Chapter 5: Differential Diagnosis of Nystagmus in Infancy and Childhood

Nystagmus in infancy and childhood outlines the understanding, evaluation, and treatments of nystagmus in infancy and childhood. Aligning this condition with advanced concepts of developmental brain-eye diseases and summarizing novel treatment paradigms, the authors provide an authoritative resource for both clinicians and scientists in the care of infants and children with nystagmus. The chapters comprised here offer valuable coverage in all relevant areas related to nystagmus: algorithms for examination; descriptions of diagnostic techniques; medical, surgical, and alternative treatments of the visual system in infants and children; methodologies for investigation, including analysis software, models of the ocular motor system, and current hypotheses on the pathophysiology of ocular motor oscillations. Unlike earlier works on this topic, emphasis is placed on the motor mechanisms that cause the various types of nystagmus rather than the diagnosis or treatment of the afferent visual deficits that may accompany them. The study of each type of nystagmus using accurate eye-movement recordings serves as the foundation for differential diagnosis and treatment options. Each chapter summarizes the results of ocular motor research in a narrative manner, identifying the important ideas and observations that point to underlying neurophysiological mechanisms. Based on insights from the authors' combined 75 years of clinical experience, Nystagmus in Infancy and Childhood is a valuable clinical reference for ophthalmologists, neurologists, and other specialists in the treatment of this condition.

OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 5 differential diagnosis of nystagmus in infancy and childhood 5.1 NYSTAGMUS WITHOUT ASSOCIATED NEUROLOGICAL DISEASE—“BENIGN” 136 5.1.1 Infantile Nystagmus Syndrome 136 5.1.1.1 Association with Strabismus 140 5.1.1.2 Clinical Signs and Symptoms 141 5.1.1.3 Differential Diagnosis 142 5.1.1.4 Alternate-Cover and Gaze-AngleCover Tests 142 5.1.2 Fusion Maldevelopment Nystagmus Syndrome 145 5.1.2.1 Association with Strabismus 145 5.1.2.2 Clinical Signs and Symptoms 145 5.1.2.3 Differential Diagnosis 146 5.1.2.4 Alternate-Cover and Gaze-AngleCover Tests 147 5.1.3 Nystagmus Blockage Syndrome 147 5.1.3.1 Association with Strabismus 147 5.1.3.2 Clinical Signs and Symptoms 147 5.1.3.3 Differential Diagnosis 148 5.1.4 Spasmus Nutans Syndrome 148 5.1.4.1 Association with Strabismus 148 5.1.4.2 Clinical Signs and Symptoms 148 5.1.4.3 Differential Diagnosis 149 5.1.5 Nystagmus and Strabismus 150 5.2 NYSTAGMUS WITH ASSOCIATED NEUROLOGICAL DISEASE—“SYMPTOMATIC” 150 5.2.1 Vestibular Nystagmus 150 5.2.1.1 Peripheral Vestibular Imbalance 150 5.2.1.2 Central Vestibular Imbalance 153 5.2.1.3 Central Vestibular Instability (Periodic Alternating) 155 5.2.2 Gaze-Holding Deficiency Nystagmus 156 5.2.2.1 Eccentric Gaze, Gaze-Evoked, Rebound 156 5.2.2.2 Gaze Instability (“Runaway”) 157 5.2.3 “Vision-Loss” Nystagmus 158 5.2.3.1 Prechiasmal, Optic Chiasm, and Postchiasmal Vision Loss 158 5.2.4 Other Pendular Nystagmus Associated with Diseases of Central Myelin 158 5.2.4.1 Oculopalatal Tremor or “Myoclonus” 159 5.2.4.2 Pendular Vergence Nystagmus Associated with Whipple Disease 160 5.2.5 Convergence/Convergence-Evoked Nystagmus 160 5.2.6 Upbeat Nystagmus 161 5.2.7 Downbeat Nystagmus 161 5.2.8 Torsional Nystagmus 162 5.2.9 “Seesaw” Nystagmus 162 5.2.10 Lid Nystagmus 163 5.3 SACCADIC INTRUSIONS/ OSCILLATIONS 164 5.3.1 Square-Wave Jerks and Oscillations 165 5.3.2 Square-Wave Pulses 167 5.3.3 Staircase Saccadic Intrusions 167 5.3.4 Macrosaccadic Oscillations 169 5.3.5 Saccadic Pulses (Single and Double) 169 5.3.6 Convergence Retraction “Nystagmus” 171 5.3.7 Dissociated Ocular Oscillations 172 5.3.8 Dysmetric Saccades 172 • 05_Hertle_Ch05.indd 135 135 9/6/2012 9:50:04 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 5.3.9 Ocular Flutter 172 5.3.10 Flutter Dysmetria 173 5.3.11 Opsoclonus 173 5.3.11.1 Opsoclonus-Myoclonus 173 5.3.12 Superior Oblique Myokymia 173 5.3.13 Ocular Bobbing 174 5.3.13.1 Typical 174 5.3.13.2 Monocular 175 5.3.13.3 Atypical 175 5.3.14 Psychogenic (Voluntary) Flutter 175 In the fields of observation, chance favors only the mind that is prepared. —Louis Pasteur (1854, 1822–1895) THE DI AGNOSTIC material in this chapter results from the past half-century of eye-movement-based research (summarized in Chapters 2–4) into the different types of nystagmus found in infancy; that research forms the foundation for the various “clinical pearls” that have also emerged from studying ocular motor data from patients exhibiting nystagmus. Also, Appendix D contains flowcharts and work sheets useful in differential diagnosis and therapeutic intervention. All forms of nystagmus are due to deficits in one or more slow-eye-movement subsystems, whereas saccadic intrusions and oscillations are due to deficits in fast-eye-movement subsystems.1 There is a large literature on the many types of nystagmus listed in Table 5.1 that have been reviewed elsewhere.2–7 5.1 NYSTAGMUS WITHOUT ASSOCIATED NEUROLOGICAL DISEASE—“BENIGN” 5.1.1 Infantile Nystagmus Syndrome Familiarity with the clinical features of infantile nystagmus syndrome (INS; also known as congenital nystagmus [CN])8 is essential. INS is an ocular motor disorder with the hypothesized etiology of undamped smooth pursuit. It presents at birth or early infancy and is clinically characterized by involuntary oscillations of the eyes. The Leicerstershire nystagmus survey estimated the prevalence of nystagmus in the general population to be 24.0 per 10,000.9 The most common forms of nystagmus are neurologic nystagmus (6.8 per 10,000 population) and infantile nystagmus associated with low vision (3.4–4.2 per 10,000). Within ethnic groups, nystagmus was significantly more common in the White European population than in the Asian population (Indian, Pakistani, other Asian backgrounds). Other estimations of the incidence of INS vary enormously from 1 in 350 to 1 in 20,000, although the generally quoted estimated incidence to be 1 in 6,550 or .015%.10 These movements most commonly have a slow and fast phase, although they may be pendular, with or without braking and foveating saccades. They are usually horizontal with a small torsional component and may (rarely) have a vertical component. The intensity of INS increases on lateral gaze and becomes right beating in right gaze and left beating in left gaze. The fact that INS “disobeys” Alexander’s law under binocular conditions (which states that, in peripheral vestibular nystagmus, the direction of the nystagmus increases in the direction of the fast phase and decreases but never reverses in the direction of the slow phase) is often useful in distinguishing it from horizontal peripheral vestibular nystagmus.11–14 Other clinical characteristics of INS, with variable association, include the following: remains horizontal in upgaze (in contrast to acquired and/or vestibular nystagmus, which changes direction in vertical gaze); increases intensity with fi xation attempt or stress and decreases with sleep or inattention; variable intensity in different positions of gaze (usually about a null position); changes direction in different positions of gaze (about a neutral position); decreased intensity (damping) with convergence; anomalous head posturing; 136 • D I F F E R E N T I A L D I A G N O S I S O F N Y S T A G M U S I N I N F A N C Y A N D C H I L D H O O D 05_Hertle_Ch05.indd 136 9/6/2012 9:50:04 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Table 5.1 Forty-Nine Types of Nystagmus Acquired “Fixation” Anticipatory Induced Arthrokinetic Induced Somatosensory Associated Induced Stransky’s Audiokinetic Induced Bartels’ Induced Bruns’ Centripetal Cervical Neck torsion Vertebral-basilar artery insufficiency Circular/elliptic/oblique Alternating windmill Circumduction Diagonal Elliptic Gyratory Oblique Radiary Convergence Gaze-evoked Deviational Gaze-paretic “Neurasthenic” “Seducible” “Sett ing-in” Horizontal Induced Provoked Infantile Congenital “Fixation” Hereditary Pursuit-system Intermittent vertical Jerk Lateral medullary Lid Miner’s1 Occupational Muscle-paretic Myasthenic Nucleus of the optic tract Optokinetic Induced “Kinetic” “Optic” Optomotor Convergence-evoked Dissociated Disjunctive Downbeat Drug-induced Barbiturate Bow tie Induced Epileptic Ictal Fusion maldevelopment Latent/manifest latent Monocular “fi xation” Unimacular Flash-induced Flicker-induced Induced Panoramic “Railway” Sigma “Train” Optokinetic afterInduced Postoptokinetic Reverse postoptokinetic Pendular Talantropia Periodic/aperiodic alternating Alternans Physiologic End-point Fatigue Pursuit afterInduced Pursuit-defect1 Pursuit-system Infantile Pseudospontaneous Induced Rebound Reflex Baer’s Seesaw Somatosensory Induced Spontaneous Stepping around Apparent/real Induced Somatosensory Torsional Rotary Uniocular Upbeat Vertical Vestibular A(po)geotropic/geotropic Alternating current Bechterew’s Caloric/caloric-after Compensatory Electrical/faradic/ galvanic Head shaking Induced LLabyrinthine Perverted Pneumatic/compression Positional/alcohol Positioning Pseudocaloric Rotational/perrotary Secondary phase Synonyms and other terms are indented under either the preferred (CEMS) or the more inclusive designation; some nystagmus types may be acquired or congenital; quoted terms are erroneous or nonspecific. 1 May not exist. 05_Hertle_Ch05.indd 137 9/6/2012 9:50:04 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN strabismus; and the increased incidence of significant refractive errors. Th is history is useful in further distinguishing the nystagmus from peripheral vestibular nystagmus, which becomes worse with occlusion and is damped by fi xation.11 To confi rm this observation, the examiner can observe one optic disc with the direct ophthalmoscope while periodically occluding the other eye. Increased nystagmus intensity with occlusion suggests a peripheral vestibular nystagmus, whereas no change, a direction reversal, or a decrease in nystagmus intensity suggests INS or fusion maldevelopment nystagmus syndrome (FMNS). Anxiety or fatigue will also increase the INS intensity and thereby degrade visual acuity. When evaluating an infant or child with INS for the fi rst time, historical points suggest afferent visual pathway dysfunction. If the child’s eyes are light sensitive, this suggests the presence of a congenital retinal dystrophy, degeneration, or albinism. If the child sees better in daytime or at night, this suggests congenital stationary night blindness or a rod-cone dystrophy.15 The presence or absence of an underlying visual sensory deficit does not affect the time of onset of INS. Often the infant is fi rst evaluated in the fi rst to third months of life when irregular eye movements are noted. When INS fi rst appears, it is often arrhythmic and intermittent, consisting of a series of irregular horizontal and oblique deviations of the eyes from side to side. At this stage, the erratic eye movements may simulate opsoclonus. INS often occurs in association with congenital or early onset (fi rst 6 months of life) acquired defects in the visual sensory system (e.g., systemic and ocular albinism, achromatopsia, aniridia, congenital retinal dystrophies and degenerations, visual cortex anomalies, and congenital cataracts, glaucoma and corneal diseases). Children with this condition frequently present with a head turn, which is used to maintain the eyes in the position of gaze of the null point (point of minimum nystagmus).11,16,17 Th is is particularly prominent when the child is concentrating on a distant object, since this form of nystagmus tends to worsen with attempted fi xation. The head turn is an attempt to improve visual function under these conditions. In most individuals with INS, the head position corresponds roughly with the minimal intensity zone of the nystagmus. A clinical algorithm to aid in the determination of the etiology of anomalous head turns in the presence of strabismus and nystagmus is shown in Figure 5.1. When the angle of the null zone exceeds 15°, however, the angle of the head turn may fall short of the null zone. In some children, the anomalous head position appears to be dictated by the velocity distribution of the slow phase (i.e., the percentage of time that the slow phase is less than or equal to 10° per second) and the nystagmus beat direction (which can be influenced both by the prior position of gaze and by the length of time a subject has maintained a fi xed gaze position). Bagolini et al. suggested that some individuals with INS utilize large head turns to place their eyes in extreme side gaze and actively block their nystagmus.18 Unlike positioning the eyes in a null zone, in which foveation is optimum, the mechanism of such blockage is unknown. Head oscillations are common in INS, but they are not used as the strategy to improve vision, except in those rare patients with abnormal gain of their vestibulo-ocular reflex.19 The INS waveform shown in Figure 5.2 (JR EF) is typical of many with periods of extended foveation. When foveation periods are 100 msec or greater, normal visual acuity is possible. Some studies of INS in infants and children suggest an age-dependent evolution of waveforms during infancy from pendular types to jerk types in some patients.20,21 Th is is consistent with the theory that jerk waveforms reflect modification of the INS oscillation by growth and development of the visual sensory system. However, we documented jerk waveforms in other infants with and without sensory deficits, suggesting that early development of the ocular motor system may be responsible. In Figure 5.3, the interactions and effects between the developing afferent and efferent systems are depicted during several stages from conception to infancy. Th is “crosstalk” is essential to the normal development of both good vision and a stable ocular motor system. Any deficits in either during this developmental period 138 • D I F F E R E N T I A L D I A G N O S I S O F N Y S T A G M U S I N I N F A N C Y A N D C H I L D H O O D 05_Hertle_Ch05.indd 138 9/6/2012 9:50:04 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.1 A clinical algorithm to aid in diagnosing the etiology of an anomalous head posture in the presence of strabismus and nystagmus. The first step is to reposition the patient’s head to the neutral position and observe the consequences on the strabismus or the nystagmus (Step 1) and whether the change improves or worsens the condition (Step 2). The major clinical differentiation occurs at this step. If the nystagmus is worse, then differentiating between a “gaze” null due to infantile nystagmus syndrome (INS) and an “adduction” null due to fusion maldevelopment nystagmus syndrome (FMNS) can be made by looking at the fi xing eye’s (Step 3) and the opposite nonfi xing eye’s (Step 4) effect on the oscillation in aBDuction and aDDuction. FIGURE 5.2 Eye-movement recording showing position and velocity of right eye of a patient with INS showing a typical jerk right with extended foveation (JRef) waveform. These 100-msec periods of high-quality foveation occur just after the fast phase of the nystagmus; time (in seconds) is shown at the bottom.The numbers outlined in red show details of foveation encompassed in the black rectangular area. L, left; R, right; RE, right eye. Nystagmus in Infancy and Childhood • 139 05_Hertle_Ch05.indd 139 9/6/2012 9:50:05 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.3 A model for development of infantile nystagmus syndrome (INS). Motor-system calibration is an active process that may start in utero and continue at least through early infancy. Sensory-system development is a parallel visual process that continues to develop through the first decade of life. Previous studies documented connections between parallel visual processes (cross-talk) that modify, instruct, and coordinate these systems, resulting in smooth and coordinated function. INS may result from a primary defect (familial, genetic) of ocularmotor calibration. INS may also result from abnormal cross-talk from a defective sensory system to the developing motor system at any time during the motor system’s development. Th is can occur from conception as a result of a primary defect (retinal dystrophy), during embryogenesis as a result of an intrauterine abnormality (optic nerve hypoplasia), or after birth during infancy (congenital cataracts). Th is hypothetical genesis of INS incorporates a pathophysiologic role for the sensory system. Although the physiologic circumstances may differ, the final common pathway is abnormal calibration of the ocular motor system. The primary ocular motor instability that underlies INS remains the same, but its clinical and oculographic expression are modified by both initial and final developmental integrity of all parallel afferent visual system processes. As the bidirectional arrows suggest, abnormal motor development also affects sensory development. will negatively affect both the system with the deficit and the other system. Thus, motor deficits may interfere with visual development and visual deficits may interfere with motor development, as is explained in the figure caption. Although INS is a lifelong condition, it may remain variable over time. Th is includes minute-to-minute variability and long-term changes associated with age and other ocular and systemic conditions. There are no good long-term, multisubject studies (greater than 10 years) that characterize the aging process and its effects on INS, but we do know that changes can occur in the INS oscillation as a result of aging, medications, and degenerative and neurological illnesses. Th is concept of INS as a dynamic disease process may be useful when evaluating and caring for patients with this condition over their lifetime. However, eye-movement data taken over decades in some subjects with INS (one, 140 over more than a 45-year span) showed no overall changes in the important waveform characteristics governing visual function. 