UNIVERSIDADE ESTADUAL PAULISTA 
“JÚLIO DE MESQUITA FILHO” 

FACULDADE DE MEDICINA 
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  

Gustavo José Luvizutto 
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  

Investigação de negligência espacial unilateral após 
Acidente Vascular Cerebral 

	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  

Tese apresentada à Faculdade 
de Medicina, Universidade 
Estadual Paulista “Júlio de 
Mesquita Filho”, Câmpus de 
Botucatu, para obtenção do título 
de Doutor em Bases Gerais da 
Cirurgia. 

	
  
	
  	
  
	
  	
  
	
  	
  
	
  	
  
	
  
	
  

Orientador: Prof. Dr. Luiz Antônio de Lima Resende 

 
 
 

Botucatu 
2016 



	
    
2 
	
  

	
  
	
  	
  	
  	
  

	
  	
  
	
  
	
  

	
  

Gustavo José Luvizutto 
 
 
 
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  

Investigação de negligência espacial unilateral 
após Acidente Vascular Cerebral 

	
  	
  
	
  

	
  
	
  
	
  
	
  
	
  
Tese apresentada à Faculdade 
de Medicina, Universidade 
Estadual Paulista “Júlio de 
Mesquita Filho”, Câmpus de 
Botucatu, para obtenção do título 
de Doutor em Bases Gerais da 
Cirurgia. 

	
  
	
  	
  
	
  	
  
	
  	
  
	
  	
  
	
  
	
  

Orientador: Prof. Dr. Luiz Antônio de Lima Resende 
 
 
 
 

Botucatu 
2016 

 



	
    
3 
	
  

 
 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
FICHA CATALOGRÁFICA ELABORADA PELA SEÇÃO TÉC. AQUIS. TRATAMENTO DA 

INFORM. DIVISÃO TÉCNICA DE BIBLIOTECA E DOCUMENTAÇÃO - CÂMPUS DE 

BOTUCATU - UNESP 

BIBLIOTECÁRIA RESPONSÁVEL: ROSEMEIRE APARECIDA VICENTE-CRB 8/5651 

 

 

 

 

Luvizutto, Gustavo José. 

Investigação de negligência espacial unilateral após 
Acidente Vascular Cerebral / Gustavo José Luvizutto. - 
Botucatu, 2016 

 

Tese (doutorado) - Universidade Estadual Paulista 
"Júlio de Mesquita Filho", Faculdade de Medicina de 
Botucatu 

Orientador: Luiz Antônio de Lima Resende 
Capes: 40101070 

 

1. Acidente vascular cerebral - Tratamento. 2. Cérebro 

- Doenças - Diagnóstico. 3. Cérebro - Ferimentos e lesões. 

	
  

	
  

	
  

Palavras-­‐chave:	
  Acidente	
  vascular	
  cerebral;	
  Negligência	
  espacial	
  
unilateral;	
  Normatização;	
  Testes	
  diagnósticos.	
  



	
    
4 
	
  

 

 

Dedicatória 

 

 

 

 

Dedico este trabalho aos meus pais – José Francisco Luvizutto e Inês 

de Fátima Gonsales Luvizutto, que de toda sua luta, construíram o ser 

humano que sou.	
  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



	
    
5 
	
  

 

Agradecimentos 

 

Ao Professor Luiz Antônio, meu orientador, pelos ensinamentos 

científicos, horas de eterno saber e aconselhamento pessoal; 

 

Ao Dr. Rodrigo Bazan, amigo e docente da disciplina de Neurovascular, 

o qual tenho enorme honra em aprender com sua determinação e luta 

diária por uma ciência de qualidade, com apoios constantes em minha 

carreira; 

 

Aos funcionários da pós-graduação, Regina (aposentada), Márcia, 

Janete, Lílian, Diego, minha gratidão por todo apoio científico e 

burocrático; 

 

Aos funcionários do comitê de ética e pesquisa (Beto e Kléber) pela 

disposição em auxiliar em todas as etapas éticas do projeto; 

 

Aos funcionários do Departamento de Neurologia, Psicologia e 

Psiquiatria, Vanessa, Geraldo, Adriano e Vanderci (aposentada) por 

todo apoio durante o período do doutorado. 

 

Aos funcionários da biblioteca pela disposição na estratégia de busca e 

pesquisa de periódicos; 

 

À Prof. Regina El Dib por aprender como realizar uma revisão 

sistemática de qualidade; 

 

 

 

 



	
    
6 
	
  

 

Ao centro Cochrane do Brasil, ao grupo de medicina baseado em 

evidência da Faculdade de Medicina de Botucatu e ao grupo Cochrane 

Stroke em nome da coordenadora Hazel Fraser pelo acompanhamento 

da revisão sistemática; 

 

Aos alunos de iniciação científica do curso de Medicina (Rodolfo 

Theotonio e Marcelo Fogaroli) pelo apoio na coleta de dados; 

 

Aos amigos, em especial, Josiela, pela companhia frequente em minha 

vida pessoal; Tamiris, pela amizade constante e apoio na coleta do 

doutorado; Sandrinha, pela dedicação ao atendimento dos pacientes em 

momentos de ausência para execução desta tese; e ao Robson que me 

auxiliou e orientou em todo crescimento pessoal durante este período. 

 

Aos funcionários da Fisioterapia, pelo apoio assistencial aos pacientes 

durante o doutorado; 

 

Aos docentes do Departamento de Neurologia, Psicologia e Psiquiatria 

pelos ensinamentos em Neurologia e apoio à pesquisa clínica de 

qualidade; 

  

Aos docentes da pós-graduação em bases gerais da cirurgia pelas 

orientações acadêmicas e profissionais;  

 

À Sandra Volpi, pela liberação aos cumprimentos dos créditos no 

programa de pós-graduação, apoio constante ao meu crescimento 

profissional durante o período de chefia do núcleo de Reabilitação; 

 

 

 



	
    
7 
	
  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
 
 

"Deus é um círculo cujo centro está em toda parte e cuja circunferência 

não está em nenhum lugar"  
 

Empédocles 



	
    
8 
	
  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Resumo da tese 
 

 



	
    
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Introdução: A negligência espacial unilateral (NEU) é caracterizada pela 

incapacidade de reportar ou responder pessoas ou objetos do lado contralateral à 

lesão cerebral, e ocorre principalmente após Acidente Vascular Cerebral (AVC) do 

lobo parietal direito, sendo associada à pior desfecho funcional à longo prazo. 

Objetivo: Os objetivos desta tese foram: normatizar os principais testes 

diagnósticos de NEU e verificar a relação com fatores sócio-demográficos na 

população brasileira; avaliar as variáveis bioquímicas que interferem na NEU na 

fase aguda do AVC; e revisar sistematicamente os principais tratamentos 

farmacológicos na NEU em pacientes após AVC. Método: Para o primeiro objetivo 

foi realizado estudo transversal em 150 indivíduos sem alterações neurológicas, 

sendo aplicados: teste face-mão (TFM), testes de cancelamento de linhas (TCL), 

cancelamento de estrelas (TCE) e bisseção de linhas (TBL). Os resultados dos testes 

foram relacionados com o perfil sócio demográfico da população, sendo estipulado 

pontos de cortes para a normalidade; para o objetivo 2 foi realizado estudo 

observacional em 40 indivíduos com diagnostico de NEU após AVC. Foram 

aplicados os TCL, TCE e TBL, sendo relacionado com o nível de hemoglobina na 

fase aguda do AVC corrigido para potenciais confundidores; para o objetivo 3 foi 

realizado revisão sistemática de literatura por meio de ensaios clínicos 

randomizados e quasi-randomizados para determinar o melhor tratamento 

farmacológico. Resultados: os resultados do objetivo 1 estão apresentados nos 

artigos 1 e 2; o objetivo 2 no artigo 3; e o objetivo 3 no artigo 4. Conclusão: Com 

base nos resultados obtidos dos artigos 1 e 2, o TFM apresenta taxa de normalidade 

entre 8 a 10 estímulos sensoriais, com prevalência de extinção associada com o grau 

de escolaridade e aumento da idade; no TCL o ponto de corte para considerar NEU 

é acima de 0 e no TCE acima de 2, ambos associados à idade. No TBL o ponto 

médio de corte para considerar NEU foi de 6,6 mm, associado com pior 

escolaridade. No artigo 3 foi observado que quanto menor o valor de hemoglobina 

na fase aguda do AVC, pior o desempenho nos testes de NEU; No artigo 4 foi 

observado que a efetividade e segurança dos tratamentos farmacológicos para NEU 

após AVC permanecem incertos, necessitando de ensaios clínicos randomizados 

adicionais para avaliar o efeito deste tratamento. 

Palavras-chave: Negligência espacial unilateral; normatização; Acidente vascular 

cerebral; testes diagnósticos; prognóstico; reabilitação; tratamento farmacológico. 



	
    
10  

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Abstract 
 



	
    
11  

 
Background: Unilateral spatial neglect (USN) is characterized by the inability to 

report or respond to people or objects presented on the side contralateral to the 

lesioned side of the brain and has been associated with poor functional outcomes. 

Objective: The objectives of this thesis were: to standardize the USN tests and 

verify the relationship with socio-demographic data in the Brazilian population; 

evaluate the biochemical variables that influence in USN tests after acute stroke; 

and systematically review the pharmacological interventions to treat USN after 

stroke. Method: For the first aim, we performed a cross-sectional study of 150 

individuals without neurological changes by applying: face-hand test (FHT), line 

cancellation test (LCT), star cancellation test (SCT) and line bisection test (LBT). 

The test results were related to the sociodemographic data, with cutoff points being 

stipulated to define USN; the second aim was achieved by conducting an 

observational study of 40 individuals with USN after acute stroke. The tests applied 

– LCT, SCT and LBT – were correlated with the hemoglobin level in the acute 

phase of stroke corrected by confounders; the third aim was analyzed by a 

systematic review of randomized controlled trials and quasi-randomized clinical 

trials to determine the efficacy of pharmacological intervention. Results: The first 

aim is presented in Articles 1 and 2, the second aim in Article 3 and the third in 

Article 4. Conclusion: Based on the results of Articles 1 and 2, the FHT shows 

normal rate between 8-10 sensory stimuli, with an extinction prevalence associated 

with the education level and increasing age; The LCT cutoff point to define is USN 

above 0 and SCT above 2, and both were associated with age. The LBT cutoff point 

to indicate NEU was 6.6 mm, associated with poorer education level. Article 3 

reveals the relationship between a lower hemoglobin level in acute phase of stroke 

with worse performance on USN tests; Article 4 reports that the effectiveness and 

safety of pharmacological treatments for USN after stroke remain uncertain, 

requiring additional randomized clinical trials to evaluate the effect of treatment. 

Keywords: stroke; unilateral spatial neglect; standardization; stroke; diagnostic 

tests; prognosis; rehabilitation; pharmacological treatment. 

 

 

 



	
    
12  

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 

 
 
 
 

 

Conteúdo 
 

 
 



	
    
13  

 
 
 
 
 
 
 

Artigo científico 1  . . . . . . . 14 
 
 

Artigo científico 2  . . . . . . . 32 
 
 

Artigo científico 3  . . . . . . . 53 
 
 

Artigo científico 4  . . . . . . . 67 
 
 

Aprovação do Comitê de Ética e Pesquisa  . . . 127 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 



	
    
14  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Artigo científico 1 
 



	
    
15  

 
 

Standardization of the face-hand test in a Brazilian population: prevalence of 

sensory extinction and implications for neurological diagnosis 

 

Short title: Standardization of the face-hand test in a Brazilian population 

 

M.Sc. Gustavo José Luvizutto¹, Marcelo Ortolani Fogaroli2, Rodolfo Mazeto 

Theotonio2, M.Sc. Hélio Rubens de Carvalho Nunes 3, PhD. Luiz Antônio de Lima 

Resende4, PhD. Rodrigo Bazan4 

 

1Neurorehabilitation. Univ. Estadual Paulista – UNESP – Botucatu Medical School. 

2Medicine student. Univ. Estadual Paulista – UNESP – Botucatu Medical School. 

3Department of Public Health. Univ. Estadual Paulista – UNESP – Botucatu Medical 

School. 

4 Departament of Neurology, Psicology and Psychiatry. Univ. Estadual Paulista – UNESP – 

Botucatu Medical School. 

