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CNS Involvement in HLH (CNS-HLH)

  • AnnaCarin Horne
  • Karin Beutel
Chapter

Abstract

CNS disease is considered to be a result of the pathologic immune response in HLH. CNS involvement is frequently found at diagnosis or can occur anytime in the further course of systemic HLH but has also been reported as primary or only manifestation. Diagnosis is based on the presence of neurological symptoms and abnormalities on neuroradiological imaging and a pathological cerebrospinal fluid analysis. Due to the unspecific clinical picture and the wide spectrum of neuroradiological findings, a variety of other inflammatory conditions and vascular diseases of the CNS have to be considered in the differential diagnosis, especially in cases in which no systemic HLH features are present. The devastating effect of ongoing inflammation in the CNS can lead to increased mortality and major long-term consequences. Therefore, rapid diagnosis and treatment are mandatory. Patients with CNS-HLH should be given systemic HLH treatment without delay. Although not evaluated systematically, it is also accepted that these patients benefit from intrathecal administration of MTX and steroids. Early stem cell transplant in genetic disease has also been shown to halt CNS disease and prevent further sequelae.

Keywords

Central nervous system Cerebrospinal fluid Neuroradiology Intrathecal treatment Long-term effects 

Abbreviations

ADEM

Acute disseminated encephalomyelitis

ANE

Acute necrotizing encephalopathy

ATG

Antithymocyte globulin

CNS

Central nervous system

CSA

Ciclosporin

CSF

Cerebrospinal fluid

CT

Computed tomography

EBV

Epstein-Barr virus

HLH

Hemophagocytic lymphohistiocytosis

HSCT

Hematopoietic stem cell transplantation

IFN-γ

Interferon y

IT

Intrathecal

JAK1/2

Janus kinase 1/2

MRI

Magnetic resonance imaging

MTX

Methotrexate

NAA

N-acetylaspartate

References

  1. 1.
    Feldmann J, Menasche G, Callebaut I, Minard-Colin V, Bader-Meunier B, Le Clainche L, Fischer A, Le Deist F, Tardieu M, de Saint BG. Severe and progressive encephalitis as a presenting manifestation of a novel missense perforin mutation and impaired cytolytic activity. Blood. 2005;105:2658–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Shinoda J, Murase S, Takenaka K, Sakai N. Isolated central nervous system hemophagocytic lymphohistiocytosis: case report. Neurosurgery. 2005;56:187.CrossRefPubMedGoogle Scholar
  3. 3.
    Moshous D, Feyen O, Lankisch P, Schwarz K, Schaper J, Schneider M, Dilloo D, Laws HJ, Schwahn BC, Niehues T. Primary necrotizing lymphocytic central nervous system vasculitis due to perforin deficiency in a four-year-old girl. Arthritis Rheum. 2007;56:995–9.CrossRefPubMedGoogle Scholar
  4. 4.
    Rostasy K, Kolb R, Pohl D, Mueller H, Fels C, Moers AV, Bergmann M, Hanefeld F, Pekrun A, Schulz-Schaeffer W. CNS disease as the main manifestation of hemophagocytic lymphohistiocytosis in two children. Neuropediatrics. 2004;35:45–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Henter JI, Elinder G. Cerebromeningeal haemophagocytic lymphohistiocytosis. Lancet. 1992;339:104–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Kieslich M, Vecchi M, Dr iever PH, Laverda AM, Schwabe D, Jacobi G. Acute encephalopathy as a primary manifestation of haemophagocytic lymphohistiocytosis. Dev Med Child Neurol. 2001;43:555–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Ramachandran B, Balasubramanian S, Abhishek N, Ravikumar KG, Ramanan AV. Profile of hemophagocytic lymphohistiocytosis in children in a tertiary care hospital in India. Indian Pediatr. 2011;48:31–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Trottestam H, Horne A, Arico M, Egeler RM, Filipovich AH, Gadner H, Imashuku S, Ladisch S, Webb D, Janka G, et al. Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol. Blood. 2011;118:4577–84.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Deiva K, Mahlaoui N, Beaudonnet F, de Saint BG, Caridade G, Moshous D, Mikaeloff Y, Blanche S, Fischer A, Tardieu M. CNS involvement at the onset of primary hemophagocytic lymphohistiocytosis. Neurology. 2012;78:1150–6.CrossRefPubMedGoogle Scholar
