Dement Neuropsychol 2024;18:e20230117 Original Article

https://doi.org/10.1590/1980-5764-DN-2023-0117

Neuropsychological aspects of reversible

cerebral vasoconstriction syndrome
Ícaro Araújo de Sousa1 , Analina de Freitas Azevedo2 , Arthur de Oliveira Veras1 ,
Marx Lima de Barros-Araújo2 , Elizeu Pereira dos Santos Neto3 ,
Maria Andreia da Nóbrega Marques4 , Maria Paula Foss5 ,
Raimundo Pereira Silva-Néto6 , Irapuá Ferreira Ricarte7 , Octávio Marques Pontes-Neto1

ABSTRACT. Despite the increasing knowledge in the past years, only minimal attention has been directed to the neuropsychological
aspects and the prevalence of cognitive impairment associated with reversible cerebral vasoconstriction syndrome (RCVS).
Objective: To describe the frequency and expand the understanding of cognitive dysfunction in RCVS. Methods: The neuropsychological
evaluation was performed using a battery consisting of specific neuropsychological instruments that were administered to patients
diagnosed with RCVS. A triage was conducted to exclude other potential causes of cognitive impairment. Performance on the tests
was treated as a categorical variable, and a cutoff of -1.5 Z-score was adopted to indicate impaired performance. Results: Seven
patients diagnosed with RCVS were evaluated, all of whom had a bachelor’s degree and normal score in the Mini-Mental State
Examination. The average time between diagnosis and neuropsychological evaluation was 1.8 years. Among the patients, 85.6%
(n=6) exhibited performance below that of the normal population in at least two of the administered tests. Specifically, 71.4% (n=5)
showed alterations in tests from the Psychological Battery for Attention Assessment, with impairment observed in concentrated
(n=1), divided (n=3), or alternating (n=4) attention. Furthermore, 28.6% (n=2) demonstrated impairments in the Phonological
Verbal Fluency Task, another 28.6% (n=2) exhibited difficulties copying elements of the Rey Complex Figure, and 14.3% (n=1)
displayed lower performance in the Five-Digit test, all indicating executive dysfunction. Conclusion: This study provides evidence
that cognitive impairment associated with RCVS is more prevalent than previously believed and has not received sufficient attention.
Specifically, attention and executive functions are the cognitive domains most significantly impacted by RCVS.
Keywords: Vasoconstriction; Cognitive Dysfunction; Neuropsychology; Ischemic Stroke.

Aspectos neuropsicológicos da síndrome de vasoconstrição cerebral reversível

RESUMO. Apesar do crescente conhecimento nos últimos anos, pouca atenção tem sido direcionada aos aspectos neuropsicológicos
e à prevalência de declínio cognitivo associado à Síndrome de Vasoconstrição Cerebral Reversível (SVCR). Objetivo: Descrever a
frequência e expandir o entendimento da disfunção cognitiva associada à SVCR. Métodos: A avaliação neuropsicológica foi realizada
por meio de uma bateria composta de instrumentos neuropsicológicos específicos, que foram aplicados aos pacientes com SVCR.
Uma triagem foi realizada para excluir outras potenciais causas de declínio cognitivo. O desempenho nos testes foi considerado
como variável categórica, e o corte de -1,5 escore z foi adotado para indicar desempenho comprometido. Resultados: Sete pacientes
com diagnóstico de SVCR foram avaliados, os quais tinham todos nível de ensino superior e pontuação normal no Miniexame
do Estado Mental. A média de tempo entre o diagnóstico e a avaliação neuropsicológica foi de 1,8 ano. Dentre os pacientes,
85,6%(n=6) apresentaram desempenho comprometido em pelo menos dois dos testes aplicados. Especificamente, 71,4%
(n=5) apresentaram alterações nos testes da Bateria Psicológica para Avaliação da Atenção, com comprometimento observado
nas atenções concentrada (n=1), dividida (n=3), ou alternada (n=4). Além disso, 28,6% (n=2) demonstraram comprometimento
na Fluência Verbal Fonológica, 28,6% (n=2) exibiram dificuldades na cópia da Figura Complexa de Rey e um paciente obteve
desempenho alterado no Teste dos Cinco Dígitos, todos indicando disfunção executiva. Conclusão: Este estudo fornece evidência
de que o declínio cognitivo associado à SVCR é mais prevalente do que se acreditava anteriormente. Especialmente, os domínios
mais significativamente comprometidos foram a atenção e as funções executivas.
Palavras-chave: Vasoconstrição; Disfunção Cognitiva; Neuropsicologia; AVC Isquêmico.