 

Corresponding author: 

M.Sc. Gustavo José Luvizutto, Neurorehabilitation, Univ. Estadual Paulista – 

UNESP – Botucatu Medical School. Botucatu, SP, 18618-970, Brasil Fax number: 

+55 14-38116049E-mail: gluvizutto@fmb.unesp.br 

 

Conflicts of interest: none 

Grant support: none 

 

 

 



	
    
16  

 

Abstract 

 

Background: The face-hand test (FHT) is a simple test with high sensitivity to 

detect psychiatric syndromes and unilateral spatial neglect after stroke. Objective: 

to standardize the FHT in a Brazilian population and relate the results to the 

sociodemographic data. Methods: This is a cross sectional study with 150 

individuals. Sociodemographic variables included age, gender, race, body mass 

index (BMI), and years of education. Standardization of the FHT occurred in 2 

rounds of 10 sensory stimuli, and the associations between FHT and 

sociodemographic variables were analyzed using Mann-Whitney tests and 

Spearman correlations. Binomial models were adjusted for the number of FHT 

variations and ROC curves evaluated sensitivity and specificity of sensory 

extinction. Results: There was no significant relationship between the 

sociodemographic variables and the number of stimuli perceived on the FHT. There 

was a high relative frequency of detection for 8 of 10 stimuli in this population. 

Sensory extinction was 25.3%, which increased with increasing age (OR=1.4[1:01–

1:07];p=0.006) and decreased significantly with increasing education 

(OR=0.82[0.71-0.94];p=0.005). Conclusion: A normal FHT score range between 

8–10 stimuli, and indicate that sensory extinction is associated with increased age 

and lower levels of education in the Brazilian population. 

 

Keywords: face-hand test; sensitivity; diagnosis; psychiatric syndromes; unilateral 

spatial neglect. 

 

 



	
    
17  

 

Introduction 

 Bender et al. (1950) developed the face-hand test (FHT) in order to 

investigate specific patterns of neurological disorders through dual concurrent 

sensory stimulation of the face and back of the hand [1]. They found that the FHT 

had 2 response patterns: sensory extinction (only one stimulus is recognized by the 

individual) or displacement (stimuli are recognized elsewhere in the body). Based 

on these findings, the FHT was proposed as a tool for assessing patients with 

psychiatric and neurologic diseases [2-3]. 

 The first standardization of the FHT occurred in 1969, based on results from 

3 groups of volunteers who were categorized by age (3–6 years old, 7–12 years, and 

older than 12 years). The results of the FHT in these 3 groups were compared to the 

FHT scores of patients with schizophrenia, organic psychosis, or aphasia. The 

authors concluded that the most common errors occurred for sensory extinction of 

face dominance in patients with organic psychosis and children who were 3–6 years 

old [4-5]. 

 The FHT has also been used to diagnose perceptual neurological syndromes, 

such as for clinical differential diagnosis of unilateral spatial neglect (USN). 

Feinberg et al. (1990) evaluated the FHT scores of patients with unilateral 

hemispheric lesions 3 months after stroke, finding both contralateral and ipsilateral 

USN in patients with right hemisphere lesions. However, similar findings did not 

occur in patients with lesions to the left hemisphere [6]. These findings are 

important to explaining ipsilateral extinction and indicate a role of the right 

hemisphere in the mechanisms of spatial attention. The findings also support that 

the test is precise enough to detect changes in the perceptions of individuals with 

neurological conditions [7-10]. 



	
    
18   

 

 The FHT is a simple test, as well as being practical and fast, with high 

sensitivity to detect psychiatric syndromes and USN after stroke. However, the FHT 

has not previously been assessed in a Brazilian sample; therefore, the objective of 

the present study was to standardize the FHT for use in the multi-cultural population 

of Brazil, as well as to identify the main sociodemographic factors affecting the test 

results. The central hypothesis was that sensory stimuli scores of approximately 10 

are typical in the population, and that abnormal patterns on the FHT, such as 

sensory extinction and displacement, may be associated with lower education levels. 

 

Patients and methods 

Participants 

This cross-sectional study included graduate students, professionals and 

patients at the Clinics Hospital of Botucatu (UNESP) between March 2013 to July 

2015. The persons were recruited through direct contact with the researcher 

followed by invitation to participate in the study. 

The study was approved by the Ethics in Human Research Committee, under 

protocol 4223/2012, and all participants gave written informed consent. Participants 

met the following inclusion criteria (Figure 1): right handed, no history of 

neurological disease in central and peripheral nervous system, systemic infections, 

no to be in use psychotropic drugs or antidepressants, conscious during testing with 

Glasgow Coma Scale of 15, and with a score > 24 on the Mini-Exam Mental State 

Examination (MMSE). The MMSE cutoff score was selected in order to correspond 

with the most commonly used value in clinical and epidemiological studies of 

dementia in Brazil [11-13]. 

 



	
    
19  

Study variables  

The sociodemographic data obtained during interviews with patients were as 

follows: age (years), gender (men and women), race (Caucasian and non-

Caucasian), body mass index (BMI, kg/m2), and years of education. 

Standardization of the FHT was performed with the participant seated to 

support the trunk, occluded vision, and in a sound-controlled environment. The 

FHT was conducted by applying 2 rounds of 10 sensory stimuli through cotton in a 

craniocaudal direction at the 3rd metacarpal, followed by 10 stimuli applied to the 

cheek region of the face and 10 simultaneous stimuli applied to the face and hand. 

All stimuli were initially applied on the left side, and then applied on the right. The 

stimulus intensity could not be measured objectively, but we did have the same 

researcher apply all stimuli, in order to reduce the potential for confounding effects. 

Finally, the number of rings and the location of touch perceived by the individual in 

each testing segment were categorized as normal sensory extinction or 

displacement. Table 1 shows the sequence of stimuli applied during the FHT. 

 

Table 1. Sequences of stimuli applied during the face-hand test (FHT). 

1st  round of stimuli: 

1. 10 sensory stimuli to the left hand 

2. 10 sensory stimuli to the left face 

3. 10 sensory stimuli to the left face and the left hand 

2nd  round of stimuli: 

4. 10 sensory stimuli to the right hand 

5. 10 sensory stimuli to the right face 

6. 10 sensory stimuli to the right hand and the right face 

 

 

 

 



	
    
20  

Statistical analyses 

 Since we are using a sample representative of the target population, our 

sampling is considered to be intentional and non-probabilistic. We needed a 

minimum of 150 subjects to obtain a maximum sampling error of 7.5% and a 

confidence level of 95%	
  based on a pilot study with 20 subjects. The comparison 

between FHT scores and the sociodemographic variables gender and race were 

analyzed using nonparametric Mann-Whitney tests. The associations between FHT 

scores and age, BMI, as well as years of education were assessed using Spearman 

correlations. The correlations was classified as a poor (0.20), fair (0.20–0.39), 

moderate (0.40–0.59), good (0.60–0.79), and excellent (>0.8). An adaptation of the 

binomial distribution assumption was used to model the perceived number of 

touches, followed by calculating maximum likelihood estimates for the binomial 

distribution parameters for each variation of the FHT. The relationships between 

sociodemographic variables and sensory extinction on the FHT were analyzed by 

multiple logistic regression, adjusted for age and years of education. After 

adjustments, receiver operating characteristic (ROC) curves were calculated for age 

and years of education, in order to establish values that maximize the sensitivity and 

specificity of sensory extinction on the FHT. Associations were considered 

statistically significant if p < 0.05. Analyses were performed using SPSS software 

(version 21.0, SPSS, Chicago, IL, USA). 

 

 

 

 

 

 



	
    
21  

Results 

 We evaluated and screened 250 individuals, but only 150 participants met 

the inclusion criteria for the study (Figure 1).  

 

 

 

 

 

 

 

 

 

 

 

Figure 1 - Screening process indicating patients excluded from the study. 
 

 

 

The sociodemographic characteristics and face-hand test examination of the 

participants are presented in Table 2. Tables 3 and 4 demonstrate that there were no 

significant associations between FHT scores and sociodemographic variables 

including gender, race, age, BMI, and years of education. 

 

 

 

 

 

 

 

250 individuals 

150 individuals 

Bad conscience level: n = 19 
 
Use of psycotropics: n = 8 
 
Use of antidepressants: n = 16  
 
MMSE < 24: n = 57 



	
    
22  

Table 2. Sociodemographic characteristics and performance of subjects in FHT 

(n=150). 

 
Variable Summary 

Gender (women:men) 76 (50.7%):74 (49.3%) 

Race (Caucasian:non-Caucasian) 112 (74.7%):38 (25.3%) 

Years of education¹ 11(6–16) 

Age1 (years) 31.5 (18.0–87.0) 

BMI1 (kg/m2) 22.9 (11.7–35.9) 

F-r1 10.0 (3.0–12.0) 

F-l1 10.0 (4.0–13.0) 

H-r1 10.0 (2.0–12.0) 

H-l1 10.0 (3.0–13.0) 

FH-r1 10.0 (2.0–11.0) 

FH-l1 10.0 (3.0–13.0) 

Sensorial extinction 38 (25.3%) 

1Summary median (min-max); BMI = body mass index; F-r = right face; F-l = left 

face; H-r = right hand; H-l = left hand; FH-r = right face-hand; FH-l = left face-hand. 

	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  
	
  



	
    
23  

Table 3. Face-hand test (FHT) scores by gender and race. 

 Gender  Race  

FHT 

Women 

(n=76) 

Men 

(n=74) p1 

Caucasian 

(n=112) 

Non-Caucasian 

(n=38) p1 

F-r 10(3–12) 10(6–12) 0.950 10(5–12) 10(3–12) 0.805 

F-l 10(4–13) 10(5–12) 0.627 10(5–12) 10(4–13) 0.686 

H-r 10(2–11) 10(3–12) 0.529 10(3–11) 10(2–12) 0.132 

H-l 10(3–13) 10(3–11) 0.124 10(5–11) 10(3–13) 0.755 

FH-r 10(2–11) 10(2–11) 0.887 10(2–11) 10(2–11) 0.466 

FH-l 10(3–13) 10(5–12) 0.880 10(5–13) 10(3–12) 0.434 

 1Mann-Whitney. Summary in median (min-max); F-r = right face; F-l = left face; H-r = right hand; 

H-l = left hand; FH-r = right face-hand; FH-l = left face-hand. 

 

 Table 4. Correlation between face-hand test (FHT) scores and age, BMI, or 

years of education. 

 
F-r = right face; F-l = left face; H-r = right hand; H-l = left hand; FH-r = right face-hand; FH-l = left 

face-hand. ρ = Spearman correlation. 

 

 

 

 

 

 

 

Factor F-r F-l H-r H-l FH-r FH-l 

 ρ (p value) ρ (p value) ρ (p value) ρ (p value) ρ (p value) ρ (p value) 

Age (years) 
-
0.29(<0.001) 0.03(0.674) 

-
0.35(<0.001) -0.10(0.218) 

-
0.27(<0.001) 

-
0.21(0.009) 

BMI (kg/m2) 
 
0.04(0.588) 0.10(0.221) -0.05(0.517) -0.006(0.941) 0.03(0.628) 0.10(0.186) 

 
Years of education 0.29(<0.001) 0.17(0.03) 0.32(<0.001) 0.34(<0.001) 0.23(0.004) 0.24(0.002) 



	
    
24  

Table 5 presents data for the number of touches perceived, according to FHT 

variations. We observed a relatively high percentage of participants who perceived 

at least 8 touches during all variations of the FHT, particularly during the Fd, Fe, 

FH-d, and FH variations, in which more than 90% of participants noticed at least 8 

touches.  The percentage of participants perceiving 8 or more touches was lower for 

the Hd and H variations, but was still >80%. 

 

Table 5. Number of touches by face-hand test (FHT) variation. 

