Pendular Nystagmus; Horizontal Gaze Palsy

Horizontal Pendular Nystagmus; Horizontal Gaze Palsy; Preservation of Convergence; Normal Vertical Gaze; Optokinetic Nystagmus Absent; Horizontal Vestibular Ocular Reflex AbsentJiggly eyesThe patient is a 29 year old retarded man with a rare autosomal recessive disorder characterized by congenital absence of conjugate horizontal eye movements, preservation of vertical gaze and convergence and horizontal pendular nystagmus. Ocular motility examination: Conjugate horizontal pendular nystagmus Absent horizontal gaze (saccadic and pursuit eye movements) Absent horizontal vestibular ocular reflex Absent optokinetic nystagmus (OKN) Normal vertical gaze Preservation of convergence Neurological examination: Normal. Congenital horizontal gaze palsy (HGP) is one of several genetic disorders of eye and lid control that are believed to result from cranial nuclear maldevelopment. Among these entities, the most closely related to HGP are Duane retraction syndrome and Mobius syndrome. Abnormal development of the abducens nucleus plays a crucial role in the pathogenesis of both these entities, as well as of HGP. These disorders, referred to as Congenital Cranial Disinnervation Syndrome, have the following features: • They are present at birth • Usually non-progressive • Have an autosomal inheritance pattern, that may occur sporadically. • May result from primary disinnervation, from failed or misguided development of neurons or • Result from aberrant innervation during development (i.e. secondary disinnervation). Brain MRI was not available in this case. Brain MRI in a 13 year old girl with HGP and progressive scoliosis (HGPPS) revealed: 1. A hypoplastic pons in which the posterior two-thirds were split into two halves by a midsagittal cleft extending ventrally from the fourth ventricular floor, generating a split pons sign on axial images. 2. The facial colliculi were absent, and the fourth ventricular floor was tent shaped. 3. The medulla was also hypoplastic and showed a butterfly configuration. 4. The inferior olivary nuclei were prominent with respect to the pyramids, and the prominence of the gracile and cuneate nuclei on the posterior aspect of the medulla was absent. The pathogenesis of the absence of horizontal gaze remains speculative. It may arise from aberrant supranuclear input onto the abducens motoneurons by axons from the pontine paramedian reticular formation that cannot cross the midline, and inability of the developing axons in the medial lateral fasciculus to cross the midline, and/or from lack of midline crossing by developing pontine neurons normally destined to cross. Children with congenital absence of conjugate horizontal eye movements may adopt several adaptive strategies to compensate for their deficit. They substitute rapid head movements (head saccades) for eye saccades to change gaze rapidly. When the head is restrained, they may use their intact vergence system to move both eyes into adduction and then cross-fixate, using the right eye to view objects seen on the left and vice versa. Additional signs reported in this syndrome include: Horizontal, elliptical or pendular nystagmus, as in this case Head shaking Intermittent slow blinking of one or both eyes Retraction of the non-fixing eye during vergence movements. Facial contraction with myokymia Progressive scoliosis which becomes disabling (Review ID162-7 Horizontal Gaze Palsy and Progressive Scoliosis alongside this case).This patient with a congenital cranial disinnervation syndrome had: Congenital horizontal pendular nystagmus Absent conjugate horizontal gaze (saccades and pursuit) Absent horizontal vestibular ocular reflex Absent optokinetic nystagmus Normal vertical gaze Plaitakis et al studied two brothers affected by HGPPS and homozygous for the E919K mutation of the ROBO3 gene. In addition to severe kyphoscoliosis and absence of conjugate lateral eye movements, the brothers had congenital horizontal pendular nystagmus, the pathology of which remains unclear. Vertical OKNs were preserved, the vestibulocular reflex (VOR) was present in the vertical but not in the horizontal plane. Cold and warm caloric irrigation of the ears was performed. Cold water abolished the nystagmus of the ipsilateral eye. Conversely, warm water increased nystagmus of the ipsilateral eye The authors concluded that the monocular effects of caloric stimulation are consistent with a lack of crossing of brainstem