Congenital Cranial Dysinnervation Disorders Research Articles

Evolution and development of extraocular motor neurons, nerves and muscles in vertebrates

The purpose of this review is to analyze the origin of ocular motor neurons, define the pattern of innervation of nerve fibers that project to the extraocular eye muscles (EOMs), describe congenital disorders that alter the development of ocular motor neurons, and provide an overview of vestibular pathway inputs to ocular motor nuclei. Six eye muscles are innervated by axons of three ocular motor neurons, the oculomotor (CNIII), trochlear (CNIV), and abducens (CNVI) neurons. Ocular motor neurons (CNIII) originate in the midbrain and innervate the ipsilateral orbit, except for the superior rectus and the levator palpebrae, which are contralaterally innervated. Trochlear motor neurons (CNIV) originate at the midbrain-hindbrain junction and innervate the contralateral superior oblique muscle. Abducens motor neurons (CNVI) originate variously in the hindbrain of rhombomeres r4–6 that innervate the posterior (or lateral) rectus muscle and innervate the retractor bulbi. Genes allow a distinction between special somatic (CNIII, IV) and somatic (CNVI) ocular motor neurons. Development of ocular motor neurons and their axonal projections to the EOMs may be derailed by various genetic causes, resulting in the congenital cranial dysinnervation disorders. The ocular motor neurons innervate EOMs while the vestibular nuclei connect with the midbrain-brainstem motor neurons.

Exome and genome sequencing to unravel the precise breakpoints of partial trisomy 6q and partial Monosomy 2q

BackgroundPatients with complex phenotypes and a chromosomal translocation are particularly challenging, since several potentially pathogenic mechanisms need to be investigated.Case presentationHere, we combined exome and genome sequencing techniques to identify the precise breakpoints of heterozygous microduplications in the 6q25.3-q27 region and microdeletions in the 2q37.1-q37.3 region in a proband. The 5-year-old girl exhibited a severe form of congenital cranial dysinnervation disorder (CCDD) in addition to skeletal dysmorphism anomalies and severe intellectual disability. This is the second case affecting chromosomes 2q and 6q. The individual’s karyotype showed an unbalanced translocation 46,XX,del(2)t(2;6)(q37.1;q25.3), which was inherited from her unaffected father [46,XY,t(2;6)(q37.1;q25.3)]. We also obtained the precise breakpoints of a de novo heterozygous copy number deletion [del(2)(q37.1q37.3)chr2:g.232963568_24305260del] and a copy number duplication [dup(6)(q25.3q27)chr6:g.158730978_170930050dup]. The parental origin of the observed balanced translocation was not clear because the parents declined genetic testing.ConclusionPatients with a 2q37 deletion and 6q25.3 duplication may exhibit severe significant neurological and skeletal dysmorphisms, and the utilization of exome and genome sequencing techniques has the potential to unveil the entire translocation of the CNV and the precise breakpoint.

Monozygotic twins discordant for a congenital cranial dysinnervation disorder with features of Moebius syndrome.

Moebius syndrome is a congenital cranial dysinnervation disorder (CCDD) that presents with nonprogressive cranial nerve (CN) VI and VII palsies resulting in facial weakness and inability to abduct the eye(s). While many CCDDs have an underlying genetic cause, the etiology of Moebius syndrome remains unclear as most cases are sporadic. Here, we describe a pair of monochorionic, diamniotic twin girls; one with normal growth and development, and one with micrognathia, reduced facial expression, and poor feeding. Magnetic resonance imaging of the brain performed on the affected twin at 19 months of age showed severely hypoplastic or absent CN IV bilaterally, left CN VI smaller than right, and bilateral hypoplastic CN VII and IX, consistent with a diagnosis of a CCDD, most similar to that of Moebius syndrome. Genomic sequencing was performed on each twin and data was assessed for discordant variants, as well as variants in novel and CCDD-associated genes. No pathogenic, likely pathogenic, or variants of uncertain significance were identified in genes known to be associated with CCDDs or other congenital facial weakness conditions. This family provides further evidence in favor of a stochastic event as the etiology in Moebius syndrome, rather than a monogenic condition.

Genetics of strabismus.