Number of 

touches on 

FHT 

FHT variation 

F-r F-l H-r H-l FH-r FH-l 

n fr n fr n fr n fr n fr n fr 

0 0 0.000 0 0.000 0 0.000 0 0.000 0 0.000 0 0.000 

1 0 0.000 0 0.000 0 0.000 0 0.000 0 0.000 0 0.000 

2 0 0.000 0 0.000 1 0.007 0 0.000 2 0.013 0 0.000 

3 1 0.007 0 0.000 2 0.013 2 0.013 1 0.007 1 0.007 

4 1 0.007 2 0.013 2 0.013 2 0.013 0 0.000 0 0.000 

5 2 0.013 1 0.007 6 0.040 4 0.027 3 0.020 3 0.020 

6 6 0.040 3 0.020 3 0.020 3 0.020 3 0.020 3 0.020 

7 2 0.013 4 0.027 9 0.060 6 0.040 1 0.007 3 0.020 

8 7 0.047 10 0.067 8 0.053 5 0.033 7 0.047 5 0.033 

9 9 0.060 13 0.087 11 0.073 19 0.127 12 0.080 13 0.087 

10 122 0.813 117 0.780 108 0.720 109 0.727 121 0.807 122 0.813 

≥ 8 touches 138 0.920 140 0.934 127 0.846 133 0.887 140 0.933 140 0.933 

Legend: n = number of touches; f = relative frequency of perceived touches; F-r = right face; F-l = left 

face; H-r = right hand; H-l = left hand; FH-r = right face-hand; FH-l = left face-hand. n = absolute 

frequency; fr = relative frequency. 

  

 



	
    
25  

 

Table 6 shows the binomial models adjusted for the number of rings 

perceived in each variation of the FHT. 

 

Table 6. Probabilistic models adjusted for the number of rings with each perceived 

change on the face-hand test (FHT), for a total of 10 stimuli. 

FHT variation Distribution Pr [t ≥ 8] 

F-d Bin (10;0.949)  0.987 

F-e Bin (10;0.950) 0.988 

H-d Bin (10;0.913) 0.950 

H-e Bin (10;0.930) 0.971 

FH-d Bin (10;0.947) 0.986 

FH-e Bin (10;0.956) 0.991 

Bin = binomial distribution; Pr = estimated probability of perceiving at least 8 of 10 stimuli received 

under the fitted distribution; F-r = right face; F-l = left face; H-r = right hand; H-l = left hand; FH-r = 

right face-hand; FH-l = left face-hand.  

 

 Table 7 shows the association between sociodemographic variables and the 

probability of sensory extinction during the FHT. We observed a statistically 

significant increase in the probability of sensory extinction with increasing age (OR 

= 1.04, range 1.01–1.07; p = 0.006 and a significantly reduction in probability of 

extinction with increasing years of education (OR = 0.82, range 0.71–0.94; p = 

0.005). 

 

 

 

 



	
    
26  

 

Table 7. Regression adjusted logistics for the probability of extinction on the face-

hand test (FHT).  

Variable β SE Wald p OR CI 95% 

Men -0.63 0.46 1.83 0.176 0.53 (0.22–1.32) 

Age (years) 0.04 0.01 7.48 0.006 1.04 (1.01–1.07) 

BMI (kg/m2) -0.01 0.05 0.01 0.904 0.99 (0.90–1.10) 

Race (non-Caucasian) -0.47 0.53 0.76 0.382 0.63 (0.22–1.79) 

Years of education -0.20 0.07 7.98 0.005 0.82 (0.71–0.94) 

Constant -0.24 1.56 0.02 0.876 0.78  

BMI = body mass index; β = estimates of the model parameters; SE = standard error; Wald = 

Wald test; p = p value; OR = odds ratio; CI = confidence interval. 

	
  
 

Figure 2 shows the ROC curves for effects of age and years of education, 

which were used to establish values that maximize the sensitivity and specificity for 

sensory extinction detected by the FHT. For age, sensitivity and specificity of 

68.4% and 72.3%, respectively, at 41.5 years of age produced an area under the 

curve of 0.78 (95% CI = 0.70–0.85; p < 0.001; Figure 2a). For years of education, 

sensitivity and specificity of 68.4% and 69.6%, respectively, were associated with 

10.5 years and generated an area under the curve of 0.77 (95% CI; 0.68–0.85; p < 

0.001; Figure 2b). 

 

 

 

 

 



	
    
27  

 

Figure 2 - Receiver operating characteristics (ROC) curves for age (2a) and years of education (2b), 

in order to determine the values that maximize the sensitivity and specificity of sensory extinction in 

the face-hand test (FHT). 

 

Discussion 

 The present study accomplished standardization of the FHT in a typical 

population without neurological disorders and demonstrated low variability for <8 

touch stimuli, with the highest frequency of stimulation between 8 and 10. The 

initial normative study suggests that no stimuli should be neglected, that the most 

common error resulted from sensory extinction by the stimulus, and that responses  

are less accurate in patients with organic psychological syndromes and in children 

3–6 years of age with face dominance [1]. 

 We found associations between sensory extinction and increasing age, as 

well as lower education. The number of years of education is associated with 

neuropsychological performance on tasks that assess various brain functions such as 

memory, attention, language, and executive functions. In studies on regulation or in  

 

 



	
    
28  

comparative analyses between groups, education is often the most relevant variable, 

followed or accompanied by age [14].  

 There is also a relationship between brain atrophy and age in individuals 

with low education, and education levels are associated with various environmental 

experiences that affect cognition and attention. Additional education may be 

associated with increased synaptic connections or cerebral vasculature, thereby 

increasing higher cortical functioning [15-16]. 

 We observed that 25.3% of participants had sensory extinction during 

double stimulation of the face and hand. Under the original classification system, 

the FHT is divided into 4 distinct groups: (A) individuals who detect all applied 

stimuli, (B) individuals who detect sensory stimuli only in the face, (C) individuals 

who detect 2 simultaneous sensory stimuli in the face, (D) individuals who detect 

sensory stimuli only in the hands. The previous results have demonstrated that most 

errors were in relation to extinction in the face [5]. In a study that found an 

association between EEG activity and sensory stimulation of the median or tibial 

nerves, EEG recordings were as predicted in the median nerve in 75% of patients, 

demonstrating cortical dominance of the upper limb functions for sensory 

stimulation; therefore, the observed results on the FHT have a neurophysiological 

basis [8]. 

 Another potential application of the FHT is for evaluation of the attention 

network, comprising the right perisylvian region (posterior parietal lobe, superior 

temporal cortex, as well as middle and prefrontal cortex). The FHT may be used to 

test errors that influence this network, with potential application to diagnosis of 

syndromes such as unilateral spatial neglect [17-20].  

 

 



	
    
29  

 The FHT may also demonstrate that patients with right hemisphere USN 

present with both ipsilateral and contralateral sensory deficits, whereas patients with 

left hemisphere damage would have deficits elicited by the FHT only the right side, 

indicating right hemisphere dominance for attention and somatosensory integration 

[21-23]. 

 Limitations of the present study include that we recruited participants 

through a single research center, and we also did not compare the findings with 

findings from participants with psychological or organic diseases. However, we 

demonstrated normal score ranges and outlined benchmarks for their application to 

clinical practice. Another limitation relates to the intensity of the stimulus applied, 

as stimulus intensity can directly interfere with sensation. Additionally, given that 

factors such as nociceptive processes, respiratory discomfort, or other sensations 

may interfere with stimulus perception, we conducted the tests in a controlled 

stimulation room with minimal external environmental stimuli. 

 In conclusion, normal responses on the FHT present patterns of 

simultaneous stimulation with scores between 8 and 10 in a Brazilian population. 

Additionally, sensory extinction is associated with increased age, with a cutoff point 

of 41 years. Sensory extinction is also associated with fewer than 5 years of 

education, with a cutoff point of 10.5 years. 

 

 

 

 

 

 

 



	
    
30  

 

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face and hand. AMA Arch Neurol Psychiatry 1951;66(3):355-62. 

2. Blay SL, Mari JJ, Ramos LR. O uso do “Face-Hand Test” como instrumento para 

rastrear as síndromes psicorgânicas. Estudo piloto. Rev saúde publ 1989;23:395-

400. 

3. Grenn MA, Fink M. Standardization of the face-hand test. Neurol 1954;4:211-7. 

4. Bender MB, Wortis SB. Organic Mental Syndrome with Phenomena of 

Extinction and Allesthesia. Arch Neurol Psychiatry 1948;59(3):273-91. 

5. Grenn MA, Fink M. Simultaneous tactile perception in pacientes with conversion 

sensory deficts. Mt Sinai J Med 1974;41(1):141-3. 

6. Feinberg TE, Haber LD, Stacy CB. Ipsilateral extinction in the hemineglect 

syndrome. Arch Neurol 1990; 47:802-4. 

7. Heilman DM, Van Den Abell T. Right hemisphere dominance for attention: the 

mechanism underlying hemispheric asymmetries of inattention (neglect). Neurol 

1980; 30:327-30. 

8. Weintraub S, Mesulam MM. Right cerebral dominance in spatial attention: 

further evidence based on ipsilateral neglect. Arch Neurol 1987; 44:621-5. 

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10. Kim M, Na DL, Kim GM, Adair JC, Lee KH, Heilman KM. Ipsilesional 

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11. Almeida, O.P. Mini-exame do estado mental e o diagnóstico de demência no 

Brasil. Arq Neuropsiquiatr 1998;56:605-12. 

12. Aevarsson O, Skoog I. A longitudinal population study of the mini-mental state 

examination in the very old: relation to dementia and education. Dement Geriatr 

Cogn Disord 2000;11:166-75. 

13. Fratiglioni L, Jorm AF, Grut M. et al. Predicting dementi from mini-mental state 

examination in an elderly. J Clin Epidemiol 1993;46(3):281-7. 

14. Ostrosky-Solis F, Ardila A, Rosseli M, Lopez-Arango G, Uriel-Mendonça V. 

Neuropsychological test performance in illiterate subjects. Arch Clin Neuropsychol 

1998;13:645-60. 

15. Piras F, Cherubini A, Caltagirone C, Spalletta G. Education mediates 

microstructural changes in bilateral hippocampus. Hum Brain Mapp 

2011;32(2):282-9. 

16. Greenwood PM, Parasuraman R. Neuronal and cognitive plasticity: a 

neurocognitive framework for ameliorating cognitive aging.	
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2010;2:150. 

17. Swan L. Unilateral Spatial Neglect. Phys The 2001;81:1572-80. 

18. Verdon V, Vuilleumier P. Neuroanatomy of hemispatial neglect and its 

functional components: a study using voxel-based lesion symptom mapping. Brain 

2010;133: 880-94. 

19. Friedland RP, Weinstein EA. Hemi-inattention and hemisphere specialization: 

introduction and historical review. Adv Neurol 1977;18:1-13.  

20. Stein JF. Representation of egocentric space in the posterior parietal cortex. Q J 

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32  

 

21. Reeves RR, Bullen JA. Misuse of the Face-Hand Test for Psychogenic 

neurological deficits. J Clin Psychiatry 1994; 55:8. 

22. Critchley M. The Phenomenon of Tactile Inattention with Special Reference to 

Parietal Lesions. Brain 1949;72:538-61. 

23. Robert Cohn MD. A Physiological Study of Rostral Dominance in 

SImultaneously Applied Ipsilateral Somatosensory Stimuli. Mt Sinai J Med 

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33  

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Artigo científico 2 
 



	
    
34  

Standardization of unilateral spatial neglect tests in a Brazilian multicultural 

population 

Short title: Standardization of USN tests in Brazil 

 

Gustavo José Luvizutto¹; Marcelo Ortolani Fogaroli2; Rodolfo Theotonio2; Tamiris 

Aparecida Monteiro¹, Hélio Rubens de Carvalho Nunes3; Luiz Antônio de Lima 

Resende4; Rodrigo Bazan4. 

 

1 – Doutorando em Bases Gerais da Cirurgia; 2 – Aluno de graduação do curso de 

Medicina; 3 – Estatístico da Faculdade de Medicina de Botucatu; 4 – Docente do 

Departamento de Neurologia, Psicologia e Psiquiatria. Universidade Estadual 

Paulista – UNESP – Faculdade de Medicina de Botucatu	
  

 

Corresponding author: 

M.Sc. Gustavo José Luvizutto 

Departamento of Neurology, Psychology and Psychiatry 

Univ. Estadual Paulista – UNESP – Botucatu Medical School 

CEP: 18618-970 Botucatu-SP-Brasil 

E-mail: gluvizutto@fmb.unesp.br 

 

Conflicts of interest: none 
 

Grant support: none 

 

 

 

 

 

 



	
    
35  

Abstract 

Objective: the aim was to standardize USN tests in a Brazilian population and 

relate the results with sociodemographic variables. Method: This is a cross-

sectional study of 150 individuals with no neurological history. The 

sociodemographic variables were: age, sex, race, body mass index, and education. 

