=Paper=
{{Paper
|id=Vol-1419/paper0061
|storemode=property
|title=Neuropsychological Deficits in Adult HIV Infected Postnatally: a Pilot Study in Patients with Hemophilia
|pdfUrl=https://ceur-ws.org/Vol-1419/paper0061.pdf
|volume=Vol-1419
|dblpUrl=https://dblp.org/rec/conf/eapcogsci/RivaCP15
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==Neuropsychological Deficits in Adult HIV Infected Postnatally: a Pilot Study in Patients with Hemophilia==
https://ceur-ws.org/Vol-1419/paper0061.pdf
Neuropsychological deficits in adult HIV infected postnatally: a pilot study in
patients with hemophilia
Silvia Riva (silvia.riva1@unimi.it)
Department of Health Science, University of Milan, via A. di Rudinì 8 Milan, Italy
Ilaria Cutica (ilaria.cutica@unimi.it)
Department of Health Science, University of Milan, via A. di Rudinì 8 Milan, Italy
Gabriella Pravettoni (gabriella.pravettoni@unimi.it)
Department of Health Science, University of Milan, via A. di Rudinì 8 Milan, Italy
European Institute of Oncology (IEO), Milan, Italy
Abstract Clifford, Franklin, Woods et al., 2010). Also, the
longitudinal observation of these patients has given
Despite advances in the management of HIV infection with
the introduction of combination antiretroviral therapy contrasting results: some studies have not shown any
(cART), it is well known that HIV can directly infect the decline in neurocognitive functions (Grassi Clerici, Perin,
central nervous system (CNS) and, as a result Zocchetti et al., 1995; Selnes, Miller, McArthur, Gordon, et
neuropsychological impairments can be manifested. al., 1990) while others have (Applebaum, Otto, Richardson,
However, in literature there are contrasting results on which & Safren, 2010; Ayuso-Mateos, Pereda, Del Barrio,
cognitive functions are mainly affected, especially when Echevarria et al., 2000; Woods Iudicello, Moran, Carey et
different HIV seropositive populations are considered. In this al., 2008;).
study, we seek to determine whether seropositivity is In addition, some authors have argued that such
associated with a poor neuropsychological performance in
difficulties might be more related to the presence of
patients infected postnatally, namely haemophilic patients.
The results suggest that HIV infection is associated with important covariates, such as CD4 nadir count (Ellis,
deficits in attention, short term spatial memory, phonemic Badiee, Vaida, Letendre et al., 2011; Heaton, Franklin,
fluency, abstraction and visual recognition. Such results have Ellis, McCutchan et al, 2011), the time of infection
important implications for day-to-day functioning, as the level (Ettenhofer, Hinkin, Castellon, Durvasula et al., 2009), drug
of impairment detected may cause difficulties in completing abuse (Shimizu, Chow, Valcour, Masaki et al., 2011),
common everyday tasks. cranial traumas, and several psychological alterations, rather
than to the direct action of HIV virus.
Keywords: HIV seropositivity; neuropsychological In our view, it is important to notice that
impairments; haemophilia. neuropsychological impairments have been mainly studied
in two HIV seropositive (henceforth, HIV+) populations:
Introduction - patients infected vertically or perinatally (e.g. through
Although neuropsychological profiles vary amongst breast milk), a condition that presents adjunctive cognitive
HIV+ individuals, several estimates indicate that as many as disorders linked to neuro-developmental growth changes
50% of HIV+ individuals display some degree of (Rondanelli, Caselli, Arico, Maccabruni et al., 2002; Van
neuropsychological impairment when impairment is derived Rossum, Gaakeer, Verweel, Hartwig et al., 2003) and
from comparisons with normative performance standards neurological changes (Antinori, Arendt, Becker, Cherner et
(e.g., Dawes, Suarez, Casey, Cherner et al., 2008). A recent al, 2007);
meta-analysis revealed that the most severe forms of HIV - patients who contracted the infection postnatally or in
associated neuropsychological impairments have decreased adulthood, often comprises participants who presented other
since the widespread use of combination antiretroviral types of confounding factors, such as cocaine and opiates
therapy (cART): Al-Khindi and colleagues (2011) found use, alcohol abuse (Buttner, 2011; Byrd, Robinson-Papp,
less attentional, motor, and executive skill impairments in Rivera Mindt, Mintz et al., 2013;Lundqvist, 2010), and
HIV+ individuals treated with cART. Notwithstanding, different risk behaviours (De Ronchi, Faranca, Berardi,
several studies revealed that impairments in learning (e.g., Scudellari et al., 2002).
