Normal saccades are characterized as rapid, bilateral, conjugate, sequential eye movements that allow visual targets to be brought to the fovea in each eye. They occur approximately three times per second between periods of fixation. In contrast, saccadic intrusions are involuntary conjugate saccades that interrupt fixation. Several types of saccadic intrusions exist including square wave jerks (SWJ), square wave pulses (SWP), macrosaccadic oscillations, saccadic pulses, ocular flutter, and opsoclonus. A few intermittent, random, saccadic intrusions (especially SWJ) may be seen in healthy patients but can also be seen as a nonspecific finding in patients with multiple neurologic conditions. More persistent saccadic intrusions (e.g., ocular flutter or opsoclonus) however are pathologic and require evaluation. Treatment may be considered if patients are symptomatic and is dependent on the underlying etiology.
Saccadic intrusions may be idiopathic or secondary to underlying neurologic condition (e.g., Parkinson disease (PD), progressive supranuclear palsy (PSP), spinocerebellar ataxia, multiple system atrophy (MSA), multiple sclerosis (MS), neoplastic, infectious encephalitis, and metabolic or toxic etiologies). Saccadic intrusions may also be associated with paraneoplastic syndromes (e.g., neuroblastoma in children or small cell lung cancer, breast cancer, and ovarian or other cancer in adults). Less commonly, saccadic intrusions have been reported in the setting of neuromyelitis optica (NMO), hepatitis C virus (HCV), Krabbe disease, amyotrophic lateral sclerosis (ALS), and locked-in syndrome.
Risk factors are dependent on the etiology described above.
The physiologic mechanism for saccades involves the stimulatory and inhibitory connections between burst neurons (BN) and omnipause neurons (OPN) in the reticular formation in the pons. During fixation, OPNs fire and keeps the BNs inhibited. The inhibition center in the superior colliculus switches before initiation of the saccade, so the inhibition of OPN to BN decreases and the inhibition from BN to OPN increases. Although the exact mechanism for saccadic intrusions is unknown and is dependent on the underlying etiology, understanding the normal physiology may aid in understanding the possible pathological mechanisms. One proposed mechanism involves altered membrane properties of BNs that result in a disturbance of the balance between excitability and inhibition that characterizes physiologic saccades. Due to the association of saccadic intrusions with underlying neurologic diseases, dysfunctional inhibition of the basal ganglia, cerebellum, cerebral hemispheres, and superior colliculus leading to inability to reinforce OPNs have been proposed. Saccadic intrusions may be associated with B and T cell immune-mediated mechanisms.
Mild, intermittent, saccadic intrusions may be asymptomatic but more constant and pathologic saccadic intrusions (e.g., ocular flutter or opsoclonus) typically cause symptomatic oscillopsia or nonspecific visual blur. Patients may also complain of concurrent neurologic symptoms, depending on the underlying etiology. Because saccadic intrusions can be due to a wide range of underlying etiologies, it is important to obtain a complete past medical history including infectious, metabolic, or toxic exposures, history of prior malignancies, neurologic disorders, and family history.
A complete ophthalmic exam should be performed in patients with suspected saccadic intrusions. The ocular motility exam, including evaluation of ocular misalignment, nystagmus, smooth pursuit, vestibulo-ocular reflex (VOR), optokinetic nystagmus (OKN), head impulse test (HIT), versions and vergence eye movements, may help with the diagnosis of saccadic intrusions. Ocular misalignment can be assessed with the cover/uncover test in primary and diagnostic positions of gaze at both near and at distance. In patients who are unable to initiate voluntary saccades, OKN may be induced. Although these exam maneuvers may be helpful, more subtle findings may require video-oculography.
Signs and Symptoms
Patient with saccadic intrusions may be asymptomatic or may present with complaints of blurred vision and oscillopsia. Other associated symptoms depend on the underlying etiology of saccadic intrusions. For example, opsoclonus-myoclonus may also present with involuntary muscle jerks and PD may have variable motor and cognitive symptoms.
