Adding evidence to the role of NEUROG1 in congenital cranial dysinnervation disorders.

Congenital cranial dysinnervation disorders (CCDDs) are a heterogeneous group of neurodevelopmental phenotypes caused by a primary disturbance of innervation due to deficient, absent, or misguided cranial nerves. Although some CCDDs genes are known, several clinical phenotypes and their aetiologies remain to be elucidated. We describe a 12-year-old boy with hypotonia, developmental delay, sensorineural hearing loss, and keratoconjunctivitis due to lack of corneal reflex. He had a long expressionless face, severe oromotor dysfunction, bilateral agenesis/severe hypoplasia of the VIII nerve with marked atresia of the internal auditory canals and cochlear labyrinth malformation. Trio-exome sequencing identified a homozygous loss of function variant in the NEUROG1 gene (NM_006161.2: c.202G > T, p.Glu68*). NEUROG1 is considered a causal candidate for CCDDs based on (i) the previous report of a patient with a homozygous gene deletion and developmental delay, deafness due to absent bilateral VIII nerves, and severe oromotor dysfunction; (ii) a second patient with a homozygous NEUROG1 missense variant and corneal opacity, absent corneal reflex and intellectual disability; and (iii) the knockout mouse model phenotype which highly resembles the disorder observed in humans. Our findings support the growing compelling evidence that loss of NEUROG1 leads to a very distinctive disorder of cranial nerves development.

Mandibular Myalgia and Miniscule Meckel's Caves.

Trigeminal neuropathy manifests as episodic sharp, shooting pain in the maxillofacial region. Contributory etiologies are myriad, ranging from central pathology affecting its origin in the brainstem to peripheral processes affecting their distal-most insertion sites. We present a case of bilateral hypoplastic Meckel's caves in an adult patient leading to the clinical symptomology of trigeminal neuralgia. To the best of our knowledge, this is the only report of its kind highlighting this anatomic variant.

Trigeminal nerve agenesis with absence of foramina rotunda in Gómez-López-Hernández syndrome.

Gómez-López-Hernández syndrome (GLHS) is a clinical condition traditionally characterized by rhombencephalosynapsis (RS), parieto-occipital alopecia, and trigeminal anesthesia. It is a neurocutaneous disorder with no known etiology. The underlying cause of the trigeminal anesthesia in GLHS has not been examined or reported; it has merely been identified on clinical grounds. In this report, a 10-month-old white female born at 37 weeks gestational age with GLHS underwent a contrast-enhanced CT for the evaluation of craniofacial dysmorphic features. Thin-section bone algorithm images showed absence of bilateral foramina rotunda and trigeminal nerve fibers. The maxillary branch of the trigeminal nerve passes through the foramen rotundum and carries sensory information from the face. This case is unique because trigeminal nerve absence has not been suggested as a possible etiology for trigeminal anesthesia associated with GLHS. It is not known how many cases of GLHS have agenesis of the trigeminal nerve; however, a review of the literature suggests that this patient is the first. The triad of RS, alopecia, and trigeminal anesthesia is specific to GLHS; therefore, early identification of trigeminal nerve agenesis in patients with RS could expedite diagnosis of GLHS, particularly given that the clinical diagnosis of trigeminal anesthesia in neonates is a challenging one. Diagnosing alopecia in newborns is likewise challenging. Early diagnosis could allow for early intervention, especially for ophthalmic complications, which are known to have significant long-term effects. This case illustrates the benefits of CT imaging in the detection of trigeminal nerve and foramina rotunda abnormalities in neonates with suspected GLHS.

Trigemino-abducens synkinesis after lateral orbitotomy.

A 30-year-old man underwent lateral orbitotomy with removal of dermoid cyst in the right orbit. One month after operation, the patient started to experience double vision. He had 25 prism diopters of esotropia in primary gaze with marked limitation of abduction in the right eye. Seven months after the operation, he developed synkinetic movement of the eye when clenching his teeth. He could abduct his right eye while gritting his teeth. This is the fourth reported case of trigemino-abducens synkinesis and the first reported case without brain trauma.

Trigeminal neuralgia and persistent trigeminal artery.

We report a case of trigeminal neuralgia caused by persistent trigeminal artery (PTA) associated with asymptomatic left temporal cavernoma. Our patient presented unstable blood hypertension and the pain of typical trigeminal neuralgia over the second and third divisions of the nerve in the right side of the face. The attacks were often precipitated during physical exertion. MRI and Angio-MRI revealed the persistent carotid basilar anastomosis and occasionally left parietal cavernoma. After drug treatment of blood hypertension, spontaneous recovery of neuralgia was observed and we planned surgical treatment of left temporal cavernoma.

