Disorders of the Eye Motility System

Chapter 4

Abstract

1. Introduction

51

Nystagmus

Ivana Mravicic, Selma Lukacevic, Maja Bohac,

Nystagmus is an involuntary rhythmical movement of the eyes. The cause of nystagmus is a disruption in the afferent, central or efferent parts of the eye movement system. If it happens in the first few months of life during the sensitive period of visual development, it is most often a case of infantile nystagmus. On the other hand, the majority of nystagmus in adult age is caused by some neurological disorder, and it is usually called acquired nystagmus. The important role of an ophthalmologist is to recognize the origin of nystagmus. Acquired forms are usually caused by some neurological disorders and do not belong in our field of treatment. However, most of the nystagmus types in a child's age require ophthalmological treatment. When we have a child with nystagmus, we have to enable the development of the visual system and help fixation and fovealization by the dampening of nystagmus. If the reason of nystagmus is of ocular origin, we have to treat the underlying disease. Optical treatment by glasses, contact lenses or magnifying devices is usually reasonable. In some cases when the patient has abnormal head posture, it is possible to treat nystagmus by surgery. Some medications are used in

several types of nystagmus as well as some new developing treatments.

albinismus, artificial divergence, Anderson surgery, Kestenbaum surgery

Keywords: nystagmus, infantile nystagmus, acquired nystagmus, spasmus nutans,

When examining the patients with nystagmus, we should start with the medical history. One of the most important questions, especially in a child's age, is at what age nystagmus started (infantile, benign form starts no later than 3 months of age). Nystagmus usually consists of slow pursuit movement or drift which is followed by a fast (jerk) or slow (pendular) movement of refixation. Though the first slow movement is pathological, nystagmus is usually named after the second, fast refixation movement. When the second movement is fast, nystagmus is called "jerk", and in the cases when second movement is slow, nystagmus is called "pendular". When describing nystagmus we usually describe the direction of the movement that can be horizontal, vertical, rotatory or chaotic as well as the magnitude of amplitude and frequency. It is important to emphasize that in cases when the movements of both eyes are asymmetric, meaning that eyes do not have the same amplitude, frequency or direction (dissociated nystagmus) or eyes moving in opposite directions (disconjugate nystagmus), we have to consider that as an alarming sign of central cause of nystagmus and send the patient immediately to a neurologist. Besides doing the clinical analysis of nystagmus, we can record eye

Maja Pauk-Gulic and Vlade Glavota

#### Chapter 4

## Nystagmus

Ivana Mravicic, Selma Lukacevic, Maja Bohac, Maja Pauk-Gulic and Vlade Glavota

#### Abstract

Nystagmus is an involuntary rhythmical movement of the eyes. The cause of nystagmus is a disruption in the afferent, central or efferent parts of the eye movement system. If it happens in the first few months of life during the sensitive period of visual development, it is most often a case of infantile nystagmus. On the other hand, the majority of nystagmus in adult age is caused by some neurological disorder, and it is usually called acquired nystagmus. The important role of an ophthalmologist is to recognize the origin of nystagmus. Acquired forms are usually caused by some neurological disorders and do not belong in our field of treatment. However, most of the nystagmus types in a child's age require ophthalmological treatment. When we have a child with nystagmus, we have to enable the development of the visual system and help fixation and fovealization by the dampening of nystagmus. If the reason of nystagmus is of ocular origin, we have to treat the underlying disease. Optical treatment by glasses, contact lenses or magnifying devices is usually reasonable. In some cases when the patient has abnormal head posture, it is possible to treat nystagmus by surgery. Some medications are used in several types of nystagmus as well as some new developing treatments.

Keywords: nystagmus, infantile nystagmus, acquired nystagmus, spasmus nutans, albinismus, artificial divergence, Anderson surgery, Kestenbaum surgery

#### 1. Introduction

When examining the patients with nystagmus, we should start with the medical history. One of the most important questions, especially in a child's age, is at what age nystagmus started (infantile, benign form starts no later than 3 months of age). Nystagmus usually consists of slow pursuit movement or drift which is followed by a fast (jerk) or slow (pendular) movement of refixation. Though the first slow movement is pathological, nystagmus is usually named after the second, fast refixation movement. When the second movement is fast, nystagmus is called "jerk", and in the cases when second movement is slow, nystagmus is called "pendular". When describing nystagmus we usually describe the direction of the movement that can be horizontal, vertical, rotatory or chaotic as well as the magnitude of amplitude and frequency. It is important to emphasize that in cases when the movements of both eyes are asymmetric, meaning that eyes do not have the same amplitude, frequency or direction (dissociated nystagmus) or eyes moving in opposite directions (disconjugate nystagmus), we have to consider that as an alarming sign of central cause of nystagmus and send the patient immediately to a neurologist. Besides doing the clinical analysis of nystagmus, we can record eye

movements by electrooculography. By using eye movement recording tests, we can analyze eye movements in detail and help better analysis of nystagmus in clinical research.

As ophthalmologists we have to pay special attention to eye conditions that are accompanied or caused by nystagmus. During a complete ophthalmological clinical examination of the eyes in the children with nystagmus, it is important to pay attention to the preferred head posture and associated eye abnormalities and take care that monocular visual acuity can be different if one eye is closed, so it is wise when performing visual acuity tests to dampen instead of close the non-tested eye [1, 2].

#### 2. Types of nystagmus

Nystagmus is a complicated disease that most of us do not see every day in our offices.

According to its origin, nystagmus is usually divided in physiological, infantile and acquired [3]. An ophthalmologist has an important role to recognize the origin of nystagmus. Acquired nystagmus is usually caused by some neurological causes, and this complex disorder is in the field of neurologists as well as ear, nose and throat (ENT) specialists and not in our field of treatment. However, we should recognize the type of nystagmus and help localize the disruption. As ophthalmologists, we usually treat nystagmus in childhood. Most of the nystagmus types in a child's age are benign, and they do not require additional neurological workup [4, 5].

After medical history and clinical examination in the child with nystagmus, we can perform measurements of nystagmus by electronystagmography, as well as measurements of the afferent part of the system with visually evoked potential (VEP), optical coherence tomography (OCT) or electroretinogram tests.

#### 2.1 Physiological nystagmus

Since the visual acuity is degraded by image slip across the retina more than 2–3°/s, some nystagmus-like movements of the eyes are physiological and unconsciously used in everyday activity (Table 1).


#### Table 1.

Physiological fixational nystagmus and nystagmus-like movements.

There are several systems that are connecting the eyes (afferent part), structures in the brain and eye movement system (efferent part). Each of them is responsible and important in the cases when our body is moving or rotating or when we are fixing a moving target (Table 2) [3].


Table 2.

Eye movement systems.

#### 2.2 Nystagmus in childhood

Benign nystagmus in childhood can be divided in several forms:

Idiopathic infantile nystagmus

Ocular/sensory nystagmus

Latent (manifest/latent) nystagmus

Spasmus nutans

Typical features of each form are listed in Table 3.