  10. 10.
    Haddad E, Sulis ML, Jabado N, Blanche S, Fischer A, Tardieu M. Frequency and severity of central nervous system lesions in hemophagocytic lymphohistiocytosis. Blood. 1997;89:794–800.PubMedGoogle Scholar
  11. 11.
    Henter JI, Nennesmo I. Neuropathologic findings and neurologic symptoms in twenty-three children with hemophagocytic lymphohistiocytosis. J Pediatr. 1997;130:358–65.CrossRefPubMedGoogle Scholar
  12. 12.
    Yang S, Zhang L, Jia C, Ma H, Henter JI, Shen K. Frequency and development of CNS involvement in Chinese children with hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2010;54:408–15.CrossRefPubMedGoogle Scholar
  13. 13.
    Horne A, Trottestam H, Arico M, Egeler RM, Filipovich AH, Gadner H, Imashuku S, Ladisch S, Webb D, Janka G, et al. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br J Haematol. 2008;140:327–35.CrossRefPubMedGoogle Scholar
  14. 14.
    Dao AT, Luong VT, Nguyen TT, Huynh QT, Phan TT, Lam MT, Ngoma AM, Koriyama C. Risk factors for early fatal outcomes among children with hemophagocytic lymphohistiocytosis (HLH): a single-institution case-series in Vietnam. Pediatr Hematol Oncol. 2014;31:271–81.CrossRefPubMedGoogle Scholar
  15. 15.
    Gratton SM, Powell TR, Theeler BJ, Hawley JS, Amjad FS, Tornatore C. Neurological involvement and characterization in acquired hemophagocytic lymphohistiocytosis in adulthood. J Neurol Sci. 2015;357:136–42.CrossRefPubMedGoogle Scholar
  16. 16.
    Mahlaoui N, Ouachee-Chardin M, de Saint BG, Neven B, Picard C, Blanche S, Fischer A. Immunotherapy of familial hemophagocytic lymphohistiocytosis with antithymocyte globulins: a single-center retrospective report of 38 patients. Pediatrics. 2007;120:e622–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Kim MM, Yum MS, Choi HW, Ko TS, Im HJ, Seo JJ, Koh KN. Central nervous system (CNS) involvement is a critical prognostic factor for hemophagocytic lymphohistiocytosis. Korean J Hematol. 2012;47:273–80.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Jovanovic A, Kuzmanovic M, Kravljanac R, Micic D, Jovic M, Gazikalovic S, Pasic S. Central nervous system involvement in hemophagocytic lymphohistiocytosis: a single-center experience. Pediatr Neurol. 2014;50:233–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Imashuku S. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit Rev Oncol Hematol. 2002;44:259–72.CrossRefPubMedGoogle Scholar
  20. 20.
    Gurgey A, Aytac S, Balta G, Oguz KK, Gumruk F. Central nervous system involvement in Turkish children with primary hemophagocytic lymphohistiocytosis. J Child Neurol. 2008;23:1293–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Voeten M, Maes P, Wojciechowski M, Vandenbossche L, Meyts I, Ceulemans B. Extremely elevated cerebrospinal fluid protein levels in a child with neurologic symptoms: beware of haemophagocytic lymphohistiocytosis. Eur J Paediatr Neurol. 2014;18:427–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Howells DW, Strobel S, Smith I, Levinsky RJ, Hyland K. Central nervous system involvement in the erythrophagocytic disorders of infancy: the role of cerebrospinal fluid neopterins in their differential diagnosis and clinical management. Pediatr Res. 1990;28:116–9.PubMedGoogle Scholar
  23. 23.
