Journal of Neuro-Ophthalmology:
Comparison of 10-mg Doses of 4-Aminopyridine and 3,4-Diaminopyridine for the Treatment of Downbeat Nystagmus
Kalla, Roger MD; Spiegel, Rainer PhD; Claassen, Jens; Bardins, Stanislavs MSc; Hahn, Ales MD; Schneider, Erich PhD; Rettinger, Nicole CO; Glasauer, Stefan PhD; Brandt, Thomas MD, FRCP; Strupp, Michael MD
Departments of Neurology and IFB (LMU) (RK, RS, JC, SB, ES, NR, SG, TB, MS) and Clinical Neurosciences (TB), Munich University Hospital, Campus Grosshadern, Munich, Germany; Psychiatric University Hospital (RS), University of Zurich, Zurich, Switzerland; Bernstein Center for Computational Neuroscience (SB, ES), Ludwig-Maximilians University, Munich, Germany; and ENT Department (AH), Third Medical Faculty, Charles University and Medical Faculty Hospital, Kralovske Vinohrady, Prague, Czech Republic.
Supported by a grant from the German Ministry of Education and Research (BMBF), grant 01EO0901 to the IFBLMU “Integriertes Forschungs - und Behandlungszentrum für Schwindel, Gleichgewichts- und Augenbewegungsstörungen.”
R. Kalla and R. Spiegel contributed equally to the study and share first authorship.
The authors report that they have no proprietary interest in the products mentioned in this article.
Ethics approval was provided in accordance with the national competence authority, the local ethics committee, and the Helsinki II legislation.
Address correspondence to Rainer Spiegel, PhD, Department of Neurology, Munich University Hospital, Campus Grosshadern, D-81377 Munich, Germany; E-mail: firstname.lastname@example.org
Objective: Animal experiments have demonstrated that aminopyridines increase Purkinje cell excitability, and in clinical studies, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP) improved downbeat nystagmus. In this double-blind, prospective, crossover study, the effects of equivalent doses of 4-AP and 3,4-DAP on the slow-phase velocity (SPV) of downbeat nystagmus were compared.
Methods: Eight patients with downbeat nystagmus due to different etiologies (cerebellar degeneration [n = 1], bilateral vestibulopathy [n = 1], bilateral vestibulopathy and cerebellar degeneration [n = 1], Arnold-Chiari I malformation and cerebellar ataxia [n = 1], cryptogenic cerebellar ataxia [n = 4]) were included. They were randomly assigned to receiving a single capsule of 10 mg of 3,4-DAP or 4-AP followed by 6 days with no medication. One week later, the treatment was switched, that is, 1 single capsule (10 mg) of the other agent. Recordings with 3-dimensional video-oculography were performed before and 45 and 90 minutes after drug administration.
Results: Both medications had a significant effect throughout time (pre vs post 45 vs post 90) (F(2,14) = 8.876; P < 0.01). Following the administration of 3,4-DAP, mean slow velocity decreased from −5.68°/s (pre) to −3.29°/s (post 45) to −2.96°/s (post 90) (pre vs post 45/post 90 P < 0.01). In 4-AP, the mean SPV decreased from −6.04°/s (pre) to −1.58°/s (post 45) to −1.21°/s (post 90) (pre vs post 45/post 90 P < 0.00001). Both after 45 and after 90, the mean SPVs were significantly lower for 4-AP than for 3,4-DAP (P < 0.05). None of the patients reported serious side effects.
Conclusion: Based on these results, 10-mg doses of 4-AP lead to a more pronounced decrease of the SPV of downbeat nystagmus than do equivalent doses of 3,4-DAP.
Downbeat nystagmus (DBN) is the most frequent type of acquired nystagmus that is present in primary position (1,2). It impairs vision due to vertical oscillopsia (2–4) and frequently leads to postural instability (1–6). DBN is often caused by an identifiable cerebellar pathology, including cerebellar degeneration (7), which affects the flocculus bilaterally (8–10). It has been hypothesized that the bias drift of DBN is caused by a reduced function of the inhibitory, vertical gaze, velocity-sensitive Purkinje cells (PCs) in the cerebellar flocculus (9). Because these cells show a physiological asymmetry, having a preponderance of cells with downward on-directions, their loss leads to disinhibition of neurons in the superior vestibular nucleus and the adjacent Y group and, hence, to spontaneous upward drift (11–13). In primary gaze, this upward drift leads to fast phases that are downward (4,14). This upward-directed drift generally increases in downgaze and decreases or even reverses in upgaze.