We used the line cancellation test (LCT), star cancellation test (SCT), and line 

bisection test (LBT) to standardize USN testing. The odds ratios (OR) for omissions 

in LCT and SCT were considered in relation to sociodemographic variables. The 

ROC curve was used to find the relationship between LCT and SCT with age. The 

association between LBT and sociodemographic variables was performed by Mann-

Whitney and Spearman correlation considering significant if p <0.05. Results: In 

LCT, 143 (95.3%) subjects had default level 0 and the occurrence of failure above 0 

was significantly associated with ageing (OR=1.1[1.02-1.2];p=0.012) with a cutoff 

age of 49.5 years. In SCT, 145 (96.6%) patients had failure below 2 and the 

occurrence of failure above 2 was significantly associated with ageing 

(OR=1.07[1.03-1.11];p<0.001) with a cutoff age of 45.5 years. In LBT, deviations 

were lower with the highest education levels (r=0.20;p=0.015) and the observed 

median deviation from the center was 6.2(5.8-6.6)mm. Conclusions: the 

appropriate cutoff point in cancellation tests should be >0 for LCT and >2 for the 

SCT to consider USN in a Brazilian population, and the failure rate increases with 

ageing. Higher education levels correspond to lower midline deviation in LBT, and 

the median value used to consider USN should be above 6.6 mm. 

 

Keywords: Unilateral spatial neglect; standardization; diagnostic tests. 

 



	
    
36 	
  

Background 

  Unilateral spatial neglect (USN) is characterized by the inability of the 

patient to report or respond to people or objects presented on the side contralateral 

to the lesioned side of the brain in the absence of motor or sensory deficits 

(Plummer, Morris, & Dunai, 2003; Tanaka, Ifukube, Sugihara, & Izumi, 2010). 

Often, USN is associated with lesions in the right hemisphere, particularly in the 

posterior parietal lobe (Halligan & Marshall, 2001; de Haan, Karnath, & Driver, 

2012; Kerkhoff, 2001). It has also been associated with poor functional outcomes 

and long stays in hospitals and rehabilitation centers, all of which predispose 

patients to falls and to semipermanent or permanent wheelchair use. These 

outcomes can in turn reduce the quality of life of patients with USN compared to 

stroke patients who do not have USN (Chen, Hreha, Fortis, Goedert, & Barrett, 

2012; Gottesman et al., 2008; Harvey et al., 2010). 

  Unilateral spatial neglect is commonly assessed using either the line 

bisection (Schenkenberg, Bradford, & Ajax, 1980) or the target cancellation task 

(Halligan, Burn, Marshall, & Wade, 1992) in the clinic. USN tests were first 

proposed by Albert in 1973. During the test, the individual was requested to find 

and cancel random lines on a sheet of paper (Line Cancellation Test). The author 

concluded that the test is sensitive in detecting spatial changes in both brain 

hemispheres (Albert, 1973).  

  Performance on visuospatial tasks change based on the presence of distractor 

symbols. Halligan et al. (1992) thus proposed the star cancellation test (SCT), which 

uses non-target distractor stimuli that should be ignored by the individual during the 

test. The authors of this study concluded that the SCT test may be a more sensitive 

method for USN detection. Another test for the detection of USN is the line  



	
    
37  

bisection test (LBT), during which the subject is asked to find the midpoint of a 

horizontal line displayed on a sheet of paper.  Schenkenberg et al. (1980) concluded 

that the LBT is sensitive in detecting unilateral neglect (UN) in patients with right 

hemisphere lesions with an accuracy of 81%. 

  All tests described here were performed using standard A4 sheets of paper. 

Although several different tests are described here, none has been used to generate 

normalized data in the Brazilian population. USN is associated with lower 

functional performance and is a major contributor to the slowing of neurological 

recovery. We thus examined the effects of demographic variables that may predict 

performance on USN tests. We obtained normative data in a healthy sample, which 

can then be used for the diagnosis of USN in patients with right hemisphere lesions 

in the clinic. 

 

Patients and Methods 

This cross-sectional study included graduate students, professionals and 

patients at the Clinics Hospital of Botucatu (UNESP) between March 2013 to July 

2015. The persons were recruited through direct contact with the researcher 

followed by invitation to participate in the study. 

The study was approved by the Ethics in Human Research Committee, as 

recorded in opinion 122/2011. The study participants had no history of neurological 

disorder (including but not limited to head trauma with loss of consciousness, 

multiple sclerosis, Parkinson’s disease, cerebrovascular disease, epilepsy, 

meningitis, mental retardation, or anoxic injury that may affect brain functioning); 

no history of substance abuse or dependence (as assessed by history, record review, 

and serum toxicology); no use of medications with central nervous system effects;  

 



	
    
38  

and no history of learning disability, and no visual deficits. The participants were 

aware of the tests they  performed, were hemodynamically stable, and had scores 

above 24 on the Mini-Mental State Examination (MMSE) (Almeida, 1998). They 

had no signs of discomfort at the time of evaluation. 

 

Variables 

We obtained and analyzed information on the following socio-demographic 

variables from the study participants by direct interview: age (years), sex (male or 

female), race (white or non-white), body mass index (BMI, kg/m2), and years of 

education. 

We standardized USN tests using the cancellation and bisection tasks 

following the procedures described below: 

 

a) Cancellation Tests 

 

- Line cancellation test (LCT): subjects were given a single sheet of paper 

containing 40 lines with a length of approximately 2.5 cm. The lines were drawn 

in 6 different orientations. The sheet contained 18 lines on each side (right or left) 

and 4 at midline (Figure 1). The examiner asked the following question from the 

subject once the test was finished: "Have all the lines been crossed?". The test was 

terminated when the answer was affirmative. The participant’s score was the 

proportion of lines omitted relative to the total number of lines (Albert, 1973). 

 

	
  

	
  

	
  



	
    
39 	
  

	
  

	
  

 

Figure 1. Line cancellation test	
  

 

- SCT: the test was carried out using a sheet containing 52 big stars, 13 

letters, and 10 words randomly interspersed with 56 smaller stars (Figure 2). The 

individual was asked to find and delete (cancel) only the smaller stars after the 

examiner demonstrated the procedure by striking out two stars in the center of the 

sheet. The number of omitted stars was subtracted from the total number of stars 

presented in the test (Halligan, Burn, Marshall, & Wade, 1992). 

 

Figure 2: Star cancellation test 

 

	
  

	
  



	
    
40 	
  

b) Bisection test 

- LBT: The subjects were presented with 18 transverse lines arranged in six 

rows of three columns (right, center, and left) with a line at the upper end of 

the sheet. The lines are 100 mm, 120 mm, 140 mm, 150 mm, 160 mm, 180 

mm, or 200 mm wide and are organized in different positions (Figure 3). 

Patients were requested to mark the middle of each line. After the test was 

completed, we determined the value in millimeters of the scratched portion 

in relation to the rest of the line using the formula: % = left half - middle x 

100, divided by half for each line, as described by Schenkenberg et al. 

(Schenkenberg, Bradford, & Ajax, 1980). In this study, we also analyze the 

absolute value of the deviation (VAD), which is obtained by adding all of 

the deviations and dividing the resulting value by the total number of test 

lines. 

 

Figure 3: Line bisection test	
  

 

In all USN tests, the examiner used A3 paper and put it in front of the patient 

so that there was a distance of 50 cm from the glabella to the center of the paper. 

 

 



	
    
41  

Statistical analyses	
  

Since we are using a sample representative of the target population, our 

sampling is considered to be intentional and non-probabilistic. We needed a 

minimum of 150 subjects to obtain a maximum sampling error of 7.5% and a 

confidence level of 95%. We estimated odds ratios for the numbers of omissions in 

the LCT and the SCT based on sociodemographic variables. We used an ROC curve 

study the relationship between performance on these tests and age. The association 

between deviation from the center in the LBT and sociodemographic variables was 

investigated using the Mann-Whitney test and Spearman correlation. All 

associations and areas under the ROC curve were treated as significant if p < 0.05. 

Analyses were performed using SPSS software (version 21.0, SPSS, Chicago, IL, 

USA). 

 

Results 

We evaluated and screened 250 individuals, but only 150 met the inclusion 

criteria for the study (Figure 4), and sociodemographic characteristics and performance 

of subjects in USN testing are presented in Table 1. 

 

 

 

 

 

 

 

Figure 4 - Screening of patients excluded for the study	
  

 

250 individuals	
  

Loss of consciousness: n = 19 

Medication with CNS effects: n = 24 

MMSE < 24: n = 57	
  

150 individuals	
  



	
    
42  

Table 1 – Sociodemographic characteristics and performance of subjects in USN testing 

(n=150). 

Variable Summary 

Sociodemographic variables  

Sex  

   Male : Female 76 (51%) : 74 (49%) 

Age (years) (1) 31.5 (18 – 87) 

BMI (Kg/m2) (1) 22.8 (11.7 – 35.9) 

Race  

   Caucasian : Non-Caucasian 112 (75%) : 38 (25%) 

Years of Education (1) 11 (6 – 16) 

USN performance  

Line Cancellation Test  

     Total number of omissions  

      0 143 (95.3%) 

      1 6 (4.0%) 

      4 1 (0.7%) 

     Omission (Total of lines not canceled > 0) 7 (4.7%) 

Star Cancellation Test  

     Total number of omissions  

      0 123 (82.0%) 

      1 16 (10.6%) 

      2 6 (4.0%) 

      > 2 5 (3.4%) 

     Omission (Total of lines not canceled > 0) 27 (18.0%) 

Line Bisection Test  

   Center deviation (AVD in mm) (1) 6.2 (2.1 – 6.6) 
Summary in median (min-max); 

AVD = absolute value of the deviation 

 

 

  

 

 



	
    
43  

Table 2 shows that the chance of failure in the LCT was significantly 

associated with age (OR = 1.1 (1.02 to 1.2); p = 0.012). The ROC curve identified 

49.5 years as the cutoff age (sensitivity = 71% and specificity = 74%) (Figure 5). 

 

Table 2 – Estimated odds ratios for the numbers of omissions in the LCT 

based on sociodemographic variables 

Variable OR (95% CI)  p 

 Sex (male) 7.9 (0.6 – 99.5)  0.109 

 Age (years) 1.1 (1.02 – 1.2)  0.012 

 BMI (km/m2) 0.9 (0.7 – 1.1)  0.543 

 Race (non-white) 3.4 (0.4 – 27.6)  0.256 

 Years of education 1.0 (0.7 – 1.4) 0.889 

 BMI = body mass index; OR = odds ratio; CI = confidence interval 

 

 

Figure 5. ROC curve relating age to the number of omissions in the LCT 

 

 

 

 



	
    
44  

Table 3 shows that the chance of failure in the SCT was significantly 

associated with increasing age (OR = 1.07 (1.03 to 1.11), p < 0.001). The ROC 

curve identified 45.5 years old as the cutoff age (sensitivity = 73% and specificity = 

78%) (Figure 6). 

 

Table 3 – Estimated odds ratios for the number of omissions in the SCT 

based on sociodemographic variables 

Variable OR (95% CI) p  

 Sex (male) 1.01 (0.34 – 2.00) 0.983  

 Age (years) 1.07 (1.03 – 1.11) 0.000  

 BMI (kg/m2) 0.88 (0.78 – 1.05) 0.062  

 Race (non-white) 2.10 (0.67 – 6.54) 0.203  

 Years of 

education 0.88 (0.75 – 1.02) 0.094 

 

 BMI = body mass index; OR = odds ratio; CI = confidence interval 

 

 

Figure 6. ROC curve relating age to the number of omissions in the SCT 

 



	
    
45   

Table 4 and Figure 7d show that deviation from the center was lower among 

subjects with the highest education levels (r = 0.20; p = 0.015). We also observe a 

greater variance in women compared to men. Specifically, the kurtosis was 

significantly higher among women (k = 13.6) compared to men (k = 3.3). 

 

Table 4 - Association between deviations from the center obtained in the LBT and 

sociodemographic variables. 

Variable Summary p 

Age (years)  r = 0.16  0.052 

BMI (kg/m2) r = 0.05  0.572 

Years of Education r = -0.20  0.015 

Sex (1)   

   Female (n = 76) 6.3 (3.0 – 38.3)  0.955 

   Male (n = 74) 6.1 (2.1 – 23.8)  

Race (1)   

   Non-white (n = 112) 6.2 (3.0 – 27.0) 0.506 

   White (n = 38) 6.8 (2.1 – 38.3)  

(1) Median (min-max) 

(2) Spearman correlation 

 

 

 

 

 

 

 

 



	
    
46  

 

 

 

Figure 7. Histogram of the deviations from the center obtained in the LBT (7a). 