5.1.1.1 A SS O C I AT I O N W I T H S T R A B I S M US Estimates of the prevalence of strabismus in INS range from 16% to 50%.22–27 Strabismus is essential for FMNS but incidental to INS. Although FMNS is intrinsically more likely to be associated with strabismus than is INS, the greater frequency of INS means that any given patient with strabismus will still be more likely to have INS (53%) than FMNS (35%).23 The presence and nature of an underlying sensory visual disorder seems to influence the likelihood of associated strabismus. In a study of 82 children with INS (diagnosed clinically), Brodsky and Fray found the prevalence of strabismus to be 82% • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 140 9/6/2012 9:50:07 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN in children with optic nerve hypoplasia, 53% in children with albinism, 36% in children with congenital retinal dystrophies, and 17% in children with idiopathic INS.28 5.1.1. 2 CL I N I C A L S I G N S A N D SYMPTOMS Patients with INS typically have several different waveforms; one study found multiple waveforms in 87% of patients.23 In addition to the quantifiable and defi nitively diagnostic characteristics of IN available through eye-movement recordings, there are clinical signs one can observe in the office. In INS, one should look for a null angle; an indication of which is the presence of a head turn. A teenager or an adult may not show a head turn because of societal pressures. They have learned to keep their heads straight at the expense of vision because it is not “appropriate” to walk around with their head turned, but a child will more likely exhibit a head turn. A positive family history and negative neurological examination also suggest INS. One study found that 48% of patients exhibited both convergence and gaze-angle nulls (28% had only convergence nulls and 9% only gaze-angle nulls) and 14% had no nulls.23 If converging the eyes damps the IN, the patient will hold reading material close. The patient may have a latent component; that can be checked by the alternate-cover test. If the nystagmus direction reverses with monocular cover, one still does not know whether it is FMN or IN with a latent component (they are different types of nystagmus). They may also have head nodding that is not compensatory. Many patients with IN exhibit an eccentric null angle of gaze, where the IN magnitude damps (“null”). A true null position is that position of gaze (eye in orbit) where changing gaze to either side of this minimal nystagmus intensity position increases the oscillation intensity. That is in contrast to FMN, where monotonic variation with gaze angle (Alexander’s law) causes patients to keep their eyes deviated to one side where the nystagmus is low. FMN does not have a true null because there is no increase on both sides. In IN, the position of the null is a function of the angle of gaze and also a function of the velocity of the eyes.29–32 Thus, the null angle during fi xation (static null) does not usually equal the null angle during pursuit, optokinetic nystagmus, or head movement, where the vestibulo-ocular reflex is stimulated (dynamic null). Usually, the null is shifted in the direction opposite to the eye movement. During pursuit to the left , the dynamic null moves to the right of the static null; and during pursuit to the right, the dynamic null moves to the left . In the IN population, 48% have both convergence and gaze angle nulls, 29% only convergence nulls, 9% only gaze angle nulls, and there are 14% with no nulls. Accurate measurement of the null position requires a well-calibrated, DC-coupled recording system. That measurement can then be used to prescribe prisms or determine the amount of surgery to be performed (see Chapter 7). In cases with nystagmus plus strabismus, it is sometimes possible to differentiate INS from FMNS. For example, if the preferred gaze angle places the fi xating eye in abduction, the nystagmus is most probably IN because, if it were FMN, the fi xating eye would most probably be in adduction due to Alexander’s law. If the fi xating eye is in adduction, either IN or FMN is possible. Clinical Pearl: When the preferred fi xating eye is kept in abduction, the nystagmus is most probably IN, not FMN. Caveat: It might still be FMN if the patient has exotropia or an angle kappa. Children with IN and a static eccentric gaze null position automatically adopt a head turn to see better. They do not have to wait to be told about the null angle; they know where it is because all visual functions improve when they turn their head, placing their eyes at the static null angle. One may think of the null as a region of ocular motor equilibrium. The brainstem (left and right) generates forces pulling the eyes both ways, and there is a position of equilibrium of forces, not necessarily in primary position, where the nystagmus is minimal. When viewing targets at the null angle, many visual functions (including acuity) should increase; when there Nystagmus in Infancy and Childhood • 141 05_Hertle_Ch05.indd 141 9/6/2012 9:50:07 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN is a severe afferent defect, or an INS waveform with well-developed foveation (i.e., high NAFX) across a large range of gaze angles (high LFD; see Chapter 2, Section 2.3.1.1), acuity may not increase measurably. Sometimes a patient will tilt the head, and sometimes the patient will turn it (vertically or horizontally) and tilt it. Perhaps the oblique muscles are involved; this has not really been studied well. It represents innervation of muscles other than the horizontal muscles that are somehow helping to reach equilibrium in predominantly horizontal oscillations; most IN is primarily horizontal with litt le or no vertical components. Again, acuity increases with vertical or torsional head positions, especially if there are no afferent defects. The mechanism causing an IN reversal when covering an eye is similar to when the person pursues; the null moves and can cause a direction reversal of the IN if gaze went from one side of the null to the other. 33 Although IN with a latent component looks clinically like FMN, it is not (because the waveform remains IN); only the IN direction changes because the null has moved with occlusion. IN with a latent component can behave as though there were two null angles since, if the fi xating eye changes with gaze angle, the induced null shift will appear to be a second null. In binocular individuals with IN, there is only one null and in those with strabismus, there is also only one null, although it shift s to a different gaze angle when fi xation shift s to the other eye. A good recording system, properly calibrated for fi xation with each eye, will detect shift s in the fi xating eye (and the tropias of the nonfi xating eye) and prevent misreading the records as showing two nulls. Also, IN and periodic (PAN) or asymmetric, (a)periodic (APAN) alternating nystagmus will mimic two nulls because of the null shift accompanying the direction reversal. Steady fi xation in primary position for several minutes will disclose either form of alternation. Table 5.2 summarizes the different types of APAN seen in INS patients and compares them to acquired PAN. The term APAN encompasses all idiosyncratic variations in 142 the timing and amplitudes of the intracycle jerk IN, including those that are periodic, but all have combinations of IN waveforms, whereas acquired PAN has a sawtooth jerk waveform. When the specific intra- and intercycle characteristics are known, the more specific nomenclature in Table 5.2 may be used. Note that the total intercycle periods (T in Table 5.2) for APAN are usually much longer than for acquired PAN. 5.1.1.3 D I F F E R E N T I A L D I A G N OS IS The localizing significance of nystagmus is often a mere indication of dysfunction somewhere in the posterior fossa (i.e., vestibular end organ, brain stem, or cerebellum). However, certain nystagmus patterns are quite specific and permit reasonably accurate neuroanatomic diagnosis. When possible, the specific and nonspecific forms are separated on the basis of clinical appearance and associated signs and symptoms. Some of the characteristics of IN and their comparison to FMN are listed in Table 5.3. Specifically, the ocular motor sites of the deficits affect both waveforms and the shape of the NAFX peak (or “null” depth). Individuals with both INS and FMNS are difficult to diagnose correctly; it is not usual, but some patients (~5%) have a combination of INS and FMNS. 23 One or the other might be dominant and result in complex waveforms and variations of nystagmus type with gaze angle. The best approach to diagnosing these patients is to first learn to accurately diagnose the more straightforward types. As Table 5.3 indicates, this combination results in many possible waveforms, NAFX peak variations, and also includes IN with a “latent component” or the nystagmus blockage syndrome. 5.1.1. 4 A LT E R N AT E- COV E R A N D G A ZEA N G L E- COV E R T E S T S It may be difficult to distinguish FMN from IN when strabismus and a “latent” component are present (fast phase movement toward uncovered eye and/or increased intensity of • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 142 9/6/2012 9:50:07 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Table 5.2 Time-Varying Types of Jerk Nystagmus I N T R AC YC L E DI R E C T ION T Y PE DU R A T ION A M P L I T U DE I N T E R C YC L E P E R IOD (T) 1 SPECI F IC T Y PE OR C H A R AC T E R I S T IC S APAN = ≠ = ≠ = = ≠ ≠ = = = = = ≠ = ≠ = = ≠ ≠ ≠ ≠ ≠ ≠ = = = IN: PAN Asymmetric duration PAN Asymmetric intensity PAN Asymmetric duration and intensity PAN Symmetric AAN Asymmetric duration AAN Asymmetric intensity AAN Asymmetric duration and intensity AAN Symmetric duration and intensity PAN Saw-tooth waveform Acquired PAN Duration indicates the time period of oscillation in a given direction. Intensity indicates the amplitude × frequency of oscillation in a given direction. 1 T of APAN is usually >> T of acquired PAN. T is the sum of left-beating, right-beating, and two neutral interval durations. AAN, aperiodic alternating nystagmus; APAN, asymmetric (a)periodic alternating nystagmus; IN, infantile nystagmus (with any combination of IN waveforms); PAN, periodic alternating nystagmus. Table 5.3 Comparative Characteristics of Infantile and Fusion Maldevelopment Nystagmus OCU L A R MOTOR S U B S Y S T E M DE F IC I T NA F X PE A K OR I N T E N S I T Y “ N U L L” T Y PE PU R SU IT VV POSSI BLE WAV E F O R M S IN Yes No IN: P-SW No Yes IN: VVSW Yes Yes Yes No Yes <<< Pursuit < Pursuit = Pursuit Yes Yes IN: P-SW IN: P-SW IN: P-SW + VVSW J L , SPT All of the above FMN IN + FMN2 G A Z E A NGL E SH A PE Idiosyncratic or none1 None1, with low NAFX (<<1) Idiosyncratic Idiosyncratic Idiosyncratic Far add of FE Idiosyncratic Broad or none1 Not applicable Broad Variable Sharp or medium Linear1 Idiosyncratic FE, fi xating eye; IN, infantile nystagmus; J L , jerk with linear slow phase; NAFX, eXpanded nystagmus acuity function; P-SW, pursuit-system waveforms (see Chapter 2, Fig. 2.1); SPT, saccadic pulse train; VV, visual vestibular; VVSW, visual vestibular system waveforms (see Chapter 2, Fig. 2.2). 1 No mathematical peak/null but may vary with gaze angle. 2 Includes IN with a latent component and the nystagmus blockage syndrome. Nystagmus in Infancy and Childhood • 143 05_Hertle_Ch05.indd 143 9/6/2012 9:50:08 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN nystagmus with monocular cover) since the two patients will appear clinically identical. The only defi nitive way to distinguish between IN with a “latent component” and FMN is with the use of eye-movement recordings. 34,35 The differences between IN with a “latent component” and FMN can be seen in Figure 5.4. FMNS patients have slow phases that are predominantly decreasing velocity and linear. Patients with frank esotropia may demonstrate FMN. Since these patients usually suppress one eye at a time, the nystagmus is present even without covering an eye. The direction of the nystagmus depends on which eye is fi xating. Manifest FMN can clinically appear to be converted to “pure,” latent FMN if the strabismus treatment results in orthophoria. Two tests are useful in attempting to differentiate INS from FMNS. The fi rst is the “alternate-cover” test, where each eye is alternately occluded while the patient is looking straight ahead. If the patient has jerk nystagmus that is stationary with time (i.e., does not change direction while maintaining fi xation on a primary-position target) and the direction does not reverse with alternate cover, it is IN rather than FMN. However, if nystagmus direction reverses with alternate cover (with the direction of the nystagmus toward the fi xating eye), then it could be either IN with a latent component or FMN. Reversal of nystagmus direction does not mean that it is FMN, although this test is oft en misinterpreted that way. One might be tempted to presume that if there is no strabismus and a reversal occurs, then the diagnosis should be INS since FMNS requires strabismus to be present (see Section 5.1.2). However, this is a clinical test and even an undetectable microtropia is sufficient for FMNS. The second test, “the gaze-angle-cover” test, is useful in this latter case where a reversal occurred in primary position. While maintaining cover, move the fi xation target into the adduction field of the fi xating eye (e.g., move it into the patient’s left field when the right eye is fi xating). If the right-beating nystagmus now reverses to a leftbeating nystagmus in left gaze, the nystagmus is IN with a latent component; if not, it still could be either FMN or IN with a large latent component (i.e., the neutral-zone shift with occlusion was so FIGURE 5.4 The differentiation between infantile nystagmus syndrome (INS) with a “latent component” and fusion maldevelopment nystagmus syndrome (FMNS). Both conditions are clinically identical, that is, horizontal nystagmus with both eyes open that changes in direction and/or intensity under monocular conditions. The top trace shows jerk-left INS under left-eye monocular fi xation. Th is is different from the bottom two traces, which show jerk right with linear/decreasing velocity slow phases under right-eye monocular fi xation and jerk left with linear/decreasing velocity slow phases with left-eye monocular fi xation typical of FMNS. Deg, degrees; LE, left eye; RE, right eye. 144 • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 144 9/6/2012 9:50:08 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN great as to preclude transversing it in far left gaze and obtaining a nystagmus reversal back to leftbeating nystagmus). 5.1.2 Fusion Maldevelopment Nystagmus Syndrome Fusion maldevelopment nystagmus syndrome (FMNS, also known as latent/manifest latent nystagmus, LMLN)8 is a benign, binocular horizontal oscillation of infantile onset; there is always associated strabismus, and ocular motor recordings show four types of slow phases with jerk in direction of fi xing eye.12,35–39 The oscillations appear conjugate, horizontal, and uniplanar, and there are usually no associated sensory system deficits (e.g., albinism, achromatopsia). Th is form of nystagmus in infancy is generally associated with the best binocular acuity potential of all the forms of childhood oscillations. The oscillations may change with exaggerated convergence, resulting in a head posture associated with fi xing eye in adduction. There is no head shaking, the eyes may exhibit “reversal” with OKN stimulus, and there is no aperiodicity to the oscillation.12,35–39 Constant horizontal and dissociated strabismus is often present. The intensity decreases with increased fusion (binocular function) and movement of the fi xing eye into adduction (toward the nystagmus slow phase) and with increasing age. 5.1. 2.1 A SS O CI AT I O N W I T H S T R A B IS M US FMNS implies strabismus, but the converse is not true; strabismus does not imply FMNS (50% have no nystagmus at all), but if an individual has FMNS, he or she also has strabismus (i.e., strabismus is a necessary, but not sufficient, condition for FMNS). Even if it is not evident clinically (it may be a microstrabismus that can be recorded), it is there. Distinguishing the FMNS waveform and the tropia of the nonfi xating eye requires DC-coupled, high-bandwidth recordings of both eyes simultaneously. In logical terminology, strabismus is a necessary (but not sufficient) condition for FMNS (i.e., all individuals with FMNS have strabismus, but not all with strabismus have FMNS). Summarizing, INS can occur with or without strabismus; all FMNS patients have strabismus. 5.1. 