This study was conducted by Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Department of Neurosciences and Behavioral Sciences, Ribeirão
Preto, São Paulo, Brazil.
1
Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Departamento de Neurociências e Ciências do Comportamento, Ribeirão Preto SP, Brazil.
2
Universidade Federal do Piauí, Hospital Universitário, Departamento de Medicina Especializada, Teresina PI, Brazil.
3
Universidade de São Paulo, Hospital das Clínicas, Instituto de Radiologia, São Paulo SP, Brazil.
4
Universidade do Estado do Piauí, Departamento de Psicologia, Teresina PI, Brazil.
5
Universidade de São Paulo, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Departamento de Psicologia, Ribeirão Preto SP, Brazil.
6
Universidade Federal do Delta do Parnaíba, Departamento de Neurologia, Paraíba PI, Brazil.
7
Universidade Federal de São Paulo Escola Paulista de Medicina, Departamento de Neurologia e Neurocirurgia, São Paulo SP, Brazil.
Correspondence: Icaro Araújo de Sousa; Email: [email protected].
Disclosure: The authors report no conflicts of interest.
Funding: none.
Received on December 09, 2023; Received in its final form on February 04, 2024; Accepted on February 29, 2024.

Sousa IA et al.   Neuropsychological aspects of reversible cerebral vasoconstriction syndrome.   1

 Dement Neuropsychol 2024;18:e20230117

INTRODUCTION was reviewed and approved by the Research Ethics

R eversible Cerebral Vasoconstriction Syndrome

(RCVS) is characterized by diffuse segmental con-
striction of the cerebral arteries that spontaneously
Committee of the Clinical Hospital of Ribeirão Preto
School of Medicine (CEP/HCFMRP), with approval
number 5.868.394.
resolves itself within three months. Typically, it usually
begins with acute and greatly intense and explosive Inclusion criteria
headache, known as a thunderclap headache, that can • Age equal to or above 18 years.
be associated with focal neurological deficits related to • Definitive diagnosis of RCVS according to criteria
swelling or cerebral ischemia1. Several names, such as defined by Calabrese et al. (2007). Angiogra-
“post-partum angiopathy”, “drug-induced angiopathy”, phy or indirect exam (Angio-MRI or CT) present-
and Call-Fleming syndrome, have been given to this con- ing multifocal segmental vasoconstrictions, acute
dition2-4. However, it was not until 2007 that Calabrese severe headaches with or without neurological
et al. proposed its current name and diagnostic criteria5. focal signs and complete reversibility of image
The clinical manifestation usually follows an acute findings after 12 weeks5.
and self-limited course without new symptoms after • RCVS2 (diagnostic score) applied to all patients12.
one month6. However, complications and neurological
comorbidities may occur during the acute phase of the Exclusion criteria
illness, mainly a few days after the onset of symptoms7. • Evidence of subarachnoid hemorrhage (SAH)
Although most patients recover well and vascular abnor- with aneurysmatic origin.
malities reverse spontaneously or after treatment with • Patients with cognitive impairment and anoth-
calcium-channel blockers, complications like extensive er cause that justifies its deficits: degenerative
ischemic lesions, cerebral swelling, severe morbidity, or diseases (Alzheimer’s, typical or atypical parkin-
death may also occur8-11. sonism, frontotemporal dementia), infectious
Yet none of these studies contain information about diseases (neurosyphilis, human immunodeficien-
such cognitive status of the individuals, not even re- cy virus [HIV] and acquired immunodeficiency
garding those who had complications and presented syndrome [AIDS]), or metabolic diseases (severe
persistent and significant neurologic deficits, after the hyperthyroidism, B12 deficiency, or alcohol-relat-
angiopathy recovery. Thus, despite the exponential ed dementia); suggestive findings in image exams
increase in knowledge about this disease in the past that justify the presence of cognitive decline or
years, little attention has been directed to the neuro- vascular dementia in any of the subtypes — se-
psychological aspects of RCVS. vere small vessel disease (radiologically defined as
This paucity of substantial evidence gave rise to sev- Fazekas scale grade II or III), strategic infarcts in
eral inquiries. Firstly, whether cognitive impairment is cerebral areas or multiple cerebral infarcts — ac-
a rare outcome of the disease or a prevalent issue that cording to the revised criteria of Sachdev et al.13.
has not been adequately studied yet. Secondly, whether • Presence of confirmed vasculitis by serological
there is a discernible pattern in cognitive occurrence or/and imaging tests.
among patients with RCVS. And thirdly, the central • Patients with severe depression, defined by Beck
question is whether RCVS could lead to neuropsycho- depression inventory (BDI), with a score >19,
logical compromise independently of its complica- without proper treatment14.
tions. Hence, the present study aimed to amplify the
understanding of cognitive dysfunctions in patients Analyzed clinical and radiological variables
with RCVS. Epidemiological and clinical data were assessed, such
as age, gender, and ethnicity; clinical data such as
trigger factors or condition of the frame, associated
METHODS complications, history of the thunderclap headaches
at the beginning of the condition, functionality
Participants evaluation, previous depression or anxiety, previous
Patients diagnosed with RCVS were recruited from migraine, neurological signs, and proposed therapeu-
practices or public hospitals in the cities of Teresina (PI) tic approach; and radiological, namely the presence
and Ribeirão Preto (SP). Those who agreed to participate of alterations in magnetic resonance imaging (MRI)
in the study signed the consent form and underwent and computed tomography (CT), presence of initial
a neuropsychological evaluation. This study protocol infarcts, presence of intraparenchymal hemorrhage

