A Case of Superior Oblique Palsy without Brown Syndrome Induced by a Dog Bite.

BACKGROUND Pseudo-Brown syndrome is characterized by dysfunction of the superior oblique tendon-trochlear complex. Canine tooth syndrome, which involves superior oblique palsy with pseudo-Brown syndrome, results from damage to the trochlear and superior oblique tendon from dog bites around the eye. This report describes a variant of canine tooth syndrome without pseudo-Brown syndrome following a dog bite around the left upper eyelid. In this case, magnetic resonance imaging (MRI) facilitated early diagnosis and therapeutic intervention. CASE REPORT A 19-year-old man presented with torsional diplopia following a dog bite around the left upper eyelid and forehead. Five days after the injury, an alternate prism cover test revealed 6 prism diopters (Δ) exotropia and 5Δ left hypertropia. Ocular motility showed no significant limitation in elevation or depression during adduction. MRI performed on the same day showed a high-signal area extending from the superior oblique tendon to the trochlear region and the superior oblique muscle belly of the left eye. A diagnosis of canine tooth syndrome without pseudo-Brown syndrome was made and oral steroids were administered. Ocular alignment did not improve, so left inferior oblique myotomy was performed 7 months after the injury. The patient's cyclovertical diplopia resolved postoperatively. CONCLUSIONS Dog bites around the eye can result in abnormalities of the extraocular muscles. Early MRI may be useful for diagnosis and determining treatment strategies. This report has highlighted the importance of rapid assessment and management of patients with dog bites involving the eye.

Acute bilateral hypotropia and esotropia complex as first manifestation of multiple sclerosis: a case report.

A 21-year-old Japanese woman presented with sudden eye movement disorders. An ophthalmic examination revealed bilateral hypotropia and esotropia complex. Brain magnetic resonance imaging revealed abnormal signals in the posterior and medial part of the lower pontine tegmentum (including periventricular and subcortical white matter) that were suggestive of demyelination. A cerebrospinal fluid test was positive for oligoclonal bands. She was subsequently diagnosed with multiple sclerosis and was administered intravenous methylprednisolone and oral dimethyl fumarate, with complete recovery from hypotropia and esotropia after two months. Bilateral hypotropia and esotropia are important clinical signs for the accurate diagnosis of multiple sclerosis.

A Treatment Approach in Congenital Fibrosis of Extraocular Muscles.

Background: Congenital fibrosis of extraocular muscles ( CFEOM) is a group of genetically defined eye-moving disorders. The syndrome is clinically characterized by congenital non-progressive ophthalmoplegia caused by dysinervation of the cranial nerves with or without ptosis. As a main sign of a CFEOM, extraocular muscles get shrunken and fibrotic, which makes surgery more technically demanding and the result more unpredictable, which makes the treatment challenging and highly customized. Our paper presents variations of the clinical picture and treatment cases of CFEOM1. Objective: To outline the importance of the clinical examination with the exact measurement of deviations for the patients with ocular fibrosis and passive duction test under general anesthesia, establishing them as the main criteria for treatment. Methods: We treated seven patients (14 eyes) with CFEOM1. The decision of the treatment was based on the measurement of the eye position in the primary position (PP), the severity of compensatory head position (CHP), restriction of motility, and passive motility test performed before surgery in general anesthesia. In 3 cases, patients were treated conservatively with the treatment of refractive error and amblyopia. However, in 4 patients, CHP and position of the eyes in PP were not acceptable, motility was severely impaired, and patients underwent surgery. The first surgery was performed on eye muscles: recession of inferior rectus muscle (IRM), anteposition, and resection of superior rectus muscle (SRM). As a second step procedure, ptosis surgery was performed. When the muscle was too tight, and it wasn't possible to have a satisfying result with conventional surgery, we used a tissue expander to improve the position and motility of the affected eyes. Results: In all operated cases, CHP has significantly improved and the position of the eyes in PP. Conclusion: Exact eye and head position measurements and a passive motility test during general anesthesia should guide the surgery. In the case when conventional surgery is not possible, implantation of a bovine pericard is a safe and effective method.

MRI topography of lesions related to internuclear ophthalmoplegia in patients with multiple sclerosis or ischemic stroke.