2.2 CL I N I C A L S I G N S A N D SYMPTOMS As stated earlier, the pure, latent form of FMNS (pure LN) is extremely rare. That is, when you record pure FMN, you must fi nd no nystagmus with eyes open at all gaze angles. There have been only a couple of cases proven by recordings to have this pure form. Many patients thought clinically to have latent FMN really have manifest FMN. When one records them or examines them with an ophthalmoscope, the FMN is visible. More common is latent FMN in primary position with manifest FMN in lateral gaze; most common is manifest FMN at all gaze angles. The intensity of FMN is greatest with gaze toward the direction of the fast phase (Alexander’s law). Jerk-right nystagmus is greater in right than in left gaze and vice versa. These are not true nulls; one cannot show increased nystagmus because the patient is at the end of the excursion of the eye. Instead, this is an example of a monotonic relationship of gaze and amplitude. It would not be uncommon for a person who fi xates with one eye and has FMNS, to keep that eye in adduction where Alexander’s law will reduce the nystagmus. In INS there is a null and increased amplitude (with increasing-velocity exponentials) as gaze is directed away from the null in both directions, whereas in FMNS (right eye or left eye fi xating), there is an Alexander’s law relationship and decreasing-velocity exponentials. Patients with FMNS usually place their fi xating eye in adduction to minimize the nystagmus and thereby maximize acuity. As in INS, the head turn minimizes the nystagmus and maximizes acuity. A patient might place his or her eye in other than the minimum position of nystagmus if he or she had an “angle kappa” that required eccentric fi xation. Better acuity results, although the nystagmus might be a litt le higher where the patient places his or her gaze. We have never recorded the FMNS waveform in patients with orthophoria; they all had Nystagmus in Infancy and Childhood • 145 05_Hertle_Ch05.indd 145 9/6/2012 9:50:09 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN latent strabismus (when you cover one eye, the other does not remain straight). Similarly, FMNS has never been recorded in patients with binocular alignment; all had manifest strabismus. Both eyes are open, but one eye must be deviated (in or out) to have FMNS. If they can straighten their eyes, the FMN disappears; in the blockage syndrome, they have INS when their eyes are aligned. 5.1. 2.3 D I F F E R E N T I A L D I A G N OS I S Waveform is also the diagnostic criterion for FMNS (see Chapter 3, Fig. 3.1 and Table 5.3); recordings show a decreasing-velocity exponential slow phase. All patients (100%) with FMNS have strabismus. Included in the defi nition of strabismus is latent strabismus (i.e., the phoria resulting when you cover an eye). Thus, FMNS includes a pure latent form, where the eyes are straight with no nystagmus when both eyes are open and when you cover one eye, an eso- or exophoria will develop followed by manifest FMN in both eyes. Th is more common, manifest form of FMN is present with both eyes open and mimics the latent form exactly if it is bidirectional. When it is unidirectional and the patient fi xates with one eye, there will be no nystagmus and the other eye will be esotropic, but when the patient fi xates with the other eye and the formerly fi xating eye is esotropic, the patient will have FMN. The latent form of FMN (i.e., no nystagmus with both eyes open) is rare. If you occlude the left eye and the right eye is fi xating, jerk-right FMN with linear or decreasing-velocity slow phases results and vice versa. The small group of patients with both INS and FMNS present a diagnostic dilemma. Some have mostly INS (designated “INS/ FMNS”) and their waveforms are any of the INS waveforms (i.e., pendular or increasingvelocity slow phases) (see Table 5.3) and one other waveform called “dual jerk” or “dual pendular” (see Chapter 2, Fig. 2.3 and Chapter 3, Fig. 3.3). The latter is a waveform where a lowamplitude, high-frequency pendular nystagmus is superimposed on a decreasing-velocity slow-phase jerk waveform. They do not exhibit 146 the pure FMNS waveform (i.e., decreasingvelocity slow phases); therefore, INS is predominant. The other group has mostly FMNS (FMNS/INS) and their waveforms are FMNS and dual-jerk FMN. There are some who have INS and FMNS equally. At various times they exhibit the INS waveform, FMNS waveform, or the dual-jerk waveform. A linear slow phase is not diagnostic of either INS or FMNS. When a pendular waveform is superimposed on a jerk waveform and the slow phase is accelerating, it is a dual-jerk IN; if the slow phase is decelerating, it is a dual-jerk FMN. One has to carefully determine what is happening to the axis of the pendular slow phase (i.e., whether it is decelerating or accelerating) to properly categorize the nystagmus. Th is small but difficult group of patients must be recorded for accurate diagnosis. Distinguishing the INS and FMNS waveforms from the combination waveforms requires DC-coupled, high-bandwidth recordings of both eyes simultaneously. Summarizing, within the different types of neurologically “benign” infantile nystagmus, there is a large category of pure INS, a significant category of pure FMNS, and a small category that is a mixture of the two; there are also individuals with the nystagmus blockage syndrome (NBS) or spasmus nutans syndrome (SNS). All are easily diagnosed with the aid of ocular motility recordings and just as easily misdiagnosed without them. There are twelve INS waveforms, two mixed INS waveforms (dual-jerk and dual-pendular IN), two FMNS waveforms, and one mixed FMNS waveform (dual-jerk FMN). If a patient walks into your office with wiggling eyes and you wish to guess what the patient has before you record him or her, your best guess would be INS. A large percentage (80%) will be INS and 15% FMNS with only a small percentage of mixtures. If you could consider just INS patients, 94% will be pure INS and only 6% a mixture. If you could restrict the population to FMNS patients, three-fourths of them will have only FMNS, but many will have mixtures. Thus, more patients with predominantly FMNS will also have some INS than patients with predominantly INS having FMNS. • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 146 9/6/2012 9:50:09 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 5.1. 2. 4 A LT E R N AT E- COV E R A N D G A ZEA N G L E- COV E R T E S T S The same two tests discussed in Section 5.1.1.4 apply here since their purpose is to help differentiate INS from FMNS. However, as can be seen from the conclusions that can be drawn from the various observations from the two tests, although INS can be identified conclusively in some cases, FMNS cannot. 5.1.3 Nystagmus Blockage Syndrome The nystagmus blockage (blockierungs, compensation) syndrome (NBS)8 denotes a particular type of nystagmus: onset of esotropia in early infancy, pseudoabducens paralysis, head turn toward the side of the fi xating eye, absence of nystagmus with the fi xating eye in adduction, and appearance of a manifest jerky nystagmus as the fi xating eye moves into primary position and abduction.40,41 Many reports have concluded from eye-movement recording analysis that patients who habitually hold their dominant eye in the position of least nystagmus (usually adduction) may develop suppression and esotropia in the fellow eye. 38,40–42 Adelstein and Cuppers analyzed this condition further and coined the term “nystagmus blockage syndrome” (NBS).43 In the majority of patients the eyes are in a convergent position; in others there is alternating fi xation. Adelstein and Cuppers separated this syndrome from bilateral abducens paralysis and explained the esotropia on the basis of hypertonicity of the medial rectus muscles, resulting from the patient’s sustained effort to block the nystagmus by adducting the eye.43 The diagnosis of nystagmus blockage syndrome can be made only when the ongoing waveform is of INS and the nystagmus markedly diminishes with esotropia.44 Therefore, true NBS is indeed a “blockage” of an ongoing nystagmus (i.e., IN) present with both eyes open, produced by an added or increasing esotropia. The esotropia may reduce the nystagmus by one of two mechanisms: it may reduce an ongoing INS much in the same manner as true binocular convergence reduces the amplitude of IN, or it may convert the nystagmus to a low-amplitude FMN. The name “nystagmus blockage syndrome” reflects the prevalent assumption that patients block their nystagmus by adducting one eye. The adducted eye may be the fi xing eye (i.e., accompanied by a head turn) or it may be the nonfi xing eye (i.e., when a patient views an object in primary position with his or her head straight). In both cases, the nystagmus is reduced when the esotropia occurs. The diagnosis of NBS is difficult to make because precise and uniform diagnostic criteria are lacking; similar, more common disorders, such as esotropia associated with FMNS, are mistaken for NBS; and the diagnosis usually is made by clinical observation rather than by accurate eye-movement recordings. 36,38,40–42,45–49 The patients commonly misdiagnosed as having NBS are those with FMNS and esotropia. 5.1.3.1 A SS O CI AT I O N W I T H S T R A B I S M US Strabismus, albeit a variable strabismus, is a necessary but not sufficient condition for the NBS since a purposive esotropia is required to damp the IN and/or transform it into FMN. That is, all patients with NBS have strabismus, but clearly all with strabismus do not have NBS. 5.1.3. 2 CL I N I C A L S I G N S A N D SYMPTOMS Patients with NBS willfully induce esotropia while fi xating at distance. Th is is something that most with INS cannot do unless they have the ability to partially suppress the esotropic eye. If INS patients with normal binocularity could make one eye esotropic, they would have oscillating diplopia. When NBS patients turn one eye in and suppress it, their nystagmus damps and they may adopt a head turn to place their fi xating eye in adduction. The INS is either reduced in amplitude or converted to a lowamplitude FMNS by this purposive esotropia; the greater the esotropia, the lower the nystagmus and, as the fi xating eye moves from adduction to abduction, the nystagmus increases and esotropia decreases. Nystagmus in Infancy and Childhood • 147 05_Hertle_Ch05.indd 147 9/6/2012 9:50:09 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 5.1.3.3 D I F F E R E N T I A L D I A G N OS I S The NBS is the source of some misunderstanding. Individuals with NBS use a convergence-like movement to damp their INS while viewing a distant target. Thus, the waveforms in NBS are those of INS when the patient is looking in the distance and the eyes are straight.41 With the imposition of the purposive esotropia (this is not a strabismus that occurs transiently but one that the patient either willfully or reflexively imposes because he or she has found that acuity is better under that condition) the waveform can either become a damped INS waveform (Type I NBS) or a small-amplitude FMNS (Type II NBS). Thus, the NBS implies ocular motor deficits capable of producing both IN and FMN waveforms (see Table 5.3). Even though the FMNS waveform is usually unsuitable for good acuity (because there are no long, postsaccadic foveation periods), it is of low amplitude and acuity increases. Thus, there are two types of blockage syndrome. NBS is often misdiagnosed in patients with FMNS and alternating fi xation who place their fi xating eye in adduction to reduce their FMNS. Since they do not have INS, and they do not have NBS. Distinguishing the INS from the FMNS waveforms and the purposive esotropia of one eye requires DC-coupled, high-bandwidth recordings of both eyes simultaneously. 5.1.4 Spasmus Nutans Syndrome The term spasmus nutans (Latin for “nodding spasm”) refers to the constellation of nystagmus, head nodding, and torticollis. Although the term “acquired nystagmus” has been applied to the spasmus nutans syndrome (SNS)8 as a differentiating feature from INS, it should be remembered that INS is also “acquired” earlier in infancy. 35,50–54 Unlike INS, which usually becomes apparent between 8 and 12 weeks of age (although it may appear at birth), the age of onset in SNS is generally quoted as 6 to 12 months of age, although cases with clinically apparent onset ranging from 2 weeks to 3 years of age have been documented. SNS may become clinically “silent” within 1 to 2 years of onset, but it persists for years if studied 148 with eye-movement recordings. There is no lasting direct effect on vision, although there is high incidence of ametropia and amblyopia in this population of patients. 5.1. 4 .1 A SS O CI AT I O N W I T H S T R A B I S M US Gott lob et al. found a high incidence of esotropia, latent nystagmus, dissociated vertical divergence, and amblyopia in children with SNS. 55,56 Conversely, rare patients with infantile esotropia display horizontal or vertical head oscillations that resolve following surgical realignment of the eyes. 5.1. 4 . 2 CL I N I C A L S I G N S A N D SYMPTOMS SNS appears as a high-frequency, asymmetric, dysconjugate ocular oscillation. It is usually horizontal in direction but may also be vertical or torsional. 35,50–54 It is often described as an intermittent nystagmus that is asymmetrical in appearance and occasionally monocular. The key eye-movement recording observation was the variable phase difference between the two eyes, which is reflected clinically as an asymmetry in the oscillations between the two eyes. On lateral gaze, the dissociation may increase, with nystagmus of the abducting eye predominating. Some case series suggest an increased prevalence of esotropia in SNS. In contradistinction to INS, visual acuity is minimally affected in SNS. SNS is more common in Black children and has been reported in several sets of identical twins. 51,53,57 Contrary what was commonly believed, eyemovement data showed that the asymmetric ocular oscillations of SNS did not always disappear. 53 There have been patients of 10 or 12 years of age whose SNS is still clinically evident. Many times it disappears to clinical observation (again, like FMNS) but when recorded, a pendular dissociated nystagmus will be found. As described in Chapter 4, Section 4.2.1.3, patients cancel the dysconjugate pendular oscillation of SNS (present with a still head) and substitute a conjugate vestibulo-ocular reflex (VOR) when the head is moving; as a result, acuity • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 148 9/6/2012 9:50:09 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN increases. The oscillating diplopia that probably results from the out-of-phase oscillations may be the main reason that head shaking is used to cancel the nystagmus. Thus, unlike the low-amplitude, uncontrolled, noncompensatory head nodding sometimes seen in INS, the larger amplitude, purposive head nodding in SNS is compensatory. 52,58,59 5.1. 4 .3 D I F F E R E N T I A L D I A G N OS IS SNS may appear at or after birth and usually, but not necessarily, ceases by the age of 3 years. The nystagmus is pendular, usually monocular or disconjugate, and is commonly accompanied by a head oscillation. Reports of “spasmus nutans” accompanying neurological disease (e.g., craniopharyngeoma, optic nerve and chiasmal glioma, 60–62 or cerebrocerebellar degeneration63) have not all included eye-movement recordings to prove that the nystagmus was the same as that of spasmus nutans. Although the nystagmus may clinically resemble that recorded in SNS, until a proper study comparing the actual waveforms of SNS with those recorded in children with known neurological disease, they should not be presumed to be identical. The term “SNS” should be reserved for the specific, benign nystagmus that has been documented (see earlier) and should not also be used to describe the nystagmus accompanying neurological disease, even if the nystagmus itself is subsequently found to be identical. Rather, a descriptive name for the nystagmus should be used for the latter. Other signs are needed to distinguish true SNS from similar looking nystagmus associated with central nervous system (CNS) disease. 54 For a century, numerous reports emphasized that SNS was a visually and systemically benign and self-limited clinical entity. 54,61,62,64–68 Since 1967, however, many infants with some of the features of spasmus nutans have been found to have congenital suprasellar tumors (most commonly chiasmal gliomas). Suprasellar tumors can produce a constellation of neuroophthalmologic signs that are clinically and electrophysiologically indistinguishable from SNS. The clinical fi ndings of hydrocephalus, café au lait spots, optic atrophy, or other clinical signs of neurofibromatosis make it more likely that a child with SNS will have a CNS glioma. A substantial proportion of patients presenting with SNS-like nystagmus have important underlying ocular, intracranial, or systemic abnormalities. Neurodegenerative disorders such as Pelizaeus– Merzbacher disease and Leigh disease may produce nystagmus and head nodding that are indistinguishable from SNS. 54–56,69–73 These disorders should be suspected in children with clinical signs of ataxia or developmental delay or with magnetic resonance evidence of white matter signal abnormalities. Achromatopsia, congenital stationary night blindness, and Bardet Biedl syndrome can also masquerade as SNS. The diagnosis of SNS can only be made using a combination of clinical characteristics and eyemovement fi ndings, which exclude other visual or nervous system disease. The pathogenesis and neuroanatomical substrate of this developmentally acquired form of asymmetric, dysconjugate nystagmus are still unknown. SNS must fi rst be distinguished from INS and FMNS. Despite the clinical similarities of SNS to INS or FMNS in some patients, eyemovement data can be used to make the correct diagnosis. The diagnostic criteria for SNS have also been defi ned by ocular motility recordings. 