Table 3.

Benign nystagmus of childhood.

#### 2.2.1 Idiopathic infantile nystagmus

Idiopathic infantile nystagmus is a primary motor dysfunction of unknown origin with no ocular pathology present. In some cases, it can be connected to some genotype but without a clear phenotypic pattern [6, 7]. Inherited forms are usually X-linked form in the FERM domain on Xq26.2 chromosome [8] or autosomal dominant situated at the chromosome 6p12 (NYS2) [9], 7p11 (BYS3) or 13q (NYS4) [10].

Idiopathic infantile nystagmus is probably present from birth but typically becomes noticeable in the first several months of life when a child starts to fixate. If it develops later, we have to suspect other kinds of nystagmus. It starts as a pendular form, later transforms into the jerk type and usually recedes spontaneously up to the 9th year of life, although it is usually present for lifetime. Idiopathic infantile nystagmus is usually horizontal and symmetrical but can have a rotatory component as well. Although it is typical that patients with infantile nystagmus do not have oscillopsia, they sometimes have head shaking or nodding, and it is also typical that nystagmus disappears during sleep. Some recent studies of patients with infantile nystagmus showed downregulation of the visual cortex which is responsible for motion processing (MT/V5 area) [11]. Typically patient with this kind of nystagmus does not have optokinetic nystagmus, and vestibulo-ocular reflex is disrupted [12]. Infantile nystagmus often (even up to 50%) comes with esotropia and is combined with some vertical movement disorders (congenital form of fourth muscle palsy or dissociated vertical deviation). Such a combination is then called infantile esotropia syndrome.

Infantile nystagmus is typically increasing when attempting to fixate a small visual object. The majority of children can dampen eye movements in convergence or some other eccentric direction of gaze. In the preferred position, sometimes called "null or neutral zone", nystagmus is dampening, so the fixation and fovealization are better, and children often have compensatory head position [13, 14]. In patients with infantile nystagmus, the development of the visual acuity is variable. Visual acuity can be 20/20 but sometimes it can be severely reduced.

#### 2.2.2 Ocular/sensory nystagmus

This is a kind of nystagmus which develops in cases when, during the early visual development (the first few months of life), the development of vision is not possible because of anatomical changes or organic defects in the eye. Disorders of the eye can be obvious, but sometimes they are subtle and not easy to define [15]. The cause of sensory nystagmus is inadequate image formation in fovea which results in disruption between afferent and efferent system and causes disturbances of oculomotor control. The most common causes are diseases of the eye such as congenital cataract, albinism, corneal opacities as well as developmental abnormalities of the optic disc and retina such as Leber's amaurosis, achromatopsia or stationary night blindness [16]. Specific form of sensory strabismus is uniocular nystagmus in deep amblyopia (Heimann-Bielschowsky phenomenon).

#### 2.2.2.1 Congenital cataract

Congenital cataract is opacification of the lens present at birth and may be responsible for amblyopia, sensory nystagmus and strabismus. The incidence varies between 2 and 4 in 10,000 worldwide [17].

The vast majority of congenital cataracts are bilateral, roughly between 60 and 70%. Identifiable cause of the cataract can be found in only half of them. Unilateral cataracts are mainly sporadic, found in otherwise healthy infants [17]. When they are associated with other local or system abnormalities, unilateral cataracts are usually found in eyes with other ocular abnormalities, and bilateral cataracts are mainly associated with system disorders (Table 4).

Not every lens opacification is equally important for normal vision development. The mostsightthreatening isif opacifications are central, more than 3 mm,located from central to the posterior parts of the lens. While sensory nystagmus usually developsin bilateral congenital cataracts,strabismus may occurin unilateral and bilateral cataracts.


\*Rubella is the most common intrauterine infection causing congenital cataract; DM, diabetes mellitus; HSV, herpes simplex virus; CMV, Cytomegalovirus; HZV, herpes zoster virus; EBV, Epstein–Barr virus.

#### Table 4.

Associated abnormalities in unilateral and bilateral cataracts.

Nystagmusisfound in at least 24% of eyes with bilateral cataract, being thought to be a poor predicting factorfor developing normal visual acuity [18].

As the risk of amblyopia is the greatest in the earliest months of life, it is of crucial importance to detect the cataract as soon as possible. That is why all infants must be screened for congenital cataracts immediately after birth and from 6 to 8 weeks of life. Screening is based on examination of red reflex. Any shadow in the reflex, absence or whitening of the reflex is an indication for complete ophthalmology examination [19]. On ophthalmology exam, it is essential to have a clear picture of fundus which is not blurred by opacification of the lens [17]. The more obscured fundus means that the vision development is more affected, and that determines timing of the surgery.

In cooperation with a pediatrician, set of laboratory examinations should be performed, even in cases without the presence of notable system abnormalities. If dysmorphic features are present, a genetic test should be suggested. Laboratory tests that should be done are TORCH titers; venereal disease research laboratory test (VDRL test); serum levels of calcium, phosphorus and blood glucose; and urine analysis for reducing substances (raised in galactosemia), galactokinase (raised in Fabry's disease), amino acids (raised in Lowe syndrome), calcium and phosphorus [19].

#### 2.2.2.2 Albinism

Albinism is a disorder which is characterized by reduced pigmentation of the skin, hair and eyes caused by inborn defects in melanin biogenesis and distribution. The defect can be present as an isolated form or, less frequently, as a part of the syndromes (Chediak-Higashi, Hermansky-Pudlak, Waardenburg) [20]. Although four genes are known to cause autosomal recessive form, it seems that, only in one-third of the patients with albinism, mutations in known genes are confirmed [21]. If the lack of pigmentation is present in the skin, hair and eyes, the disorder is called oculocutaneous albinism (OCA); if the hypopigmentation is present only in the eyes, it is called ocular albinism (OA) [22]. Pigments have multiple functions in the development and protection of the visual system. Although the exact molecular mechanisms are not yet completely understood, it is well known that pigment is crucial in some critical steps of the visual development as well as a factor of

protection of damaging light and cellular protection by being a trap for free radicals [23]. Important features of ocular albinism that causes reduced visual acuity are macular hypoplasia and abnormal decussation of the visual pathways [24, 25]. Because of the reduced visual acuity in patients with albinism amblyopia, nystagmus and strabismus often develop. Macular hypoplasia is the most important factor responsible for the reduced visual acuity in patients with albinism and is easily diagnosed by inspection (lack of foveal pit, abnormal growth of blood vessels) and confirmed by OCT (optical coherence tomography). Another important feature is the abnormal decussation of the visual pathways. In a normal eye, one half of the nerve fibers decussate to the contralateral side. On the other side, in patients with albinism, 75–85% of fibers project to the contralateral side [26]. The reason for that is lack of melanin in the specific time of development when melanin and its precursors have an important role in linking reception in the retina and perception in the brain [27].

