CPC - An Unusual Case…

1. CPC -An Unusual Case… November 13th 2008 Prof Orla Sheils

2. Scenario: • The patient, who was previously well, presented to the Emergency Department in an obtunded state following 24 hr of headache and drowsiness. • Both pupils were dilated and the left was unresponsive to light. • Hepatomegaly and massive splenomegaly were present. • Cranial computed tomography (CT) revealed a left-sided extradural mass.

3. CT scan at presentation showing left sided extradural mass causing mass effect with compression of the ipsilateral ventricle and midline shift to the right.

4. What is your differential Diagnosis?

6. RAISED INTRACRANIAL PRESSURE • Compensatory Mechanisms: • Displacement of blood • Displacement of CSF • Loss of Brain Tissue

7. RAISED INTRACRANIAL PRESSURE • EFFECTS: • -Compression of Brain • -Stretching of IIIrd nerve • -Stretching of Posterior Cerebral Artery • HERNIATION • Subfalcine (supracallosal) • Tentorial • Cerebellar Tonsillar Coning

9. RAISED INTRACRANIAL PRESSURE • SIGNS & SYMPTOMS: • -----Headache • -----Vomiting • -----Papilloedma • DANGER OF LUMBAR PUNCTURE!

10. IMPACT INJURIES • Scalp (abrasions,bruises,lacerations) • Skull Fractures • Cerebral Contusions • Extradural Haemorrhage • Intracranial Haemorrhage

11. ACCELERATION/ DECELERATION INJURIES • Subdural Haemorrhage • Diffuse Axonal Injury (DAI)

12. EXTRADURAL HAEMORRHAGE POTENTIAL space between inner skull and the dura • Fall, RTA, Strike on side of skull • 90% have skull # (squamous portion of temporal bone) • Lacerated middle meningeal artery • Unilateral • Disc-shaped, centrally thickened • Classically have a Lucid Interval • Symptoms 4 to 8 hours after injury • 25-30% immediate Loss of Conciousness • Death due to displacement & herniation of brain

14. Back to our case… • A full blood count showed that the: • Hb was 7.5 g/dl, • leucocytes 750 x109/l, and • platelets 968 x109/l, • and a blood film was consistent with chronic myeloid leukaemia.

15. What other tests would you order? • Bone Marrow Biopsy/Aspirate

16. Bone marrow Hypercellular marrow

17. Bone marrow Mitotic fig.

18. Bone marrow Mitotic fig. Eosinophil

19. Bone marrow Neutrophil Promyelocyte Monocyte

20. Immediate surgical decompression of the left extra-dural space was performed with evacuation of a 55 cm friable, solid, purplish mass.

21. Fresh dab slides made from the mass showed it to be composed of myeloblasts and subsequent cytogenetic studies revealed a karyotype of 46 XX, all cells examined having the Philadelphia translocation, t(9:22).

22. What is this cytogenetic finding characteristic of?

23. CML • Chronic myelogenous (or myeloid) leukemia (CML) is a form of leukemia characterized by the increased and unregulated growth of predominantly myeloid cells in the bone marrow and the accumulation of these cells in the blood.

24. CML is a clonal bone marrow stem cell disorder in which proliferation of mature granulocytes (neutrophils, eosinophils, and basophils) and their precursors is the main finding.

25. Incidence • Chronic myelogenous leukemia is a rare form of leukemia, affecting only one to two of every 100,000 people. • In the United States, about 4,600 people are diagnosed with CML each year. • It tends to affect more men than women, and the incidence increases with age. • CML rarely occurs in children.

26. What is CML?

27. CML • It is a type of myeloproliferative disease associated with a characteristic chromosomal translocation called the Philadelphia chromosome.

28. How does the ‘Philadelphia Chromosome’ occur? • What changes have been introduced with regard to treatment of CML?

29. CML • Historically, it has been treated with chemotherapy, interferon and bone marrow transplantation, although targeted therapies introduced at the beginning of the 21st century have radically changed the management of CML. • Interphase and metaphase FISH demonstrating a variant of the Philadelphia chromosome. • The genes that are rearranged are: • BCR(green on chromosome 22)/ABL (orange on chromosome 9) • The Ph’ translocation appears as dual fusion (yellow) signals.

30. Molecular Pathology • The process begins with the creation of a mutated chromosome called the "Philadelphia chromosome," named after the city where researchers discovered it in the early 1960s. • The abnormal Philadelphia chromosome develops from a translocation, or switching, of material between two previously normal chromosomes.

32. Back to our case (again)… • Postoperatively there was a deterioration in the conscious level. • Repeated CT showed re-accumulation of the mass, which was evacuated a second time. Recollection of extradural mass contiguous with subcutaneous haematoma following surgery.