53 Based on that data we can now diagnose SNS immediately and distinguish it from INS and FMNS; it is no longer necessary to wait 3 or 4 years before making the diagnosis based on its possible clinical disappearance. The diagnostic key is the variable phase difference between the oscillations in both eyes, unlike INS and FMNS, where the oscillations are always phase-locked, if not totally conjugate. At present, however, even positive identification of SNS or SNS-like waveform is insufficient to preclude further imaging studies to rule out neurological disease. However, if it is subsequently found that the nystagmus associated with neurological disease differs from that of SNS, then identification of the latter by eye-movement data could provide sufficient evidence to remove the need for expensive imaging studies. Similarly, eye-movement identification of a type of nystagmus that is found to be specific Nystagmus in Infancy and Childhood • 149 05_Hertle_Ch05.indd 149 9/6/2012 9:50:09 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN for neurological disease would require imaging studies. 5.1.5 Nystagmus and Strabismus The prevalence of strabismus in general population has been reported to be between 0.80% and 6.0%.15,74–77 Chia et al. in a study of 3009 Singaporean children, aged 6 to 72 months found a prevalence of strabismus of 0.80%.78 The MEPEDS Study Group found that in 3007 African American children and 3007 Hispanic children, ages 30 to 72 months, incidence of strabismus was similar in both groups (2.4% for Hispanic children vs. 2.5% for African American children).79,80 Graham reported that the prevalence of strabismus is 5.66% based on a study done on 4784 children. 81 Of 1187 children, 4.2% were found to have strabismus in a study done by Chew et al. 82 In a study done in Sweden, the prevalence of strabismus was found to be 3.2%. 83 Compared to the general population, the prevalence of strabismus in patients with nystagmus is higher than in the general population. In a study by Forssman the prevalence of strabismus was reported to be 16%. 84,85 In another study by Brodsky and Fray the prevalence of strabismus was reported to be 17%– 50%. 28 Self et al. reported that the prevalence of strabismus is 44% in INS due to mutations in FRMD7. 86,87 From a combination of studies of over 500 infants, children, and adults with childhood forms of nystagmus reported by multiple authors, incidences from 25% to 72% were reported. 21,25,28,35–37,39,88–96 Thus, those eye care professionals who care for patients with strabismus are as likely, if not more so, as any in health care to be confronted with the disorders of nystagmus and other ocular oscillations. 5.2 NYSTAGMUS WITH ASSOCIATED NEUROLOGICAL DISEASE—“SYMPTOMATIC” In addition to the benign types of nystagmus in infancy discussed earlier, there are also symptomatic types of nystagmus that may appear 150 • 05_Hertle_Ch05.indd 150 in infancy as well as adulthood. Various types of acquired nystagmus may be localized, as Figure 5.5 illustrates. Knowing how each type of nystagmus varies with gaze angle is important for differential diagnosis. In Figure 5.6, the waveforms and their variation with gaze angle of INS, FMNS (both linear and decelerating slow phases), GEN, and VN are illustrated. These variations are shown in Figure 5.7 as they would appear when recorded. The target position for the FMNS waveforms with decelerating slow phases has been corrected from illustrations published prior to the discovery of the substitution of saccadic pulse trains for linear FMNS when the slow-phase velocities were too high for good foveation.97 5.2.1 Vestibular Nystagmus Certain characteristics of vestibular nystagmus can localize the etiology to the peripheral or central neuronal pathways of the vestibular systems. Central vestibular nystagmus is frequently uniplanar in contrast to peripheral vestibular nystagmus, which is usually torsional or multiplanar.98,99 Visual fi xation easily inhibits peripheral vestibular nystagmus, but not central vestibular nystagmus. Vertigo and tinnitus are common in peripheral vestibular nystagmus and uncommon in central vestibular nystagmus. 5. 2.1.1 P E R I P H E R A L V E S T I B U L A R IMBAL ANCE The child with peripheral vestibular nystagmus has, in many ways, similar etiologies, signs, symptoms, and treatment options as an adult. The VOR normally generates eye rotations, after a short latency, in the same plane as the head rotation that elicits them. Disorders of the vestibular periphery cause nystagmus in a direction that is determined by the pattern of involved labyrinthine-semicircular canals.99–106 The complete, unilateral loss of one labyrinth causes a mixed horizontal-torsional nystagmus that is suppressed by visual fi xation. Another consequence of vestibular disease is a change in the size (gain) of the overall dynamic VOR response. As a result of this change, patients complain DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 9/6/2012 9:50:10 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.5 Sagitt al section of brainstem, midbrain, cortex, and cerebellum. Anatomical areas responsible for ocular motor control and nystagmus types localized to brainstem and cerebellar areas are indicated. CN III, cranial nerve three; MLF, medial longitudinal fasciculus; PAN, periodic alternating nystagmus; PC, posterior commissure. of oscillopsia during rapid head movements. A VOR gain larger than 1 (eye speed exceeds head speed) results from a disinhibition of the brainstem circuits responsible for the VOR and is caused by vestibulo-cerebellar dysfunction. Loss of peripheral vestibular function causes impaired vision and oscillopsia during locomotion, due to the inability to compensate for the high-frequency head perturbations that occur with body and head movements. Symptoms include vertigo, nausea, dizziness, and oscillopsia, and signs include mixed horizontal-torsional trajectory of the oscillation (which usually beats away from the side of a vestibular lesion), associated neurologic signs and symptoms, usually acute onset, and unsteady gait. Common associated fi ndings include relatively preserved saccades and smooth pursuit, skew deviation, and an increase in the intensity of the oscillation when eyes are turned in the direction of the quick phases (Alexander’s law). The nystagmus is suppressed by visual fi xation and increased when fi xation is removed. The horizontal component is diminished when the patient lies with the intact ear down and is exacerbated with the affected ear down. The nystagmus is increased or precipitated by changes in head position, vigorous head shaking, hyperventilation, mastoid vibration, or Valsalva maneuver. There is unilaterally impaired ability to modulate spontaneous nystagmus. A magnetic resonance image (MRI) or computed tomography (CT) scan of the brain may show disease and, importantly, ocular motility recordings show linear (constant velocity) slow phases.99–106 The prognosis of the oscillation depends on underlying disease. The characteristics of peripheral vestibular nystagmus are listed in Table 5.4; peripheral positional nystagmus, in Table 5.5; and its variation with gaze angle is illustrated in Figures 5.6 and 5.7. Nystagmus in Infancy and Childhood • 151 05_Hertle_Ch05.indd 151 9/6/2012 9:50:10 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.6 Waveform variation with gaze angle for different types of nystagmus. Note that the target positions for FMNS with decelerating slow phases are at the ends of the slow phases; thus, these are defoveating saccadic pulse trains, not true nystagmus. The basic FMNS waveforms (JR for right-eye fi xation and JL for left-eye fi xation) have linear slow phases and are shown with VN. FMNS, fusion maldevelopment nystagmus syndrome; GEN, gaze-evoked nystagmus; INS, infantile nystagmus syndrome; L, left; |N|, nystagmus magnitude; R, right; t, time; VN, vestibular nystagmus. FIGURE 5.7 Waveform variation with gaze angle for different types of nystagmus as would be recorded by an eye-movement data acquisition system. FMNS, fusion maldevelopment nystagmus syndrome; GEN, gaze-evoked nystagmus; INS, infantile nystagmus syndrome; JL, jerk left; JR, jerk right; LE, fi xation with left eye; RE, fi xation with right eye; VN, vestibular nystagmus. 152 • 05_Hertle_Ch05.indd 152 DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 9/6/2012 9:50:11 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Table 5.4 Vestibular Nystagmus S Y M P T O M O R S IG N P E R I P H E R A L (E N D O R G A N) C E N T R A L (N U C L E A R ) Direction of nystagmus Unidirectional, fast phase opposite lesion Uncommon Bidirectional or unidirectional Common Never present May be present Inhibits nystagmus and vertigo Marked Toward fast phase Toward slow phase Toward slow phase Changes Romberg fall Finite (minutes, days, weeks) but recurrent Often present Infection (labyrinthitis), Meniere disease, neuronitis, vascular, trauma, toxicity No inhibition Mild Variable Variable Variable No effect May be chronic Purely horizontal nystagmus without torsional component Vertical or purely torsional nystagmus Visual fi xation Severity of vertigo Direction of spin Direction of past-pointing Direction of Romberg fall Effect of head turning Duration of symptoms Tinnitus and/or deafness Common causes 5.2.1. 2 CE N T R A L V E S T I B U L A R IMBAL ANCE The child with central vestibular nystagmus also has, in many ways, similar etiologies, signs, symptoms, and treatment options as an adult. There is a mixed horizontal-torsional trajectory to the fast phase with beats away from the side of the vestibular lesion.98,103,107,108 Usually absent Vascular, demyelinating, and neoplastic disorders There are almost always associated neurologic signs and symptoms, that is, the acute onset of vertigo, nausea, dizziness, and oscillopsia, associated with other signs of vestibulocerebellar dysfunction. Common associated findings may include other ocular oscillations such as downbeat, upbeat, torsional, horizontal, jerk, and SSN. Slow phases may be linear or have increasing- or decreasing-velocity Table 5.5 Positional Nystagmus FE AT U R ES PER I PH ER A L CENTR A L Latency Fatigability Rebound Habituation Intensity of vertigo Reproducibility Directionality and waveforms 3–40 sec Yes Yes Yes Severe Poor Stereotyped None; nystagmus begins immediately No No No Mild Good Variable Nystagmus in Infancy and Childhood • 153 05_Hertle_Ch05.indd 153 9/6/2012 9:50:12 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.8 Velocity trace from eye-movement recordings of a patient with infantile nystagmus syndrome and periodic alternating nystagmus (PAN) looking in primary position for about 13 minutes showing classic rhythmic change in intensity and direction of the oscillation. Spontaneous nystagmus in the primary position, which beats jerk right with increasing then decreasing intensity for 1 to 2 minutes, followed by a quiet period, and then reappearance of the nystagmus in the opposite direction with similar crescendodecrescendo in intensity for a similar length of time. Both eyes had same tracing. waveforms. The nystagmus is poorly suppressed by fixation of a visual target and may be precipitated, exacerbated, or changed in direction by altering head position, vigorous head shaking (horizontal or vertical), or hyperventilation. Convergence may increase, suppress, or convert upbeat to downbeat nystagmus and vice versa. The oscillation is commonly associated with impaired smooth pursuit, gaze-evoked nystagmus, gait instability, and ataxia. An MRI/CT scan of the brain ref lects underlying disease. The prognosis depends on the underlying disease. The characteristics of central vestibular nystagmus are FIGURE 5.9 Eye-movement recording of right eye from a patient with symmetric infantile periodic alternating nystagmus (PAN) performed under binocular conditions over 200 seconds illustrating a typical periodic, symmetric, jerk right with extended foveation (Jerk Ref) when the infantile nystagmus syndrome direction was to the right and jerk left with extended foveation (Jerk Lef) when the direction was to the left . L, left; R, right; OD, right eye; OS, left eye. 154 • 05_Hertle_Ch05.indd 154 DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 9/6/2012 9:50:13 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN listed in Table 5.4 and central positional nystagmus, in Table 5.5. 5.2.1.3 CE N T R A L V E S T I B U L A R I N S TA B I L I T Y ( P E R I O D I C A LT E R N AT I N G) Periodic alternating nystagmus (PAN) is an extraordinary ocular motor phenomenon in which a persisting horizontal jerk nystagmus periodically changes directions; it may be congenital or acquired. The congenital variety (i.e., INS nystagmus), which may be associated with albinism,109,110 has slow-phase waveforms of both linear and increasing velocity, usually lacks the well-defi ned stereotyped periodicity seen in acquired PAN (i.e., it is asymmetric (a)periodic alternating nystagmus, APAN), and can persist for many minutes in either direction or spontaneously change direction after a few seconds.111,112 The addition of variable pendular nystagmus to these APAN jerk waveforms can produce complex waveforms that may mimic those of FMNS nystagmus.113–115 The periodicity of INS APAN is markedly influenced by changes in gaze position, supporting the hypothesis that the direction reversals are a result of a temporal shift in the null zone (see Chapter 2, Fig. 2.12). 33 INS with APAN may also be hereditary.116 In contrast, the usual, fi xed sequence in acquired PAN consists of about 90 seconds of nystagmus beating in one direction, 10 seconds of a neutral phase in which the eyes stop or beat downward irregularly, and 90 seconds of beating in the opposite direction (see Fig. 5.8 where the velocity trace demonstrated this periodicity). Th is periodicity is continuous during waking hours and may prevail during sleep. Some patients demonstrate asymmetries in the timing of the two major phases, but the basic pattern for each patient is usually invariable; for a contrast to APAN, see Table 5.2. In Figure 5.9 the symmetric PAN of a patient with INS is shown. The JLef waveform is shown gradually diminishing in amplitude and, after a neutral period, reversing to JRef and increasing in amplitude. In acquired PAN the waveform would be a sawtooth jerk nystagmus. Acquired PAN is usually seen in older children or adults but may present in early childhood. Causes of acquired PAN include head trauma, multiple sclerosis, posterior fossa lesions, vascular insufficiency, spinocerebellar degenerations, encephalitis, otitis media, syphilis, aqueductal stenosis, and Arnold–Chiari malformation.95,110,117 PAN may coexist with downbeat nystagmus, which also suggests a Chiari malformation. Unlike PAN in the INS, acquired PAN is usually associated with structural lesions involving the cerebellum or its central connections. Reports of acquired PAN following visual loss (e.g., vitreous hemorrhage or cataract) and its disappearance with restoration of vision provide an important clue to the underlying pathophysiology. Patients with acquired PAN usually have vertigo, nausea, dizziness, and oscillopsia. It can be associated with other signs of vestibulocerebellar involvement (e.g., Arnold-Chiari, platybasia). The nystagmus is a mixed horizontal-torsional trajectory showing a peculiar, spontaneous, rhythmic, regular, crescendo-decrescendo intensity and directional change direction of the fast phase with the complete cycle lasting about 3 minutes. It is usually acute in onset and may be associated with periodic alternating head turns—the head turns in the direction of the quick phase, and the eyes are moved into a position in the orbit that is the same as the direction of the slow phase—thereby minimizing the nystagmus induced by Alexander’s law. The nystagmus cycle is not affected by visual fi xation. Vestibular stimuli, such as head rotations, can change or transiently stop nystagmus, downbeat nystagmus and square-wave jerks may become more obvious in the brief null period when the horizontal nystagmus wanes and then reverses, MRI/CT scan of brain reflects underlying disease, and ocular motility recordings show linear (“constant velocity”) slow phases. The prognosis depends on the underlying disease. Campbell described PAN secondary to phenytoin intoxication in a patient with alcoholic cerebellar degeneration.118 The antispasticity drug baclofen abolishes acquired PAN but does have some unpredictable effects on the INS variety.119 The drug abolished experimentally created PAN in the monkey,120 as well as a single case of aperiodic alternating nystagmus in a patient Nystagmus in Infancy and Childhood • 155 05_Hertle_Ch05.indd 155 9/6/2012 9:50:14 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN with vertebrobasilar insufficiency.121 Baclofen damped the APAN of some patients with INS,122 whereas memantine damped acquired PAN in a case where baclofen was ineffective.123 PAN may be associated with a periodic alternating skew deviation.124 Periodic alternating gaze deviation (“ping-pong gaze”), regardless of whether associated with alternating nystagmus or alternating head turning, is a rare, related phenomenon.125 Periodic alternating gaze deviation is a cyclic disorder of eye (and head) movements characterized by slow, spontaneous, alternating, pendular, conjugate, horizontal eye and/or compensatory head movements. A complete cycle lasts seconds to minutes and consists of a conjugate horizontal eye movement to one side followed by a slow conjugate eye movement to the opposite side. Th is disorder is usually clinically evident as part of a larger cerebral dysfunction such as a cerebrovascular accident, brain tumor, obtunded states, sleep, anesthesia, and coma. Although the exact mechanism is unknown, the midline cerebellum, pons, and bilateral cerebral hemisphere