With the clinical picture of the nystagmus alone, it is not possible to tell the difference between this kind of nystagmus and idiopathic infantile type. However, in this type visual acuity is severely reduced with no chances of improvement in contrast to the idiopathic form where the visual acuity can be normal. This type of nystagmus does not reduce during the years.

#### 2.2.3 Latent nystagmus

Latent/manifest nystagmus is benign, jerk kind of nystagmus that starts early in the childhood. Although this type of nystagmus is bilateral and conjugated, the main characteristic is that the nystagmus is not visible (or much less visible) when both eyes are open. It increases when one eye is closed. Other typical feature of latent nystagmus is that it changes direction. The fast phases are always towardsthe open eye. When the right eye is closed, it beats left, and when the left eye is closed, fast phase is right [28]. Sometimes this kind of nystagmus is called fusion defect nystagmus (FDN) because it is present (or more pronounced) with one eye closed when fusion is disrupted [29]. This kind of nystagmus is usually combined with other anatomical eye abnormalities, and most often it is part of the early esotropia syndrome [30].

#### 2.2.4 Spasmus nutans

Spasmus nutans is a benign nystagmus of childhood which is dissociated (different amplitudes, directions or frequencies between two eyes). The frequency is usually high, movement pendular, with a small amplitude, and disconjugated oscillations. The movements can be horizontal, vertical or torsional. It typically starts later than the idiopathic form, usually at the age of 4–12 months. If it starts after 3 years of age, the possibility of an intracranial tumor is strong. It is often preceded by the head nodding several months before the appearance of the nystagmus itself. Spasmus nutans is a specific form that can be a problem for diagnostics since there is no certain clinical sign that can differentiate this kind of nystagmus from the nystagmus caused by neurological problems (tumors in diencephalon) [31]. It is necessary for this kind of nystagmus to perform a complete neurological and endocrinological workup. Spasmus nutans typically disappears spontaneously in the 4th year of life [31].

#### 2.3 Acquired nystagmus

As mentioned in (Table 2), several systems working in synchrony are responsible for involuntary movements of our eyes. The disorder that creates


#### Table 5.

Acquired nystagmus.

pathological nystagmus can be situated in some parts of these systems or in the surrounding parts of the brain, brain stem and cerebellum. Most often the reasons are strokes or mass lesions, trauma, multiple sclerosis, some malformations and drugs (Table 5).

Another important characteristic that usually makes difference between acquired and benign forms is that acquired nystagmus is usually combined with other neurological signs like nausea, vomiting, headache, vertigo or tinnitus. In some cases the type or direction of the nystagmus can help us localize the place of lesion. For example, vestibular system is responsible for moving eyes in the opposite direction of the moving of the head. Both sides of system work in balance. When one side of the system is damaged, balance is lost, and the eyes will beat towards the not affected side and do not change side when the gaze changes direction. It is typical for this kind of disruption that nystagmus is increasing when the patient is not fixing. Lesions of the peripheral part of vestibular system (labyrinth) are accompanied by ataxia, vertigo and other signs of disturbances of the vegetative system. On the other hand, in the cases when damage is in the brainstem, often involving vestibular nuclei (fasciculus longitudinalis medialis), the direction of nystagmus is changing with the direction of the gaze, with the amplitude increasing when looking at the affected side. The intensity of nystagmus is increasing with fixation. In the cases of cerebellum diseases, nystagmus is increasing with fixation, more pronounced with the bigger amplitude and slower frequency when the gaze is towards the affected side. Vertical nystagmus is usually of central origin, and in some cases, it can be caused by excessive sedative medications intake. Acquired nystagmus can be a life-threatening condition which sometimes requires urgent neurological treatment [3]. Although in child's age the incidence of acquired nystagmus is smaller than in adult groups (17% in children compared to 40% in adult groups) [4, 5]. In our clinical work, it is of crucial importance when examining a child with nystagmus to notice the signs that are warning us that nystagmus is neurological in its origin, which means that the cause which is central does not require our treatment but needs neurological examinations, imaging and treatment [1].

Signs for neurological cause of nystagmus are:


#### 3. Treatment

In the cases when nystagmus is acquired, it is necessary to treat the reason that caused nystagmus. That treatment is usually in the hands of neurologists or neurosurgeons. When we have a child with some type of benign nystagmus, the primary goal is to improve proper development of the visual system which is in the hands of ophthalmologists. When the baby is born, the visual system is not fully developed, and it needs proper stimulation at the proper time for the cells in visual parts of the brain to develop to their full potential. We can say that a child has to learn how to see. Children with nystagmus often have refractive errors such as astigmatisms, myopia or hyperopia, given prescription can enable better development of the visual system and with improvement of fixation and fovealization nystagmus can dampen. In the cases of very poor visual acuity, some magnifying visual aids can be helpful [32].

Often children with nystagmus can have abnormal head positon to enable better fixation so the optical axis of the glasses is not the same as the visual axis of the eye. In cases like that it is wise to prescribe contact lenses. The reason of the preferred position of the head is so called null zone of nystagmus. Certain types of nystagmus have eye position in which nystagmus is less pronounced. By abnormal head position, the child is positioning the eyes in the preferred position where nystagmus is dampening. Prescribing the prismatic correction (base towards the head turn) can shift the null zone and correct head position. Prism correction can correct only mild head turn and the does not have permanent effect so cannot be prescribed like a definite therapy. Bigger amounts of prism correction are heavy and cause chromatic aberration, and Fresnel prisms will degrade visual acuity.

In the cases when the preferred position is bigger than 10°, there is a possibility to perform surgery on the eye muscles to move the eyes in the direction of the head turn, in order to shift the dampening zone from the decentralized position to straight ahead, to enable the patient a better and easier fixation. When considering a possibility of surgery, we have to think that some kinds of nystagmus spontaneously dampen by the age of 8–9 years, so the surgery can be planned in older children.

Most commonly performed surgeries are:

Anderson type of surgery

Kestenbaum type of surgery

Artificial convergence

Y-splitting

Posterior suture (Faden surgery)

Anderson type of surgery consists of recession of horizontal muscles of both eyes. Which muscles will be operated depends on the position of the eye and the head. Anderson started with the recession of one muscle on each eye with the idea that with the recession of the muscle he will weaken the tension and contact between the eye and the muscle which can help in the dampening of the nystagmus [33]. But the main effect of this kind of surgery is shifting the gaze direction in to the dampening zone. His original idea was recession of yoke muscles of 4 mm [33]. After his idea many modifications are made from other authors with different amounts of recession but taking into consideration that the amount must be symmetrical on both eyes in order to prevent induction of strabismus. The advantage of this method

#### Nystagmus DOI: http://dx.doi.org/10.5772/intechopen.82743

is that we are not only shifting eyes in the right direction but weakening the contact between the eye and the muscle and by that helping to dampen nystagmus.

