- Email: [email protected]
Clinical Use of 4-aminopyridine in Patients With Downbeat Nystagmus
Acta Otorrinolaringol Esp. 2020;71(1):40---44
www.elsevier.es/otorrino
BRIEF COMMUNICATION
Clinical use of 4-aminopyridine in patients with downbeat nystagmus夽 Emilio Domínguez-Durán,a,∗ Irene Mármol-Szombathy,a Úrsula Ba˜ nos-Roldán,b Serafín Sánchez-Gómeza a b
Unidad de Gestión Clínica de Otorrinolaringología, Hospital Universitario Virgen Macarena, Sevilla, Spain Unidad de Gestión Clínica de Farmacia Hospitalaria, Hospital Universitario Virgen Macarena, Sevilla, Spain
Received 22 September 2018; accepted 30 November 2018
KEYWORDS Downbeat nystagmus; Fampridine
PALABRAS CLAVE Nistagmo vertical inferior; Fampridina
Abstract Objective: To present the results of treatment with sustained-release fampridine (4-AP-SR) in patients with downbeat nystagmus. Material and method: Series of cases with downbeat nystagmus treated with 10 mg of 4-AP-SR every 12 h. The clinical improvement and the variation of the nystagmus before and after the treatment were evaluated, recording the score in the Dizziness Handicap Inventory (DHI), the velocity of the slow phase of the nystagmus and its frequency. Results: Three patients were treated, none of whom reported significant subjective changes during the treatment. No significant differences were detected in the Dizziness Handicap Inventory score or in the studied videonystagmographic variables. Conclusion: This communication does not present positive results on the use of 4-AP-SR. The contradiction with previous studies may be caused by a small sample size, by the aetiology of the cases or by the way in which the results were measured. © 2019 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Experiencia de uso de fampridina en pacientes con nistagmo vertical inferior Resumen Objetivo: Presentar los resultados del tratamiento con fampridina de liberación prolongada (4-AP-SR) en pacientes con nistagmo vertical inferior.
夽
Please cite this article as: Domínguez-Durán E, Mármol-Szombathy I, Ba˜ nos-Roldán Ú, Sánchez-Gómez S. Experiencia de uso de fampridina en pacientes con nistagmo vertical inferior. Acta Otorrinolaringol Esp. 2020;71:40---44. ∗ Corresponding author. E-mail address: [email protected] (E. Domínguez-Durán). 2173-5735/© 2019 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Clinical use of 4-aminopyridine in patients with downbeat nystagmus
41
Material y método: Serie de casos de nistagmo vertical inferior tratados con 10 mg de 4-APSR cada 12 h. Se valoraron la mejoría clínica y la variación del nistagmo antes y después del tratamiento, registrando la puntuación en el Dizziness Handicap Inventory, la velocidad de la fase lenta del nistagmo y su frecuencia. Resultados: Se trataron 3 pacientes, ninguno de los cuales notó cambios durante el tratamiento en relación con los síntomas visuales, aunque 2 pacientes notaron mejoría subjetiva de la marcha. No se detectaron diferencias significativas en la puntuación del Dizziness Handicap Inventory ni en las variables videonistagmográficas estudiadas. Conclusión: No se han detectado cambios en los síntomas visuales con el tratamiento con 4-APSR. La contradicción con estudios previos puede estar producida por un bajo tama˜ no muestral, la etiología de los casos o la forma de medir los resultados. © 2019 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Downbeat nystagmus (DBN) is a vertical nystagmus where the rapid phase bats towards the inferior pole of the eye. It is normally associated with lesions of the vestibulocerebellum and the region adjacent to the medulla oblongata. These lesions alter the inhibition existing on the upper vestibular nucleus under normal conditions.1 Consequently, hyperexcitability of the motor neurons in the elevating musculature of the eye occurs, which gives rise to a nystagmus with a slow upwards phase. Fampridine or 4-aminopyridine (4-AP) is a drug that acts as a blocking antagonist of potassium channels.2 This drug is used in the hospital setting, which in our environment is dispensed as a sustained release drug, dalfampridine (4AP-SR). In Spain its use is authorized for improving walking ability in adult patients with multiple sclerosis who have a score of between 4 and 7 on the Expanded Disability Status Scale. Initial prescription should be limited to between 2 and 4 weeks, since generally the clinical benefits must be identified within this time period. Treatment must be suspended if no improvement in gait is observed or if the patients do not state they have received any benefit.3 During recent years, several studies have demonstrated the effectiveness of 4-AP in improving the slow phase velocity (SPV) of DBN,4 with 4-AP-SR being profiled for clinical usage, and obtaining an improvement in some of the patients treated.5 However, the use of this drug has not yet been systematized within therapeutic algorithms in most Spanish hospitals. The aim of this brief report is to present the results of treatment with 4-AP-SR in patients with DBN treated in our centre.
