SHORT COMMUNICATION
Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations K. R. Servelherea, I. Fabera, J. A. M. Sauteb, M. Moscovichc, A. D’Abreua, L. B. Jardimb, H. A. G. Teivec, I. Lopes-Cendesd and M. C. Franca Jra a Department of Neurology, University of Campinas – UNICAMP, Campinas, SP; bMedical Genetics Service, Federal University of Rio a – UFPR, Curitiba, PR; and dDepartment Grande do Sul – UFRGS, Porto Alegre, RS; cNeurology Service, Federal University of Paran of Medical Genetics, University of Campinas – UNICAMP, Campinas, SP, Brazil
EUROPEAN JOURNAL OF NEUROLOGY
Keywords:
depression, fatigue, nonmotor symptoms, pain, spastic paraplegia, SPG4 Received 13 April 2015 Accepted 3 August 2015 European Journal of Neurology 2016, 23: 408–411 doi:10.1111/ene.12839
Background and purpose: Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4HSP). Methods: Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student’s t test was used to compare groups and linear regression was used to assess correlations. Results: Patients had higher fatigue scores than controls (31.0 16.5 vs. 14.5 16.0, P = 0.002) as well as pain (3.4 2.7 vs. 1.0 1.6, P = 0.001) and depression (12.7 8.9 vs. 4.4 3.8, P < 0.001, respectively). Fatigue was associated with depression and possibly with disease severity (P = 0.008 and 0.07, respectively). Conclusions: Fatigue, pain and depression are frequent and often severe manifestations in patients with SPG4-HSP.
Introduction Progressive spasticity and weakness of the lower limbs are the core clinical features of hereditary spastic paraplegia (HSP) [1,2]. Mutations in the SPG4 gene are the most frequent cause of autosomal dominant HSP (SPG4-HSP), accounting for 40%–50% of all cases [3,4]. Non-motor manifestations have been increasingly recognized in neurodegenerative disorders and may even overshadow motor handicap, but little is known about their impact in HSP [5–7]. Therefore, a study was designed to investigate the frequency and severity of pain, fatigue, depression and daytime sleepiness in a representative cohort of patients with SPG4-HSP [8].
Methods Subject selection
Thirty adult patients with molecular confirmation of SPG4-HSP from three Brazilian centers [University of Campinas (UNICAMP), Federal University of Rio Grande do Sul (UFRGS) and Federal University of Paran a (UFPR)] and 30 age- and sex-matched healthy controls were evaluated between June 2013 and June 2014. Patients with concomitant neurological disorders and those younger than 15 years were excluded. This research protocol was approved by each institution’s research ethics committee and a written informed consent was obtained from all patients. Clinical assessment
Correspondence: M. C. Franca Jr, Department of Neurology, University of Campinas – Rua Tess alia Vieira de Camargo, 126 Campinas, SP-13083-887, Brazil (tel.: +551935219217; fax: +551935217933; e-mail: [email protected]).
408
Disease severity was quantified through the Spastic Paraplegia Rating Scale (SPRS). Patients and controls answered Brazilian Portuguese validated versions of
© 2016 EAN
NON-MOTOR SYMPTOMS IN SPG4
P value
Patients had more fatigue (P = 0.002), pain (P = 0.001) and depressive symptoms (P < 0.001) than controls. There was no difference between groups regarding daytime sleepiness (P = 1.00). Eleven patients had BDI scores higher than 11, in contrast to only one matched control (36.6% vs. 3.3%, P < 0.001). Average pain severity was significantly higher amongst patients (P = 0.001). Twenty-two of the 30 patients (73.3%) had pain, most frequently in the legs (n = 16) and lumbar region (n = 13). Neuropathic pain (burning, paresthesias) was present in eight cases; six of these underwent nerve conduction studies and electromyography, but only one had polyneuropathy. Eighteen patients had daily pain, which lasted more than 5 h/day on average. Nineteen patients described relief factors, most commonly stretching/physical rehabilitation (n = 7) and resting (n = 3). The most frequently reported pain-aggravating factor was physical activity (n = 11). Patients used several different classes of drugs for pain relief (paracetamol, non-steroidal anti-inflammatory drugs, muscle relaxants, codeine and carbamazepine) and most of them described significant but incomplete improvement. Depression was associated with higher fatigue scores (r = 0.868, P = 0.008). Disease severity, expressed by SPRS score, fell short of reaching statistical significance for association with fatigue (P = 0.490, P = 0.07). None of the above-described variables was significantly associated with pain in SPG4-HSP. Patients were divided into those with missense (n = 16) and non-missense (n = 14) mutations to compare the severity of non-motor manifestations (Table 2). There was no significant difference regarding SPRS, MFIS, BDI and pain scores between these groups (P > 0.05).