In some cases, it is impossible to correct the head positioning only with recessions, so we have to add resections. That kind of surgery is named after Kestenbaum who published his method at the same year as Anderson [34]. Depending on the position of the head, a combination of recessions and resections is performed. This kind of surgery can be done on vertical and oblique muscles in cases when the patient is lifting, lowering or tilting the head [35]. During the years, many modifications of these surgeries have been done, mostly with recommendations for bigger amounts of surgery. Originally, Kestenbaum proposed recessions and resections of 5 mm; one of the most popular recommendations is done by Parks "5,6,7,8 procedure" with 13 mm of surgery in each eye [36]. Calhoun, Harley, Nelson and Pratt-Johnson suggested "augmented Parks surgery"; some of them prefer up to 10 mm of recess resect surgery [37, 38].

A different type of surgery is recommended for patients who are turning the head when looking at far distance and having their head straight when reading. The reason for dampening of nystagmus is convergence that they are using for near work. In such patients, we can perform a procedure called "artificial divergence", meaning that we create a latent divergence by surgery so the patient has to use convergence when looking at far distance (like during reading at near) and by that is dampening the nystagmus. When performing this type of surgery, we have to be sure that the patient has binocularity (possibility to use both eyes together); otherwise we will not achieve the goal of the surgery. It is always wise to simulate the wanted postoperative position by using prisms before the surgery. In the case of artificial divergence, we can check the amount of wanted divergence by putting prisms on both eyes and checking whether the patient is converging or accommodating and by that better estimate the amount of the needed surgery [39].

Some patients are changing their preferred head position, sometimes turning left and other time right with dampening nystagmus when the eyes are in convergent position. Often they do not have binocularity as the group mentioned previously, so we cannot use their active convergence to dampen nystagmus. In cases like this, Ysplitting of the medial rectus can be performed. By splitting both medial recti in two half up to 15 mm from the insertions, we create two arms of one muscle and fixate them away from each other. The exact position of placing the respective arms is calculated using a mathematical model in which axial length and angle of additional squinting must be added to the formula. By this kind of surgery, we block action of medial muscle only in adduction and by that we enable the patient to have convergence without active power of binocularity [40].

Similar effect has posterior fixation surgery or Faden surgery. When performing this kind of surgery, we suture the muscle to the globe at 15 mm behind the limbus and with that block the action of the muscle in the desired position [41]. Both kinds of surgeries are usually used on medial rectus muscles but can be used on other rectus muscles of the eye if we want to reduce the action of the operated muscle [42].

Nowadays we have some medications that are used for treating nystagmus (memantine, gabapentin, baclofen 4, aminopyridine, etc.), but because of a number of side effects, they are usually not used for children [43]. Some modern therapies like biofeedback (making the patients aware of the eye bobbling by sound or touch, and by that teach the patient to control nystagmus) are sometimes performed, but since there is no permanent effect, it is not widely used [44, 45].

Recently some proprioceptive nerve endings have been found at the place of the insertion of the eye muscle at the globe. Some authors advocate the idea that the cutting of the eye muscle at their insertions with reattaching or giving some

medications (brinzolamide) that act on these endings can change signals and re-boost ocular motor connection and with that dampen the nystagmus [46, 47].

### Conflict of interest

The authors declare no conflict of interest.

### Author details

Ivana Mravicic\*, Selma Lukacevic, Maja Bohac, Maja Pauk-Gulic and Vlade Glavota Eye Clinic "Svjetlost" Medical School University of Rijeka, Zagreb, Croatia

\*Address all correspondence to: ivana.mravicic@svjetlost.hr

© 2019 The Author(s). Licensee IntechOpen. This chapteris distributed underthe terms oftheCreative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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[31] Weissman BM, Dell'Osso LF, Abel LA, Leigh RJ. Spasmus nutans. A quantitative prospective study. Archives of Ophthalmology. 1987;105(4):525-528

[32] Brodsky MC. Nystagmus in children. In: Pediatric Neuro-Ophthalmology. New York, NY: Springer; 2016

[33] Anderson JR. Causes and treatment of congenital eccentric nystagmus. The British Journal of Ophthalmology. 1953; 37:267

[34] Kestenbaum A. Nouvelle operation de nystagmus. Bull Soc Ophthalmol France. 1954;2:1071-1078

[35] Conrad HG, De Decker W. Torsional Kestenbaum procedure: Evolution of a surgical concept. In: Reinecke RD, editor. Strabismus II. New York: Grune and Stratton; 1982. p. 301

[36] Parks MM. Congenital nystagmus surgery. The American Orthoptic Journal. 1973;23:35-39

#### Nystagmus DOI: http://dx.doi.org/10.5772/intechopen.82743

[37] Nelson LB, Erwin-Mulley LD, Calhoun JH, Harley RD, Keisler MS. Surgical management for abnormal head position in nystagmus: The augmented modified Kestenbaum procedure. The British Journal of Ophthalmology. 1984;68:796-800

[38] Pratt-Johnson JA. Results of surgery to modify the null-zone position in congenital nystagmus. Canadian Journal of Ophthalmology. 1991;26:219-223

[39] Sedler S, Shallo-Hoffman J, Muhlendyck H. Die Artifizielle-Divergenz-Operation beim kongenitalen Nystagmus. Fortschritte der Ophthalmologie. 1990;87:85-89

[40] Hoeranter R, Priglinger S, Halswanter T. Reduction of ocular muscle torque by splitting of the rectus muscle II: Technique and results. The British Journal of Ophthalmology. 2004; 88:1409-1413

[41] Leitch RJ, Burke JP, Strachan IM. Convergence excess esotropia treated surgically with fadenoperation and medial rectus recessions. The British Journal of Ophthalmology. 1990;74: 278-279

[42] Hoerantner R, Priglinger S, Koch M, Halswanter T. A comparison of two different techniques for oculomotor torque reduction. Acta Ophthalmologica Scandinavica. 2007;85(7):734-738

[43] McLean R, Proudlock F, Thomas S, Degg C, Gottlob I. Congenital nystagmus:randomized, controlled, double-masked trial of memantine/ gabapentin. Annals of Neurology. 2007; 61:130-138

[44] Glasauer S, Kalla R, Buttner U, Strupp M, Brandt T. 4-aminopyridine restores visual ocular motor function in upbeat nystagmus. Journal of Neurology, Neurosurgery, and Psychiatry. 2005;76:451-453

[45] Sharma P et al. Reduction of congenital nystagmus amplitude with auditory biofeedback. Journal of AAPOS. 2000;4:287-290

[46] Hertle RW, Chan CC, Galita DA, et al. Neuroanatomy of the extraocular muscle tendon enthesis in macaque, normal human, and patients with congenital nystagmus. Journal of AAPOS. 2002;6(5):319-327

[47] Hertle RW, Dell'Osso LF, FitzGibbon EJ, et al. Horizontal rectus muscle tenotomy in children with infantile nystagmus syndrome: A pilot study. Journal of AAPOS. 2004;8(6): 539-548

**65**

**Chapter 5**

**Abstract**

**1. Introduction**

functions [2, 3].