dysfunction have all been postulated. Animal experiments combined with additional data in humans suggest that acquired PAN probably requires concurrent CNS dysfunction at two separate levels.108,126 The nodulus and uvula of the cerebellum are believed to control postrotational nystagmus, which is prolonged following ablation. PAN can be produced in animals following ablation of these structures if visual deprivation is superimposed. It is believed that normal vestibular repair mechanisms act to reverse the direction of the nystagmus. Under normal circumstances, the oscillations of PAN would be blocked by visual fi xation, smooth pursuit, and optokinetic mechanisms. When these visual stabilization systems do not work (in the setting of visual deprivation and disease of the cerebellar flocculus), removal of Purkinje cell inhibition upon the vestibular nuclei allows the central velocity storage mechanism to become unstable. Pharmacological evidence suggests that the nodulus and uvula maintain inhibitory control on the vestibular rotational responses via the inhibitory neurotransmitter gamma-aminobutyric- acid (GABA).117,119,127,128 Halmagyi et al. were the fi rst to report the successful treatment 156 • 05_Hertle_Ch05.indd 156 of the acquired form of PAN with the GABAergic drug Baclofen.119 The fi nding that acquired PAN is abolished by Baclofen, both in humans and in animals following ablation of the nodulus and uvula, further supports this pathogenetic mechanism in acquired PAN. In a clinical and control-system study,129 it was proposed that PAN arises from (1) a defect in the brainstem neural networks that generates slow phases of vestibular and optokinetic nystagmus, (2) the action of an adaptive network that normally acts to null prolonged, inappropriate nystagmus, and (3) an inability to use retinal-error velocity information. They proposed a control system model that denied access of visual signals to the visual vestibular system. Th is model is particularly appealing because of the occasional relationship between impaired vision and PAN. Support for their hypothesis of impairment in the velocity storage element was presented by Furman et al.,130 who studied four PAN patients. PAN has occurred after bilateral vitreous hemorrhages (associated with a massive subarachnoid hemorrhage) and after cataracts and disappeared after bilateral vitrectomy and cataract surgery, respectively. Ablation of the nodulus and ventral uvula of the cerebellum in monkeys produces PAN.120 5.2.2 Gaze-Holding Deficiency Nystagmus There are several forms of nystagmus that are directly related to problems with gaze holding; they usually manifest at eccentric gaze angles, although one type may be present in primary position. 5 . 2 . 2 .1 ECC E N T R I C G A Z E , G A Z EE VO K E D, R E B O U N D Gaze-evoked nystagmus (GEN) is a rhythmic oscillation of the eyes while attempting to maintain an eccentric eye position. It is caused by a deficiency, usually a structural lesion, in the neural integrator network.131 Gaze cannot be held at an eccentric position, and the eyes drift back toward the null point of the integrator, which often is straight-ahead gaze. A corrective DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 9/6/2012 9:50:14 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN saccade is attempted to move the gaze back to the eccentric position, and the process repeats. The variation of GEN with gaze angle is illustrated in Figures 5.6 and 5.7. Saccadic eye movements are made by a neural signal composed of a rapid increase in neural discharge (pulse) and then a rapid decrease to a new discharge rate (step). When the pulse component is not accurate, the eyes will over- or undershoot their target and then make a corrective second saccade to bring the gaze to the intended fi xation. When the step component is not maintained, the eyes will drift back to primary gaze with a decelerating slow phase, make a corrective saccade, and repeat to cause GEN.126 It is the neural integrator that is responsible for mathematically “integrating” the pulse of neural activity into a step discharge. If there is a minimal abnormality in integrator function, GEN will manifest itself only at extreme angles of gaze. However, if there is a major defect in function, GEN can appear in primary gaze. It should also be remembered that vertical GEN almost always indicates brainstem or cerebellar dysfunction. Gaze-evoked nystagmus is the most common form of nystagmus encountered in clinical practice. There is an important difference between GEN and physiologic end-point nystagmus (EPN). With EPN, the eyes attempt a saccade out to an extreme gaze position and have an initial difficulty holding this position. After a short amount of jerk nystagmus with fairly linear slow phases, the eyes may be able to maintain the eccentric gaze. EPN is a normal finding and differs from GEN by the fact that GEN is a constant nystagmus with larger amplitude (defined as 4° or more) and is often asymmetric. Physiologic end-point nystagmus is not a type of GEN but a nystagmus that may be inconsistent and that is seen in most normal individuals, some when attempting to fixate an eccentric target of only 20°132 or even 10°.133 The jerk phase may occur for a few beats, and then the integrators will hold and the nystagmus will disappear. Physiologic EPN has been found to occur in up to 60% of individuals and is maximally deviated after 30 seconds of eccentric gaze holding (or attempted holding).134 Included in the causes of GEN are medications and brainstem or cerebellar disorders. Brainstem and cerebellar lesions also cause pathological rebound nystagmus. After holding eccentric gaze between 30° and 45° from primary gaze for more than 30 seconds, a patient is directed to look straight (assume primary gaze). If an abnormal amount of rebound nystagmus is present (more than three beats of nystagmus), with the jerk directed away from the prolonged eccentric gaze, it is rebound nystagmus. Because the neural integrator is found in the brainstem, tumors that favor this area should be suspected when GEN is found. 5. 2. 2. 2 G A Z E I N S TA B I L I T Y (“ R U N AWAY ” ) Th is is usually an acquired oscillation in which the slow phases are directed centrifugally (away from) primary position. There are often associated neurologic signs and symptoms. The nystagmus usually has an acute onset and is associated with other signs of vestibulocerebellar involvement. The nystagmus slow phases carry the eyes away from a fi xing position and the slow phases show an accelerating velocity.135 Th is is different from the accelerating slow phases of INS where they are directed back to the null position (see Chapter 2, Section 2.1.2.6, discussion of the neural integrator). The oscillation may have a vertical or horizontal or horizontal component. An MRI/ CT scan of brain often reflects underlying diseases and eye-movement recordings show slow phases that are accelerating.126 CNS pathology is almost always present. Arnold et al. reported the effects on gaze stability of microinjections of eight different drugs into the NPH-MVN of monkeys.136 Agents with either agonist or antagonist actions at GABA, glutamate, and kainate receptors all caused gaze-evoked nystagmus, while agents acting at the glycine receptor (glycine and strychnine) had no effect. In contrast, when muscimol was injected near the center of the MVN, the eyes sometimes drifted away from the central position with increasing velocity waveforms. Clinically, patients who show nystagmus with Nystagmus in Infancy and Childhood • 157 05_Hertle_Ch05.indd 157 9/6/2012 9:50:15 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN increasing velocity waveforms have cerebellar, not brainstem, lesions. 5.2.3 “Vision-Loss” Nystagmus Nystagmus may occur in complete blindness and may also accompany incomplete visual impairment due to lesions anywhere along the visual pathways. Visual loss may facilitate nystagmus in two ways—through loss of visual inputs to the fi xation system that are used to detect and immediately correct ocular drift and through loss of visual signals that are used, over the long term, to calibrate the ocular motor systems.70,137 The first of these components may be regarded as “visual fi xation,” and it is easily demonstrated when a normal subject attempts to fi xate on the remembered location of an eccentric target after the room is switched to darkness: the eye drifts centripetally off target several times faster than when the subject was actually viewing it. The visual fi xation mechanism by which smooth eye movements correct for drifts of gaze depends on the motion vision system (especially portions of the cerebral cortex, such as the middle temporal area or V5). Although such visually mediated eye movements are important for maintaining steady fi xation, they have one important limitation, a response time of longer than 70 milliseconds. If this response time is delayed further by disease of the visual system, then the brain’s attempts at correcting eye drifts might actually add to the retinal error rather than reducing it, leading to ocular oscillations. Th is type of nystagmus is similar to normal physiological “end-point” nystagmus. The second component of the visual influence on gaze control concerns the need for continuous calibration and optimizing all types of eye movements.70,137 Th is optimization depends heavily on visual projections to the cerebellum. The cerebellum receives visual signals from motion vision areas of the cerebral cortex via the pontine nuclei. In addition, visual signals for calibration probably also pass to the cerebellum via the inferior olivary nucleus on climbing fibers. Calibration of the ocular motor system requires that visual signals be compared with eye-movement commands (efference copy), and the latter probably reach the cerebellum from the cell 158 • 05_Hertle_Ch05.indd 158 groups of the paramedian tracts, which lie diffusely throughout the midline of the brainstem and receive input from all premotor structures that project to ocular motor neurons. Lesions at any part of this visual motor calibration pathway deprive the brain of signals that are essential for fi xation, resulting in drifts of the eyes away from the target, leading to nystagmus. Th is type of nystagmus is similar to that produced by a tonic imbalance from the visual vestibular system. Thus, “vision-loss” nystagmus is not a specific type of nystagmus but rather nystagmus due to ocular motor system drifts and imbalances that may become manifest when the stabilizing effects of vision are absent. 5. 2.3.1 P R EC H I A S M A L , O P T I C C H I A S M , A N D P OS T C H I A S M A L V I S I O N L OSS These ocular oscillations occur with loss of vision after early infancy (~6–9 months) and have associated afferent visual system eye and/ or brain disease. Acquired prechiasmal bilateral visual loss in children causes continuous jerk nystagmus, with horizontal, vertical, and torsional components, and a drift ing “null” position. Monocular visual loss causes slow vertical oscillations and low-amplitude horizontal, mainly pendular, nystagmus predominantly in the blind eye.20 Lesions at the optic chiasm can result in SSN with bitemporal visual field loss. Postchiasmal vision loss results in low-amplitude horizontal nystagmus beating toward the side of the lesion. 5.2.4 Other Pendular Nystagmus Associated with Diseases of Central Myelin Acquired pendular nystagmus usually has horizontal, vertical, and torsional components with the same frequency, although one component may predominate.126,137 If the horizontal and vertical oscillatory components are in phase, the trajectory of the nystagmus is diagonal (oblique). If the horizontal and vertical oscillatory components are out of phase, the trajectory is elliptical. A special case is a phase difference of 90° and equal amplitude of DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 9/6/2012 9:50:15 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN the horizontal and vertical components, when the trajectory is circular. When the oscillations of each eye are compared, the nystagmus may be conjugate, but oft en the trajectories are dissimilar, and the size of oscillations is different (sometimes appearing monocular), and there may be an asynchrony of timing (phase shift). The latter may reach 180°, in which case the oscillations are again diagonal. The temporal waveform usually approximates a sine wave, but more complex oscillations have been noted. The frequency of oscillations ranges from 1 to 8 Hz, with a typical value of 3.5 Hz. For any particular patient, the frequency tends to remain fairly constant; only rarely is the frequency of oscillations different in the two eyes. In some patients, the nystagmus stops momentarily after a saccade. Th is phenomenon is called postsaccadic suppression. A more common feature is that the oscillations are “reset” or phase-shifted by saccades. Acquired pendular nystagmus may be suppressed or brought out by eyelid closure or evoked by convergence. In some patients with this condition, smooth pursuit may be intact. Acquired pendular nystagmus is a common feature of acquired and congenital disorders of central myelin, such as multiple sclerosis, toluene abuse, Pelizaeus-Merzbacher disease, and peroxisomal disorders. The observation that acquired pendular nystagmus is “reset” or phase-shifted after saccades (more so with large saccades) suggested that the oscillations arise in the brainstem-cerebellar gaze-holding network (the neural integrator for eye movements). Th is form of nystagmus also occurs with the syndrome of oculopalatal tremor and Whipple disease of the CNS. 5. 2. 4 .1 O C U L O PA L ATA L T R E M O R O R “ M YO C L O N US ” Acquired pendular nystagmus may be one component of the syndrome of oculopalatal (pharyngo-laryngo-diaphragmatic) myoclonus.138–140 Th is condition usually develops several months after brainstem or cerebellar infarction, although it may not be recognized until years later. Oculopalatal myoclonus also occurs with degenerative conditions. The term “myoclonus” is misleading, since the movements of affected muscles are approximately synchronized, typically at a rate of about two cycles per second. The palatal movements may be termed “tremor,” rather than myoclonus, and the eye movements are really a form of pendular nystagmus. Although the palate is most often affected, movements of the eyes, facial muscles, pharynx, tongue, larynx, diaphragm, mouth of the eustachian tube, neck, trunk, and extremities may occur. The ocular movements typically consist of oscillations less sinusoidal than with typical multiple sclerosis, and often with a large vertical component, although they may also have small horizontal or torsional components. The movements may be somewhat dysconjugate (both horizontally and vertically), with some orbital position dependency. Some patients show cyclovergence (torsional vergence) oscillations. Occasionally, patients develop the eye oscillations without movements of the palate, especially following brainstem infarction. Eyelid closure may bring out the vertical ocular oscillations. The nystagmus sometimes disappears with sleep, but the palatal movements usually persist. The condition is usually intractable, and spontaneous remission is uncommon. The main pathologic fi nding with palatal myoclonus is hypertrophy of the inferior olivary nucleus, which may be seen during life using MRI.139 There may also be destruction of the contralateral dentate nucleus. Histologically, the olivary nucleus has enlarged, vacuolated neurons with enlarged astrocytes. Guillain and Mollaret proposed that disruption of connections between the dentate nucleus and the contralateral inferior olivary nucleus, which run via the red nucleus and central tegmental tract, are responsible for the syndrome.141,142 However, neither the dentate nucleus nor the red nucleus has been shown to have a specific role in ocular motor control. Thus, it has thus been postulated that the nystagmus results from instability in the projection from the inferior olive to the cerebellar flocculus, a structure thought to be important in the adaptive control of the VOR. It is also possible that disruption of Nystagmus in Infancy and Childhood • 159 05_Hertle_Ch05.indd 159 9/6/2012 9:50:15 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN projections from the cell groups of the paramedian tracts to the cerebellum leads to the ocular oscillations. 5.2. 4 . 