Congenital Cranial Dysinnervation Disorder: An Unusual Phenotype With Multiple Cranial Neuropathies and Novel Neuroimaging Findings

Congenital cranial dysinnervation disorders result from a maldevelopment of brainstem nuclei and/or cranial nerves. In some cases, specific genetic abnormalities have been identified. We expand the clinical phenotype of these disorders with the report of a 28-month-old girl who was initially evaluated for seizures and was found to have right sixth nerve palsy, small optic discs with reduced vision in her right eye. Her development was delayed. Brain MRI showed multiple abnormalities involving other cranial nerves, the optic chiasm and brainstem. Her developmental delay and seizure disorder suggest additional cortical involvement.

Original Contribution Congenital Cranial Dysinnervation Disorder: An Unusual Phenotype With Multiple Cranial Neuropathies and Novel Neuroimaging Findings Michael S. Salman, MBBS, BSc, MRCP, MSc, PhD, Conor Mulholland, FRCSC, Jens Wrogemann, MD, Samantha E. Marin, MD Abstract: Congenital cranial dysinnervation disorders result from a maldevelopment of brainstem nuclei and/or cranial nerves. In some cases, specific genetic abnormalities have been identified. We expand the clinical phenotype of these disorders with the report of a 28-month-old girl who was initially evaluated for seizures and was found to have right sixth nerve palsy, small optic discs with reduced vision in her right eye. Her development was delayed. Brain MRI showed multiple abnormalities involving other cranial nerves, the optic chiasm and brainstem. Her developmental delay and seizure disorder suggest additional cortical involvement. Journal of Neuro-Ophthalmology 2019;39:348-351 doi: 10.1097/WNO.0000000000000762 © 2019 by North American Neuro-Ophthalmology Society C ongenital cranial dysinnervation disorders (CCDDs) result from a disturbance in development of brainstem nuclei and/or cranial nerves (1,2). The genetic abnormalities identified play an important role in the Section of Pediatric Neurology (MSS, SEM), Children's Hospital; Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Section of Pediatric Ophthalmology (CM), Children's Hospital; Department of Ophthalmology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Section of Pediatric Radiology (JW), Children's Hospital; Department of Radiology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada. The authors report no conflicts of interest. The mother gave consent for the photographs and the case to be published. Ethical approval for the case report was given by the Research Ethics Board of the University of Manitoba. Address correspondence to Michael S. Salman, MBBS, BSc, MRCP, MSc, PhD, Section of Pediatric Neurology, Children's Hospital, AE 308, 820 Sherbrook Street, Winnipeg, MB, R3A 1R9, Canada; E-mail: [e-mail] 348 development of the brainstem, specific cranial nerve nuclei, and/or their axonal connections to their targets including extraocular and facial muscles (2). The disorders are congenital, may be sporadic or familial, and are nonprogressive. In primary dysinnervation, there is absence of normal innervation where neurons do not develop or are misguided. In secondary dysinnervation, there is aberrant developmental innervation by branches of another nerve. The dysinnervation can cause secondary changes in muscular, orbital, and bony structures (1). We describe a patient who expands the clinical phenotype of CCDD. CASE REPORT A 28-month-old girl was evaluated for 2 generalized febrile seizures occurring 2 months apart. Further history revealed development delay and longstanding, nonprogressive ocular misalignment. Her prenatal course was unremarkable. There was no maternal gestational hypertension, diabetes, seizures, or exposure to illicit drugs, alcohol or smoking. Her mother was on levetiracetam for primary generalized epilepsy diagnosed in childhood. Labor was prolonged resulting in delivery by cesarian section. Birth weight was 7 pounds. After an unremarkable postnatal course, she went home on Day 3 of life. Her parents were nonconsanguineous and of white descent. On examination, her