ABSTRACT

The objective of the study was to describe the clinical characteristics, treatment response and possible associated factors of patients with Guillain-Barré syndrome at the National Institute of Neurological Sciences. A descriptive study on hospital discharges was conducted during the period 2017-2019. Treatment response was evaluated based on Hughes’ disability scale. From 31 patients 61.3% were males and the mean age was 50 years. At admission, 87.1% of patients were on grade 3 or 4 of Hughes scale, most of them with axonal compromise which was associated to disability. Only 22 patients received plasma exchange; 6 months thereafter, 90.9% of patients decreased by at least one degree in Hughes scale and 42.8% were left without disability. In conclusion, a male and axonal subtype predominance was found, been the latter associated to disability.

Keywords:
Cerebrospinal Fluid; Axonal Neuropathy; Demyelinating Neuropathy; Poliradiculoneuropathy; Plasmapheresis; Peru; Plasmatic Therapeutic Exchange; Guillain-Barré Syndrome

INTRODUCTION

Guillain Barré syndrome (GBS) is an acute autoimmune polyradiculoneuropathy, characterized by progressive muscle weakness, sometimes with bulbar and respiratory impairment, and reaches maximum severity at between 2 to 4 weeks ¹1. Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA, Jacobs BC. Diagnosis of Guillain-Barre syndrome and validation of Brighton criteria. Brain. 2014;137: 33-43. doi: 10.1093/brain/awt285.
https://doi.org/10.1093/brain/awt285... . The incidence in Peru per 100,000 inhabitants/year varies between 0.62 and 0.92 ²2. Munayco CV, Soto M, Reyes M, Arica J, Napanga O. Epidemiología del síndrome de Guillain-Barré en el Perú. Rev Peru Med Exp Salud Publica. 2019;36(1):10-6. doi:10.17843/rpmesp.2019.361.3729.
https://doi.org/10.17843/rpmesp.2019.361... and at international level, it varies between 0.4 and 2.12 ³3. Capasso A, Ompad DC, Vieira DL, Wilder-Smith A, Tozan Y. Incidence of Guillain-Barré Syndrome (GBS) in Latin America and the Caribbean before and during the 2015-2016 Zika virus epidemic: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2019;13(8):e0007622. doi: 10.1371/journal.pntd.0007622.
https://doi.org/10.1371/journal.pntd.000... . The most affected age group in Peru is 20-59 years, mostly men and with an overall case fatality rate of 8.4% ²2. Munayco CV, Soto M, Reyes M, Arica J, Napanga O. Epidemiología del síndrome de Guillain-Barré en el Perú. Rev Peru Med Exp Salud Publica. 2019;36(1):10-6. doi:10.17843/rpmesp.2019.361.3729.
https://doi.org/10.17843/rpmesp.2019.361... . In the first half of 2018, 53 patients with GBS were reported in Lima ⁴4. Sistema de vigilancia epidemiológica del Centro Nacional de Epidemiologia, Prevención y Control de Enfermedades. Síndrome de Guillain Barré, Perú al 12 de Julio (SE 28) del 2018. Lima: CDC; 2018. Disponible en http://www.dge.gob.pe/portal/docs/vigilancia/boletines/2018/28.pdf.
http://www.dge.gob.pe/portal/docs/vigila... and in May of the same year the Ministerio de Salud declared a regional epidemiological alert for the presence of 15 cases in La Libertad region ⁵5. Equipo técnico. Brotes y epizootias en el Perú, SE 19-2018;27(SE 19):384-5. Lima: CDC; 2018. Disponible en http://www.dge.gob.pe/portal/docs/vigilancia/boletines/2018/19.pdf..

