Current Opinion in Neurology:
NEURO-OPHTHALMOLOGY AND NEURO-OTOLOGY: Edited by Francois-Xavier Borruat and Michael Strupp
Saccadic intrusions: review and update
Lemos, João; Eggenberger, Eric
Department of Neurology, Coimbra University Hospital, Coimbra, Portugal
Correspondence to Eric Eggenberger, DO, MSEpi, Department of Neurology & Ophthalmology, Michigan State University, 804 Service, A217 Clinical Center, East Lansing, MI 48824-313, USA. Tel: +1 517 884 2276; e-mail: email@example.com
Purpose of review: This work reviews saccadic intrusions focusing on recent developments in pathophysiology and treatment.
Recent findings: Saccadic intrusions have been recognized as features of oculomotor apraxia type 2 and neuromyelitis optica. Novel fixation instabilities have been identified such as ‘staircase’ square wave jerks, or the pervasive ocular microtremor seen in Parkinson's disease. Although evidence supports a network underlying the pathophysiology of square wave jerks involving cerebral hemispheres, subcortex, brainstem and cerebellum, the debate regarding the pathogenesis of ocular flutter and opsoclonus centres on a cerebellar and brainstem hypotheses. The cerebellar hypothesis explains functional imaging findings, whereas the brainstem hypothesis provides possible explanations for some therapeutic responses as well as accompanying myoclonus, startle and tremor. A study of immunotherapies in children with opsoclonus-myoclonus syndrome found that treatment combinations were more effective than corticotropin alone.
Summary: Recognition of saccadic intrusions can assist in the diagnosis of neurological disease. We are gaining new insights about pathogenesis through models, functional imaging and genetic approaches.
Normal ocular fixation is never completely stable, with frequent small involuntary eye movements including saccadic intrusions and fixational eye movements. Although some of these may be seen in normal individuals, others are pathologic and illustrative of cerebral pathophysiologies. Saccadic intrusions are involuntary conjugate saccades (fast eye movements) that interrupt fixation (Fig. 1) . Saccadic intrusions have a larger amplitude (usually >0.5°) than miniature fixational eye movements (microsaccades, tremors and drifts), the latter are believed to help visual perception during fixation, preventing visual adaptation  and correcting fixation [3▪▪], although this differentiation is progressively becoming tenuous [3▪▪,4–6]. Saccadic intrusions are called intrusions due to their sporadic character, but when their occurrence is continuous, they should be considered oscillations (saccadic oscillation) . Although saccadic intrusions may be found in healthy individuals, they also accompany certain neurological disorders (usually manifesting higher frequency and/or amplitude) reflecting dysfunction of brainstem, cerebellum, superior colliculus, basal ganglia and/or cerebral hemispheres . We may distinguish two groups of saccadic intrusions by the presence or absence of an intersaccadic interval (ISI), a latent period that usually lasts 180–200 ms between sequential saccades. Novel fixation instabilities have been reported [8▪▪,9▪▪,10,11,12▪,13] and recent attempts to tackle saccadic intrusions terminology and phenomenology have been made as well [4,14].
Below, we review each type of saccadic intrusion, focusing on recent developments, and subsequently, we present an update to the treatment of these disorders.
Saccadic intrusions can be divided into two broad categories on the basis of the presence or absence of a normal intersaccadic interval.
SACCADIC INTRUSIONS WITH INTERSACCADIC INTERVALS
Saccadic intrusions with a normal intersaccadic interval include square wave jerks (SWJs), square wave pulses (SWPs), macrosaccadic oscillations and saccadic pulses.
Square wave jerks
SWJs are the most common type of saccadic intrusions  and consist of small conjugate couplets of horizontal back-to-back saccades ranging from 0.5° to 5°, taking the eye from the fixation point and then return it after a normal length intersaccadic interval of about 200 ms (Fig. 1) . Oscillopsia is uncommon in SWJ . Occasional SWJs often occur in healthy elderly patients; however, certain features of saccadic intrusions alert the physician to the presence of a neurological dysfunction. Several conditions including Huntington chorea [15,16], progressive supranuclear palsy (PSP) [3▪▪,17], Friedereich ataxia [18–20] and cerebral hemispheric disease [21,22] harbour pathologic saccadic intrusions such as:
1. frequent SWJ, also called square wave oscillations (9–16 per minute or >20 per minute in the dark) [23,24],
2. SWJ larger than 5°  and
3. multiplanar and disconjugate saccadic intrusion .
SWJs have recently been described or further characterized in a few other diseases, including oculomotor apraxia type 2 [25▪], chorea–acanthocytosis , Langerhan cell histiocytosis , Friedreich ataxia [18,19] and motor neurone disease .
Although some studies [17,28–30] have suggested that Parkinson's disease is associated with an increased rate of SWJ, others disagree with this and suggest that ocular fixation deficits in Parkinson disease (PD) patients may be related to persistent ocular tremor; this small amplitude oscillation has been proposed as a potential physiological biomarker for the diagnosis of PD [9▪▪]. Challenging the traditional view that a SWJ amplitude higher than 1° is characteristically more frequent in PSP and multisystem atrophy (MSA) or Parkinson-plus syndrome than in PD, Shaikh et al. [8▪▪] recently provided evidence of large SWJ (mean amplitude 2°) in a small group of patients with early PD. Otero-Millan et al. [3▪▪] replicated results from prior studies emphasizing more frequent [29,30] and larger [9▪▪,30] SWJs characterize PSP and also demonstrated that abnormally large microsaccades were the best distinguishing feature between PSP patients and controls, reinforcing the role of miniature fixational eye movements as possible biomarkers.