2   Neuropsychological aspects of reversible cerebral vasoconstriction syndrome.   Sousa IA et al.

 Dement Neuropsychol 2024;18:e20230117

(IPH), convexity subarachnoid hemorrhage (cSAH), was 47 standard deviation±13.2, and the most common
vasogenic edema, condition recurrence, and involved ethnicity was Latin (42.8%), followed by white and black
arterial encephalic segments. ethnicity (both 28.6%). Of the total, 71.4% of patients
had a trigger condition, and all were taking antidepres-
Neuropsychological evaluation sants (80.0% serotonergic antidepressants), with only
Initially, patients underwent the Mini-Mental State 28.6% using oral decongestants. Regarding the psychiat-
Examination (MMSE) as a screening test. The neuropsy- ric disorder, 71.4% had anxiety (n=4) or depression (n=1).
chological evaluation included a battery of assessments Only 28.5% of patients reported previous migraines.
formed by specific psychological and neuropsychological All patients exhibited thunderclap headaches at the
instruments recommended in the literature. The instru- beginning of their condition and most (71.4%) had
ments and evaluated cognitive domains are listed below: recurrence. Only one patient showed a focal neurolog-
• Semantic Verbal Fluency (SVF) test-Animals — ical deficit in the condition manifestation, which was
semantic fluency assessment15, also mental and characterized by left temporal hemianopsia. One single
cognitive flexibility related to the frontal lobe and patient exhibited a completely normal initial imaging
executive functions16. exam (CT or MRI). Regarding the radiological findings,
• Phonological Verbal Fluency (PVF) test — pho- 28.5% (n=2) of patients displayed ischemia in initial
nological fluency evaluation. It is sensible to exams, both at the right occipital location. cSAH in the
evaluate the frontal lobe functions17. initial exam was present in 57.1% (n=4) of patients.
• Boston Naming Test (BNT) — language assess- Only one had IPH in the left occipital location, associ-
ment in naming aspects and semantic memory18,19. ated with left parietal cSAH.
• Five-Digit Test (FDT) — processing speed evalu- Each patient underwent digital subtraction angi-
ation of attentiveness and executive functions20. ography (DSA) or angioresonance (MRA) imaging as a
• Rey Complex Figure (RCF) — planning, vi- brain vascular study. Only one did not exhibit initial al-
suo-constructive skills, and non-verbal cognitive teration in the vessels study (MRA), but the presence of
function assessment21. recurrent thunderclap headache associated with cSAH,
• Psychological Battery for Attention Assessment and consequently an RCVS2 score of 7, sustained the
(BPA) — general attention capacity assessment diagnosed hypothesis. None of the patients presented
and individually focused attention, divided at- internal carotid artery (ICA) intracranial involvement.
tention, and alternated attention22. The most frequently involved arteries were the anterior
• Beck Depression Inventory (BDI-II) — assess- cerebral artery (ACA) and middle cerebral artery (MCA),
ment of depression symptoms14. representing 57.1%, followed by the posterior cerebral
artery (PCA), with 42.9%. Apart from the patient who
The raw data of these instruments were transformed presented no alteration in the initial MRA, all the oth-
into Z-scores accordingly with normative values within ers exhibited vascular stenosis reversion. All patients
their age reference and schooling groups. Then it was displayed a good clinical outcome, demonstrated by
applied the Shapiro-Wilk test for a normality defini- modified ranking scale (mRS) scores of zero or one.
tion in the sample results. For the normal samples, Interestingly, one patient had a relapse in the condition
it was selected a cutoff of -1.5 Z-score as a definition approximately three years after the initial event.
of performance below the normal population. For the All patients had an RCVS2 score ≥5. Concerning the
samples that did not follow the regular distribution, it appointed treatment, 71.4% (n=5) received nimodipine
was considered an inferior performance result, those in the acute phase, one patient received verapamil, and
below the 10th percentile. Next, those variables were another received other medications. Table 1 summa-
classified above or below the respective cutoff value for rizes the main clinical/radiological characteristics of
impairment. Accordingly, the patients’ performance the patients.
were considered a categorical variable.
Neuropsychological evaluation
The transformation of raw data into Z-scores was made,
RESULTS presenting the achievement of each patient individ-
ually in each of the neuropsychological tests applied.
Epidemiological, clinical, and radiological data All patients had bachelor’s degrees and normal MMSE
Seven patients diagnosed with RCVS were analyzed, of scores ≥28. The time average between RCVS diagnosis
whom 85.7% (n=6) were female. The patients’ average age and neuropsychological evaluation was 1.8±1.05 years.