Strabismus, or misalignment of the eyes, is the most common ocular disorder in the pediatric population, affecting approximately 2%-4% of children. Strabismus leads to the disruption of binocular vision, amblyopia, social and occupational discrimination, and decreased quality of life. Although it has been recognized since ancient times that strabismus runs in families, its inheritance patterns are complex, and its precise genetic mechanisms have not yet been defined. Family, population, and twin studies all support a role of genetics in the development of strabismus. There are multiple forms of strabismus, and it is not known if they have shared genetic mechanisms or are distinct genetic disorders, which complicates studies of strabismus. Studies assuming that strabismus is a Mendelian disorder have found areas of linkage and candidate genes in particular families, but no definitive causal genes. Genome-wide association studies searching for common variation that contributes to strabismus risk have identified two risk loci and three copy number variants in white populations. Causative genes have been identified in congenital cranial dysinnervation disorders, syndromes in which eye movement is limited or paralyzed. The causative genes lead to either improper differentiation of cranial motor neurons or abnormal axon guidance. This article reviews the evidence for a genetic contribution to strabismus and the recent advances that have been made in the genetics of comitant strabismus, the most common form of strabismus.

Palpebral Fissure Changes in the Contralateral Eye in Duane Retraction Syndrome

Duane retraction syndrome (DRS) is a congenital cranial dysinnervation disorder that is characterized by paradoxical lateral rectus muscle innervation of the affected eye by axons meant to innervate the ipsilateral medial rectus muscle, with resultant varying degrees of co-contraction. It is characterized by severe abduction deficiency, variable limitation of adduction, globe retraction with narrowing of the palpebral fissure, and oblique elevation or depression on adduction. A total of 16 patients with unilateral DRS were identified. The mean age was 13 ± 8 years (range: 6 to 28 years). There were 5 males and 11 females. The cohort included 8 patients with DRS type I, 3 patients with DRS type II, 4 patients with DRS type III, and 1 patient with synergistic divergence (DRS type IV). The mean width of the palpebral fissure in primary gaze was 9.95 ± 0.25 mm, increased in abduction to 11.11 ± 1.16 mm, and changed on adduction to 10.03 ± 1.19 mm. The mean reduction in the size of the palpebral fissure on adduction was 11.7 ± 10.2% (range: 0 to 30%). The difference in the palpebral fissure width between adduction and abduction was statistically significant (P = .0018). Of the 16 patients, 8 (50%) showed narrowing of the palpebral fissure of the contralateral eye on adduction compared to abduction of more than 10%. In this case series of unilateral Duane retraction syndrome, there was a common association between widening of the palpebral fissure of the unaffected eye and adduction of the eyes with DRS in DRS types II, III, and IV and DRS type I with upshoot or downshoot. [J Pediatr Ophthalmol Strabismus. 2023;60(3):e22-e25.].

Modified Nishida Procedure Combined with Lateral Rectus Disabling for Duane Retraction Syndrome

ABSTRACT Duane retraction syndrome (DRS) is a complex congenital cranial dysinnervation disorder. The choice of surgical procedure in esotropic-DRS depends upon several factors that include: the amount of esotropia in the primary position, the presence and severity of palpebral fissure narrowing, globe retraction, presence of medial rectus muscle (MR) contracture, the likelihood of improving abduction, age of the patient, and the presence of binocularity and stereopsis. In the presence of MR contracture, MR recession is performed either alone (unilaterally or bilaterally) or in conjunction with Y splitting plus recession of the lateral rectus muscle (LR) for reducing globe retraction. MR recession, with or without adjustable sutures, may be simultaneously combined with partial thickness vertical rectus muscle transposition (VRT) or with superior rectus muscle transposition (SRT). We describe a novel combination of surgical procedures in the management of esotropic-DRS in two patients. In our first patient, following an initial MR recession combined with LR disinsertion and periosteal fixation (LRDAPF), a modified Nishida procedure was performed. In our second patient following a prior simultaneous MR recession and LR Y splitting with recession, we combined periosteal fixation of the LR with a modified Nishida procedure of the vertical rectus muscles.

