CNS Involvement in Hemophagocytic Lymphohistiocytosis Syndrome (HLH)

Hemophagocytic Lymphohistiocytosis Syndrome (HLH) is a rare and life-threatening disorder characterized by excessive immune activation. Central Nervous System (CNS) involvement in HLH, although not well standardized in definition, presents a significant cause of morbidity and mortality. Early recognition and treatment of CNS manifestations are crucial in preventing long-term sequelae and irreversible damage. This case study highlights the challenges in managing HLH with CNS involvement, emphasizing the importance of prompt intervention to improve outcomes.

• HLH
• Hemophagocytic Lymphohistiocytosis
• CNS involvement
• Neurological complications
• Pediatrics

rheault_s Follow

Uploaded on Oct 01, 2024 | 0 Views

Download Presentation

Please find below an Image/Link to download the presentation.

The content on the website is provided AS IS for your information and personal use only. It may not be sold, licensed, or shared on other websites without obtaining consent from the author. Download presentation by click this link. If you encounter any issues during the download, it is possible that the publisher has removed the file from their server.

Presentation Transcript

1. In the name of God CNS INVOLVEMENT IN Hemophagocytic Lymphohistiocytosis Syndrome(HLH) Bibi Shahin Shamsian Mofid Children s Hospital Shaid Beheshti Universuity of Medical Sciences Tehran. Iran

2. B.Sh. Shamsian MD, M.T. Arzanian MD, S. Alavi MD, S. Zareifar MD Iran J Child Neurology Feb. 2007 Type2 GRISCELLI SYNDROME GRISCELLI SYNDROME Type II & CNS Involvement Hair with giant melanin in granules

3. Case Presentation patient :a 5 months old girl . 4th child , parents - First cousins. beginning of disorder ; at age of 5 month Presentation : Fever , hepatosplenomegaly, silvery gray hair, eyelashes,eyebrows, Lab data ; Pancytopenia, ESR 50 mm/hr Reticulocyte 3.3%, D&I coombs test :neg. No giant cytoplasmic granules in peripheral blood smear of leukocytes. ALT:247 U/L (10-40), AST 227 U/L (10-40) LDH 1150 U/L (225-400), Total BIL/DBIL: 4/ 2 mg/dl TP 6 g/dl ALB in 3gr/dl PT,& PTT were 24 (control of 12") & 48" (control of 43 ) Fibrinogen; 92 mg (200-400 mg %) , TG: 750 mg/dl (50-200 mg/dl), Ferritin :300 ng/ml (6-140 ng/ml) B.Sh.shamsain . Iran J Child Neurology Feb. 2007 .

4. Case Presentation BMA and BMB : EH & Hemophagocytosis Flowcytometry; CD56 (21), CD11c (26), CD64 (81), CD14 (10), CD45 (82), CD4 (26), CD8 (31) with CD4/CD8 ratio of0.83 Hair exam: irregular agglomerations of pigment in hair shafts. Diagnosis: Griscelli syndrome type II No gene analysis. Treatment : Corticosteroied, IVIG 1gr/kg/day for 2 days and cyclosporine . She had good response to treatment HLA typing; No Match Donor After 2 months :she developed neurological symptoms including seizure, Ptosis , facial palsy and left hemiplegia. Brain CT: Brain atrophy Brain MRI : abnormal enhancement in the white matter CSF : WBC; 8 increase pr level No Hemophagocytosis Treatment: ( Dexa, VP16 ) was not effective and she died because of multiorgan failure in the absence of HSCT B.Sh.shamsain . Iran J Child Neurology Feb. 2007

5. Definition of CNS disease in HLH CNs HLH: Important cause of morbidity &mortality in HLH Definition of CNS disease in HLH has not been standardized, there is no consensus regarding its definition Most HLH experts : An Abnormal CSF or/and MRI of the brain with or without distinct neurological signs or symptoms Infiltration of activated lymphocytes and macrophages into the meninges and brain Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3 .