Sousa IA et al.   Neuropsychological aspects of reversible cerebral vasoconstriction syndrome.   3

 Table 1. Epidemiological, clinical, and radiological data from the patients.
Angio­
Clinical Trigger Prior Initial Intracranial mRS
Initial CT Angiography Artery graphic RCVS2
Patient presentation Gender Age Race associated comorbi­ MRI ICA invol­ at dis­ Recurrence Treat­ment
findings modality involved rever­ score
at onset condition dities findings vement charge
sibility
TCH +
Not Convexity Bilateral Other
1 confusional Female 59 Black Sertraline Depression DSA No Yes 0 No 10
performed SAH ACA medications
state
Convexity Bilateral
Recurrent Hispanic/ Convexity SAH, MCA,
2 Female 48 Absent Absent MRA No No 0 No 7 Nimodipine
Dement Neuropsychol 2024;18:e20230117

TCH Latin SAH vasogenic bilateral

edema PCA
Left
parieto-
Recurrent Decongestant occipital Not Bilateral
3 Female 49 Black Anxiety DSA No Yes 0 Yes 10 Nimodipine
TCH and fluoxetine IPH, performed ACA
convexity
SAH
Right
Right MCA
TCH at wake Not
4 Male 47 White Absent Absent occipital MRA No (M2), Yes 0 No 5 Nimodipine
up performed
infarct right
PCA (P2)

4   Neuropsychological aspects of reversible cerebral vasoconstriction syndrome.   Sousa IA et al.

Bilateral
ACA.
Recurrent Hispanic/ Anxiety and Bilateral
5 Female 30 Sertraline Normal Normal DSA No Yes 0 No 9 Verapamil
TCH Latin migraine MCA,
bilateral
PCA
Recurrent Right Right
Hispanic/ Anxiety and Right
6 TCH + Female 31 Trazodone occipital occipital MRA No Yes 1 No 9 Nimodipine
Latin migraine PCA (P1)
hemianopsia infarct infarct
Recurrent
TCH + Convexity Bilateral
persistent Sertraline and Convexity SAH, DSA and ACA,
7 Female 65 White Anxiety No Yes 0 No 10 Nimodipine
headache isometheptene SAH vasogenic MRA bilateral
with edema MCA
drowsiness
Abbreviations: ACA, anterior cerebral artery; CT, computed tomography; ICA, internal carotid artery; IPH, intraparenchymal hemorrhage; MCA, middle cerebral artery; MRI, magnetic resonance imaging; mRS, modified ranking scale; PCA, posterior
cerebral artery; SAH, subarachnoid hemorrhage; TCH, thunderclap headache; RCVS2, reversible cerebral vasoconstriction syndrome diagnostic score; DSA, digital subtraction angiography; MRA, magnetic resonance angiography.
 Dement Neuropsychol 2024;18:e20230117

