Introduction

Beta-thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in the synthesis of beta-globin chains. In the homozygous state, beta-thalassemia (i.e., thalassemia major, b-TM) causes severe, transfusion-dependent anemia. In the heterozygous state, the beta-thalassemia trait (i.e., thalassemia minor) causes mild to moderate microcytic anemia [1, 2]. The term “beta-thalassemia intermedia” refers to patients with symptomatic beta-thalassemia who do not require transfusion during at least the first few years of life and are able to survive into the second decade of life without chronic hypertransfusion therapy. While most patients with thalassemia intermedia do not need regular blood transfusions to survive, the effects of the disease, including bone marrow expansion, hepatosplenomegaly, and chronic hemolytic anemia, are present, even in milder forms of the disorder [3, 4]. The life expectancy of thalassemia patients has markedly improved over the last few decades, but patients still suffer from many complications of their congenital chronic disease, and several new complications are now being recognized, including neurological complications. This review highlights the most important neurological complications and the precautionary exams that are needed and provides guidelines for early treatment, where documented knowledge is available.

Neurological complications

Central and peripheral nervous system complications have been demonstrated in several reports. In most cases, these complications remained subclinical and were detected only during neurophysiological or neuroimaging evaluation. Chronic hypoxia, iron overload, desferrioxamine (DFO) neurotoxicity, and bone marrow expansion are implicated as possible causes, but sufficient explanatory evidence and biomarker development are lacking. An increased understanding and improved biomarkers are critical because as survival rates improve, nervous system involvement is expected to become more conspicuous.

Intelligence quotient–cognitive function

Intellectual impairment in b-TM was first reported by Orsini et al. [5]. Later, Monastero et al. [6] performed a comprehensive neuropsychological battery including tests of abstract reasoning, attention, executive functions, language, and constructional and visuospatial skills, as well as memory and reported cognitive impairment in adult patients with b-TM, particularly in those patients presenting with hemosiderosis. Economou et al. [7] described mild mental retardation in three of 22 children with b-TM and abnormal total intelligence quotient (IQ) scores (<85) in 36.4 % of children with b-TM. Anemia, which leads to hypoxia, was the first factor correlated with intellectual impairment. Iron deposition, which leads to brain damage in the long term, is another important factor that has been linked to developing central nervous system (CNS) complications in b-TM patients. Metafratzi et al. [8] reported higher iron depositions in the putamen, caudate nucleus, and motor and temporal cortex of patients with b-TM. These areas are important for cognitive function as well as for implicit and explicit memory. Better monitoring, increased time interval between the transfusions, earlier onset of blood transfusions, and earlier onset of DFO therapy can all reduce impairment. Recently, Karimi and Duman [9, 10] reported that the IQ of b-TM patients does not differ significantly from the normal population. However, in Duman’s study, cognitive impairment and impaired stimulus recognition and information processing were more frequently noted in the patient group. The discordance in the IQ results can be attributed to the exclusion from the study of patients with abnormal evoked related potentials (ERPs). Intellectual impairment has also been described in thalassemia intermedia patients. In Teli’s study [11], patients with thalassemia intermedia were tested using Wechsler intelligence scales for children. The evaluation revealed a normal mean IQ, but 11.7 % had an IQ below 85 and 5.88 % had mild mental deficiency. Cognitive impairment in thalassemia intermedia could be attributed either to high iron deposition [12] or to the high percentage of cerebral atrophy (37 % of splenectomized patients) according to Taher et al. [13]. It is indeed well documented from the LADIS study that brain atrophy accelerates cognitive decline [14]. In conclusion, it is suggested that regular neuropsychological testing is essential for early diagnosis and appropriate management of cognitive dysfunction to improve the quality of life of patients with thalassemias.

Evoked potentials (VEPs, BAEPs, SSEPs)