A potential role of cerebellum in the generation of SWJ has been emphasized by several studies. This includes notation of the simultaneous occurrence of SWJ and downbeat nystagmus (’bow tie’ nystagmus) in patients who share similar cerebellar cortical disease such as spinocerebellar ataxia type 6 (SCA6) and familial cortical myoclonic tremor with epilepsy (FCMTE) . An increased incidence of SWJ has been reported in patients suffering from ataxia with ocular apraxia type 2 (AOA 2) [25▪]. Further, frequent SWJs were observed in a case of Langerhan histiocytosis .
An increase in saccadic intrusion amplitude and/or frequency generally correlates with the severity of neurological disorders. According to Donaghy et al. , the larger the amplitude of saccadic intrusion, the more pronounced the impairment in measures of frontal lobe dysfunction in motor neuron disease patients supporting previous evidence that saccadic intrusion can also arise from the involvement of frontal–collicular pathway dysfunction. Similarly, in children and adolescents with Arnold Chiari type 2 malformation, the duration of SWJ correlated with the number of shunt revisions in those patients who underwent surgery for hydrocephalus .
The underlying mechanism of pathological SWJ is still unclear. One theory holds that pathologic SWJs represent a dysfunctional inhibitory system (basal ganglia, cerebellum, cerebral hemispheres or superior colliculus), which is no longer suppressing unwanted saccades by reinforcing omnipause neurons (OPNs) inhibition . Alternatively, pathologic SWJ may be a larger variant of fixational eye movements such as microsaccades [3▪▪,5,6,34,35▪▪,36▪▪,37]. In addition, they might constitute the influence of attentional shifts superimposed on a normal saccadic system possibly through increased neural activity involving the superior colliculus [6,38,39]. This issue remains uncertain, and these hypotheses are not mutually exclusive.
Square wave pulses
Commonly known as macro-SWJ , SWPs are similar to SWJ in their morphology and conjugacy, but they usually oscillate on one side of fixation , have an higher amplitude (usually greater than 5°) and a distinctive shorter ISI (about 80 ms) (Fig. 1) . The term SWP has been proposed to emphasize the potential importance of the intersaccadic interval over the saccadic intrusion amplitude in distinguishing SWP from typical SWJ. Constituting a rare type of saccadic intrusion, SWP may be seen in multiple sclerosis (MS) [40,41▪], PSP  and MSA . In contrast to SWJ, they are not seen in healthy individuals. They probably reflect an anomalous input from superior colliculus or fastigial nucleus to OPN and/or a disorder of gamma-amino butyric acid (GABA)-mediated synaptic inhibition from substantia nigra pars reticulata (SNpr) to superior colliculus [43,44].
Macrosaccadic oscillations share a similar duration intersaccadic interval with SWJ, but occur in bursts of conjugate and mainly horizontal saccades that increase and then damp in amplitude, oscillating around a fixation point (Fig. 1) . Midline cerebellar disease affecting fastigial nucleus is among the most frequent causes of MSO [45,46]. Brainstem lesions can also promote MSO possibly related to dysfunction of the afferent pathways to OPN, originated either in superior colliculus or fastigial nucleus [47,48]. It is unclear whether microsaccades also trigger MSO [2,46], or whether disruption of cerebellar mossy fibres hypothesized to occur in spinocerebellar ataxia with saccadic intrusions (SCASI) patients reduce inhibition on the deep nuclei .
Saccadic pulses are brief saccadic intrusions that take the eye from the fixation point, being immediately followed by a slow glissadic drift that returns them to the previous position (Fig. 1) . They may be single saccadic pulse (SSP) or double saccadic pulse (DSP), the former being in fact a pair of back-to-back saccades without an ISI . Saccadic pulse may occur in runs or as doublets, usually in pathological states such as MS [50,51] and posttraumatic lesions . Saccadic pulse might result from lack of eye position error feedback, damage to neural integrator structures and impaired supranuclear control of omnipause cells .
SACCADIC INTRUSIONS WITHOUT INTERSACCADIC INTERVALS
Saccadic intrusions without a normal intersaccadic interval include ocular flutter and opsoclonus.
Ocular flutter and opsoclonus
Ocular flutter consists of back-to-back horizontal conjugate saccades without an ISI, limited to one plane (usually horizontal), with amplitude ranging from 1° to 5° and rate 10–25 Hz (Fig. 1) . Rarely, it can be unidirectional  or positional [12▪]. Opsoclonus shares the same properties as ocular flutter, but has multidirectional saccades of varying amplitudes (Fig. 1); opsoclonus is more frequently continuous and may be accompanied by ataxia, encephalopathy and myoclonus (nonepileptic involuntary jerks of the limbs and trunk), hence the term ‘opsoclonus–myoclonus syndrome’ (OMS) . Contrary to the saccadic intrusion discussed so far, ocular flutter and opsoclonus often cause oscillopsia and blur [7,33,52–55].
