Answers

Short answers
1 Acute spinal cord compression with a sensory level at T5 caused by extramedullary haematopoiesis.

2 The magnetic resonance image shows spinal cord compression, maximal at T5 and T8, caused by masses of extramedullary haematopoiesis behind the spinal canal compressing the cord.

View larger version (61K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Figure 2 The magnetic resonance image of the spine shows extensive soft tissue masses of extramedullary haematopoietic tissue (red circles) cause cord compression at levels T5 and T8 (arrows)

Long answers
1 Diagnosis
The spine is affected in 11-15% of patients with β thalassemia,^{1 2} but spinal cord compression caused by extramedullary haematopoiesis is a rare complication, with an incidence of 0.8%.³ Most cases present with paraparesis, sensory impairment, and occasionally sphincter disturbances. Magnetic resonance imaging of the spine is the diagnostic procedure of choice. It shows a hypointense mass on both T1 and T2 weighted images.⁴ Biopsy (guided by a computed tomogram) of paraspinal masses can be done for tissue diagnosis, but as it carries the risk of catastrophic bleeding it is not usually advocated.^{2 5}

Extramedullary haematopoiesis can occur in many disorders such as thalassaemias and other haemoglobinopathies, chronic haemolytic anaemias, as well as primary myeloproliferative disorders such as polycythaemia rubra vera and myelofibrosis.⁶

Thalassaemia is one of the most common genetic disorders worldwide. It causes anaemia secondary to defects in haemoglobin production. The incidence of thalassaemia varies greatly from country to country with a worldwide birth rate of 0.44 per 1000 births.⁷ In England an estimated 150 000 people carry thalassaemia, and about 600 patients have β thalassaemia major. About 30-60 babies are born with β thalassaemia major in the United Kingdom each year.⁸

β thalassaemia is caused by a decrease in production from the β globin chain. Haemolysis and ineffective erythropoiesis are responsible for the anaemia. Accelerated apoptosis is the main cause for the ineffective erythropoiesis. It is caused by excess chain deposition in erythroid precursors. The bone marrow of patients with thalassaemia contains five to six times the number of erythroid precursors compared with the bone marrow of healthy people.⁷

Expansion of the bone marrow and extramedullary haematopoiesis occur to compensate for chronic anaemia, which results from the over-expression of erythropoietin. They often affect the liver, spleen, and lymph nodes, but can involve any site of normal haematopoiesis in fetal life, including the adrenal glands, heart, thymus, lungs, renal pelvis, retroperitoneal fat, gastrointestinal lymphatics, and dura mater.⁹

2 The magnetic resonance image
See short answer 2.

3 Management
Immediate—Spinal cord compression is an emergency that needs urgent imaging to confirm the diagnosis and localise the culprit lesion accurately. No formal guidelines exist for managing spinal cord compression caused by extramedullary haematopoiesis. Management is on the basis of expert opinion and case reports. Options include surgical decompression, radiotherapy, intensification of red cell transfusions, hydroxycarbamide treatment, or combinations of these.^{1 2 3 4 6}

Laminectomy or hemilaminectomy gives immediate relief of cord compression and provides material for histological diagnosis. It is, however, associated with a high risk of major haemorrhage,⁵ haemodynamic instability in an already anaemic patient, incomplete excision where there is diffuse involvement, and spinal instability and kyphosis associated with multilevel laminectomy.^{4 10}

Radiotherapy alone produces excellent results with symptomatic improvement seen three to seven days after starting treatment.^{4 5} Initial deterioration of symptoms has been reported and it is attributed to the development of oedema, an effect that can be overcome by the concomitant use of corticosteroids.³ Haematopoietic tissue is extremely radiosensitive and small doses of radiotherapy (750-3500 cGy) have been reported to be sufficient. Using low dose radiation, the only toxicity that can be seen is further deterioration of the anaemia. Blood counts need to be monitored often.³ A high risk of recurrence exists after radiotherapy alone, and relapse rates of 19-37.5% have been reported.^{3 4} Recurrences can be treated with further radiotherapy. An intensified transfusion programme or treatment with hydroxycarbamide can help reduce the rate of relapse after any initial intervention.^{3 4}

Long term—Hypertransfusion alleviates anaemia by reducing the production of erythropoietin, minimising the endogenous ineffective erythropoiesis, and reducing the need for extramedullary haematopoiesis. Although blood transfusions can prevent progression of extramedullary haematopoiesis, they cannot reverse pre-existing pathology. Their use in the acute setting is limited and only complementary to radiotherapy or surgery.⁶ Hypertransfusion, however, can suppress extramedullary haematopoiesis in the long term, and can reduce the chance of recurrence.^{2 11}

The disadvantages of this intervention are the long term complications of transfusional iron loading—the need to increase iron chelation with greater likelihood of poor compliance, further increases in subsequent risk of cardiac and liver toxicity, and effect on life expectancy.⁷ More exposure to blood increases the risk of alloimunisation, and transmission of blood borne pathogens, including variant Creutzfeldt-Jakob disease.¹²

Hydroxycarbamide (hydroxyurea) is an antimetabolite (ribonucleotide reductase inhibitor) with known cytostatic effects that is widely used to treat myeloproliferative diseases such as polycythaemia rubra vera and essential thrombocytosis. It increases the production of fetal haemoglobin and is used to manage sickle cell disease.¹³ A higher level of fetal haemoglobin improves the underlying anaemia and reduces the incidence of extramedullary haematopoiesis, although the cytostatic effect of hydroxycarbamide can lead to reduction of the extramedullary haematopoietic tissue.^{3 4 6}

This long term treatment requires careful monitoring because of the risk of cytopenia. Patients must be told of the adverse effect on gametogenesis. The effects seem to be temporary and reversible, although only limited data exist and no large studies have been done.¹³

Animal studies have shown the potential teratogenic effect of hydroxyurea. Women of child bearing age should be counselled about this.¹³

Leukaemogenesis is another serious long term theoretical risk of hydroxyurea. Evidence on this is difficult to interpret as the cohort of patients with whom we have the greatest experience—those with polycythaemia rubra vera or essential thrombocytosis— can progress spontaneously to acute leukaemia. There does not seem to be an increased incidence of cancer in patients with sickle cell anaemia treated with hydroxyurea but evidence is scanty. The current consensus is to tell patients there is a potential risk.¹³

Patient consent obtained.

Competing interests: None declared.

References

Cite this as: BMJ 2008;337:a2304