6. CNS-HLH CNS-HLH :one of the most important reason ,long-term sequelae, -motor and cognitive deficits. Early recognition and prompt treatment of CNS disease may prevent irreversible CNS injury CNS -HLH incidnece: 30 73% presentation : At /or during the course of the disease Clinical presentation of CNS disease in HLH is highly variable Occurrence of neurological symptoms is not included as a diagnostic criterion of HLH, It is important to consider HLH in a child with unexplained neurologic manifestations, especially one with fever, pancytopenia, & hepatosplenomegaly Michael M. Henry(USA). 2018 . 34th Annual Meeting of the Histiocyte Society lisbon AnnaCarin Horne, Curr Treat Options Neurol (2017) 19: 3 Gritta E. janka .Hemophagocytic syndromes an updates. Blood Rev (2014)

7. CNS Involvement in HLH in Adults: A Retrospective Analysis of 96 Patients in a Single Center. 96 adult, HLH -CNS( 2003-2016) Incidneces; 20.7% (96/463). Median age of HLH :34 (range: 18 79) years and there were 48 men and48 women. Most common type of HLH was infection-associated HLH, 2 case : primary HLH 86 had various CNS symptoms and 33 (38.4%) had already presented symptoms before the HLH diagnosis was confirmed 23 patients (39.0%): CSF abnormlaity 50 ( 71.4% :Imaging changes Repeated IT injection ( 65.4%): improved EBV infection is a risk factor Intrathecal injection is a protective factor Yue Song. Chinese Medical Journal April 5, 2018 Volume 131 Issue 7

8. Pathophysiology of CNS-HLH pathogenesis of HLH : Excessive activation of CD8+ T Cell & the release of cytokines such as; TNF - , IL-1 , IL-6,IL-8,IF CNS-HLH:Neuroinflammatory markers such as Neopterin,CXCL 13 Massive hyper-inflammation leading to destruction of brain tissue o So Reduce inflammatory HLH activity: to prevent CNS injury Maria F. Ibarra, Clin Vaccine Immunol. 2011 Apr; 18(4): 609 614 o Gritta E. janka .Hemophagocytic syndromes an updates. Blood Rev (2014) AnnaCarin Horne, Curr Treat Options Neurol (2017) 19: 3

9. Diagnosis In CNS-HLH

10. Evaluation or possible CNS HLH 3 specific areas of investigation: presence of neurological signs/symptoms (2/3 of all HLH patients) Evaluation of CSF Neuroimaging abnormalities Neurological symptoms and CSF abnormalities ;negative prognostic marker, reducing 5-year survival from 67 to 40% K. Deiva. Neurology 78 April 10, 2012. France. Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3

11. Neurologic symptoms Children( 2012 France) / (China 2018) Children Adults Disturbance of consciousness Headache/dizziness Seizure Psychiatric symptoms Irritability Ataxia Hypotonia Meningeal irritation Cranial nerve palsies Seizures 33-83% Impaired consciousness 31-47% Meningismus 1/3-P Microcephaly Hypotonia Motor deficit (hemiparesis, Tetraparesis) Cranial nerve palsy Ataxia

12. Neurological symptoms at diagnosis and their relation to abnormal CSF in 193 children with HLH. Horn . BJH. 2007

13. CSF/ CNS-HLH Abnormal CSF : 16 76% of HLH cases CSF abnormalities : may be with or without neurological symptoms LP: routinely should be performed in all children in suspicion of HLH and where no contraindications are present LP: Cells, protein, glucose, lactate, and microbiology , hemophagocytosis. CSF pleocytosis is seen in 10 47%, sometimes ; late sign and repeat LP may be of value Increased protein levels, :11 41% o Moderately elevated (between 500 and 1000 mg/L, o If > 2500mg/L = stage 3 Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3 Horn . BJH. 2007

