BDNF Influence on Adult Terminal Axon Sprouting after Partial Deafferentation.

BDNF is a neurotrophin family member implicated in many different neuronal functions, from neuronal survival during development to synaptic plasticity associated with processes of learning and memory. Its presence in the oculomotor system has previously been demonstrated, as it regulates afferent composition of extraocular motoneurons and their firing pattern. Moreover, BDNF expression increases after extraocular motoneuron partial deafferentation, in parallel with terminal axon sprouting from the remaining axons. To elucidate whether BDNF could play an active role in this process, we performed partial deafferentation of the medial rectus motoneurons through transection of one of the two main afferents, that is, the ascending tract of Deiters, and injected BDNF into the motoneuron target muscle, the medial rectus. Furthermore, to check whether BDNF could stimulate axon sprouting without lesions, we performed the same experiment without any lesions. Axon terminal sprouting was assessed by calretinin immunostaining, which specifically labels the remaining afferent system on medial rectus motoneurons, the abducens internuclear neurons. The results presented herein show that exogenous BDNF stimulated terminal axon growth, allowing the total recovery of synaptic coverage around the motoneuron somata. Moreover, calretinin staining in the neuropil exceeded that present in the control situation. Thus, BDNF could also stimulate axonal sprouting in the neuropil of intact animals. These results point to an active role of BDNF in plastic adaptations that take place after partial deafferentation.

The Abducens Nerve: Anatomy and Pathology.

The abducens, or the sixth cranial nerve, is purely motor and runs a long course from the brainstem to the lateral rectus. Travels with the inferior petrosal sinus through the Dorello's canal before entering the cavernous sinus. Based on the location of an abnormality, other neurologic structures may be involved with the disturbs related to this nerve. This article aims to review the abducens nerve anatomy and demonstrates the imaging aspect of the diseases that most commonly affect it.

Cavernous Sinus Swelling and Abducens Nerve Paresis Due to Intracranial Hypotension.

The most common neurological symptom of spontaneous intracranial hypotension (SIH) is abducens nerve paresis, and the precise pathophysiology is unclear. The accepted explanation is traction on the cranial nerves caused by the downward displacement of the cranial content. We herein report magnetic resonance imaging of SIH that can explain the mechanism underlying abducens nerve paresis. The cavernous sinuses were particularly thickened compared with the surrounding dura. This phenomenon can be explained by venous swelling, which can occur after leakage of cerebrospinal fluid in a closed cavity. This swelling pushes the abducens nerve up, which then causes abducens nerve paresis.

Review of the Petroclinoid Ligament.

An ossified left petroclinoid ligament was found during routine dissection of the skull base in an adult male cadaver. The petroclinoid ligament is clinically and surgically important given its anatomical relationships to cranial nerves III, V, and VI, so its ossification is a risk factor for injuries due to trauma, increased intracranial pressure, and vascular and tumor compression resulting in abducens and oculomotor palsies. The causes of petroclinoid ligament ossification are yet to be completely elucidated although several reports have associated them with age-related and physiological processes. Assessing the integrity of the petroclinoid ligament is important during skull base surgical interventions to avoid postoperative complications. Therefore, this paper reviews the petroclinoid ligament and its variation, the ossified petroclinoid ligament.

Abducens Nerve Schwannoma: First Case to Be Treated With an Expanded Endonasal Approach.

Abducens nerve schwannomas are incredibly rare, with very few cases being reported previously. Our patient is the first to have been treated through use of an endoscopic endonasal approach. A 61-year-old woman presented with diplopia over a 1-year period. Magnetic resonance imaging identified a 2.8-cm lesion expanding into her right sphenoid sinus. She underwent an endoscopic endonasal approach for histological diagnosis and clearance of the lesion. Intraoperative exploration found the lesion to be originating from Dorello canal. Histological analysis confirmed a benign schwannoma. Following a multidisciplinary case review, we have followed a conservative approach and she remains well on radiological surveillance. In patients presenting with a sixth nerve palsy/paresis and a concomitant sphenoid lesion, clinicians should consider an abducens schwannoma as a possible diagnosis.

Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.

The complete features of the neurological complications of coronavirus disease 2019 (COVID-19) still need to be elucidated, including associated cranial nerve involvement. In the present study we describe cranial nerve lesions seen in magnetic resonance imaging (MRI) of six cases of confirmed COVID-19, involving the olfactory bulb, optic nerve, abducens nerve, and facial nerve. Cranial nerve involvement was associated with COVID-19, but whether by direct viral invasion or autoimmunity needs to be clarified. The development of neurological symptoms after initial respiratory symptoms and the absence of the virus in the cerebrospinal fluid (CSF) suggest the possibility of autoimmunity.

Can Ophthalmologic Examination Predict Abducens Nerve Recovery After Endoscopic Skull Base Surgery?

OBJECTIVES: While abducens nerve palsy (ANP) is a known risk in the setting of some endoscopic endonasal skull base surgery (ESBS), frequency and prognosis of post-operative palsy remain unknown. Our goals were to determine the frequency and prognosis of ANP after high-risk ESBS, and identify factors associated with recovery. METHODS: Retrospective case series of all patients with pathology at highest risk for abducens nerve injury (pituitary adenoma, chordoma, meningioma, chondrosarcoma, cholesterol granuloma) generated a list of patients with abducens nerve palsy after ESBS performed from 2011-2016. A validated ophthalmologic clinical grading scale measuring lateral rectus duction from 0 to -5 (full motion to inability to reach midline) was measured at multiple time points to assess recovery of ANP. RESULTS: Of 655 patients who underwent ESBS with increased risk of abducens injury, 40 (6.1%) post-operative palsies were identified and 39 patients with dedicated examination at multiple time points were included in subsequent analysis. Complete resolution was noted in 25 patients (64%) within 12 months. While 19 of 23 (83%) with a partial palsy had complete resolution, only six of 16 (38%) with a complete palsy resolved entirely (P = .005; Fisher's exact test). All six patients with delayed onset of palsy resolved (P = .070; Fisher's exact test). Meningioma and chordoma had higher rates of both temporary and permanent post-operative ANP (P < .0001; Fisher's exact). CONCLUSIONS: The frequency of post-operative ANP following ESBS is low, even in high-risk tumors. While only a minority of complete abducens nerve palsies recover, patients with partial or delayed palsy post-operatively are likely to recover function without intervention. LEVEL OF EVIDENCE: IV Laryngoscope, 131:513-517, 2021.

A clinical study of ocular motor nerve functions after petroclival meningioma resection.

BACKGROUND: Ocular motor dysfunction is one of the most common postoperative complications of petroclival meningioma. However, its incidence, recovery rate, and independent risk factors remain poorly explored. METHODS: A prospective analysis of 31 petroclival meningiomas was performed. Operative approaches were selected by utilizing a new 6-region classification of petroclival meningiomas we proposed. Two scores were used to evaluate the functions of the oculomotor and abducens nerves. Pearson correlation analysis and binary logistic regression analysis were used to identify independent risk factors for intraoperative oculomotor and abducens nerve injury. RESULTS: Postoperative new-onset dysfunctions in the pupillary light reflex and eye/eyelid movements as well as abducens paralysis were detected in eight (25.8%), ten (32.3%) and twelve (38.7%) cases, respectively. Their corresponding recovery rates after 6 months of follow-up were 75% (6/8), 80% (8/10), and 83.3% (10/12), respectively, and their mean times to start recovery were 4.03, 2.43, and 2.5 months, respectively. Tumor invasion into the suprasellar region/sphenoid sinus was the only risk factor for dysfunctions in both the pupillary light reflex (p = 0.001) and eye/eyelid movements (p = 0.002). Intraoperative utilization of the infratrigeminal interspace was the only risk factor for dysfunction in eyeball abduction movement (p = 0.004). CONCLUSIONS: Dysfunctions of the oculomotor and abducens nerves recovered within 6 months postoperatively. Tumor extension into the suprasellar region/sphenoid sinus was the only risk factor for oculomotor nerve paralysis. Eye/eyelid movements were more sensitive than the pupillary light reflex in reflecting nerve dysfunctions. Intraoperative utilization of the infratrigeminal interspace was the only risk factor for abducens nerve paralysis.