Material and method A case series of patients treated in our centre over the past 12 months with DBN. This nystagmus was an acquired nystagmus, present when seated, in primary gaze position and observable at a glance with a non instrumental examination. In all patients, non instrumental examination was
completed with a head impulse test and Pagnini-McClure y Dix-Hallpike benign paroxystic positional vertigo provocation manoeuvres. All patients underwent a cranial magnetic resonance. Evaluation prior to treatment was made with a videonystagmography, measuring the SPV and the frequency of the nystagmus. The nystagmus was measured with the patient lying down on his or her back with the head flexed at 30◦ . Nystagmus measurement was made using the interacoustic videonystagmography module in its 7.0.4.45 version through the software Otoaccess in its version 1.2.1. Before treatment, the patients were informed that a drug was going to be used in different conditions to those authorised on the specification sheet, in accordance with Royal Decree 1015/2009, of 19th June, governing the availability of medication in special situations, obtaining their informed consent. For at least 4 weeks, the patients were treated with 10 mg of oral 4-AP-SR every 12 h. Between 4 and 6 weeks after treatment initiation, the patients were asked about any subjective changes in their symptoms and a further videonystagmography was performed. Furthermore, the score in the Dizziness Handicap Inventory was taken before and after treatment. All results were compared using the Student’s t-test for paired samples. The patients included in this case series gave their written informed consent for the publication of their cases.
Results Three patients with DBN, whose characteristics are summarised in Table 1, were treated with 4-AP-SR. No changes were found from the head impulse test in any of them. In the benign paroxystic positional vertigo provocation test no nystagmus were found to suggest comorbidity with this disease. Magnetic resonance of patient number 2 was normal; the findings described in Table 1 appeared in patients numbers 1 and 3. During the review interview, regarding visual symptoms, none of the patients stated they had found themselves to be subjectively ‘‘better’’ during treatment nor after it had
42
Table 1 [1,0]Sex
Patient characteristics presented in this publication. [1,0]Age
[1,0]Time of nystagmus evolution
[1,0]Aetiology
[1,0]Ineffective previous treatments
51
1.5 years
Ischaemic or demyelinising lesion in protuberance
Amitriptyline
Male
69
5.5 years
In context of dystonic non filiated tremor
Baclofen
Male
27
1 year
One month after surgery for frontotemporal cyst, with no observable lesions in the posterior fossa,
Baclofen
Worse, Did not notice any improvement at any time whilst taking the drug The same. Noticed an improvement in visual stability some days during the third week of the drug which disappeared during the fourth week. Noticed greater security of gait. The same. Noticed an improvement in visual stability just one day during the third week of the drug which disappeared during the fourth week. Noticed greater security of gait.