head circumference was 48 cm (50th percentile). She had no dysmorphic features or neurocutaneous stigmata. Visual acuity was less than 20/ 300 in the right eye and 20/50 in the left eye. Pupils were equal in size and reactive to light. She had a right esotropia of 35 prism diopters and limitation of abduction of the right eye. Her ocular movements were otherwise normal, and there was no palpebral fissure narrowing on adduction. Both optic discs appeared small, right greater than left. She had mild asymmetry of her right facial muscles when she Salman et al: J Neuro-Ophthalmol 2019; 39: 348-351 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution smiled raising concerns for right facial nerve palsy but forced eyelid closure and upward eyebrow movement were normal bilaterally. Examination of her lower cranial nerves (IX-XII) was normal. She had axial and appendicular hypotonia but normal strength, coordination, and reflexes. Stances and gait were normal. Complete blood count and serum chemistries were normal. Renal ultrasound was unremarkable and cardiac assessment including an echocardiogram revealed no abnormalities. Brain MRI was obtained at age 28 months and showed thinning of the right optic nerve and right side of the optic chiasm (Fig. 1). The right fifth, sixth and seventh nerves were thin (Fig. 2A, B). The vestibulocochlear nerves, semicircular canals, and middle ears appeared normal bilaterally (Fig. 2B). The right-sided muscles of mastication, right lateral rectus muscle, and right-sided muscles of facial expression were all correspondingly small (Fig. 3). There were bilateral, symmetric, nonenhancing T2 signal abnormalities in the posterior pons deep to the facial colliculi with evidence of restricted diffusion (Fig. 4). By age 4 years, these T2 changes persisted, but there was resolution of the diffusion abnormalities. At age 38 months, a formal developmental assessment revealed mild-moderate delay. At 44 months, the patient was found to have normal bilateral middle ear function and otoacoustic emissions. At age 46 months, her chewing, swallowing, and movements of her facial, tongue, shoulder, and neck muscles were normal. Sensation to her face was FIG. 2. A. Axial FIESTA MRI through the pons reveals a small right (arrow) but not left (arrowhead) trigeminal nerve. B. Axial FIESTA MRI at the pontomedullary junction demonstrates small right but not left sixth (arrows) and seventh (arrowheads) nerves. The vestibulocochlear nerves (hatched arrows) are normal. FIESTA, fast imaging employing steady‐state acquisition. intact to touch and pinprick. By age 51 months, photographic documentation showed normal facial muscle strength (Fig. 5) and evidence of small bilateral optic discs, right greater than left (Fig. 6). The patient developed afebrile seizures and was treated with levetiracetam with good results. At 54 months of age, her examination remained unchanged. She was treated for amblyopia with glasses and occlusion treatment. Surgery for esotropia has been offered but not pursued. FIG. 1. Oblique axial FIESTA brain MRI shows the optic chiasm (white arrow) and the optic nerves (black arrows). The optic chiasm on the right and the right intracranial optic nerve are small. FIESTA, fast imaging employing steady‐ state acquisition. Salman et al: J Neuro-Ophthalmol 2019; 39: 348-351 FIG. 3. Coronal FIESTA MRI of the orbits shows a small right optic nerve compared with the left, and fatty replacement of the right lateral rectus (white arrowhead), masseter (black arrowhead), and temporalis (black arrow) muscles. The left masseter and temporalis muscles are normal. FIESTA, fast imaging employing steady‐state acquisition. 349 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 4. A. Diffusion-weighted imaging through the pons shows restricted diffusion in the superior cerebellar peduncles (arrows), which is confirmed on the ADC map (B). C. Axial T2 brain MRI reveals bilateral nonenhancing T2 signal abnormalities in the posterior pons (arrows) deep to the facial colliculi, which appear symmetric. DISCUSSION The spectrum of disorders defined as CCDD has expanded, with increasing reports of different combinations of cranial nerves (2). Our patient's CCDD was characterized by: a) unique neuroimaging findings, b) small optic discs and involvement of the right fifth, sixth, and seventh cranial nerves, and c) FIG. 5. There is normal bilateral facial nerve function with eyelid closure. 