*and Luis Velázquez-Pérez*

Eye Movement Abnormalities in

Neurodegenerative disorders consist in heterogeneous group of neurological conditions characterized by a wide spectrum of clinical features resulting from a progressive involvement of distinct neuron populations. Oculomotor abnormalities take a key place in the clinical picture of these disorders because the neurodegenerative processes involve the brain circuits of eye movements. The most common abnormalities include the saccadic dysfunction, fixation instability, and abnormal smooth pursuit. The clinical assessment of oculomotor function can help to differentiate diagnosis, while electrophysiological measures provide useful biomarkers for the understanding of disease physiopathology and progression. In this chapter, we review the state of the art of the eye movement's deficits in some neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral

**Keywords:** eye movements, oculomotor abnormalities, neurodegenerative disorders, biomarkers, Parkinson's disease, Alzheimer's disease, dementia, hereditary ataxias

Neurodegenerative disorders encompass a highly heterogeneous group of complex neurological disorder characterized by progressive dysfunction and loss of neuron populations leading a wide spectrum of clinical features that cause notable motor and/or intellectual disabilities regularly incompatible with the life [1]. Consequently, some of these conditions represent important public health concern and has been identified as a research priority. Although physiopathological mechanisms generally differ among neurodegenerative diseases, a great number of them are characterized by abnormal accumulation of misfolded protein resulting in the loss of their physiological function and/or the gain of toxic

Classification of neurodegenerative disorders can be established by both the cardinal clinical features and the disease proteins (**Figure 1**). The former characterization distinguishes those conditions characterized by dementia syndromes and the movement disorders. Among dementias, the most commonly recognized disorder is the Alzheimer's disease. Other dementia syndromes include the frontotemporal dementia, the posterior cortical atrophy, the corticobasal syndrome, and others. Movement disorders comprise hypokinetic (such as Parkinson's disease) and hyperkinetic (such as Huntington's disease) conditions, as well

Neurodegenerative Diseases

sclerosis, Huntington's disease, and the hereditary ataxias.

*Roberto Rodríguez-Labrada, Yaimeé Vázquez-Mojena*

#### **Chapter 5**

## Eye Movement Abnormalities in Neurodegenerative Diseases

*Roberto Rodríguez-Labrada, Yaimeé Vázquez-Mojena and Luis Velázquez-Pérez* 

#### **Abstract**

 Neurodegenerative disorders consist in heterogeneous group of neurological conditions characterized by a wide spectrum of clinical features resulting from a progressive involvement of distinct neuron populations. Oculomotor abnormalities take a key place in the clinical picture of these disorders because the neurodegenerative processes involve the brain circuits of eye movements. The most common abnormalities include the saccadic dysfunction, fixation instability, and abnormal smooth pursuit. The clinical assessment of oculomotor function can help to differentiate diagnosis, while electrophysiological measures provide useful biomarkers for the understanding of disease physiopathology and progression. In this chapter, we review the state of the art of the eye movement's deficits in some neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and the hereditary ataxias.

**Keywords:** eye movements, oculomotor abnormalities, neurodegenerative disorders, biomarkers, Parkinson's disease, Alzheimer's disease, dementia, hereditary ataxias

#### **1. Introduction**

 Neurodegenerative disorders encompass a highly heterogeneous group of complex neurological disorder characterized by progressive dysfunction and loss of neuron populations leading a wide spectrum of clinical features that cause notable motor and/or intellectual disabilities regularly incompatible with the life [1]. Consequently, some of these conditions represent important public health concern and has been identified as a research priority. Although physiopathological mechanisms generally differ among neurodegenerative diseases, a great number of them are characterized by abnormal accumulation of misfolded protein resulting in the loss of their physiological function and/or the gain of toxic functions [2, 3].

 Classification of neurodegenerative disorders can be established by both the cardinal clinical features and the disease proteins (**Figure 1**). The former characterization distinguishes those conditions characterized by dementia syndromes and the movement disorders. Among dementias, the most commonly recognized disorder is the Alzheimer's disease. Other dementia syndromes include the frontotemporal dementia, the posterior cortical atrophy, the corticobasal syndrome, and others. Movement disorders comprise hypokinetic (such as Parkinson's disease) and hyperkinetic (such as Huntington's disease) conditions, as well

**Figure 1.** 

*Classification of neurodegenerative diseases according to cardinal syndrome (A) and disease proteins (B).* 

as cerebellar ataxias and motor neuron diseases (such as amyotrophic lateral sclerosis) [1, 4].

 The protein-based classification includes the tauopathies, the a-synucleinopathies, the TDP-43 and FUS proteinopathies, the polyglutamine diseases, and the prion disease. Tauopathies are caused by abnormal accumulation of tau protein and B-amyloids and are represented by the Alzheimer dementia, whereas among the a-synucleinopathies are recognized as the Parkinson's disease, dementia with Lewy bodies, and multisystem atrophy. Abnormal accumulation of TDP-43 and FUS proteins defines the physiopathology of the amyotrophic lateral sclerosis and frontotemporal lobar degeneration, whereas the polyglutamine diseases result from the accumulation of proteins with abnormally expanded polyglutamine domains and include the Huntington's disease; the spinocerebellar ataxias 1, 2, 3, 6, 7, and 17; the dentatorubral-pallidoluysian atrophy; and the spinal and bulbar muscular atrophy. Finally, the Creutzfeldt-Jakob disease is classified as a prion disease [1, 4].

Although the phenotypical features of neurodegenerative disorders generally differ between distinct disorders due to the differential involvement of specific functional systems, most of these conditions are characterized by altered oculomotor function as a result of the high vulnerability of the oculomotor system to the toxic protein deposition and other physiopathological mechanisms causing neurodegenerative diseases [5, 6]. Accordingly, the assessment of oculomotor function has become a helpful approach to diagnose some of the neurodegenerative diseases. Besides, eye movements are usually used for monitoring of disease progression [6, 7].

This chapter is focused to review the state of the art of the eye movement's deficits in some neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease, and the hereditary ataxias.

#### **2. Brief overview of eye movements**

Eye movements facilitate the clear vision stabilizing images on the retina, particularly against head and body movements, capturing and keeping specific stimuli on the fovea and aligning the retinal images in the two eyes to ensure the single vision and stereopsis. Ocular motility is guaranteed by five basic types of eye movements: the vestibulo-ocular reflex, the optokinetic reflex, the saccadic movements, the smooth pursuit movements, and the vergence [8].

Although they differ in various aspects, such as their velocity, reaction time, reflexivity/volitional degree, and their neurobiological substrates [9], all have generic kinematic properties and share a common final path represented by three cranial nerve nuclei and the three pairs of eye muscles that they control [8, 10]. Cranial nerve III (oculomotor) innervates the superior, inferior, and medial rectus muscles as well as the inferior oblique muscle, whereas trochlear (IV) and abducens (VI) nerves innervate the superior oblique and lateral rectus, respectively [10].