The cause of ocular flutter and opsoclonus includes parainfectious brainstem encephalitis, metabolic toxic states, demyelinating diseases, inherited disorders and paraneoplastic conditions (primarily neuroblastoma in children, and small cell lung carcinoma, breast carcinoma or ovarian carcinoma in adults), although in many cases, the cause remains unknown. Anecdotally, opsoclonus and/or ocular flutter have been recently been reported in a presumed case of neuromyelitis optica [56▪], hepatitis C infection , Krabbe disease [12▪], amyotrophic lateral sclerosis  and locked-in syndrome .
Paraneoplastic and idiopathic ocular flutter and opsoclonus is probably mediated by heterogeneous B and T-cell immune mechanisms [60,61]; associated antibodies may include anti-rostral interstitial, antiamphiphysin [62,63], anti-N-methyl-D-aspartate receptor (anti-NMDAR) , antiganglioside Q1b  and antiglutamic acid decarboxylase (anti-GAD) antibodies .
In a prospective case–control study of 132 children, Pranzatelli et al.[67▪▪] observed that 35% of OMS patients had cerebrospinal fluid (CSF) oligoclonal bands (OCBs), with higher frequency in severe cases (56%). Despite this finding, the presence of OCB did not correlate with previous or subsequent relapses, OMS duration or neuroblastoma detection [67▪▪]. B cell-attracting C-X-C motif chemokine 13 (CXCL13), an inflammatory chemokine, may function as a biomarker of disease activity and treatment response, as shown in a prospective, case–control study enrolling 289 symptomatic OMS patients. CSF CXCL13 concentration was 16.5-fold higher in untreated OMS than controls, relating directly to OMS severity and inversely to OMS duration [68▪▪].
The prognosis of children with OMS is often suboptimal with or without neuroblastoma, and about 80% of reported cases have neurological sequelae [69,70]. A recent retrospective study [71▪▪] of 101 patients found that very young children at disease onset with severe initial symptoms seem to ultimately predict a chronic-relapsing disease course with neurobehavioural sequelae. In contrast to the effect in children, idiopathic OMS in adults is usually monophasic and patients often make a good recovery. Adults with paraneoplastic OMS are usually older than the idiopathic group and display a worse outcome, especially without antineoplastic therapy .
The pathophysiology of ocular flutter/opsoclonus has been a matter of dispute, encompassing two main theories: the brainstem and the cerebellar theory. The brainstem theory states that saccadic oscillations primarily arise from alterations in the membrane properties of saccadic burst neurons, which makes them prone to excessive postinhibitory rebound (PIR) excitation after sustained inhibition from OPN or alternatively from the malfunction of glycine receptors (GlyRs) causing a reduction in efficacy of OPN inhibition . Therefore, either an increase in neuronal excitability or a reduction of OPN inhibition can cause instability or oscillations [72–74]. This theory, with the help of a neuromimetic model (a model that more accurately represents brain structure and activation patterns taking into account neural signals and their encoding, at both the single neuron and population level), has become the basis to explain:
1. a rare, presumably genetic–inherited disorder evidencing microsaccadic oscillations accompanying limb tremor (mSOLT) ,
2. patients with ataxia–telangectasia exhibiting saccadic intrusions/oscillations and limb tremor ,
3. the presence of multidirectional microsaccadic oscillations in a patient with Still disease ,
4. marked saccadic oscillation in a patient following surgical resection of the fastigial nucleus ,
5. associated features such as tremor  and cervical dystonia  and
6. the coexistence not only of myoclonus but also exaggerated startle response in a patient with OMS [78▪].
Despite this, Iizuka et al.[79▪▪] were unable to document the presence of GlyR antibodies in any of 13 patients they studied with opsoclonus and ocular flutter, highlighting the complexity and possibility of other antibodies or immune factors involved in this condition.
The cerebellar theory relies on a different model on the basis of dysfunctional cerebellar Purkinje cells incapable of exerting inhibitory influence on the fastigial nucleus, thus reinforcing OPN inhibition and rendering saccadic burst neurons free to oscillate . This has been corroborated by recent case reports of OPS documenting dysfunctional cerebellar Purkinje cells by either single photon emission computed tomography  or functional MRI . Similarly, ocular flutter has recently been shown to correlate with hypermetabolism of deep cerebellar nuclei in a 18F-fluoro-2-deoxyglucose PET [83▪]. In 2012, the first heterozygous missense mutation and a large deletion in the potassium channel tetramerization domain containing 7 (KCTD7) gene were reported in a patient with a clinical syndrome including OMS and progressive myoclonic epilepsy (PME), reinforcing the role of cerebellum in the pathophysiology of saccadic oscillations [80,84▪].
TREATMENT OF SACCADIC INTRUSIONS (AND OSCILLATIONS)
SWJs are rarely symptomatic and do not usually require treatment. However, in symptomatic patients, there are single case reports documenting efficacy with deep brain stimulation , diazepam, clonazepam, phenobarbital or valproate [44,85], perhaps mediated through restoration of the GABAergic system tonic inhibitory system from substantia nigra to superior colliculus. In contrast, patients with MSO are more often symptomatic and may benefit from treatment. In addition to medications affecting the GABA system , case reports have shown partially positive results with gabapentin  and memantine .
Symptomatic treatment of opsoclonus and ocular flutter is limited to single case reports. Propanolol, clonazepam, gabapentin, topiramate, levetiracetam and ethosuximide have been reported to abate opsoclonus or ocular flutter, possibly by enhancing GABAergic transmission of Purkinje cells over the fastigial nucleus or by blocking the membranal T-type calcium channel on saccadic burst neurons [52,59,74,86,87▪,88,89▪▪].