2 P E N D U L A R V E R G E N CE N Y S TA G M US A SS O C I AT E D W I T H WHIPPLE DISE A SE Vergence nystagmus has also been called “convergent-divergent” nystagmus, but that redundant term is needlessly convoluted (e.g., horizontal is not called “left ward-rightward” nor is vertical called “upward-downward” nystagmus). Th is ocular oscillation occurs with the gastrointestinal disease “Whipple;” thus, patients have associated signs and symptoms of gastrointestinal illness with neurological involvement.143,144 These dysconjugate, vergence, pendular oscillations are often small in amplitude and thus easily overlooked by clinicians. More widespread use of the magnetic search coil technique has made it easier to identify the vergence components of this form of nystagmus. Averbuch-Heller et al. reported three patients with pendular oscillations that were about 180° out of phase in the horizontal and torsional planes but had conjugate vertical components.145 In one of these patients, the torsional component of the oscillations had the largest amplitude. Thus, the patient actually had a cyclovergence nystagmus. Vergence, pendular oscillations also occur in patients with multiple sclerosis and brainstem stroke. In Whipple disease, the oscillations typically have a frequency of about 1.0 Hz and are accompanied by concurrent contractions of the masticatory muscles, a phenomenon called oculomasticatory myorhythmia. Supranuclear paralysis of vertical gaze also occurs in this sett ing and is similar to that encountered in progressive supranuclear palsy. At least two possible explanations have been offered to account for the vergence nature of these pendular oscillations: a phase shift between the eyes, produced by dysfunction in the normal yoking mechanisms, or an oscillation affecting the vergence system itself. Patients who have been studied show no phase shift (i.e., are conjugate) vertically. Under experimental conditions, the vergence system 160 can be made to oscillate at frequencies up to 2.5 Hz—lower than that reported in patients with conditions other than Whipple disease. To account for these higher frequency oscillations, it seems necessary to postulate instability within the brainstem-cerebellar connections of the vergence system, for example, between the nucleus reticularis tegmenti pontis and cerebellar nucleus interpositus, which may help hold vergence angle steady. 5.2.5 Convergence/ConvergenceEvoked Nystagmus The act of convergence usually damps INS (see Chapter 2, Section 2.1.6). Convergence can also damp146 or evoke147 lid nystagmus and may damp or enhance downbeat nystagmus.148 Upbeat nystagmus may change to downbeat with convergence.149 A slow divergence movement followed by a rapid convergence to the primary position is called “repetitive divergence.” It occurs at irregular intervals, distinguishing this from nystagmus.150 The only reported instance of this phenomenon was in a patient with hepatic encephalopathy; an entire cycle lasted from 4 to 10 seconds, and the interval between cycles was 1 to 15 seconds. Conjugate nystagmus evoked by convergence (convergence-evoked nystagmus) is not the same as “convergence nystagmus” (a vergence nystagmus) and convergence-retraction “nystagmus” (a saccadic oscillation discussed in Section 5.3.6). The latter is a manifestation of the dorsal midbrain syndrome; because the initiating convergence movements are saccadic,151 it is not a true nystagmus. Fast divergent movements, followed by a slow convergence, associated with epileptic electroencephalographic activity, occurred in a neonate with an intraventricular hemorrhage.152 Vergence nystagmus must also be distinguished from psychogenic flutter (the so-called voluntary “nystagmus” discussed in Section 5.3.14), which is often best induced when the eyes are slightly converged. With the exception of pure convergence nystagmus in infants with SNS, true pendular convergence nystagmus is rare but does occur most commonly in Whipple • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 160 9/6/2012 9:50:15 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN disease. Th ree patients with convergence nystagmus with phase shift s of about 180° in both the horizontal and torsional planes with conjugate nystagmus in the vertical plane were studied.153 Convergence increased the nystagmus in two of the patients. The waveforms were either sinusiodal or complex sums of sinusoids, and in one patient they were cycloidal. There were no initiating saccades to these cycloidal movements, unlike the pseudocycloid waveform of INS. A visually mediated vergence instability was hypothesized to induce low-frequency vergence nystagmus, whereas instability of brainstem pathways associated with vergence might have induced high-frequency forms. Backward and forward motion in the ground plane can also induce vergence nystagmus in normals.154 Nystagmus evoked by convergence is unusual and may be either conjugate or disjugate, congenital or acquired.155 No defi nite clinical correlation could be made with a specific lesion in the two cases reported. The neuropathologic examination revealed no morphologic explanation for nystagmus in the patient with congenital convergence-evoked nystagmus; the patient with the acquired form had demyelinating disease with a spastic paraparesis and no cranial nerve abnormality other than the ocular motor fi ndings. Horizontal pendular nystagmus rarely is evoked by accommodative vergence.156 5.2.6 Upbeat Nystagmus Upbeat nystagmus that is present with the eyes close to central position occurs in many clinical conditions.157,158 Nystagmus intensity is usually greatest in upgaze, and it usually does not increase on right or left gaze. Removal of visual fi xation has litt le influence on slow-phase velocity. Convergence is variously reported to enhance, suppress, or convert upbeat nystagmus to downbeat. Placing the patient in a headhanging position increases the nystagmus in some individuals. As is the case with downbeat nystagmus, patients with upbeat nystagmus often show asymmetries of vertical vestibular and smooth-pursuit eye movements, as well as associated cerebellar eye-movement fi ndings. Upbeat nystagmus is present with the eyes close to the central position and usually increases on upgaze. Causes of upbeat nystagmus are lesions in the ascending pathways from the anterior canals (and/or the otoliths) at the pontomesencephalic or pontomedullary junction, near the perihypoglossal nuclei, most often seen after medullary lesions. The main causes are multiple sclerosis, tumors of the brainstem, Wernicke’s encephalopathy, cerebellar degeneration, and intoxication (e.g., nicotine). 5.2.7 Downbeat Nystagmus Downbeat nystagmus occurs in a variety of disorders, but it is most commonly associated with disease affecting the cerebellum, the craniocervical junction, or the blood vessels in these regions.126,158,159 It may also be a manifestation of drug intoxication, especially lithium. Downbeat nystagmus is usually present with the eyes in central position, but its amplitude may be so small that it can only be detected by viewing the ocular fundus with an ophthalmoscope. The nystagmus intensity is greatest in downgaze and down and lateral gaze and least in upgaze. Usually the waveform is linear. Downbeat nystagmus may also be evoked by placing the patient in a head-hanging position. Some normal subjects may show “chin-beating” nystagmus when they are placed upside down in darkness (or wear Frenzel goggles). Convergence may influence the amplitude and frequency of the nystagmus or convert it to upbeat nystagmus. Some patients show combined divergent and downbeat nystagmus. In most patients, removal of fi xation (e.g., with Frenzel goggles) does not substantially influence slow-phase velocity, although the frequency of quick phases may diminish. A variety of ocular motor abnormalities often accompany downbeat nystagmus and reflect coincident cerebellar involvement.160 Vertical smooth pursuit and the vertical VOR are abnormal because of impaired ability to generate smooth downward eye movements. Sometimes, the VOR for upward eye movements has a gain exceeding 1.0. Impairment of eccentric horizontal gaze holding, smooth pursuit, and combined eyehead tracking are coincident fi ndings. Vertical Nystagmus in Infancy and Childhood • 161 05_Hertle_Ch05.indd 161 9/6/2012 9:50:15 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN diplopia usually reflects associated skew deviation.161 The visual consequences of downbeat nystagmus are oscillopsia and postural instability. Visual fi xation has litt le effect on its slow-phase speed; convergence may suppress or enhance it in some patients. In general, the nystagmus is accompanied by a vestibulocerebellar ataxia. The pathophysiological mechanism of downbeat nystagmus appears to be due to a central imbalance of the vertical VOR to an abnormality of the vertical-torsional gazeholding mechanism (neural integrator). The most common cause of downbeat nystagmus is cerebellar degeneration (hereditary, sporadic, or paraneoplastic). Other important causes are Chiari malformation, multiple sclerosis, and a rare congenital form. In practice cerebellar atrophy, Arnold–Chiari malformation, various cerebellar lesions (multiple sclerosis, vascular, tumors), and idiopathic causes account for approximately one-fourth of the cases each. Downbeat nystagmus occurs in the channelopathy episodic ataxia type 2.162 5.2.8 Torsional Nystagmus Torsional nystagmus is a less commonly recognized form of central vestibular nystagmus than downbeat or upbeat nystagmus.163 To retain consistency with other forms of nystagmus, the clockwise and counterclockwise torsional directions are based on the patient’s point of view. Thus, clockwise torsional movement describes motion of the top of the eyeball toward the patient’s right shoulder. It is often difficult to detect except by eye-movement recordings, careful observation of conjunctival vessels, or by noting the direction of retinal movement on either side of the fovea using an ophthalmoscope or contact lens. Although both peripheral vestibular and INS may have torsional components, purely torsional nystagmus, like purely vertical nystagmus, indicates disease affecting central vestibular connections. Torsional nystagmus shares many of the features of downbeat and upbeat nystagmus, including modulation by head rotations, variable slow-phase waveforms, and suppression by convergence. Nonrhythmic but continuous 162 torsional eye movements may be a feature of paraneoplastic encephalopathy.164 5.2.9 “Seesaw” Nystagmus In pendular and jerk seesaw nystagmus (SSN), one half-cycle consists of elevation and intorsion of one eye and synchronous depression and extorsion of the other eye; during the next half-cycle, the vertical and torsional movements reverse.165,166 The waveform may be pendular or jerk. In the latter case, the slow phase corresponds to one half-cycle. A seesaw component is present in many central forms of nystagmus. Seesaw nystagmus may be congenital or acquired.167–169 Quantitative studies have done much to clarify the characteristics and pathogenesis of SSN. It has been proposed that jerk SSN (hemi-SSN) occurs in patients with lesions in the region of the interstitial nucleus of Cajal (INC), although experimental inactivation of this structure has not produced this nystagmus. With a right INC lesion, the reaction consists of a left head tilt, a skew deviation with a right hypertropia, tonic intorsion of the right eye and extorsion of the left eye, and misperception that earth-vertical is tilted to the left. Isolated INC lesions may be characterized by ipsilesional torsional nystagmus and a restricted range of vertical saccades that are not slowed. Pendular SSN has most often been reported in patients with large tumors in the region of the optic chiasm and diencephalon; thus, these oscillations have been att ributed to either compression of the diencephalon or to the effects of chiasmal visual field defects. Both the jerk and pendular variants of SSN probably arise from imbalance or miscalibration of vestibular responses that normally function to optimize gaze during head rotations in roll. The frequency is lower in pendular (2–4 Hz) than in jerk SSN.170 The latter has been att ributed to unilateral meso-diencephalic lesions, affecting the interstitial nucleus of Cajal and its vestibular afferents from the vertical semicircular canals. The term “hemi seesaw” has been used to describe jerk SSN; it is neither accurate (a full cycle of jerk SSN is the same as for the pendular variety) nor descriptive (hemi seesaw motion would stop after one-half cycle). The pendular • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 162 9/6/2012 9:50:15 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN form is associated with lesions affecting the optic chiasm. Loss of crossed visual input seems to be the crucial element in the pathophysiology of pendular SSN. In the early 1990s a remarkable new visual system abnormality (canine “achiasma”) was fi rst described by Williams et al. in a group of Belgian sheepdogs in whom optic nerve fibers fail to cross at the optic chiasm and who manifested SSN. 26,169,171,172 Williams et al. reported that the optic nerves, in seven of eight dogs studied, did not approach each other to form a chiasm. Achiasma or “nondecussating retinal fugal fiber syndrome” was subsequently recognized in two children who presented with poor distant vision.173 They had asymmetries in the distribution of the monocular, pattern-onset, visually evoked potential (VEP) and SSN, similar to that seen in the achiasmatic dogs; the latter was recognized by Dell’Osso in 1993 from a video of one of these achiasmatic children174 (see Appendix F, Section F1.4). These fi ndings suggested a chiasmal anomaly that subsequent MRI scans confi rmed. Hertle et al. reported and reviewed a total of 11 cases and found that in all a “crossed asymmetry” (right cortex receives the right eye’s visually evoked response and the left cortex receives the left eye’s visually evoked response) in the monocular VEP occipital distribution existed; this is consistent with a paucity of fibers crossing at the chiasm.175 Experimental analysis of the achiasmatic mutant Belgian sheepdogs demonstrated that the entire nasal hemiretina with its misdirected ipsilateral projection made functional connections in the thalamus and in the ipsilateral primary visual cortex.169,172 A critical fi nding was that input from nasal and temporal sides of the same retina was integrated at the cortical level. Adjacent neurons often responded to visual stimuli that were far apart—often on opposite sides of the vertical meridian. Given this radical misarrangement of maps of visual space, it is not surprising that the ocular motor system of these achiasmatic dogs did not develop normally. The syndrome is associated with INS, SSN, and strabismus. Th is condition is a developmental anomaly of the midline CNS that may or may not have other systemic fi ndings, for example, craniofacial or heart. In children this condition presents in early infancy or childhood with decreased visual behavior, nystagmus, and strabismus (a fairly common combination of clinical characteristics). The outstanding clinical sign is the presence of SSN in addition to the more typical oscillation of INS.169,175 There are fi ndings of optic pathway (nerve/disc) anomalies (hypoplasia, dysplasia, and coloboma) in all patients seen clearly with three-dimensional volumetric MRI acquisition. Other systemic or CNS signs or symptoms can be present. Due to this we recommend that these patients be followed for signs of central pituitary dysfunction. The presence of the triad of SSN/ISN, strabismus, and optic disc anomalies should prompt the clinician to conduct further electrophysiologic and/ or radiographic investigations in search of structural abnormalities of the optic chiasm. 5.2.10 Lid Nystagmus Upward movements of the eyelids frequently accompany upward movements of vertical nystagmus. In fact, the absence of lid nystagmus in a patient with upbeat nystagmus may suggest disconnection between the premotor signals for the superior rectus and levator palpebrae superioris, implicating the region between the riMLF and the oculomotor nucleus.176,177 For the same reasons, lid nystagmus unaccompanied by vertical eye nystagmus may reflect midbrain lesions. In patients with long-standing compression of the central caudal nucleus, “midbrain ptosis” may occur and this may lead to lid nystagmus. Occasionally, twitches of the eyelid accompany horizontal nystagmus. In other patients, eyelid nystagmus may be induced by convergence. Th is is called Pick’s sign.176 In both cases, lesions are often present in the medulla, cerebellum, or both structures. Eyelid nystagmus has been likened to the pathologic form of gaze-evoked nystagmus that occurs in patients with cerebellar disease and that is often associated with downward drift s of the eyelids, followed by corrective rapid upward movements. Eyelid nystagmus can be classified into three types.178 The most common is associated with vertical ocular nystagmus with the Nystagmus in Infancy and Childhood • 163 05_Hertle_Ch05.indd 163 9/6/2012 9:50:16 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN lid movement being synchronous with the eyes, but with greater amplitude. The second type is associated with gaze-evoked horizontal nystagmus and may occur in the lateral medullary syndrome, and the third is Pick’s sign. 5.3 SACCADIC INTRUSIONS/ OSCILLATIONS In addition to benign and symptomatic types of nystagmus in infancy, there are also other types of ocular motor instabilities that may appear in infancy as well as adulthood. They take the form of either saccadic intrusions or saccadic oscillations. There is a large literature on the many types of saccadic intrusions and oscillations listed in Table 5.6 that have been reviewed elsewhere. 2–7 Several types of inappropriate saccadic eye movements may intrude upon steady fi xation (see Fig. 5.10). Saccadic intrusions must be differentiated from nystagmus, in which a drift of the eyes from the Table 5.6 Saccadic Intrusions and Oscillations Bobbing/dipping Inverse bobbing Reverse bobbing Convergence-retraction “nystagmus” “Nystagmus” retractoris Double saccadic pulses (single/multiple) Saccadic intrusions/oscillations Dynamic overshoot “Quiver” Dysmetria Flutter Flutter dysmetria Macrosaccadic oscillations Myoclonus Laryngeal “nystagmus” “Lightning eye movements” Pharyngeal “nystagmus” Opsoclonus “Dancing eyes” “Lightning eye movements” Saccadomania Psychogenic flutter Hysterical flutter Hysterical “nystagmus” “Ocular fibrillation” “Ocular shuddering” Psychological “nystagmus” Voluntary flutter Voluntary “nystagmus” Saccadic lateropulsion Ipsipulsion Contrapulsion Saccadic pulses/pulse trains Abduction “nystagmus” Ataxic “nystagmus” Saccadic intrusions/oscillations Stepless saccades Square-wave jerks/oscillations Gegenrucke Hopping “nystagmus” “Lightening eye movements” Myoclonus Saccadic intrusions/oscillations Zickzakbewegungen Square-wave pulses (bursts/single) “Macro square-wave jerks” Kippdeviationen/ “Kippnystagmus” “Pendular macro-oscillations” Saccadic “nystagmus” Saccadic oscillations/intrusions Staircase saccadic intrusions Superior oblique myokymia Synonyms and other terms are indented under either the preferred or the more inclusive designation; quoted terms are erroneous or misleading. 