[1,0]Moment of medication
[0,8-9] Dizziness Handicap Inventory
[0,1011]Angular velocity of slow phase of the nystagmus
[0,1213]Frequency of the nystagmus
Before
Before
After
◦
After
Before
After
◦
One day after terminating 4 weeks of treatment
92
92
1.7 /s
7.2 /s
0.1 Hz
0.3 Hz
During the sixth week of treatment
84
62
20.5◦ /s
22.7◦ /s
1.9 Hz
1.9 Hz
Eleven days after terminating 4 weeks of treatment
80
86
32.6◦ /s
52.7◦ /s
2.1 Hz
2.5 Hz
E. Domínguez-Durán et al.
Male
[1,0]General subjective state during treatment
Clinical use of 4-aminopyridine in patients with downbeat nystagmus terminated. In a more exhaustive anamnesis 2 of the patients stated a slight occasional subjective improvement during the third week of treatment, which lasted a day in the case of one patient and several in the case of the other. In these 2 cases this subjective improvement disappeared during the fourth week of treatment. The third patient stated they felt worse, but could not clarify if this was due to a worsening of their symptoms or the feeling of frustration of not have obtained the expected benefit. Data prior to the treatment of the 3 variables studied were normally distributed. The Student’s 2-tailed t-test for paired samples did not detect any significant differences in the Dizziness Handicap Inventory score before and after treatment (p = 0.595), nor for the SPV of the nystagmus (p = 0.234) or its frequency (p = 0.225). However, patients umber 2 and 3 referred to a subjective improvement in gait, which initially was not supposed to be treated and which had been initially attributed to the oscillopsia produced by the nystagmus. They both therefore decided to continue with medication.
43
Up until now, in our clinical experience, the use of 4AP-SR has not been shown to have positive results with regard to the reduction of the SPV. We have established 3 hypotheses to explain the results obtained and their apparent contradiction with the previous studies in the literature, where it does. Firstly it is possible that out results were due to the small sample size, unlike other studies,7,8 where the result of the low prevalence of DBN in the population, has prevented any statistical significance from being reached. Secondly, the 3 cases treated in our centre could be considered secondary, the group described with a lower response to treatment. Finally, it is possible that in one case the time between termination of treatment and performing the videonystagmography affected its result, although in previous studies an absence of significant differences were detected between the SPV prior to treatment and the SPV after 4 weeks of treatment.5 Notwithstanding, we believe the results obtained should be reported, particularly for the witness accounts of the patients during the clinical interview, in which none of them clearly referred to a subjective improvement in visual symptoms but they did to subjective improvement in gait.
Discussion Conclusion In 2003, a controlled clinical trial on 3.4 diaminopyridine (3.4-DAP) compared with placebo concluded that a single dose of this drug was able to improve the SPV of the DBN.6 This was a major step in the research with pyridines for the treatment of DBN, which up until that time continued without having any curative treatments. Several years later, in 2011, another clinical trial showed the superiority of the 4AP over the 3.4-DAP in reducing the SPV of the nystagus,7 which was attributed to higher liposolubility of the 4-AP and its ability to cross the haemoencephallic barrier. Due to this, a sustained-release formula was made, the 4-AP-SR, facilitating its use in clinical practice by providing a more constant concentration in the blood.5 It is known that not all cases of DBN respond to treatment with pyridines; the percentage of patients who respond, bearing in mind the improvement in SPV, has been estimated to be 57% for treatment with 4-AP.8 None of the 3 patients treated in our unit showed any reduction of SPV in their check-ups. This 0% of improvement of SPV does not significantly differ from the success rate referred to in the literatura8 (exact Fisher test p = 0.22). This absence of any significant difference is due to the low sample size which gives rise to a very broad confidence interval. DBN is not actually a disease in itself. It is a symptom which may present in several pathologies which affect the posterior cerebral fossa. It has therefore been reported that when no structural lesions are observed to confirm the presentation of nystagmus, i.e. when the DBN is primary and not secondary, the results obtained are better.6,8,9 This could be explained because the 4-AP, as a blocker of potassium channels, may act when the neurons present change at a molecular level, which are not detectable in imaging studies. Nevertheless, this could not be achieved in secondary cases, such as ischaemic or atrophic areas, where the nature of the damage would lead to the drug not being able to change the functioning of the affected neurons or complete their absence.