Bilateral Marcus Gunn jaw winking synkinesis with monocular elevation deficiency: a case report and literature review.

Marcus Gunn jaw winking synkinesis (MGJWS) occurs due to an aberrant innervation of the levator palpebrae superioris muscle by a branch of the motor division of the trigeminal nerve that supplies the muscles of mastication. MGJWS is mostly unilateral occurring in isolation and is less frequently associated with ocular or systemic abnormalities. Although MGJWS is mostly unilateral, few bilateral cases have been reported. Here we describe a rare case of bilateral MGJWS in an 18 year-old male patient with asymmetric bilateral ptosis and monocular elevation deficiency in the right eye.

Pediatric Use of Recombinant Human Nerve Growth Factor 20 µg/mL Eye Drops (Cenegermin) for Bilateral Neurotrophic Keratopathy in Congenital Corneal Anesthesia.

PURPOSE: This study aimed to present the efficacy and safety of cenegermin eye drop (Oxervate; Dompè Farmaceutici, Milan, Italy) treatment in a pediatric patient affected by neurotrophic keratopathy (NK) with Goldenhar syndrome. METHODS: This case reports an infant presenting ulceration and a small central opacity in the cornea of the right and left eyes, respectively. The NK bilaterally worsened despite the use of therapeutic contact lenses and temporary partial tarsorrhaphy. Magnetic resonance imaging showed absence and hypoplasia of the right and left trigeminal nerves, respectively. Cenegermin eye drops were administered 1 drop/each eye, 6 times daily for 8 weeks to promote corneal healing. RESULTS: Complete healing was achieved in both eyes after treatment. During the 16-month follow-up period, no epithelial defect, recurrence, or complications were noticed, whereas corneal opacities progressively became clearer, although insignificant improvements in corneal sensitivity or in the reflex tearing were observed. CONCLUSIONS: Cenegermin was effective in treating NK in an infant with Goldenhar syndrome.

Marcus Gunn jaw-winking synkinesis: clinical features and management.

OBJECTIVE: To evaluate the clinical features including eyelid excursion and management of Marcus Gunn jaw-winking synkinesis (MGJWS). DESIGN: Observational case series. PARTICIPANTS: Forty-eight consecutive patients with MGJWS. METHODS: Clinical features and management of 48 patients with MGJWS were reviewed retrospectively. Upper eyelid excursion was measured and graded. Complications of surgical intervention were evaluated. MAIN OUTCOME MEASURES: Resolution of MGJWS and symmetry of upper eyelids in primary position. RESULTS: Excursion of the ptotic eyelid with jaw movement in MGJWS was graded as mild (<2 mm) in 16% of patients, moderate (2-4 mm) in 76% of patients, and severe (> or = 5 mm) in 8% of patients. Thirty patients with moderate or severe MGJWS underwent disabling of the involved levator muscle and bilateral or unilateral frontalis suspension and had more than 6 months of follow-up. After a mean follow-up of 62 months, MGJWS resolved in 29 (97%) patients and improved from 6 mm to 2 mm in 1 (3%) patient. Relative upper eyelid height was within 1 mm in 87% of patients in primary position and within 1 mm in 80% of patients in downgaze. Twenty-six patients had bilateral frontalis suspension with disabling of unilateral levator muscle on the involved side. Relative upper eyelid height was within 1 mm in 88% of patients in the primary position and within 1 mm in 88% of patients in downgaze. Four non-amblyopic patients had unilateral frontalis suspension with levator muscle disabling. Relative upper eyelid height was symmetrical in 75% of the patients in primary position and in 25% of patients in downgaze. Complications included eyelash ptosis in 10% of the patients, loss of eyelid crease in 10%, and entropion in 3%. CONCLUSIONS: Most of the patients with MGJWS exhibited moderate eyelid excursion. Disabling of the involved levator muscle and bilateral frontalis suspension and, in selected cases, disabling of the involved levator muscle and unilateral frontalis suspension were effective in the treatment of MGJWS. Eyelash ptosis and loss of eyelid crease were the most common complications, each occurring in 10% of the patients. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

mGluR5 regulates glutamate-dependent development of the mouse somatosensory cortex.

