Upbeat nystagmus: Clinicopathological and pathophysiological considerations

Journal of the Neurological Sciences, 105 (1991) 159-167

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© 1991 Elsevier Science Publishers B.V. All rights reserved 0022-510X/91/$03.50 JNS 03621

Upbeat nystagmus: clinicopathological and pathophysiological considerations Genjiro Hirose 1, Junya Kawada 1, Katsuyuki Tsukada 1, Akira Yoshioka 1 and James A. Sharpe 2 1Department of Neurology Kanazawa Medical University, Uchinada, Ishikawa (Japan), and 2 The Toronto Hospital, Universityof Toronto, Toronto, Ontario (Canada)

(Received 28 February, 1991) (Revised, received 10 May, 1991) (Accepted 24 May, 1991) Key words: Upbeat nystagmus; Vertical vestibulo-ocular reflex; Ventral tegmental pathway

Summary We describe an electro-oculographic study of upbeat nystagmus in 4 patients, with neuropathological correlation in one. All patients had lesions in the pontine tegmentum. The electro-oculographic data may be explained by imbalanced vertical vestibular or smooth pursuit eye movement control. The nystagmus stopped or reversed direction during convergence or in supine head positions. We propose that changes in the intensity or direction of upbeat nystagmus that are induced by convergence or changes in head position, are caused by vertical imbalance in the otolithic-ocular reflex, when superimposed on an imbalanced vestibulo-ocular reflex (VOR). Imbalance of the otolithic-ocular reflex and the vertical VOR are caused by damage in the pontomedullary tegmentum.

Introduction Upbeat nystagmus is an ocular oscillation in which the fast phase of the nystagmus is directed upward during gaze in the primary position. It usually increases in intensity during upward gaze and decreases during downward gaze but occasionally the reverse effect occurs (Fisher et al. 1983). Some cases of primary position upbeat nystagmus have been associated clinically with lesions of the midbrain (Troost et al. 1980; Keane 1990), cerebellar vermis (Bender and Gorman 1949), brachium conjunctivum (Nakada and Remler 1981), and lower brainstem particularly in the medulla (Gilman et al. 1977; Kato et al. 1985). However, only the latter two sites have been pathologically confirmed. Although the mechanism of this disorder is unknown, an imbalance in the central vertical vestibulo-ocular pathway (Nakada and Remler 1981; Baloh and Spooner 1981; Ranalli and Sharpe 1988) or an imbalance in the vertical smooth pursuit (Gilman et al. 1977; Zee et al.

Correspondence to: Genjiro Hirose, M.D., Department of Neurology, Kanazawa Medical UniversityUchinada, Kahoku-gun, Ishikawa Prefecture, Japan, 920-02. Tel.: 0762-86-2211; Fax: 0762-86-3259,

1974; Medhorn et al. 1979) have been suggested as the cause of this nystagmus. We report here clinical electro-oculographic (EOG), computed tomography (CT) and magnetic resonance image correlations of the responsible lesions from 4 patients with primary position upbeat nystagmus. We describe the neuropathological findings in one patient and discuss the pathophysiology of primary position upbeat nystagmus.

Patients and methods

Patient 1

A 35-year-old woman had progressive hicough, vomiting, oscillopsia and bulbar weakness over a month. Examination revealed primary position upbeat nystagmus which increased in amplitude with upward gaze and decreased in amplitude with downward gaze, and right beating nystagmus on gaze to the right. Voluntary saccades appeared to be normal in all directions. She had normal convergence and pupillary reactions. She had normal corneal reflexes but hypalgesia around both sides of her nose, mild facial diplegia of periph-

100

era1 origin were observed. Hearing was intact. She had decreased palatal movements with deviation of the uvula to the left and abolished gag reflex bilaterally. Her tongue was weak and showed bilateral fasciculation and atrophy. The left Sterno-cleidomastoid muscle was weak. She had left hemiparesis with bilateral extensor plantar responses and hyperactive tendon reflexes, but no cerebellar signs. Cerebrospinal fluid examinations revealed normal pressure, cytology, protein and sugar. Oligoclonal IgG bands and increased myelin basic protein were present. A magnetic resonance scan revealed a high signal lesion in the pontomedullary junction in T, weighted images (Fig. 1). She had two remissions and exacerbations within a year with documented MRI lesions in the pons and cervical cord and retrobulbar neuritis in each eye on different occasions. Multiple sclerosis was diagnosed. Patient 2