Specific aetiological treatment depends largely on the cause and patient's age. In a prospective, exploratory, rater-blinded, active comparator-controlled study of corticotropin-based immunotherapies in 74 children with OMS, treatment combinations (three- or four-agent) were shown to be more effective than corticotropin alone, and response to corticotropin was greater than for oral steroid therapy alone. Importantly, a greater decline of disease severity was evidenced when corticotrophin was initiated earlier, underlining the importance of a timely treatment. Serious adverse events were reported in 10% of the patients [90▪▪]. Rituximab, an anti-CD20 mAb, appears to be one of the most promising agents in treating children with OMS; as an adjunctive therapy, it depletes CSF B cells and decreases both the motor symptoms and the relapse rate [91,92]. Ofatumumab, a second-generation, fully humanized, anti-CD20 biological antibody, was successfully used in a rituximab-allergic child with severe OMS [93▪].
In adults with the idiopathic form of opsoclonus, treatment with steroids, intravenous immunoglobulin (IVIG) and azathioprine seems to accelerate recovery , although plasmapheresis has been less frequently successful [94▪]. In parainfectious cases, immunotherapy may be added to the antibiotic treatment [95▪]. In the adult paraneoplastic form of OPS, contrary to children, treatment of the tumour seems to be the cornerstone for neurological recovery ; adjunction immunotherapy with protein A column immunoadsorption therapy , steroids [35▪▪,86,97,98▪] or IVIG  may provide additional assistance.
Ocular fixation assessment constitutes a very promising tool for study in neurology. Future ocular fixation studies should employ sensitive oculomotor recording devices, allowing the assessment of all types of saccadic intrusions and fixational eye movements, and additionally quantifying parameters such as fixation periods and displacement characteristics.
The exact pathophysiology of most saccadic intrusions remains unknown. Although radiological and pathological evidence favours a cerebellar origin of opsoclonus and ocular flutter, the neuromimetic model proposed an alternative hypothesis encompassing associated features such as myoclonus, startle or tremor. This and similar models promise to enhance our knowledge of saccadic intrusions.
Although CSF B cells have become a biomarker of disease severity in childhood OMS, further studies in both children and adults are necessary to find specific pathogenic antibodies and antigens that reflect disturbed humoral immunity. Prospective multicentre trials remain the gold standard for treatment efficacy, but are difficult to organize for rare conditions, leaving the clinician dependent upon case reports to guide therapy. Long-term efficacy results for agents such as rituximab focusing on late neurological sequelae are needed.
Conflicts of interest
The authors have no conflicts of interest related to this article and subject.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 000–000).
1. Leigh RJ, Zee DS. The neurology of eye movements, vol. 70 in the Contemporary Neurology Series. New York: Oxford University Press, 2006; p. 762.
2. Martinez-Conde S, Macknik SL, Hubel DH. The role of fixational eye movements in visual perception. Nat Rev Neurosci 2004; 5:229–240.
3▪▪. Otero-Millan J, Serra A, Leigh RJ, et al. Distinctive features of saccadic intrusions and microsaccades in progressive supranuclear palsy. J Neurosci 2011; 31:4379–4387.
This important case–control study compared SWJ and microsaccades from 10 PSP patients and 14 controls. The authors elegantly demonstrate that microsaccades lacking a vertical component were a distinctive feature separating patients from controls. Interestingly, they propose that SWJ may not be a pathological entity itself, but an otherwise normal saccadic intrusion usually coupled to abnormally large microsaccades, the latter possibly signalling brainstem and/or cerebellum disease.
4. Abadi RV, Gowen E. Characteristics of saccadic intrusions. Vision Res 2004; 44:2675–2690.
5. Feldon SE, Langston JW. Square-wave jerks: a disorder of microsaccades? Neurology 1977; 27:278–281.
6. Gowen E, Abadi RV, Poliakoff E, et al. Modulation of saccadic intrusions by exogenous and endogenous attention. Brain Res 2007; 1141:154–167.
7. Sharpe JA, Fletcher WA. Saccadic intrusions and oscillations. Can J Neurol Sci 1984; 11:426–433.
8▪▪. Shaikh AG, Xu-Wilson M, Grill S, et al. ‘Staircase’ square-wave jerks in early Parkinson's disease. Br J Ophthalmol 2011; 95:705–709.
This study suggests that the presence of large and frequent SWJ may not clearly differentiate MSA or PSP from Parkinson's disease. In addition, a new form of saccadic intrusion was found in PD, possibly representing the interaction of colliculo-frontral dysfunction and phasic inhibition of SNpr.
9▪▪. Gitchel GT, Wetzel PA, Baron MS. Pervasive ocular tremor in patients with Parkinson disease. Arch Neurol 2012; 69:1011–1017.
An excellent case–control study, showing for the first time that fixational eye movement such as persistent ocular tremor might constitute a potential diagnostic biomarker in early PD. SWJ parameters did not seem to differentiate patients from controls in this study.
10. Rucker JC, Dell’Osso LF, Garbutt S, et al. Staircase saccadic intrusions plus transient yoking and neural integrator failure associated with cerebellar hypoplasia: a model simulation. Semin Ophthalmol 2006; 21:229–243.
11. Wark HA, Garell PC, Walker AL, et al. A case report on fixation instability in Parkinson's disease with bilateral deep brain stimulation implants. J Neurol Neurosurg Psychiatry 2008; 79:443–447.