We have previously reported that mGluR5 signaling via PLC-beta1 regulates the development of whisker patterns within S1 (barrel) cortex of mice (Hannan et al., 2001). However, whether these defects arise from the loss of postsynaptic mGluR5 signaling, and whether the level of mGluR5 is important for barrel formation, was not examined. Furthermore, whether mGluR5 regulates other developmental processes that occur before or after barrel development is not known. We now show that mGluR5 is present postsynaptically at thalamocortical synapses during barrel formation. In addition, Mglur5(+/-) mice exhibit normal TCA patch formation but reduced cellular segregation in layer 4, indicating a dose-dependent role for mGluR5 in the regulation of pattern formation. Furthermore Mglur5(-/-) and Mglur5(+/-) mice display normal cortical arealization, layer formation, and size of PMBSF indicating the defects within S1 do not result from general abnormalities of cortical mapping during earlier stages of development. At P21 layer 4 neurons from Mglur5(-/-) and Mglur5(+/-) mice show a significant reduction in spine density but normal dendritic complexity compared with Mglur5(+/+) mice indicating a role in synaptogenesis during cortical development. Finally, mGluR5 regulates pattern formation throughout the trigeminal system of mice as the representation of the AS whiskers in the PrV, VpM, and S1 cortex was disrupted in Mglur5(-/-) mice. Together these data indicate a key role for mGluR5 at both early and late stages of neuronal development in the trigeminal system of mice.

Pontine tegmental cap dysplasia: the severe end of the clinical spectrum.

Pontine tegmental cap dysplasia (PTCD) is a newly described hindbrain malformation with distinct neuroradiological findings. Only 12 cases of PTCD have been described so far, all sporadic. We report 2 further patients. Both children presented after birth with significant feeding problems due to impaired mouth opening (previously not reported) and sucking difficulties. Facial, cochlear, and glossopharyngeal nerves were involved resulting in bilateral sensory deafness and a significant swallowing disorder requiring a gastrostomy. In one patient the trigeminal sensory nerve was also involved causing severe bilateral corneal clouding with impaired vision. Both patients showed only minimal developmental progress since birth and had no speech production. Furthermore, they had vertebral and rib anomalies. The patients died at the age of 15 and 32 months, respectively, due to intercurrent infections. The majority of patients reported previously were affected less severely. The presented patients may represent the severe end of the spectrum.

Trigeminal Nerve Compression Without Trigeminal Neuralgia: Intraoperative vs Imaging Evidence.

BACKGROUND: While high-resolution imaging is increasingly used in guiding decisions about surgical interventions for the treatment of trigeminal neuralgia, direct assessment of the extent of vascular contact of the trigeminal nerve is still considered the gold standard for the determination of whether nerve decompression is warranted. OBJECTIVE: To compare intraoperative and magnetic resonance imaging (MRI) findings of the prevalence and severity of vascular compression of the trigeminal nerve in patients without classical trigeminal neuralgia. METHODS: We prospectively recruited 27 patients without facial pain who were undergoing microvascular decompression for hemifacial spasm and had undergone high-resolution preoperative MRI. Neurovascular contact/compression (NVC/C) by artery or vein was assessed both intraoperatively and by MRI, and was stratified into 3 types: simple contact, compression (indentation of the surface of the nerve), and deformity (deviation or distortion of the nerve). RESULTS: Intraoperative evidence of NVC/C was detected in 23 patients. MRI evidence of NVC/C was detected in 18 patients, all of whom had intraoperative evidence of NVC/C. Thus, there were 5, or 28% more patients in whom NVC/C was detected intraoperatively than with MRI (Kappa = 0.52); contact was observed in 4 of these patients and compression in 1 patient. In patients where NVC/C was observed by both methods, there was agreement regarding the severity of contact/compression in 83% (15/18) of patients (Kappa = 0.47). No patients exhibited deformity of the nerve by imaging or intraoperatively. CONCLUSION: There was moderate agreement between imaging and operative findings with respect to both the presence and severity of NVC/C.

Disruption of semaphorin III/D gene causes severe abnormality in peripheral nerve projection.

The molecules of the collapsin/semaphorin gene family have been thought to play an essential role in axon guidance during development. Semaphorin III/D is a member of this family, has been shown to repel dorsal root ganglion (DRG) axons in vitro, and has been implicated in the patterning of sensory afferents in the spinal cord. Although semaphorin III/D mRNA is expressed in a wide variety of neural and nonneural tissues in vivo, the role played by semaphorin III/D in regions other than the spinal cord is not known. Here, we show that mice homozygous for a targeted mutation in semaphorin III/D show severe abnormality in peripheral nerve projection. This abnormality is seen in the trigeminal, facial, vagus, accessory, and glossopharyngeal nerves but not in the oculomotor nerve. These results suggest that semaphorin III/D functions as a selective repellent in vivo.

