Central ocular motor disorders, including gaze palsy and nystagmus

An abnormal position of the head toward the right or left shoulder is observed particularly in patients with paresis of the oblique eye muscles (e.g., palsy of the trochlear nerve or the superior oblique muscle, in which the head is turned to the non-affected side to lessen diplopia), or in those with an ocular tilt reaction (OTR) due to a tonus imbalance of the VOR in the roll plane [7, 8]. In the OTR the head is tilted to the side of the lower eye. A tilting of the head to the side of the lesion indicates either an acute unilateral peripheral vestibular lesion or an acute unilateral central lesion in the medulla oblongata (e.g., in Wallenberg’s syndrome) [9]. A head tilt to the contralateral side occurs in pontomesencephalic lesions [10, 11].

When examining the patient, attention should be paid to the primary position of the eyes when the patient looks straight ahead, when one eye is covered or when each eye is covered alternately (alternating cover test), that is parallel position or horizontal or vertical misalignment. These tests allow diagnosis of latent or manifest strabismus. The prerequisite for all cover tests is the presence of foveal fixation.

In the one-eye cover test heterotropia (i.e. manifest strabismus) can be observed in the uncovered eye; the latter moves when the other eye is covered (Fig. 1). Heterotropia is defined as a misalignment of the visual axes, even during binocular fixation. First, the patient is asked to fixate either a near target (at a distance of 30–40 cm) or one 5–6 m away. Then the examiner covers one eye and looks for correction movements of the now uncovered eye. If the uncovered eye moves: (a) from the inside outward, esotropia is present; (b) from the outside inward, exotropia; (c) from above downward, hypertropia and; (d) from below upward, hypotropia. The other eye is then examined. An acute vertical divergence (so-called skew deviation; one eye is higher than the other) indicates a central lesion of graviceptive pathways as part of the so-called OTR.

The one-eye cover/uncover test is used to prove the presence of heterophoria (i.e. latent strabismus) (Fig. 1). This is a misalignment of the eye axes when a target is fixated with one eye only. It is important to perform the above-mentioned cover part of the test before the cover/uncover part to first exclude heterotropia. First, one eye is covered for about 10 s, then uncovered; the possible corrective movements of the previously covered eye are observed. If it moves: (a) outward, esophoria is present; (b) inward, exophoria; (c) downward, hyperphoria; and (d) upward, hypophoria.

This test is also useful to determine the maximum misalignment of the eye axes in both a tropia as well as a phoria. The alternating cover test is also helpful when establishing a vertical divergence/skew deviation (in the context of an OTR), i.e. a vertical misalignment of the eyes that cannot be explained by an ocular muscle palsy or damage to a peripheral nerve. In contrast to trochlear nerve palsy or superior oblique muscle palsy, in skew deviation as a component of the OTR the vertical misalignment changes little or not at all during different directions of gaze [12].

The magnifying lenses (+16 diopters) with light inside, on the one hand, prevent visual fixation, which typically suppresses a peripheral vestibular spontaneous nystagmus, and on the other, facilitate the observation of the patient’s eye movements (Fig. 2). The examination should include peripheral vestibular spontaneous nystagmus, head-shaking nystagmus (for this test the patient is instructed to turn their head quickly to the right and to the left about 20 times; then the eye movements are observed), positioning and positional nystagmus, as well as hyperventilation-induced nystagmus. Spontaneous nystagmus indicates a tonus imbalance of the VOR. If it is caused by a peripheral vestibular lesion, as in vestibular neuritis, the nystagmus is typically dampened by visual fixation, whereas central fixation nystagmus is not suppressed by fixation or may become even worse. Head-shaking nystagmus is due to a latent asymmetry of the so-called velocity storage of the VOR, which can be due to peripheral and central vestibular disorders. In a peripheral vestibular deficit, the head-shaking nystagmus beats toward the ear with intact labyrinthine function. So-called cross-coupling can occur in central cerebellar disorders: the horizontal head-shaking maneuver induces vertical nystagmus (see [1]).

The position of the eyes should be examined when the patient is looking straight ahead in the eight eccentric positions to look for: (a) a range of eye movements and thereby positional deficits of one eye (e.g., in cases of paresis of the ocular muscle with a misalignment of the axes of the eyes) or both eyes (e.g., in progressive supranuclear gaze palsy (PSP)); (b) gaze-evoked nystagmus (GEN; i.e. disorders of the gaze-holding function, described below); and (c) nystagmus, whether its intensity changes depending on the direction of gaze (e.g., in DBN an increase in intensity when looking to the right, left and downward, or in peripheral vestibular spontaneous nystagmus an increase when looking in the direction of the quick phase and a decrease when looking in the opposite direction (‘Alexander’s law’).