14. (CNS) involvement is a critical prognostic factor for HLH . 1983 Janka etal : CSF abnormalities in 17 /33 patients and Neurological symptoms in 10% of the patients. 1991- Henter etal :CSF abnormalities in 4 of 7 patients, with neurological symptoms in 3 of them. 1996 Arico etal :CSF abnormalities at the time of diagnosis for 55/ 94 patients (58%) 2012 Korean. neurological manifestations ; 46 % patients Strong association between CNS involvement and Familial forms of HLH (P=0.01) yung-Mi Kim. VOLUME 47 NUMBER 4 December 2012 .korean

15. Neurologic complications: HLH 2004 ; duo to early administration of cyclosporine (Posterior reversible encephalopathy syndrome PRES). Bergsten E .Blood.2017 Dec 21;130(25):2728-2738

16. Hemophagocytosis/CNS-HLH Hemophagocytosis HLH : 25%-100% 1-10 hemophagocytes / 500 cells BM ;92% Brain Biopsies,Mostly located in the Meninges-91% : CSF : (39%) Less commonly seen in the of pediatric cases Relation between hemophagocytosis in the CSF and duration and severity of disease(in brain tissue is ) not known?? Michael B. JordanBLOOD, 13 OCTOBER 2011 VOLUME 118, NUMBER 15. Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3

17. Post-mortem pathological diagnosis of primary B-cell lymphoma of the CNS (A and B) & intravascular lymphoma (C and D). (A) Numerous macrophages with ingested lymphocytic cells (hemophagocytosis) (H&E 1000 acrophages are CD68 positive) .

18. Neuroimaging MRI of the brain with gadolinium :modality of choice in CNS-HLH CT scan MRI with contrast is beneficial : Multifocal and bilateral abnormalities seen on T2-weighted imaging o primary HLH (89%), with a high rate of symmetric involvement (53%), Atrophy & calcifications CNS hemorrhage K. Deiva. Neurology 78 April 10, 2012. France.

19. K. Deiva. Neurology 78 April 10, 2012. France. (A) 22 mo old boy - Chediak-Higashi syndrome multiple lobes B ) 8-month-old boy - FHLH /left frontal fuzzy lesion in large area. C) 2 year old boy with Griscelli syndrome type 2 with periventriculaR in large area D) 3y old boy - X-linked lymphoproliferative syndrome, isolated left frontal (E) 4 y old boy with FHLH, showing a Cerebellar lesion.( 2012 France)

20. Central Nervous System Imaging Findings of Hemophagocytic Syndrome.Tara L. Anderson. Journal of Clinical . 2015 Left picture ;normal MRI . Right picture ; enhanced MRI .Leptomeninges are enhanced on the right picture (white arrow) Deep white matter of the brain with multiple spotted abnormal signals (white arrow), and high signal on diffusion-weighted image (black arrow)

21. Neuroradiological MRI findings in HLH -T2w image showing bilateral hyperintense lesions in the cerebellum. B- T2w image with hyperintense signal and edema in the left posterior hemisphere C-weighted imaging of the same region as in b with lesions imitating cerebral infarction CNs Imaging Findings of Hemophagocytic Syndrome.Tara L. Anderson. Journal of Clinical . 2015

22. CNS- Imaging Findings of HLH & Differntial Diagnosis o Neuroimaging presentation of HLH is nonspecific.Some times , inflammation of the CNS may be the primary and only clinical presentation of HLH . o DD of MRI finding ; o Vasculitis Acute disseminated encephalomyelitis (ADEM) o Multifocal infarction o Infection To narrow differential diagnosis and diagnosis of HLh ,Correlation of: neuroimaging, Clinical findings ,Laboratory data, pathology findings Tara L Anderson, MD. Clinical Imaging.2015 o