Intramuscular Distribution of the Abducens Nerve in the Lateral Rectus Muscle for the Management of Strabismus.

AIMS: To elucidate the intramuscular distribution and branching patterns of the abducens nerve in the lateral rectus (LR) muscle so as to provide anatomical confirmation of the presence of compartmentalization, including for use in clinical applications such as botulinum toxin injections. METHODS: Thirty whole-mount human cadaver specimens were dissected and then Sihler's stain was applied. The basic dimensions of the LR and its intramuscular nerve distribution were investigated. The distances from the muscle insertion to the point at which the abducens nerve enters the LR and to the terminal nerve plexus were also measured. RESULTS: The LR was 46.0 mm long. The abducens nerve enters the muscle on the posterior one-third of the LR and then typically divides into a few branches (average of 1.8). This supports a segregated abducens nerve selectively innervating compartments of the LR. The intramuscular nerve distribution showed a Y-shaped ramification with root-like arborization. The intramuscular nerve course finished around the middle of the LR (24.8 mm posterior to the insertion point) to form the terminal nerve plexus. This region should be considered the optimal target site for botulinum toxin injections. We have also identified the presence of an overlapping zone and communicating nerve branches between the neighboring LR compartments. CONCLUSION: Sihler's staining is a useful technique for visualizing the entire nerve network of the LR. Improving the knowledge of the nerve distribution patterns is important not only for researchers but also clinicians to understand the functions of the LR and the diverse pathophysiology of strabismus.

Distinct functional consequences of ECEL1/DINE missense mutations in the pathogenesis of congenital contracture disorders.

Endothelin-converting enzyme-like 1 (ECEL1, also termed DINE in rodents), a membrane-bound metalloprotease, has been identified as a gene responsible for distal arthrogryposis (DA). ECEL1-mutated DA is generally characterized by ocular phenotypes in addition to the congenital limb contractures that are common to all DA subtypes. Until now, the consequences of the identified pathogenic mutations have remained incompletely understood because of a lack of detailed phenotypic analyses in relevant mouse models. In this study, we generated a new knock-in mouse strain that carries an ECEL1/DINE pathogenic G607S missense mutation, based on a previous study reporting atypical DA hindlimb phenotypes in two siblings with the mutation. We compared the morphological phenotypes of G607S knock-in mice with C760R knock-in mice that we previously established. Both C760R and G607S knock-in mouse embryos showed similar axonal arborization defects with normal trajectory patterns from the spinal cord to the target hindlimb muscles, as well as axon guidance defects of the abducens nerves. Intriguingly, distinct phenotypes in DINE protein localization and mRNA expression were identified in these knock-in mouse lines. For G607S, DINE mRNA and protein expression was decreased or almost absent in motor neurons. In the C760R mutant mice DINE was expressed and localized in the somata of motor neurons but not in axons. Our mutant mouse data suggest that ECEL1/DINE G607S and C760R mutations both lead to motor innervation defects as primary causes in ECEL1-mutated congenital contracture disorders. However, the functional consequences of the two mutations are distinct, with loss of axonal transport of ECEL1/DINE in C760R mutants and mRNA expression deficits in G607S mutants.

Radiosurgery in trochlear and abducens nerve schwannomas: case series and systematic review.

