Ординатура / Офтальмология / Английские материалы / Ocular Disease Mechanisms and Management_Levin, Albert_2010

the retinal pathway to the NOT.26 With development of binocular vision OKN usually becomes symmetrical. If development of binocular function is interrupted in MT/ MST then asymmetry persists27 and can become exaggerated, leading to a nasalward drift under monocular conditions,

i.e., MLN.21,22 Since the NOT projects to the vestibular nuclei which integrate visual and vestibular inputs, MLN can be considered as an imbalance between visual and vestibular inputs caused by deficient binocular input from MT/MST cortex.

Section 5  Neuro-ophthalmology Chapter 45  Nystagmus

Idiopathic infantile nystagmus

Clinical background

IIN is an often hereditary condition that usually appears in the first few months of life. The oscillations are usually horizontal and conjugate but may also rarely appear as primarily vertical or even torsional nystagmus.2,28 The term “idiopathic infantile nystagmus” is used in preference to “congenital idiopathic nystagmus” as the nystagmus is not always present at birth.29 The waveform is typically a large slow pendular or triangular oscillation when the nystagmus first appears in infancy and develops into a smaller jerk waveform with age (Box 45.2).30,31 This has led to the view that individuals with IIN develop a “foveation strategy” during visual development to improve vision.32 The jerk nystagmus develops with age as individuals learn how to use “foveating saccades” to maximize the time periods when the eyes are moving slowly. Individuals use these slow periods (called foveation periods) to line up the fovea with targets of interest.

The intensity of the nystagmus will usually change with the direction of gaze, with the region of lowest nystagmus intensity and longest foveation periods being described as the “null region.”3 The patient will often prefer to take up fixation at the null region to improve vision and this may result in an anomalous head posture if the null region is eccentric.13 Although IIN is often described in the literature as being a jerk nystagmus with accelerating slow phase, IIN may show different waveforms that usually vary with eccentricity. Often IIN consists of an underlying pendular oscillation interrupted by regularly occurring foveating saccades (quick phases). Typically, the oscillation drifts towards the null region with the drift becoming accentuated further away from the null region. This results in the quick phases usually beating away from the null region. At the null region the

Box 45.2  Idiopathic infantile nystagmus (IIN)

Characteristics

348

quick phases may beat in either direction or the nystagmus may be pendular. Twelve types of waveform have been described by Del’Osso and Daroff.32 The majority of these are variations in the timing, amplitude, and direction of foveating saccades with respect to the underlying pendular oscillation.

Apart from the correction of head posture using eye muscle surgery the treatment of IIN has mainly been empirical with most previous research lacking placebo-controlled comparisons.33 Since IIN dampens on convergence, artificial divergence introduced with eye muscle surgery or prisms has been used to treat patients with IIN and binocular vision.15 Recession of all four horizontal muscles15 and, more recently, tenotomy (disinsertion and reattachment on the original insertion) of the four horizontal muscles have been reported to improve visual function and eye movements in nystagmus.34 Gabapentin and memantine, drugs which may both have an antiglutaminergic action, have also been recently shown to improve vision in IIN patients in a randomizedcontrolled trial.35,36 The mechanism behind how these interventions improve nystagmus is unclear. Several treatments are now becoming available, although they are still at trial stage.

Pathology

The mechanisms underlying IIN are still unknown; however, the genetic basis of the most common form of inherited IIN is just beginning to emerge.

Etiology

IIN can be sporadic or inherited. The most common mode of inheritance is due to X-linked mutations.37,38

Pathophysiology

The cause of IIN is still unknown, with suggested mechanisms remaining in the realm of speculation. In many respects the visual system of IIN patients has been found to be normal. IIN patients can make smooth pursuit eye movements and vestibular responses if foveation is considered.39,40 They show normal saccadic oculomotor dynamics, although latencies are delayed.41 IIN patients also perceive a stable world and can localize targets in space accurately, even outside foveation periods.42

Because disorders of the optic chiasm such as seen in albinism lead to nystagmus with many similarities to IIN it has been suggested that the anatomical cause of IIN could be developmental miswiring of the visual system.43 Physiologically, the sinusoidal-like oscillations commonly lying behind IIN suggest an unstable feedback loop of some sort. Various models have been proposed based around current knowledge of oculomotor circuitry. However, there is no consensus concerning the dysfunctional neuronal structure(s) in IIN, with suggestions including the fixational eye movement system,44 the pursuit system,45 and the saccadic system.45 Recently, it has also been suggested that IIN is a developmental response to poor high-contrast foveal vision where contrast sensitivity to low spatial frequencies is enhanced by moving images across the retina.46

Tangible developments in understanding the pathophysiology of IIN have been made with respect to the genetic basis

The FRMD7 gene

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Section 5  Neuro-ophthalmology Chapter 45  Nystagmus

Albinism

Clinical background

Oculocutaneous albinism (OCA) is characterized by a lack of pigmentation in the eyes, skin and hair (Figure 45.5A and Box 45.3) and is caused by disruption in the production of melanin due to a number of genetic mutations.48 In certain forms of albinism there is no apparent lack of pigmentation in hair or skin (Figure 45.5B) and only disorders in the visual system are evident (listed below). This is described as ocular albinism (OA) and has a different genetic basis.