BACKGROUND AND PURPOSE: Internuclear ophthalmoplegia is a dysfunction of conjugate eye movements, caused by lesions affecting the medial longitudinal fasciculus (MLF). Multiple sclerosis (MS) and ischemic stroke represent the most common pathophysiologies. While magnetic resonance imaging (MRI) allows for localizing lesions affecting the MLF, comprehensive comparative studies exploring potential different spatial characteristics of lesions affecting the MLF are missing until now. METHODS: We retrospectively investigated MRI examinations of 82 patients (40 patients with MS and 42 patients with ischemic stroke). For lesion localization, the brainstem was segmented into (1) ponto-medullary junction, (2) mid pons, (3) upper pons, and (4) mesencephalon. RESULTS: Corresponding lesions affecting the MLF were observed in 29/40 (72.5%) MS and 38/42 (90.5%) stroke patients. Compared to stroke patients, MS patients had significantly more lesions in multiple locations (P < .001). Stroke patients showed more lesions at the level of the mesencephalon (P < .001), while lesions at the level of the ponto-medullary junction, mid, and upper pons did not statistically differ between the groups. CONCLUSION: Our results demonstrate that multiple lesions affecting the MLF make inflammatory-demyelination due to MS more likely, while lesion localization at the level of the mesencephalon favors ischemia.

Bosley-Salih-Alorainy syndrome in patients from India.

Bi-allelic HOXA1 pathogenic variants clinically manifest as two distinct syndromes, Bosley-Salih-Alorainy syndrome (BSAS) and Athabascan brainstem dysgenesis syndrome, mainly reported in two different populations from Saudi Arabia and southwest North America, respectively. Here we report two siblings of Indian origin with BSAS phenotype caused by a novel homozygous exon 2 HOXA1 pathogenic variants.

Wall-Eyed Bilateral Internuclear Ophthalmoplegia by Ischemic Stroke: Case Report and Literature Review.

INTRODUCTION: Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is a rare symptom. Several studies have reported that a small brainstem lesion could cause WEBINO. CASE REPORT: The authors present the case of an 88-year-old female individual who developed sudden-onset diplopia and gait disturbance. Neurological examination revealed WEBINO with convergence impairment, gaze-evoked upward nystagmus on upward gaze, and bilateral limb ataxia. Brain magnetic resonance imaging revealed a small paramedian pontine tegmentum infarction, responsible for the symptoms. A literature review of WEBINO in ischemic stroke revealed that most patients exhibited impaired convergence and other neurological symptoms. CONCLUSION: Gaze-evoked upward nystagmus on upward gaze and bilateral limb ataxia accompanied by WEBINO due to a small brainstem lesion were the characteristic findings of our case.

Eye movement abnormalities are associated with brainstem atrophy in Wilson disease.

BACKGROUNDS: This study aims to characterize eye movement abnormalities in Wilson disease and examine their association with the degree of brainstem atrophy. METHODS: Twenty patients (10 males, mean age 46.8, SD 8.9 years) with genetically confirmed neurological WD on stable anti-copper treatment and 20 age- and sex-matched healthy subjects were examined. Eye movements, including prosaccade and antisaccade tasks, were evaluated using infrared videooculography. MRI was performed using 1.5 T system, and T2-weighted images were used for the measurement of midbrain and pontine area on mid-sagittal slices. Clinical severity was assessed using the Unified Wilson's Disease Rating Scale (UWDRS). RESULTS: Compared to healthy controls, WD patients showed prolonged latencies of horizontal prosaccades and hypometry of both horizontal (p = 0.04) and vertical (p = 0.0046) prosaccades. In the antisaccade task, WD patients showed prolonged latency of both horizontal (p = 0.04) and vertical antisaccades (p = 0.047) and increased error rate of vertical antisaccades (p = 0.04). There is a significant association between midbrain area and horizontal latencies (r = -0.53; p = 0.02) and vertical maximum speed in prosaccades (r = 0.47; p = 0.04). The pons area inversely correlated with horizontal prosaccade and antisaccade latencies (p = 0.007). CONCLUSIONS: We showed impairments of ocular saccades such as prolonged latencies, hypometry, and increased error rate in antisaccades. The strong association between prolonged latencies of prosaccades and the brainstem atrophy suggests that VOG might serve as a sensitive electrophysiological marker of brainstem dysfunction in WD.

Clinical features and disease course of neurological involvement in Behcet's disease: HUVAC experience.