164 • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 164 9/6/2012 9:50:16 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.10 Diagrammatic representation of ocular motility recordings of major types of saccadic disorders. 0, point of origin of eye; D, dysmetria; DSP, double saccadic pulses; F, flutter; FD, flutter dysmetria; MSO, macrosaccadic oscillations; SP, saccadic pulses; SPT, saccadic pulse trains; SSI, staircase saccadic intrusions; SWJ, square-wave jerks; SWO, square-wave oscillations; SWP, square-wave pulses; T, target; t, time axis. desired position of gaze is the primary abnormality, and from saccadic dysmetria, in which the eye over- or undershoots a target, sometimes several times, before achieving stable fi xation. Because all of these movements are often rapid and brief, it may be necessary to measure eye and target position, as well as eye velocity, in order to identify the saccadic abnormality accurately. The saccadic command is generated by burst neurons of the brainstem reticular formation that project monosynaptically to ocular motoneurons.179–181 The burst neurons for horizontal saccades are located in the PPRF, and the burst neurons for vertical and torsional saccades are located in the riMLF. Burst neurons discharge only during saccadic eye movements. The activity of all saccadic burst neurons is gated by omnipause neurons, which are crucial for suppressing unwanted saccades during fi xation and slow eye movements. The omnipause neurons are located in the caudal pons within the raphe interpositus nucleus (RIP), adjacent to the abducens nucleus. Inputs into omnipause neurons arise in the superior colliculus, frontal eye fields, and mesencephalic reticular formation. 5.3.1 Square-Wave Jerks and Oscillations Square-wave jerks (SWJ, also called Gegenrucke) are a common fi nding in healthy persons. They have a typical profi le on eyemovement records, and it is this profi le from which their name is derived.182–184 As illustrated in Figure 5.10, they are small, conjugate saccadic intrusions, ranging from 0.5 to 5.0° in size, that take the eye away from the fi xation position and return it after about 200 milliseconds. They are often more prominent during smooth pursuit, are most easily detected during ophthalmoscopy, and are also present in darkness. SWJ with an increased frequency (up to 2 Hz) occur in certain cerebellar syndromes, in progressive supranuclear palsy, and in cerebral hemispheric disease. The characteristics of SWJ are summarized in Table 5.7. Although present in many normals, when they are prominent during fi xation, they should Nystagmus in Infancy and Childhood • 165 05_Hertle_Ch05.indd 165 9/6/2012 9:50:16 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Table 5.7 Characteristics of Saccadic Instabilities S QUA R E -WAV E JER KS S QUA R E -WAV E S QUA R E -WAV E M AC R O S AC C A DIC O S C I L L A T ION S P U L S E S * O S C I L L A T ION S Amplitude 0.5°–5°1 Constant 0.5°–5°1 Constant 4°–30° Variable Time course Latency Foveation Presence in darkness Sporadic/bursts 200 msec Yes Yes Bursts 200 msec Yes Yes Bursts/sporadic 50–150 msec Yes Yes 1°–30° Increasing then decreasing Bursts 200 msec No No *Previously designated macro square-wave jerks. 1 Occasionally up to 10°. be considered abnormal, although lacking diagnostic specificity, much like saccadic pursuit. SWJ are a subtle disturbance that is easily missed clinically. However, they are obvious with eyemovement recordings, which also allow other types of saccadic intrusions to be identified.185 Because the individual saccades in SWJ are usually small, they may contain dynamic overshoots. Clinically, they are often best identified during slit-lamp biomicroscopy or funduscopy, but they may be difficult to distinguish from other intrusions (e.g., square-wave pulses). As was pointed out in earlier chapters, SWJ may also appear in individuals with nystagmus (benign or symptomatic); they are merely superimposed on the nystagmus and do not represent a different type of nystagmus. SWJ is significantly more common in the elderly population than in young subjects. Their appearance at a rate greater than 9/minute in young patients is considered abnormal. SWJ frequency in normals is approximately 7/min and they were unidirectional in 94% of the subjects.186 Other types of saccadic intrusions were also found in this study: saccadic pulses and double saccadic pulses (see later) were found in 22% and 68% of the subjects, respectively. The effect of age on the prevalence of SWJ is unclear as that study did not fi nd an age factor. However, a subsequent study did fi nd an increase with age.187 166 SWJ are also found in 70% of patients with acute or chronic focal cerebral lesions and are the rule in progressive supranuclear palsy and Parkinson disease. Schizophrenic patients and their parents188 exhibit SWJ, which are also present during smooth pursuit and have been mistaken for a deficit in the pursuit system. The frequency and metrics of SWJ are influenced by the task being performed.189 A postfl ight increase in SWJ in an astronaut may have been responsible for his increased postfl ight dynamic visual function.190 The mechanism of SWJ may be linked to attention and its effect on the balance between fi xation and saccade generation191; endogenous rather than exogenous attention was the major factor.192 SWJ correlated with the velocities of steady drift s were found in albinos without INS, suggesting that both might be related to a failure in saccadic system development.193 When SWJ form a continuous train, they are called square-wave oscillations (SWO). These continuously occurring SWJ have been recorded in patients with a variety of neurologic deficits (see Fig. 5.10). The characteristics of SWO are identical to those of SWJ (see Table 5.7). In a patient with progressive supranuclear palsy, SWO appeared to be part of a continuum with SWJ; at times, single or several SWJ occurred, and at other times there were long runs of SWJ that were identified as SWO.194 • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 166 9/6/2012 9:50:17 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN During steady fi xation, the threshold for electrical stimulation of saccades in either the frontal eye fields or the superior colliculus is elevated, mediated through the projections of these structures to the omnipause neurons.195 In the rostral superior colliculus, a distinct population of “fi xation neurons” has been identified and in the frontal eye fields, neurons active during suppression of saccades have been identified. Pharmacologic inactivation at both sites leads to disruption of fi xation by these saccadic intrusions, but not by flutter or opsoclonus. Impairment of any projections to the omnipause neurons can lead to saccadic intrusions. Mechanistically, SWJ and SWO are hypothesized to occur when there is dysfunction in the internal reconstruction of target position, as shown in Figure 5.11. When this hypothesis was incorporated into our behavioral ocular motor system model, SWJ were generated, as demonstrated in Figure 5.12, top left and top right panels. 5.3.2 Square-Wave Pulses Square-wave pulses (SWP), originally given the misleading name “macro square-wave jerks,” are usually larger in amplitude than SWJ (typically greater than 5°), are related to fi xation, and have a frequency of about 2 Hz.182,183,196,197 They generally occur in bursts but may appear as a single saccadic intrusion. Both eyes suddenly and conjugately move off target with a saccade, and after a latent period of only about 80 milliseconds, a non–visually evoked reflex saccade brings them back on target (see Fig. 5.10). SWP are not merely large SWJ; the characteristics of both are summarized in Table 5.7. These saccadic intrusions occur in light or darkness. SWP usually occur in patients with marked extremity ataxia suggestive of cerebellar outflow disease, especially when the patient has demyelinating lesions.196 A unique variety of SWP, present with binocular fi xation at distance but stopping when either eye was closed, prompted the designation “inverse latent SWP.”198 The underlying mechanism for SWP was hypothesized to rely on efference copy of the motor output signal that could program the short-latency return saccade in response to the initial spurious saccade that initially drove the eyes off target.196 5.3.3 Staircase Saccadic Intrusions We identified a unique type of saccadic intrusion in a patient with cerebellar atrophy, named “staircase saccadic intrusions” (SSI) because of its appearance in eye-movement recordings.199 Fixation would be interrupted by a series of saccades in one direction or the other with normal intersaccadic intervals (see Fig. 5.10). The individual saccades could be of equal amplitude or could vary. Staircase saccadic intrusions were also present during smooth pursuit. In normals, such “staircase” eye movements can be generated by feeding back the eye-movement signal and allowing it to move the target in the same direction. Th is produces a constant retinal error signal that drives the saccadic system in a staircase manner with normal intersaccadic intervals, as shown in the simulation of Figure 5.12, bottom left panel. We modeled SSI using a behavioral OMS model 200 by simultaneously interfering with the retinal error signal and creating a constant reconstructed error signal (see Fig. 5.11); the simulation is shown in Figure 5.12, bottom right panel. The individual hypotheses for SWJ/SWO and SSI embodied in the model were severely tested during simulation of the eye movements of a patient with Joubert syndrome, shown in Figure 5.13, who exhibited SWJ, SWO, and SSI in various mixtures. 201 By combining our hypothetical mechanisms for each of the simultaneous dysfunctions, the model accurately simulated the mixtures recorded from the patient (see Fig. 5.14), ruled out the loss of efference copy as a cause, and led us to the specific mechanisms for each that are shown in Figure 5.11. 5.3.4 Macrosaccadic Oscillations Macrosaccadic oscillations (MSO) usually consist of horizontal saccades that occur in bursts, initially building up and then decreasing in amplitude, with intersaccadic intervals of about 200 milliseconds. The characteristics of MSO Nystagmus in Infancy and Childhood • 167 05_Hertle_Ch05.indd 167 9/6/2012 9:50:17 PM FIGURE 5.11 Behavioral ocular motor system (OMS) model with an expanded view (dark lines) of the portion of the relevant functional circuitry within the internal monitor that is responsible for target reconstruction from retina error and efference copy of eye position, reconstructed sampled target position (i.e., perceived target position), reconstruction of retinal position error (sampled), and generation of the saccadic motor command after accounting for internally generated eye movement (e.g., nystagmus). Shown are the mechanistic sites of dysfunction producing square-wave jerks/oscillations (SWJ/SWO), staircase saccadic intrusions (SSI), flutter (FLUT), double saccadic pulses (DSP), neural integrator leak (NI), or low/no-gain smooth pursuit. OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN 05_Hertle_Ch05.indd 168 9/6/2012 9:50:17 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.12 Behavioral ocular motor system (OMS) model simulations of the individual components of the saccadic intrusions and oscillations found in subjects with cerebellar atrophy or Joubert syndrome. (Top left) Square-wave jerks (SWJ) before and after response to a step change in target position. (Top right) SWJ before and square-wave oscillations (SWO) after response to a step change in target position. (Bottom left) Simulation of a rightward, equal-step staircase saccadic intrusions (SSI) due to opening the retinal loop. (Bottom right) Simulation of a rightward, equal-step SSI during fi xation. are summarized in Table 5.7. Described originally in cerebellar patients, MSO are thought to be an extreme form of saccadic dysmetria, in which the patient’s saccades are so hypermetric that they overshoot the target continuously in both directions and thus oscillate around the fi xation point.182,183,197 They are usually induced by a gaze shift, but they may also occur during attempted fi xation or even in darkness. They are often visually disabling and have vertical or torsional components. MSO are occasionally encountered in patients with myasthenia gravis after administration of edrophonium.202 5.3.5 Saccadic Pulses (Single and Double) Saccadic pulses (SP), originally called “stepless saccades,” are brief intrusions on fi xation caused by a spurious pulse of innervation, provided by the burst cells without the usual accompanying step. The resultant eye movement consists of a saccade away from the fi xation position followed immediately by a glissadic drift back to the target (see Fig. 5.10). The glissadic drift in SP represents failure of the neural integrator to produce a step of innervation from the burst producing the SP. Th is difference from SWJ suggests dysfunction in the pause cell/burst cell circuitry for SP and a more central dysfunction for SWJ. Saccadic pulses may occur in series or as doublets.164,203 They are encountered in some normal subjects and in patients with multiple sclerosis. Saccadic pulse trains (SPT) are continuous runs of SP and, as Figure 5.10 shows, may be easily confused with nystagmus. Even on good eye-movement records, SPT cannot Nystagmus in Infancy and Childhood • 169 05_Hertle_Ch05.indd 169 9/6/2012 9:50:22 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.13 Examples of the complex ocular motor disorders occurring during attempted fi xation of a target in primary position from a subject with Joubert syndrome. (Top left) Left ward, equal-step staircase saccadic intrusions (SSI) including a left ward square-wave jerks (SWJ) and uniocular neural integrator leak of the left eye in left gaze (LE, left). (Top right) Rightward, unequal-step SSI with uniocular neural integrator leak of the right eye in right gaze (RE, right) followed by flutter during the refi xation and SWO with neural integrator leak of both eyes in left gaze (BE, left). (Bottom left) Rightward, unequal-step SSI followed by divergent flutter during the refi xation. (Bottom right) Divergent-saccade (D-S) followed by D-S nystagmus with neural integrator leak of both eyes. FLUT, flutter; LEH, left eye horizontal (thin trace); REH, right eye horizontal (heavy trace), and both eyes were viewing. be distinguished from jerk nystagmus with decreasing-velocity slow phases, unless both eye position and target position are known. The initiation of an SP is a saccade off target, whereas jerk nystagmus is initiated by the slow phase off target, with the saccadic 170 fast phase bringing the eye back to the target. The so-called abduction “nystagmus” of internuclear ophthalmoplegia is an SPT. 204 Several patients with congenital achromatopsia thought to have INS did not contain any of the known INS waveforms but instead had • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 170 9/6/2012 9:50:23 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN FIGURE 5.14 Behavioral ocular motor system (OMS) model simulations of the complex saccadic intrusions and oscillations found in a subject with Joubert syndrome by different combinations of their individual components. (Top left) Square-wave jerks (SWJ) before and after a rightward, equal-step staircase saccadic intrusions (SSI) and refi xation during attempted fi xation. (Top right) Square-wave oscillations (SWO) after a rightward, equal-step SSI and refi xation during attempted fi xation. (Bottom left) Simulation of a rightward, unequal-step SSI during fi xation, preceded by a SWJ and followed by a SWO. (Bottom right) Simulation of a rightward, unequal-step SSI during fi xation, followed by a SWO. oscillations consistent with SPT. Although the waveforms mimicked those of FMNS, there were no effects of monocular fixation. 5.3.6 Convergence-Retraction “Nystagmus” Convergence-retraction “nystagmus” is a misnomer since the abnormality is in the vergence and fast eye movement systems.153,205 It is characterized by quick phases that converge or retract the eyes on attempts to look up. It is elicited either by asking the patient to make an upward saccade or by using a handheld optokinetic drum or tape and moving the stripes or figures down. Th is maneuver produces slow, downward, pursuit eye movements, but upward quick phases are replaced by rapid convergent movements, retractory movements, or both. Affected patients usually have impaired or absent upward gaze for both pursuit and saccadic eye movements; however, in some cases upward pursuit appears normal, whereas upward saccades are obviously abnormal. Convergence-retraction “nystagmus” is commonly produced by lesions of the mesencephalon that damage the posterior commissure, such as pineal tumors. It probable that convergence-retraction nystagmus is, in fact, a vergence and saccadic disorder rather than nystagmus because the primary adductive movements are asynchronous adducting saccades and some studies have indicated that the movements may be vergence in origin. Convergenceretraction “nystagmus” may also occur with a Chiari malformation or epileptic seizures.206 It is usually intermittent, being determined by Nystagmus in Infancy and Childhood • 171 05_Hertle_Ch05.indd 171 9/6/2012 9:50:26 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN saccadic activity, and it thus can be differentiated from other more continuous forms of disjunctive nystagmus, such as pendular vergence nystagmus and the oculomasticatory myorhythmia characteristic of Whipple disease. A jerkwaveform divergence nystagmus is rare, but it may occur in patients with cerebellar disease, such as the Chiari malformation. In such cases, combined divergent and downbeat nystagmus produces slow phases that are directed upward and inward. Other components of this clinical syndrome include light-near dissociation, dorsal midbrain lesions, and vertical gaze palsy. 