0.887 1.000
Discussion
the Modified Fatigue Impact Scale (MFIS), Epworth Sleepiness Scale (ESS), Brief Pain Inventory and Beck Depression Inventory (BDI) [9–12]. MFIS, ESS and BDI were considered abnormal if scores were higher or equal to 38, 9 and 11, respectively. For subjects with pain, data regarding verbal descriptors, painful sites, pain duration, relief and aggravating factors, and therapeutic schemes were obtained. Statistical analyses
Student’s t test and the chi-squared test were used to compare means and proportions between patients and controls. A general linear model was employed to evaluate factors associated with fatigue and pain scores. Level of significance was set at P = 0.05 (with DunnSidak correction for multiple comparisons). SYSTAT v 13.0 (Cranes Software International, San Jose, CA, USA) was used for all statistical analyses.
Results Patients came from 15 unrelated families and had a mean disease duration of 17.0 9.5 years. Seventeen were evaluated at UNICAMP, 11 at UFPR and two at UFRGS. One patient was wheelchair bound, two needed walkers and three required canes. Table 1 shows additional clinical and demographic data of patients and controls. Table 2 shows the SPG4 mutational spectrum found in our cohort. Table 1 Clinical and demographic data of patients with SPG4-HSP and controls
Age (mean SD, years) Gender (M/F) SPRS (mean SD) MFIS total (mean SD) MFIS physical (mean SD) MFIS cognitive (mean SD) MFIS psychosocial (mean SD) Average pain severity (mean SD) BDI (mean SD) ESS (mean SD)
SPG4-HSP (n = 30)
Controls (n = 30)
48.3 13.4 17/13 19.0 11.1 31.0 16.5 20.2 10.0
48.8 13.6 17/13 – 14.5 16.0 6.9 7.5
6.9 7.0
6.4 7.7
1.000
3.8 2.7
1.1 1.8
T 30 7 F c.1267G>T 61 25 M c.1651G>C 40 10 M c.1651G>C 62 23 F c.1651G>C 32 8 M c.1651G>C 67 10 F c.1651G>C 46 10 F c.1378C>T 38 16 M c.1291C>T 39 5 M c.1291C>T 61 7 M c.1291C>T 39 11 F c.1360_1361insGGG 61 19 F c.1360_1361insGGG 51 19 M c.1495C>T with frameshift, nonsense and non-stop mutations 39 14 M c.1741C>T 53 23 M c.1255G>T 16 8 M c.1255G>T 43 23 F c.1849T>G 60 20 M c.1849T>G 43 20 M c.1849T>G 43 28 M c.1849T>G 57 6 M c.839_840delAG 64 35 F c.839_840delAG 58 22 M c.839_840delAG 22 2 F c.839_840delAG 56 30 M c.1667_1668delCA 51 27 F c.1667_1668delCA 68 28 M c.1535_1536delA
Mutation Type
SPRS
MFIS (total)
DBI
BPI (mean)
missense missense missense missense missense missense missense missense missense missense missense missense missense missense missense missense
18 43 20 19 29 8 34 11 15 11 4 17 13 22 11 11
18 43 20 19 29 8 34 11 15 11 4 17 13 22 11 11
24 7 33 25 8 3 7 8 13 10 11 20 5 26 9 6
0 9 0 2 4 6 2 7 5 1 4 7 5 5 0 3
nonsense nonsense nonsense non-stop non-stop non-stop non-stop Frameshift Frameshift Frameshift Frameshift Frameshift Frameshift Frameshift
23 21 5 7 5 31 20 5 39 17 39 21 37 16
23 21 5 7 5 31 20 5 39 17 39 21 37 16
11 25 9 27 2 24 17 0 10 8 4 4 20 5
3 5 0 0 5 0 5 2 5 9 5 5 0 0
deletion deletion deletion deletion deletion deletion deletion
SPRS, spastic paraplegia rating scale; MFIS total, total score modified fatigue impact scale; BPI, brief pain inventory; BDI, beck depression inventory.
