Clinical/Scientific Notes Effect of 3,4-diaminopyridine on the gravity dependence of ocular drift in downbeat nystagmus

The pathomechanism of downbeat nystagmus (DBN) remains controversial but each mechanism has to account for 1) its gazeevoked vertical centripetal component which increases on down and lateral gaze,1 and 2) the vertical bias component of the upward slow phase velocity (SPV) in gaze straight ahead. The vertical velocity bias of DBN has a gravity-dependent component which leads to maximal drift velocity when patients lie in prone position and minimal in supine position.2 Recently, 3,4diaminopyridine (3,4-DAP)3 has been shown to be effective in reducing DBN in patients with their heads upright. However, DBN of several of those patients3 showed only small changes. One reason might be that gravity-dependent mechanisms were not considered. Patients and methods. A 63-year-old woman had a 4-year history of vertical oscillopsia, diplopia, blurred vision, and postural instability. Symptoms increased on downward gaze and considerably more when she bent her head forward. Clinically she showed DBN. In the head forward bending position there was a marked increase of DBN. Except for the tendency to fall backward, the neurologic examination was unremarkable. MRI, CSF, and blood screening were normal. Electronystagmography was normal except for mildly impaired horizontal smooth pursuit. DBN was superimposed on downward vertical smooth pursuit (gain: 0.54 at 0.3 Hz), upward pursuit was only slightly impaired (gain: 0.79). Saccades, subjective visual vertical, and funduscopy were normal.4 After the patient gave written consent DBN was recorded using the video-based Eyelink II system (SR Research, Toronto, Canada). Head-fixed LEDs attached to the headband of the Eyelink system were presented in front of the patient at a fixed distance (0.6 m) in gaze straight ahead and 10° up and down. Horizontal targets were presented at 40°. The head position was monitored by an inclinometer. The following five pitch positions of the head relative to the upright position were examined: head upright (0°), bending backward by 45° ( 45°) and 90° ( 90°), bending forward by 45° ( 45°) and 90° ( 90°). Eye position calibration was performed in vivo. Each eye movement channel was recorded with a sampling rate of 500 Hz and filtered using a Gaussian filter (50 Hz). Recordings of DBN were performed 15, 45, and 90 minutes after 20 mg 3,4-DAP ingestion (university hospital pharmacy). Nystagmus was detected semiautomatically, using a velocity criteria of 30°/second.4 Negative SPV indicates upbeating, positive downbeating nystagmus. Results. Prior to 3,4-DAP ingestion, the SPV of DBN was small, ranging from 0.8 0.3°/second in gaze straight ahead to 3.7 0.93°/second on lateral gaze. SPV of ocular drift varied as a function of head position (figure, A), e.g., SPV in gaze straight ahead increased from 0.8 0.3°/second in the upright head position to 12.6 1.1°/second in the 45° head position (anteflexion), and on lateral gaze from 3.7 0.9°/second to 23.6 1.7°/second (figure, B, baseline). In the 90° (“supine”) head position, DBN changed into an upbeat nystagmus (UBN) of 8.43 2.8°/second in gaze straight ahead. There were three main effects after 3,4DAP ingestion. First, SPV of DBN was hardly changed in the upright head position, either with gaze straight ahead (see figure, A) or in the lateral gaze position (see figure, B). Second, in the 90° (“prone”) head position SPV of DBN was reduced from 11.1 1.3°/second to 3.2 1.3°/second ( 70%) (see figure, A). In lateral gaze, in the 45° head position 15 minutes after ingestion, SPV was reduced from 23.6 1.7°/second to 14.8 2.8°/second (see figure, B). Third, SPV of UBN increased in the 90° head (“supine”) position 90 minutes after ingestion from 8.4 2.8°/second to 14.1 1.3°/second in gaze straight ahead (see figure, A), whereas it did not change in lateral gaze. These effects on positional DBN started after 15 minutes and lasted for at least 1 hour (see figure, B). In the 45° and 90° head position the patient noticed a strong improvement of blurred vision and oscillopsia disappeared. Thirty minutes after ingestion visual acuity was improved from 20/60 to 20/30. About 60 minutes after ingestion she noticed perioral and digital paresthesia for 10 minutes. Discussion. We show that 3,4-DAP exerts a distinct influence on the gravity-dependent component of the vertical velocity bias of DBN.2 This effect might account for why some DBN patients did not benefit from the therapy.3 The spontaneous upward drift in DBN may be due to a vestibular tone imbalance,5 an upward shift of the eyes’ null position for vertical gaze holding,6 or an asymmetry of vertical smooth pursuit signals.7 The reduction of DBN in the prone pitch position after 3,4-DAP ingestion seems to occur at the cost of increasing UBN, i.e., the velocity bias is shifted in a downward direction. However, the curve relating SPV to head position (see figure, A) was not shifted since differences of DBN in gaze straight ahead between baseline and 3,4-DAP were only found for prone and supine head positions. This indicates specific but asymmetric effects of 3,4-DAP on the gravity-dependent component but only minor effects on the gravity-independent bias. 3,4-DAP seems to reduce DBN by influencing the vestibulocerebellar inhibition, not only of anterior semicircular canal afferents3 but also of the physiologically overactive otolith-ocular reflex2 in an asymmetric way.