The vestibulo-ocular reflex (VOR) is elicited by the vestibular system in response to body/head rotations and consists on compensatory eye movements in opposite direction to body/head movements to guarantee the image stabilization on the retina [11]. When head/body rotations are very large and continued, the VOR is depressed, and thus, it is complemented by the optokinetic reflex (OKR), in which the speed and direction of a full-field image motion are computed to develop eye movements with two phases: a slow phase that alternates with resetting a quick phase [12].

Saccades are ballistic and conjugate eye movements that redirect the fovea from one object of interest to another, allowing to explore accurately the visual scenes. For that, saccadic system processes information about the distance and direction of a target image from the current position of gaze. Saccades are the fastest eye movements, reaching up to 800/s. Behaviorally, saccades may be classified as reflexguided saccades and intentional or volitional saccades. The first ones are evoked by suddenly appearing targets, whereas the second ones, called also as higher-order saccades, are made purposefully. Therefore, intentional saccades involve highcognitive processing and include voluntary, memory-guided and delayed saccades, as well as antisaccades [13, 14].

Smooth pursuit eye movements enable us to maintain the image of a moving object relatively stable on or near the fovea by matching eye velocity to target velocity [10]. Smooth pursuit performance is optimal for target speeds ranging between 150/s and 300/s, but pursuit velocity can reach up to 100/s [8, 15].

Vergence eye movements are disjunctive movements that provide the binocular alignment in response to changing fixation of target distances, requiring that both eyes point in contrary directions. These movements are elicited by retinal disparity (when a fixation target is not on both foveae) and retinal blur (when a target is not in focus). Therefore, these movements are closely related to the lens accommodation and pupillary reflexes [16].

#### **3. Oculomotor disturbances in neurodegenerative diseases**

#### **3.1 Parkinson's disease and other parkinsonian disorders**

#### *3.1.1 Parkinson's disease*

Parkinson's disease is a progressive disorder pathologically defined by the degeneration of the dopaminergic neurons in the *substantia nigra* and formation of α-synuclein-containing Lewy bodies in the residual dopaminergic neurons. Consequently, the clinical picture is characterized by progressive motor symptoms that include bradykinesia, muscular rigidity, rest tremor, as well as postural and gait impairment. The disease is also associated with many non-motor symptoms, some of which precede the motor dysfunction by more than a decade [17]. Global prevalence of PD ranges between 100 and 200 cases per 100,000 inhabitants, with an annual incidence around 15 cases per 100,000 [18]. Although the etiology of PD is commonly unknown, monogenic causes can be considered in 5–10% of the cases [19].

Findings about oculomotor function in PD are certainly inconsistent due to the reduced number of patients included in the majority of the studies and the heterogeneity of the disease phenotype [7]. Nevertheless, saccadic hypometria is recognized as the most striking oculomotor feature in PD patients, which can be documented both at bedside and by electrophysiological approaches even early in the disease course. As a result of the saccade hypometria, PD patients frequently require multistep sequences to reach the target [20]. This behavior is more pronounced during memory-guided saccades, and it is considered as a disease biomarker [21, 22]. The marked saccade hypometria in PD can be explained by the neurodegenerative changes in the basal ganglia causing the decrease of pre-oculomotor drive through the substantia nigra to the superior colliculus [21]. Alongside the saccade hypometria, PD patients also show abnormally prolonged latency of voluntary saccades such as the memory-guided saccades and the antisaccades; nevertheless, the latency of externally triggered saccades to visual targets is normal [23]. Distinct to the saccade hypometria, the deficits in the saccade initiation are detectable later in the disease course and are closely related with the cognitive impairments and the involvement of non-dopaminergic pathways such as the frontal and parietal eye fields, the premotor cortex, and the lateral prefrontal cortex [24].

The delayed prosaccade and the antisaccade tasks reveal an impaired inhibition of saccades as evidence of deficit of automatic response inhibition. PD patients show increased timing error rates in the delayed prosaccade paradigm, which are closely associated with abnormal neuropsychological performance, whereas antisaccade paradigm reveals higher directional error rates [25]. Antisaccade errors can be detected early in the disease course [26]. Beyond saccadic impairments, PD patients show slight alterations in other eye movements, such as reduced gain of the smooth pursuit movements [27] and slow and hypometric divergence movements, but normal convergence movements [28].

#### *3.1.2 Other parkinsonian disorders*

 Oculomotor findings of patients suffering from other parkinsonian disorders are varied and usually distinctive to the PD. In cases with multisystem atrophy with predominant Parkinsonism (MSA-P), the clinical assessments of oculomotor function usually reveal increased square wave jerks, saccade hypometria, as well as abnormal smooth pursuit and vestibulo-ocular reflex [29, 30]. Less common oculomotor features in MSA-P include downbeat nystagmus, head-shaking nystagmus, and mild vertical supranuclear gaze palsy [29, 31].

In the progressive supranuclear palsy with Parkinsonism (PSP-P), the most important oculomotor feature is the slowing of vertical saccades, which progresses to supranuclear gaze palsy in the 70% of the cases but appear lately in the disease course than in the classic PSP [32]. In addition, these patients show reduced gains of the smooth pursuit movements and saccadic eye movements at similar extent that in classic PSP [27].

#### **3.2 Alzheimer's disease and other dementias**

#### *3.2.1 Alzheimer's disease*

Alzheimer's disease (AD) is the most common neurodegenerative disorder worldwide with a global prevalence above 20 million of affected people, which is estimated to grow notably in the next decades. The histopathological hallmark of the disease is the deposition of insoluble protein aggregates such as amyloid-β (Aβ) plaques and neurofibrillary tangles of tau in the brain, causing a significant brain atrophy and subsequent cognitive features such as memory disturbances, executive dysfunction, difficulties with language, and other cognitive skills that affect a person's ability to perform every day [33]. Similar to PD, the etiology of Alzheimer's disease (AD) is not fully understood, but several environmental and genetic factors are assumed to contribute to the disease etiopathogenesis [34].

Oculomotor testing in Alzheimer's disease reveals a varied group of eye movement abnormalities, but no specific oculomotor feature is distinguished. Among oculomotor features of AD patients, the saccadic intrusions are one of the most common [35, 36]. These unwanted microsaccades are mainly oblique and can be detected even in subjects with mild cognitive impairment which identify this oculomotor feature as a potential biomarker of Alzheimer's disease at early stages [37]. These microsaccades are more frequent in those patients with higher dementia scores [38], which support the notion that gaze-fixation instability in AD results from the involvement of cognitive processes such as the attention and working memory. Nevertheless, the impairment of the saccade pathways could also explain the high occurrence of saccadic intrusions, mainly at later disease stages [39].