The examination can be performed with a small object for fixation or a small rod-shaped flashlight (Fig. 3). Using a small rod-shaped flashlight has the advantage that the corneal reflex images can be observed and thus ocular misalignments can easily be detected. It should be noted that it is important to observe the corneal reflex images from the direction of the illumination and to ensure that the patient attentively fixates the object. In the primary position one should first look for misalignment of the axes of the eyes and periodic eye movements, especially spontaneous nystagmus or so-called saccadic oscillations/intrusions. A nystagmus can be horizontal rotatory (typical for an acute vestibular neuritis), vertical downward or upward (DBN and UBN), or purely torsional. One should look for suppression of the nystagmus by visual fixation [typical for peripheral vestibular spontaneous nystagmus (see below)] or only slight suppression during fixation (or even an increase) of the intensity of the fixation (typical for central fixation nystagmus). Infantile/congenital nystagmus beats horizontally as a rule at various frequencies and amplitudes and increases during fixation.

Impaired visual fixation includes square-wave jerks (small saccades of 0.5°–5° with an inter-saccadic interval) which cause the eyes to oscillate around the primary position and are observed in progressive supranuclear palsy (PSP) or certain cerebellar syndromes. Other forms are ocular flutter (intermittent rapid bursts of horizontal oscillations without an inter-saccadic interval) or opsoclonus (combined horizontal, vertical and torsional oscillations also without an inter-saccadic interval) [13] which are not strictly forms of nystagmus but are so-called saccadic oscillations/intrusions. They occur in various disorders, for example, in brainstem encephalitis, tumors of the brainstem or cerebellum, intoxication, or most often in paraneoplastic syndromes.

The distinction between GEN (Fig. 3) and so-called end-point nystagmus is a widespread clinical problem. Many healthy subjects have physiological end-point nystagmus during maximal eccentric gaze. End-point nystagmus is pathological if it lasts for longer than 20 s (sustained end-point nystagmus), is notably asymmetrical, and/or is accompanied by other ocular motor disturbances [14].

GEN often allows a topographic anatomical diagnosis: (a) GEN in all directions occurs in cerebellar disorders, particularly impaired function of the flocculus/paraflocculus, and above all in neurodegenerative diseases, but can also be caused by drugs such as anticonvulsants, benzodiazepines or alcohol; (b) purely horizontal GEN can indicate a structural lesion in the area of the brainstem [nucleus prepositus hypoglossi, vestibular nuclei, and cerebellum (flocculus/paraflocculus)]—the neural integrator for horizontal gaze-holding function; (c) purely vertical GEN is observed in midbrain lesions involving the interstitial nucleus of Cajal (INC)—the neural integrator for vertical gaze-holding function; (d) dissociated horizontal GEN (greater in the abducting than the adducting eye) in combination with an adduction deficit is the sign of internuclear ophthalmoplegia (INO) due to a defect of the medial longitudinal fascicle (MLF), ipsilateral to the adduction deficit; (e) DBN usually increases when looking down, and especially to the side, most likely due to an additional gaze-holding deficit [15], so that the nystagmus beats diagonally downward in the sideward gaze (the cause of DBN is generally bilaterally impaired function of the flocculus/paraflocculus; (f) patients with GEN also often show a rebound nystagmus. To examine for so-called rebound nystagmus, the patient should gaze for at least 60 s to one side and then return the eyes to the primary position. This can cause a transient nystagmus to appear with slow phases in the direction of the previous eye position. Rebound nystagmus generally indicates damage to the flocculus/paraflocculus or cerebellar pathways.

The generation of smooth pursuit eye movements, which keep the image of an object stable on the fovea, involves diverse supra- and infratentorial structures: the visual cortex, medial temporal area, medial superior temporal area (MST), frontal eye fields (FEF), dorsolateral pontine nuclei, cerebellum (flocculus), and vestibular and ocular motor nuclei. These eye movements are influenced by alertness, a number of drugs and age. The patient is asked to track visually an object moving slowly in horizontal and vertical directions (10–20°/s) while keeping the head stationary. It is important that the subject is able to fixate the target. Corrective (catch-up or back-up) saccades are looked for; they indicate a smooth pursuit gain (ratio of eye movement velocity and gaze target velocity) that is too low or too high: a saccadic smooth pursuit in all directions indicates an impaired function of the flocculus/paraflocculus [e.g., in spinocerebellar ataxias, drug poisoning (anticonvulsants, benzodiazepines), or alcohol abuse]. However, marked asymmetries of smooth pursuit indicate a structural lesion. If the smooth pursuit is saccadic to the left, this indicates a left-sided lesion of the flocculus/paraflocculus.

