Ординатура / Офтальмология / Английские материалы / Essentials in Ophthalmology Pediatric Ophthalmology Neuro-Ophthalmology Genetics_Lorenz, Borruat_2008

286 Treatment of Specific Types of Nystagmus

thitis (otitis media), stroke, or trauma; however, in most cases there is viral involvement of the vestibular nerve (vestibular neuritis is its idiopathic form).

Auditory dysfunction is absent in vestibular neuritis, which is characterized by a partial rather than a complete vestibular paresis. This condition mainly affects patients between the ages of 30 and 60. Caloric testing of the ears shows ipsilateral hypo-responsiveness (33%) or non-responsive- ness (66%) of the horizontal semicircular canal function, which resolves in 70%–80% of the patients after a few months. Relief of the symptoms within 2–3 weeks (rarely up to 6 weeks) is due to the central compensation of the vestibular tonus imbalance. Later on, restoration of peripheral function takes place, which may lead to a mild spontaneous nystagmus beating in the opposite direction. In the few cases of no or only minor

peripheral restoration of labyrinthine function, oscillopsia may persist during rapid head movements. This is caused by a deficit of the VOR in the higher frequency range, which cannot be compensated for centrally.

16.2.1.1 Etiology

Vestibular neuritis most likely has a viral etiology such as “idiopathic facial paresis,” but this has not yet been proven [4, 23, 47]. Arguments that support a viral etiology are the endemic occurrence at certain seasons, autopsy studies showing inflammatory degeneration of the vestibular nerve, and the presence of elevated protein levels in the cerebrospinal fluid. The detection of latent herpes simplex virus type 1 in human vestibular ganglia has been interpreted to be a sign of viral inflam-

mation of the vestibular nerve or of its superior part in vestibular neuritis [1, 22, 56]. This is further supported by recent magnetic resonance imaging (MRI) findings using a 3-tesla magnet and high-dose contrast enhancement, which showed an isolated enhancement of the vestibular nerve only on the affected side [32].

16.2.1.2Therapeutic Recommendations

For symptomatic relief, vestibular sedatives (e.g., dimenhydrinate) should be administered parenterally on days 1–3, when nausea and vomiting are severe. The patient should rest in bed and avoid head movements. These drugs should be given only as long as nausea lasts, because antivertiginous drugs suppress and prolong the mechanisms of central compensation. Treatment with steroids (methylprednisolone) should be considered in cases of viral vestibular neuritis, since a prospective, placebo-con- trolled study found evidence that early treatment with cortisone improves the long-term outcome (Fig. 16.2) [55]. In a total of 141 patients who were randomized within 3 days of symptom onset to one of four treatment options – placebo, methylprednisolone (starting with 100 mg daily), valacyclovir, or a combination of valacyclovir and methylprednisolone – the group receiving methylprednisolone had a better final outcome with about 60% recovery of peripheral vestibular function after 12 months compared to 36%–39% for the placebo/valacyclovir groups. The combination of methylprednisolone and valacyclovir gave no additional benefit.

Further management includes early physical therapy, i.e., starting with exercises in bed (days 3–5). To suppress nystagmus by visual fixation, the patient should perform voluntary saccades and eccentric gaze-holding, as well as practice sitting freely. During days 5–7, when the spontaneous nystagmus is suppressed by fixation but there is continued gaze nystagmus in the direction of the fast phase, upright stance and then head oscillations during free stance should be trained. Afterwards during weeks 2–3 and later on, balance exer-

cises should become more complex, gradually increasing in difficulty (e.g., during active head oscillations with increasing frequencies) to reach a level above the demands for postural control under everyday life conditions. Early physical therapy at least two times per day has been proven to normalize impaired body sway of patients with vestibular neuritis within 2–3 weeks [53]. All these exercises are used to recalibrate the VOR in its three major planes of action (yaw, pitch, and roll) for perfect eye–head coordination.

Summary for the Clinician

■Patients with vestibular neuritis should be given cortisone (e.g., methylprednisolone for about 14 days, starting with 100 mg daily, reducing the dosage by 20 mg every 3 days) as early as possible (within the first 3 days after disease onset), since it significantly improves the long-term outcome. This is especially mandatory in patients with severe vestibular deficits (e.g., caloric unresponsiveness) to prevent deficits in the high-frequency range of the VOR, which will persist despite central compensation.

■Physical therapy should also start as early as possible to improve the recalibration of the VOR in its three major planes of action.

