    Article  CAS  PubMed  Google Scholar 

  8. Grimm SA, Chamberlain MC (2013) Brainstem glioma: a review. Curr Neurol Neurosci Rep 13:346

    Article  PubMed  Google Scholar 

  9. Singh TD, Fugate JE, Rabinstein AA (2014) Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 21:1443–1450

    Article  CAS  PubMed  Google Scholar 

  10. van der Knaap MS, Arts WF, Garbern JY et al (2008) Cerebellar leukoencephalopathy: most likely histiocytosis-related. Neurology 71:1361–1367

    Article  PubMed  Google Scholar 

  11. Diamond EL, Dagna L, Hyman DM et al (2014) Consensus guidelines for the diagnosis and clinical management of Erdheim–Chester disease. Blood 124:483–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cavalli G, Guglielmi B, Berti A et al (2013) The multifaceted clinical presentations and manifestations of Erdheim–Chester disease: comprehensive review of the literature and of 10 new cases. Ann Rheum Dis 72:1691–1695

    Article  PubMed  Google Scholar 

  13. Salsano E, Savoiardo M, Nappini S et al (2008) Late-onset sporadic ataxia, pontine lesion, and retroperitoneal fibrosis: a case of Erdheim–Chester disease. Neurol Sci 29:263–267

    Article  CAS  PubMed  Google Scholar 

  14. Cangi MG, Biavasco R, Cavalli G et al (2015) BRAFV600E-mutation is invariably present and associated to oncogene-induced senescence in Erdheim–Chester disease. Ann Rheum Dis 74:1596–1602

    Article  CAS  PubMed  Google Scholar 

  15. Cavalli G, Biavasco R, Borgiani B et al (2014) Oncogene-induced senescence as a new mechanism of disease: the paradigm of Erdheim–Chester disease. Front Immunol 5:281

    Article  PubMed  PubMed Central  Google Scholar 

  16. Arnaud L, Hervier B, Néel A et al (2011) CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim–Chester disease: a multicenter survival analysis of 53 patients. Blood 117:2778–2782

    Article  CAS  PubMed  Google Scholar 

  17. Euskirchen P, Haroche J, Emile JF et al (2015) Complete remission of critical neurohistiocytosis by vemurafenib. Neurol Neuroimmunol Neuroinflamm 2:e78. https://doi.org/10.1212/NXI.0000000000000078

    Article  PubMed  PubMed Central  Google Scholar 

  18. Haroche J, Cohen-Aubart F, Emile JF et al (2015) Reproducible and sustained efficacy of targeted therapy with vemurafenib in patients with BRAF(V600E)-mutated Erdheim–Chester disease. J Clin Oncol 33:411–418

    Article  CAS  PubMed  Google Scholar 

  19. López RF, Báñez IA, Robles MB et al (2017) 18F-FDG PET/CT in Erdheim–Chester disease. Eur J Nucl Med Mol Imaging 44:1247–1248

    Article  PubMed  Google Scholar 

  20. Ayrignac X, Boutiere C, Carra-Dalliere C et al (2016) Posterior fossa involvement in the diagnosis of adult-onset inherited leukoencephalopathies. J Neurol 263:2361–2368

    Article  CAS  PubMed  Google Scholar 

  21. Campochiaro C, Tomelleri A, Cavalli G et al (2015) Erdheim–Chester disease. Eur J Intern Med 26:223–229

    Article  CAS  PubMed  Google Scholar 

  22. Lachenal F, Cotton F, Desmurs-Clavel H et al (2006) Neurological manifestations and neuroradiological presentation of Erdheim–Chester disease: report of 6 cases and systematic review of the literature. J Neurol 253:1267–1277

    Article  PubMed  Google Scholar 

  23. Bianco F, Iacovelli E, Tinelli E et al (2009) Characteristic brain MRI appearance of Erdheim–Chester disease. Neurology 73:2120–2122

    Article  CAS  PubMed  Google Scholar 

  24. Adle-Biassette H, Chetritt J, Bergemer-Fouquet AM et al (1997) Pathology of the central nervous system in Chester-Erdheim disease: report of three cases. J Neuropathol Exp Neurol 56:1207–1216

    Article  CAS  PubMed  Google Scholar 

  25. Diamond EL, Hatzoglou V, Patel S et al (2016) Diffuse reduction of cerebral grey matter volumes in Erdheim–Chester disease. Orphanet J Rare Dis 11:109

    Article  PubMed  PubMed Central  Google Scholar 

  26. Tien R, Kucharczyk J, Kucharczyk W (1991) MR imaging of the brain in patients with diabetes insipidus. AJNR Am J Neuroradiol 12:533–542

    CAS  PubMed  Google Scholar 

  27. Prosch H, Grois N, Bökkerink J et al (2006) Central diabetes insipidus: is it Langerhans cell histiocytosis of the pituitary stalk? A diagnostic pitfall. Pediatr Blood Cancer 46:363–366