First, it is necessary to observe spontaneous saccades, for instance, when taking patient history and when triggered by visual or auditory stimuli. The patient is then asked to glance back and forth between two horizontal and two vertical targets (Fig. 4). The velocity, accuracy and the conjugacy of the saccades should be noted: (a) normal individuals can immediately reach the target with a single fast movement or one small corrective saccade; (b) slowing of saccades in all directions—often accompanied by hypometric saccades—occurs, for example, in neurodegenerative disorders or with intoxication (and with medication, particularly anticonvulsants and benzodiazepines); (c) isolated slowing of horizontal saccades is observed in pontine brainstem lesions due to a dysfunction of the ipsilateral paramedian pontine reticular formation (PPRF); this can be caused by ischemia, bleeding, pontine gliomas but also in Gaucher disease type 3, the later stages of NP-C and PSP; (d) isolated slowing of vertical saccades indicates a midbrain lesion in which the rostral interstitial medial longitudinal fascicle (riMLF) is involved, as in ischemic or neurodegenerative diseases, especially progressive supranuclear palsy or inherited disorders such as NP-C (in the latter, typically first downward and then downward and upward because there is a double innervation for upward saccades from the riMLF [16]—a bilateral lesion of the INC impairs the range of all types of vertical eye movements and is accompanied by a vertical GEN, and a lesion of the posterior commissure (PC) also impairs all types of vertical eye movements and is associated with a convergence-retraction nystagmus (see [1])); (e) hypermetric saccades, which can be identified by a corrective saccade back to the object, indicate lesions of the cerebellum (especially the vermis) or the cerebellar pathways. Patients with Wallenberg’s syndrome make hypermetric saccades toward the side of the lesion and hypometric saccades toward the opposite side due to a dysfunction of the inferior cerebellar peduncle (conversely, defects of the superior cerebellar peduncle lead to contralateral hypermetric saccades); (f) a slowing of the adducting saccade ipsilateral to a lesion of the MLF is pathognomonic for INO; (g) delayed initiation of saccades is most often due to supratentorial cortical dysfunction affecting the frontal or parietal eye field (e.g., Balint’s syndrome) and is called ocular motor apraxia. Nowadays, the velocity of saccades can be quantified in clinical routine by video-oculography (Fig. 5), which also allows the detection of mild to moderate slowing of saccades that could be the first clinical sign of PSP, NP-C or Gaucher disease type 3.

Vergence is tested by moving a target from a distance of about 50 cm toward the patient’s eyes or the patient looks back and forth between a distant and a near target. Looking at a nearby target causes vergence, accommodation and miosis (i.e. the convergence reaction). Neurons that are important for the convergence reaction are in the area of the mesencephalic reticular formation and the oculomotor nucleus. This explains why the convergence reaction is disturbed in rostral midbrain lesions and tumors of the pineal region and thalamus, and why abnormalities of vertical gaze are often associated with these defects. In certain neurodegenerative disorders such as PSP, convergence is also often impaired.

Inborn defects of the convergence reaction also occur in some forms of strabismus. Convergence-retraction nystagmus can be provoked by inducing upward saccades or by looking at a moving optokinetic drum with its stripes going downward. Instead of vertical saccades, rapid convergent eye movements that are associated with retractions of the eyeball occur. The cause is damage to the posterior commissure or, in rare cases, a bilateral disorder of the rostral interstitial nucleus of medial longitudinal fasciculus (riMLF). A spasm of the near reflex is a voluntary convergence accompanied by pupillary constriction. The latter is an important clinical sign for the diagnosis. Occasionally, spasm of the near reflex is psychogenic; it can mimic bilateral abducens palsy.

The examination of eye movements with the optokinetic drum allows combined testing of smooth pursuit movements and saccades in horizontal and vertical directions (Fig. 6). It is especially helpful with uncooperative or drowsy patients and with children. Intact horizontal and vertical optokinetic nystagmus probably indicates intact function of the midbrain and the pons. One should look for: asymmetries (e.g., between right and left (indicates a unilateral cortical or pontine lesion); vertical worse than horizontal (indicative of a vertical supranuclear gaze palsy due to a mesencephalic lesion); dissociations of the two eyes (a sign of diminished adduction in INO); and reversal of pursuit (indicates congenital nystagmus).