Evoked potentials constitute a noninvasive method of evaluating the CNS. Evoked potentials lack disease specificity but remain sensitive tools in detecting even subclinical CNS lesions. Gelmi et al. [15] reported that visual evoked potential (VEP) abnormalities in b-TM patients correlated with iron overload. Pathological VEPs findings that were partially reversible were attributed to DFO neurotoxicity in several studies [7, 16, 17]. With regard to brainstem auditory evoked potentials (BAEPs), Wong [18] reported five (15 %) of the patients in his study with mild sensorineural loss and Triantafyllou [17] found that 14 out of 120 patients presented abnormal BAEP findings, mostly reversible and related to DFO neurotoxicity. The use of deferasirox [19] or deferiprone [20] in the management of iron overload has not been implicated in causing such abnormalities, but a limited number of studies exist. Wong [18] evaluated somatosensory evoked potentials (SSEPs) and described that 12 % of the patients in his study had increased cortical latencies of median or posterior tibial somatosensory evoked potentials. Pathological evoked potentials have also been described in thalassemia intermedia. Recently, Teli et al. [11] in an extensive study found that four out of 24 (16 %) patients with thalassemia intermedia presented with pathological BAEPs. Additionally, 4 % of the patients in their study revealed abnormal findings on SSEPs and all patients had normal VEPs. Because the majority of the latter patient group were nontransfused and under no iron chelation treatment, hypoxia and coagulopathy may be responsible for such lesions. The aforementioned results indicate that central nervous system lesions are not rare in either b-TM patients or in thalassemia intermedia, even if they remain subclinical and can be detected only by a careful assessment with specialized exams.

Extramedullary hematopoiesis and neurological complications

Extramedullary hematopoiesis (EMH) is a physiological compensatory phenomenon caused by insufficient bone marrow function that becomes unable to meet circulatory demands. EMH is seen in many hematological diseases; however, it commonly occurs in chronic anemias. The formation of extramedullary hematopoietic foci is slow and initially subclinical. Skull changes consist of the widening of diploid spaces and displacement and thinning of the outer surface and may lead to brain compression by the mass effect of the lesion. Since the first case described by Gatto et al. [21] in 1954, a large number of cases have been cited in the literature. Most frequently reported are cases concerning a paraspinal location of the hematopoietic tissue. The spectrum of the various clinical presentations that have been reported includes back pain, lower extremity pain, paresthesia, abnormal proprioception, exaggerated or brisk deep tendon reflexes, Babinski response, Lasegue sign, paraparesis, paraplegia, ankle clonus, spastic gait, urgency of urination, and bowel incontinence. The size and location of lesions and the extent of spinal cord involvement determine the severity, acuteness, and multiplicity of signs and symptoms [22, 23]. In thalassemia intermedia, the occurrence of extramedullary hematopoiesis is even higher and rare complications have been reported. Particularly, narrowing of the optical canal with subsequent optic neuropathy and visual failure has been described [24, 25]. Meara [26] reported extramedullary hematopoiesis of the middle ear in a patient with thalassemia intermedia resulting in conductive hearing loss. Treatment options are transfusion therapy, irradiation of the masses, and synovectomy. Recently, induction of fetal hemoglobin with hydroxycarbamide has also been proposed as an efficient first-line treatment option for patients with EMH [27]. Early diagnosis of EMH will affect the course of management and may reduce the incidence of irreversible neurological damage that would otherwise occur with prolonged undiagnosed cord compression.