Carey, Woods, Rippeth, Heaton et al., 2006; Maki, Cohen, By contrast, a population of HIV patients generally
Weber, Little et al., 2009), verbal memory (Seider, Assawin infected postnatally at an older age, and that usually do not
Gongvatana, Devlin et al., 2014) and prospective memory present the drug-user populations confounding factors,
(e.g., Doyle, Loft, Morgan, Weber et al., 2013; Martin, consists of patients medically induced to HIV infection
Nixon, Pitrak, Weddington et al., 2007) still occur even in through blood transfusions (Ettenhofer, Hinkin, Castellon,
patients treated with cART (e.g., Grant et al., 2014; Heaton, Durvasula, et al., 2009). Hemophiliacs treated with factor
383
infusions before 1985 have been at risk of acquiring HIV cytomegalovirus infection, multiple sclerosis, stroke,
(Brookmeyer & Goedert, 1989): several studies have shown seizures/epilepsy, drug use.
that about 60–80% of patients with hemophilia, exposed to
infected blood concentrates, contracted the HIV virus (e.g., Tests were also administered to a control group consisting
Goedert, 1995). of fifteen adults (mean age 49,3+6.84), comparable for age
The interest in neurocognitive dysfunctions in hemophilia and education (Mann–Whitney test: z=-1.41, p=.16; z=-.35,
HIV+ patients is quite innovative in the literature. Findings p=.77, respectively). Participants’ educational and
are often inconsistent and difficult to summarize (for a professional characteristics are presented in Table 1.
review, see Riva, Cutica, Pravettoni, 2014); most of the
early research findings are based on the Hemophilia Growth Table 1. Patients’ and controls’ educational and
and Development Study (HGDS; Hilgartner, Donfield, employment characteristics
Willoughby, Contant et al., 1993), a multicenter study of the HIV+ Controls
long-term effects of HIV infection on growth and haemophiliacs (n = 15)
neurodevelopment in HIV+ hemophilia children and (n = 15)
adolescent, that found that such patients did not differ Primary 1 -
significantly from HIV- hemophilic controls on a variety of school
neuropsychological tests. However, as indicated in follow- Secondary 8 9
up studies of HGDS patients (Iudicello, Woods, Weber, Educational
school
Dawson et al., 2008; Loveland, Stehbens, Mahoney, Sirois level
High 5 4
et al., 2000; Watkins Cool, Usner, Stehbens, et al. 2000) School
there was a significant decline in neurocognitive functions University 1 2
such as memory, attention and language over 5 years, Currently occupied 9 11
directly related to a decline in immune functioning and to
socio-educational covariates such as school absenteeism and
Material
a poorer academic achievement that frequently marked these
young patients. Participants completed six neuropsychological tests from
Although there are some data available in the context of the Italian Brief Neuropsychological Examination battery
paediatric populations, studies are totally underrepresented (ENB: Mondini, Mapelli, Vestri, Arcara, et al., 2003) to
in the adult population with mixed and confusing results investigate:
(e.g., Riedel, Helmstaedter, Bülau, Durwen et al., 1992). - visual attention and cognitive processing speed (Trail
Some studies found cognitive impairment in attention, Making Test A, in which participants have to connect a
motor skills, and visual performance in HIV+ haemophiliacs series of 25 number in ascending order as quickly as
to be related to the decrement of immunological possible: Tombaugh, 2004);
functioning, especially when the CD4+ cell count was lower - visual attention and executive functioning (Trail Making
than 200/mm3 (e.g., Blanchette, Smith, King, Fernandes- Test B, in which participants have to alternate between
Penney et al., 2002). No clear data on cognitive impairment numbers and letters (1, A, 2, B, etc.) connecting them in
of HIV+ haemophiliacs with CD4+ cell count higher than sequential order as quickly as possible:Tombaugh, 2004);
200 are available. - digit span memory (Letter-Number Sequencing from the
The present study aimed to assess the presence and the WAIS-III, which measures the number storage capacity of
extent of neuropsychological impairments in such a the working memory: Weschler, 1995);
patients’ group. - phonemic fluency (Verbal Fluency test, in which
participants have to say as many words beginning with a
certain letter as possible in 60 seconds: Lezak, 1995),
Method
- abstraction (Italian Test of abstraction from the ENB, in
Participants which, given three words, the participant have to tell what
Fifteen HIV+ male haemophiliacs (mean age 45+8.4) the three concepts have in common: Mondini, et al., 2003).