23. CNS involvement at the onset of Primary HLH . 1994- 2010 46 children with primary HLH, neurologic evaluation within 2 weeks, MRI within 6 months of diagnosis Comparison :44 children with acute disseminated encephalomyelitis (ADEM). primary HLH :Symmetric & periventricular lesions Conclusion: In cases of abnormal brain MRI, the observed lesions differ from those of ADEM. K. Deiva. Neurology 78 April 10, 2012. France

24. Staging / CNS-HLH Imaging presentations had a strong correlation with the brain tissue biopsies in CNS-HLH patients CNS disease has been divided into 3 neuropathological stages: o stage I with leptomeningeal inflammation o stage II with perivascular infiltration o stage III with massive tissue infiltration, blood vessel destruction, and tissue necrosis Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3 Myung-Mi Kim.THE KOREAN JOURNAL OF HEMATOLOGY.VOLUME 47 NUMBER 4 December 2012

25. Treatment IN CNS- HLH

26. Treatment of CNS- HLH No consensus on treatment directed at CNS involvement in HLH protocols of HLH-94 and HLH-2004 HLH 94 : First line CNS symptoms improve with systemic therapy alone in most cases, and data are insuffi cient to determine whether additional It therapy can further improve CNS inflammation. [Strong Consensus] Stephan Ehl, MD. HLH-94: 2018 consensus recommendations. -Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3

27. Stephan Ehl, MD * Etal7 collegues :J ALLERGY CLIN IMMUNOL PRACT VOLUME -, NUMBER -. HLH-94: 2018 consensus recommendations. IT(MTX) therapy is recommended for patients with CNS involvement not improving during systemic HLH-94 therapy In patients with neurological signs or symptoms persisting after 2 weeks of systemic therapy 3-4 doses prior to re-evaluation preferably until all (CSF) indices and CNS symptoms normalize It MTX alone is recommended In HLh 2004 protocol prednison was added , No additional benefit HLH-94 therapy can be indicated in patients with primary HLH who present with isolated CNS disease. [Strong Consensus]

28. HSCT/CNS-HLH More often allo-HSCT is required. CNS-HLH : cure by initiation of HSCT soon after onset HSCT : may prevent both CNS disease progression & reactivartion o Improve the prognosis o Prolonged the survival times Lounder DT .Biol Blood Marrow Transplant.. 2017 Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3

29. HSCT/CNS-HLH Even if HLH is still active, an early transplant should be considered., as the risk of late effects is more severe than the risk of transplantation Reactivation of CNS disease may occur after HSCT. If CNS HLH recurs/worsens after HSCT, as indicated by clinical findings or CSF, additional IT and system therapy should be considered. Biol Blood Marrow Transplant. Lounder DT. 2017 Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3

30. Incidence of HLH CNS Relapse after Treatment with RIC HSCT. Rebecca Marsh, Dana Lounder, Bibi Shahin shamsian . 32ndAnnual Meeting of the Histiocyte Society .Dublin, Ireland October 17 19, 2016 Lounder DT .Biol Blood Marrow Transplant. 2017 Retrospective Study / 94 patients RIC - HSCT : Alemtuzumab, Fludarabine, and& Melphalan Incidence of CNS relapse and/or continued CNS disease after RIC HSCT ;approximately 8% Overall survival for patients with CNS relapse or continued CNS disease was 50%, compared to 75% for patients without CNS disease (p = 0.079). Risk factors : Active CNS disease at the time of transplant o Low level donor chimerism o All patients : good response :IT Hydrocortisone &MTX and/or IV dexa

31. Treatment of CNS-Restricted Familial HLH with Allogeneic HSCT FHL mutations and CNS-restricted inflammation, as well as their subsequent treatment with Allo- HCT.( Perf1 , MUNc 13-4) HSCT ( MSD , MUD , miss match UD 8/10-B,C): 4 patients RIC Conditiong : FLU, Mel, Alemtuzumab Glucocorticoids & cyclosporine as prophylaxis All patients: enhancement on brain MRI, and 3 of 4 had symptoms of CNS Inflammation, including seizures, cognitive decline, dystonia, ataxia, and hemorrhagic stroke Duration of symptoms prior to FHL diagnosis ranged from 2 to 6 years. Elevated Neopterin levels in CSF of both Prf1 All had initial MRI responses after receiving dexamethasone, and the 2 Prf1patients also received IT MTX & hydrocortisone No clinically acute or chronic GVHD All patients are currently alive and without clinical evidence of disease progression, Boston, MA. Biol Blood Marrow Transplant 23 (2017) S18 S391