pain related to spasticity was the most common pain subtype. In contrast, some patients reported burning or dysesthesic pain in the legs, not aggravated by movement and truly suggestive of a neuropathic component. In HSP, not only the corticospinal tracts but also the sensory pathways in the spinal cord are damaged. Therefore, it is possible that neurodegeneration extends to spinothalamic tracts and this might contribute to the painful sensations. The hypothesis of a dual mechanism for pain (nociceptive versus neuropathic) is similar to that reported in a closely related disorder, tropical spastic paraplegia caused by HTLV1 [13]. Pain treatment approaching both nociceptive and neuropathic mechanism could prove more effective for SPG4-HSP patients. In conclusion, it has been shown that fatigue, pain and depression are frequent manifestations in SPG4HSP. In future clinical trials, it would be important to assess the impact of potential disease-modifying
therapies on non-motor manifestations, since they are often more disabling than motor handicap per se.
Acknowledgements The work was supported by Fundac~ ao de Amparo a Pesquisa do Estado de S~ ao Paulo (FAPESP) and Coordenac~ ao de Aperfeicoamento de Pessoal de Nıvel Superior (CAPES).
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
References 1. Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenic mechanisms. Lancet Neurol 2008; 7: 1127–1138.
© 2016 EAN
NON-MOTOR SYMPTOMS IN SPG4
2. Faber I, Servelhere KR, Martinez ARM, D’Abreu A, Lopes-Cendes I, Franca MC Jr. Clinical features and management of hereditary spastic paraplegia. Arq Neuropsiquiatr 2014; 3: 219–226. 3. Sauter S, Miterski B, Klimpe S, et al. Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum Mutat 2002; 20: 127–132. 4. Franca M Jr, Dogini D, D’Abreu A, et al. SPG4-related hereditary spastic paraplegia: frequency and mutation spectrum in Brazil. Clin Genet 2014; 86: 194–196. 5. Franca MC Jr, D0 Abreu A, Friedman JH, Nucci A, Lopes-Cendes I. Chronic pain in MachadoJoseph disease: a frequent and disabling symptom. Arch Neurol 2007; 64: 1767–1770. 6. Da Silva CB, Chevis CF, D0 Abreu A, Lopes-Cendes I, Franca MC Jr. Fatigue is frequent and multifactorial in Friedreich’s ataxia. Parkinsonism Relat Disord 2013; 19: 766–767. 7. Brusse E, Brusse-Keizer MGJ, Van Swieten JC. Fatigue in spinocerebellar ataxia: patient self-assessment of an early and disabling symptom. Neurology 2011; 76: 953–959.
© 2016 EAN
411
8. Vahter L, Braschinsky M, Haldre S, Gross-Paju K. The prevalence of depression in hereditary spastic paraplegia. Clin Rehabil 2009; 23: 857–861. 9. Pavan K, Schmidt K, Marangoni B, Mendes MF, Tilbery CP, Lianza S. Multiple sclerosis: cross-cultural adaptation and validation of modified fatigue impact scale. Arq Neuropsiquiatr 2007; 65: 669–673. 10. Bertolazi AN, Fagondes SC, Hoff LS, Pedro VD, Menna-Barreto SS, Johns MW. Portuguese-language version of Epworth sleepiness scale: validation for use in Brazil. J Bras Pneumol 2009; 35: 877–883. 11. Ferreira KA, Teixeira MJ, Mendonza TR, Cleeland CS. Validation of brief pain inventory to Brazilian patients with pain. Support Care Cancer 2011; 19: 505–511. 12. Gorenstein C, Andrade L. Validation of a Portuguese version of the Beck Depression Inventory and StateTract Anxiety Inventory in Brazilian subjects. Braz J Med Biol Res 1996; 29: 453–457. 13. Tavares IR, Franzoi AC, Ara ujo AQ-C. Low back pain in HTLV-I associated myelopathy/tropical spastic paraparesis: nociceptive or neuropathic? Spinal Cord 2010; 48: 134–137.