An 81-year-old hypertensive woman suddenly fell to the floor, became unconscious with vomiting and laboured respiration and was brought to hospital. She was stuporous with a blood pressure of 238/148 mm Hg, and irregular respiration. She had bilateral pinpoint pupils and a skew deviation with her right eye deviating downward and medially. Horizontal eye movements were not elicited by doll’s eye (oculocephalit) maneuver nor ice water caloric tests bilaterally, but she had full vertical eye movements by oculocephalic maneuvers. She had occasional ocular bobbing and quadriplegia with decerebrate rigidity to painful stimuli. CT scans on admission revealed pontine hemorrhage. Nine days after admission, she developed

Fig.

I, Sagittal and coronal magnetic

prominent upbeat nystagmus in primary gaze at 3 Hz which persisted until she died from progressive respiratory failure 4 months later. Neuropathological examination. The cerebrum was atrophic with enlarged sulci and ventricles. Pontine hemorrhage involved the tegmentum, destroying the medial lemniscus bilaterally, the right brachium conjunctivum, right medial longitudinal fasciculus and right central tegmental tract (Fig. 2). No lesions were found in the medulla, including the hypoglossal and prepositus hypoglossal nuclei (Fig. 2d). The right inferior olivary nucleus was hypertrophic, a change secondary to the right central tegmental tract damage. Patient 3

A 6O-year-old hypertensive woman was admitted to a local hospital because of the sudden onset of unconsciouness. CT showed pontine hemorrhage. Thirteen days later, she was transferred to our hospital. On admission she was deeply comatous. Her pupils were small with a diameter of 2 mm on the right and 1.5 mm on the left and both reacted to light. Horizontal eye movements were not elicited by oculocephalic maneuvers or by bilateral caloric tests but a full range of vertical eye movements were elicited. She had occasional ocular bobbing. She was totally areflexic without any limb movements or plantar responses. Twenty days after presentation, she showed spontaneous horizontal eye movements. On the 30th day, she started to react to verbal commands by eye opening and closure. On the 69th day, she started to move her right hand. Eighty days after onset, she was noted to have upbeat nystagmus in primary gaze, which became prominent

resonance images m patient 1 with multlple sclerosis. Increased signals in the caudal ponto-medullary junction were seen in the T2 images (TR: 1600, TE: 70).

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161 gradually and persisted over nine years of follow up. She also developed palatal myoclonus 1.5 years after the ictus. This palatal tremor was not synchronous with the upbeat nystagmus. Her upbeat nystagmus was more intense in the sitting position than in the supine position, and inverted to downbeat nystagmus by the head hanging position. The nystagmus was decreased in intensity during binocular fixation to a near (20 cm) target. The recent MRI revealed a lesion in the mid pontine tegmentum, which had a low signal in the T 1 image and a high signal in the T 2 image (Fig. 3). Patient 4 A 59-year-old hypertensive man suddenly fell and became comatous with severe vomiting. He was brought to a local hospital where brain CT showed a pontine hemorrhage. A neurologist reported that he had bilateral horizontal gaze palsy, bulbar palsy and quadriplegia. Bulbar palsy and quadriplegia gradually improved over 2 months. Five months after the onset, he was found to have primary gaze upbeat nystagmus and 6 months later, palatal myoclonus. He was transferred to our hospital, alert and oriented to three spheres. His

speech was dysarthric but he was able to communicate. His pupils were equal and reacted to light. He had continuous upbeat nystagmus in primary gaze. He had a complete leftward gaze palsy, and left internuclear ophthalmoplegia, indicating a left one-and-a-half syndrome. Right lateral gaze and adduction of the right eye were moderately restricted in range. Vertical saccades were slow but the eye movements were full with superimposed upbeat nystagmus, which was more intense in upward gaze. The upbeat nystagmus was more intense in erect than in supine position. The upbeat nystagmus changed to downbeat nystagmus when he bent forward with his headdown position. He had mild facial diplegia and loss of pin and light touch sensation over the right face. He had occasional palatal and right hand myoclonus which were not synchronous with the upbeat nystagmus. He had right arm and leg weakness and hemisensory loss, and bilateral hyperreflexia and extensor plantar responses. The MRIs revealed a well localized pontine tegmental lesion, which was low in the T 1 and high in signal in T z images, consistent with old pontine hemorrhage (Fig. 4).