32. Rituximab, CNS-HLH Rituximab: systemic , It Thiotepa: IV, IT ???( refractory HLH, CNS-HLH) ATG Rabbit and Methyl-P ,followed by cyclosporine A, which is given until (HSCT), + iT MTX & corticosteroids

33. NEW Treatments CNs-HLH ??? Hybrid immunotherapy for HLH (HIT-HLH, NCT01104025) USA & Euro-HIT,2 clinical trials utilizing ATG, Etoposide, & dexamethasone ;additive or synergistic effects Results ??? Alemtuzumab, methylprednisone, and cyclosporine (NCT02472054), Result??? IL-1 receptor antagonists Anti-IFN monoclonal antibody NI-0501 (NCT01818492) JAK1/2 inhibitor (Ruxolitinib) Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3

34. Novel Targeted Approach to the Treatment of (HLH) with an Anti-Interferon Gamma (IFN ) Monoclonal Antibody (mAb), NI-0501. First Results from a Pilot Phase 2 Study in Children with Primary HLH. 13 patients 1.0y (range 2.5mo-13y) , USA and europe An open-label Phase 2 study safety and efficacy In confirmed or suspected p HLH. Initial dose of 1 mg/kg every 3 days, with possible dose increase guided by PK data and/or clinical response in each patient, on initial background dexa dose of 5-10 mg/m2. Treatment duration ; 4 to 8 weeks. Sharp decrease in CXCL9, a chemokine exquisitely IFN -induced. CNS signs and symptoms resolved in the 2 evaluable patients Conclusion: safe and effective therapeutic option in patients with pHLH who have demonstrated unsatisfactory response, or are intolerant, to conventional therapy Michael Jordan. Blood 2015 126:LBA-3

35. Therapeutic effect of JAK1/2 blockade on the manifestations of HLH 9 including (CNS HLH) in mice. JAK INHIBITION IN MURINE HLH: CAREFUL REEXAMINATION REVEALS SIGNIFICANT TOXICITY(marrow and liver ???) Murine models of primary HLH, In vivo, ruxolitinib JAK1/2 inhibitor : suppressed STAT1 activation Downstream of the receptors for IFN- and other inflammatory cytokines (such as IL2 and IL6) JAK1/2 inhibitor therapy in mice is effective on survival, cytopaenia, inflammatory syndrome, CNS involvement and liver tissue repair. In Rab27a -/- mice, central nervous system involvement was significantly reduced by ruxolitinib therapy. 2016 American Society of Hematology. Sophia Maschalidi. France Michael Jordan.2018. 3 4th Annual Meeting of the Histiocyte Society Lisbon

36. work up ; CNS disease in HLH Anna Carin Horne., Curr Treat Options Neurol (2017) 19: 3

37. Stephan Ehl, MD * Etal7 collegues :J ALLERGY CLIN IMMUNOL PRACT VOLUME -, NUMBER -. HLH-94: 2018 consensus recommendations.

38. Stephan Ehl, MD * Etal7 collegues :J ALLERGY CLIN IMMUNOL PRACT VOLUME -, NUMBER -. HLH-94: 2018 consensus recommendations.

39. First step towards optimal treatment of CNS-HLH is prompt and accurate Diagnosis All patients should receive a brain MRI and lumbar puncture, Treatment : should be started in all HLH cases with neurological symptoms even if a LP or MRI have not been obtained or results are still pending. Summery

40. Thank You