In the 3 cases of DBN treated in our centre with sustainedrelease famprydine during one month with a 10 mg dose every 12 h no significant changes were found in the magnitude of the videonystagmographic parameters or in the Dizziness Handicap Inventory. Also, there was no subjective improvement for visual symptoms in the clinical interview but there was some subjective improvement with regards to gait.
Financing This research did not receive any specific funding from public agencies, commercial entities or non profit-making agents.
Conflict of interests The authors have no conflict of interests to declare.
References 1. Wray SH. Oscillopsia, nystagmus, saccadic oscillations, and intrusions. In: Eye movement disorders in clinical practice [Internet]. Oxford, UK: Oxford University Press; 2014. Disponible en: http://oxfordmedicine.com/view/10.1093/med/97801999 21805.001.0001/med-9780199921805-chapter-10 2. EMA. Fampyra Assessment report. EMA/555661/2011. Committee for Medicinal Products for Human Use (CHMP). 23 June 2011. [Internet] [citado 2 Sep 2018]. Disponible en: http://www.ema. europa.eu/docs/en GB/document library/EPAR - Public assessment report/human/002097/WC500109957.pdf. 3. Ficha técnica Fampyra 10 mg [Internet] [citado 30 Ago 2018]. Disponible en: https://cima.aemps.es/cima/ pdfs/es/ft/11699003/FT 11699003.pdf.
44 4. Strupp M, Teufel J, Zwergal A, Schniepp R, Khodakhah K, Feil K. Aminopyridines for the treatment of neurologic disorders. Neurol Clin Pract. 2017;7:65---76. 5. Claassen J, Feil K, Bardins S, Teufel J, Spiegel R, Kalla R, et al. Dalfampridine in patients with downbeat nystagmus----an observational study. J Neurol. 2013;260:1992---6. 6. Strupp M, Schüler O, Krafczyk S, Jahn K, Schautzer F, Büttner U, et al. Treatment of downbeat nystagmus with 3,4-diaminopyridine: a placebo-controlled study. Neurology. 2003;61:165---70. 7. Kalla R, Spiegel R, Claassen J, Bardins S, Hahn A, Schneider E, et al. Comparison of 10-mg doses of 4-aminopyridine and 3,4diaminopyridine for the treatment of downbeat nystagmus. J Neuroophthalmol. 2011;31:320---5.
E. Domínguez-Durán et al. 8. Claassen J, Spiegel R, Kalla R, Faldon M, Kennard C, Danchaivijitr C, et al. A randomised double-blind, cross-over trial of 4-aminopyridine for downbeat nystagmus-effects on slowphase eye velocity, postural stability, locomotion and symptoms. J Neurol Neurosurg Psychiatry. 2013;84:1392---9. 9. Kalla R, Glasauer S, Büttner U, Brandt T, Strupp M. 4aminopyridine restores vertical and horizontal neural integrator function in downbeat nystagmus. Brain J Neurol. 2007;130 Pt 9:2441---51.
www.elsevier.es/otorrino
BRIEF COMMUNICATION
Clinical use of 4-aminopyridine in patients with downbeat nystagmus夽 Emilio Domínguez-Durán,a,∗ Irene Mármol-Szombathy,a Úrsula Ba˜ nos-Roldán,b Serafín Sánchez-Gómeza a b
Unidad de Gestión Clínica de Otorrinolaringología, Hospital Universitario Virgen Macarena, Sevilla, Spain Unidad de Gestión Clínica de Farmacia Hospitalaria, Hospital Universitario Virgen Macarena, Sevilla, Spain
Received 22 September 2018; accepted 30 November 2018
KEYWORDS Downbeat nystagmus; Fampridine
PALABRAS CLAVE Nistagmo vertical inferior; Fampridina
Abstract Objective: To present the results of treatment with sustained-release fampridine (4-AP-SR) in patients with downbeat nystagmus. Material and method: Series of cases with downbeat nystagmus treated with 10 mg of 4-AP-SR every 12 h. The clinical improvement and the variation of the nystagmus before and after the treatment were evaluated, recording the score in the Dizziness Handicap Inventory (DHI), the velocity of the slow phase of the nystagmus and its frequency. Results: Three patients were treated, none of whom reported significant subjective changes during the treatment. No significant differences were detected in the Dizziness Handicap Inventory score or in the studied videonystagmographic variables. Conclusion: This communication does not present positive results on the use of 4-AP-SR. The contradiction with previous studies may be caused by a small sample size, by the aetiology of the cases or by the way in which the results were measured. © 2019 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Experiencia de uso de fampridina en pacientes con nistagmo vertical inferior Resumen Objetivo: Presentar los resultados del tratamiento con fampridina de liberación prolongada (4-AP-SR) en pacientes con nistagmo vertical inferior.