were administered neuropsychological tests. Patients were - visual recognition (Rey Tangled Lines Task, in which
recruited through their treating physicians via the participants have to recognize the greatest possible number
haemophilia and thrombosis outpatient clinics in three of figures within a table in which the figures are drawn
Italian centres. The inclusion criteria were as follow: tangled: Rey, 1964).
diagnosis of haemophilia, diagnosis of HIV with CD4+
counts consistently > 200cells/mm3, treatment with cART, Procedure
age > 18. Exclusion criteria were diagnosis of AIDS, serious
Patients were met immediately after a routine medical
mental illness with a certificated diagnosis (e.g., major
appointment, in which –among other things- overall clinical
depression, anxiety, bipolar disorder) or known central
status, including the presence of concomitant diseases, was
nervous system pathology, including progressive multifocal
evaluated. After signing the data protection form, they were
leukoencephalopathy, brain cancer, neurosyphilis, active
presented with the neuropsychological tests; each of them
384
dealt with the tests individually in a quiet room. According with 13 to 18 years as “high educational level”. Nine
to each test requirements, the answers were recorded either patients and 9 controls fell into the low educational level,
by the patient or by the experimenter. Patients completed and 6 patients and 6 controls into the high educational level.
the tests in about twenty minutes. Controls were tested Low school level patients performed worse than the high
individually in a quiet room; they completed the test in education group only in Trial Making B Test (Mann-
about twenty minutes. Whitney Test: z=-2.125, p=.036).
We then divided patients according to their occupational
Results status: employed individuals on one side (n=9) versus
unemployed or with disability pension individuals (n=6).
As only three test out of six have the corrected score that We found that the unemployed/disability pension group has
allows to correct raw scores for age and educational level, a worse performance than the employed group only in Trial
we decided to analyse the raw data for all the tests, also Making A Test (Mann-Whitney Test: z=-2.239; p=.026).
considered that age and education do not differs in the two As these results were inconsistent with most of the
groups. existing literature, in addition we performed an ANCOVA
Between groups comparisons. Table 2 shows the mean analysis, controlling for the effect of age, education and
raw data for each neuropsychological test, for patients and working status. The analysis controlled for such covariates
controls. revealed that patients performed worse than controls on
Attention with regard to the Trail Making A Test (F=8.470,
Table 2. Mean raw scores patients and controls p=.005), and Trail Making Test B (F=5.811,
(standard deviation in parentheses) p=.022). However, the predicted main effect of education
was not significant (F=4.89, p = .066, ηp2 = .004), neither
Patients Controls was the predicted main effect of working status (F=.595, p =
Tests (n =15)) (n=15) .455, ηp2= .004), and nor the main effect of age (F= 1.226,
p = .292, ηp2 = .004). Although the introduction of
Trial Making 60.93seconds* 32.27 seconds covariates reduced the distance between the two groups of
Test A (24.52) (8.54) participants, they did not eliminate the effect of HIV
Trial Making 173.53seconds 92.73 seconds infection on neuropsychological impairment completely.