The most common bedside test of the examination of the VOR is the head impulse test, which examines the VOR at a high frequency [17]. To test the horizontal VOR the examiner holds the patient’s head between both hands, asks him to fixate a target in front of his eyes, and very rapidly turns the patient’s head horizontally approximately 20–30° to the right and then to the left [18]. This is the most important bedside test for VOR function. In a healthy subject this rotation of the head causes rapid, compensatory eye movements in the opposite direction with the same angular velocity as the head movements, so that the eye position in space remains the same. In this way the target also remains stable on the retina. For instance, in unilateral right-sided labyrinthine failure the eyes move during head rotations with the head to the right, and the patient has to perform a so-called re-fixation saccade to the left to fixate the target again. This is the clinical sign of a deficit of the VOR (in the high frequency range) to the right. If the findings of the bedside test are unclear, the use of a video-based head-impulse test is indicated; this allows the gain of the VOR to be quantified [19].

Before testing the visual fixation suppression of the VOR, the examiner must be sure that the VOR is intact (see above). The patient is then asked to fixate a target in front of his eyes while turning his head as uniformly as possible with the same angular velocity as the target in front of the eyes, first horizontally and then vertically, back and forth at moderate speed. The examiner should watch for corrective saccades, which indicate a disorder of the visual fixation suppression of the VOR. If the visual fixation suppression of the VOR is intact, the eye position relative to the head position does not change, but if it is not intact (which is indicated by small corrective saccades and as a rule occurs with smooth pursuit abnormalities, as these two functions use the same neural pathways) this typically indicates lesions of the cerebellum (flocculus or paraflocculus) or of cerebellar pathways [20]. Drugs, particularly anticonvulsants, sedatives and alcohol can also impair visual fixation suppression of the VOR because of their effects on the cerebellum. It is important to note that, in the case of a concomitant bilateral vestibulopathy, visual fixation suppression looks normal because the VOR is not working.

The center for vertical saccades is the rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), and the center for vertical gaze-holding function (the vertical and torsional neural integrator) is the interstitial nucleus of Cajal (INC). It is important to note that a normal floccular function is also required for gaze holding. Clinically, this means that an isolated vertical saccadic paresis or isolated vertical gaze deviation nystagmus would suggest a midbrain lesion.

The center for horizontal saccades is the paramedian pontine reticular formation (PPRF); clinically this means that isolated horizontal saccadic palsy indicates a pontine lesion, and a unilateral PPRF lesion will result in saccadic disturbances on the side of the lesion. The center for the horizontal gaze-holding function is the nucleus prepositus hypoglossi together with the vestibular nuclei and the vestibulocerebellum (the horizontal neuronal integrator). Purely horizontal GEN originates from a pontine lesion.

Cerebellar lesions are often accompanied by easily clinically identifiable ocular motor disturbances. For example, defects of the flocculus/paraflocculus are characterized by saccadic pursuit, DBN, and impairments of the visual fixation suppression of the VOR (Table 2b). Lesions of the ocular motor vermis (Lobulus VII) and the fastigial nucleus lead to saccadic dysmetria, whereas nodulus/uvula lesions can induce periodic alternating nystagmus. Paraneoplastic cerebellar disorders often lead to opsoclonus (see above) in addition to the ocular motor disturbances mentioned above.

Niemann–Pick disease type C (NP-C) is an autosomal recessive neurovisceral disorder caused by mutations in either the NPC1 or the NPC2 gene (see [22]). The estimated disease incidence is 1:120,000 live births, but may be higher, as the disease is probably under-diagnosed due to its heterogeneous presentation [23]. NP-C is characterized by visceral, neurological and psychiatric manifestations that are not specific to the disease as they are often observed in other diseases. Sufferers accumulate massive amounts of cholesterol and other lipids in the late endosome/lysosomal compartment caused by a defect in intracellular lipid trafficking; cholesterol accumulation mainly occurs in the peripheral organs, while glycosphingolipids principally accumulate the central nervous system. These alterations in lipid storage lead to organ enlargement cell functional impairment, with subsequent cell loss [24, 25].

Vertical saccade paresis (Fig. 8) may be present before the internal, neurological or psychiatric manifestation and is sometimes the only symptom of NP-C in adults [26], thus representing a ‘red flag’ signaling the need for further diagnostic work-up. Initially, slow vertical saccades, especially downwards, often accompanied by horizontal oscillations (as an expression of activation of the intact horizontal saccade system) and frequent blinking occur. The other ocular motor systems may also be affected to varying degrees. Vertical optokinetic nystagmus, as tested by an optokinetic drum, is often absent. At the beginning of the disease, smooth pursuit might be intact. As the disease progresses, complete vertical gaze palsy with the inability to look upward or downward occurs [27‐29]. The VOR is often preserved until very late, indicating that the gaze palsy is truly supranuclear in nature [16]. The pathological vertical saccades, which are the first indications of this disease, may be overlooked in a superficial examination due to the initial discrepancy between smooth pursuit and saccades. Therefore, a detailed and careful neuro-ophthalmological examination is crucial for the diagnosis of inherited disorders.