Treatment consists of plasmapheresis or therapeutic plasma exchange (TPE) and intravenous immunoglobulin (IVIG) ⁶6. Hughes RA, Swan AV, Raphaël JC, Annane D, van Koningsveld R. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain. 2007;130:2245-57. doi: 10.1093/brain/awm004.
https://doi.org/10.1093/brain/awm004... . TPE is effective within the first 4 weeks, mainly in the first 7 days ⁽⁷7. Chevret S, Hughes RAC, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2017;(2): CD001798. doi: 10.1002/14651858.CD001798.pub3.
https://doi.org/10.1002/14651858.CD00179... , hence the importance of early recognition of GBS. However, these treatments are not always available in all hospitals. The Instituto Nacional de Ciencias Neurológicas (INCN) currently has TPE and IVIG; but the clinical response is variable due to the influence of other factors such as age, time to treatment ⁸8. Rong-Kuo Lyu, Wei-Hung Chen, and Sung-Tsang Hsie. Plasma Exchange Versus Double Filtration Plasmapheresis in the Treatment of Guillain-Barré Syndrome. Therapeutic Apheresis. 2002;6(2):163-166. doi: 10.1046/j.1526-0968.2002.00382.x.
https://doi.org/10.1046/j.1526-0968.2002... , type of neurophysiological involvement (axonal or demyelinating) ⁹9. Del Carpio-Orantes L, Cerda-Méndez C, Jimenez-García A, Garma-García N, López-Cabrera Y, Flores-Salguero S, et al. Síndrome de Guillain Barré asociado a los brotes de Zika, de Brasil a México. Neurol Arg. 2012;(3): 147-152. doi: https://doi.org/10.1016/j.neuarg.2020.06.002.
https://doi.org/https://doi.org/10.1016/... ⁾ and preceding diarrhea ¹⁰10. Walgaard C, Lingsma HF, Ruts L, van Doorn PA, Steyerberg EW, Jacobs BC. Early recognition of poor prognosis in Guillain-Barré syndrome. Neurology. 2011;76(11);968-975. doi: 10.1212/WNL.0b013e3182104407.
https://doi.org/10.1212/WNL.0b013e318210... ; on the other hand, the severity of motor involvement or degree of disability, in-hospital infections and the need for ventilation lead to a worse prognosis ¹¹11. Jayasena Y, Mudalige S, Manchanayaque G, Dharmapala H, Kumarasiri R, Weerasinghe V, et al. Physiological changes during and outcome following 'filtration' based continuous plasma exchange in Guillain Barre Syndrome. Trans Apher Sci. 2010;42(2):109-113. doi: https://doi.org/10.1016/j.transci.2010.01.002.
https://doi.org/https://doi.org/10.1016/... .

The INCN receives patients with GBS from all over the country; Peru has a multicultural population; this allows us to describe our own clinical profile and to compare it with foreign publications; in addition, it is important to know if our response rate to treatment is comparable with other investigations. The objectives of our study are: 1) to describe the clinical and paraclinical characteristics of patients with GBS at INCN; 2) to determine the percentage of response to RPE; and 3) to identify the factors that influenced treatment.

THE STUDY

Design and population

A descriptive observational study was conducted at INCN, which is a specialized level IV health care institute that, being a national referral center, serves patients from all regions, languages, and cultures of Peru. We included all patients over 18 years of age hospitalized with the diagnosis of GBS, according to Brighton criteria ¹1. Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA, Jacobs BC. Diagnosis of Guillain-Barre syndrome and validation of Brighton criteria. Brain. 2014;137: 33-43. doi: 10.1093/brain/awt285.
https://doi.org/10.1093/brain/awt285... , between January 2017 and April 2019; medical records with incomplete data were excluded.

Procedures

A list of patients hospitalized during the study period with ICD-10 codes G61, G62, G63, G64 and G65 was requested from the Statistics Unit. After reviewing the medical records, those that met the study criteria were selected. The information was recorded on an anonymous card and then transferred to an electronic database, maintaining confidentiality at all times.

