The Incidence Of Posterior Reversible Encephalopathy Syndrome Is Increased In BMT For Haemoglobinopathies

Posterior reversible encephalopathy syndrome (PRES) is a neurological syndrome characterised by clinical findings - including hypertension, seizures, behavioural changes and altered vision - coupled with MRI abnormalities, most commonly in the occipital lobe. Previous data suggestes that PRES may occur more frequently in patients undergoing BMT for haemoglobinopathies (9%, Noe et al 2010) than for other conditions (1-5%, Reece et al 1991 and Wong et al 2003).

To further study this, the incidence and characteristics of PRES were investigated in all consecutive BMT for haemoglobinopathies performed at St Mary’s Hospital, London, between February 2006 and February 2013. The median follow up of 287 days (range 80-1,199). Ninety-six BMT were performed for patients with sickle cell disease (SCD, n=31) or thalassemia major (TM, n=65), with a median age of 9 years (range 3-16). Two different regimens were used during this period of time. The conventional conditioning protocol (P1; SCD=20, TM=4) consisted of busulfan 14 mg/kg, cyclophosphamide 200 mg/kg and alemtuzumab 0.3 mg/kg achieving a DFS of 94.5%. In order to reduce busulfan toxicity, minimise mixed chimerism and enable the use of related mismatched and unrelated donors, a second regimen was adopted in 2011 (P2; SCD=11, TM=24) achieving a DFS of 96%: fludarabine 160 mg/m², treosulfan 42 g/m², thiotepa 10 mg/kg and ATG (Thymoglobulin) 7.5 mg/kg or 11.25 mg/kg. P1 used short course ciclosporine (CSA) and methotrexate as GvHD prophylaxis and phenytoin during busulfan treatment, continued for 6 months for sickle cell patients. P2 used CSA and MMF as GvHD prophylaxis, only SCD patients received clonazepam prophylaxis.

Nineteen cases of PRES were identified from 18 patients occurring from day 0 to +75 post-transplantion, an incidence of PRES (18.8%). There was no difference in the incidence by diagnosis (p=0.39). The most common symptoms were headache (72%, n=13) and vomiting (62.5%, n=10), and hypertension was present in 88% of the patients. Other features included behavioural/conciousness changes (50%), seizures (41.2%), altered vision (27.7%) and altered limb neurology (27.7%). All patients made a complete recovery, but 2 patients required intubation and assisted ventilation for 12 and 26 hours, respectively. MRI detected changes in 78%, most commonly in the occipital lobe (55%), but abnormalities were also noted in the parietal (22.2%) and frontal lobes (22.2%). Abnormalities were commonly bilateral (61.1%), but not necessarily symmetrical.

The cases were investigated to highlight any risk factors leading to the higher rate of PRES in this patient group. The occurrence of PRES was not associated with previous history of stroke, seizures or silent infarcts in SCD patients (p=1.00), nor renal function (eGFR) or liver function (biopsy structure and liver function tests) in any of the patients. There was an increased incidence of PRES in P2, approaching but not reaching statistical significance (P1 13.1%, P2 28.6%, p=0.06). The alteration of consciousness (GCS) was not different between the two regimens (p=0.07). Although the majority of patients were on CSA (n=16), 2 presented on tacrolimus alone.

In conclusion, the incidence of PRESS is increased in BMT for haemoglobinopathies, with no difference seen between SCD and TM patients and may underlie the vascular damage found in all these patients. New fludarabine based conditioning regimens may have a greater incidence and better prophylactic strategies are required, which may include the use of alternatives to calcineurin inhibitors.