Cerebrovascular disease

The literature presents an increasing number of studies concerning hemoglobinopathies and cerebrovascular disease. In 1972, Logothetis et al. described a “stroke syndrome” compatible with transient ischemic attacks in about 20 % of 138 cases of b-TM in Greece [28]. Transient ischemic attacks presenting with headache, seizures, and hemiparesis were also found in 2.2 % of patients with b-TM by Borgna Pignatti et al. [29]. Most recent studies usually involve thromboembolic events in a mixed patient population with thalassemia major and thalassemia intermedia, with percentages ranging between 0.9–4 % and 3.9–29 %, respectively [18, 30–34]. Patients with b-TM seem to suffer mainly from large hemispheric territorial infarcts [35–37]. Cardioembolism due to siderotoxic cardiomyopathy and arrhythmias is assumed as one important etiology of stroke in b-TM [38]. Hemosiderosis-related disease, including cardiomyopathy, liver dysfunction, and diabetes mellitus [39], can be prevented by proper chelation therapy, and this therapy is also important in prevention of cerebrovascular accidents. Chronic anemia may lead to cerebral injury in patients who already have multiple risk factors for stroke [40]. The close monitoring and proper adjustment of hemoglobin levels that is prerequisite for thalassemia patients may prevent cerebral events due to hypoxia. However, because Metarugcheep et al. [41] and Taher et al. [13] were not able to correlate anemia as a contributing factor for brain lesions, caution is suggested in intensive transfusions, especially when giving large and rapid transfusions to thalassemic patients [42]. Cerebrovascular disease in beta-thalassemia intermedia patients usually presents with asymptomatic ischemic lesions that are smaller and affect deeper structures while sparing the cortex [32, 43, 44]. According to the OPTIMAL CARE study [45], thromboembolic disease, mostly venous, was the fifth most common complication, affecting 14 % of the patient population. The majority of thalassemia intermedia patients with silent cerebral infarcts were splenectomized [33, 34]. Taking into account the additional complications of splenectomy, reconsidering the latter as a procedure of choice (e.g., to improve anemia), and restricting it to cases of severe splenomegaly or hypersplenism leading to profound anemia or thrombocytopenia should be considered [33, 46]. Iron chelation therapy in transfusion-independent patients should also be considered, especially in the light of studies that associate abnormal brain magnetic resonance angiography and positron-emission tomography–computed tomography findings with iron overload parameters in patients with thalassemia intermedia [47–49]. Finally, a hypercoagulable state is one of the most notable risk factors associated with thrombotic stroke in beta-thalassemia major, as well as in thalassemia intermedia patients [11, 30, 31, 33, 34, 50–54]. The underlying mechanism of hypercoagulability primarily involves a dual role of activated platelets and hemolyzed red blood cells with thrombin generation potential. Other associated factors involve endothelial activation and disturbances in the coagulation system, collectively leading to a prothrombotic state [46]. Hence, diagnostic magnetic resonance imaging (MRI) is recommended in high-risk groups (patients of advanced age, splenectomy, transfusion independence, and iron toxicity) [34, 43], to screen for early asymptomatic brain damage. In cases where a recent infarction is suspected, diffusion-weighted MRI (DW-MRI) is the method of choice to detect it [34, 55]. Interestingly, in a recent study, hydroxycarbamide administration was associated with a lower incidence of white matter lesions in untransfused patients [55]. If brain ischemia is found, the administration of antiplatelet aggregants or blood transfusion is likely to be beneficial. In addition, in thalassemia patients with the complication of a thromboembolic event, secondary prophylaxis could be helpful in preventing cerebral thromboembolic events [33]. At this point, it is important to mention that caution is warranted because, although rare, cerebral hemorrhage has also been described, usually presenting with headache, hypertension, and convulsions and following the post transfusion period [56–58].

Peripheral neuropathy and myopathy

The literature concerning nerve conduction velocity (NCV) studies in thalassemic patients remains limited. Logothetis et al. [28] first described a myopathic syndrome in b-TM patients with proximal weakness, mainly in the lower limbs, accompanied by a myopathic electromyographic pattern. However, patients in their study were children and were treated quite differently than current patients. Papanastasiou et al. [59] reported that 22 % of the patients in their study developed a mild peripheral neuropathy, mainly motor, during the second decade of life. In contrast, Zafeiriou et al. [60] reported that 10 % of patients had clinical evidence of a sensory neuropathy (absent or diminished deep tendon reflexes and loss of sensation in a stock-glove distribution) and additionally 25 % had decreased sensory conduction velocities, and only 10 % also had decreased motor NCVs. A mainly sensory polyneuropathy in 53 to 78 % of patients has been also described in more recent studies [61, 62]. Thalassemia intermedia patients also suffer from a mild motor peripheral neuropathy according to Papanastasiou et al. [59]. In the latter study, no difference in the frequency of peripheral neuropathy among the patients with thalassemia intermedia and thalassemia major was observed. Interestingly, differences in the neurophysiological findings between the different thalassemia types were found in a study by Sawaya et al. The neuropathy was mainly sensory and seemed to be worse in the intermedia type. Thalassemic patients who received blood transfusions and deferoxamine had a better nerve function than those who did not, irrespective of the dose of deferoxamine. The neuropathy was worse for older patients, irrespective of sex [62]. Peripheral neuropathy is a reality that reduces daily activities and hampers the quality of life of a high proportion of thalassemic patients. It has been attributed to multiple factors, but a sufficient illustration of the causative reasons is limited. Precautionary neurophysiological monitoring to achieve the appropriate management has been proposed [63].

Conclusion

As life expectancy for beta-thalassemia patients increases, several new neurological complications are now being recognized. Early detection of these initially subclinical complications with the use of neurophysiological, neuropsychological, or neuroimaging monitoring becomes imperative, enabling the evaluation of neural pathway impairment. The clarification of the pathophysiological mechanisms underlying these complications and development of biomarkers will facilitate the appropriate management needed to achieve a better quality of life for this patient group.