12▪. Brodsky MC, Hunter JS. Positional ocular flutter and thickened optic nerves as sentinel signs of Krabbe disease. J AAPOS 2011; 15:595–597.
This is the first case report describing positional ocular flutter in a child with Krabbe's disease, but unfortunately did not employ eye movement recording.
13. Verhaeghe S, Diallo R, Nyffeler T, et al. Unidirectional ocular flutter. J Neurol Neurosurg Psychiatry 2007; 78:764–766.
14. Canice McGivern R, Mark Gibson J. Characterisation of ocular fixation in humans by analysis of saccadic intrusions and fixation periods: a pragmatic approach. Vision Res 2006; 46:3741–3747.
15. Leigh RJ, Newman SA, Folstein SE, et al. Abnormal ocular motor control in Huntington's disease. Neurology 1983; 33:1268–1275.
16. Blekher T, Johnson SA, Marshall J, et al. Saccades in presymptomatic and early stages of Huntington disease. Neurology 2006; 67:394–399.
17. Altiparmak UE, Eggenberger E, Coleman A, et al. The ratio of square wave jerk rates to blink rates distinguishes progressive supranuclear palsy from Parkinson disease. J Neuroophthalmol 2006; 26:257–259.
18. Fahey MC, Cremer PD, Aw ST, et al. Vestibular, saccadic and fixation abnormalities in genetically confirmed Friedreich ataxia. Brain 2008; 131 (Pt 4):1035–1045.
19. Ribai P, Pousset F, Tanguy ML, et al. Neurological, cardiological, and oculomotor progression in 104 patients with Friedreich ataxia during long-term follow-up. Arch Neurol 2007; 64:558–564.
20. Spieker S, Schulz JB, Petersen D, et al. Fixation instability and oculomotor abnormalities in Friedreich's ataxia. J Neurol 1995; 242:517–521.
21. Sharpe JA, Herishanu YO, White OB. Cerebral square wave jerks. Neurology 1982; 32:57–62.
22. Donaghy C, Pinnock R, Abrahams S, et al. Ocular fixation instabilities in motor neurone disease. A marker of frontal lobe dysfunction? J Neurol 2009; 256:420–426.
23. Herishanu YO, Sharpe JA. Normal square wave jerks. Invest Ophthalmol Vis Sci 1981; 20:268–272.
24. Shallo-Hoffmann J, Petersen J, Muhlendyck H. How normal are ‘normal’ square wave jerks? Invest Ophthalmol Vis Sci 1989; 30:1009–1011.
25▪. Clausi, S, De Luca, M, Chiricozzi, FR, et al.
Oculomotor deficits affect neuropsychological performance in oculomotor apraxia type 2. Cortex 2012 [Epub ahead of print].
This case report shows for the first time increased saccadic intrusions in two patients with AOA 2 compared with one control, emphasizing that reading disabilities in these patients may be caused by fixational disturbances, and not cognitive problems.
26. Gradstein LDA, Grafman J, Fitzgibbon EJ. Eye movements in chorea-acanthocytosis. Invest Ophthalmol Vis Sci 2005; 46:1979–1987.
27. Anagnostou E, Papageorgiou SG, Potagas C, et al. Square-wave jerks and smooth pursuit impairment as subtle early signs of brain involvement in Langerhans’ cell histiocytosis. Clin Neurol Neurosurg 2008; 110:286–290.
28. White OB, Saint-Cyr JA, Tomlinson RD, et al. Ocular motor deficits in Parkinson's disease. II. Control of the saccadic and smooth pursuit systems. Brain 1983; 106 (Pt 3):571–587.
29. Rascol O, Sabatini U, Simonetta-Moreau M, et al. Square wave jerks in parkinsonian syndromes. J Neurol Neurosurg Psychiatry 1991; 54:599–602.
30. Pinnock RA, McGivern RC, Forbes R, et al. An exploration of ocular fixation in Parkinson's disease, multiple system atrophy and progressive supranuclear palsy. J Neurol 2010; 257:533–539.
31. Bour LJ, van Rootselaar AF, Koelman JH, et al. Oculomotor abnormalities in myoclonic tremor: a comparison with spinocerebellar ataxia type 6. Brain 2008; 131 (Pt 9):2295–2303.
32. Salman MS, Sharpe JA, Lillakas L, et al. Visual fixation in Chiari type II malformation. J Child Neurol 2009; 24:161–165.
33. Zee DS, Robinson DA. A hypothetical explanation of saccadic oscillations. Ann Neurol 1979; 5:405–414.
34. Hafed ZM, Clark JJ. Microsaccades as an overt measure of covert attention shifts. Vision Res 2002; 42:2533–2545.
35▪▪. Hafed ZM. Mechanisms for generating and compensating for the smallest possible saccades. Eur J Neurosci 2011; 33:2101–2113.
A comprehensive review on microsaccades, going through its history and then describing the shared neural mechanisms with their larger counterparts, on the basis of a model that proposes that microsaccades are triggered when neural activity in the superior colliculus exceeds a hypothetical threshold. The need for studies on cortical control of microsaccades is further emphasized.
36▪▪. Otero-Millan J, Macknik SL, Serra A, et al. Triggering mechanisms in microsaccade and saccade generation: a novel proposal. Ann N Y Acad Sci 2011; 1233:107–116.