Various structures along the visual pathway are affected by albinism:

•  Iris: lack of pigmentation causes transillumination of the iris, which is most clearly seen on slit-lamp examination (Figure 45.5Aii and Bii).

•  Retina: hypopigmentation of the retinal pigmentary epithelial layer leads to greater reflection of light within the eye. The fovea does not develop fully, leading to a poorly demarcated foveal pit (foveal hypoplasia) (Figure 45.5 Aiii and Biii). Optical coherence tomography shows a spectrum of foveal development in albinism, sometimes with complete absence of development (Figure 45.5C) or with a central depression with thickened fovea. The abnormal foveal development frequently leads to reduced visual acuity. Also, optic discs can be small and dysplastic.

•  Chiasm: the most distinguishable feature of albinism is abnormal crossing of axons at the chiasm.49 This can be detected diagnostically as an asymmetry in the visual evoked potential when measuring the response of the two visual cortices to monocular light stimulation (flash) or checkerboard pattern (pattern-onset) (Figure 45.5D).

•  Visual cortex: albinism is often associated with a loss of cortical stereoscopic vision due to misrouting of axons through to the cortex and also strabismus. This leads to reorganization of the visual cortex which can be measured using retinotopic mapping of visual cortex with functional magnetic resonance imaging50 (Figure 45.6).

•  Eye movements: albinism is associated with nystagmus and also strabismus. The nystagmus shows many similarities to that observed in IIN patients (Figure 45.5Aiv and Biv). It is usually horizontal, conjugate, with increasing slow-phase velocities and the nystagmus intensity and waveform changing with gaze direction.3 These patients also typically show a null zone and often have an anomalous head posture.13

Just as with IIN, anomalous head postures can also be corrected using eye muscle surgery. The methods used to treat nystagmus associated with IIN, i.e., muscle tenotomy34 and drug therapy,35 have also been used to treat albinism. Although improvements in intensity of nystagmus have been shown to be effective, improvements in visual acuity are limited by the underdeveloped fovea in these patients.35 Optimal refractive correction is particularly important in these patients to prevent amblyopia and assist visual development.

350

Pathology

OCA and OA are caused by disruption in melanin synthesis or transport due to mutations in a series of genes.

Etiology

To date four types of OCA have been found (not associated with syndromes) linked to mutations in four genes.48,51 OCA1 is present in most populations except AfricanAmericans and can present with either a complete lack of melanin production (OCA1A) or partial melanin production (OCA1B). It is caused by mutations in the tyrosinase gene (TYR). OCA2 and OCA3 are more common in African populations and are milder forms of albinism. OCA2 is linked to mutations in a gene involved in melanosome production (OCA2 or P gene) and OCA3 is caused by mutations in a tyrosine-related gene (TYRP1). OCA4 is another mild form of albinism that has recently been found in Turkish, Japanese, German, and Korean patients. The OCA4 gene codes for a protein called MATP. The function of this protein is not entirely clear but it is thought it may have a role in the transport of melanosomes.

There are two known causes of OA: (i) due to mutations in the OA1 gene which follows an X-linked recessive inheritance or (ii) autosomal-recessive ocular albinism (AROA).52 The OA1 gene codes for a transmembrane glycoprotein which appears to function as a G-protein-coupled receptor, although the exact function of the protein is unknown. In at least some cases AROA results from mutations in TYR and OCA2 genes.