Non-motor symptoms in patients with hereditary spastic paraplegia caused by SPG4 mutations K. R. Servelherea, I. Fabera, J. A. M. Sauteb, M. Moscovichc, A. D’Abreua, L. B. Jardimb, H. A. G. Teivec, I. Lopes-Cendesd and M. C. Franca Jra a Department of Neurology, University of Campinas – UNICAMP, Campinas, SP; bMedical Genetics Service, Federal University of Rio a – UFPR, Curitiba, PR; and dDepartment Grande do Sul – UFRGS, Porto Alegre, RS; cNeurology Service, Federal University of Paran of Medical Genetics, University of Campinas – UNICAMP, Campinas, SP, Brazil
EUROPEAN JOURNAL OF NEUROLOGY
Keywords:
depression, fatigue, nonmotor symptoms, pain, spastic paraplegia, SPG4 Received 13 April 2015 Accepted 3 August 2015 European Journal of Neurology 2016, 23: 408–411 doi:10.1111/ene.12839
Background and purpose: Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4HSP). Methods: Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student’s t test was used to compare groups and linear regression was used to assess correlations. Results: Patients had higher fatigue scores than controls (31.0 16.5 vs. 14.5 16.0, P = 0.002) as well as pain (3.4 2.7 vs. 1.0 1.6, P = 0.001) and depression (12.7 8.9 vs. 4.4 3.8, P < 0.001, respectively). Fatigue was associated with depression and possibly with disease severity (P = 0.008 and 0.07, respectively). Conclusions: Fatigue, pain and depression are frequent and often severe manifestations in patients with SPG4-HSP.
Introduction Progressive spasticity and weakness of the lower limbs are the core clinical features of hereditary spastic paraplegia (HSP) [1,2]. Mutations in the SPG4 gene are the most frequent cause of autosomal dominant HSP (SPG4-HSP), accounting for 40%–50% of all cases [3,4]. Non-motor manifestations have been increasingly recognized in neurodegenerative disorders and may even overshadow motor handicap, but little is known about their impact in HSP [5–7]. Therefore, a study was designed to investigate the frequency and severity of pain, fatigue, depression and daytime sleepiness in a representative cohort of patients with SPG4-HSP [8].
Methods Subject selection
Thirty adult patients with molecular confirmation of SPG4-HSP from three Brazilian centers [University of Campinas (UNICAMP), Federal University of Rio Grande do Sul (UFRGS) and Federal University of Paran a (UFPR)] and 30 age- and sex-matched healthy controls were evaluated between June 2013 and June 2014. Patients with concomitant neurological disorders and those younger than 15 years were excluded. This research protocol was approved by each institution’s research ethics committee and a written informed consent was obtained from all patients. Clinical assessment
Correspondence: M. C. Franca Jr, Department of Neurology, University of Campinas – Rua Tess alia Vieira de Camargo, 126 Campinas, SP-13083-887, Brazil (tel.: +551935219217; fax: +551935217933; e-mail: [email protected]).
408
Disease severity was quantified through the Spastic Paraplegia Rating Scale (SPRS). Patients and controls answered Brazilian Portuguese validated versions of
© 2016 EAN
NON-MOTOR SYMPTOMS IN SPG4
P value
Patients had more fatigue (P = 0.002), pain (P = 0.001) and depressive symptoms (P < 0.001) than controls. There was no difference between groups regarding daytime sleepiness (P = 1.00). Eleven patients had BDI scores higher than 11, in contrast to only one matched control (36.6% vs. 3.3%, P < 0.001). Average pain severity was significantly higher amongst patients (P = 0.001). Twenty-two of the 30 patients (73.3%) had pain, most frequently in the legs (n = 16) and lumbar region (n = 13). Neuropathic pain (burning, paresthesias) was present in eight cases; six of these underwent nerve conduction studies and electromyography, but only one had polyneuropathy. Eighteen patients had daily pain, which lasted more than 5 h/day on average. Nineteen patients described relief factors, most commonly stretching/physical rehabilitation (n = 7) and resting (n = 3). The most frequently reported pain-aggravating factor was physical activity (n = 11). Patients used several different classes of drugs for pain relief (paracetamol, non-steroidal anti-inflammatory drugs, muscle relaxants, codeine and carbamazepine) and most of them described significant but incomplete improvement. Depression was associated with higher fatigue scores (r = 0.868, P = 0.008). Disease severity, expressed by SPRS score, fell short of reaching statistical significance for association with fatigue (P = 0.490, P = 0.07). None of the above-described variables was significantly associated with pain in SPG4-HSP. Patients were divided into those with missense (n = 16) and non-missense (n = 14) mutations to compare the severity of non-motor manifestations (Table 2). There was no significant difference regarding SPRS, MFIS, BDI and pain scores between these groups (P > 0.05).