vestibular pathways. They presumed that the loss of voluntary conjugate horizontal eye movements is on a similar basis.No neuroimaging studies are available in this patient. MRI Images obtained in a 13 year old girl with HGPPS and early onset thoracolumbar scoliosis showed: Figure 1A. Sagittal T1-weighted image of the brain shows depression of the floor of the fourth ventricle (arrowhead). The pons and medulla oblongata have a reduced volume. Figure 1B. Axial T2-weighted image at the level of the medulla oblongata shows rectangular configuration of the medulla. The floor of the fourth ventricle is tent shaped (arrows), with missing prominence of the cuneate and gracile nuclei. The inferior olivary nuclei (IO) are prominent with respect to the pyramids (P). Figure 1C. Axial T2-weighted image at the level of the pons shows absence of the facial colliculi, with tent shaped configuration of the floor of the fourth ventricle (arrows). A deep midsagittal cleft extends ventral from the fourth ventricular floor, producing the split pons sign (arrowhead). Figure 2. MRI of the spine showing prominent scoliosis. Courtesy Andrea Rossi, M.D.Brainstem hypoplasiaLinkage studies have localized a mutation of the ROBO 3 gene on chromosome 11q23 -25 which is important for hindbrain midline axon crossing.Genetic disorder Mutation of the ROBO 3 gene on chromosome 11q23-q25.1. Bosley TM, Salih MA, Jen JC, Lin DD, Oystreck D, Abu-Amero KK, MacDonald DB, al Zayed Z, al Dhalaan H, Kansu T, Stigsby B, Baloh RW. Neurologic features of horizontal gaze palsy and progressive scoliosis with mutations in ROBO3. Neurology. 2005;64:1196-1203. http://www.ncbi.nlm.nih.gov/pubmed/15824346 2. Engle EC, Leigh RJ. Genes, brainstem development and eye movements. Neurology 2002;59:304-305. http://www.ncbi.nlm.nih.gov/pubmed/12177361 3. Jen J, Coulin CJ, Bosley TM Salih MAM, Sabatti C, Nelson SF, Baloh RW. Familial horizontal gaze palsy with progressive scoliosis maps to chromosome 11q23-25. Neurology 2002;59:432-435. http://www.ncbi.nlm.nih.gov/pubmed/12177379 4. Jen JC, Chan WM, Bosley TM, Wan J, Carr JR, Rüb U, Shattuck D, Salamon G, Kudo LC, Ou J, Lin DD, Salih MA, Kansu T, Al Dhalaan H, Al Zayed Z, MacDonald DB, Stigsby B, Plaitakis A, Dretakis EK, Gottlob I, Pieh C, Traboulsi EI, Wang Q, Wang L, Andrews C, Yamada K, Demer JL, Karim S, Alger JR, Geschwind DH, Deller T, Sicotte NL, Nelson SF, Baloh RW, Engle EC. Mutations in a human ROBO gene disrupt hindbrain axon pathway crossing and morphogenesis. Science. 2004 Jun 4;304(5676):1509-1513. http://www.ncbi.nlm.nih.gov/pubmed/15105459 5. Kruis JA, Houtman WA, Van Weerden TW. Congenital absence of conjugate horizontal eye movements. Doc Ophthalmol. 1987; 67:13-18. http://www.ncbi.nlm.nih.gov/pubmed/3428093 6. Pieh C, Lengyel D, Neff A, Fretz C, Gottlob I. Brainstem hypoplasia in familial horizontal gaze palsy and scoliosis. Neurology. 2002;59:462-463. http://www.ncbi.nlm.nih.gov/pubmed/12177390 7. Plaitakis A, Tzagournissakis M, Christodoulou P, Jen JC, Baloh RW. Vestibular modification of congenital pendular nystagmus in HGPPS with the ROBO3 mutation (abstract). Neurology 2005;64(suppl 1):A33. 8. Rossi A, Catala M, Biancheri R, Di Comite R, Tortori-Donati P. MR imaging of brain-stem hypoplasia in horizontal gaze palsy with progressive scoliosis. Am J Neuroradiol. 2004;25:1046-1048. http://www.ncbi.nlm.nih.gov/pubmed/15205146 9. Sharpe JA, Silversides JL, Blair RD. Familial paralysis of horizontal gaze. Associated with pendular nystagmus, progressive scoliosis, and facial contraction with myokymia. Neurology 1975;25:1035-1040. http://www.ncbi.nlm.nih.gov/pubmed/1237821 10. Sicotte NL, Plaitakas A, Salamon G, et al. Brainstem axon crossing defects in horizontal gaze palsy with progressive scoliosis assessed with diffusion tensor imaging and neurophysiological testing. Neurology 2005;64(Suppl1):A2. 11. Thomsen M, Steffen H, Sabo D, Niethard FU. Juvenile progressive scoliosis and congenital horizontal gaze palsy. J Pediatr Orthop B 1996;5:185-189. http://www.ncbi.nlm.nih.gov/pubmed/8866284 12. Yee RD, Duffin RM, Baloh RW, Isenberg SJ. Familial congenital paralysis of horizontal gaze. Arch Ophthalmol. 1982;100:1449-1452. http://www.ncbi.nlm.nih.gov/pubmed/7115172 13. Zweifach PH, Walton DS, Brown RH. Isolated congenital horizontal gaze paralysis. Occurrence of the near reflex and ocular retraction on attempted lateral gaze. Arch Ophthalmol 1969;81:345-350. http://www.ncbi.nlm.nih.gov/pubmed/577429