INTRODUCTION: Schwannomas involving the occulomotor cranial nerves  (CNs; III, IV and VI), can be disabling, due to the associated diplopia and decreased quality of life and are extremely rare. We evaluated the role of Gamma Knife surgery (GKS) in these cases. METHODS: Five patients with CN IV and VI schwannomas (three and two, respectively) were treated in Lausanne University Hospital between 2010 and 2015. Four benefitted from upfront GKS and one from a combined approach (planned subtotal resection followed by GKS), due to a large preoperative tumour volume (size, 3 × 2 × 2.5 cm; volume, 7.9 ml), with symptomatic mass effect and oedema, as well as an entrapement cyst at the brainstem interface, in a young patient. Neuro-ophtalmological evaluation was performed at baseline and during each follow-up time-point. A systematic literature review is presented and compared to the present report. RESULTS: The mean follow-up was 44.4 months (12-54). Initial clinical presentation was diplopia in four cases and cavernous sinus syndrome in one. The marginal dose was 12 Gy in all cases. The mean target volume was 1.51 cm3 (0.086-5.8). The mean prescription isodose volume (PIV) was 1.71 cm3 (0.131-6.7). At last follow-up, all patients presented with disappearance of the baseline symptoms. Tumour control was achieved in 100%, with decrease in volume in all cases. The systematic review analysed 11 peer-reviewed studies, with a total of 35 patients. For uniformly reported CN VI, the mean marginal radiation dose ranged between 12 and 12.5 Gy, with disappearance of symptoms in 12.5%, improvement in 31.25%, stabilisation in 6.25%, worsening in 12.5%. Tumour volume decreased in all cases. CONCLUSIONS: Our data suggest that first intention GKS is a safe and effective option for patients with small to medium size oculomotor schwannomas, providing a high rate of clinical alleviation and tumour control. When the initial tumour volume is too large for first intention GKS, a combined approach with planned subtotal resection followed by GKS can be performed, with favourable and comparable outcomes as in upfront GKS.

Abducens nerve palsy due to inferior petrosal sinus thrombosis.

Isolated unilateral abducens nerve palsy is usually due to ischemia, trauma or neoplasm. Dorello's canal is the space between the petrous apex and superolateral portion of the clivus, bound superiorly by Gruber's ligament. The abducens nerve travels with inferior petrosal sinus (IPS) though the Dorello's canal before entering the cavernous sinus. A 31-year-old man presented with neck pain, and binocular horizontal diplopia, worse looking towards left and at distance. He had a history of intravenous drug abuse but no history of hypertension or diabetes. On examination, he had complete left 6th nerve palsy with normal fundi, pupils, and other cranial nerves. Methicillin-resistant Staphylococcus aureus bacteremia was detected with naïve tricuspid valve endocarditis and multiple septic emboli to lungs with infarcts. His cerebrospinal fluid was normal. MRI of the brain was normal. MRV of head and neck showed thrombosis of the left internal jugular vein, left sigmoid sinus and left inferior petrosal sinus with normal cavernous sinus and no evidence of mastoiditis. He was treated with broad spectrum antibiotics. He was not anticoagulated for fear of pulmonary hemorrhage from pulmonary infarcts. Although cerebral venous sinus thrombosis commonly presents with elevated intracranial pressure, isolated ipsilateral 6th nerve palsy from its compression in Dorello's canal due to thrombosis of the ipsilateral inferior petrosal sinus is extremely rare. To our knowledge, only two patients have been reported with isolated abducens palsy due to IPS thrombosis; one caused by septic emboli and the other developed it during IPS cortisol level sampling.

[Diplopia: An important symptom in internal medicine!] / Diplopie : un symptôme important en médecine interne !

Diplopia is defined as "double vision" when looking at a single object. Monocular diplopia is related to an ocular disorder and must be differentiated from binocular diplopia which is secondary to ocular misalignment. The examination of the patient with binocular diplopia is often challenging for non-specialists. However, a careful and systematic clinical examination followed by targeted ancillary testing allows the clinician to localize the lesion along the oculomotor pathways. The lesion may involve the brainstem, the ocular motor nerves III, IV or VI, the neuromuscular junction, the extraocular ocular muscles, or the orbit. Causes of binocular diplopia are numerous and often include disorders typically managed by internal medicine such as inflammatory, infectious, neoplastic, endocrine, and metabolic disorders. In addition to treating the underlying disease, it is important not to leave diplopia uncorrected. Temporary occlusion of one eye by applying tape on one lens or patching one eye relieves the diplopia until more specific treatments are offered should the diplopia not fully resolve.