■To ensure adequate therapy is administered for vertigo, it is necessary to consider that antivertiginous drugs will suppress compensatory mechanisms, because most of these drugs are vestibular sedatives. Therefore, vestibular suppressants should only be administered for the first few days when vertigo is accompanied by distressing nausea and vomiting, i.e., in acute peripheral vestibulopathy or acute brainstem and cerebellar lesions.

■These antivertiginous drugs are contraindicated for patients with chronic dizziness or positioning vertigo.

288 Treatment of Specific Types of Nystagmus

16.2.2 Superior Oblique Myokymia

Superior oblique myokymia (SOM) is a peripheral ocular motor disorder of the trochlear nerve. Patients with SOM complain of recurrent attacks of oscillopsia and double vision with oblique images due to monocular oscillations [29]. Phasic episodes with oscillations caused by high-frequency torsional nystagmic eye movements as well as tonic episodes with diplopia secondary to an intorsion and elevation of the affected eye may occur sequentially or simultaneously. Spontaneous remissions for days or weeks, even up to years, are known to occur [34, 37].

facial spasm has to be assumed as the underlying cause [28, 61].

16.2.2.2Therapeutic Recommendations

Anticonvulsants such as carbamazepine [10, 52] and gabapentin have been reported to be effective [57] as has propranolol [59]. Microvascular decompression of the fourth nerve was found to be a beneficial surgical treatment [46]; however, the danger of a transient or persistent fourth nerve palsy as a side-effect of this surgical decompression is great.

16.2.2.1 Etiology

To date the mechanism of this condition has not been completely clarified. In recent years evidence has accumulated showing that a vascular compression of the trochlear nerve (Fig. 16.3) similar to that in trigeminal neuralgia and hemi-

Summary for the Clinician

■Patients with longer-lasting symptoms of superior oblique myokymia should be administered anticonvulsants (carbamazepine, gabapentin).

290 Treatment of Specific Types of Nystagmus

Despite many clinical reports on downbeat nystagmus (DBN) and upbeat nystagmus (UBN) as well as multiple hypotheses about their possible mechanisms, their pathophysiology is still not completely understood [33, 40]. Several clinical findings and experimental data now suggest that asymmetries in the cerebello-brainstem network, which normally stabilizes vertical gaze, could cause an imbalance in the following structures:

(1) the vertical cerebello-vestibular “neural integrator,” (2) the central connections of the vertical VOR including both the semicircular canal and the otolith responses, or (3) the vertical smooth pursuit system. In a recent review by Pierrot-De- seilligny and Milea [42], DBN is attributed to a floccular lesion that results in disinhibition of the pathway from the superior vestibular nucleus via the central ventral tegmental tract and thereby in relative hyperactivity of the elevator muscles, which induce an upward slow phase. Indeed, the crucial role of the flocculus in DBN was confirmed only recently in a 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) study, which detected glucose hypometabolism in the cerebellar flocculus and tonsil. The DBN was improved by effective medical therapy with 4-aminopyridine (Fig. 16.5) [6].

ceptive VOR (impairment in the projection of otolithic information), e.g., imbalance by dysfunction of the neuronal ocular motor integrator, the saccade-burst generator, or the vertical smooth pursuit system [24, 40].

16.3.1.1.1.1 Etiology

DBN is often the result of a bilateral lesion of the flocculus or the paraflocculus (e.g., intoxication due to anticonvulsant drugs) or is caused by a lesion at the bottom of the fourth ventricle [3, 34]. Accordingly, it is mostly a drug-induced dysfunction or congenital: about 25% of patients have craniocervical junction anomalies (Chiari malformation), approximately 20% have cerebellar degeneration, and about 50% of the cases are of unknown etiology. It can also be caused by a paramedian lesion of the medulla oblongata [13] and more rarely by multiple sclerosis, hemorrhage, infarction, or tumor. DBN occurs in channelopathy episodic ataxia type 2, for which a new treatment option was recently developed [54]. DBN due to a lesion in the upper medulla at the level of the rostral nucleus prepositus hypoglossi has so far only been found in monkeys, not in humans [62].

16.3.1.1.2 Upbeat Nystagmus

Upbeat nystagmus (UBN) is rarer than downbeat nystagmus. It is also a fixation-induced nystagmus that beats upward in primary gaze position, and is combined with a disorder of the vertical smooth pursuit eye movements, a visual and vestibulospinal ataxia with a tendency to fall backward, and past-pointing downward [9, 30]. UBN usually increases on upgaze. In some patients it changes to DBN during convergence.