A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report

IntroductionNEUROG1 gene is yet to be associated with a set of human phenotypes in the OMIM database. Three cases have previously been diagnosed with cranial dysinnervation due to biallelic variants in the NEUROG1 gene. This is the fourth and a novel report of a sibling pair harboring a homozygous variant in the NEUROG1 gene with autism as an additional phenotype. A brief review of the literature in conjunction with a genotype–phenotype correlation has been described. A potential hypothesis for the presence of the autistic phenotype in the present case has also been elucidated.Case presentationA female aged 6 years and 9 months born to endogamous and phenotypically healthy parents was diagnosed with global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her MRI of the brain revealed mild peritrigonal white matter hyperintensity, and MRI and CT scan of the temporal bones showed abnormal cranial nerves. The proband’s younger sister, aged 4-years, was similarly affected. Whole exome sequencing was performed in the proband, which revealed a novel homozygous, likely pathogenic, truncating frameshift variant, c.228_231dup (p.Thr78ProfsTer122) in exon 1 of the NEUROG1 gene (ENST00000314744.4). Segregation analysis by Sanger sequencing showed the proband and her younger sister to be homozygotes and their parents to be heterozygous carriers.ConclusionThis is the fourth report across the globe with a variant identified in the NEUROG1 gene to be associated with cranial dysinnervation phenotype. An additional phenotype of autism in two female siblings was a novel observation. We provide a hypothetical framework which could explain the pleiotropic effect of a dysfunctional NEUROG1 protein leading to autism and posit it as a candidate for diagnosis of autism spectrum disorder with congenital cranial dysinnervation disorder.

Duane syndrome: An overview on the current management.

Duane syndrome is one of the most common restrictive congenital strabismus characterized by variable horizontal duction deficits with globe retraction and shoots on attempted adduction and narrowing of the palpebral aperture. It is now listed as a congenital cranial dysinnervation disorder. The disease is usually unilateral with female preponderance. Basic etiopathogenesis involves dysinnervation of the lateral rectus (LR) due to aplastic/hypoplastic abducens nucleus with a secondary aberrant supply to the LR by the medial rectus (MR) subnucleus of the oculomotor nerve. Diagnosis of the disease is usually clinical. Due to the variable presentation of the disease, surgical management is a challenge and has to be individualized to achieve alignment in the primary gaze, reduction in globe retraction, upshoots and downshoots, and correction of any abnormal head posture. Differential recessions of the lateral and MR muscles are done to correct esotropia or exotropia in the primary gaze. For globe retraction and shoots, Y-split or periosteal fixation of the LR muscles is done depending on the severity.

Clinical and genetic characteristics of Chinese patients with congenital cranial dysinnervation disorders

Congenital cranial dysinnervation disorders (CCDDs) are a group of diseases with high clinical and genetic heterogeneity. Clinical examinations combined with Magnetic resonance imaging (MRI) and whole exome sequencing (WES) were performed to reveal the phenotypic and genotypic characteristics in a cohort of Chinese CCDDs patients. A total of 122 CCDDs patients from 96 families were enrolled. All patients showed restrictive eye movements, and 46 patients from 46 families (47.9%, 46/96) were accompanied by multiple congenital malformations.Multi-positional high-resolution MRI was performed in 94 patients from 88 families, of which, all patients had hypoplasia of the cranial nerves except HGPPS patientsand 15 patientsfrom 15 families (17.0%,15/88) were accompanied by other craniocerebral malformations. WES wasperformed in 122 CCDDspatients.Tenpathogenic variants were detected in KIF21A, TUBB3, and CHN1 genes in 43 families. Three variants were unreported, including KIF21A (c.1064T > C, p.F355S), TUBB3 (c.232T > A, p.S78T) and CHN1 (c.650A > G, p.H217R). Of the 43 probands harboring pathogenic variants, 42 were diagnosed with Congenital Fibrosis of Extraocular Muscles (CFEOM)and one was Duane Retraction Syndrome (DRS). No definite pathogenic variants in known candidate genes of CCDDs were found in sporadic DRS, Möbius Syndrome (MBS) and Horizontal Gaze Palsy with Progressive Scoliosis (HGPPS) patients. The CFEOM patients harboring R380C, E410K and R262H variants in TUBB3 gene and F355S variant in KIF21A gene exhibited syndromic phenotypes. This study broadened the phenotypic and genotypic spectrums of CCDDs, and it was the largest clinical and genetic investigation for CCDDs patients from China. KIF21A and TUBB3 were the common pathogenic genes in Chinese CFEOM. MRI coupled with WES can provide a supportive diagnosis in patients with clinically suspected CCDDs.

Echoencephalography of Möbius sequence: A congenital cranial dysinnervation disorder with brainstem calcifications.