Fig. 2. Neuropathologicai findings in patient 2. Pontine hemorrhage extended to the level of the meseneephalon on the right side. At the midpontine level, the ventral pontine tegmentum was involved bilaterally (c), whereas the dorsal tegmentum was destroyed on the right side (b) with the involvement of the central tegmental tract. Pseudohypertrophy of the right inferior olive was present (d).

Electro-oculographic study Eye movements were recorded using direct current coupled electro-oculography (EOG). Horizontal movements were recorded by electrodes at the inner and outer canthi and vertical movements were recorded with electrodes placed above the eyebrow and below the lower eyelid. The bandwidth of the recording system was 0-20 Hz ( - 6 dB). The nystagmus was recorded with the eyes open and closed in the primary position and on gaze to the right, left, up and down. The effect of loss of fixation on the spontaneous nystagmus was assessed by recording in the dark with the eyes open. The effects of tilt were examined by tilting patients from sitting position to supine, and to a head-hanging position. Saccadic and pursuit eye movements were tested using a hand-held target and with a dot on a projection screen that moved stepwise and at constant velocities in a sinusoidal pattern. Vestibular function was tested using bithermal (30°C and 44 °C) caloric stimulation of each horizontal semicircular canal. Results

In patient one, upbeat nystagmus in the primary position of gaze was recorded with 10-20 degree am-

plitude and 3-4 Hz. The nystagmus increased in amplitude with upward gaze and decreased in amplitude with downward gaze (Fig. 5). In lateral gaze, right beating horizontal nystagmus in right gaze and a low amplitude left beating nystagmus in left gaze were noted with some upward components in both directions. Horizontal and upward vertical smooth pursuit was impaired (Fig. 6). The upbeating nystagmus changed to downbeating nystagmus as the eyes converged on an near target (Fig. 7). Static tilt between supine and upright position influenced the upbeat nystagmus in this patient; the nystagmus intensity (frequency and amplitude) was greatest at the 40 degree upright position (Fig. 8). The frequency of the nystagmus changed from 5 to 3 Hz from the supine to the upright position. The upbeat nystagmus in the sitting position changed to fine downbeat nystagmus in the head-hanging position. It is of particular note that nystagmus attenuated markedly in the darkness with the eyes open (Fig. 9). The nystagmus was abolished with Frenzel's glasses in the supine position and attenuated in the upright position. The responses to caloric irrigation of each ear were normal except for poor visual suppression. In patient 2, similar upbeat nystagmus was recorded in primary gaze with a frequency of about 3 Hz. No

Fig. 3. Magnetic resonance Tz weighted images of patient 3. A high signal lesion indicated a cavitation connected to the 4th ventricle with surrounding low signal areas, which probably reflect liquefying necrotic lesions.

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Fig. 4. Magnetic resonance T2 weighted images of patient 4. A similar lesion was found in the pontine tegmentum. A notable feature is the pseudohypertrophy of the inferior olivary complex (arrow).

further EOG studies were successful due to her clinical conditions and bilateral horizontal gaze palsy. In patient 3, the upbeat nystagmus was more promi-

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20 cm. In patient 4, nystagmus was also intense with higher amplitude during upward gaze and less prominent during downward gaze. The nystagmus was more pronounced while in upright position than in supine position. The direction of the nystagmus changed to downward when his head was hanging in supine posi-

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tion and bending forward with the head down in an upright position (Fig. 10). His nystagmus did not change frequency or amplitude in darkness. The effects of position change on the upbeat nystagmus in these patients are summarized in Table 1.

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Discussion

Pathologically confirmed lesions associated with primary position upbeat nystagmus have involved the pontomedullary tegmentum (Fisher et al. 1983; Gilman et al. 1977; Keane and Itabashi 1987) with the exception of a case with a rostral cerebellar tumor (Nakada and Remler 1981). Our patients also had lesions in the caudal brainstem. Because of these correlations, Ranalli and Sharpe (1988) proposed that a ventral tegmental pathway subserving the upward VOR was responsible for upbeat nystagmus. According to their proposal, destruction of either the ascending route of the upward VOR pathway from the superior vestibular nuclei via the superior cerebellar peduncles to the midbrain, or destruction of a ventral tegmental pathway from the superior vestibular nucleus within the