Among the assessed patients, 85.7% (n=6) exhibited Our population has characteristics similar to the
an output below the normal population in at least two cohorts described in the literature, especially relating to
of the instruments in one cognitive domain or differ- age average (47 vs 42 years); female prevalence; associat-
ent ones. Specifically, 71.4% (n=5) showed alterations ed triggers (vasoconstrictor medication and serotoner-
in tests from the BPA, with impairments observed in gic antidepressants); clinical presentation (thunderclap
concentrated (14.2%), divided (42.3%), or alternating headaches); and prognosis, which is favorable in most
(57.1%) attention. Furthermore, 28.6% (n=2) demon- cases6. Specifically, regarding associated comorbidities
strated impairments in the PVF task, another 28.6% (psychiatric disorders), it could be inquired whether
(n=2) exhibited difficulties copying elements of the RCF, these would not alter the neuropsychological perfor-
and 14.3% (n=1) displayed lower performance in the mance of the patients, once these disorders may be the
FDT, all indicating executive dysfunction. The frequency cause of cognitive complaints (mostly depression) and
of compromised performance on these neuropsycho- since studies suggest that anxiety disorder alone does
logical instruments is presented in Figure 1. It can be not cause cognitive decline25. However, of the five pa-
remarked that none of the patients exhibited alterations tients that took antidepressants, four were prescribed
in SVF, BNT, and RCF memory. because of anxiety disorder and only one because of
When assessed individually, patients 4, 6, and 7 dis- depression; besides, all were being treated for at least
played inferior achievements only in BPA tests; patient 2 six months. The patient with depression presented with
exhibited inferior achievement in BPA and RCF (copy); pa- a BDI-II <19 and was receiving adequate treatment for
tient 5 presented inferior achievement in PVF, RCF (copy), more than six months.
and BPA. The graph in Figure 2 and Supplementary Mate- Concerning radiological findings, most patients
rials (https://www.demneuropsy.com.br/wp-content/up- (n=4) had hemorrhagic complications, with three of
loads/2024/05/DN-2023.0117-Supplementary-Materials. them presenting cSAH alone and one presenting cSAH
zip) represents the individualized achievement of each and IPH, in the locations occipito-parietal and parietal,
patient in the applied neuropsychological tests. respectively, both of small volume and occurring in the
left hemisphere. Curiously, this patient was the only
that presented no alteration on the neuropsychological
DISCUSSION tests. RCVS is commonly associated with hemorrhagic
We described a case series of patients diagnosed with complications, the main one being cSAH followed by
RCVS who underwent neuropsychological evaluation. IPH, and is rarely associated with cerebral ischemia26.
Most presented an inferior outcome in tests related to In our study, we conducted a comprehensive assess-
attention and executive functions in cognitive domains. ment of neuropsychological test results in patients
To date, only one complete study had addressed this is- with cSAH, revealing that three out of four exhibited
sue, which described a young patient who had multi-do- cognitive performance alterations. This intriguing
main impairment initiated a few months after the syn- finding raises questions about the relationship between
drome. There is also a second case report, available only the location of cSAH and cognitive decline in individ-
in abstract, which described dysfunction in visuospatial uals diagnosed with RCVS. While it is established that
skills beyond what is expected due to the parenchymal spontaneous subarachnoid hemorrhage is linked to
lesion formed after resolution of vasoconstriction23,24. cognitive decline, the evidence connecting cSAH to
cognitive decline beyond cerebral amyloid angiopathy
(CAA) remains limited27. However, it is crucial to em-
phasize that our findings do not definitively establish a
causal link between cSAH and cognitive decline in RCVS
patients. The extent to which cSAH may contribute to
cognitive impairment in individuals with RCVS remains
uncertain, and further research is needed to explore
this potential association.
In the context of neuropsychological aspects, in our
Abbreviations: BPA, Psychological Battery for Attention Assessment; BPA (AA),
study, it is important to highlight that the relatively
BPA alternated attention; BPA (DA), BPA divided attention; BPA (FA), BPA focused
attention; BPA (GA), BPA General Attention; FDT (I), Five-Digit test (inhibition);
good performance observed in the MMSE within our
PVF, Phonological Verbal Fluency; RCF, Rey Complex Figures. sample may be due to its lower sensitivity in individ-
Figure 1. Number of patients for each compromised uals with higher education levels, as well as its limited
performance on neuropsychological tests. assessment of attention and executive functions28,29.