350 additional features of global developmental delay, hypotonia, and epilepsy, implying additional cerebral involvement. The evolution of high-resolution MRI has allowed for more accurate anatomical evaluation of patients with CCDD (3-6). The neuroimaging results correlate strongly with pathologic findings (7,8). Our patient demonstrated thinning of the right optic nerve and right side of the optic chiasm and decreased caliber of the right fifth, sixth, and seventh cranial nerves. On repeated testing, she had no clear sensory abnormality within the trigeminal dermatomes and had no dysfunction in chewing. Our patient has normal facial movements despite the reduced size of the right facial nerves on MRI. Neuroimaging is important in patients with CCDD to determine the extent of cranial nerve involvement, as clinical symptoms or signs may underestimate the degree of cranial nerve dysinnervation. It is possible that some of the affected muscles of mastication and facial muscles in our patient may have been reinnervated by the surviving branches of the fifth and seventh cranial nerves, respectively, thus explaining their subclinical involvement. Alternatively, adequate number of muscle fibers may have been innervated by the surviving axons of the thin cranial nerves to explain their otherwise normal function on clinical examination despite atrophy of the muscles seen on neuroimaging. We are unaware of the finding in CCDD patients of hyperintense T2 signal within the dorsal pons. This abnormality was unchanged in appearance on 2 MRI studies completed approximately 1.5 years apart. The T2 hyperintensities may represent dysplastic or gliotic nuclei of the seventh nerve. Interestingly, the reduction the size of the seventh nerve was detected only on the right side despite the hyperintense signal being bilateral. In addition, there were no clinical manifestations of seventh nerve dysfunction on either side. This also supports the assertion that imaging of the cranial nerves in patients with CCDD may disclose abnormalities that are subclinical, as described in some patients with congenital fibrosis of the extraocular muscles Type 1, in whom the significant reduction in mean optic nerve size did not affect visual function (9). The neuroimaging abnormality that involved the superior cerebellar peduncles on the first MRI, which subsequently resolved, remains unexplained. Salman et al: J Neuro-Ophthalmol 2019; 39: 348-351 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited. Original Contribution FIG. 6. Both optic discs appear small, particularly in the right eye. In addition to the cranial nerve abnormalities, our patient presented with global developmental delay, hypotonia, and seizures. Global development delay and intellectual disability have been reported in a small proportion of patients with CCDD (10,11) and are typically associated with certain syndromes, such as Athabascan brainstem dysgenesis syndrome or TUBB3-associated congenital fibrosis of the extraocular muscles (2). Seizures also rarely occur in patients with CCDD and have been reported in patients with DURS2-associated CCDD and patients with Athabascan brainstem dysgenesis syndrome (2,6). The pathogenesis of CCDD has been proposed as either primary genetic resulting in maldevelopment of the brainstem, its nuclei, and axons; or ischemic due to toxins/teratogens interrupting brainstem blood supply during embryologic development (10). In some patients, we postulate that this maldevelopment or disruption may be associated with aberrant cortical development as well, resulting in a phenotype with developmental delay and epilepsy. Our patient did have a prenatal course complicated by levetiracetam exposure and a prolonged labor resulting in a cesarean section. Levetiracetam is prescribed widely in epilepsy due to its