Test B (63.39) (9.59) Therefore the presence of these covariates (age, educational
Digit Span 3.93 items 5.87 items level and working status) did not explain group differences
memory per se.
(1.71) (.74)
Phonemic 27.53 words 34.14 words Discussion
fluency (6.20) (5.06) Although neuropsychological impairments are well
Test of 4.40 abstr. 5.73 abstr. described in some specific HIV populations, very few
abstraction (1.29) (.46) studies investigated the cohort of adults seropositive
patients with haemophilia, especially in the cART era.
Rey Tangled 25.19 figures 4.67 figures
Furthermore, the few existing studies on children and
Lines Task (1.20) (.62)
*
adolescents, and on adults before the widespread use of
In Trial Making Test A and B, a longer time corresponds to a worst cARTs, often obtain inconsistent results.
performance
Our pilot study, conducted on a small but well-controlled
sample of HIV + hemophiliacs, reveals that such patients
Results show that patients’ performance in each show signals of neuropsychological impairments when
neuropsychological test is worse than the corresponding compared with the controls’ performances.
performance by healthy controls. More in detail, we found In particular, considering the whole group of HIV+
that patients performed significant worse than controls in patients, we found an HIV detrimental effect on tests
Trail Making A (T-test: t= 3.53, p=.001), in Trail Making B requiring attention and rapid information processing (Trail
(T-test: t= 4.88, p<.0001), in Digit Span (T-test: t=-4.02, Making Test A, and Trail Making B for patients with low
p<.0001), in Phonemic Fluency (T-test: t= -3.19, p=.003), educational level), consistently with the classic
and in Rey Tangled Test (T-test: t=-5..836, p<.0001). conceptualization of HIV as a subcortical disease targeting
frontal-striatal circuits supporting these abilities (e.g.,
Within-group comparisons. As the HIV literature reveals a Baldewicz, Leserman, Silva, Petitto et al., 2004; Reger,
correlation between cognitive disorders and patients’ socio- Welsh, Razani, Martin et al., 2002).
demographic factors such as education and job status, we Patient’s results on these two attention tasks, on the visual
performed some comparisons to figure out whether the same recognition task (Rey Tangled Lines), and on phonemic
effect holds for our participants. We thus divided both fluency are also consistent with one of the two existing
groups into two into sub-groups according to the study on adult seropositive hemophiliacs, by Riedel and
educational level. We considered participants with 5 to 8 colleagues (1992), who found that patients are impaired in
education years as “low educational level”, and participants
385
visual attention, visuoperceptual speed, and verbal memory haemophilia and HIV), as well as holding down a full-time
and fluency. However, they also found that patients’ job. Continued research into the mechanisms related to HIV
impairment was a linear relationship with the decreasing of seropositivity and neurocognitive dysfunction may provide
immune functioning, whereas we found deficits also in targets for meaningful interventions.
patients with high immune functioning (as all our patients
are).
Our patients’ impairment on Digit span memory is in line
with Riedel’s work, and with several previous findings Acknowledgments
showing that deficits in memory, and in particular in short The first author was supported from Novo Nordisk grant
term memory, are among the strongest cognitive complain “Changing possibilities in Haemophilia”. The authors wish
in HIV (non-haemophilic) patients (e.g., Doyle Suarez, to thank prof. Mannuccio Mannucci for his support, and the
Casey, Cherner et al., 2013; Maki, Cohen, Weber, Little et huand the AICE (Italian Association of Haemophilia
al., 2009; Seider et al., 2014). Also, our data are consistent Centres) for allowing to conduct this study in three
with results from the other existing study on adults Haemophilia centres.
seropositive haemophiliacs, a case-study of four patients
(Turnbull, Saling, Kaplan-Solms, Cohn, et al, 1991),
according to which patients are impaired in visual memory
and spatial perception.
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