Scatterplot of the offset from the center in relation to age (7b), BMI (7c), and years 

of education (7d). Boxplot of the deviations values in relation to sex (7e) and race 

(7f). 

 

 

In the LBT, we observed median deviations from the center of 6.2 and a 

range of 5.8 to 6.6 mm using a 95% confidence interval.	
  

	
  

	
  

	
  

	
  

 

 

 

 

 

 



	
    
47  

Discussion 

  This study aims to standardize USN tests in a Brazilian population without 

neurological disorders. The subjects in our study demonstrated a higher frequency 

of omissions in the SCT compared with the LCT. Initial normative studies in other 

populations suggest that none of the LCT lines should be omitted, and the authors 

found that the most common error in this test was the omission of the lower left 

quadrant in patients with right posterior parietal lesions. Some authors believe that 

the clearing of up of 51 stars or the omission of less than 3 stars should be used as a 

benchmark in the SCT. This test is influenced by distractors that hinder attention 

and is indicated for diagnosing mild cases of USN (Wilson, Cockburn, & Halligan, 

1987; Azouvi et al., 1996).   

  Cancellation tasks that employ a random arrangement of complex symbols 

are more difficult and subsequently more sensitive in detecting neglect than similar 

tests that are arranged in organized rows and columns. Cancellation tests are most 

frequently used to detect USN and are more sensitive for this purpose (Mesulam, 

2000; Ferber & Karnath, 2001). The line bisection tasks involve marking the 

midpoint of one or more horizontal lines. Patients with left neglect tend to make 

errors in the area right of the true center. The average deviation from the center in 

the LBT in this study was 6.2 (5.8 to 6.6) mm. A greater deviation indicates USN. 

Previous studies have shown that this test has a lower sensitivity compared to 

cancellation tests. It is thus used as a complementary test in USN diagnosis. A 

battery of tests is therefore more sensitive to the presence of neglect than one single 

task (Gainotti, Messerli, & Tissot, 1972; Lindell et al., 2007). 

   

 

 



	
    
48  

  These two USN tests activate the same underlying cortical processes. The 

patients who have problems on the line bisection task have more posterior lesions 

(occipitotemporal extrastriate areas). Verdon et al. (2010) found that lesions in the 

right inferior parietal lobule were more associated with problems on the line 

bisection task and lesions in the right dorsolateral prefrontal cortex were more 

associated with problems on the cancellations task. However, in a recently study, 

the authors concluded that USN is a disorder usually associated with right parietal 

damage to the angular gyrus and can be tested in the clinical setting with both 

cancellation and line bisection tasks (Zihl, Sämann, Schenk, Schuett, & Dauner, 

2009; Baier, Mueller, Fechir, & Dieterich, 2010; Molenberghs & Sale, 2011; 

Verdon & Vuilleumier, 2010). 

  The main factor that affects performance in the lines and stars cancellation 

tests is age. The older the patient is, the worse their performance in the tests is likely 

to be. Several studies have reported factors that may affect performance on USN 

tests, and the age is a well-discussed factor in the literature. The authors aimed to 

correlate age with performance in USN tests in a cross-sectional study of ischemic 

stroke patients in the acute phase at Johns Hopkins Hospital. They found that USN 

occurs more frequently in elderly individuals regardless of the size of injury or the 

severity of neurological symptoms. One of the proposed hypotheses is that older 

patients have greater attention deficits and difficulty in neural adaptations following 

central nervous system injury. In addition, total brain volume tends to decrease with 

age, which may lead to cognitive impairment (Bailey, Riddoch, & Crome, 2000; 

Agrell, Dehlin, & Dahlgren, 1997). 

   

 

 



	
    
49  

  Azouvi et al. (2006) observed that in healthy individuals, the higher age 

associated with lower educational levels can lead to more errors in USN tests. The 

level of education affected the numbers of omissions on left vs. the right. 

Specifically, subjects with higher education levels had more mistakes on the right 

and subjects with less schooling made more mistakes on the left. There is a 

possibility that these differences are due to the fact that school subjects are taught to 

write from left to right, making it more likely that individuals with high levels of 

education have reduced omissions on the left side (Feinberg, Haber, & Stacy, 1990; 

Azouvi et al., 2006; Bowers & Heilman, 1980). 

  In the line bisection test, the main confounding factor related to the absolute 

value of deviation from the center was educational level. Azouvi et al. (2006) 

reported that factors such as education, age, and dominant hand should be taken into 

account in the diagnosis of USN. In a meta-analysis of the LBT, the authors 

concluded that young people make mistakes to the left, while older individuals tend 

to err to the right of center. There is inconsistency in reports on the influence of sex 

on deviation from the midline. Different stages of the menstrual cycle in a woman 

have modulating effects on the location of the sagittal-median plane, but there are 

no significant reports on gender differences (Silva, Cardoso, & Fonseca, 2012; 

Jewell & McCourt, 2000; McCourt, Mark, Radonovich, Willison, & Freeman, 

1997).  

  The main limitations of the study relate to the testing of individuals within a 

single center. We also did not compare our results to those obtained other existing 

assays in the literature, such as the Behaviour Inattention Test, which uses 9 tests 

and is the gold standard for the detection of USN. Our aim was to establish 

objectives and practical and rapidly implemented tests that are useful in clinical  

 



	
    
50  

practice to facilitate the timely diagnosis of USN in acute neurological conditions 

arising from stroke, tumors, or trauma.  

  Based on our results, we can conclude that the cutoff points for USN 

diagnosis in the cancellation tests are more than 0 in the LCT and more than 2 in the 

SCT. We also found that the numbers of omissions in these tests are greater with 

increasing age. In the LBT, the absolute deviation from the median used as the 

maximum confidence interval to consider USN should be above 6.6 mm. In this 

test, the deviation from the median was higher with less education. 

References 

Agrell BM, Dehlin OI, & Dahlgren CJ. (1997) Neglect in elderly stroke patients: a 

comparison of five tests. Psychiatry Clin Neurosci 51:295–300. 

Albert ML. (1973) A simple test of visual neglect. Neurology 23:658–64. 

Almeida, O.P. (1998) Mini-exame do estado mental e o diagnóstico de demência no 

Brasil. Arq Neuropsiquiatr 56:605–12. 

 

Azouvi P, Olivier S, de Montety G, Samuel C, Louis-Dreyfus A, Tesio L. (1996) 

Functional consequences and awareness of unilateral neglect: study of an evaluation 

scale. Neuropsychol Rehab 6:133–50. 

 

Azouvi P, Bartolomeo P, Beis JM, Perennou D, Pradat-Diehl P, & Rousseaux M. 

(2006) A battery of tests for the quantitative assessment of unilateral neglect. Restor 

Neurol Neurosci. 24:273–85. 

	
  

Baier B, Mueller N, Fechir M, & Dieterich M. (2010) Line bisection error and its 

anatomic correlate. Stroke. 41(7):1561–3.	
  

 

 



	
    
51  

Bailey MJ, Riddoch MJ, & Crome P. (2000) Evaluation of a test battery for 

hemineglect in elderly stroke patients for use by therapists in clinical practice. 

Neuro Rehabil 14:139–50. 

Bowers D & Heilman KM. (1980) Pseudoneglect: effectofhemispace on a tactile 

line bisection task, Neuropsychologia. 18:491–98. 

Chen P, Hreha K, Fortis P, Goedert KM, & Barrett AM. (2012) Functional 

assessment of spatial neglect: a review of the Catherine Bergego Scale and an 

introduction of the Kessler Foundation Neglect Assessment Process. Topics in 

Stroke Rehabilitation 19:423–35. 

 

Silva, R. F. C., Cardoso, C., Fonseca, R. P. (2012) Diferenças quanto à escolaridade 

em adultos no desempenho no Teste de Cancelamento dos Sinos. Estudos de 

Psicologia (Natal. Online). 17:215-2. 

 

Feinberg TE, Haber LD, & Stacy CB. (1990) Ipsilateral extinction in the 

hemineglect syndrome. Arch Neurol. 47:802–4. 

Ferber S & Karnath HO. (2001) How to assess spatial neglect—line bisection or 

cancellation tasks? J Clin Exp Neuropsychol 23:599–607. 

Gainotti G, Messerli P, & Tissot R. (1972) Qualitative analysis of unilateral spatial 

neglect in relation to laterality of cerebral lesions. J Neurol Neurosurg Psychiatry 

35:545–50. 

Gottesman RF, Kleinman JT, Davis C, Heidler-Gary J, Newhart M, Kannan V, 

Hillis AE. (2008) Unilateral neglect is more severe and common in older patients 

with right hemispheric stroke. Neurology 71:1439–44.  

de Haan B, Karnath HO, & Driver J. (2012) Mechanisms and anatomy of unilateral 

extinction after brain injury. Neuropsychologia. 50(6):1045–53. 

 

 



	
    
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Halligan PW, Burn JP, Marshall JC, & Wade DT. (1992) Visuo-spatial neglect: 

qualitative differences and laterality of cerebral lesion. Journal of Neurology, 

Neurosurgery, and Psychiatry 55:1060–8. 

Halligan PW & Marshall JC. (2001) Graphic neglect– more than the sum of the 

parts. Neuroimage. 14:91–7. 

Harvey M, Muir K, Reeves I, Duncan G, Birschel P, Roberts M, Livingstone K, 

Jackson H, Hogg C, Castle P, Learmonth G, Rossit S. (2010) Long term 

improvements in activities of daily living in patients with hemispatial neglect. 

Behavioural Neurology 23:237–9. 

Jewell G & McCourt ME. (2000) Pseudoneglect: a review and meta-analysis of 

performance factors in line bisection tasks. Neuropsychologia. 38:93–110. 

Kerkhoff G. (2001) Spatial hemineglect in humans. Prog. Neurobiol. 63:1–27. 

Lindell AB, Jalas MJ, Tenovuo O, Brunila T, Voeten MJ, Hämäläinen H.. (2007) 

Clinical assessment of hemispatial neglect: evaluation of different measures and 

dimensions. Clin Neuropsychol 21:479–97. 

McCourt ME, Mark VW, Radonovich KJ, Willison SK, & Freeman P. (1997) The 

effects of gender, menstrual phase and practice on the perceived location of the 

midsagittal plane. Neuropsychologia. 35:717–24. 

Mesulam, M. M. (Ed.). (2000). Principles of behavioral and cognitive neurology. 

New York, NY: Oxford University Press. 

Molenberghs P & Sale MV. (2011) Testing for spatial neglect with line bisection 

and target cancellation: are both tasks really unrelated? PLoS One. 6(7):e23017. 

Plummer P, Morris ME, & Dunai J. (2003). Assessment of unilateral neglect. 

Physical Therapy 83:732–40. 

Schenkenberg T, Bradford DC, & Ajax ET. (1980) Line bisection and unilateral 

visual neglect in patients with neurologic impairment. Neurology 30:509–17. 

 



	
    
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Tanaka T, Ifukube T, Sugihara S, & Izumi T. (2010). A case study of new 

assessment and training of unilateral spatial neglect in stroke patients: effect of 

visual image transformation and visual stimulation by using a Head Mounted 

Display system (HMD). Journal of Neuroengineering and Rehabilitation 7:20. 

Verdon V & Vuilleumier P. (2010) Neuroanatomy of hemispatial neglect and its 

functional components: a study using voxel-based lesion symptom mapping. Brain. 

133:880–94. 

Wilson, B.A., Cockburn, J. & Halligan, P.W. (1987). Development of a behavioural 

test of visuo-spatial neglect. Archives of Physical Medicine and Rehabilitation 

68:98–102. 

Zihl J, Sämann P, Schenk T, Schuett S, & Dauner R. (2009) On the origin of line 

bisection error in hemianopia. Neuropsychologia. 47:2417–2426. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



	
    
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Artigo científico 3 
 



	
    
55  

Publicado no Arquivos de Neuropsiquiatria (11 de Julho de 2014) 

 

Low haemoglobin levels increase unilateral spatial neglect in acute phase of 

stroke. 

 

Running title: Low haemoglobin levels and neglect in stroke. 