16.3.1.1.2.1 Etiology

The anatomic location of most acute lesions is near the median plane in the medulla oblongata in neurons of the paramedian tract (PMT), close to the caudal part of the perihypoglossal nucleus [30, 49], which are responsible for ver-

tical gaze-holding (Fig. 16.6) [11]. These lesions probably affect the ascending pathways from the anterior semicircular canals (and/or otoliths) at the pontomedullary or pontomesencephalic junction [20]. However, lesions have been reported near the median plane in the tegmentum of the pontomesencephalic junction, the bra-

chium conjunctivum, and probably in the anterior vermis [41]. Only recently a lesion of the paramedian pontine brainstem was described which affected the central ventral tegmental tract [43].

The symptoms of UBN persist as a rule for several weeks but are usually not permanent. Be-

292 Treatment of Specific Types of Nystagmus

Fig. 16.6  MRI of a patient with upbeat nystagmus syndrome due to an acute paramedian infarction of the medullary brainstem (arrow) at the level of the vestibular nerves and nuclei. The infarction affects neurons of the paramedian tract close to the caudal part of the perihypoglossal nucleus

cause the eye movements generally have larger amplitudes, oscillopsia in UBN is very distressing and significantly impairs vision. Upbeat nystagmus due to damage to the pontomesencephalic brainstem is frequently combined with a unilateral or bilateral internuclear ophthalmoplegia (INO), indicating that the medial longitudinal fasciculus (MLF) is affected.

The main etiologies are bilateral lesions in multiple sclerosis (MS), brainstem ischemia or 16 tumor, Wernicke’s encephalopathy, cerebellar degeneration, and dysfunction of the cerebellum

due to intoxication (e.g., nicotine).

16.3.1.1.3Therapeutic Recommendations

The course and prognosis ofUBN and DBN depend on the underlying illness. Positive effects have been seen in non-placebo-controlled studies with a limited number of patients. It is therapeutically expedient to attempt to treat the symptoms of persisting DBN by administering gabapentin, probably a calcium channel blocker (3× 200 mg/ day p.o.) [2], the GABA-B agonist baclofen (3× 5–15 mg/day p.o.) [18], or the GABA-A agonist clonazepam (3× 0.5 mg/day p.o.) [15]. Treatment of UBN with baclofen led to an improvement in several patients (3× 5–10 mg/day p.o.) [18].

Recently, the potassium channel blockers 3,4-diaminopyridine and 4-aminopyridine were shown to effectively reduce DBN in some but not all patients with DBN and UBN [31, 54]. Potassium channels are abundant in cerebellar Purkinje cells, the output neurons from cerebellar cortex. The related agent, 4-amino- pyridine, is reported to increase the discharge of these neurons by affecting the slow depolarizing potential [19]. Such enhancement of Purkinje cell activity could restore the inhibitory influence of the cerebellar cortex on vertical vestibular eye movements to normal [33]. This appeared to hold true in a patient with DBN who showed an improvement of both DBN and pursuit deficits after 4-aminopyridine as well as improvement of the hypometabolism of the cerebellar flocculus/tonsil in FDG-PET (Fig. 16.5) [6]. From these studies it was concluded that: (1) 4-ami- nopyridine reduces the downward drift in UBN by augmenting smooth pursuit commands, and

(2) 3,4-diaminopyridine minimizes the gravityindependent velocity bias and improves deficient inhibitory cerebellar control on overacting oto- lith-ocular reflexes.

A surgical decompression, in which parts of the occipital bone were removed in the region of the foramen magnum, proved beneficial to isolated patients with a craniocervical anomaly [48]. Sometimes base-down prisms may help to reduce DBN during reading, because DBN is generally less pronounced during upward gaze.

Summary for the Clinician

■The treatment options for patients with persisting symptoms of DBN and UBN should include GABAergic substances such as baclofen and clonazepam, gabapentin (probably a calcium channel blocker), and the potassium channel blocker 4-aminopyridine.

16.3.1.1.4 Seesaw Nystagmus

Seesaw and hemi-seesaw nystagmus are rare pendular or jerk oscillations. One half-cycle consists of elevation and intorsion of one eye with

concurrent depression and extorsion of the other eye. During the next half-cycle there is a reversal of the vertical and torsional movements. The frequency in the pendular form (2–4 Hz) is lower than in the jerk form.

semicircular canals [44]. It was also seen in patients with Chiari malformation (Fig. 16.7a) [7]. The pendular form was observed in patients with lesions that affected the optic chiasm. The loss of crossed visual input seems to be crucial for its pathophysiology [49].