Clinical studies have shown that aminopyridines improve DBN (2,6,15–17). In patients with episodic ataxia type 2, aminopyridines also reduces interictal cerebellar ataxia (18) and the frequency of attacks (19). In addition, 3,4-DAP has been used in Lambert-Eaton myasthenic syndrome and 4-AP (in the sustained release form, Ampyra; Biogen Idec, Cambridge, MA) for gait impairment in multiple sclerosis (20–27).
Aminopyridines increase the resting activity and excitability of the PCs, which may restore their inhibitory influence on deep cerebellar nuclei and vestibular nuclei (28). It has also been demonstrated that therapeutic concentrations of 4-aminopyridine restore the diminished precision of pacemaking in PCs of the ataxic P/Q channel mutant mouse by prolonging the action potential and increasing the action potential after hyperpolarization (29). The effects of 4-AP on the cerebellum were confirmed by a positron emission tomographic study that showed that 4-AP increased metabolic activity bilaterally in the cerebellar flocculus (20).
We conducted a double-blind, crossover study to look at the effects of single doses (10 mg) of 4-AP or 3,4-DAP on the mean slow-phase velocity (SPV) in 8 patients with DBN prior to, 45 minutes after, and 90 minutes after administration. Obtaining our first measurement 45 minutes following the oral administration of the drugs was chosen because prior studies in patients with multiple sclerosis have shown that both drugs are rapidly absorbed with peak serum levels ranging from 20 to 60 minutes after dosing (21). We chose 90 minutes as our second measurement because serum half-life was reported to lie between 1 and 3 hours (21).
Eight patients with DBN were included in our study (Table 1). Mean duration of DBN was 7.8 years (range, 3–24 years) and patient age ranged from 58 to 76 years (mean, 68 ± 5.93 years). Patients were randomly assigned capsules of 10 mg of 3,4-DAP or 4-AP; they received 1 single capsule of either substance. There was a washout period of 6 days when no medication was given. One week later, the treatment was switched (i.e., they received a single capsule of the other substance). On both days of testing, the patients' eye movements were recorded prior to the administration of medication and 45 minutes and 90 minutes later. In the intervals between the recordings, patients rested in an upright position.
As in our previous studies (14), all patients underwent a complete clinical examination, including neuro-ophthalmological, neuro-otological, and neurological tests, high-resolution MRI of the brainstem and the cerebellum, electronystagmography with caloric irrigation, electrocardiography, and hematological tests, including vitamin B12 and magnesium levels. No patient was taking medication that affected the vestibular or ocular motor systems, and DBN was not caused by medication or a metabolic disorder. All patients gave informed consent, and the study was performed in accordance with the Helsinki II Declaration and was approved by the Ethics Committee of the Ludwig-Maximilians University Medical Faculty.
Recording of Eye Movements
During the 3 measurement sessions (before medication, 45 minutes and 90 minutes after medication), patients were monitored in an upright position. A 30-second eye movement recording was made with 3-dimensional video-oculography (GN Otometrics Hortmann Vestlab 100 (GN Store Nord, Ballerup, Denmark), with a 50 Hz sampling rate, 0.1° resolution in horizontal and vertical directions, accuracy of 0.6°, a range of ±30° in the horizontal and vertical directions) (14,23). It took place in the following order (calibration in 8.5° position): 1) gaze straight ahead with fixation turned on; 2) gaze straight ahead in darkness (with no possibility to fixate on a fixation point); 3) 17° rightward gaze; 4) 17° leftward gaze; 5) 17° upward gaze; and 6) 17° downward gaze. The target was projected by laser onto a white background placed 60 cm in front of the patient. For every recording, the chair and head restriction were adjusted so that the target appeared at eye level and the head was fixed in position.
Monitoring of Side Effects
Before providing their informed consent, all patients had received information about possible medication side effects. They were asked immediately, 30 minutes, 1 hour, and 2 hours after taking the medication whether they were experiencing any side effects.
Data Acquisition and Calibration
Eye position was measured with 3-dimensional video-oculography (23) for 30 seconds. Data were analyzed off-line using Matlab (Mathworks, Natick, MA). The calibrated data were low-pass filtered applying a digital Gaussian filter with a bandwidth of 30 Hz, smoothing out higher-frequency components above 30 Hz in the eye position data. The calculated filter coefficients were convolved with the eye position data in Matlab software (Mathworks). Eye velocity was calculated from this smoothed signal by numerical differentiation. Saccades were detected automatically by the software program and manually checked by a trained technician. This was particularly important in patients with a high frequency of saccades. Possible detection errors were corrected manually, and the mean SPV was computed from this data.
Statistical Data Analysis
Repeated measurement analysis of variances (Statistica 6.1; Statsoft, Tulsa OK) were carried out along with post hoc Scheffé tests for individual comparisons. SPV of vertical eye movements was the dependent variable. The values of all the following figures were transformed so that DBN indicated by SPV degrees/second (°/s) appears as a negative value on the scale, whereas the absence of DBN appears as a (close to) zero value. The analysis included the following: fixation (=light on) vs viewing in the dark (=light off), medication type (4-AP vs 3,4-DAP), and time (before medication, 45 minutes after medication, 90 minutes after medication).
