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S. Riva et al.
taking into account a whole assessment of cognitive, emo- tional and health-related quality of life (HrQoL) dimen- sions.2-3 Cognitive domains required for complex atten- tion, concentration skills and high level memory functions may be involved in patients with TTP due to diffuse microvascular subcortical lesions, similarly to neurologi- cally normal individuals with untreated hypertension, sickle cell disease and multi-infarct dementia. Two widely accepted measures to evaluate HrQoL are the Short-Form 36 (SF-36)4 and the EuroQol 5D (EQ-5D).5 They are self- reported scales providing a numerical score to identify the level of perceived health status. For their generic nature, the SF-36 and the EQ-5D are frequently used in chronic conditions (e.g. hemophilia) and are applicable to many diseases.
With this background and gaps of knowledge, we set up a study in order to investigate persistent cognitive abnor- malities, emotional wellbeing and quality of life in patients who had recovered from an acute episode of acquired TTP. We also analyzed whether or not the pres- ence of neurological involvement during the acute phase of TTP or severe ADAMTS13 deficiency during disease remission were related to persistent neurocognitive defects. Finally, we investigated whether there was an association between the emotional status of the patients and their quality of life.
Methods
Patients
We performed a cross-sectional study of 35 patients with acquired TTP regularly followed at our out-patient clinic of throm- botic microangiopathies in Milan (Italy). Patients were enrolled at least three months after their last acute TTP event (median time of 36 months, interquartile range [IQR]: 17-54) from December 2015 to October 2016, when they underwent a comprehensive neu- ropsychological evaluation including memory and attentional functions, emotional wellbeing and HrQoL. Demographic and clinical variables were recorded, including age, sex, ethnicity, job status, level of education, clinical and biochemical data at the time of acute TTP (neurological involvement, platelet count and haemoglobin level at presentation, number of plasma exchange procedures required to attain remission), and plasma ADAMTS13 activity levels at the time of the neuropsychological assessment (± three months). Enrolment criteria are described in the Online Supplementary Table S1.
Written informed consent was obtained from all subjects with approval of the Ethics Committee of Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, in accordance with the Declaration of Helsinki.
Neurocognitive, emotional and HrQoL assessments
Neurocognitive and psychological assessments were adminis- tered by a board-certified psychologist in the standardized fashion in the frame of a single assessment session, which required approximately 1 hour to be completed, and included a test battery measuring two major cognitive domains, memory and attention,6- 8 the Hamilton Depression (HAM-D)9 and Anxiety (HAM-A)10 rat- ing scales for emotional wellbeing, and the Short-Form (SF) 364 form for HrQoL (Online Supplementary Material and Methods and Online Supplementary Table S2).
Statistical analysis
Descriptive statistics were used for demographic, clinical and
laboratory characteristics. Categorical variables were expressed as counts and percentages, continuous variables as means or medians with standard deviation (SD) or IQR. With regards to neuropsychological and HrQoL analyses, each subject’s raw score on each test was converted to a standardized score based on normative data generated from the value of the normal pop- ulation according to the subject’s age and education level, as appropriate.11-15 Standardized scores of TTP patients were then compared with norm-referenced data from the Italian popula- tion11-15 by calculating the difference of means with 95% confi- dence intervals (CI) using unpaired and paired t-tests. Similarly, difference of means with 95% CI from unpaired and paired t- tests were used to compare neurocognitive assessment results in acquired TTP patients with and without neurological manifesta- tions during the first acute episode of TTP, and with and with- out reduced ADAMTS13 activity during disease remission, close to the neuropsychological evaluation. For this analysis, an ADAMTS13 activity cut-off of 45% was used (i.e. the lower limit of the normality range in our ADAMTS13 activity assays). With regards to HrQoL, a standardized score of 50 was consid- ered the cut-off for an acceptable quality of life.15-16 Finally, non- parametric correlation analyses were performed to evaluate the relationship between the results of emotional wellbeing tests and those of neurocognitive assessments or aggregated HrQoL scales.
Statistical analyses were performed by SPSS, release 25.0 (IBM Corp., Armonk, NY, USA), and GraphPad Prism, version 7.03 (GraphPad Software, La Jolla, CA, USA).
Results
Between December 2015 and October 2016, 41 acquired TTP patients were approached for participating in the study during a follow-up visit at our out-patient clinic of thrombotic microangiopathy. Of them, one patient refused to participate and one patient was exclud- ed owing to a pre-existing psychiatric disease. Four were not constantly attended at our center, and therefore they were excluded from the study. Thus, 35 patients were included in the study and underwent psychological tests and neurocognitive examinations (see the Online Supplementary Material and Methods). Patient characteris- tics are reported in Table 1. All but one patient were Caucasian, with a female to male ratio of about 3:1 and a median age at TTP onset of 41 years (IQR: 35-48). At the time of neuropsychological evaluation, 10 (29%) of 35 patients had suffered from recurrent TTP bouts. 22 patients (63%) presented with neurological signs and symptoms at presentation of the first acute TTP episode (including coma [n=2], focal neurological signs [n=12], personality changes [n=2], transient ischemic attack [n=4], seizures [n=1], stroke [n=3]). During the psycho- logical consultation, 17 (49%) patients reported persisting subjective neurological impairment in the remission phase, with at least one symptom as disorientation, loss of concentration, dizziness, lack of balance (unable to control and maintain the body position all the time) headache, and diplopia.
Results of neurocognitive assessment
At the digit span test, 25 (71%) and 23 (66%) patients had a scoring lower than the mean of the general popula- tion in direct (mean difference -1.26; 95% CI: -1.64-- 0.87]) and backward (mean difference -1.49; 95% CI: -
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