夽
Please cite this article as: Domínguez-Durán E, Mármol-Szombathy I, Ba˜ nos-Roldán Ú, Sánchez-Gómez S. Experiencia de uso de fampridina en pacientes con nistagmo vertical inferior. Acta Otorrinolaringol Esp. 2020;71:40---44. ∗ Corresponding author. E-mail address: [email protected] (E. Domínguez-Durán). 2173-5735/© 2019 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Clinical use of 4-aminopyridine in patients with downbeat nystagmus
41
Material y método: Serie de casos de nistagmo vertical inferior tratados con 10 mg de 4-APSR cada 12 h. Se valoraron la mejoría clínica y la variación del nistagmo antes y después del tratamiento, registrando la puntuación en el Dizziness Handicap Inventory, la velocidad de la fase lenta del nistagmo y su frecuencia. Resultados: Se trataron 3 pacientes, ninguno de los cuales notó cambios durante el tratamiento en relación con los síntomas visuales, aunque 2 pacientes notaron mejoría subjetiva de la marcha. No se detectaron diferencias significativas en la puntuación del Dizziness Handicap Inventory ni en las variables videonistagmográficas estudiadas. Conclusión: No se han detectado cambios en los síntomas visuales con el tratamiento con 4-APSR. La contradicción con estudios previos puede estar producida por un bajo tama˜ no muestral, la etiología de los casos o la forma de medir los resultados. © 2019 Sociedad Espa˜ nola de Otorrinolaringolog´ıa y Cirug´ıa de Cabeza y Cuello. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction Downbeat nystagmus (DBN) is a vertical nystagmus where the rapid phase bats towards the inferior pole of the eye. It is normally associated with lesions of the vestibulocerebellum and the region adjacent to the medulla oblongata. These lesions alter the inhibition existing on the upper vestibular nucleus under normal conditions.1 Consequently, hyperexcitability of the motor neurons in the elevating musculature of the eye occurs, which gives rise to a nystagmus with a slow upwards phase. Fampridine or 4-aminopyridine (4-AP) is a drug that acts as a blocking antagonist of potassium channels.2 This drug is used in the hospital setting, which in our environment is dispensed as a sustained release drug, dalfampridine (4AP-SR). In Spain its use is authorized for improving walking ability in adult patients with multiple sclerosis who have a score of between 4 and 7 on the Expanded Disability Status Scale. Initial prescription should be limited to between 2 and 4 weeks, since generally the clinical benefits must be identified within this time period. Treatment must be suspended if no improvement in gait is observed or if the patients do not state they have received any benefit.3 During recent years, several studies have demonstrated the effectiveness of 4-AP in improving the slow phase velocity (SPV) of DBN,4 with 4-AP-SR being profiled for clinical usage, and obtaining an improvement in some of the patients treated.5 However, the use of this drug has not yet been systematized within therapeutic algorithms in most Spanish hospitals. The aim of this brief report is to present the results of treatment with 4-AP-SR in patients with DBN treated in our centre.