Both medications had a salutary effect on DBN. Representative eye movement recordings are illustrated in Figure 1. The analysis of variance included a comparison between both medications over time (pre vs post 45 minutes vs post 90 minutes). This analysis was significant (P < 0.01) with the F test reaching a value of 8.88 (numerator degrees of freedom = 2, denominator degrees of freedom = 14).
Following the administration of 3,4-DAP, mean SPV decreased from −5.68°/s (pre) to −3.29°/s (post 45) to −2.96°/s (post 90) (with Scheffé post hoc comparisons between pre and post 45/post 90; P < 0.01). Following the administration of 4-AP, mean SPV decreased from −6.04°/s (pre) to −1.58°/s (post 45) to −1.21°/s (post 90) (with Scheffé post hoc comparisons between pre and post 45; P < 0.00001, and between pre and post 90; P < 0.00001). While the pre-mean SPV measurements of both medications did not significantly differ from each other (−6.04°/s vs −5.68°/s; P = 0.97), both post 45 and post 90 SPV measurements were significantly lower for 4-AP than for 3,4-DAP (–1.58°/s vs −3.29°/s and –1.21°/s vs –2.96°/s with each Scheffé test; P < 0.05) (Fig. 2).
All patients apart from Cases 2 and 5 responded with a mean SPV decline after the administration of 3,4-DAP. After the administration of 4-AP, Case 2 again did not respond with a decline in mean SPV, while Case 5 showed a reverse from negative mean SPV values (DBN) to positive values (indicating upbeat nystagmus).
Additional significant findings included the effect of time for both medications: pre vs post 45 vs post 90 (F(1,7) = 10.72; P < 0.01); individual Scheffé tests between pre and post 45 (P < 0.01), between pre and post 90 (P < 0.01), and between post 45 and post 90 (P > 0.05). DBN also had a lower mean SPV in light (F(1,7) = 14.14; P < 0.01). Fixation on the target (=light on) was associated with an average SPV value of –2.23°/s. No fixation (=light off) was associated with an average SPV value of −4.69°/s.
All 8 patients reported mild paresthesias from 30 minutes to 2 hours after ingestion of both medications. No other side effects were reported.
It had been previously shown that both 4-AP and 3,4-DAP decrease the mean SPV of DBN (2,21,23–25). It was unclear whether they differ in terms of their treatment efficacy. Therefore, identical single 10-mg doses of both aminopyridines were compared in our double-blind study with crossover design. Our results demonstrate that 4-AP decreased the intensity of DBN significantly more than did 3,4-DAP. This may be due to the different pharmacokinetics and the action of the 2 aminopyridines in blocking cellular potassium channels. Would these results be different if we had observed the effects of 3,4-DAP and 4-AP over a longer period of time? We do not expect a different outcome because both medications reach their peak serum level approximately 60 minutes after oral administration (21). There are conflicting reports that the 2 drugs may have similar half-lives (21) or that 4-AP has a longer half-life than 3,4-DAP (26,27,30,31). In addition, 4-AP has a better ability to cross the blood-brain barrier because it is highly lipid soluble and able to block K+ channels in both the central and peripheral nervous systems (21,26,27,30–32). 3,4-DAP is only soluble in aqueous solution and does not cross the blood-brain barrier easily. It acts primarily to block K+ channels in the peripheral nervous system (23). Given that DBN is a central ocular motor disorder, one would expect 4-AP to have a greater effect on DBN.
With the exception of paresthesias, none of our patients experienced side effects after ingestion of either medication. There were similar complaints following the administration of both medications. This is consistent with previous studies (2,15–17,21,33–35). Not all patients may be eligible for aminopyridines due to prolonged frequency-corrected QT intervals in the electrocardiogram, where potassium-blocking drugs, such as aminopyridines, could lead to dangerous cardiac arrhythmias. As an alternative, one might want to consider behavioral approaches to reduce DBN, for example, to rest in upright head position (36).
Our study was limited in that we only assessed mean SPV as a measure of improvement in DBN. For future studies, it will be important to look at other parameters, including visual acuity, nystagmus amplitude, and nystagmus frequency.
The authors thank Judy Benson for proofreading the manuscript and all patients for taking part in the study. They also thank Dr Rainer Spiegel and Dr Stefan Glasauer who carried out the statistical analyses and Dr Erich Schneider and by Dr Ales Hahn for providing additional technical and statistical advice (with an emphasis on the 3D video-oculographic device).
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