Loss of neuronal projections in the dystrophin-deficient mdx mouse is not progressive.

Lack of dystrophin is known to reduce several cerebral fiber systems. To investigate if the loss of fibers is progressive, we analyzed projections of the trigeminal sensory system to the red nucleus in 3, 6, and 12 month old dystrophin-deficient mdx mice. The retrograde tracer fluorogold was injected in the magnocellular part of the red nucleus, and the number of labeled neurons in the oral part of the spinal trigeminal nucleus (Sp5O) was counted. We found that the number of labeled Sp5O neurons was reduced by 50% in mdx mice compared to age-matched control mice. The number of labeled Sp5O neurons did not change significantly between 3 and 12 months neither in mdx nor in control mice. In addition, the number of labeled neurons in the interstitial system of the trigeminal nerve was reduced by 43% in mdx mice. We conclude that fiber loss did not continue beyond the age of 3 months. Our data suggest that lack of full-length dystrophin impairs neuronal migration or axonal outgrowth, or increases neuronal death during fetal or early life.

Congenital corneal anesthesia.

Congenital corneal anesthesia is a rare clinical entity that poses a diagnostic dilemma, particularly in the pediatric age group. The sensory deficit may be confined to the cornea, or extend to other divisions of the trigeminal nerve. The sensory deficit may occur as an isolated abnormality, as part of a complex neurological syndrome, or it may occur in association with multiple somatic abnormalities and congenital insensitivity to pain. This condition usually presents between the ages of 8 to 12 months. Poor vision, photophobia, conjunctival injection, and corneal ulceration in the absence of pain and distress in a child should alert the clinician to the possibility of anesthetic cornea. In the early stages of presentation, punctuate keratopathy is the main feature, which may progress to non-healing persistent corneal epithelial defects. This stage may progress to acute corneal lysis and perforation. In most patients, conservative approaches such as copious lubrication, prevention of self-harm and cautious use of bandage contact lenses are effective in preventing progressive corneal damage. Tarsorrhapy is effective in promoting epithelial healing and permanent lateral tarsorraphy may prevent further development of epithelial defects. Amniotic membrane graft may be considered in order to improve epithelial healing. Corneal grafts carry a poor prognosis. Accurate initial diagnosis, evaluation, and proper management are paramount to prevent visual loss due to long-term complications of corneal anesthesia. This review of the literature outlines the problems and approaches in diagnosis, evaluation, and management of this rare condition.

[Locked-in syndrome due to bilateral cerebral peduncular infarctions with occlusion of persistent primitive trigeminal artery].

A 61-year-old woman with diabetes mellitus was admitted to our hospital with right hemiparesis and dysarthria. Brain MRI showed bilateral cerebral peduncular infarctions. Three days after admission, she was unable to generate any voluntary movements, except for those of the eye, suggesting locked-in syndrome (LIS). She could not speak, but showed good comprehension by blinking in response to verbal commands. Brain CT 5 days later revealed subarachnoid hemorrhage (SAH) around quadrigeminal and ambient cistern. Cerebral angiogram on the following day revealed no aneurysm, occlusion of right persistent primitive trigeminal artery (PPTA) and a little flow of the bilateral vertebral arteries. Eye movements were impossible in all directions on the 11th day and MRI showed new infarctions of the midbrain and the ventral portion of the pons. However, an EEG on the 20th day was almost normal. We speculated that low blood flow in the basilar artery from the PPTA caused bilateral cerebral peduncular infarctions, and that weakness of the PPTA caused SAH.

[Clinical characteristics of moderate and severe Marcus-Gunn jaw-winking synkinesis and its surgical treatment].

OBJECTIVE: To investigate the clinical characteristics of moderate and severe Marcus-Gunn jaw winking synkinesis and it surgical management. METHODS: Thirty-three patients with Marcus-Gunn syndrome were enrolled from 1997 to 2003 in Zhongshan Ophthalmic Center. The clinical characteristics were analyzed based on the records. Unilateral levator excision and frontalis flap suspension were performed for the correction of ptosis and the results were analyzed. RESULTS: The follow-up period varied from 1 to 6 years. Sixteen patients were male and 17 were female. The left eye was involved in 22 patients and the right eye in 11 patients. There was no family history. The amount of ptosis in each patient was more than 2 mm. At the end of observation, good results were achieved for ptosis correction in 26 (87%) of 30 patients, fair results in 3 (10%) patients. CONCLUSIONS: The ptosis of patients with moderate and severe Marcus-Gunn syndrome needs to be treated surgically. Unilateral frontalis flap suspension combined levator excision can correct ptosis very well for patients with moderate and severe Marcus-Gunn syndrome.