Reflexive and voluntary saccades of AD patients are usually characterized by prolonged latencies, reduced velocity, and hypometria. Antisaccadic paradigm reveals increased directional error rate alongside with the reduction of the error correction, which are closely associated with the severity of dementia [40]. Both prosaccadic and antisaccadic alterations in AD are proposed to result from impaired inhibitory control and attentional failures, as well as from the later involvement of saccadic circuitry at brainstem [39]. In addition, AD patients show increased latency to initiate smooth pursuit movements, with decreased gain velocity and increased catch-up (compensatory) saccades. Similar to the saccadic intrusions and antisaccadic deficits, the rate of compensatory saccades during the smooth pursuit is narrowly related with the dementia severity [40–42].

#### *3.2.2 Other dementias*

In the posterior cortical atrophy (PCA), an atypical variant of AD, the most frequent oculomotor abnormalities include increased saccade latency and decreased saccade amplitude, but the saccade velocity is normal. Also, the PCA patients show increased time to saccadic target fixation, even higher than subjects with typical AD. Moreover, these patients show large saccadic intrusions whose frequency is correlated with generalized reductions in cortical thickness. Smooth pursuit gain is slightly reduced in these patients [43, 44]. Moreover, individuals with frontotemporal dementia (FTD) show increased reflexive saccade latency and higher rates of antisaccadic errors, but the error correction abilities are preserved. In addition, the smooth pursuit movements are characterized by the reduction of gains and accelerations [40, 45, 46].

#### **3.3 Huntington's disease**

Huntington's disease is a neurodegenerative disorder caused by the abnormal expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin gene on chromosome 4, encoding the huntingtin protein. The mutation results in an excessively long polyglutamine stretch near the N-terminus of this protein, which identify this disorder as a polyglutamine disease. Mutant HTT affects some cellular processes, including protein-protein interaction, protein clearance, mitochondrial function, axonal trafficking, gene transcription, posttranslational modification, and others that ultimately cause the loss of striatal neurons [47].

Clinically, the disease is characterized by a progressive motor, cognitive, and psychiatric disturbance. The motor phenotype includes chorea as cardinal feature, as well as dystonia and Parkinsonism, whereas the cognitive dysfunction comprises dysexecutive signs, as well as memory and attentional dysfunction. Psychiatric features are usually depression, anxiety, apathy, obsessive-compulsive behaviors, and others. Similar to other polyglutamine disorders, the age at onset of HD is highly influenced by the CAG repeat length, but other genetic and environmental modifying factors are proposed to also control the age at onset variability [47, 48].

Oculomotor abnormalities of patients with HD include saccade slowing and deficits in the initiation and suppression of these movements. The reduction of saccade velocity appears in around 60% of patients and is commonly observed in the vertical plane, but in those cases in advanced disease stages, the saccade slowing reaches also the horizontal movements [49, 50]. Saccade latencies are significantly prolonged and show a marked variability, which is more pronounced in patients showing higher disease severity. Studies using the antisaccadic paradigm have revealed and increased rate of directional errors, which are also closely correlated with the severity of the disease. Moreover, increases of latency variability and timing errors are observed in the memory-guided saccade task. The deficits of the suppression and initiation of the saccades can be explained by the neurodegenerative changes in the frontal cortex and in the basal ganglia [51, 52]. So, a recent imaging research revealed a close association between the voluntary saccade inhibition deficits and the white-matter corticobasal atrophy in patients [53].

Several authors have evaluated saccadic eye movements in asymptomatic carriers of the HD mutation. These studies have found a significant delay in the initiation of voluntary eye movements, increase in the variability of saccadic latency, and increase in the rate of antisaccadic errors [54–56]. A longitudinal follow-up of these alterations demonstrated their usefulness as preclinical markers due to the high replicability and consistency of these measures [22]. Imaging studies in asymptomatic carriers of HD have shown a significant correspondence between alterations in saccadic latency and the decrease in the number of fronto-striatal fibers that project into the caudate nucleus and the atrophy of gray matter in cortical structures, which deepens in the pathophysiology of saccadic alterations in this disease [57, 58]. A recent paper demonstrated that the horizontal ocular pursuit item of the Unified Huntington's Disease Rating Scale is useful for detecting differences between premanifest individuals and controls [59].

#### **3.4 Amyotrophic lateral sclerosis**

Amyotrophic lateral sclerosis (ALS) is the most common and devastating age-related motor neuron disease, characterized by a progressive loss of upper and lower motoneurons, causing paralysis and death in approximately 3 years. The pathological hallmark of ALS is the presence of abundant cytoplasmic inclusions containing ubiquitin and TDP-43, a RNA-binding protein. The clinical picture

*Eye Movement Abnormalities in Neurodegenerative Diseases DOI: http://dx.doi.org/10.5772/intechopen.81948* 

comprises progressive muscle weakness alongside hyperreflexia and spasticity associated with fibrillations and fasciculations [60]. The disease has a global prevalence around five cases per 100,000 inhabitants. Most of ALS cases are sporadic, and only the 5% of patients are familial, with at least 12 genes implicated, such as the superoxide dismutase 1(SOD1), trans-activate response DNA-binding protein (TARDBP), C9ORF72, FUS, and the ataxin-2 genes [61, 62].

Some evidences have demonstrated the involvement of the oculomotor system in ALS, leading a broad range of eye movement deficits affecting the saccades and the smooth pursuit movements [63–66]. The most prominent and early oculomotor alterations of ALS patients are related with abnormal executive oculomotor control as evidence of frontal lobe involvement. They primarily includes the increase of error rates in anti-saccades and delayed saccade paradigms as well as reduced voluntary gaze shift and increased number of saccadic intrusions. In general, these oculomotor alterations are correlated with the severity of the disease and the neurocognitive measures. In a following stage of oculomotor abnormalities, some ALS cases can show slow saccades, saccade hypometria, and interrupted smooth pursuit, as evidences of the involvement of the brainstem and pre-cerebellar/pontine circuits [67].

#### **3.5 Hereditary ataxias**

Hereditary ataxias consist in a heterogeneous group of genetic disorders phenotypically characterized by gait ataxia, limb incoordination, dysmetria, dysarthria, oculomotor disturbances, and other motor and non-motor features. These disorders are associated with atrophy of the cerebellum, which can be accompanied with the degeneration of other regions in the central and peripheral nervous system in various genetic subtypes [68].

 Hereditary ataxias are classified into four main groups regarding their inheritance patterns: autosomal dominant (also referred as spinocerebellar ataxias), autosomal recessive, X-linked, and mitochondrial ataxias [68, 69]. Till now, 46 subtypes of spinocerebellar ataxias have been identified, which imply at least 37 distinct genes [70]. The most common subtypes are caused by polyglutamine (polyQ )-coding CAG repeat expansions (SCA1,2,3,6,7,17, DRPLA) [71]. Regarding the recessive ataxias, nearly 100 genes have been identified, with the highest prevalence for the Friedreich's ataxia (FRDA), caused by GAA repeat expansions or point mutations in the frataxin (FXN) [68, 72]. Global prevalence of hereditary ataxias is estimated around three cases per 100,000 inhabitants, but there are large regional variations of prevalence due to founder effects of some genes [73].