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brainstem tegmentum to the oculomotor and trochlear nuclei (Carpenter and Cowie 1985), would imbalance the vertical VOR. Downward bias of the VOR would cause the eyes to glide down and corrective quick phases would account for upbeat nystagmus. Disruption of tegmental circuits that transmit an otolithic

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166 TABLE 1 EFFECTS OF POSITION CHANGE ON THE INTENSITY OR DIRECTION OF UPBEAT NYSTAGMUS Patient No. l 2 3

Statictilt: supine vs. upright Upright - increased (40 upright : maximal) Upright - increased Upright - increased

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Head-hanging position Inverted to downbeat nystagmus Not done Inverted to downbeat nystagmus Inverted to downbeat nystagmus (Bending forward head position also inverted)

contribution of the upward V O R may explain the variable influence of static head tilt on upbeat nystagmus (Fisher et al. 1983). In our patients 1, 3, and 4, the upbeat nystagmus was maximal in the erect position, decreased in the supine position, and in patients 1 and 4, reversed direction in the head hanging supine position or bending forward sitting position. The neuropathological findings in our patient 2 showed consistent damage to the ventral tegmentum as a mechanism of primary position upbeat nystagmus (Ranalli and Sharpe, 1988) since the pontine hemorrhage located in the tegmentum would disrupt the ventral tegmental pathway (Carpenter and Cowie 1985). It spared most of the brachium conjunctivum (Fig. 2), which also transmits excitatory projections from the anterior semicircular canals that activate the upward V O R (Ito et al. 1976). According to one theory, primary position vertical nystagmus is caused by vertical imbalance in the smooth pursuit system, be it upbeating or downbeating (Gilman et al. 1977; Zee et al. 1974). The nystagmus beats in the direction of impaired pursuit. However a subsequent study identified imbalance in the vertical V O R in downbeat nystagmus (Baloh and Spooner 1981) supporting central vestibular imbalance as the mechanism for primary position vertical nystagmus. In patients 3 and 4, the nystagmus was seen in conjunction with palatal myoclonus, caused by the involvement of the central tegmental tract by pontine hemorrhage. In these patients, the upbeat nystagmus was distinguished from the pendular nystagmus, that is sometimes associated with palatal myoclonus, by the upward quick phases. The simultaneous E O G and palatal recordings failed to show synchrony between the eye movements and branchial muscle myoclonus. The palatal myoclonus in these 2 patients varied irregularly around a fixed frequency of 150 per min and responded to treatment with clonazepam, whereas the upbeat nystagmus was regular and persisted with the medication.

The nystagmus in patient 1 was enhanced by fixation and abolished by darkness. Since vestibular nystagmus of peripheral nerve or labyrinthine origin is characteristically enhanced by darkness and suppressed by fixation, our patient provides evidence that upbeat nystagmus might not be caused by imbalance of a vestibuloocular pathway alone. Simultaneous involvement of smooth pursuit pathways or circuits that cancel the V O R (Sharpe et al. 1981; Barr et al. 1976) may explain the failure of fixation to suppress the upbeat nystagmus. In contrast to peripheral vestibular nystagmus, fixation actually enhanced the upbeat nystagmus in patient 1. In patient 1 the upbeat nystagmus disappeared during binocular fixation of a target 25-30 cm away and changed to downbeating nystagmus when the target moved closer to the patient, as documented in a previously reported case (Cox et al, 1981). This unusual effect of convergence on the nystagmus (Kelly et al. 1989) might be related to effects of vergence on V O R gain. When normal subjects fixated a nearby object, V O R gain must increase in order to stabilize images on the retina during head movement (Viirre et al. 1986). This physiological increase in V O R gain is required since the eyes are anterior to the center of rotation of the head, and must move through a larger angle of rotation than the head in order to view the target (Viirre et al. 1986). Otolithic receptors sense translation of the head and otolithic-ocular reflex gain (the ratio of eye velocity to head translation velocity) is added to the gain of the semicircular canal-based V O R (Viirre et al. 1986). In upbeat nystagmus the vertical V O R seems to be imbalanced for both the canal mediated reflex and the otolith based reflex, as indicated by the variable effect of head position on upbeat nystagmus in patient 1 and 4, and other reported patients (Fisher et al. 1983). We postulate that convergenceevoked changes in primary position vertical nystagmus are caused by the effects of vergence on an imbalanced otolith-ocular reflex. This convergence induced change in the imbalanced vertical V O R may stop the upbeat nystagmus or reverse its direction.

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