CPC -An Unusual Case…

November 13th 2008

Prof Orla Sheils

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.

CT scan at presentation showing left sided extradural masscausing mass effect with compression of the ipsilateral ventricle andmidline shift to the right.

What is your differential Diagnosis?

RAISED INTRACRANIAL PRESSURE

Compensatory Mechanisms:Displacement of bloodDisplacement of CSFLoss of Brain Tissue

RAISED INTRACRANIAL PRESSURE

EFFECTS:-Compression of Brain-Stretching of IIIrd nerve-Stretching of Posterior Cerebral ArteryHERNIATION

Subfalcine (supracallosal) Tentorial Cerebellar Tonsillar Coning

RAISED INTRACRANIAL PRESSURE

SIGNS & SYMPTOMS:-----Headache-----Vomiting-----Papilloedma

DANGER OF LUMBAR PUNCTURE!

IMPACT INJURIES

Scalp (abrasions,bruises,lacerations) Skull Fractures Cerebral Contusions Extradural Haemorrhage Intracranial Haemorrhage

ACCELERATION/ DECELERATION INJURIES

Subdural Haemorrhage Diffuse Axonal Injury (DAI)

EXTRADURAL HAEMORRHAGEPOTENTIAL 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

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.

What other tests would you order?

Bone Marrow Biopsy/Aspirate

Bone marrow

Hypercellular marrow

Bone marrow

Mitotic fig.

Bone marrow

Mitotic fig.

Eosinophil

Bone marrow

Promyelocyte

Neutrophil

Monocyte

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

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).

What is this cytogenetic finding characteristic of?

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.

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.

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.

What is CML?

CML

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

How does the ‘Philadelphia Chromosome’ occur?

What changes have been introduced with regard to treatment of CML?

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.

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.

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 subcutaneoushaematoma following surgery.

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

problem?

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.

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.

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.

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

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.

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

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.

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.

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.

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

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%

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

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).

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.

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.

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.

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.

Epidural or extradural hematoma is a type of traumatic brain injury (TBI) in which a buildup of blood occurs between the dura mater and the skull. The dura mater also covers the spine, so epidural bleeds may also occur in the spinal column.

Often due to trauma, the condition is potentially deadly because the buildup of blood may increase pressure in the intracranial space and compress brain tissue.

The condition is present in one to three percent of head injuries. Between 15 and 20% of patients with epidural hematomas die of the injury.