Möbius sequence (MBS) previously known as Möbius syndrome is a rare nonprogressive developmental defect of the rhombencephalon leading to congenital abducens (VIth) and facial (VIIth) nerve palsy. Echoencephalography is the first, safe, noninvasive, and cost-effective imaging modality available at bedside. No study on the use of echoencephalography in neonates for the diagnosis of MBS has been previously reported. In this single tertiary center study, more than 18,000 neonates underwent echoencephalographic imaging over the span of two decades. Imaging was performed through the anterior, posterior, and lambdoid fontanelles. All neonates found to have calcifications of brainstem tegmental nuclei underwent additional imaging studies. Each neonate with MBS was carefully examined by the same investigator. Five neonates were shown to have punctate, bilateral, symmetrical tegmental pontine calcifications through all three acoustic windows. These calcifications extended caudally in most patients, and rostrally in 2 patients. Brainstem hypoplasia was best seen through the posterior fontanelle. Three out of five infants were noted to have brainstem hypoplasia with straightening of the floor of the fourth ventricle. In two children, facial collicular bulges and hypoglossal eminences were present. All five infants fulfilled clinical diagnostic criteria of MBS. In addition, a wide array of cerebral defects is identified. Echoencephalographic findings were confirmed by other imaging modalities. Knowledge of echoencephalographic features of MBS should improve its early recognition. A detailed description of the various imaging phenotypes of MBS is necessary to characterize the etiology of this heterogeneous congenital cranial dysinnervation disorder.

Congenital Fibrosis of the Extraocular Muscles: An Overview from Genetics to Management.

Congenital fibrosis of the extraocular muscles (CFEOM) is a genetic disorder belonging to the congenital cranial dysinnervation disorders and is characterized by nonprogressive restrictive ophthalmoplegia. It is phenotypically and genotypically heterogeneous. At least seven causative genes and one locus are responsible for the five subtypes, named CFEOM-1 to CFEOM-5. This review summarizes the currently available molecular genetic findings and genotype-phenotype correlations, as well as the advances in the management of CFEOM. We propose that the classification of the disorder could be optimized to provide better guidance for clinical interventions. Finally, we discuss the future of genetic-diagnosis-directed studies to better understand such axon guidance disorders.

Recessive variants in COL25A1 gene as novel cause of arthrogryposis multiplex congenita with ocular congenital cranial dysinnervation disorder.

A proper interaction between muscle-derived collagen XXV and its motor neuron-derived receptors protein tyrosine phosphatases σ and δ (PTP σ/δ) is indispensable for intramuscular motor innervation. Despite this, thus far, pathogenic recessive variants in the COL25A1 gene had only been detected in a few patients with isolated ocular congenital cranial dysinnervation disorders. Here we describe five patients from three unrelated families with recessive missense and splice site COL25A1 variants presenting with a recognizable phenotype characterized by arthrogryposis multiplex congenita with or without an ocular congenital cranial dysinnervation disorder phenotype. The clinical features of the older patients remained stable over time, without central nervous system involvement. This study extends the phenotypic and genotypic spectrum of COL25A1 related conditions, and further adds to our knowledge of the complex process of intramuscular motor innervation. Our observations indicate a role for collagen XXV in regulating the appropriate innervation not only of extraocular muscles, but also of bulbar, axial, and limb muscles in the human.

Superior Rectus Transposition in the Management of Duane Retraction Syndrome: Current Insights.

Various surgical approaches have been described for the management of Duane retraction syndrome (DRS), a type of congenital cranial dysinnervation disorder (CCDD), the goals of which include correcting the primary position deviation and abnormal head posture (AHP), minimizing globe retraction and overshoots and improving the ocular rotations. Vertical rectus transposition (VRT) is one such technique, found more effective in improving abduction and thereby expanding the field of binocular vision, as compared to horizontal muscle surgery. VRT, however, is associated with the risk of inducing vertical deviations and also poses a risk for development of anterior segment ischemia. To overcome these concerns, transposition of only the superior rectus to the lateral rectus was proposed and evaluated to reveal improvement in alignment, AHP and motility comparable to VRT but with lesser surgical time and fewer post-operative complications. With promising results in the management of DRS, superior rectus transposition (SRT) has been extensively studied and has evolved over the last decade with several modifications to further increase the efficiency and reduce the risk of post-operative complications. This article focusses on the pre-operative considerations while planning SRT in DRS, various approaches and surgical techniques described, and the outcomes and complications of SRT in DRS. The role of SRT in the management of other CCDDs may be explored with further studies.