Variables

Age, muscle strength (quantified from 0 to 5 points according to the Medical Research Council for each extremity), time of illness on admission, time of hospitalization, time of illness at the time of TPE and at the time of lumbar puncture and cytochemical characteristics were analyzed as quantitative variables. Sex, degree of functionality, in-hospital infection, presence of albumin-cytological dissociation and type of neurophysiological involvement were analyzed qualitatively. The response to treatment was evaluated according to the modified Hughes functionality scale ⁶6. Hughes RA, Swan AV, Raphaël JC, Annane D, van Koningsveld R. Immunotherapy for Guillain-Barré syndrome: a systematic review. Brain. 2007;130:2245-57. doi: 10.1093/brain/awm004.
https://doi.org/10.1093/brain/awm004... ; according to the grade reached after six months of evolution, the patients were divided into two groups: a) without disability (grade 0 or 1) and b) with disability (grades 2, 3, 4 and 5).

Statistical analysis

Frequencies and percentages were calculated for qualitative variables. For quantitative variables that did not show normal distribution according to the Shapiro-Wilk test, the median and interquartile range (IQR) were used. The Chi-square test (or Fisher’s exact test, as appropriate) and the Mann Whitney U test were applied for the analysis of quantitative variables in relation to the presence of disability. A p value <0.05 was considered statistically significant. Data were analyzed with the Statistical Package for the Social Sciences (SPSS) version 20 program.

Ethical aspects

The study was reviewed and approved by the Institutional Research Ethics Committee of the INCN by certificate No 584-2019-CIEI-INCN. Only the investigators had access to patient information.

FINDINGS

Thirty-one medical records of patients with GBS were reviewed (28 patients belonged to level 1, and 3 patients belonged to level 2 of diagnostic certainty in the Brighton scale), most of them were male and had an average age of 50 years. At admission, the most frequent clinical findings were: quadriparesis in 28 patients, 13 of them also showed sensory symptoms in lower limbs, one patient also had cranial neuropathy, two patients presented Miller Fisher syndrome and one patient had the pharyngo-cervico-brachial variant. In addition, 16 (51.6%) presented dysautonomia (13 patients had altered heart rate and/or constipation, four had altered blood pressure and four had urinary retention). Seventeen patients were from the department of Lima. Only 22 patients (71%) received TPE; IVIG was not yet available (Table 1).

Cerebrospinal fluid (CSF) analysis was conducted in 27 (87.1%) patients (Table 2). In patients with normal CSF the analysis was carried out between 1 and 24 days of illness.

The neurophysiological test was carried out in 30 patients; nine cases (29%) were identified with the demyelinating variant or AIDP (acute inflammatory demyelinating neuropathy), 13 (41.9%) with the pure motor axonal form or AMAN (acute motor axonal neuropathy) and 5 (16%) with the acute motor-sensitive axonal form or AMSAN (acute motor-sensitive axonal neuropathy). Two patients had normal results from the test, and one patient had incomplete recruitment information; however, the presence of albumin-cytological dissociation supported the diagnosis according to Brighton criteria.

The TPE was conducted in 22 patients, all of whom received five sessions per day, 14 of whom were male (63.6%). One patient, who also had HIV infection, died of pneumonia two weeks after receiving TPE. After six months, 20 patients (90.9%) decreased at least one grade on the Hughes scale and nine patients (42.8%) had no disability (Table 3). No clinical complications associated with TPE were reported.

Of the total number of patients, 7 (22.6%) had in-hospital infections (three had urinary tract infection and four had pneumonia), of which 2 (6.4%) died of complicated pneumonia. Of these seven patients, five received TPE.

After analyzing age, sex, time of illness, time to initiation of TPE and the type of neurophysiological impairment, we found statistical significance in the latter, since the presence of axonal injury was significantly associated with disability after six months of evolution (p=0.02) (Table 4).

DISCUSSION

Our findings show male predominance, with an average age of 50 years; axonal involvement was associated with persistent disability, although most responded to treatment.