Early identification of NP-C and the appropriate application of symptomatic and disease-specific therapies can dramatically improve the quality of life of these patients. Visceral manifestations comprise neonatal jaundice during infancy, present in 39 % of patients; hepatomegaly during infancy in 39 %; and splenomegaly in 54 % [30]. However, in adulthood, hepatosplenomegaly may be very mild and is not always present. Neurologically, the disease manifests with clumsiness and frequent falls as an expression of stance and gait ataxia, changes in muscle tone leading to dystonia, myoclonus, epilepsy, dysarthria, and dysphagia. Cognitive impairment is one of the most consistent neurological findings, reported in 60–70 % of patients across all age-at-onset categories. Impaired cognition frequently manifests in poor school performance in juveniles and adolescents and, as NP-C progresses, patients experience a general decline leading to dementia in many cases. In younger-onset patients, NP-C is more likely to be identified initially as developmental delay [30]. So-called gelastic cataplexy—a sudden loss of muscle tone especially in emotional situations such as laughing or crying—is a pathognomonic symptom that is sometimes present in children.

Establishing a diagnosis of NP-C in adults can be difficult as the disease may only manifest psychiatrically in the form of schizophrenia-like psychosis, but psychiatric disorders such as depression or bipolar disorder have also been described [31]. The diagnostic algorithm encompasses biochemical examination of plasma chitotriosidase activity and oxysterol levels, as well as filipin staining of patient skin fibroblasts, molecular-genetic examination by NPC1 and NPC2 gene sequencing, and abdominal ultrasonography [32].

Therapy with miglustat 200 mg t.i.d. has been shown to stabilize the neurological manifestations of the disease, and it has been suggested that early therapy in affected children may halt or slow neurological disease progression [32‐35].

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by the absence of the enzyme glucocerebrosidase, leading to accumulation of glucocerebroside in tissue macrophages [36]. GD is classified as GD1 (non-neuronopathic), GD2 (acute neuronopathic), and GD3 (chronic neuronopathic) depending on the presence of neurological deterioration, age at identification and disease progression rate. The chronic neuronopathic form (GD3) may be divided into three subtypes: type 3a has a fulminant neurological course complicated by myoclonic seizures but with mild visceral involvement; type 3b has severe visceral symptoms and signs such as massive hepatosplenomegaly, moderate to severe kyphosis, but no neurological involvement; and type 3c is characterized by mild visceral involvement, mild kyphosis and life-threatening progressive heart valve calcification.

GD3 is associated with a severe slowing of the horizontal saccades, which leads progressively to horizontal supranuclear palsy with impairment of all horizontal eye movements including smooth pursuit and the VOR [37]. To compensate for the deficits of the horizontal saccades, patients perform torsional saccades as an expression of compensation by the initially intact vertical saccade system. The other compensatory mechanism is the VOR: the head is quickly rotated to the contralateral side, bringing the eyes to the desired position. This manifests clinically as fast thrusting head movements (differential diagnosis: Cogan syndrome, see below). As the disease progresses, a vertical saccade palsy may also develop.

Testing of enzyme activity in leukocytes, genetic testing, and abdominal ultrasonography represent a clinical standard to establish the diagnosis of GD. Disease-specific enzyme replacement therapy (ERT) with intravenous infusions of the enzyme imiglucerase 5–60 IU/kg for 2 weeks, or alternatively taliglucerase or velaglucerase alfa improves disease symptoms and outcomes in patients with non-neuronopathic Gaucher disease type 1, but published data on the treatment of GD3 are very limited, primarily because these large protein-based therapies do not cross the blood–brain barrier [38]. The efficacy of the oral substrate reduction therapy (SRT), miglustat, in GD3 has been evaluated in one randomized, controlled clinical trial as miglustat is a small molecule that is able to access the CNS, but findings were inconclusive with regard to beneficial effects on neurological symptoms [39]. A second oral SRT, eliglustat, is currently under clinical development but has been shown not to cross the blood–brain barrier and, as with ERT, is therefore not expected to be of therapeutic use for neuronopathic GD [40]. Treatment with the chaperone, ambroxol, has also been shown to restore enzyme activity in vivo, leading to clinical improvements [41].