 

Gustavo José Luvizutto1, Tamiris Aparecida Monteiro1, Gabriel Pereira Braga2, 

Silméia Garcia Zanati Bazan3, Luiz Antônio de Lima Resende4, Rodrigo Bazan5. 

1 – Physiotherapist in Rehabilitation Department; 2 – Assistant Doctor in Stroke 

Unit; 3 – Professor Doctor of the Clinical Medicine Department; 4 – Professor of 

Neurology; 5 - Assistant Professor of Neurology. Botucatu School of Medicine 

Neurology Service, University Estadual Paulista Júlio de Mesquita Filho, São 

Paulo, Brazil. 

 

Funding: None 

 

Author for correspondence:  

Gustavo José Luvizutto.  

Botucatu School of Medicine Neurology Service. District of Rubião Júnior, no 

number, Botucatu, SP 18618-970, Brazil.  

Email: gluvizutto@fmb.unesp.br.  

Telephone: +55 (14) 38116049 

	
  



	
    
56 

 

Abstract 

Objective: The objective of this study was to evaluate the relationship between 

unilateral spatial neglect (USN) and Haemoglobin (Hb) level in acute phase of 

stroke. Methods: Cross-sectional study was performed after right hemisphere 

ischemic stroke. Independent variable: Hb level (mg/dL); Outcome: USN; Potential 

confounding factors: Age, National Institutes of Health Stroke Scale (NIHSS), and 

glycaemia (mg/dL); Characterization variables were obtained from electronic 

medical records, Hb, mean corpuscular volume (MCV) and glycaemia by laboratory 

exams, and USN by cancellation and bisection tasks. The relationship between Hb 

and USN was assessed by Spearman correlation and linear regression model. 

Results: 40 individuals were evaluated; it was observed that the higher the Hb level, 

the better the USN test performance, with negative correlation between them. There 

was no significant correlation between VCM level and USN performance. 

Conclusion: a lower Hb level worsens performance on the USN tests in acute phase 

of stroke. 

Keywords: Stroke, perceptual disorders, haemoglobins. 

	
  



	
    
57 

Introduction  

 Low Haemoglobin (Hb) is a common condition in the elderly population and 

is associated with increased mortality and worsening functional performance, 

independent of cause (1,2). Many people in acute phase of stroke present low 

haematocrit levels, which are associated with higher mortality and worsening long-

term results; but the importance of low haemoglobin in stroke clinical presentation 

has not been clearly established (3-7).  

Currently, interest is growing in the effects of Hb concentration on cognitive 

decline. Critical Hb levels, high or low, have been associated with worsening 

cognitive performance in the elderly, but their mechanisms are poorly understood, 

with the hypothesis on the presence of ischemia, hypoxia or central nervous system 

oxidative stress (8,9). Based on the results of several studies, there is speculation 

that reduced aerobic capacity and cerebral vascular dysfunction could also 

contribute to cognitive decline, and that normal haematocrit levels reduce the 

transfer velocity within cerebral capillaries, improve oxygen extraction by cerebral 

tissue, and have a positive effect on cortex functions (10,11). 

In the present study, we evaluated the relationship between Unilateral 

Spatial Neglect (USN) by means of cognitive with perception tests, haemoglobin 

(Hb) and mean corpuscular volume (MCV) level in acute phase of stroke. The study 

hypothesizes that low haemoglobin values are associated with poorer performance 

on tests of unilateral spatial neglect, being that anaemia may influence the 

performance of activities that place high demands on the perceptual system, 

increasing errors on tests of cancelling and bisection of lines. 

 

 



	
    
58  

Methods 

This was a cross-sectional study of ischemic stroke patients of both sexes 

with right hemisphere lesion – confirmed by cranial computerized tomography (CT) 

or magnetic resonance imaging (MRI) – of anterior circulation origin, with defined 

aetiology, in the acute ictus phase (in the first 48 hours after ictus), under 

conservative treatment and admitted to the Stroke Unit at Botucatu Medical School 

University Hospital - UNESP. Patients were excluded if they presented at least one 

of the following conditions: haemorrhagic or posterior circulation stroke, left 

hemisphere ischemia, previous Modified Rankin Scale (mRS) ≥1, pre-existing 

dementia, aphasia, visual deficits, other neurological diseases, as were patients who 

had undergone surgical procedures, thrombolytic treatment, blood transfusion or 

presented a history of alcohol abuse, hypothyroidism, chronic obstructive 

pulmonary disease, liver disease, kidney failure or marked leukocytosis on 

laboratory exams. 

Procedures 

Individuals were evaluated by three USN exams, two for cancellation and 

one for bisection: a) Cancellations tests: Line Cancellation Task (LCT), scored by 

lines cancelled in relation to a total number of 40 lines on a sheet of paper (12); Star 

Cancellation Task (SCT), scored by 52 stars cancelled in between distractors (13); 

b) Bisection test: Line Bisection Task (LBT), based on absolute value of deviation 

to the right in relation to middle of line marked by patient on each line of the sheet 

(14). In all USN tests the examiner placed the test sheet in front of the patient with 

the centre of the sheet 50 cm from the glabella, the objective being to measure USN 

severity. 



	
    
59  

Hb level (in g/dL), MCV (in fL) and other laboratory exams were performed 

through a standard protocol by nurses trained in vein puncture to collect blood 

samples using a sterile technique. The blood sample was collected in a 10ml tube on 

the same day that USN tests were applied, and transferred to the clinical laboratory 

for automated processing. After analysis of the exams, anaemia was defined as Hb 

<12 g/dL in women and Hb <13 g/dL in men (15). The individuals classified as 

anaemic were divided into microcytic (MCV < 80 fL), normocytic (MCV = 80-100) 

or macrocytic (MCV > 100 fL) (16). 

The National Institutes of Health Stroke Scale (NIHSS) and mRS were 

applied at same time as the USN tests to define neurological deficit severity and 

functional independence; demographic and anthropometric data were obtained from 

electronic hospital records on the same USN test date. 

Statistical Analysis 

The relationship between potential confounding factors (age, neurological 

deficit severity, functional independence and glycaemia) and USN was assessed by 

the Spearman correlation and Mann-Whitney test, whereas the relationship between 

Hb level, MCV and NSU was explored by the Spearman correlation and linear 

regression model. 

 

Ethics 

The study was approved by Human Research Ethics Committee of 

UNESP/Botucatu. All individuals or relatives consented to participate in the study. 

 



	
    
60  

Results 

Between June and December 2012, a total of 40 patients were included in 

present data. The general demographic data and baseline characteristics are 

displayed in Table 1, and the potential confounders are presented in Table 2. 

 

Table 1. Sample Description 

 
Variables* Values 

Age, y  66 (34 - 87) 

Sex, male  25 (62.5%) 

Race, White 23 (57.5%) 

Weight (Kg)  72.4 (43.8 - 99.0) 

Height (m)  1.69 (1.50 - 1.78) 

BMI (Kg/m2) 23.5 (16.4 - 38.2) 

NIHSS 5 (3 - 12) 

mRS 3 (0 - 4) 

Laboratory Exams  

Glycaemia, mg/dL  101.5 (69.0 - 237.0) 

Urea, mg/dL  20 (12.0 - 37.0) 

Creatinine, mg/dL  0.8 (0.5 – 1.2) 

Haemoglobin, mg/dL  14.1 (8.6 - 16.9) 

MCV, fl 91.4 (66.9 – 116.0) 

USN exams  

    Score on LCT 15.5 (0 - 36) 

    Score on SCT 33.5 (4 - 51) 

    Score on LBT  

        Deviation from centre line 64.4 (14.3 - 90.9) 

      BMI indicates Body Mass Index; mRS, modified Rankin Scale; NIHSS, National Institutes 

of Health Stroke Scale; MCV, mean corpuscular volume; USN – Unilateral Spatial Neglect. 

*Numbers are mean (SD) or counts (percentages). 

 

 

 

 

 



	
    
61  

 

 

Table 2 – Relationship between age, neurological deficit and 

glycaemia as potential confounders for NSU. 

  
Variable*   LCT SCT LBT 

Age, y r 0.20 0.18 0.19 

 

p(1) 0.339 0.391 0.375 

NIHSS r -0.19 -0.22 -0.32 

 

p(1) 0.402 0.332 0.155 

mRS r 0.32 0.35 0.30 

 

p(1) 0.134 0.090 0.155 

Glycaemia (mg/dL) r -0.07 -0.11 0.06 

      NIHSS indicates National Institutes of Health Stroke Scale; mRS, modified Rankin 

Scale LCT, Line Cancellation Test; SCT: Star Cancellation Test; LBT: Line Bisection 

Test. 

      *Numbers are mean (SD) or counts (percentages). 

(1) p – value associated with Spearman’s correlation  

        r : estimate of Spearman’s correlation  

 

Figures 1 and 2 show the negative correlation between Hb and LCT (r= -

0.35; p = 0.02) and SCT (r=- 0.27; p=0.09). The relationship between Hb level and 

USN evaluated by LBT (Figure 3) reveals a negative correlation with absolute 

deviation value (r=-0.27; p=0.11), number of deviations to the right (r = -0.36; 

p=0.03), mean percentage of deviations to the right (r= - 0.15; p = 0.35), and mean 

percentage of deviations to the left (r= - 0.15; p=0.35). These associations were 

independent of age, neurological deficit, incapacity level or blood glucose. 

  

 



	
    
62  

 

Figure 1 – (A) Correlation between Hb level and LCT; (B) Correlation between Hb 

level and SCT. 

 

Figure 3 - Correlation between Hb level and LBT. 

 

In the linear regression model, it was demonstrated that the higher the Hb 

level, the fewer lines and stars were cancelled, with an average of around three lines 

(β = -3.1) and three stars (β = -3.2) left un-cancelled for each unit increase in Hb 

(tables 3 and 4).  

 

Table 3. Adjusted linear regression models to explain the number of lines 

cancelled in LCT as a function of haemoglobin. 

 β Standard error p CI (β: 95%) 

Constant 56.2 15.1 0.001 (24.9 - 87.4) 

Haemoglobin (mg/dL) -3.1 1.1 0.010 (-5.4 - -0.8) 

Residual analysis: p=0.591 (Shapiro-Wilk); 

 



	
    
63  

Table 4. Adjusted linear regression models to explain the number of stars 

cancelled in SCT as a function of haemoglobin. 

 β Standard error p CI (β: 95%) 

Constant 71.3 17.3 0.001 (35.6 - 107.0) 

Haemoglobin (mg/dL) -3.2 1.3 0.018 (-5.9 - -0.6) 

Residual analysis: p=0.829 (Shapiro-Wilk); 

 

Table 5 demonstrates an absence of a statistically significant correlation 

between the VCM level and the degree of unilateral spatial neglect by means of 

LCT (r=-0.089; p = 0.616), SCT (r = 0.001; p = 0.997) and LBT (r=0.063; 

p=0.723). 

 

Table 5. Correlation between MCV and scores of tests for unilateral spatial neglect. 

    LCT SCT LBT 

MCV r -0.089 0.001 0.063 

 

p 0.616 0.997 0.723 
MCV, mean corpuscular volume; LCT, Line Cancellation Task; SCT, Star Cancellation Task; 

LBT, Line Bisection Task.	
  

Discussion 

In our study we found a relationship between Hb level and the presence or 

absence of USN, and that age, severity (NIHSS), incapacity (mRS) and glycaemia 

are not confounding factors in the final NSU result. This result is consistent with a 

physiological mechanism, as the much lower haemoglobin levels reduce cerebral 

oxygen, and thus worsen USN in the acute phase by establishing a larger area of 

ischemic penumbra and delimiting the lesion area much earlier (8). Studies have 

shown that erythropoietin levels have neuroprotective properties that can regulate  

 



	
    
64  

some caspases, and therefore prevent neuron death, which is important for reducing 

the ischemic area and improving neurological deficits (17).  

In the first study where this association was found, a “U” pattern was suggested in 

the correlation between Hb and USN, where the critical levels, high or low, had 

determined worse USN (3). Our results highlight the drop in Hb in the acute phase 

as a factor of severity and cognitive decline through the USN tests. In an 

observational study (6), the authors reported that anaemia in stroke acute phase 

results in worse functional performance in the first three months and that this 

association is associated with increased penumbra area and cerebral infarct (7). An 

association was demonstrated between the Hb level and the all USN tests, with poor 

correlation with LBT, because this test has a relatively poor sensitivity for detecting 

USN. The other tests applied (LCT and SCT) are generally the most sensitive in 

perceptual disorders (18,19). This information is important because the association 

of Hb with LBT can be influenced by the sensitivity of the test to detect USN. 

