Patients with infantile-onset saccade initiation delay (ISID), also known as congenital ocular motor apraxia, are unable to initiate voluntary saccadic eye movements and usually present with head thrusts. Random small-amplitude saccadic eye movements may be present (1,2). The clinical features reported in patients with ISID are variable and may include abnormalities in smooth ocular pursuit and the slow phases of the optokinetic response (OKR) (3). In addition to the neuro-ophthalmological findings, other deficits have been described, including developmental or cognitive delay and speech or language deficits (2–6). Tone is typically decreased, and clumsiness or ataxia is reported frequently (2–4,7).
A normal brain magnetic resonance imaging (MRI) is common in patients with ISID (3,4). In addition, there are a variety of neuroradiological findings associated with ISID, most frequently involving the cerebellum, particularly the inferior vermis (2–4,7,8). Other abnormalities have been reported in the corpus callosum, thalamus, brainstem, and cerebral cortex (2–4,9,10).
We are unaware of any studies attempting to correlate the clinical features with neuroradiological findings among patients with ISID. We reviewed the reported cases of ISID to determine if there are any associations between their clinical features and neuroradiological findings.
Search Strategy and Selection Criteria
We performed a detailed search of the English medical literature using PubMed for publications relating to ISID or congenital ocular motor apraxia between 1952, when the condition was first described (11), and December 2012. Each author (M.S.S. and K.M.I.) performed the search independently and compiled the results. Titles and abstracts were screened and, if appropriate, were included for review. References of relevant studies were also searched for additional cases.
Inclusion criteria were studies with patients who had 1) a diagnosis of ISID with a clinical description consistent with the disorder, 2) brain MRI, and 3) adequate description of eye movements, other neuro-ophthalmological findings, and/or developmental outcomes. Exclusion criteria were studies in which patients had acquired saccade initiation delay, Joubert syndrome, ataxia telangiectasia, ataxia with ocular motor apraxia types 1 and 2, Niemann-Pick disease, spinocerebellar degeneration, and other neurodegenerative conditions because the clinical findings and pathology in these disorders are not typical of ISID (12). Patients with both supratentorial and infratentorial abnormalities on MRI were also excluded.
Once studies were selected for inclusion, the patients were divided into 1 of 3 groups based on their brain MRI findings: normal, supratentorial abnormalities, or infratentorial abnormalities. The patients' clinical features were extracted, and the frequency of their findings was calculated for each MRI group. The clinical features were divided into 4 categories: neuro-ophthalmological, other ophthalmological, developmental, and motor outcomes. Neuro-ophthalmological findings included the presence and direction of head thrusts, direction of eye movements during head thrusts, use of blinks during or independent of head thrusts to initiate saccades, smooth ocular pursuit, slow and fast phases of both the vestibular ocular reflex and OKR. Other ophthalmological abnormalities included the presence of strabismus and pigmentary retinopathy. Developmental outcomes collected included global, cognitive, and speech or language delays, and reading and behavioral difficulties. Motor outcomes included tone, motor delay, and the presence or absence of ataxia or clumsiness. Demographic information collected included age at diagnosis, gender, and familial cases.
Statistical analyses were performed using a Statistical Package for Social Sciences (version 22.0; SPSS, Inc, Chicago, IL). The data were compared and analyzed among the 3 MRI groups using Pearson χ2 test or Fisher exact test. Statistical significance was set at P ≤ 0.05. Variables that reached statistical significance were further analyzed for specific differences among the 3 groups (post hoc analyses). We assumed that the nonreported variables in the studies analyzed were randomly distributed among the 3 MRI groups.
Sixty-seven studies were identified as having patients with possible ISID through a PubMed search. There were 91 patients from 26 studies (1,2,4–10,13–29), who met the inclusion criteria. The age range at diagnosis was 3 months to 45 years. The 91 patients were subsequently divided into 3 groups according to their brain MRI findings: normal (n = 55), supratentorial abnormalities (n = 17), and infratentorial abnormalities (n = 19). There were 4 familial cases, all of whom were in the normal MRI group.
Supratentorial abnormalities (frequency) included abnormalities in the thalamus (7), basal ganglia (2), and cerebral white matter (2), heterotopia (2), periventricular encephalomalacia (2), corpus callosum hypoplasia (1), bilateral occipital infarcts (1), leukodystrophy (1), encephalomalacia (1), temporal lobe asymmetry (1), left hemispheric subependymal hemorrhage (1), and multiple infarcts (1) (4,6,9,10,14–16,18,21,27). Infratentorial abnormalities included hypoplastic or absent cerebellar vermis (10), other cerebellar abnormalities (5), midbrain abnormalities (2), pontine abnormalities (2), and thin intercollicular commissure (1) (2,4,7–9,13,15,17,18,24,28,29). Some patients had more than 1 abnormal MRI finding within their respective MRI group.