Saccadic intrusions can be divided by the presence of absence of an intersaccadic interval (ISI). Saccadic intrusions with ISI include square wave jerks (SWJ), square wave pulses (SWP), macrosaccadic oscillations (MSO), and saccadic pulses (SP).SWJ are characterized by small conjugate couplets of horizontal saccades between 0.5 and 5 degrees of amplitude with an ISI of approximately 200 ms. SWJ associated with neurologic disorders such as PSP or Friedrich ataxia may have amplitudes larger than 5 degrees, be more frequent compared to SWJ in healthy individuals, or be multiplanar and/or disconjugate.SWP are similar to SWJ, but typically have higher amplitude, shorter ISI, and oscillate on one side of fixation. Unlike SWJ, they are almost always associated with underlying neurologic disorders such as MS, PSP, MSA. MSO are typically induced by a gaze shift and are characterized by horizontal saccades with crescendo-decrescendo amplitudes. The ISI is similar to that of SWJ.SP are characterized as brief saccades away from target objects with rapid refixation. SP are most commonly observed in the setting of MS or trauma.
Saccadic intrusions without ISI are ocular flutter and opsoclonus. Ocular flutter is a horizontal conjugate saccade with an amplitude of 1-5 degrees and a frequency of 10-25 hz.Unlike ocular flutter, opsoclonus may have vertical and torsional components, resulting in multidirectional saccades. Underlying etiologies may be evaluated with laboratory tests and imaging studies as discussed below.
Although the diagnosis is typically made clinically, laboratory tests may be helpful. Reported antibodies associated with saccadic intrusions and paraneoplastic syndromes are anti-rostral interstitial, anti-N-methyl-D-aspartate receptor (anti-NMDAR), anti-ganglioside Q1b, anti-ri, and anti-glutamic acid decarboxylase (anti-GAD); however, no common biomarker for saccadic intrusions currently exists.
Imaging studies may demonstrate variable findings in patients with saccadic intrusions. Magnetic resonance imaging (MRI) may show cerebellar atrophy or decrease in cortical and subcortical gray matter volume. Single photon emission computerized tomography (SPECT) has shown involvement of deep cerebellar nuclei in some patients. Fluorodeoxyglucose positron emission tomography (FDG-PET) coupled with MRI has demonstrated hypermetabolism of bilateral deep cerebellar nuclei.
The differential diagnosis for saccadic intrusions includes commonly associated neurologic disorders such as PD, PSP, MS, or MSA. Other associated conditions include infectious encephalitis, toxic/metabolic conditions, and paraneoplastic conditions such as neuroblastoma in children, small cell lung carcinoma, breast cancer, and ovarian cancer. When underlying causes of saccadic intrusions are ruled out, idiopathic saccadic intrusions may be considered.
General management goals include abolishing or decreasing abnormal eye movements without affecting physiologic saccades and gaze holding. Treatment typically targets the suspected underlying etiology.
Medical therapy is variable and depends on the underlying etiology. In idiopathic saccadic intrusions, botulinum toxin injections have been reported to improve symptoms, but may impair VOR, resulting in blurred vision. Saccadic intrusions in PD may respond to levodopa-carbidopa. Macrosaccadic oscillations associated with cerebellar ataxia has reportedly been suppressed with memantine. Patients with viral encephalitis may improve with intravenous immunoglobulins (IVIG), steroids, and azathioprine. In cases of paraneoplastic syndromes, treatment of the cancer in addition to IVIG or plasmapheresis may alleviate saccadic intrusions. In neuroblastoma, patients may respond to rituximab, steroids, or IVIG.
Treatment based on the type of saccadic intrusion has also been reported. Improvement of SWJ has been reported with diazepam, clonazepam, phenobarbital, and valproate. Studies show MSO may benefit from gabapentin or memantine. Opsoclonus and ocular flutter may be reduced with propranolol, clonazepam, gabapentin, topiramate, levetiracetam, or ethosuximide.
Deep brain stimulation (DBS) may be considered for surgical treatment of saccadic intrusions. Studies have demonstrated improvement with DBS in the setting of PD and SWJ due to other causes.No other surgical therapy for saccadic intrusions currently exists.
Prognosis depends largely on the underlying etiology. Although many associated neurologic disorders are not curable, symptomatic saccadic intrusions may be decreased with medical or surgical management. In cases of opsoclonus-myoclonus in pediatric patients with neuroblastoma, prognosis is typically poor, with approximately 80% of children having neurologic sequelae such as chronic-relapsing disease. In contrast, idiopathic opsoclonus-myoclonus syndrome in adults is typically monophasic and generally has favorable prognosis.
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