The results of MCV did not show a statistical correlation with performance 

on NSU tests. In a descriptive analysis of our data, the patients with macrocytic 

anaemia presented worse performance on tests of cancelling of lines and stars. This 

datum has been little explored in the literature, where worsening has been reported 

only in patients with a deficit in the spatial attention network and cognitive decline 

in patients with macrocytic anaemia (20-21). This finding presents little consistency 

with our study in which only 4 patients presented macrocytic anaemia. 

The limitations of the present study were small sample size, the fact that individuals 

could have received electrolyte replacement therapy, and other confounding factors, 

such as tobacco smoking. However, our results not onlyconsistently demonstrate a 

negative association between Hb and USN severity, bu also demonstrate the 

importance of the research objective of establishing ideal haemoglobin levels in the  



	
    
65  

acute phase to avoid cognitive and perceptual decline and improve functional 

prognosis. We recommend that longitudinal follow-up studies be performed to 

observe long-term functional outcome and verify whether USN is reduced with 

haemoglobin replacement. To conclude, the lower the haemoglobin level, the worse 

the development in USN cancellation tests in acute phase of stroke. 

 

References 

1 - Hao Z, Wu B, Wang D, Lin S, Tao W, Liu M. A cohort study of patients 

with anemia on admission and fatality after acute ischemic stroke. J ClinNeurosci 

2013;20:37-42. 

2 - Tanne D, Molshatzki N, Merzeliak O, Tsabari R, Toashi M, Schwammenthal Y. 

Anemia status, haemoglobin concentration and outcome after acute stroke: a cohort 

study. BMC Neurol 2010; 10:22 

3 - Gottesman RF, Bahrainwala Z, Wityk RJ, Hillis AE. Neglect is more common 

and severe at extreme haemoglobin levels in right hemispheric stroke. 

Stroke 2010;41:1641-1645. 

4 - Kimberly WT, Wu O, Arsava E, et al. Lower haemoglobin correlates with larger 

stroke volumes in acute ischemic stroke. Cerebrovasc Dis Extra 2011;1:44–53. 

5 - Sico JJ, Concato J, Wells CK, et al. Anemia Is Associated with Poor Outcomes 

in Patients with Less Severe Ischemic Stroke. J Stroke Cerebrovasc Dis; 2011. 6 - 

Kellert L, Martin E, Sykora M, Bauer H, Gussmann P, Diedler J, et al. Cerebral 

oxygen transport failure?: decreasing haemoglobin and hematocrit levels after 

ischemic strokepredict poor outcome and mortality: STroke: RelevAnt Impact of 

haemoglobin, Hematocrit and Transfusion (STRAIGHT)--an observational study.  



	
    
66  

Stroke 2011;42:2832-2837.7 - Kimberly WT, Wu O, Arsava EM, Garg P, Ji R, 

Vangel M, et al. Lower haemoglobin correlates with larger stroke volumes in acute 

ischemic stroke. Cerebrovasc Dis Extra 2011; 1:44-53. DOI: 10.1159/000328219 

8 - KurellaTamura M, Wadley VG, Newsome BB, Zakai NA, McClure LA, Howard 

G, et al. Haemoglobin concentration and cognitive impairment in the renal REasons 

for Geographic And Racial Differences in Stroke (REGARDS) Study. J Gerontol A 

BiolSci Med Sci 2010;65:1380-1386. 

9 - Shah RC, Wilson RS, Tang Y, Dong X, Murray A, Bennett DA. Relation of 

haemoglobin to level of cognitive function in older persons. Neuroepidemiology 

2009; 32:40-46. 

10 - Hare GM. Anaemia and the brain. Curr Opin Anaesthesiol 2004;17:363–369. 

11 - Metry G, Wikstrom B, Valind S, et al. Effect of normalization of hematocrit on 

brain circulation and metabolism in hemodialysis patients. J Am SocNephrol 

1999;10:854–863. 

12 - Albert ML. A simple test of visual neglect. Neurol 1973;23:658-664. 

13 - Schenkenberg T, Bradford DC, Ajax ET. Line Bisection and unilateral visual 

neglect in patients with neurologic impairment. Neurol 1980; 30:509-517.  

14 - Halligan PW, Burn JP, Marshall JC, Wade DT. Visuo-spatial neglect: 

qualitative differences and laterality of cerebral lesion. J Neurol Neurosurg 

Psychiatry 1992;55:1060-1068. 

 



	
    
67  

15 - World Health Organization. Nutritional Anaemias: Report of a WHO Scientific 

Group. Geneva: World Health Organization; 1968. 

16 - Bross MH, Soch K, Smith-Knuppel T. Anemia in older persons. Am Fam 

Physician. 2010;82(5):480-487. 

17 - Ismailov RM. Cognitive Decline in the Stroke Belt and Erythropoietin. Ann 

Neurol 2013;73:146. 

18 - Agrell BM, Dehlin OI, Dahlgren CJ. Neglect in elderly stroke patients: a 

comparison of five tests. Psychiatry Clin Neurosci 1997;51(5):295-300. 

19 - Ferber S, Karnath HO. How to assess spatial neglect--line bisection or 

cancellation tasks? J Clin Exp Neuropsychol 2001;23(5):599-607. 

20 - Kaferle J, Strzoda CE. Evaluation of macrocytosis. Am Fam Physician 2009;79 

(3):203-208. 

21 - Gamaldo AA, Ferrucci L, Rifkind J, Longo DL, Zonderman AB. 

Relationship between mean corpuscular volume and cognitive performance in 

older adults. J Am Geriatr Soc 2013;61(1):84-9.  

 

 

 

 

 

 

 



	
    
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Artigo científico 4 

	
  
	
  

	
  
	
  



	
    
69  

 
Publicado na Cochrane Library (6 de Novembro de 2015) 

 
 

Pharmacological interventions for unilateral spatial neglect after stroke 

 

Gustavo José Luvizutto1, Gabriel Pereira Braga2, Silméia Garcia Zanati Bazan3, 

Luiz Antônio de Lima Resende4, Rodrigo Bazan5, Regina El Dib 

1 – Physiotherapist in Rehabilitation Department; 2 – Assistant Doctor in Stroke 

Unit; 3 – Professor Doctor of the Clinical Medicine Department; 4 – Professor of 

Neurology; 5 - Assistant Professor of Neurology. Botucatu School of Medicine 

Neurology Service, University Estadual Paulista Júlio de Mesquita Filho, São 

Paulo, Brazil. 

 

Funding: None 

 

Author for correspondence:  

Gustavo José Luvizutto.  

Botucatu School of Medicine Neurology Service. District of Rubião Júnior, no 

number, Botucatu, SP 18618-970, Brazil.  

Email: gluvizutto@fmb.unesp.br.  

Telephone: +55 (14) 38116049 

	
  
 

 

 

 

 

 

 



	
    
70  

 

Abstract 

 

Background: Unilateral spatial neglect (USN) is characterized by the inability to 

report or respond to people or objects presented on the side contralateral to the 

lesioned side of the brain and has been associated with poor functional outcomes 

and long stays in hospitals and rehabilitation centers. Pharmacological interventions 

(medical interventions only, use of drugs to improve the health condition), such as 

dopamine and noradrenergic agonists or pro-cholinergic treatment, have been used 

in people affected by USN after stroke, and effects of these treatments could 

provide new insights for health professionals and policy makers. Objectives: To 

evaluate the effectiveness and safety of pharmacological interventions for USN after 

stroke. Search methods: We searched the Cochrane Stroke Group Trials Register 

(April 2015), the Cochrane Central Register of Controlled Trials (April 2015), 

MEDLINE (1946 to April 2015), the Cumulative Index to Nursing and Allied 

Health Literature (CINAHL) (1982 to April 2015), EMBASE (1980 to April 2015), 

PsycINFO (1806 to April 2015) and Latin American Caribbean Health Sciences 

Literature (LILACS) (1982 to April 2015). We also searched trials and research 

registers, screened reference lists, and contacted study authors and pharmaceutical 

companies (April 2015). Selection criteria: We included randomized controlled 

trials (RCTs) and quasi-randomized controlled trials (quasi-RCTs) of 

pharmacological interventions for USN after stroke. Data collection and analysis: 

Two review authors independently assessed risk of bias in the included studies and 

extracted data. Main results: We included in the review two studies with a total of 

30 randomly assigned participants. We rated the quality of the evidence as very low 

as the result of study limitations, small numbers of events, and small sample sizes, 

with imprecision in the confidence interval (CI). We were not able to perform meta-

analysis because of heterogeneity related to the different interventions evaluated 

between included studies. Very low-quality evidence from one trial (20 participants) 

comparing effects of rivastigmine plus rehabilitation versus rehabilitation on overall 

USN at discharge showed the following: Barrage (mean difference (MD) 0.30, 95% 

confidence interval (CI) -0.18 to 0.78); Letter Cancellation (MD 10.60, 95% CI 2.07 

to 19.13); Sentence Reading (MD 0.20, 95% CI -0.69 to 1.09), and the Wundt-

Jastrow Area Illusion Test (MD -4.40, 95% CI -8.28 to -0.52); no statistical 

significance was observed for the same outcomes at 30 days' follow-up.  



	
    
71  

 

In another trial (10 participants), study authors showed statistically significant 

reduction in omissions in the three cancellation tasks under transdermal nicotine 

treatment (mean number of omissions 2.93 ± 0.5) compared with both baseline 

(4.95 ± 0.8) and placebo (5.14 ± 0.9) (main effect of treatment condition: F (2.23) = 

11.06; P value < 0.0001). One major adverse event occurred in the transdermal 

nicotine treatment group, and treatment was discontinued in the affected participant. 

None of the included trials reported data on several of the prespecified outcomes 

(falls, balance, depression or anxiety, poststroke fatigue, and quality of life). 

Authors' conclusions: The quality of the evidence from available RCTs was very 

low. The effectiveness and safety of pharmacological interventions for USN after 

stroke are therefore uncertain. Additional large RCTs are needed to evaluate these 

treatments. 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 



	
    
72  

 

 

Background 

 

Various non-pharmacological rehabilitation techniques have been explored 

for unilateral (restricted to one side of the body) spatial neglect (USN). The aim of 

these techniques has been to facilitate the recovery of perception and behavior. 

These techniques have included right half-field eye-patching (Tsang 2009), mirror 

therapy (Thieme 2013), prism adaptation (Mizuno 2011), left-hand somatosensory 

stimulation with visual scanning training (Polanowska 2009), contralateral 

transcutaneous electrical nerve stimulation and optokinetic stimulation (Schröder 

2008), trunk rotation (Fong 2007), repetitive transcranial magnetic stimulation 

(Cazzoli 2012), galvanic vestibular stimulation (Nakamura 2015), and dressing 

practice (Walker 2011). These studies demonstrated a positive effect on visuospatial 

neglect after stroke, but their results do not support use of these techniques in 

isolation for improvement of secondary outcomes such as performance and 

sensorimotor functions, activities of daily living, or quality of life (Cazzoli 

2012; Turton 2010; Thieme 2013). 

Most recently, pharmacological interventions, such as use of dopamine or 

noradrenergic agonists, have been shown to improve perception as measured by the 

Line Bisection task (Schenkenberg 1980) and the Line Cancellation task (Albert 

1973) in people affected by USN, and they seem to represent a promising approach 

to treatment of patients with this condition (Bartolomeo 2012; Luauté 

2006; Malhotra 2006). 

 

Description of the condition 

Stroke is the second leading cause of death worldwide and the primary cause 

of chronic disability in adults (Bonita 1992). In the United States, it is the fourth 

leading cause of death overall (Jauch 2013). Each year in the UK, 110,000 people 

suffer a stroke (Bray 2013), and in Asia the incidence is two to three times higher 

than in Europe (Hata 2013). In Brazil, stroke is the leading cause of death overall 

(Pontes-Neto 2008). Among people who survive a stroke, USN is the most frequent 

disorder for right hemisphere lesions (Gorgoraptis 2012). The incidence of USN 

varies widely from 10% to 82% (Chen 2012; Stone 1993; Vanier 1990). 