The neuro-ophthalmological features did not differ significantly among the 3 MRI groups with the exception of the direction of head thrusts and the slow phases of the OKR (see Table 1). Post hoc analyses revealed that the direction of head thrusts was significantly different in patients with a normal MRI in comparison with those with supratentorial abnormalities (P = 0.001) but similar to those with infratentorial abnormalities (P = 0.417). Horizontal head thrusts were frequently reported in patients with normal MRI or patients with infratentorial abnormalities, whereas vertical head thrusts occurred more commonly in patients with supratentorial abnormalities. Within the supratentorial MRI group, 4 (80%) of 5 patients with vertical head thrusts had lesions in their thalami, while 3 (37.5%) of 8 patients with horizontal head thrusts had lesions in their thalami; however, the difference was not statistically significant (P = 0.266).
Post hoc analyses of the OKR slow phases revealed that patients in the normal MRI group had significantly different OKR slow phases than those in the groups with supratentorial (P = 0.025) and infratentorial abnormalities (P = 0.012). The latter 2 groups showed similar OKR slow phases. Patients with normal MRIs frequently had normal slow phases of the OKR, whereas patients with abnormal MRIs (i.e., supratentorial or infratentorial abnormalities) more commonly had impaired slow phases of the OKR.
The following variables could not be analyzed among the MRI groups due to the absence of clearly dichotomized data in the articles analyzed (i.e., whether a variable was present/absent or normal/impaired): the presence of blinks without head thrusts to initiate saccades, blinks during head thrusts, spontaneous saccades, oculocephalic maneuver response, and fast phases of both the vestibulo-ocular reflex and OKR. Other neuro-ophthalmological, motor, and developmental outcomes were similar among the 3 MRI groups (Table 1).
ISID is associated with a variable clinical phenotype and diverse neuroimaging findings (3). The etiology of ISID is unknown (12). Whether the clinical features, including head thrusts and slow phases of the OKR, and neuroradiological abnormalities are correlated has not been explored previously. The results of this study show that there remains significant clinical and neuroradiological heterogeneity among patients with ISID; however, there are 2 clinical features, head thrusts and slow phases of the OKR, that are associated with certain brain MRI findings.
Horizontal head thrusts were one of the cardinal features of ISID when it was first described by Cogan in 1952 (11). Although not present in all patients, horizontal head thrusts remain a hallmark feature and correlate with brain MRI findings. In contrast, vertical head thrusts are a rare feature of ISID (10,14,21). The overwhelming majority of patients with ISID who have normal neuroimaging or infratentorial abnormalities display horizontal head thrusts, while vertical head thrusts are more commonly reported in patients with supratentorial abnormalities. The reason for this is not clear. The neural substrate for eye and head saccades is thought to be similar (30). Multiple brain structures located both supratentorially and infratentorially are involved in processing head movements and both horizontal and vertical saccades (30). We speculate that neural projections between supratentorial structures and rostral brainstem structures specifically involved in processing vertical saccades were affected by lesions in the patients with vertical head thrusts and supratentorial abnormalities.
Abnormalities in the slow phases of the OKR, as well as smooth ocular pursuit, have been increasingly recognized as part of the spectrum of ISID (3,15). Our results indicate that patients with MRI abnormalities, either supratentorially or infratentorially, are more likely to have impaired slow phases of the OKR. Our findings are consistent with the neuroanatomical pathways and structures involved in processing the OKR, which include cerebral, brainstem, and cerebellar projections (31,32). However, only 3 studies of patients with ISID have used a large-field visual stimulus to examine the OKR (1,7,15). The rest of the studies either used the optokinetic drum (2,13,20,28) or did not report how the OKR was examined. Examining the OKR using the rotating handheld optokinetic drum may in fact be stimulating the smooth ocular pursuit system because global large-field visual motion is needed to elicit the OKR (30,32). Therefore, the data on OKR slow phases extracted from the studies analyzed in our study may, in fact, reflect smooth ocular pursuit. However, such proposition contradicts our finding of similar smooth ocular pursuit impairment among patients in the 3 MRI groups. Such discrepancy may be explained by the relatively small power of our study to detect differences in smooth ocular pursuit response among patients in the 3 MRI groups, nonrandom biases in reporting neuro-ophthalmological findings among patients in the publications included, and the different methods used to examine the OKR.
The large variety of clinical features reported in ISID that were not significantly different among the 3 MRI groups likely reflects the widespread central nervous system dysfunction in patients with ISID.
Interestingly, although ataxia or clumsiness is frequently reported in ISID, there was no significant association of patients with ataxia and infratentorial abnormalities. Although patients with cerebellar abnormalities were not analyzed separately due to small numbers, the majority of the patients with infratentorial abnormalities had cerebellar abnormalities (15/19 patients). This finding also suggests a more widespread dysfunction in patients with ISID than is appreciable on brain MRI. This dysfunction may reflect the involvement of a variety of cerebellar inflow and outflow tracts outside the cerebellum that play an important role in the coordination of movement.
One of the limitations of this investigation is that data were gathered from published cases, which did not always have all the information we included in the analysis. This may have resulted in an underrepresentation of the frequency of abnormalities associated with ISID and potentially biased the results, especially if the unreported data were not randomly distributed among the 3 MRI groups. In addition, the number of published cases of ISID with MRI findings is relatively small, which may have decreased the statistical power needed to find clinical-neuroradiological associations. Selecting patients with a brain MRI was necessary because brain computed tomography has a lower spatial resolution in general, and it is not ideal for imaging infratentorial structures.
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