    Rettwitz W, Sauer O, Burow HM, Lenard HG, Raute-Kreinsen U, Tornow K. Neurological and neuropathological findings in familial erythrophagocytic lymphohistiocytosis. Brain and Development. 1983;5:322–7.CrossRefPubMedGoogle Scholar
  24. 24.
    Fitzgerald NE, MacClain KL. Imaging characteristics of hemophagocytic lymphohistiocytosis. Pediatr Radiol. 2003;33:392–401.CrossRefPubMedGoogle Scholar
  25. 25.
    Goo HW, Weon YC. A spectrum of neuroradiological findings in children with haemophagocytic lymphohistiocytosis. Pediatr Radiol. 2007;37:1110–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Guandalini M, Butler A, Mandelstam S. Spectrum of imaging appearances in Australian children with central nervous system hemophagocytic lymphohistiocytosis. J Clin Neurosci. 2014;21:305–10.CrossRefPubMedGoogle Scholar
  27. 27.
    Rego I, Severino M, Micalizzi C, Faraci M, Pende D, Dufour C, Arico M, Rossi A. Neuroradiologic findings and follow-up with magnetic resonance imaging of the genetic forms of haemophagocytic lymphohistiocytosis with CNS involvement. Pediatr Blood Cancer. 2012;58:810–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Decaminada N, Cappellini M, Mortilla M, Del Giudice E, Sieni E, Caselli D, Arico M, Fonda C. Familial hemophagocytic lymphohistiocytosis: clinical and neuroradiological findings and review of the literature. Childs Nerv Syst. 2010;26:121–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Rooms L, Fitzgerald N, McClain KL. Hemophagocytic lymphohistiocytosis masquerading as child abuse: presentation of three cases and review of central nervous system findings in hemophagocytic lymphohistiocytosis. Pediatrics. 2003;111:e636–40.CrossRefPubMedGoogle Scholar
  30. 30.
    Chiapparini L, Uziel G, Vallinoto C, Bruzzone MG, Rovelli A, Tricomi G, Bizzi A, Nardocci N, Rizzari C, Savoiardo M. Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis. Neurol Sci. 2011;32:473–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Del Giudice E, Savoldi G, Notarangelo LD, Di Benedetto L, Manganelli F, Bruzzese E, Romano A, Santoro L. Acute inflammatory demyelinating polyradiculoneuropathy associated with perforin-deficient familial haemophagocytic lymphohistiocytosis. Acta Paediatr. 2003;92:398–401.CrossRefPubMedGoogle Scholar
  32. 32.
    Thompson PA, Allen CE, Horton T, Jones JY, Vinks AA, McClain KL. Severe neurologic side effects in patients being treated for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2009;52:621–5.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Lee G, Lee SE, Ryu KH, Yoo ES. Posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors. Blood Res. 2013;48:258–65.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Foley JM, Borders H, Kurt BA. A diagnostic dilemma: similarity of neuroradiological findings in central nervous system hemophagocytic lymphohistiocytosis and aspergillosis. Pediatr Blood Cancer. 2016;63:1296–9.CrossRefPubMedGoogle Scholar
  35. 35.
    Moshous D. The many faces of hemophagocytic lymphohistiocytosis - a challenge in diagnosis and therapy. Clin Biochem. 2014;47:726–7.CrossRefPubMedGoogle Scholar
  36. 36.
    Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48:124–31.CrossRefPubMedGoogle Scholar
  37. 37.
    Marsh RA, Allen CE, McClain KL, Weinstein JL, Kanter J, Skiles J, Lee ND, Khan SP, Lawrence J, Mo JQ, et al. Salvage therapy of refractory hemophagocytic lymphohistiocytosis with alemtuzumab. Pediatr Blood Cancer. 2013;60:101–9.CrossRefPubMedGoogle Scholar
  38. 38.
    Eadie MJ, Brophy TR, Ohlrich G, Tyrer JH. Dexamethasone: pharmacokinetics in neurological patients. Clin Exp Neurol. 1984;20:107–18.PubMedGoogle Scholar
  39. 39.