GBS predominantly affects males ³3. Capasso A, Ompad DC, Vieira DL, Wilder-Smith A, Tozan Y. Incidence of Guillain-Barré Syndrome (GBS) in Latin America and the Caribbean before and during the 2015-2016 Zika virus epidemic: A systematic review and meta-analysis. PLoS Negl Trop Dis. 2019;13(8):e0007622. doi: 10.1371/journal.pntd.0007622.
https://doi.org/10.1371/journal.pntd.000... . However, in an Indian study of 1,166 patients, Sudulagunta et al. found no sex differences and reported a mean age of 42.8 years ¹²12. Sudulagunta SR, Sodalagunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barré syndrome: clinical profile and management. Ger Med Sci. 2015;21:1-15. doi: 10.3205/000220.
https://doi.org/10.3205/000220... . On the other hand, in a multicenter study of 925 patients, Doets et al. found a slight male predominance (59.6%) and an average age of 51 years ¹³13. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al. Regional variation of Guillain-Barré syndrome. Brain.2018;141:2866-2877. doi: 10.1093/brain/awy232.
https://doi.org/10.1093/brain/awy232... . Finally, in the Peruvian epidemiological study of 955 patients by Munaico et al. the male sex represented 60.6% of the population and the average age was 40 years ²2. Munayco CV, Soto M, Reyes M, Arica J, Napanga O. Epidemiología del síndrome de Guillain-Barré en el Perú. Rev Peru Med Exp Salud Publica. 2019;36(1):10-6. doi:10.17843/rpmesp.2019.361.3729.
https://doi.org/10.17843/rpmesp.2019.361... . The average age and the predominance of the male sex found by our study is in concordance with what has been previously published, although there is currently a lack of studies that propose a biological explanation for the latter finding.

Most patients arrived at the INCN during the second week of illness, while in European and North American studies they arrived during the first week ¹³13. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al. Regional variation of Guillain-Barré syndrome. Brain.2018;141:2866-2877. doi: 10.1093/brain/awy232.
https://doi.org/10.1093/brain/awy232... ; this reflects the difficulty in accessing hospitals and the delay in diagnosis in developing countries, such as Peru. Consequently, the time of illness at the time of treatment was longer than what was described in other publications ¹⁴14. Maheshwari A, Sharma R, Prinja S, Hans R, Modi M, Sharma N, et al. Cost-minimization analysis in the Indian subcontinent for treating Guillain Barre Syndrome patients with therapeutic plasma exchange as compared to intravenous immunoglobulin. J Clin Apher. 2018;33(6):631-637. doi:10.1002/jca.21646.
https://doi.org/10.1002/jca.21646... . Hospital stay was longer than in other reports ²2. Munayco CV, Soto M, Reyes M, Arica J, Napanga O. Epidemiología del síndrome de Guillain-Barré en el Perú. Rev Peru Med Exp Salud Publica. 2019;36(1):10-6. doi:10.17843/rpmesp.2019.361.3729.
https://doi.org/10.17843/rpmesp.2019.361... ^,1212. Sudulagunta SR, Sodalagunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barré syndrome: clinical profile and management. Ger Med Sci. 2015;21:1-15. doi: 10.3205/000220.
https://doi.org/10.3205/000220... , since after treatment patients should continue with in-hospital rehabilitation until they reach the highest degree of independence possible, which is often not achieved due to lack of access to healthcare.

The classic presentation (sensorimotor) of GBS can reach up to 85% and the rest corresponds to atypical presentations ¹⁵15. Leonhard SE, Mandarakas MR, Gondim FAA. Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol. 2019;15:671-683. https://doi.org/10.1038/s41582-019-0250-9.
https://doi.org/10.1038/s41582-019-0250-... , as shown in our results. Dysautonomia is well described in the literature ¹⁵15. Leonhard SE, Mandarakas MR, Gondim FAA. Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol. 2019;15:671-683. https://doi.org/10.1038/s41582-019-0250-9.
https://doi.org/10.1038/s41582-019-0250-... and coincides with our results, the most frequent types are heart rate and rectal sphincter alteration.