This thorough review addresses current evidence suggesting a common pathway for saccades and microsaccades, and more importantly, introduces an innovative proposal for the generation of (micro)saccades involving random fluctuations of neural activity in superior colliculus, influencing the reciprocal inhibition between OPNs and long-lead burst neurons.
37. Rolfs M, Laubrock J, Kliegl R. Shortening and prolongation of saccade latencies following microsaccades. Exp Brain Res 2006; 169:369–376.
38. Gowen E, Abadi RV. Saccadic instabilities and voluntary saccadic behaviour. Exp Brain Res 2005; 164:29–40.
39. Shaffer DM, Krisky CM, Sweeney JA. Frequency and metrics of square-wave jerks: influences of task-demand characteristics. Invest Ophthalmol Vis Sci 2003; 44:1082–1087.
40. Dell’Osso LF, Troost BT, Daroff RB. Macro square wave jerks. Neurology 1975; 25:975–979.
41▪. Tilikete C, Jasse L, Vukusic S, et al. Persistent ocular motor manifestations and related visual consequences in multiple sclerosis. Ann N Y Acad Sci 2011; 1233:327–334.
This study enrolled 24 patients with MS without any anterior visual pathway deficit, having found a significant correlation between decreased visual acuity, decreased visual functional scores and persistent ocular motor manifestations, including macrosquare pulses.
42. Tetrud JW, Golbe LI, Forno LS, et al. Autopsy-proven progressive supranuclear palsy in two siblings. Neurology 1996; 46:931–934.
43. Klotz L, Klockgether T. Multiple system atrophy with macrosquare-wave jerks. Mov Disord 2005; 20:253–254.
44. Fukazawa T, Tashiro K, Hamada T, et al. Multisystem degeneration: drugs and square wave jerks. Neurology 1986; 36:1230–1233.
45. Selhorst JB, Stark L, Ochs AL, et al. Disorders in cerebellar ocular motor control. II. Macrosaccadic oscillation. An oculographic, control system and clinico-anatomical analysis. Brain 1976; 99:509–522.
46. Swartz BE, Li S, Bespalova I, et al. Pathogenesis of clinical signs in recessive ataxia with saccadic intrusions. Ann Neurol 2003; 54:824–828.
47. Kim JS, Choi KD, Oh SY, et al. Double saccadic pulses and macrosaccadic oscillations from a focal brainstem lesion. J Neurol Sci 2007; 263:118–123.
48. Averbuch-Heller L, Kori AA, Rottach KG, et al. Dysfunction of pontine omnipause neurons causes impaired fixation: macrosaccadic oscillations with a unilateral pontine lesion. Neuroophthalmology 1996; 16:99–106.
49. Serra A, Liao K, Martinez-Conde S, et al. Suppression of saccadic intrusions in hereditary ataxia by memantine. Neurology 2008; 70:810–812.
50. Herishanu YO, Sharpe JA. Saccadic intrusions in internuclear ophthalmoplegia. Ann Neurol 1983; 14:67–72.
51. Doslak MJ, Dell’Osso LF, Daroff RB. Multiple double saccadic pulses occurring with other saccadic intrusions and oscillations. Neuro-Ophthalmology 1983; 3:109–116.
52. Ashe J, Hain TC, Zee DS, et al. Microsaccadic flutter. Brain 1991; 114 (Pt 1B):461–472.
53. Shaikh AG, Miura K, Optican LM, et al. A new familial disease of saccadic oscillations and limb tremor provides clues to mechanisms of common tremor disorders. Brain 2007; 130 (Pt 11):3020–3031.
54. Shaikh AG, Hain TC, Zee DS. Oculomotor disorders in adult-onset Still's disease. J Neurol 2010; 257:136–138.
55. Foroozan R, Brodsky MC. Microsaccadic opsoclonus: an idiopathic cause of oscillopsia and episodic blurred vision. Am J Ophthalmol 2004; 138:1053–1054.
56▪. Hage R Jr, Merle H, Jeannin S, et al. Ocular oscillations in the neuromyelitis optica spectrum. J Neuroophthalmol 2011; 31:255–259.
This is the first case report describing opsoclonus in patient with a presumed neuromyelitis optica, showing extensive pontine lesions in MRI. The authors propose that eye movement disorders be added to the neurological manifestations of neuromyelitis optica.
57. Ertekin V, Tan H. Opsoclonus-myoclonus syndrome attributable to hepatitis C infection. Pediatr Neurol 2010; 42:441–442.
58. Balaratnam MS, Leschziner GD, Seemungal BM, et al. Amyotrophic lateral sclerosis and ocular flutter. Amyotroph Lateral Scler 2010; 11:331–334.
59. Pistoia F, Conson M, Sara M. Opsoclonus-myoclonus syndrome in patients with locked-in syndrome: a therapeutic porthole with gabapentin. Mayo Clin Proc 2010; 85:527–531.
60. Bataller L, Rosenfeld MR, Graus F, et al. Autoantigen diversity in the opsoclonus-myoclonus syndrome. Ann Neurol 2003; 53:347–353.
61. Pranzatelli MR, Travelstead AL, Tate ED, et al. B- and T-cell markers in opsoclonus-myoclonus syndrome: immunophenotyping of CSF lymphocytes. Neurology 2004; 62:1526–1532.
62. Ko MW, Dalmau J, Galetta SL. Neuro-ophthalmologic manifestations of paraneoplastic syndromes. J Neuroophthalmol 2008; 28:58–68.