Axonal Growth Abnormalities Underlying Ocular Cranial Nerve Disorders.

Abnormalities in cranial motor nerve development cause paralytic strabismus syndromes, collectively referred to as congenital cranial dysinnervation disorders, in which patients cannot fully move their eyes. These disorders can arise through one of two mechanisms: (a) defective motor neuron specification, usually by loss of a transcription factor necessary for brainstem patterning, or (b) axon growth and guidance abnormalities of the oculomotor, trochlear, and abducens nerves. This review focuses on our current understanding of axon guidance mechanisms in the cranial motor nerves and how disease-causing mutations disrupt axon targeting. Abnormalities of axon growth and guidance are often limited to a single nerve or subdivision, even when the causative gene is ubiquitously expressed. Additionally, when one nerve is absent, its normal target muscles attract other motor neurons. Study of these disorders highlights the complexities of axon guidance and how each population of neurons uses a unique but overlapping set of axon guidance pathways.

Optic Nerve Head and Retinal Abnormalities Associated with Congenital Fibrosis of the Extraocular Muscles.

Congenital fibrosis of the extraocular muscles (CFEOM) is a congenital cranial dysinnervation disorder caused by developmental abnormalities affecting cranial nerves/nuclei innervating the extraocular muscles. Autosomal dominant CFEOM arises from heterozygous missense mutations of KIF21A or TUBB3. Although spatiotemporal expression studies have shown KIF21A and TUBB3 expression in developing retinal ganglion cells, it is unclear whether dysinnervation extends beyond the oculomotor system. We aimed to investigate whether dysinnervation extends to the visual system by performing high-resolution optical coherence tomography (OCT) scans characterizing retinal ganglion cells within the optic nerve head and retina. Sixteen patients with CFEOM were screened for mutations in KIF21A, TUBB3, and TUBB2B. Six patients had apparent optic nerve hypoplasia. OCT showed neuro-retinal rim loss. Disc diameter, rim width, rim area, and peripapillary nerve fiber layer thickness were significantly reduced in CFEOM patients compared to controls (p < 0.005). Situs inversus of retinal vessels was seen in five patients. Our study provides evidence of structural optic nerve and retinal changes in CFEOM. We show for the first time that there are widespread retinal changes beyond the retinal ganglion cells in patients with CFEOM. This study shows that the phenotype in CFEOM extends beyond the motor nerves.

Congenital abducens-oculomotor dysinnervation: A novel congenital cranial dysinnervation disorder phenotype

In a boy aged 6 years left unilateral congenital ptosis with medial rectus-levator palpebrae superioris (MR-LPS) synkinesis; the coexisting hitherto unreported likely lateral rectus-superior rectus (LR-SR) dysinnervation is reported. Ocular movements were full and cover test did not reveal any ocular misalignment. Such a presentation can only arise from two concurrent dysinnervations: first one between inferior and superior divisions of third nerve and second one between third and sixth cranial nerve. The dysinnervation may conform to a forme-fruste TUBB3 (Tubulin, Beta 3 Class III Gene) pathogenic variant phenotype and may be classed as a novel congenital cranial dysinnervation disorder (CCDD).

Varied presentations of congenital ocular synkinesis: do they all fit congenital cranial dysinnervation disorder spectrum?

Synkinesis results from nerve miswirings and causes aberrant movements of the affected muscles. We present a series of cases of rare congenital ocular synkinesis involving the extraocular muscles and the levator palpebrae superioris and speculate the possibility of classifying these entities in the spectrum of congenital cranial dysinnervation disorder. Records of patients with the diagnosis of congenital ocular synkinesis were analyzed retrospectively. We analyzed the sex, laterality, and complete features of the ocular motility of each patient. Nine patients with congenital ocular synkinesis were included. A slight predominance of women was noted. In terms of laterality, four patients had only the right eye involved, four had only the left eye, and one had both eyes involved. Notably, 55.5% were orthotropic in the primary position. The third, fourth, and sixth cranial nerves were involved in the miswiring in 100%, 44.4%, and 11.1% of the cases, respectively. Congenital synkinesis might present in a very eclectic and uncommon fashion. The aberrant innervation in these cases classifies them into the group of congenital cranial dysinnervation disorders.