Albuminocytological dissociation is defined as an increase in CSF proteins and cellularity lower than 50 ¹1. Fokke C, van den Berg B, Drenthen J, Walgaard C, van Doorn PA, Jacobs BC. Diagnosis of Guillain-Barre syndrome and validation of Brighton criteria. Brain. 2014;137: 33-43. doi: 10.1093/brain/awt285.
https://doi.org/10.1093/brain/awt285... . However, normal protein levels do not rule out the diagnosis and the presence of marked pleocytosis forces the search for infectious causes ¹⁵15. Leonhard SE, Mandarakas MR, Gondim FAA. Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol. 2019;15:671-683. https://doi.org/10.1038/s41582-019-0250-9.
https://doi.org/10.1038/s41582-019-0250-... . The frequency of this dissociation coincides with the medical literature.

Neurophysiological tests are not essential for diagnosis, but are recommended for atypical presentations ¹⁵15. Leonhard SE, Mandarakas MR, Gondim FAA. Diagnosis and management of Guillain-Barré syndrome in ten steps. Nat Rev Neurol. 2019;15:671-683. https://doi.org/10.1038/s41582-019-0250-9.
https://doi.org/10.1038/s41582-019-0250-... . In the patients of this study, the axonal subtype predominated, similar to what was described in other national publications ¹⁶16. Ballón-Manrique B, Campos-Ramos N. Características clínicas y paraclínicas del Síndrome de Guillain-Barré en el Hospital Regional Lambayeque. Rev Neuropsiquiatr. 2017;80(1):22-26. doi: https://doi.org/10.20453/rnp.v80i1.3056.
https://doi.org/https://doi.org/10.20453... ; however, in an investigation conducted at Hospital Dos de Mayo, the demyelinating subtype predominated ¹⁷17. Calle Vilca ML. Influencia de la plasmaféresis en la evolución clínica de los pacientes con síndrome de Guillain Barré en el Hospital Nacional Dos de Mayo. Enero 2005 - mayo 2010. [Tesis para especialidad]. Lima: Facultad de Medicina, Universidad Nacional Mayor de San Marcos; 2015. Disponible en http://repebis.upch.edu.pe/cgi-bin/wxis.exe/iah/scripts/.
http://repebis.upch.edu.pe/cgi-bin/wxis.... . In Latin America, demyelinating predominance has also been described when GBS was associated with arboviruses ¹⁰10. Walgaard C, Lingsma HF, Ruts L, van Doorn PA, Steyerberg EW, Jacobs BC. Early recognition of poor prognosis in Guillain-Barré syndrome. Neurology. 2011;76(11);968-975. doi: 10.1212/WNL.0b013e3182104407.
https://doi.org/10.1212/WNL.0b013e318210... . Other studies in Bangladesh and India also report a predominance of the demyelinating subtype ¹²12. Sudulagunta SR, Sodalagunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barré syndrome: clinical profile and management. Ger Med Sci. 2015;21:1-15. doi: 10.3205/000220.
https://doi.org/10.3205/000220... ^,1313. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al. Regional variation of Guillain-Barré syndrome. Brain.2018;141:2866-2877. doi: 10.1093/brain/awy232.
https://doi.org/10.1093/brain/awy232... . This variation could be explained by genetic determination, local exposure to infections (Campylobacter jejuni associated with the axonal subtype) and geographical origin ⁽¹³13. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al. Regional variation of Guillain-Barré syndrome. Brain.2018;141:2866-2877. doi: 10.1093/brain/awy232.
https://doi.org/10.1093/brain/awy232... .