16.3.1.1.4.1 Etiology

Jerkhemi-seesawnystagmuswasfoundinpatients with unilateral meso-diencephalic lesions [27], which affected the interstitial nucleus of Cajal (INC) and its vestibular afferents from the vertical

16.3.1.1.4.2Therapeutic Recommendations

An improvement of the seesaw component of the pendular nystagmus was observed in a small group of only three patients who received gabapentin [2]. Older case reports described beneficial effects with clonazepam [12] and ethanol (1.2 g alcohol/kg body weight), more recent ones with the GABA-B agonist baclofen (Fig. 16.7b) [7].

16.3.1.1.5Periodic Alternating Nystagmus

Patients with acquired periodic alternating nystagmus (PAN) often complain of increasing or decreasing oscillopsia for specific time intervals. This is due to a horizontally beating spontaneous nystagmus that periodically changes its direction. The nystagmus amplitude of PAN gradually

294 Treatment of Specific Types of Nystagmus

decreases, then the nystagmus reverses its direction, and the amplitude increases again. The periods of oscillation typically last 1–2 min (range: 1 s to 4 min). Patients with PAN experience no spontaneous improvement.

16.3.1.1.5.1 Etiology

Periodic alternating nystagmus is caused by instability of the velocity storage mechanism for vestibular eye movements; an adaptive mechanism produces the oscillations that have a period of about 4 min [36]. Animal experiments showed causative lesions of the inferior cerebellar vermis (e.g., nodulus and uvula), which lead to disinhibition of the GABA-ergic velocity storage mechanism mediated in the vestibular nuclei [21, 60]. Vestibulocerebellar lesions are commonly found in humans with MS, cerebellar degenerations, craniocervical anomalies, tumors, brainstem infarctions, or rarely intoxication (e.g., lithium). Periodic alternating nystagmus can also be caused by bilateral visual loss. It resolves when vision improves [14].

16.3.1.1.5.2Therapeutic Recommendations

Case reports described beneficial effects of the 16 GABA-B agonist baclofen (3× 5–10 mg p.o. per day) as well as of barbiturates and phenothiazine

[12].

16.3.2Central Ocular Motor Disorders

16.3.2.1Acquired Pendular Nystagmus

Acquired pendular nystagmus (APN) is characterized by monocular or binocular sinusoidal oscillations with a predominant horizontal, vertical, or oblique trajectory and a frequency of 2–7 Hz [25, 35]. The nystagmus is often associated with visual impairment; head, trunk, and limb ataxia; and head titubation that is not synchronized with the nystagmus [52].

16.3.2.1.1 Etiology

The most common etiologies of APN are lesions due to MS or brainstem infarctions [38, 52]. Other etiologies include toluene abuse, Whipple’s and Pelizaeus-Merzbacher diseases, and brainstem cavernoma or hemorrhage. It can also occur as a component of oculopalatal tremor syndrome (myoclonus). Observations in patients with brainstem lesions at different sites (inferior olive, medial vestibular nucleus, central tegmental tract, red nucleus in the midbrain; Fig. 16.8) led to the hypothesis that APN may arise from instability in the neural integrator for eye movements [49].

16.3.2.1.2Therapeutic Recommendations

Most of the older case reports or case series described the beneficial effect of anticholinergic treatment with trihexiphenidyl (20–40 mg p.o. daily). However, in a double-blind study only one of six patients experienced any improvement [52]. More recently significant improvements of the nystagmus and visual acuity were reported in 10 of 15 patients who received gabapentin [2] and in all 9 tested patients on memantine, a glutamate antagonist and N-methyl-d-aspartate (NMDA) modulator (15–60 mg p.o. daily; Fig. 16.9) [50]. This was confirmed in a recent examiner-blind, cross-over study on 11 patients with MS, in which gabapentin (up to 1200 mg p.o. daily) and memantine (40 mg or 60 mg daily) were compared [51]. Both drugs significantly reduced APN and increased near visual acuity from 0.35 to 0.46 (40 mg memantine) and to 0.43 (1200 mg gabapentin) or 0.60 (60 mg memantine). Reduction of nystagmus amplitude and frequency was consistent for the horizontal and vertical planes with memantine, but significantly stronger for the vertical than the horizontal plane with gabapentin. Memantine appeared to be even more effective for the horizontal component of APN and the visual acuity, especially at the higher dosage of 60 mg/day. Both medications were well tolerated [51].

Gabapentin was superior to vigabatrin in a small series of patients [5]. Cannabis, which