CONGENITAL MUSCULAR DYSTROPHIES: P.203 Recessive variants in COL25A1 are responsible for arthrogryposis multiplex congenita with an ocular congenital cranial dysinnervation disorder

Arthrogryposis multiplex congenita (AMC) is an extremely heterogeneous congenital disorder characterized by reduced fetal mobility and multiple congenital contractures at birth, occurring in 1/300-1/5000 newborns. AMC have various etiologies, including environmental and genetic causes such as neurological and neuromuscular disorders. Genetic diagnosis of AMC remains challenging. Here we present two unrelated patients from UK (pt 1) and USA (pt 2) with AMC due to recessive COL25A1 gene variants, a known cause of ocular congenital cranial dysinnervation disorder (CCDDs).

Non-classical 1p36 deletion in a patient with Duane retraction syndrome: case report and literature review

BackgroundMonosomy of 1p36 is considered the most common terminal microdeletion syndrome. It is characterized by intellectual disability, growth retardation, seizures, congenital anomalies, and distinctive facial features that are absent when the deletion is proximal, beyond the 1p36.32 region. In patients with proximal deletions, little is known about the associated phenotype, since only a few cases have been reported in the literature. Ocular manifestations in patients with classical 1p36 monosomy are frequent and include strabismus, myopia, hypermetropia, and nystagmus. However, as of today only one patient with 1p36 deletion and Duane retraction syndrome (DRS) has been reported.Case presentationWe describe a patient with intellectual disability, facial dysmorphism, and bilateral Duane retraction syndrome (DRS) type 1. Array CGH showed a 7.2 Mb de novo deletion from 1p36.31 to 1p36.21.DiscussionOur patient displayed DRS, which is not part of the classical phenotype and is not a common clinical feature in 1p36 deletion syndrome; we hypothesized that this could be associated with the overlapping deletion between the distal and proximal 1p36 regions. DRS is one of the Congenital Cranial Dysinnervation Disorders, and a genetic basis for the syndrome has been extensively reported. The HES3 gene is located at 1p36.31 and could be associated with oculomotor alterations, including DRS, since this gene is involved in the development of the 3rd cranial nerve and the 6th cranial nerve’s nucleus. We propose that oculomotor anomalies, including DRS, could be related to proximal 1p36 deletion, warranting a detailed ophthalmologic evaluation of these patients.

Lack of Torsion in the Type-III Duane Retraction Syndrome (DRS-III) Affected Left Eye During Dix -Hallpike Test

Abstract Background Duane retraction syndrome (DRS) is a congenital cranial dysinnervation disorder (CCDD) of ocular movements, characterized by deficits in horizontal duction associated with narrowing of palpebral fissure, retraction of eye globe on attempted adduction and occasionally accompanied by upshoot or downshoot of the eye globe. It is caused by congenital absence of sixth cranial nerve, which results in fibrotic changes in the extraocular muscles leading to an abnormal ocular motility--a concept known as CCDD. Depending on whether only abduction/adduction or both are affected, DRS has been classified into three types designated as type-I, type-II and type-III. The torsional movements of the affected eye in DRS have not been reported to be deficient hitherto, which could be due to difficulties in the routine bedside evaluation of such movements. Case Presentation An unusual case of a patient of left unilateral type-III DRS is reported, who presented with a short history of vertigo on getting up from supine to sitting position and on assuming right lateral recumbent position. The diagnostic right Dix-Hallpike test (DHT) revealed upbeating torsional geotropic positioning nystagmus in the normal right eye and upbeating positioning nystagmus without torsional component in the abnormal left eye and this clinical finding was video recorded. Conclusion The observed lack of incyclotorsion of the left eye, affected with DRS-III during right Dix-Hallpike positioning, is primarily due to the absence of initial slow-phase excyclotorsional component. If the slow phase of VOR does not occur, then the fast-phase VOR, which is a refixation saccade, will be lacking too. An anastomosis, either in the lateral wall of the cavernous sinus or within the orbit, between the trochlear nerve and fibers of the oculomotor nerve can lead to simultaneous co-contraction of the inferior and superior oblique muscles. This is the most probable explanation for such finding of asymmetrical absence of torsional component in the left eye affected by DRS-III, during right Dix -Hallpike positioning. Thus, the recording of eye movements (voluntary and involuntary) opened a window into the brain to conceptualize neural and mechanical factors influencing the human eye movements.