 



	
    
73  

 

USN is characterized by the inability to report or respond to people or 

objects presented on the side contralateral to the lesioned side of the brain, when 

this symptom cannot be accounted for by motor or sensory deficits (Plummer 

2003;Tanaka 2010). Diagnoses are made by paper-and-pen tests, for example, 

cancellation and bisection tests (Agrell 1997) and, in subacute or chronic stages of 

neglect, after stroke diagnosis is made on the basis of behavioral measures derived 

from assessment of functional abilities in everyday life (Azouvi 2003). USN has 

been associated with poor functional outcomes and long stays in hospitals and 

rehabilitation centers, all of which predispose patients to the risk of falls and to semi 

permanent or permanent wheelchair use (Chen 2012; Gottesman 2008; Tanaka 

2010), which can reduce their quality of life compared with that of other stroke 

patients who do not have USN (Harvey 2010). Furthermore, USN decreases a 

patient's work productivity, which has a socioeconomic impact, thus affecting a 

community's public health status (Brown 2006; Treger 2007). 

 

Description of the intervention 

Pharmacological intervention has been used in people affected by USN after 

stroke to enhance their performance on neglect tests and assessment of daily life 

functions. Some studies aiming to explain the effects of dopamine and 

noradrenergic agonists, which have been shown to modulate cognitive function, 

have shown that they most likely act via postsynaptic α2 receptors in the 

dorsolateral prefrontal cortex (a region of the brain responsible for working 

memory) (Malhotra 2006). Dopamine agonists have been shown to improve tests of 

visuospatial neglect such as line bisection, letter cancellation, and reading (Fleet 

1987; Geminiani 1998; Hurford 1998; Mukand 2001), and to act in perceptual 

attentional systems and premotor components of visuospatial neglect (Mukand 

2001). Noradrenergic agonists showed improvement on paper-and-pencil tasks as 

well as on visual exploration in participants who had a lesion that spared the 

dorsolateral prefrontal cortex (Malhotra 2006). Other pharmacological approaches 

for USN after stroke include pro-cholinergic drugs, which also work to modulate 

the activity of the attention system in the brain (Thiel 2005). 

 

 

 



	
    
74  

 

 

How the intervention might work 

Dopamine is a biological amine synthesized in the hypothalamus, the basal 

ganglia, and many areas of the central and peripheral nervous system. Dopamine 

and its agonists play an important role in central nervous system regulation through 

stimulation of α- and β-adrenergic and dopaminergic receptors. Dopaminergic 

agonists, which cross the blood-brain barrier, have neurological and endocrine 

central effects and act directly at postsynaptic receptors within the basal ganglia, 

increasing the availability of dopamine in the synaptic cleft (Velasco 1998). 

Dopamine-selective D1 agonists are one type of pharmacological intervention that 

have been used for USN. Dopamine D1 receptors can have an effect on visual areas 

of attention and could provide a possible mechanism for facilitating spatial attention 

and working memory (Castner 2000; Funahashi 1994). Noradrenergic agonists have 

been associated with increased output from the locus coeruleus (a part of the 

brainstem) to both inferior parietal and frontal lobes of the cortex (the outer 

covering of the brain) via the thalamus (portion of the diencephalon), which may be 

involved in USN (Singh-Curry 2011). Cholinergic drugs work to increase levels of 

acetylcholine and subsequently enhance the function of neural cells; they can 

modulate activity in the frontoparietal attention system of the brain and working 

memory tasks (Thiel 2005), and may increase selective attention during spatial 

exploration (Witte 1997). 

 

Why it is important to do this review 

Stroke is a prevalent disease that has high morbidity and mortality 

worldwide; it is characterized as a serious public health problem. People who 

develop USN after stroke have major functional disabilities, as well as decreased 

rates of adherence to rehabilitation programs (Paolucci 2001; Wee 2008). 

Understanding the effects of a pharmacological intervention, given alone or in 

combination with non-pharmacological strategies for rehabilitation, could provide 

new insights for health professionals and policy makers. 

 

 

 

 



	
    
75  

 

Objectives 

To evaluate the effectiveness and safety of pharmacological interventions 

for unilateral spatial neglect (USN) after stroke. 

 

Methods 

 

Criteria for considering studies for this review 

 

Types of studies 

We included randomized controlled trials (RCTs) and quasi-randomized controlled 

trials (quasi-RCTs). 

 

Types of participants 

Adults over 18 years of age, regardless of gender and ethnicity, with USN after 

stroke diagnosis measured by clinical examination or radiographically by computed 

tomography (CT) or magnetic resonance imaging (MRI), regardless of whether they 

were included after evaluation by a paper-and-pencil test. We included people 

diagnosed with any type of stroke (ie, ischemic or hemorrhagic) from the acute 

phase (the first 24 to 72 hours (Furlan 2012)) until one year after the stroke. 

 

Types of interventions 

We included trials that compared: 

a) drug A versus placebo or control; 

b) drug A + rehabilitation versus rehabilitation; and 

c) drug A versus drug B (with or without rehabilitation). 

 

We considered any non-pharmacological therapy provided with the aim of 

improving USN as rehabilitation therapy, such as right half-field eye-patching, 

mirror therapy, prism adaptation, left-hand somatosensory stimulation, visual 

scanning training, contralateral transcutaneous electrical nerve stimulation, 

optokinetic stimulation, trunk rotation, repetitive transcranial magnetic stimulation, 

galvanic vestibular stimulation, and dressing practice. 

 

 



	
    
76  

 

Types of outcome measures 

 

Primary outcomes 

 

Test of neglect 

Overall USN measured by any paper-and-pencil tests, such as the Line 

Cancellation task (Albert 1973), the Line Bisection test (Schenkenberg 1980), or the 

Star Cancellation Test (Halligan 1992); and by any validated specific instrument, 

such as the Catherine Bergego Scale (Azouvi 2003) and the Behavioural Inattention 

Test (Wilson 1987). 

 

Secondary outcomes 

 

a) Disability in neurological and functional abilities as measured by any validated 

specific instrument, such as the National Institutes of Health Stroke Scale and the 

Modified Rankin Scale (Cincura 2009), the Box and Block Test (Mathiowetz 1985), 

or the Fugl-Meyer Assessment (Sanford 1993) after treatment and over the long 

term. 

b) Daily life functions as measured by any validated measurement scale, such as the 

Barthel Index (Cincura 2009). 

c) Number of reported falls as measured by diaries of falls, by the Morse Fall Scale 

(Morse 1989), or by the Hendrich II Fall Risk Model (Hendrich 2003) after 

treatment and over the long term. 

d) Balance as measured by the Berg Balance Scale, the balance subscale of the 

Fugl-Meyer test, and the Postural Assessment Scale for Stroke Patients (Mao 2002) 

after treatment and over the long term. 

e) Depression or anxiety as measured by the Beck Depression Inventory, the 

Hospital Anxiety and Depression Scale, Symptom Checklist-90 (SCL-90), and the 

Hamilton Depression Rating Scale (Aben 2002) after treatment and over the long 

term. 

f) Evaluation of poststroke fatigue by the Fatigue Severity Scale (Lerdal 2011) after 

treatment and over the long term. 

 

 



	
    
77  

g) Quality of life (however defined by the study authors) after treatment and over 

the long term. 

h) Adverse events (eg, euphoria, hallucinations, orthostatic hypotension, nausea, 

insomnia, dizziness, syncope) after treatment and over the long term. 

i) Death. 

 

Search methods for identification of studies 

See the "Specialized register" section of the Cochrane Stroke Group module. 

We searched for trials in all languages and when possible arranged for translation of 

relevant articles. 

 

Electronic searches 

We searched the Cochrane Stroke Group Trials Register (April 2015) and 

the following electronic databases and trials registers. 

- Cochrane Central Register of Controlled Trials (CENTRAL) (2015, April 

issue) (Appendix 1). 

- MEDLINE (Ovid) (1948 to April 2015) (Appendix 2). 

- Cumulative Index to Nursing and Allied Health Literature (CINAHL) 

(Ebsco) (1982 to April 2015) (Appendix 3). 

- EMBASE (Ovid) (1980 to April 2015) (Appendix 4). 

- PsycINFO (Ovid) (1806 to April 2015) (Appendix 5). 

- Latin American and Caribbean Health Sciences Literature (LILACS) (1982 

to April 2015) (Appendix 6). 

- ClinicalTrials.gov (April 2015) (www.clinicaltrials.gov/). 

- Stroke Trials Registry (April 2015) (www.strokecenter.org/trials/). 

- International Standardized Randomized Controlled Trial Number 

(ISRCTN) Registry (June 2015) (http://www.isrctn.com/). 

- European Union (EU) Clinical Trials Register (June 2015) 

(www.clinicaltrialsregister.eu). 

- World Health Organization (WHO) International Clinical Trials Registry 

Platform (June 2015) (http://www.who.int/ictrp/en/). 

- Australian-New Zealand Clinical Trials Registry (June 2015) 

(www.anzctr.org.au/). 

 

 



	
    
78  

We developed search strategies for CENTRAL, MEDLINE, CINAHL, 

EMBASE and PsycINFO with the help of the Cochrane Stroke Group Trials Search 

Co-ordinator, and we adapted the MEDLINE strategy for LILACS and the trials 

registers. 

 

Searching other resources 

In an effort to identify additional published, unpublished and ongoing trials, 

we: screened the reference lists of identified studies; contacted the following 

pharmaceutical companies: Aché, Boehringer Ingelheim, Novartis, Sanofi-Aventis, 

GlaxoWellcome, and Pfizer (July 2015); contacted study authors and experts; and 

used Science Citation Index Cited Reference Search for forward tracking of 

important articles. 

 

Data collection and analysis 

 

Selection of studies 

Two review authors (GJL and RB) independently screened titles and 

abstracts of records obtained through electronic database searches and excluded 

obviously irrelevant reports. We retrieved full-text articles for the references that 

remained; two review authors (GJL and RB) independently screened the articles to 

identify studies for inclusion, and identified and recorded the reasons for exclusion 

of ineligible studies. We resolved disagreements through discussion, or, if required, 

we consulted a third person (RED). We collated multiple reports on the same study, 

so that each study, not each reference, was the unit of interest in the review. We 

recorded the selection process and completed a PRISMA (Preferred Reporting Items 

for Systematic Reviews and Meta-Analyses) flow diagram. 

 

Data extraction and management 

Two review authors (GJL and GPB) independently extracted data from the 

included studies. We resolved discrepancies by discussion and used a standard data 

extraction form based on the one recommended by the Cochrane Handbook for 

Systematic Reviews of Interventions (Higgins 2011) to extract the following 

information: characteristics of the study (design, methods of randomization); 

participants; interventions; and outcomes (types of outcome measures, adverse  

 



	
    
79  

events). We contacted the authors of the included studies for clarification about 

missing data, or for further information. 

 

Assessment of risk of bias in included studies 

Two review authors (GJL and RB) independently assessed the risk of bias 

for each study, using the criteria outlined in the¬Cochrane Handbook for Systematic 

Reviews of Interventions¬(Higgins 2011). We resolved disagreements by discussion 

or by consultation with another review author (RED). We assessed risk of bias 

according to the following domains. 

• Random sequence generation. 

• Allocation concealment. 

• Blinding of participants and personnel. 

• Blinding of outcome assessment. 

• Incomplete outcome data. 

• Selective outcome reporting. 

• Other bias. 

We graded the risk of bias for each domain as high, low, or unclear and 

provided information from the study report, together with justification for our 

judgment, in the "Risk of bias" tables. 

 

Measures of treatment effect 

 

Binary outcomes 

For dichotomous data, we planned to use risk ratio (RR) as the effect 

measure, along with the 95% confidence interval (CI). 

 

Continuous outcomes 

For continuous data, we presented the results as mean differences (MDs) 

with 95% CIs. We planned to use the standardized mean difference (SMD) to 

combine trials that measured the same outcome but used different measures. 

 

Unit of analysis issues 

The unit of analysis was each participant recruited into the trial. 

 

 



	
    
80  

 

Dealing with missing data 

An intention-to-treat analysis (ITT) is one in which all participants in a trial 

are analyzed according to the intervention to which they were allocated, whether or 

not they received the intervention. We assumed that participants who dropped out 

were non-responders. For each trial, we reported whether investigators stated if the 

analysis was performed according to the ITT principle. If participants were 

excluded after allocation, we reported in full any details provided. Therefore, we 

planned to perform the analysis on an ITT basis (Newell 1992) when possible. 

Otherwise, we planned to adopt the per-protocol analysis. 

 

Assessment of