Mechanical ventilation was required in 6.5% of the population, this proportion was lower than in other studies ¹²12. Sudulagunta SR, Sodalagunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barré syndrome: clinical profile and management. Ger Med Sci. 2015;21:1-15. doi: 10.3205/000220.
https://doi.org/10.3205/000220... ^,1313. Doets AY, Verboon C, van den Berg B, Harbo T, Cornblath DR, Willison HJ, et al. Regional variation of Guillain-Barré syndrome. Brain.2018;141:2866-2877. doi: 10.1093/brain/awy232.
https://doi.org/10.1093/brain/awy232... , even reaching 26% ⁽¹⁸18. Raphaël JC, Chevret S, Hughes RAC, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2): CD001798. doi: 10.1002/14651858.CD001798.
https://doi.org/10.1002/14651858.CD00179... . Our rate of in-hospital infections (19.3%) was also lower than other reports (37.5% to 49%)¹²12. Sudulagunta SR, Sodalagunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barré syndrome: clinical profile and management. Ger Med Sci. 2015;21:1-15. doi: 10.3205/000220.
https://doi.org/10.3205/000220... ^,1414. Maheshwari A, Sharma R, Prinja S, Hans R, Modi M, Sharma N, et al. Cost-minimization analysis in the Indian subcontinent for treating Guillain Barre Syndrome patients with therapeutic plasma exchange as compared to intravenous immunoglobulin. J Clin Apher. 2018;33(6):631-637. doi:10.1002/jca.21646.
https://doi.org/10.1002/jca.21646... . Finally, we found a mortality of 6.4%, which is within the 5% to 10% range reported in population-based studies ²2. Munayco CV, Soto M, Reyes M, Arica J, Napanga O. Epidemiología del síndrome de Guillain-Barré en el Perú. Rev Peru Med Exp Salud Publica. 2019;36(1):10-6. doi:10.17843/rpmesp.2019.361.3729.
https://doi.org/10.17843/rpmesp.2019.361... ^,1818. Raphaël JC, Chevret S, Hughes RAC, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2): CD001798. doi: 10.1002/14651858.CD001798.
https://doi.org/10.1002/14651858.CD00179... .

TPE was introduced in 1980 as the first treatment and in 1992 IVIG started to be used, both with the same effectiveness ¹⁹19. Kusunoki S. History of Guillain-Barré Syndrome. Brain Nerve. 2015;67(11):1295-1303. doi: 10.11477/mf.1416200299.
https://doi.org/10.11477/mf.1416200299... . INCN has had TPE since 2017 and IVIG since May 2019. Nine patients did not receive TPE mainly because they were outside the therapeutic window (4 weeks); of the remaining 22, 43.8% did not present disability after six months. In most patients, the Hughes scale decreased by at least one grade.

Improvement rates increase when the follow-up time is longer, as described in a systematic review where 57.1% reached at least one grade of improvement on the Hughes scale at four weeks after TPE, and complete recovery after 12 months in 67.8% of patients ¹⁸18. Raphaël JC, Chevret S, Hughes RAC, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2002;(2): CD001798. doi: 10.1002/14651858.CD001798.
https://doi.org/10.1002/14651858.CD00179... ; likewise, a multicenter study found that, after 12 months, 93.6% reached grade 0 and the remaining 6.4%, grade 1 ¹²12. Sudulagunta SR, Sodalagunta MB, Sepehrar M, Khorram H, Bangalore Raja SK, Kothandapani S, et al. Guillain-Barré syndrome: clinical profile and management. Ger Med Sci. 2015;21:1-15. doi: 10.3205/000220.
https://doi.org/10.3205/000220... .

Our study has limitations inherent to its design. The type of previous infection was not recorded in all cases. The lack of association of the factors influencing treatment can be explained by the size of the population. However, this is the first study in our setting in which the response to treatment after prolonged follow-up is analyzed. It is important to develop prospective studies in larger populations, including patients treated with IVIG.

In conclusion, GBS was more frequent in males, most with grade 3 or higher according to the Hughes scale, accompanied by dysautonomia in more than 50%. Most patients responded to treatment, which is evidenced by long-term follow-up. Finally, axonal impairment is corroborated as a factor associated with long-term disability.

References

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