Tay–Sachs disease (TS) is an autosomal recessive, predominantly cerebellar disease of the sphingolipid metabolism caused by a beta-hexosaminidase A deficiency with a subsequent accumulation of GM2 gangliosides in organ systems including the central nervous system. The disease manifests in early childhood (in the case of homozygotes with full enzyme deficiency), although in heterozygotes (normally G269S mutation) with residual beta-hexosaminidase A activity (late-onset Tay–Sachs [LOTS]), the first disease symptoms occur in adolescence (mean age 18.1 years) [42]. Clinical presentations feature a range of neurological signs that are not specific to the disease, with the functional impairment of primary motor neurons expressed in spastic stance and gait combined with secondary motor neuron impairment, leading to muscle atrophies with fasciculations and consecutive fatigue. Furthermore, patients present with cerebellar ataxia with postural instability, and extrapyramidal symptoms. Psychiatric disorders, including psychotic episodes, depression, and cognitive decline, may occur as part of the clinical picture [43, 44]. Previous MRI studies have shown cerebellar atrophy as a morphological correlate [43].

In terms of ocular motor deficits, patients demonstrate hypometric saccades with a distinctive saccade abnormality consisting of abrupt fluctuations in saccade velocity with premature termination (in general, velocity does not decrease below 50°/s). In general, saccades stop sooner and faster in LOTS patients. Moreover, lower smooth pursuit gain and a reduction of the slow phase of the optokinetic nystagmus may occur. Currently, there is no disease-specific therapy. Treatment with pyrimethamine, up to a maximum of 75 mg/day, which is believed to increase hexosaminidase A activity, has induced a discrete improvement of dysarthria, dysthymia and fall frequency [45].

ISID is characterized by the inability to initiate saccades on command [46]. Saccades are prolonged and hypometric, and reflexive saccades, including the quick optokinetic and VOR phases, may also be impaired [47]. In contrast, saccadic velocity is normal. Head thrust and thereby the VOR act as a compensatory mechanism using the VOR to initiate saccades, which is present in 85 % of patients, and is characteristic of this disease. Blinking without the VOR initiates saccades in 41 % of cases reported to date [47]. The saccadic impairment is not isolated, as smooth pursuit is impaired in around 33 % of cases. This, in combination with the reported developmental delay, hypotonia and speech disturbances in these children, indicates a complex impairment of the central nervous system. The term ‘ocular motor apraxia’ should not be used, because saccades on command and reflexive saccades are disturbed. In apraxia, reflexive saccades should be intact.

AOA1 is an autosomal recessive disease characterized in all cases by the presence of cerebellar ataxia, cognitive impairment, and high-grade sensorimotor polyneuropathy. In some cases, AOA1 is also associated with ocular motor apraxia (86 %), hypoalbuminemia, and hypercholesterolemia. The disease manifests between 2 and 18 years (mean age at onset 6.8 years). Saccades are prolonged and may imitate slow saccades but, in fact, hypometric saccades are elicited [48].

Ocular motor apraxia type 2 (AOA2) is an autosomal recessive cerebellar ataxia with a typical age at onset between 3 and 30 years, and characterized by high-grade axonal sensorimotor neuropathy, ocular motor apraxia and a high alpha-fetoprotein concentration. Saccades are hypometric with a typical staircase pattern. The VOR in the form of head thrusts may be used as a compensatory mechanism [49, 50].

Spinocerebellar ataxia type 2 (SCA 2) belongs to the family of autosomal dominant diseases. SCA 1, 2, 3, 6, 7 and 17 and dentatorubral-pallidoluysian atrophy are caused by an expansion of a polyglutamine (polyQ)-coding CAG triplet within the respective genes [51, 52]. SCA 2 is a ‘cerebellar plus’ syndrome which manifests with cerebellar ataxia with postural instability, uncoordinated stance and gait, dysmetria, dysarthria, dysphagia and dysdiadochokinesia [53]. Moreover, an l-Dopa-responsive akinetic-rigid syndrome might be present in some cases. Retinitis pigmentosa (gradual loss of retinal epithelium with initial night blindness, and progression to total blindness; pigmentation of the retina is typical) and myoclonic epilepsy could be part of the clinical picture. Moreover, patients show an action and postural tremor, peripheral neuropathy with early-onset areflexia of the upper extremities, executive dysfunction and cognitive decline.

Regarding eye movements, patients with SCA 2 exhibit early and dominant slowness of the horizontal saccades up to complete saccade paresis; vertical saccades are also impaired [54]. One prospective ocular motor study found that absence of GEN or dysmetric saccades in these patients has a high negative predictive value for the presence of SCA 2 [55]. Proper saccade generation is necessary to evoke GEN, and for performance of correcting hypo-/hypermetric saccades, while in the case of saccade impairment, the correcting saccades cannot be performed. It is not possible to distinguish between different types of spinocerebellar ataxia on the basis of the ocular motor examination. However, in some cases, such as in SCA 3, saccadic intrusions as well as saccadic oscillations in the form of square-wave jerks (short eye movements with an inter-saccadic interval), or ocular flutter (horizontal oscillations without an inter-saccadic interval) help to establish the diagnosis with targeted genetic testing. DBN, vertical positional nystagmus, as seen in positioning maneuvers, and abnormal head-shaking nystagmus (vertical nystagmus elicited by horizontal head shaking) are pathognomonic for SCA 6.