Material and method A case series of patients treated in our centre over the past 12 months with DBN. This nystagmus was an acquired nystagmus, present when seated, in primary gaze position and observable at a glance with a non instrumental examination. In all patients, non instrumental examination was
completed with a head impulse test and Pagnini-McClure y Dix-Hallpike benign paroxystic positional vertigo provocation manoeuvres. All patients underwent a cranial magnetic resonance. Evaluation prior to treatment was made with a videonystagmography, measuring the SPV and the frequency of the nystagmus. The nystagmus was measured with the patient lying down on his or her back with the head flexed at 30◦ . Nystagmus measurement was made using the interacoustic videonystagmography module in its 7.0.4.45 version through the software Otoaccess in its version 1.2.1. Before treatment, the patients were informed that a drug was going to be used in different conditions to those authorised on the specification sheet, in accordance with Royal Decree 1015/2009, of 19th June, governing the availability of medication in special situations, obtaining their informed consent. For at least 4 weeks, the patients were treated with 10 mg of oral 4-AP-SR every 12 h. Between 4 and 6 weeks after treatment initiation, the patients were asked about any subjective changes in their symptoms and a further videonystagmography was performed. Furthermore, the score in the Dizziness Handicap Inventory was taken before and after treatment. All results were compared using the Student’s t-test for paired samples. The patients included in this case series gave their written informed consent for the publication of their cases.
Results Three patients with DBN, whose characteristics are summarised in Table 1, were treated with 4-AP-SR. No changes were found from the head impulse test in any of them. In the benign paroxystic positional vertigo provocation test no nystagmus were found to suggest comorbidity with this disease. Magnetic resonance of patient number 2 was normal; the findings described in Table 1 appeared in patients numbers 1 and 3. During the review interview, regarding visual symptoms, none of the patients stated they had found themselves to be subjectively ‘‘better’’ during treatment nor after it had
42
Table 1 [1,0]Sex
Patient characteristics presented in this publication. [1,0]Age
[1,0]Time of nystagmus evolution
[1,0]Aetiology
[1,0]Ineffective previous treatments
51
1.5 years
Ischaemic or demyelinising lesion in protuberance
Amitriptyline
Male
69
5.5 years
In context of dystonic non filiated tremor
Baclofen
Male
27
1 year
One month after surgery for frontotemporal cyst, with no observable lesions in the posterior fossa,
Baclofen
Worse, Did not notice any improvement at any time whilst taking the drug The same. Noticed an improvement in visual stability some days during the third week of the drug which disappeared during the fourth week. Noticed greater security of gait. The same. Noticed an improvement in visual stability just one day during the third week of the drug which disappeared during the fourth week. Noticed greater security of gait.
[1,0]Moment of medication
[0,8-9] Dizziness Handicap Inventory
[0,1011]Angular velocity of slow phase of the nystagmus
[0,1213]Frequency of the nystagmus
Before
Before
After
◦
After
Before
After
◦
One day after terminating 4 weeks of treatment
92
92
1.7 /s
7.2 /s
0.1 Hz
0.3 Hz
During the sixth week of treatment
84
62
20.5◦ /s
22.7◦ /s
1.9 Hz
1.9 Hz
Eleven days after terminating 4 weeks of treatment
80
86
32.6◦ /s
52.7◦ /s
2.1 Hz
2.5 Hz
E. Domínguez-Durán et al.
Male
[1,0]General subjective state during treatment
Clinical use of 4-aminopyridine in patients with downbeat nystagmus terminated. In a more exhaustive anamnesis 2 of the patients stated a slight occasional subjective improvement during the third week of treatment, which lasted a day in the case of one patient and several in the case of the other. In these 2 cases this subjective improvement disappeared during the fourth week of treatment. The third patient stated they felt worse, but could not clarify if this was due to a worsening of their symptoms or the feeling of frustration of not have obtained the expected benefit. Data prior to the treatment of the 3 variables studied were normally distributed. The Student’s 2-tailed t-test for paired samples did not detect any significant differences in the Dizziness Handicap Inventory score before and after treatment (p = 0.595), nor for the SPV of the nystagmus (p = 0.234) or its frequency (p = 0.225). However, patients umber 2 and 3 referred to a subjective improvement in gait, which initially was not supposed to be treated and which had been initially attributed to the oscillopsia produced by the nystagmus. They both therefore decided to continue with medication.