Pathophysiology

Melanin is the most common light-absorbing pigment in living organisms. It is synthesized from tyrosine to DOPA by the tyrosinase enzyme and subsequently to DOPAquinone. Consequently, mutations to the tyrosinase enzyme can render it either completely or partially functional, resulting in the two variants of the OCA1 form of albinism (OCA1A and OCA1B). Disorders of melanosome production, the organelles used to store melanin, also lead to the physical and visual abnormalities associated with albinism (OCA2). The mechanisms by which the visual system abnormalities arise in association with albinism are unclear. Several authors suggest that abnormal retinal development could lead to the incorrect axonal pathfinding which causes abnormal chiasmal crossing.49,51

Spasmus nutans

Spasmus nutans is a rare form of infantile nystagmus that is characterized by a triad of nystagmus, head nodding, and head torticollis. It appears around 1–3 years of age but abates to subclinical levels at around 5–12 years of age.53 It is an intermittent, fine, high-frequency, pendular dissociated nystagmus. Spasmus nutans is not inherited and is more common in low socioeconomic classes.54 Interestingly, head nodding suppresses nystagmus in spasmus nutans (Figure 45.7), whereas in other nystagmus forms head nodding has not been found to benefit the patient and might be an associated pathological phenomenon.55 Spasmus nutans can be easily mistaken for nystagmus associated with retinal disease56 or nystagmus caused by lesions to the anterior

A

i

iii

iv

C

Albinism

Infantile nystagmus

iii

iv

Optical Coherence Tomography

Normal

D

Visual Evoked Potentials

Right Eye Open

Left Eye Open

Box 45.3  Albinism

Characteristics

352

visual pathway caused by tumors, for example, optic nerve and chiasmal gliomas.57 Therefore, thorough neuroophthalmological (including electrophysiology), neuropediatric, and possibly neuroradiological workup of the patient is necessary.

Nystagmus associated with retinal diseases and low vision

Lesions at numerous locations along the sensory visual pathway are associated with nystagmus. The term “sensory nystagmus” has been used to describe these types of nystagmus, although in some diseases it is not entirely clear whether the sensory deficits cause the nystagmus or whether the nystagmus is intrinsic to the disease.58 Deficits of rod and cone systems, such as congenital stationary night blindness, achromatopsia (complete or partial, e.g., blue-cone monochromatism) and Leber’s amaurosis are all associated with nystagmus.59 Congenital cataract can lead to nystagmus if not operated on early enough.18 Aniridia, bilateral optic nerve hypoplasia, and retinopathy of prematurity are also associated with nystagmus. Achiasmatic subjects have been described to have congenital seesaw nystagmus.60 Cortical visual impairments such as periventricular leukomalacia also lead to a range of oculomotor deficits, including nys-

Retina

tagmus.61 Nystagmus associated with retinal diseases and low vision often consists of small horizontal or vertical movements superimposed on larger oscillations.62

Nystagmus associated with neurological syndromes

Nystagmus occurs in a number of neurological syndromes such as Down syndrome, Joubert syndrome, Pelizaeus– Merzbacher syndrome, fetal alcohol syndrome, and Cockayne’s syndrome. These are usually related to abnormalities in the lower-level oculomotor circuitry in the brainstem and cerebellum. The underlying mechanisms and nystagmus characteristics are similar to those seen in many acquired nystagmus types.

Acquired nystagmus

Acquired nystagmus can result from both vestibular and/or neurological disorders and is often extremely disabling due to the associated oscillopsia.1,63,64

Nystagmus caused by disorders of vestibular sensory organs or nerves is characterized by a pure jerk waveform (linear slow phase) in a plane equivalent to that monitored by the defective sense organ(s). Causes include paroxysmal positional vertigo, vestibular neuronitis, and Ménière’s disease.65 Vestibular nystagmus is characterized by sensitivity to altering vestibular input through head movements.

A range of neurological disorders, including tumors and strokes, can cause acquired nystagmus, presenting in many

Box 45.4  Acquired nystagmus

Characteristics

different forms. However, several forms of nystagmus are characteristic of acquired neurological nystagmus.

Acquired pendular nystagmus

Acquired pendular nystagmus (APN) is commonly associated with multiple sclerosis.66 Here, the nystagmus is often disconjugate and may be a combination of horizontal, vertical, and torsional nystagmus (e.g., elliptical or oblique) (Box 45.4). APN also occurs in Whipple’s disease, brainstem stroke, spinocerebellar degeneration, encephalopathy, and syndromes such as Pelizaeus–Merzbacher syndrome and Cockayne’s syndrome.1

One hypothesis about the cause of APN in multiple sclerosis is that it is due to instability in the neural integrator,

354

the neural circuitry used to generate the tonic neural signal that allows the eyes to be held eccentrically. This was based on observations that saccades cause a phase shift, apparently resetting the integrator.67 Also, the paramedian tracts, which form an important part of the neural integrator, frequently show plaques.68 Several drugs have proved to be successful in treating APN in multiple sclerosis, including gabapentin, baclofen, and memantine.69