Sousa IA et al.   Neuropsychological aspects of reversible cerebral vasoconstriction syndrome.   5

 Dement Neuropsychol 2024;18:e20230117

Abbreviations: SVF, Semantic Verbal Fluency; PVF, Phonological Verbal Fluency; BNT, Boston Naming Test; FDT, Five-Digit test; FDT (R), FDT reading; FDT (C), FDT counting; FDT (CH),
FDT choice; FDT (A), FDT alternation; FDT (I), FDT inhibition; FDT (F), FDT flexibility; RCF, Rey Complex Figures; RCF (C), RCF copy; RCF (M), RCF memory; BPA, Psychological Battery
for Attention Assessment; BPA (FA), BPA focused attention; BPA (D), BPA divided attention; BPA (A), BPA alternated attention; BPA (GA), BPA general attention.
Figure 2. Individual performance of all patients on each neuropsychological test.

This emphasizes the necessity of including comprehen- might have led to an underestimation of cognitive
sive neuropsychological assessments when evaluating decline, particularly in light of findings from Perdices
patients with RCVS who report cognitive complaints. and Herkes24, suggesting that cognitive decline can
Additionally, we acknowledge the potential limitation manifest significantly within the first few months fol-
of our study, which is the approximately 1.8-year gap lowing the event. To definitively address this concern,
between the onset of symptoms and the administra- a prospective study conducted immediately after the
tion of neuropsychological assessments. This duration resolution of the RCVS condition would be required.

6   Neuropsychological aspects of reversible cerebral vasoconstriction syndrome.   Sousa IA et al.

 Dement Neuropsychol 2024;18:e20230117

Nevertheless, the persistence of cognitive impairment patient (5). None of the patients presented abnormal
beyond one year in our cohort raises the possibility that performance in BNT and in the memory of RCF. Thus, in
this clinical finding could be associated with persistent our population, cognitive functions of language and
post-RCVS symptoms. Notably, previous research has visual memory, at first, seemed preserved. Therefore, it
demonstrated a 50% prevalence of headache persisting is possible to conclude that the most affected cognitive
after three months of vasoconstriction resolution, with domains in our population were attention and executive
half of these patients requiring drug therapies for up to functions — both primarily located in the frontal lobe.
two years30. Given our study’s primary goal of assessing The profile of neuropsychological impairment in this
chronic and potentially permanent cognitive decline study differs from the report by Perdices and Herkes24,
associated with RCVS, we believe that our chosen time- which besides presenting selective executive function
frame was appropriate. deficits and a mild attentional deficit, revealed a severe
The main affected cognitive domain of patients was decline in learning, delayed recall, and autobiographical
attention, evaluated by BPA tests (Figure 1). Attention is memory. Possibly, we did not observe similar patterns in
a cognitive domain that has a complex organization our patient group due to the absence of a more in-depth
of multiple cerebral networks. Among them, is the investigation into learning and memory.
dorsal attention network, associated with attention’s Furthermore, despite the wide age range in our
external direction, related to the prefrontal cortex, population (30–65 years), our average age closely
ventral premotor, parietal, and temporal; the network aligns with that reported in the RCVS literature.
“default mode”, related to attention’s internal direc- We constructed the neuropsychological battery using
tion, associated with the prefrontal ventromedial area, tests with normative values adjusted for age and ed-
inferior parietal and posterior cingulate cortex; and ucation, suggesting that age was not a decisive factor
the executive frontoparietal network that involves the in cognitive decline. The elderly patient in our sample
lateral prefrontal cortex, anterior cingulate cortex, and also performed satisfactorily in tests assessing various
inferior parietal31,32. cognitive domains (excluding attention), suggesting the
Next, the PVF and RCF tests exhibited a higher absence of other common causes of cognitive decline in
prevalence of abnormal performance (Figure 1); the individuals of this age group.
fluency tests are essentially used for measuring execu- Regarding the physiopathological mechanism,
tive function, and the PVF is sensible to assess frontal current literature does not allow the establishment
lobe functions, especially the left pre-frontal areas. of neuropathological bases of how RCVS would cause
However, as previously mentioned, RCF is a test that cognitive impairment independently of its structural
allows the assessment of several domains such as visuo- complications, but it is possible an association with
constructive functions, executive functions, and visual cerebral vasoconstriction, as suggested by Perdices
memory16,20. Particularly on the figure copying task, and Herkes24. In our population, as described, the main
there is a specific recruitment of cognitive functions, cerebral region related to inferior performance in the
like operative memory, inhibitory control, sustained neuropsychological tests was the frontal lobe, and six
attention, deep concentration, and information orga- patients presented involvement of arteries of anterior
nization. These activities are intimately related to the circulation (ACA, MCA, or both). However, since it
frontal lobe functions and their connections, especially regards complex cerebral functions, in which there is
with the occipital and parietal, and they are related to a wide neuron network involved, it is hard to establish
executive functions32,33. Therefore, it is likely that the a precise cause between the cognitive domains and
affected cognitive domains in these patients are the ex- impaired arteries.
ecutive functions and the visuoconstructive ability with If in the macroscopic field, the answer is uncertain,
relative preservation of non-verbal memory. Yet there the molecular field can provide some clarification. It is
were no patients with alterations in evocation (second known that the vasoconstriction action of catechol-
stage) of the RCF test. amines and endothelin-1 in the abrupt deregulation
Lastly, only one patient presented an abnormal per- of cerebral vascular tonus is one of the component
formance at FDT, which assesses, among other abilities, mechanisms of RCVS’ proposed physiopathology34.
the attention interference effect (Stroop effect), using Besides, an experimental study with rats assessed the
conflicting information about numbers and quantities20. effect of intraventricular injection of endothelin-1 on
The compromise in inhibitory control for cognitive in- the cognitive performance of these animals, and after
terference is common in executive dysfunction, which seven days from the injection, there was an episodic
was also evident in the PVF alteration in this same memory decline. It also exhibited the reduction in CD31