0.887 1.000
Discussion
the Modified Fatigue Impact Scale (MFIS), Epworth Sleepiness Scale (ESS), Brief Pain Inventory and Beck Depression Inventory (BDI) [9–12]. MFIS, ESS and BDI were considered abnormal if scores were higher or equal to 38, 9 and 11, respectively. For subjects with pain, data regarding verbal descriptors, painful sites, pain duration, relief and aggravating factors, and therapeutic schemes were obtained. Statistical analyses
Student’s t test and the chi-squared test were used to compare means and proportions between patients and controls. A general linear model was employed to evaluate factors associated with fatigue and pain scores. Level of significance was set at P = 0.05 (with DunnSidak correction for multiple comparisons). SYSTAT v 13.0 (Cranes Software International, San Jose, CA, USA) was used for all statistical analyses.
Results Patients came from 15 unrelated families and had a mean disease duration of 17.0 9.5 years. Seventeen were evaluated at UNICAMP, 11 at UFPR and two at UFRGS. One patient was wheelchair bound, two needed walkers and three required canes. Table 1 shows additional clinical and demographic data of patients and controls. Table 2 shows the SPG4 mutational spectrum found in our cohort. Table 1 Clinical and demographic data of patients with SPG4-HSP and controls
Age (mean SD, years) Gender (M/F) SPRS (mean SD) MFIS total (mean SD) MFIS physical (mean SD) MFIS cognitive (mean SD) MFIS psychosocial (mean SD) Average pain severity (mean SD) BDI (mean SD) ESS (mean SD)
SPG4-HSP (n = 30)
Controls (n = 30)
48.3 13.4 17/13 19.0 11.1 31.0 16.5 20.2 10.0
48.8 13.6 17/13 – 14.5 16.0 6.9 7.5
6.9 7.0
6.4 7.7
1.000
3.8 2.7
1.1 1.8
T 30 7 F c.1267G>T 61 25 M c.1651G>C 40 10 M c.1651G>C 62 23 F c.1651G>C 32 8 M c.1651G>C 67 10 F c.1651G>C 46 10 F c.1378C>T 38 16 M c.1291C>T 39 5 M c.1291C>T 61 7 M c.1291C>T 39 11 F c.1360_1361insGGG 61 19 F c.1360_1361insGGG 51 19 M c.1495C>T with frameshift, nonsense and non-stop mutations 39 14 M c.1741C>T 53 23 M c.1255G>T 16 8 M c.1255G>T 43 23 F c.1849T>G 60 20 M c.1849T>G 43 20 M c.1849T>G 43 28 M c.1849T>G 57 6 M c.839_840delAG 64 35 F c.839_840delAG 58 22 M c.839_840delAG 22 2 F c.839_840delAG 56 30 M c.1667_1668delCA 51 27 F c.1667_1668delCA 68 28 M c.1535_1536delA
Mutation Type
SPRS
MFIS (total)
DBI
BPI (mean)
missense missense missense missense missense missense missense missense missense missense missense missense missense missense missense missense
18 43 20 19 29 8 34 11 15 11 4 17 13 22 11 11
18 43 20 19 29 8 34 11 15 11 4 17 13 22 11 11
24 7 33 25 8 3 7 8 13 10 11 20 5 26 9 6
0 9 0 2 4 6 2 7 5 1 4 7 5 5 0 3
nonsense nonsense nonsense non-stop non-stop non-stop non-stop Frameshift Frameshift Frameshift Frameshift Frameshift Frameshift Frameshift
23 21 5 7 5 31 20 5 39 17 39 21 37 16
23 21 5 7 5 31 20 5 39 17 39 21 37 16
11 25 9 27 2 24 17 0 10 8 4 4 20 5
3 5 0 0 5 0 5 2 5 9 5 5 0 0
deletion deletion deletion deletion deletion deletion deletion
SPRS, spastic paraplegia rating scale; MFIS total, total score modified fatigue impact scale; BPI, brief pain inventory; BDI, beck depression inventory.