    Article  PubMed  Google Scholar 

  28. Drier A, Haroche J, Savatovsky J et al (2010) Cerebral, facial, and orbital involvement in Erdheim–Chester disease: CT and MR imaging findings. Radiology 255:586–594

    Article  PubMed  Google Scholar 

  29. Grois N, Prayer D, Prosch H et al (2005) Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 128:829–838

    Article  PubMed  Google Scholar 

  30. Ferrero E, Corti A, Haroche J et al (2016) Plasma Chromogranin A as a marker of cardiovascular involvement in Erdheim–Chester disease. Oncoimmunology 5:e1181244

    Article  PubMed  PubMed Central  Google Scholar 

  31. Bargagli E, Maggiorelli C, Rottoli P (2008) Human chitotriosidase: a potential new marker of sarcoidosis severity. Respiration 76:234–238

    Article  CAS  PubMed  Google Scholar 

  32. Mossetti G, Rendina D, Numis FG et al (2003) Biochemical markers of bone turnover, serum levels of interleukin-6/interleukin-6 soluble receptor and bisphosphonate treatment in Erdheim–Chester disease. Clin Exp Rheumatol 21:232–236

    CAS  PubMed  Google Scholar 

  33. Tiacci E, Trifonov V, Schiavoni G et al (2011) BRAF mutations in hairy-cell leukemia. N Engl J Med 364:2305–2315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sedrak P, Ketonen L, Hou P et al (2011) Erdheim–Chester disease of the central nervous system: new manifestations of a rare disease. AJNR Am J Neuroradiol 32:2126–2131

    Article  CAS  PubMed  Google Scholar 

  35. Shamburek RD, Brewer HB Jr, Gochuico BR (2001) Erdheim–Chester disease: a rare multisystem histiocytic disorder associated with interstitial lung disease. Am J Med Sci 321:66–75

    Article  CAS  PubMed  Google Scholar 

  36. Birnbaum DC, Shields D, Lippe B et al (1989) Idiopathic central diabetes insipidus followed by progressive spastic cerebral ataxia. Report of four cases. Arch Neurol 46:1001–1003

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We wish to dedicate this manuscript to Dr. Mario Savoiardo, passed away on January 2014. His love for life taught us not to observe things superficially, but to investigate in depth all clinical and instrumental data of the patients, because even a small detail can be decisive for their care.

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Authors and Affiliations

  1. Unit of Neuroradiology, IRCCS Foundation “Carlo Besta” Neurological Institute, Via Celoria 11, 20133, Milan, Italy

    Luisa Chiapparini & Sergio Raspante

  2. Unit of Internal Medicine and Clinical Immunology, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy

    Giulio Cavalli, Giacomo De Luca & Lorenzo Dagna

  3. Unit of Molecular Neuro-oncology, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy

    Tiziana Langella

  4. Unit of Clinical Pathology and Medical Genetics, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy

    Anna Venerando

  5. Department of Neuroradiology, Niguarda Hospital, Milan, Italy

    Sergio Raspante

  6. Department of Nuclear Medicine, IRCCS Foundation “Ca’ Granda” Ospedale Maggiore Policlinico, Milan, Italy

    Giorgio Marotta

  7. Unit of Neuropathology, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy

    Bianca Pollo

  8. Unit of Neuroalgology, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy

    Giuseppe Lauria

  9. Department of Biomedical and Clinical Sciences “Luigi Sacco”, University of Milan, Milan, Italy

    Giuseppe Lauria

  10. Unit of Pathology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Maria Giulia Cangi

  11. Unit of Neuroradiology, IRCCS San Raffaele Scientific Institute, Milan, Italy

    Simonetta Gerevini

  12. Unit of Clinical Neuro-oncology, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy

    Andrea Botturi

  13. Unit of Neurodegerative and Neurometabolic Rare Diseases, IRCCS Foundation “Carlo Besta” Neurological Institute, Milan, Italy

    Davide Pareyson & Ettore Salsano

Authors
  1. Luisa Chiapparini
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  2. Giulio Cavalli
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  3. Tiziana Langella
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  4. Anna Venerando
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  5. Giacomo De Luca
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  8. Bianca Pollo
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  9. Giuseppe Lauria
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  10. Maria Giulia Cangi
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  11. Simonetta Gerevini
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  13. Davide Pareyson
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  14. Lorenzo Dagna
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  15. Ettore Salsano
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Corresponding author

Correspondence to Luisa Chiapparini.

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All authors declare that they have no conflict of interest.

Ethical standards

This study was performed as per local ethics committee-approved guidelines in accordance with the Declaration of Helsinki principles, and all the involved patients gave their written informed consent.

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Chiapparini, L., Cavalli, G., Langella, T. et al. Adult leukoencephalopathies with prominent infratentorial involvement can be caused by Erdheim–Chester disease. J Neurol 265, 273–284 (2018). https://doi.org/10.1007/s00415-017-8692-8

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  • DOI: https://doi.org/10.1007/s00415-017-8692-8

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