Mash1 and Math3 are required for development of branchiomotor neurons and maintenance of neural progenitors.

Basic helix-loop-helix (bHLH) transcription factors are known to play important roles in neuronal determination and differentiation. However, their exact roles in neural development still remain to be determined because of the functional redundancy. Here, we examined the roles of neural bHLH genes Mash1 and Math3 in the development of trigeminal and facial branchiomotor neurons, which derive from rhombomeres 2-4. In Math3-null mutant mice, facial branchiomotor neurons are misspecified, and both trigeminal and facial branchiomotor neurons adopt abnormal migratory pathways. In Mash1;Math3 double-mutant mice, trigeminal and facial branchiomotor neurons are severely reduced in number partly because of increased apoptosis. In addition, neurons with migratory defects are intermingled over the midline from either side of the neural tube. Furthermore, oligodendrocyte progenitors of rhombomere 4 are reduced in number. In the absence of Mash1 and Math3, expression of Notch signaling components is severely downregulated in rhombomere 4 and neural progenitors are not properly maintained, which may lead to intermingling of neurons and a decrease in oligodendrocyte progenitors. These results indicate that Mash1 and Math3 not only promote branchiomotor neuron development but also regulate the subsequent oligodendrocyte development and the cytoarchitecture by maintaining neural progenitors through Notch signaling.

GAP-43 heterozygous mice show delayed barrel patterning, differentiation of radial glia, and downregulation of GAP-43.

GAP-43 heterozygous (HZ) mice exhibit abnormal thalamocortical pathfinding, fasciculation, and terminal arborization at postnatal day 7 (P7). Here we tested whether these defects are correlated with delayed development of HZ cortical patterns. We assessed the rate of barrel segregation and radial glia differentiation in wild-type (WT) and HZ cortices. Since GAP-43 is involved in some forms of neural plasticity, we also compared the duration of the critical period for lesion-induced plasticity in both genotypes. Cytochrome oxidase histochemistry revealed a delay of approximately 1 day in barrel pattern formation in GAP-43 HZ mice. GAP-43 WT barrels showed complete segregation between P2-P3, while HZ barrels did not reach the same level of segregation until P3-P4. We found a similar delay in the transformation of radial glia from monopolar to multipolar phenotypes, from P5 in WT to P7 in HZ cortex. Radial glial cells represent many of the neuronal progenitors in developing cortex and aid in cell migration. Thus, the delay in radial glial differentiation may contribute to the delay in HZ barrel segregation. Interestingly, we found no change in the extent of the critical period for HZ cortical responsiveness to early peripheral damage or in the time course of the cortical response. As expected, GAP-43 expression in HZ cortex is significantly reduced early in development. However, HZ GAP-43 expression remains at maximum levels after P9, when it is normally downregulated. As a result, HZ GAP-43 expression is near-normal by P26, by which time near-normal barrel dimensions have been restored. Our findings indicate that GAP-43 deficiency leads to early delays in barrel development and suggest that these failures are followed by homeostatic responses, including prolonged GAP-43 expression. These compensatory mechanisms may rescue normal cortical reorganization in neonates and near-normal barrel morphology and GAP-43 expression in adulthood.

Early habituation of severe blepharoptosis in marcus gunn jaw-winking syndrome.

A 23-day-old neonate had severe unilateral Marcus Gunn jaw-winking syndrome (MGJWS). By 2 1/2 months of age, she controlled the ptosis with jaw positioning. Habituation of the pterygoid-levator synkinesis has not been reported this early. Surgery can be delayed until a safer time in MGJWS with severe ptosis that lacks objective signs of amblyopia.

Neurotrophic keratopathy secondary to trigeminal nerve aplasia in patient with Goldenhar syndrome.

CASE REPORT: A 4-year-old male diagnosed with Goldenhar syndrome, with an unremarkable ophthalmic history, develops a neurotrophic ulcer secondary to trigeminal nerve aplasia. It was treated with multilaminar amniotic membrane transplantation. DISCUSSION: Trigeminal nerve aplasia is not usually reported in Goldenhar syndrome. Therefore, it seems necessary to perform routine eye examinations, from an early age, to prevent serious complications associated with corneal anaesthesia.