33. Why might this have happened? • What other tests would you perform? • What would you do to ameliorate the problem?

34. Prothrombin time and activated partial thromboplastin time were within, or just outside, normal values for her age. • Fibrinogen and a coagulation screen, including factors VIII, IX, XI, XIII alpha subunit, alpha-2 anti-plasmin, and quantitative and functional von Willebrand Factor assays, were normal.

35. In the following week the would oozed blood continuously, there was intra-operatrative bleeding under the scalp and the extradural haematoma re-accumulated, requiring a third evacuation. • Tranexamic acid was given post-operatively for three days and the bleeding settled. • Tranexamic acid (commonly marketed as Cyklokapron in the U.S. and as Transamin in Asia) is often prescribed for excessive bleeding. • It is an antifibrinolytic that competitively inhibits the activation of plasminogen to plasmin, a molecule responsible for the degradation of fibrin.

36. Initially, the patient was at high risk of developing further sequelae of the hyperviscosity syndrome with such a high white cell count, and in addition, the degree of leucocytosis was thought to be contributing to continuing oozing of blood.

37. Two cycles of leucodepletion were carried out and the white cell count fell to 426 x 109/l. • The Hb fell to 5.3 g/dl • and the patient required transfusion. • This was done cautiously in view of the patient's leucocytosis as this is known to increase blood viscosity and can lead to worsening of the clinical state

38. Extensive leukaemic retinopathy was present with widespread haemorrhages and white deposits, swollen discs and sheathed vessels. • At follow up at 1 month there was marked improvement in the fundoscopic appearance. • No specific treatment was given for the retinal changes.

39. Retinal view at presentation showing retinal haemorrhages, white (leukaemic) deposits and sheathed vessels.

40. The white count was successfully controlled with oral hydroxyurea until an unrelated donor bone marrow transplant was performed using total body irradiation (TBI), Campath, and cyclophosphamide as conditioning.

41. No CNS directed therapy was given until transplant and she did not receive a cranial boost as part of TBI. • She is now 12 months post-transplant and remains well. • There is no evidence of long term neurological sequelae and she has suffered no major transplant related problems.

42. Hyperleucocytosis is frequently present in adult type chronic myeloid leukaemia in children. Signs of leucostasis may be present in up to 60% of cases at presentation. • It is known to be a risk factor for early death in myeloproliferative disorders, due to the hyperviscosity syndrome, a result of leucostasis in the : • cerebral, • renal, • ophthalmic, and • intestinal vascular beds.

43. It commonly coexists with anaemia. • Transfusion of blood in the presence of a hyperleucocytosis has been associated with death as a result of a further increase in the blood viscosity and leucostasis in the cerebral vessels

44. The priority at diagnosis is lowering of the white cell count. • Numerous strategies are possible and include leucopheresis and plasma exchange. • The results of these procedures are variable but have been reported to achieve a reduction in the white cell count of the order of 60%

45. Thrombocytosis is also known to be associated with increased haemorrhagic tendency.

46. Various mechanisms have been postulated to account for this tendency. • The high platelet count may cause intravascular activation, degranulation, and loss of haemostatic effectiveness of platelets. • Another putative mechanism is abnormal consumption of von Willebrand factor. • Clot fragility, due to a mechanical disturbance of a high platelet number on the fibrin network of thrombi, may play a part. • Alternatively, clot fragility could be due to inadequate fibrin stabilisation of platelet thrombi as a consequence of the local concentration of platelet glycoprotein Ib (previously shown to have an inhibitory effect on the thrombin fibrinogen interaction).

47. In our case, the aetiology of the presenting bleed is only speculative, possibilities including: • the presence of a chronic granulocytic sarcoma in the extradural space, • haemorrhage secondary to local vessel wall • Ischaemia caused by leucostasis and • bleeding as a result of abnormal platelet quantity and/or function.

48. Continued local bleeding into the site of the haematoma despite normal systemic haemostasis was probably multifactorial. • Thrombocythaemia of functionally abnormal platelets and persisting vessel wall ischaemia may have led to an ongoing slow leak of blood. • In addition the presence of a large organising haemorrhage may have led to consumption of local haemostatic factors at a rate exceeding their supply at the site.

49. Although relatively rare as a presenting feature, ocular disease has been well documented in adults. • One large study in children with acute leukaemia found that 9% had ocular involvement. • Retinopathy may take the form of tortuous, dilated veins, retinal vascular sheathing or, more commonly, haemorrhages which may be sub-hyaloid or intra-retinal.

50. Although this patient presented with both retinal disease and extra-axial intra-cranial disease, she received no extra CNS directed treatment as part of chemotherapeutic induction. • She did, however, receive total body irradiation as part of conditioning prior to bone marrow transplantation. • There has been no evidence of recurrence of disease in her CNS one year from presentation.