43
Up until now, in our clinical experience, the use of 4AP-SR has not been shown to have positive results with regard to the reduction of the SPV. We have established 3 hypotheses to explain the results obtained and their apparent contradiction with the previous studies in the literature, where it does. Firstly it is possible that out results were due to the small sample size, unlike other studies,7,8 where the result of the low prevalence of DBN in the population, has prevented any statistical significance from being reached. Secondly, the 3 cases treated in our centre could be considered secondary, the group described with a lower response to treatment. Finally, it is possible that in one case the time between termination of treatment and performing the videonystagmography affected its result, although in previous studies an absence of significant differences were detected between the SPV prior to treatment and the SPV after 4 weeks of treatment.5 Notwithstanding, we believe the results obtained should be reported, particularly for the witness accounts of the patients during the clinical interview, in which none of them clearly referred to a subjective improvement in visual symptoms but they did to subjective improvement in gait.
Discussion Conclusion In 2003, a controlled clinical trial on 3.4 diaminopyridine (3.4-DAP) compared with placebo concluded that a single dose of this drug was able to improve the SPV of the DBN.6 This was a major step in the research with pyridines for the treatment of DBN, which up until that time continued without having any curative treatments. Several years later, in 2011, another clinical trial showed the superiority of the 4AP over the 3.4-DAP in reducing the SPV of the nystagus,7 which was attributed to higher liposolubility of the 4-AP and its ability to cross the haemoencephallic barrier. Due to this, a sustained-release formula was made, the 4-AP-SR, facilitating its use in clinical practice by providing a more constant concentration in the blood.5 It is known that not all cases of DBN respond to treatment with pyridines; the percentage of patients who respond, bearing in mind the improvement in SPV, has been estimated to be 57% for treatment with 4-AP.8 None of the 3 patients treated in our unit showed any reduction of SPV in their check-ups. This 0% of improvement of SPV does not significantly differ from the success rate referred to in the literatura8 (exact Fisher test p = 0.22). This absence of any significant difference is due to the low sample size which gives rise to a very broad confidence interval. DBN is not actually a disease in itself. It is a symptom which may present in several pathologies which affect the posterior cerebral fossa. It has therefore been reported that when no structural lesions are observed to confirm the presentation of nystagmus, i.e. when the DBN is primary and not secondary, the results obtained are better.6,8,9 This could be explained because the 4-AP, as a blocker of potassium channels, may act when the neurons present change at a molecular level, which are not detectable in imaging studies. Nevertheless, this could not be achieved in secondary cases, such as ischaemic or atrophic areas, where the nature of the damage would lead to the drug not being able to change the functioning of the affected neurons or complete their absence.
In the 3 cases of DBN treated in our centre with sustainedrelease famprydine during one month with a 10 mg dose every 12 h no significant changes were found in the magnitude of the videonystagmographic parameters or in the Dizziness Handicap Inventory. Also, there was no subjective improvement for visual symptoms in the clinical interview but there was some subjective improvement with regards to gait.
Financing This research did not receive any specific funding from public agencies, commercial entities or non profit-making agents.
Conflict of interests The authors have no conflict of interests to declare.
References 1. Wray SH. Oscillopsia, nystagmus, saccadic oscillations, and intrusions. In: Eye movement disorders in clinical practice [Internet]. Oxford, UK: Oxford University Press; 2014. Disponible en: http://oxfordmedicine.com/view/10.1093/med/97801999 21805.001.0001/med-9780199921805-chapter-10 2. EMA. Fampyra Assessment report. EMA/555661/2011. Committee for Medicinal Products for Human Use (CHMP). 23 June 2011. [Internet] [citado 2 Sep 2018]. Disponible en: http://www.ema. europa.eu/docs/en GB/document library/EPAR - Public assessment report/human/002097/WC500109957.pdf. 3. Ficha técnica Fampyra 10 mg [Internet] [citado 30 Ago 2018]. Disponible en: https://cima.aemps.es/cima/ pdfs/es/ft/11699003/FT 11699003.pdf.
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