Acute Abducens Nerve Paralysis in the Pediatric Emergency Department: Analysis of 14 Patients.

OBJECTIVES: Sixth cranial nerve (SCN) palsy is an uncommon but important neurological problem in patients admitted to pediatric emergency department. The underlying etiology of SCN palsy has a wide range from viral infections to intracranial tumors; therefore, a careful and systematic approach is necessary while examining these patients. METHODS: Fourteen patients who presented with acute SCN paralysis to pediatric emergency department during the last 10 years were examined. RESULTS: The age at the time of admission ranged between 14 months and 16 years (median, 9.5 years). Of the 14 patients, 5 were girls and 9 were boys. A total of 3 of the 14 patients had bilateral cranial nerve VI paralysis, and 9 patients had additional abnormal findings on neurological examination. Neuroimaging studies included cranial tomography (n = 3) and brain magnetic resonance imaging in all patients. The underlying etiology was malignancy (n = 3); glioma, medulloblastoma, acute lymphoblastic leukemia, and dural sinus thrombosis (n = 2); as well as Guillain-Barre syndrome (n = 2), multiple sclerosis (n = 1), pseudotumor cerebri (n = 1), and meningitis (n = 1). The remaining 4 patients had miscellaneous benign etiologies. CONCLUSIONS: Other lesions of primary brain tumors causing increased intracranial pressure constitute 50% of the underlying etiology, followed by Guillain-Barre syndrome (14.2%). However, these patients had neurological symptoms signs, in addition to diplopia or SCN paralysis. Patients admitted to pediatric emergency department with acute SCN paralysis should be examined in detail to disclose the underlying etiology especially if they present with additional clinical signs or symptoms.

Gruber, Gradenigo, Dorello, and Vail: key personalities in the historical evolution and modern-day understanding of Dorello's canal.

A century ago an ambitious young anatomist in Rome, Primo Dorello, who sought to understand the cause of abducent nerve palsy that often occurred in patients with severe middle ear infections, conducted intricate studies on the intracranial course of the nerve. In his findings, he identified that the abducent nerve passes through a narrow sinus near the apex of the petrous bone, which formed an osteofibrous canal. Dorello suggested that in this enclosed region the abducent nerve may be particularly vulnerable to compression due to the vascular edema accompanying the infection. Although his work was widely appreciated, it was not well received by all. Interestingly, Giuseppe Gradenigo, one of the most prominent Italian otologists of the early 20th century, who was known for his work on a triad of symptoms (Gradenigo's syndrome) that accompanies petrous apicitis, a result of severe middle ear infections, was obstinate in his criticism of Dorello's findings. Thus a scientific duel began, with a series of correspondence between these two academics-one who was relatively new to the otological community (Dorello) and one who was well reputed in that community (Gradenigo). The disagreement ultimately ebbed in 1909, when Dorello published a report in response to Gradenigo's criticisms and convinced Gradenigo to change his views. Today Dorello's canal is widely recognized as a key landmark in skull base surgery of the petroclival region and holds clinical significance due to its relation to the abducent nerve and surrounding vascular structures. Yet, although academics such as Dorello and Gradenigo are recognized for their work on the canal, it is important not to forget the others throughout history who have contributed to the modern-day understanding of this anatomical structure. In fact, although the level of anatomical detail found in Dorello's work was previously unmatched, the first description of the canal was made by the experienced Austrian anatomist Wenzel Leopold Gruber in 1859, almost 50 years prior to Dorello's landmark publication. Another critical figure in building the understanding of Dorello's canal was Harris Holmes Vail, a young otolaryngologist from Harvard Medical School, who in 1922 became the first person to describe Dorello's canal in the English language. Vail conducted his own detailed anatomical studies on cadavers, and his publication not only reaffirmed Dorello's findings but also immortalized the eponym used today-"Dorello's canal." In this article the authors review the life and contributions of Gruber, Dorello, Gradenigo, and Vail, four men who played a critical role in the discovery of Dorello's canal and paved the way toward the current understanding of the canal as a key clinical and surgical entity.