63. Bataller L, Graus F, Saiz A, et al. Clinical outcome in adult onset idiopathic or paraneoplastic opsoclonus-myoclonus. Brain 2001; 124 (Pt 2):437–443.
64. Kurian M, Lalive PH, Dalmau JO, et al. Opsoclonus-myoclonus syndrome in anti-N-methyl-D-aspartate receptor encephalitis. Arch Neurol 2010; 67:118–121.
65. Zaro-Weber O, Galldiks N, Dohmen C, et al. Ocular flutter, generalized myoclonus, and trunk ataxia associated with anti-GQ1b antibodies. Arch Neurol 2008; 65:659–661.
66. Markakis I, Alexiou E, Xifaras M, et al. Opsoclonus-myoclonus-ataxia syndrome with autoantibodies to glutamic acid decarboxylase. Clin Neurol Neurosurg 2008; 110:619–621.
67▪▪. Pranzatelli MR, Slev PR, Tate ED, et al. Cerebrospinal fluid oligoclonal bands in childhood opsoclonus-myoclonus. Pediatr Neurol 2011; 45:27–33.
This is a very interesting, prospective, case–control study of 132 children with OMS, in which the authors tried to determine the role of OCB occurrence in CSF as a possible biomarker in OMS. OCBs were present in 35% of OMS patients, and were more frequent in severe cases (56%). OCB decreased by 75% in pilot treatment utilizing adrenocorticotropic hormone, IVIGs and rituximab.
68▪▪. Pranzatelli MR, Tate ED, McGee NR, et al. Key role of CXCL13/CXCR5 axis for cerebrospinal fluid B cell recruitment in pediatric OMS. J Neuroimmunol 2012; 243 (1–2):81–88.
This is a large, prospective, case–control study enrolling 289 children with OMS, in which CSF CXCL13 concentration emerged as a new candidate biomarker of disease severity and treatment response, correlating with CSF CD19+ B cell frequency, OCB presence, disease severity, disease duration and treatment status.
69. Gorman MP. Update on diagnosis, treatment, and prognosis in opsoclonus-myoclonus-ataxia syndrome. Curr Opin Pediatr 2010; 22:745–750.
70. De Grandis E, Parodi S, Conte M, et al. Long-term follow-up of neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome. Neuropediatrics 2009; 40:103–111.
71▪▪. Brunklaus A, Pohl K, Zuberi SM, et al. Outcome and prognostic features in opsoclonus-myoclonus syndrome from infancy to adult life. Pediatrics 2011; 128:e388–e394.
This retrospective study concerns 101 patients with OMS over a 53-year period. The majority had a chronic-relapsing course ultimately showing neurological sequelae, especially if early and severe initial presentation. The need for early diagnosis and treatment is emphasized.
72. Shaikh AG, Ramat S, Optican LM, et al. Saccadic burst cell membrane dysfunction is responsible for saccadic oscillations. J Neuroophthalmol 2008; 28:329–336.
73. Ramat S, Leigh RJ, Zee DS, et al. Ocular oscillations generated by coupling of brainstem excitatory and inhibitory saccadic burst neurons. Exp Brain Res 2005; 160:89–106.
74. Ramat S, Leigh RJ, Zee DS, et al. What clinical disorders tell us about the neural control of saccadic eye movements. Brain 2007; 130 (Pt 1):10–35.
75. Shaikh AG, Marti S, Tarnutzer AA, et al. Gaze fixation deficits and their implication in ataxia-telangiectasia. J Neurol Neurosurg Psychiatry 2009; 80:858–864.
76. Shaikh AG, Miura K, Optican LM, et al. Hypothetical membrane mechanisms in essential tremor. J Transl Med 2008; 6:68.
77. Shaikh AG, Jinnah HA, Tripp RM, et al. Irregularity distinguishes limb tremor in cervical dystonia from essential tremor. J Neurol Neurosurg Psychiatry 2008; 79:187–189.
78▪. Yonekawa T, Saito Y, Sakuma H, et al. Augmented startle responses in opsoclonus-myoclonus syndrome. Brain Dev 2011; 33:335–338.
This is a case report of a 1-year-old boy with OMS and concomitant exaggerated startle response and blink reflex, presumably due to hyperexcitability in independent but neighbouring structures within the pontine tegmentum, favouring the brainstem hypothesis for the generation of opsoclonus.
79▪▪. Iizuka T, Leite MI, Lang B, et al. Glycine receptor antibodies are detected in progressive encephalomyelitis with rigidity and myoclonus (PERM) but not in saccadic oscillations. J Neurol 2012; 259:1566–1573.
This interesting study is based on the assumption that ocular flutter or opsoclonus pathophysiology is related to an inhibitory glycinergic transmission defect. Disappointingly, none of the 13 patients tested had significant increase of GlyR antibodies.
80. Wong AM, Musallam S, Tomlinson RD, et al. Opsoclonus in three dimensions: oculographic, neuropathologic and modelling correlates. J Neurol Sci 2001; 189:71–81.
81. van Toorn R, Rabie H, Warwick JM. Opsoclonus-myoclonus in an HIV-infected child on antiretroviral therapy: possible immune reconstitution inflammatory syndrome. Eur J Paediatr Neurol 2005; 9:423–426.
82. Helmchen C, Rambold H, Sprenger A, et al. Cerebellar activation in opsoclonus: an fMRI study. Neurology 2003; 61:412–415.