Spinocerebellar ataxia type 7 (SCA 7) is characterized by severe cerebellar atrophy and retinal dystrophy with initial yellow–blue blindness, which usually progresses to total blindness due to retinitis pigmentosa. The neurological manifestation comprises high-grade ataxia and dysarthrophonia, dysphagia, pyramidal signs, pathological somatosensory responses (pathological somatosensory evoked potentials in terms of sensory-axonal polyneuropathy), pathological acoustic evoked potentials (AEP), or pathological visual evoked potentials (VEP) with P100 wave loss.

Anatomical studies have shown severe cerebellar degeneration and region-specific neocortical atrophy in SCA 7 patients [56]. Functional imaging has shown reduced functional interaction between the cerebellum and the middle and superior frontal gyri, and disrupted functional connectivity between the visual and motor cortices compared with healthy controls. With respect to eye movements, patients with SCA 7 have slow (especially horizontal) saccades. However, other ocular motor signs are unspecific and allow no specific differentiation of this disease from the other types of cerebellar ataxia [52]. Therapy of ataxia is symptomatic as no disease-specific therapy exists. For the treatment of different types of cerebellar ataxias, a positive effect of acetyl-dl-leucine 5 g/day on stance and gait stability, fine motor skills, and tremor was demonstrated in terms of an improvement in cerebellar ataxia rating scores was described [57]. Therapy with the potassium channel blocker, 4-aminopyridine, at doses of 5 mg t.i.d. under regular ECG checks (a prolonged QT is a possible side effect) might be considered to treat the ocular motor abnormalities, especially if DBN is present (see [58]). If diplopia is present, prism goggles might be used.

Mutations in mitochondrial DNA (mtDNA) lead to multisystem symptomatology with a heterogonous manifestation dependent on the organ system and the number of mutated mitochondria in cells [59]. If all the mtDNA molecules present in a cell are identical (all wild type or all carrying a mutation), this condition is known as homoplasmy. When mtDNA with different sequences (pathogenic or not) are present in a single cell, the condition is known as heteroplasmy. The latter is common for pathogenic mutations, as only a portion of the cellular mtDNA content is affected. Heteroplasmy is a major factor that determines the clinical severity of mitochondrial diseases because mitochondrial function only begins to be affected when there is a relatively high number of mutated mtDNA compared to wild type, usually N > 70–80 % [15]. This phenomenon is known as the ‘threshold effect’ and it can vary depending on the mutation, the cell type, the tissue or even the affected individual. Heteroplasmy can be dynamic, changing during the lifetime in both mitotic and post-mitotic tissues due to cell cycle-independent mtDNA replication.

Chronic progressive external ophthalmoplegia (CPEO) begins in young adulthood (mean age 17.5 years without further symptoms) [59]. The cardinal symptom is conjugated horizontal and vertical gaze palsy (symmetrical impairment of external eye muscles) [59]. Initially, horizontal as well as vertical saccades are very slow; the saccade latency is prolonged. Patients suffering from diplopia or oscillopsia [60] present with asymmetrically affected eye muscles when the eye axes are not aligned. The disease progresses, as the name suggests, to complete ophthalmoplegia; ‘staring eyes’ with no possible eye movement are typical. The gaze palsy is associated with a bilateral, usually symmetrical ptosis. Gains of VOR and smooth pursuit are also reduced [61]. CPEO is often isolated and represents the mild variant of complex mitochondrial disorder. When other symptoms are also present (e.g., weakness of the oropharyngeal muscles with related speech and swallowing difficulties), it is referred to as CPEO plus syndrome. Moreover, weakness of proximal muscles and muscle cramps occurs during physical activity. Volumetric brain measurements revealed cortical and cerebellar atrophy as a morphological correlate of ocular motor disturbances.