Vertical jerk nystagmus

Vertical jerk nystagmus is frequently associated with disorders of the vestibulocerebellum. A hypothetical scheme has been proposed to explain upbeat and downbeat jerk nystagmus based on specific pathological lesions in human and animal models63,64,70 (Figure 45.8). The pathway from the anterior semicircular canal through to the eye elevators is under inhibitory control by the cerebellar flocculus at the level of the superior vestibular nucleus. Only upward movement of the eyes is under this inhibitory control with no direct equivalent for downward movements of the eyes. The level of inhibition is controlled by a feedback loop that synapses at the level of the caudal medulla. This mechanism appears to be prone to insult at various levels. Firstly, the pathway from the superior vestibular nucleus through to the motoneurons of the superior rectus in the third nerve (the ventral tegmental tract) can be injured through pontine lesions (Figure 45.8, arrow 1). Hypoactivity of eye elevator muscles leads to downward drift of the eyes with corrective upbeating, i.e., upbeat nystagmus. The inhibitory pathway can also be damaged, leading to hyperexcitability of eye elevator motoneurons causing upward drift of the eyes with corrective downbeating, i.e., downbeat nystagmus. This can result from lesions to the flocculus directly (Figure 45.8, arrow 3) or to the caudal medulla (Figure 45.8, arrow 2) affecting the integrity of the inhibitory feedback mechanism.

Vertical downbeat nystagmus is associated with abnormalities of the vestibulocerebellum and can be caused by cerebellar degeneration, tumor, stroke, Chiari malformation (downward displacement of cerebellar tonsils), multiple sclerosis, or head trauma. Downbeat nystagmus can also be

Elevator muscles

Brainstem and

medulla

2

Caudal medulla

Cerebellar

flocculus

3

Figure 45.8  A hypothetical scheme to explain upbeat and downbeat nystagmus. Injury to (1) the ventral tegmental tract can lead to upbeat nystagmus. Damage to (2) the caudal medulla or the flocculus can cause downbeat nystagmus (based on data from references 59, 60, and 66).

caused by intoxication through substances such as lithium or anticonvulsants, and depletion of substances such as thiamine (Wernicke’s encephalopathy), vitamin B12 and magnesium.1 Upbeat nystagmus is associated with disorders of the medulla, pons, midbrain, and cerebellum as caused by stroke, tumor, cerebellar degeneration or demyelination (multiple sclerosis).

Acknowledgments

RE

LE

2°

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Figure 45.9  Acquired periodic alternating nystagmus (APAN). The lower traces indicate the change in nystagmus over the time course of several minutes for right (RE) and left (LE) eyes. The upper traces show expanded sections of data lasting 3 seconds (adapted from reference 72).

ablated cause APAN in animals. This is thought to be caused by abnormally exaggerating the time constant of the velocity storage mechanism. Causes of APAN include Chiari malformation, cerebellum dysfunction due to tumor, infection (e.g., syphilis) or degeneration, multiple sclerosis, and toxic effects of anticonvulsants and lithium.1

Conclusion

Nystagmus can result from an array of conditions leading to diverse but characteristic eye oscillations. The nature of these oscillations provides clues concerning the underlying pathogenesis; however, the majority of nystagmus forms are still poorly understood. It is likely that disturbances to sensory systems have an important role in the genesis of many infantile nystagmus forms: MLN, albinism, and nystagmus associated with retinal disease and low vision are all strongly allied with visual loss in some way. Acquired nystagmus forms are more commonly associated with motor dysfunction due to lesions imposed on oculomotor circuitry in the cerebellum and brainstem. Our understanding of the genetic basis of nystagmus and the mechanisms underlying nystagmus is rapidly becoming clearer. Clinically proven treatments for nystagmus are now beginning to emerge.

Acquired periodic alternating nystagmus

Acquired periodic alternating nystagmus (APAN) consists of a horizontal jerk nystagmus that is modulated so that the nystagmus goes through cycles of left-beating and rightbeating nystagmus, reversing about every 1–2 minutes (Figure 45.9). It appears to be caused by lesions of the cerebellar nodulus and uvula, which control the velocity storage mechanism.63,64,71 This is a neural mechanism that effectively expands the time course of signal from the semicircular canals, which decay rapidly during sustained rotations. Experimental models in which the nodulus and uvula are

Acknowledgments

We would like to acknowledge the contributions of Shery Thomas, Nagini Sarvananthan, Nitant Shah, Rebecca McLean, and Mervyn Thomas. We would like to thank the Nystagmus Network for their continued interest in and support for nystagmus research. We acknowledge the financial support of Ulverscroft Foundation, Medisearch, National Eye Research Centre and “Fight for Sight”. We would also like to thank the many willing volunteers who have assisted in these studies.

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