83▪. Newey CR, Sarwal A, Wu G. Radiological correlate of ocular flutter in a case with paraneoplastic encephalitis. J Neuroimaging 2011 [Epub ahead of print].
This is the first case report showing fluorodeoxyglucose–PET correlation of ocular flutter. The hypermetabolism of the deep cerebellar nuclei, seen in this case, favours the disinhibition of the fastigial oculomotor system as the underlying mechanism for the generation of flutter.
84▪. Blumkin L, Kivity S, Lev D, et al.
A compound heterozygous missense mutation and a large deletion in the KCTD7 gene presenting as an opsoclonus-myoclonus ataxia-like syndrome. J Neurol 2012 [Epub ahead of print].
This is a case report describing a child with OMS with an atypical course complicated by epilepsy, prompting genetic testing. This case highlights the possible role of nongated potassium channels in the generation of opsoclonus, as KCTD7 is strongly expressed at the Purkinje cells of cerebellum.
85. Traccis S, Marras MA, Puliga MV, et al. Square-wave jerks and square-wave oscillations: treatment with valproic acid. Neuro-ophthalmology 1997; 18:51–58.
86. Pranzatelli MR. The neurobiology of the opsoclonus-myoclonus syndrome. Clin Neuropharmacol 1992; 15:186–228.
87▪. Fernandes TD, Bazan R, Betting LE, et al. Topiramate effect in opsoclonus-myoclonus-ataxia syndrome. Arch Neurol 2012; 69:133.
This is a case report describing improvement of opsoclonus with topiramate, invoking the stabilization of hyperexcited neuronal membranes as a hypothetic therapeutic mechanism.
88. Eggenberger E, Cherian V. Levetiracetam effect in demyelinating ocular flutter with myoclonus. Neuro-Ophthalmology 2006; 30:105–108.
89▪▪. Shaikh AG, Zee DS, Optican LM, et al. The effects of ion channel blockers validate the conductance-based model of saccadic oscillations. Ann N Y Acad Sci 2011; 1233:58–63.
In this small study, the authors support the hypothesis raised by predictions of a conductance-based neuromimetic model of saccadic burst neurons, stating that the membrane properties and PIR are determined by hyperpolarization-activated, inward cation current (Ih) and low-threshold calcium current (IT).
90▪▪. Tate ED, Pranzatelli MR, Verhulst SJ, et al. Active comparator-controlled, rater-blinded study of corticotropin-based immunotherapies for opsoclonus-myoclonus syndrome. J Child Neurol 2012; 27:875–884.
This is the largest, prospective, controlled study to compare efficacies of corticotropin-based immunotherapies in children with OMS. Treatment combinations seem to be more effective than corticotrophin alone, and the latter seems to promote a greater response than corticosteroid-based therapy.
91. Pranzatelli MR, Tate ED, Swan JA, et al. B cell depletion therapy for new-onset opsoclonus-myoclonus. Mov Disord 2010; 25:238–242.
92. Pranzatelli MR, Tate ED, Travelstead AL, et al. Rituximab (anti-CD20) adjunctive therapy for opsoclonus-myoclonus syndrome. J Pediatr Hematol Oncol 2006; 28:585–593.
93▪. Pranzatelli MR, Tate ED, Shenoy S, et al. Ofatumumab for a rituximab-allergic child with chronic-relapsing paraneoplastic opsoclonus-myoclonus. Pediatr Blood Cancer 2012; 58:988–991.
This is a case study that points out the favourable clinical response after the administration of ofatumumab, a novel drug in phase II–III trials, to treat a child with OMS severely allergic to rituximab.
94▪. Smith JH, Dhamija R, Moseley BD, et al. N-methyl-D-aspartate receptor autoimmune encephalitis presenting with opsoclonus-myoclonus: treatment response to plasmapheresis. Arch Neurol 2011; 68:1069–1072.
This is one of the rare case reports in which plasmapheresis seemed to dramatically improve a presumed case of idiopathic OMS in whom NMDAR antibodies were detected.
95▪. Nunes JC, Bruscato AM, Walz R, et al. Opsoclonus-myoclonus syndrome associated with Mycoplasma pneumoniae infection in an elderly patient. J Neurol Sci 2011; 305:147–148.
This is the first case report describing mycoplasma pneumoniae infection presenting as OMS in an elderly patient, who has completely recovered after macrolides and IVIG treatment.
96. Cher LM, Hochberg FH, Teruya J, et al. Therapy for paraneoplastic neurologic syndromes in six patients with protein A column immunoadsorption. Cancer 1995; 75:1678–1683.
97. Wirtz PW, Sillevis Smitt PA, Hoff JI, et al. Anti-Ri antibody positive opsoclonus-myoclonus in a male patient with breast carcinoma. J Neurol 2002; 249:1710–1712.
98▪. Groiss SJ, Siebler M, Schnitzler A. Full recovery of adult onset opsoclonus myoclonus syndrome after early immunotherapy: a case report. Mov Disord 2011; 26:1805–1807.
This is a case report emphasizing the importance of early immunosupressive therapy, even in paraneoplastic adult OMS, describing an elderly woman with OMS who has improved after corticosteroids. Later, a breast cancer was found.
macrosaccadic oscillations; ocular flutter; opsoclonus; opsoclonus–myoclonus syndrome; saccadic intrusions; square wave jerks; square wave pulses
© 2013 Lippincott Williams & Wilkins, Inc.
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