pain related to spasticity was the most common pain subtype. In contrast, some patients reported burning or dysesthesic pain in the legs, not aggravated by movement and truly suggestive of a neuropathic component. In HSP, not only the corticospinal tracts but also the sensory pathways in the spinal cord are damaged. Therefore, it is possible that neurodegeneration extends to spinothalamic tracts and this might contribute to the painful sensations. The hypothesis of a dual mechanism for pain (nociceptive versus neuropathic) is similar to that reported in a closely related disorder, tropical spastic paraplegia caused by HTLV1 [13]. Pain treatment approaching both nociceptive and neuropathic mechanism could prove more effective for SPG4-HSP patients. In conclusion, it has been shown that fatigue, pain and depression are frequent manifestations in SPG4HSP. In future clinical trials, it would be important to assess the impact of potential disease-modifying
therapies on non-motor manifestations, since they are often more disabling than motor handicap per se.
Acknowledgements The work was supported by Fundac~ ao de Amparo a Pesquisa do Estado de S~ ao Paulo (FAPESP) and Coordenac~ ao de Aperfeicoamento de Pessoal de Nıvel Superior (CAPES).
Disclosure of conflicts of interest The authors declare no financial or other conflicts of interest.
References 1. Salinas S, Proukakis C, Crosby A, Warner TT. Hereditary spastic paraplegia: clinical features and pathogenic mechanisms. Lancet Neurol 2008; 7: 1127–1138.
© 2016 EAN
NON-MOTOR SYMPTOMS IN SPG4
2. Faber I, Servelhere KR, Martinez ARM, D’Abreu A, Lopes-Cendes I, Franca MC Jr. Clinical features and management of hereditary spastic paraplegia. Arq Neuropsiquiatr 2014; 3: 219–226. 3. Sauter S, Miterski B, Klimpe S, et al. Mutation analysis of the spastin gene (SPG4) in patients in Germany with autosomal dominant hereditary spastic paraplegia. Hum Mutat 2002; 20: 127–132. 4. Franca M Jr, Dogini D, D’Abreu A, et al. SPG4-related hereditary spastic paraplegia: frequency and mutation spectrum in Brazil. Clin Genet 2014; 86: 194–196. 5. Franca MC Jr, D0 Abreu A, Friedman JH, Nucci A, Lopes-Cendes I. Chronic pain in MachadoJoseph disease: a frequent and disabling symptom. Arch Neurol 2007; 64: 1767–1770. 6. Da Silva CB, Chevis CF, D0 Abreu A, Lopes-Cendes I, Franca MC Jr. Fatigue is frequent and multifactorial in Friedreich’s ataxia. Parkinsonism Relat Disord 2013; 19: 766–767. 7. Brusse E, Brusse-Keizer MGJ, Van Swieten JC. Fatigue in spinocerebellar ataxia: patient self-assessment of an early and disabling symptom. Neurology 2011; 76: 953–959.
© 2016 EAN
411
8. Vahter L, Braschinsky M, Haldre S, Gross-Paju K. The prevalence of depression in hereditary spastic paraplegia. Clin Rehabil 2009; 23: 857–861. 9. Pavan K, Schmidt K, Marangoni B, Mendes MF, Tilbery CP, Lianza S. Multiple sclerosis: cross-cultural adaptation and validation of modified fatigue impact scale. Arq Neuropsiquiatr 2007; 65: 669–673. 10. Bertolazi AN, Fagondes SC, Hoff LS, Pedro VD, Menna-Barreto SS, Johns MW. Portuguese-language version of Epworth sleepiness scale: validation for use in Brazil. J Bras Pneumol 2009; 35: 877–883. 11. Ferreira KA, Teixeira MJ, Mendonza TR, Cleeland CS. Validation of brief pain inventory to Brazilian patients with pain. Support Care Cancer 2011; 19: 505–511. 12. Gorenstein C, Andrade L. Validation of a Portuguese version of the Beck Depression Inventory and StateTract Anxiety Inventory in Brazilian subjects. Braz J Med Biol Res 1996; 29: 453–457. 13. Tavares IR, Franzoi AC, Ara ujo AQ-C. Low back pain in HTLV-I associated myelopathy/tropical spastic paraparesis: nociceptive or neuropathic? Spinal Cord 2010; 48: 134–137.
