Neurological Manifestations Due to Extramedullary Hematopoiesis in Greek Patients with Thalassemia Intermedia: Not Such a Rare Clinical Finding

INTRODUCTION: The incidence of extramedullary hematopoiesis (EH) in patients with thalassemia intermedia (TI) may reach up to 20%, because they are not transfused regularly, in contrast to poly-transfused β-thalassemia patients, where the incidence is significantly lower and varies from 1-5%. Transfusion independence in TI increases the incidence of EH, because the body attempts to compensate for ineffective erythropoiesis, insufficient bone marrow function and inadequate red cell replacement, leading to unsuccessful expansion of the hematopoietic tissue, outside of the bone marrow medulla in the form of masses. However, the rare possibility of localization of these masses in anatomic areas of the body, causing nerve compression and neurological manifestations of various degrees, from mild or moderate symptoms to severe paraplegia, fecal and urinary incontinence has not been studied thoroughly.

MATERIALS AND METHODS: 7 patients, all male, diagnosed with TI were evaluated. All these patients presented with neurological manifestations due to EH at a median young age of 32 years (range 18 - 40).

RESULTS: In the majority of the patients, the masses of EH were located in the thoracic and/or lumbar part of the spinal cord. In 4 of them, magnetic resonance imaging (MRI) showed additional expansion of these masses inside the vertebral and sacral canal, causing severe nerve compression, leading to paraparesis, paraplegia and hypoesthesia of the corresponding neurotomes. 2 patients presented with bowel and urinary incontinence. An impressive deterioration of the ability to walk to complete paraplegia within a week was observed in 3 cases. Milder manifestations, such as difficulty in ladder climbing, various sensory derangements, and numbness in the cauda were also described. 6 of them received radiotherapy (dose range 500-2000 cGy) at the affected areas and resolution of the masses, along with massive improvement in the clinical setting was observed. The administration of hydroxycarbamide (hydroxyurea), corticosteroids, and red blood cell (RBC) transfusions with the goal of increasing hemoglobin over 11gr/dl was also applied. However, all patients relapsed and needed additional radiotherapy, RBC transfusions and hydroxyurea. 6 of them are alive until today, and one has died due to a gastrointestinal neoplasm, 21 years after the first and 7 years after the last radiotherapy. 5 patients were splenectomised, 1 due to visceral leishmaniasis and 4 during the 1970s, because this was the recommended approach for TI in the past. Nevertheless, splenectomy in TI has been associated with increased rates of pulmonary hypertension (PH) and thrombosis and is generally contraindicated. 2 patients of our cohort were diagnosed with PH and 1 with deep vein thrombosis (the latter harboured a heterozygous G2021A prothrombin mutation). Almost all patients had medium or severe iron liver overload and received chelation treatment with deferasirox. Finally, genotypes such as IVSI-110 G>A/IVSI-6 T>C, β39/IVSI-110 and cd39/Ter6 C-G+1480 were noted among our patients.

DISCUSSION: Our study indicates that the neurological manifestations, due to EH are not such a rare clinical finding, can be various, severe and life-threatening and that radiotherapy, hydroxycarbamide, corticosteroids, and RBC transfusions are essential as therapeutic approaches. An important observation of our study is that all the patients were male, hinting that there might be a connection between the male sex and the predilection for the localization of EH inside the spinal canal and requiring further investigation.

*The first four authors contributed equally to the study.