5.3.7 Dissociated Ocular Oscillations In dissociated nystagmus, there is a significant asymmetry in either amplitude or direction of the two eyes. The pendular nystagmus in patients with multiple sclerosis is usually dissociated. There are a variety of nystagmus dissociations with lesions of the posterior fossa (e.g., asymmetric vertical nystagmus greater in one eye on looking up and in the other eye on looking down). A common type of dissociation occurs in internuclear ophthalmoplegias, where the most marked oscillation is in the abducting eye. However, this abduction “nystagmus,” sometimes designated by the confusing term “ataxic” nystagmus, is not really a nystagmus. Instead, it is a saccadic oscillation secondary to lesions of the medial longitudinal fasciculus and is discussed in Section 5.3.5. 5.3.8 Dysmetric Saccades Ocular dysmetria is provided by refi xation saccades and consists of undershooting (hypometria) or overshooting (hypermetria) followed by brief small-amplitude saccadic oscillations before the eyes come to a new fi xation point, or conjugate overshooting followed by a single corrective saccade to bring the eye back to the target. There is an intersaccadic latency between the various corrective saccades. One type of dysmetria, hypermetria, is illustrated in Figure 5.10. Dysmetria is a common sign of cerebellar system disease.207 172 5.3.9 Ocular Flutter The pathogenesis of saccadic oscillations without an intersaccadic interval, for example, ocular flutter and opsoclonus, seems closely related to the properties of the burst neurons themselves.164 Burst neurons have very high discharge rates (up to 1000 spikes per second), and they discharge vigorously even for small saccades. The anatomical connections between burst neurons in the brainstem and their high discharge rates (“gain”) predisposes to oscillations if the omnipause neurons are not actively inhibiting them and no specific saccadic command has been issued. Disease affecting omnipause neurons, or their afferents, might be expected to lead to saccadic oscillations such as ocular flutter and opsoclonus. Contrary to this, studies have shown that chemical lesions of the omnipause neurons are reported to cause slowing of both horizontal and vertical saccades. Attempts to demonstrate histopathologic changes in omnipause neurons in some patients with paraneoplastic saccadic oscillations have usually failed to show any changes. It has been suggested that, in paraneoplastic opsoclonus, the tumor and certain CNS structures share an epitope.208 Th is common epitope elicits an efficient immune response against the tumor, thus conferring a more indolent oncologic course, but it also elicits an immune response against normal neural tissue, causing the neurologic syndrome. There is some evidence that impaired glycinergic transmission may play a role in the pathogenesis of both ocular flutter and opsoclonus. Poisoning with a glycinergic antagonist, strychnine, can produce both myoclonus and opsoclonus and in hyperekplexia, abnormal receptors to glycine are found. The concurrent appearance of opsoclonus with myoclonus may suggest a similar mechanism. Glycine is identified as the neurotransmitter of the omnipause neurons and their glycinergic dysfunction, presumably caused by autoantibodies, might be responsible for the opsoclonus-myoclonus syndrome. Cerebellar dysfunction has traditionally been blamed for ocular flutter and opsoclonus. Functional imaging in patients with opsoclonus has shown activation of deep cerebellar nuclei. • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 172 9/6/2012 9:50:28 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN However, experimental lesions of the cerebellum do not produce these oscillations, even though striking saccadic dysmetria can be produced, especially when the caudal fastigial nuclei of the cerebellum are inactivated.209,210 5.3.10 Flutter Dysmetria Flutter dysmetria (FD) is the occurrence of flutter immediately after a saccade (Fig. 5.10).211 It superficially resembles dysmetria, but eyemovement recordings reveal that FD is an oscillation about the intended fi xation angle and consists of back-to-back saccades with no intersaccadic latencies. Th is contrasts with dysmetria in which the saccadic oscillation has normal intersaccadic latencies. FD is seen in a sett ing of cerebellar disease. 5.3.11 Opsoclonus There is a continuum between saccadic pulses and saccadic oscillations without an intersaccadic interval. The latter may occur in one direction, usually the horizontal plane, in which case they are called ocular flutter. If they are multivectorial, they are termed “opsoclonus” or “saccadomania.” The frequency of oscillations is usually high, typically 10–15 Hz, being higher with smaller-sized movements. Ocular flutter may be intermittent and mainly associated with voluntary saccades (flutter dysmetria) or convergence movements. Occasionally, the amplitude of the oscillations is very small (“microflutter”). In such cases, the movements may be detected only with a slit lamp, an ophthalmoscope, or eye-movement recordings. Sustained opsoclonus is a striking finding, in which multidirectional conjugate saccades, usually of large amplitude, interfere with steady fi xation, smooth pursuit, or convergence. These movements may persist during sleep. 5.3.11.1 O P S O C L O N US - M YO C L O N US Opsoclonus is often accompanied by myoclonus—brief jerky involuntary limb movements— hence the term “opsoclonus-myoclonus.” In children, this syndrome is called “dancing eyes and dancing feet.” Ataxia and encephalopathy may also accompany opsoclonus. In about 50% of cases, the etiology remains obscure. In children, about half the cases of opsoclonus are associated with tumors of neural crest origin, such as neuroblastoma.203 Low cerebrospinal fluid concentrations of 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA) can often be demonstrated in children with the opsoclonusmyoclonus syndrome. However, cerebrospinal fluid abnormalities may occur in opsoclonus associated with both tumor and encephalitis; thus, they may not help to distinguish between the infectious and paraneoplastic etiologies. Various autoantibodies can be detected in sera of some patients with opsoclonus. Of these, anti-Ri antibody is the most common.212,213 Anti-Hu antibody has been reported with opsoclonus in two children with neuroblastoma and in an adult with small-cell lung cancer. Th is is an ant neuronal antibody that binds nuclear RNA and is usually associated with paraneoplastic sensory neuronopathy, cerebellar degeneration, and limbic encephalitis. The prognosis of idiopathic opsoclonus (including patients with manifestations of brainstem encephalitis) is generally good. Some patients with paraneoplastic opsoclonus myoclonus show spontaneous remissions, irrespective of the underlying tumor. Patients whose tumor can be identified and treated may recover neurologically; those who are not treated have a more severe course. 5.3.12 Superior Oblique Myokymia Superior oblique myokymia (SOM) was fi rst described by Duane in 1906, but clinicians became generally aware of the disorder following the description by Hoyt and Keane in 1970. 214 Typical symptoms include monocular blurring of vision, tremulous sensations in the eye, brief episodes of vertical or torsional diplopia, and vertical or torsional oscillopsia. 215 Att acks last less than 10 seconds and may occur many times per day; they may be elicited on by looking downward, by tilting the head toward the side of the affected eye, and by blinking. The majority of patients with SOM have no underlying disease, although cases have been reported following trochlear nerve palsy, after Nystagmus in Infancy and Childhood • 173 05_Hertle_Ch05.indd 173 9/6/2012 9:50:28 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN mild head trauma, in the sett ing of multiple sclerosis, after brainstem stroke, and in patients with cerebellar tumor. The eye movements of SOM are often difficult to appreciate on gross examination, although they are usually apparent during examination with the ophthalmoscope or slit-lamp biomicroscope. They consist of spasms of cyclotorsional and vertical movements. Measurement of the movements of SOM using the magnetic search coil technique reveals an initial intorsion and depression of the affected eye, followed by irregular oscillations of small amplitude and variable frequency.216 Some resemble jerk nystagmus, with frequencies of 2–6 Hz, but superimposed upon these oscillations are low-amplitude, irregular oscillations with frequencies ranging up to 50 Hz. Electromyographic recordings from superior oblique muscles affected by SOM reveal some fibers that discharge either spontaneously or following contraction of the muscle. These muscle potentials are abnormal, with increased duration (greater than 2 milliseconds) and amplitude, and they are polyphasic, with a spontaneous discharge rate of approximately 45 Hz. Spontaneous activity is absent only with large saccades in the “off ” (upward) direction and is less affected by vestibular eye movements. Some fi ring units show an irregular discharge following muscle contraction before subsiding to a regular discharge of 35 Hz. These fi ndings suggest that the etiology of SOM is neuronal damage and subsequent regeneration, leading to desynchronized contraction of muscle fibers. Indeed, experimental lesions of the trochlear nerve demonstrate regenerative capacities such that the remaining motor neurons increase their number of axons to hold the total constant. Superior oblique myokymia only rarely is preceded by an ipsilateral trochlear nerve palsy. Ocular neuromyotonia is a rare disorder characterized by episodes of diplopia that are usually precipitated by holding the eyes in eccentric gaze, often sustained adduction. 217 Most reported patients have undergone radiation to the parasellar region, but idiopathic cases have been reported. The episodic nature of the diplopia associated with ocular neuromyotonia often suggests myasthenia gravis, 174 but anticholinergic medicines are ineffective in this condition. Other conditions that may mimic ocular neuromyotonia include superior oblique myokymia, thyroid eye disease, and cyclic oculomotor palsy. The symptoms of ocular neuromyotonia are caused by involuntary, and at times painful, contraction of the lateral rectus muscle, the superior oblique muscle, or one or more extraocular muscles innervated by the oculomotor nerve. Extraocular muscles innervated by more than one ocular motor nerve may occasionally be affected, and rare patients with bilateral ocular neuromyotonia have been reported. Comparing symptoms with attempts at eccentric gaze holding may aid in making the diagnosis, as symptoms may be absent in primary position but evoked by sustained eccentric gaze. The mechanism responsible for ocular neuromyotonia is unknown, although both ephaptic neural transmission and changes in the pattern of neuronal transmission following denervation have been suggested, since spontaneous activity is seen in the ocular electromyogram of some affected patients. Axonal hyperexcitability caused by dysfunction of potassium channels has also been implicated in the production of neuromyotonia by analogy with systemic neuromyotonia. 5.3.13 Ocular Bobbing Ocular bobbing is a distinctive spontaneous vertical eye-movement disturbance, readily distinguished from downbeat nystagmus and ocular myoclonus. Bobbing refers to fast downward jerks of both eyes followed by a slow drift to midposition.218 The downward jerks may be disjugate in the two eyes, and often the eyes remain deviated for several seconds before returning to midposition. Bobbing can be divided into three types: typical, monocular, and atypical.219 5.3.13.1 T Y P I C A L Ocular bobbing consists of intermittent, usually conjugate, rapid downward movement of the eyes, followed by a slower return to primary position. Reflex horizontal eye movements are usually absent; that is, it appears in patients with • DI F F E R E N T I A L DI AG NOS I S OF N Y STAG M US I N I N FA NC Y A N D C H I L DHOOD 05_Hertle_Ch05.indd 174 9/6/2012 9:50:28 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN paralysis of horizontal conjugate eye movements. The pathophysiology of all types of ocular bobbing is uncertain, but putative hypotheses are numerous. Bobbing usually occurs in comatose patients with extensive destruction of the pons, but extrapontine compressions, obstructive hydrocephalus, metabolic encephalopathy, and encephalitis occasionally are causative.220 5.3.13. 2 M O N O C U L A R Monocular bobbing reflects coexisting contralateral third-nerve paresis.219 In two cases, a pontine lesion plus an oculomotor lesion resulted in monocular bobbing221; in some cases, no explanation could be found.222 5.3.13.3 AT Y P I C A L The third category, atypical bobbing, includes downward bobbing with convergence movements, asymmetric bobbing without an associated oculomotor palsy, and bobbing with intact spontaneous or reflex horizontal eye movements; the latter variety suggests diff use encephalopathy, hydrocephalus, or organophosphate poisoning, rather than severe intrinsic pontine disease.223 Atypical bobbing may be disconjugate.222 Associated signs and symptoms of pontine damage, inverse bobbing has an initial downward movement that is slow and the return to midposition is rapid; this has also been called ocular dipping.224 Reverse ocular dipping or converse bobbing has been used to describe a slow upward drift of the eyes followed by a rapid return to central position; variants of ocular bobbing are less diagnostically specific. Two reports of comatose patients who demonstrated a slow downward eye movement, followed, after a variable delay, by a quick saccade up to midposition. Th is disorder was called “inverse bobbing” in one report225 and “ocular dipping” in the other.226 The latter term (dipping) seems to have achieved favor.227–230 The upward jerking of the eyes is occasionally associated with contraction of the orbicularis oculi.231 The phenomenon is regarded as mechanistically similar to the sustained downgaze deviation seen occasionally in comatose patients and has occurred in a patient with a pinealoblastoma. A depressed level of consciousness is not a prerequisite for its appearance. Some patients in coma may demonstrate all three types of spontaneous vertical movements: ocular bobbing, ocular dipping, and reverse bobbing.232 Ocular dipping may lead to a vertical gaze paresis (e.g. in JacobCreutzfeldt disease)233 or may coexist with pingpong gaze (e.g., hypoxic encephalopathy). 234 In addition to these three types of bobbing (typical, monocular, and atypical), we described a phenomenon designated “reverse bobbing,” in which the eyes jerked upward with a fast movement and then slowly returned to the horizontal; the patients were deeply comatose as a result of metabolic encephalopathy. Reverse bobbing may coexist with typical bobbing with lesions of the dorsal median portion of the pontine tegmentum.235 5.3.14 Psychogenic Flutter (Voluntary “Nystagmus”) Voluntary (hysterical, psychological) “nystagmus” is not nystagmus at all but a series of backto-back saccades, interrupting fi xation, whose timing is such that the waveform traced out appears to be pendular (i.e., a psychogenic or voluntary flutter). The most accurate and inclusive term for this oscillation (which has also been called “ocular fibrillation” and “ocular flutter”) is “psychogenic flutter,” introduced in 1980.2 Psychogenic flutter consists of bursts of an extremely rapid, conjugate, horizontal oscillation that appears pendular but actually consists of back-to-back saccades.236 As shown in Table 5.6, voluntary “nystagmus” is actually flutter.211 It may be used as a party trick or as a conscious attempt to feign illness. The oscillation is readily identified by the extreme rapidity (approximately 20 Hz, with a range of 8 to 23 Hz) and brevity of each burst (maximum duration usually less than 30 seconds). Most subjects do not sustain the oscillation for more than 10 seconds and manifest facial distortions with eyelid closure to “rest” their eyes in preparation for another outburst. The ability to perform this stunt may be hereditary, and it is present in about 5%–8% of the population but in 79% of their relatives.237,238 Nystagmus in Infancy and Childhood • 175 05_Hertle_Ch05.indd 175 9/6/2012 9:50:28 PM OUP UNCORRECTED PROOF – REVISES, 09/06/12, NEWGEN Rarely, psychogenic flutter may be vertical 239 or multidirectional, mimicking opsoclonus. 240 In a family we recorded in the 1970s, it was exhibited by a father and two sons, with the father able to maintain it the longest, less by the elder son, and least by the younger son. 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