Oculomotor disturbances of SCA patients are varied and result from the cerebellar and/or brainstem involvement. The former abnormalities are the most common and include the presence of pathological nystagmus, abnormal smooth pursuit, and saccadic dysmetria, whereas the impaired VOR, saccadic slowing, and ophthalmoplegia are related with pontine degeneration. Nevertheless, the notable overlapping of oculomotor features between SCA subtypes implies the requirement of other clinical criteria or the genetic testing for sensitively discriminating among these diseases [74–78] (**Figure 2**).

In the case of SCA2, an early and severe saccadic slowing is observed even more than a decade before the ataxia onset [79], which identifies it as important preclinical biomarker of the disease. Interestingly, the SCA2 saccade slowing is tightly influenced by the expanded CAG repeats in the ATXN2 gene [80] and shows a significant familiar aggregation which leads to the suitability of this disease feature as endophenotype marker [81], with potential usefulness for the search of modifier genes and neurobiological underpinnings of the disease and as outcome measure

#### **Figure 2.**

*Cerebellar and/or brainstem origin of oculomotor features in SCAs.* 

in future neuroprotective clinical trials. Moreover, the saccade slowing in SCA2 progresses significantly along time providing novel insight into the cumulative polyglutamine neurotoxicity and supporting the usefulness of saccade peak velocity as a sensitive biomarker during the natural history of the disease [82]. Saccade pathology in SCA2 is also characterized by abnormal prolongation of reflexive and voluntary latencies and increases of the antisaccade error rate. The later feature is also detected in prodromal stage and is significantly correlated with the mutation size [83–85].

The main eye movement abnormalities of SCA1 patients include saccadic dysmetria, gaze-evoked nystagmus, and depressed smooth pursuit [86]. Saccadic hypermetria is observed in majority of cases, appears at an early stage of the disease, and progresses quickly [75, 76, 87]. SCA3 is characterized by a higher frequency of gaze-evoked and rebound nystagmus [88], in addition to decreased smooth pursuit gain and saccadic dysmetria. These patients also show decreased VOR gain, which correlated with the CAG repeats, suggesting the pathologic involvement of the vestibular nuclei in the lateral brainstem [74–76]. Divergence insufficiency and strabismus are also common oculomotor features of these patients [89, 90].

 In SCA6, a higher frequency of spontaneous downbeat nystagmus and square wave jerks is detected [76, 91, 92]. The square wave jerks together with subtle abnormalities of saccades and smooth pursuit movements can be detected even before the disease onset [93]. The major saccadic alteration in SCA7 is the slowing of saccades, together with saccadic dysmetria [94, 95]. These alterations may precede cerebellar and retinal manifestations by some years [96]. Patients with SCA17 show hypometric saccades which are increased with disease duration but neither with ataxia score nor CAG repeats number [97].

 Eye movement disturbances are frequent in FRDA. The most prominent abnormalities consist in fixation instability such as multiple square wave jerks and ocular flutter, which are also complemented by abnormal smooth pursuit, saccadic dysmetria, prolongation of saccade latency, gaze-evoked nystagmus, and impaired VOR. Interestingly, the prolongation of saccade latency and the square wave jerks are significantly correlated with the disease severity and age at disease onset, respectively [98, 99]. Moreover, antisaccades and memory-guided saccades are also abnormal in these patients as evidence of the disruption of the higher-order processes controlling the saccade movements [100].

### **4. Concluding remarks**

 Eye movement abnormalities are among the most common phenotypic manifestations of patients with neurodegenerative diseases. The prominent features include the saccadic abnormalities, fixation instability, and abnormal smooth pursuit. Thus, the examination of eye movements is a very useful, but not determinant, approach for the differential diagnosis of these disorders. For example, the increased square wave jerks and the slowing of vertical saccades may be useful features for the clinicians in order to distinguish between the MSA-P and the PSP-P from the idiopathic Parkinson's disease, respectively. In addition, the early and severe saccadic slowing with rare pathological nystagmus distinguishes SCA2 from other autosomal dominant ataxias, whereas the marked abnormalities of smooth pursuit, VOR and OKR, in association with pathological nystagmus and rare saccadic slowing may help to define a SCA6 phenotype. Nonetheless, the notable overlapping of oculomotor features between neurodegenerative disorders suggests the necessity of other diagnostic criteria for sensitively discriminating among diseases with similar symptomatology.

Besides, the assessment of oculomotor function in neurodegenerative disorders leads to the identification of disease biomarkers, which acquire key values in the clinical and research practice of neurodegenerations. Many eye movement markers of neurodegenerative disorders allow to assess the disease stage and disease progression, because their changes over time are significantly linked with clinical outcome of syndrome severity, and interestingly some oculomotor disturbances precede the clinical diagnosis of the disease, which identify them as useful preclinical markers to detect the early stages of the neurodegenerative process, to evaluate the genetic susceptibility of the asymptomatic relatives, and to identify individuals for enrolment in early intervention trials.

Moreover, the study of eye movements in neurodegenerative diseases offers valuable advantages to assess the cognitive functioning in these conditions, mainly those measures that reflect the high-order processes underlying the oculomotor functions such as the antisaccade and memory-guided saccade task outcomes, the saccade latency, and others.

 In conclusion, although by decades the oculomotor system has been widely studied in neurodegenerative diseases, further efforts are warranted to study their involvement in other—less common—disorders, to understand the physiopathological mechanisms underlying oculomotor disturbances and to certify the role of oculomotor features as sensitive outcome measures in further neuroprotective trials.

#### **Acknowledgements**

We are very indebted to Cuban Ministry of Public Health for their collaboration.

#### **Conflict of interest**

Authors declared no conflict of interest.

#### **Appendices and nomenclature**



#### **Author details**

Roberto Rodríguez-Labrada1 \*, Yaimeé Vázquez-Mojena1 and Luis Velázquez-Pérez1,2

1 Centre for the Research and Rehabilitation of Hereditary Ataxias, Holguin, Cuba

2 Cuban Academy of Sciences, Havana, Cuba

\*Address all correspondence to: robertrl1981@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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### *Edited by Ivana Mravicic*

Visual processing refers to the ability to perceive three-dimensional images. To accomplish this, our eyes have to be perfectly tuned and work together. Each eye perceives a slightly diferent image that the brain then has to unite into a single three-dimensional picture. Tis book explains the motor and sensory steps necessary for forming binocular and stereo vision, discusses tests to assess the diferent steps and describes disruptions that can occur in the eyes and the brain. Because of the sensitivity of the developing child's eye, the book also addresses the assessment of children's vision. Tis book will appeal to ophthalmologists, paediatricians, neurologists and other interested readers.

Published in London, UK © 2019 IntechOpen © kwasny221 / iStock