favorable side effect profile. Many observational studies are available and suggest a low risk of major congenital malformations with exposure to levetiracetam (12-15). Therefore, it is unlikely that levetiracetam contributed to the pathology seen in this patient. Although the patient was born through cesarean section, no resuscitation was required in the postnatal period, and no signs or symptoms suggestive of hypoxic brain injury were present in the perinatal period. Although the unilateral cranial nerves' involvement in our patient may be suggestive of local factors rather than a genetic etiology, the bilateral changes in the dorsal pons are suggestive of a genetic etiology. Therefore, the etiology of the findings in this case remains to be determined. STATEMENT OF AUTHORSHIP Category 1: a. conception and design: M. S. Salman and S. E. Marin; b. acquisition of data: M. S. Salman, C. Mulholland, J. Wrogemann, and S. E. Marin; c. analysis and interpretation of data: M. S. Salman, C. Mulholland, J. Wrogemann, and S. E. Marin. Category 2: a. drafting the manuscript: M. S. Salman and S. E. Marin; b. revising it for intellectual content: M. S. Salman, C. Mulholland, J. Wrogemann, and S. E. Marin. Category 3: a. final approval of the completed manuscript: M. S. Salman, C. Mulholland, J. Wrogemann, and S. E. Marin. Salman et al: J Neuro-Ophthalmol 2019; 39: 348-351 REFERENCES 1. Gutowski NJ, Bosley TM, Engle EC. 110th ENMC International Workshop: the congenital cranial dysinnervation disorders (CCDDs). Naarden, The Netherlands, 25-27 October, 2002. Neuromuscul Disord. 2003;13:573-578. 2. Bosley TM, Abu-Amero KK, Oystreck DT. Congenital cranial dysinnervation disorders: a concept in evolution. Curr Opin Ophthalmol. 2013;24:398-406. 3. Gupta C, Sharma P, Saxena R, Garg A, Sharma S. Clinical correlation of imaging findings in congenital cranial dysinnervation disorders involving abducens nerve. Indian J Ophthalmol. 2017;65:155-159. 4. Verzijl HT, Valk J, de Vries R, Padberg GW. Radiologic evidence for absence of the facial nerve in Möbius syndrome. Neurology. 2005;64:849-855. 5. Verzijl HT, Padberg GW, Zwarts MJ. The spectrum of Mobius syndrome: an electrophysiological study. Brain. 2005;128:1728-1736. 6. Santos G, Pereira S, Machado O, Sales F, Robalo C, Machado E. Möbius syndrome and epilepsy. J Neuroradiol. 2010;37:305- 307. 7. Towfighi J, Marks K, Palmer E, Vannucci R. Möbius syndrome. Neuropathologic observations. Acta Neuropathol. 1979;48:11-17. 8. Verzijl HTFM, van der Zwaag B, Lammens M, ten Donkelaar HJ, Padberg GW. The neuropathology of hereditary congenital facial palsy vs. Mobius syndrome. Neurology. 2005;64:649- 653. 9. Demer JL, Clark RA, Engle EC. Magnetic resonance imaging evidence for widespread orbital dysinnervation in congenital fibrosis of extraocular muscles due to mutations in KIF21A. Invest Ophthalmol Vis Sci. 2005;46:530-539. 10. Verzijl HTFM, van der Zwaag B, Johannes RM, Cruysberg JR, Padberg GW. Mobius syndrome redefined: a syndrome of rhombencephalic maldevelopment. Neurology. 2003;61:327- 333. 11. Sjögreen L, Andersson-Norinder J, Jacobsson C. Development of speech, feeding, eating, and facial expression in Möbius sequence. Int J Pediatr Otorhinolaryngol. 2001;60:197-204. 12. Mawhinney E, Craig J, Morrow J, Russell A, Smithson WH, Parsons L, Morrison PJ, Liggan B, Irwin B, Delanty N, Hunt SJ. Levetiracetam in pregnancy: results from the UK and Ireland epilepsy and pregnancy registers. Neurology. 2013;80:400- 405. 13. Hunt S, Craig J, Russell A, Guthrie E, Parsons L, Robertson I, Waddell R, Irwin B, Morrison PJ, Morrow J. Levetiracetam in pregnancy: preliminary experience from the UK Epilepsy and Pregnancy Register. Neurology. 2006;67:1876-1879. 14. Longo B, Forinash AB, Murphy JA. Levetiracetam use in pregnancy. Ann Pharmacother. 2009;43:1692-1695. 15. Weston J, Bromley R, Jackson CF, Adab N, Clayton-Smith J, Greenhalgh J, Hounsome J, McKay AJ, Tudur Smith C, Marson AG. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev. 2016;11:CD010224. 351 Copyright © North American Neuro-Ophthalmology Society. Unauthorized reproduction of this article is prohibited.