Sousa IA et al.   Neuropsychological aspects of reversible cerebral vasoconstriction syndrome.   7

 Dement Neuropsychol 2024;18:e20230117

expression in endothelial cells in the vessels surround- difficult. Second, some cognitive domains were less
ing the hippocampus and the “downregulation” of the represented by our neuropsychological test battery, like
cell signaling cascade proteins Akt1-mTOR, which led visuospatial functions and verbal memory, although
to the loss of activity-dependent protein translation, they have been assessed indirectly. Further studies
an essential factor in synaptic activity. Thus, this study with a larger population and representativeness of the
shows that vasoconstriction may lead to cognitive cognitive domains are necessary to clarify more about
function decline and poses protein translation as a key cognitive dysfunction in RCVS patients.
mechanism in synaptic plasticity. Curiously, this effect In conclusion, this study provides evidence that
reverted after 30 days35. Still, in the molecular field, cognitive impairment associated with RCVS is more
there has been a significant growth in the physiopathol- prevalent than previously believed and has not received
ogy of neurological diseases and microribonucleic acids sufficient attention. Importantly, attention and exec-
(miRNAs). The miRNAs are small non-coding RNAs that utive functions are the cognitive domains most sig-
regulate gene expression and are, presently, promising nificantly impacted by RCVS. These results underscore
targets for interventions and mighty cell function the need for increased recognition and consideration
regulators. Recently, some specific miRNAs were asso- of cognitive deficits in patients with RCVS to ensure
ciated with hematoencephalic barrier dysfunction and appropriate management and intervention strategies.
cerebral vasomotor tonus loss in patients with RCVS36.
Besides, evidence suggests a central role of miRNAs
in mechanisms associated with the pathogenesis of AUTHORS’ CONTRIBUTIONS
vascular dementia, like in the regulating function of IAS: conceptualization, data curation, investigation,
hematoencephalic barrier, apoptosis, oxidative stress, writing – original draft. AFA: data curation, project
and neuroinflammation; and this has indicated these administration. AOV: data curation, resources, soft-
structures as potential biomarkers for cognitive de- ware. MLBA: investigation, visualization. EPSN: data
cline37. Thus, miRNAs may be involved in the decline curation, investigation. MANM: data curation, meth-
mechanisms associated with RCVS. odology. MPF: data curation, methodology, visualiza-
Our results should be interpreted in the context of tion. RPSN: visualization, writing – review & editing.
the study design. First, the small number of patients IFR: conceptualization, investigation, visualization,
hinders any analytical statistics, although the rarity writing – review & editing. OMPN: supervision, writing
of the disease makes studies with large populations – review & editing.

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