    Balis FM, Lester CM, Chrousos GP, Heideman RL, Poplack DG. Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia. J Clin Oncol. 1987;5:202–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Chellapandian D, Das R, Zelley K, Wiener SJ, Zhao H, Teachey DT, Nichols KE. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens. Br J Haematol. 2013;162:376–82.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Balamuth NJ, Nichols KE, Paessler M, Teachey DT. Use of rituximab in conjunction with immunosuppressive chemotherapy as a novel therapy for Epstein Barr virus-associated hemophagocytic lymphohistiocytosis. J Pediatr Hematol Oncol. 2007;29:569–73.CrossRefPubMedGoogle Scholar
  42. 42.
    So MW, Koo BS, Kim YJ, Kim YG, Lee CK, Yoo B. Successful rituximab treatment of refractory hemophagocytic lymphohistiocytosis and autoimmune hemolytic anemia associated with systemic lupus erythematosus. Mod Rheumatol. 2014;24:855–7.CrossRefPubMedGoogle Scholar
  43. 43.
    Al Asad O, Salam A, Mannem S, Ninan M, Markowitz A, Jana B. Alternative therapy for epstein-barr virus related hemophagocytic lymphohistiocytosis. Case Rep Oncolo Med. 2015;2015:508387.Google Scholar
  44. 44.
    Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint BG. Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic lymphohistiocytosis in mice. Blood. 2016;128(1):60–71.CrossRefPubMedGoogle Scholar
  45. 45.
    Das R, Guan P, Sprague L, Verbist K, Tedrick P, An QA, Cheng C, Kurachi M, Levine R, Wherry EJ, et al. Janus kinase inhibition lessens inflammation and ameliorates disease in murine models of hemophagocytic lymphohistiocytosis. Blood. 2016;127:1666–75.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Ruggiero A, Conter V, Milani M, Biagi E, Lazzareschi I, Sparano P, Riccardi R. Intrathecal chemotherapy with antineoplastic agents in children. Paediatr Drugs. 2001;3:237–46.CrossRefPubMedGoogle Scholar
  47. 47.
    Duffner PK, Armstrong FD, Chen L, Helton KJ, Brecher ML, Bell B, Chauvenet AR. Neurocognitive and neuroradiologic central nervous system late effects in children treated on pediatric oncology group (POG) P9605 (standard risk) and P9201 (lesser risk) acute lymphoblastic leukemia protocols (ACCL0131): a methotrexate consequence? A report from the children’s oncology group. J Pediatr Hematol Oncol. 2014;36:8–15.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Sparber-Sauer M, Honig M, Schulz AS, zur Stadt U, Schutz C, Debatin KM, Friedrich W. Patients with early relapse of primary hemophagocytic syndromes or with persistent CNS involvement may benefit from immediate hematopoietic stem cell transplantation. Bone Marrow Transplant. 2009;44:333–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Ouachee-Chardin M, Elie C, de Saint BG, Le Deist F, Mahlaoui N, Picard C, Neven B, Casanova JL, Tardieu M, Cavazzana-Calvo M, et al. Hematopoietic stem cell transplantation in hemophagocytic lymphohistiocytosis: a single-center report of 48 patients. Pediatrics. 2006;117:e743–50.CrossRefPubMedGoogle Scholar
  50. 50.
    Jackson J, Titman P, Butler S, Bond K, Rao A, Veys P, Chiesa R, Leiper A, Riley L, Gilmour K, et al. Cognitive and psychosocial function post hematopoietic stem cell transplantation in children with hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol. 2013;132:889–95. e881–883CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Pediatric Rheumathology Clinic and Childhood Cancer Research UnitKarolinska universitets sjukhuset and Karolinska InstitutetStockholmSweden
  2. 2.Pediatric Hematology and OncologyChildren’s Hospital München-Schwabing, Städtisches Klinikum München and University Hospital München Rechts der lsar, Technical University MünchenMünchenGermany

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