Progressive external ophthalmoplegia is a part of Kearn–Sayre syndrome, a multisystem disorder with central nervous system involvement caused by a large-scale mtDNA deletion. Onset before 20 years of age, cerebellar ataxia, pigmentary retinopathy (usually rod-cone dystrophy), and in some cases, cardiac conduction block (usually the cause of death in young adulthood) and elevated cerebrospinal fluid protein level are typical for this syndrome [62]. Other neurological problems may include proximal myopathy, exercise intolerance, ptosis, oropharyngeal and esophageal dysfunction, sensorineural hearing loss, dementia, and choroid plexus dysfunction resulting in cerebral folate deficiency. Moreover, CPEO may be present in MELAS syndrome (mitochondrial myopathy, encephalopathy, lactate acidosis and stroke-like episodes), MERRF syndrome (myoclonic epilepsy with ragged red fibers), or ARCO syndrome (autosomal recessive cardiomyopathy, ophthalmoplegia).

Whipple’s disease (WD) is a rare chronic poly-systemic infection by a Gram-positive bacillus, Tropheryma whipplei (T. whipplei) and represents an important differential diagnosis for PSP. Ocular motor symptoms include initial vertical gaze palsy, with later horizontal gaze palsy and the picture of complete ophthalmoplegia (with impaired saccade and smooth pursuit systems). This symptomatology may develop within months. In PSP patients, horizontal saccades are usually hypometric and slow, but complete horizontal gaze palsy is rather rare. Moreover, PSP patients develop square-wave jerks, which are absent in WD patients. In a study with 18 WD patients [63], 17 % developed complete ophthalmoplegia. Part of the clinical picture is a systemic symptomatology, such as gastrointestinal symptoms, weight loss and, in the majority of cases, transient, recurrent and roughly symmetric polyarthralgia or nonerosive polyarthritis.

The neurological manifestations of the disease are diverse and can mimic almost any neurological condition. They include cerebellar ataxia and extrapyramidal signs presented in a different pattern than in PSP: absence of rigidity and normal gait and balance functions are typical for WD patients. Oculomasticatory myorhythmia (eye pendular vergence oscillations with a frequency of 1 Hz and concurrent contractions of the masticatory muscles) is rare, but pathognomonic [64]. Moreover, agrypnia excitata, a condition of severely reduced or absent sleep due to organic disorders with generalized motor and autonomic hyperactivation related to dysfunction in the thalamo-limbic circuits, occurs. Tremor, postural instability, dystonia, myoclonus, cognitive deficits, and delirium, progressing to coma and epileptic seizures may also be present. The diagnosis can be confirmed by the polymerase-chain reaction of all body samples as well as by immunohistochemistry methods. Therapeutically, treatment with trimethoprim–sulfamethoxazole and—in complicated cases—in combination with third-generation cephalosporins or doxycycline is indicated [65].

DBN is the most common form of persistent nystagmus. It is a type of fixation nystagmus with the fast-phase beating in a downward direction. It generally increases when looking to the side and down and when lying prone. DBN manifests in 80 % of patients with uncertain posture and gait and in 40 % with vertical oscillopsia [66], and is usually due to a bilateral defect of the cerebellar flocculus [69]. The causes are degenerative disorders of the cerebellum, cerebellar ischemia, or Arnold–Chiari malformation. In some cases, it can be caused by paramedian lesions of the medulla oblongata.

The defect of the flocculus will result in reduced release of gamma-aminobutyric acid (GABA) and thus, the disinhibition of the vestibular nuclei. On the basis of this pathological mechanism, a prospective, randomized, placebo-controlled study of the effects of aminopyridines has indicated a significant improvement of symptoms [68], and the observed effects have since been supported by findings from other studies [70, 71]. The strongest effect was observed in patients with cerebellar atrophy [63]. Currently, 4-aminopyridine 2 × 5–2 × 10 mg/day is recommended off-label for therapy. However, such off-label medication should always be undertaken based on clinicians’ judgment of potential risks versus benefit, and with a control ECG performed 1 h before and after the first ingestion of the drug. The QTc interval should not be prolonged. Since the drug only has a symptomatic effect, continuous treatment is required. The stipulated mechanism of action is an increase in the resting activity and excitability of Purkinje cells; this was confirmed by in vitro studies [72]. Animal studies have also shown that aminopyridines synchronize the irregular spontaneous activity of Purkinje cells [73]. By means of an increased release of GABA, this is assumed to strengthen the inhibitory influence of Purkinje cells on vestibular/cerebellar nuclei.

Upbeat nystagmus (UBN) is rarer than DBN and is also a fixation nystagmus. In primary position, the UBN beats upward. Oscillopsias are often very irritating, but the symptoms are usually transient. In most cases, paramedian lesions in the medulla oblongata or the midbrain are found, for example, in patients with multiple sclerosis, brainstem ischemia or tumors, or Wernicke’s encephalopathy [19]. Observational studies have shown a positive effect of baclofen (15–30 mg/day) [74] and 4-aminopyridine (5–10 mg/day) [75].