BACKGROUND/AIM: Neurological involvement (Neuro-Behcet's Disease: NBD) is a rare manifestation of Behcet's Disease (BD) and it is related with significant mortality and morbidity. We aimed to evaluate disease course and outcome of NBD patients registered in Hacettepe University Vasculitis Center (HUVAC) prospective database starting from October 2014. METHODS: Totally, 419 patients (329 of the patients had fulfilled the International Study Group (ISG) criteria and 90 patients were considered as incomplete BD) were recorded as BD to March 2018. We retrospectively reviewed the charts of 123 patients with neurological complaints/ symptoms according International Consensus Recommendations (ICR) Criteria for Neuro-Behçet's disease. In final analysis, 77 NBD patients (Definite NBD = 61, possible NBD = 16) were included. Demographics, clinical features, treatment characteristics, disability status and survival status of the patients were evaluated. RESULTS: Forty-seven (61%) of the patients were male. Median time to neurological involvement from first diagnosis of BD is 6 (IQR = 8.8) years in patients who had diagnosis of BD before neurological involvement. Distribution of NBD: parenchymal (pNBD), non-parenchymal (npNBD), mixed (mNBD) and peripheral nervous system (pnsNBD) were 47 (61%), 22 (28.6%), 5 (6.5%), 3 (3.9%), respectively. Eye involvement was more frequent in pNBD compared to npNBD. Brainstem (72.9%) was the most frequently affected parenchymal area and followed by cerebellum (43.8%) and diencephalon (37.5%). Twelve patients had spinal cord involvement (n = 12, 24.5%). Among the patients with pNBD and mNBD (total n = 52), 48 patients were considered as acute onset parenchymal disease and 4 patients were evaluated as chronic progressive disease. Fifty-eight percent of the patients with acute onset parenchymal disease had only one attack. Totally 14 BD patients deceased during a median 9.4 (IQR = 13) years disease duration and 9 of these patients had NBD (pNBD = 6, mNBD = 2, pnsNBD = 1). Corticosteroids (IV pulse = 75.5% and oral medium-high dose = 90%), alpha-interferon (76.9%), cyclophosphamide (57.1%), and TNF inhibitors (23.5%) were the most frequently preferred treatment options for pNBD. CONCLUSIONS: Neurological involvement is seen about 5 years after the diagnosis of BD, and ocular involvement more commonly seen in these patients than non-NBD patients. More than half of the patients with acute onset parenchymal NBD had only one attack. No death was observed in the patients with non-parenchymal NBD. Biologic agents (Interferon-alpha and anti-TNF agents) were used in most patients.

Roles of Collagen XXV and Its Putative Receptors PTPσ/δ in Intramuscular Motor Innervation and Congenital Cranial Dysinnervation Disorder.

Intramuscular motor innervation is an essential process in neuromuscular development. Recently, mutations in COL25A1, encoding CLAC-P/collagen XXV, have been linked to the development of a congenital cranial dysinnervation disorder (CCDD). Yet the molecular mechanisms of intramuscular innervation and the etiology of CCDD related to COL25A1 have remained elusive. Here, we report that muscle-derived collagen XXV is indispensable for intramuscular innervation. In developing skeletal muscles, Col25a1 expression is tightly regulated by muscle excitation. In vitro and cell-based assays reveal a direct interaction between collagen XXV and receptor protein tyrosine phosphatases (PTPs) σ and δ. Motor explant assays show that expression of collagen XXV in target cells attracts motor axons, but this is inhibited by exogenous PTPσ/δ. CCDD mutations attenuate motor axon attraction by reducing collagen XXV-PTPσ/δ interaction. Overall, our study identifies PTPσ/δ as putative receptors for collagen XXV, implicating collagen XXV and PTPσ/δ in intramuscular innervation and a developmental ocular motor disorder.

Seesaw nystagmus with internuclear ophthalmoplegia from bilateral dorsomedial pons and left thalamus infarction: a case report.

BACKGROUND: We describe for the first time the clinical features and mechanisms of a bilateral dorsomedial pons and left thalamus infarction with seesaw nystagmus and internuclear ophthalmoplegia. CASE PRESENTATION: A 62-year-old Chinese man was hospitalized for sudden-onset dizziness, diplopia, and gait disturbance. A neurological examination revealed seesaw nystagmus and internuclear ophthalmoplegia. Magnetic resonance imaging disclosed an acute infarction confined to the bilateral dorsomedial pons and left thalamus. Subsequently, 2 weeks of antithrombotic therapy led to an improvement in his symptoms. CONCLUSIONS: This case illustrates that the acute onset of seesaw nystagmus and internuclear ophthalmoplegia accompanied by risk factors for cerebrovascular diseases are highly suggestive of brainstem infarction.

Trochlear-oculomotor synkinesis: another congenital cranial dysinnervation disorder? / Sincinesia troclear-oculomotora: outro distúrbio congênito de denervação craniana?

ABSTRACT This report documents an unusual phenomenon. A 6-year-old girl with trochlear-oculomotor synkinesis presented with superior oblique and palpebral levator co-contraction. The literature was reviewed and the possibility of classifying this entity as a congenital cranial dysinnervation disorder was speculated.

RESUMO Este relato descreve um fenômeno incomum. Uma menina de 6 anos com sincinesia troclear-oculomotora apresentou co-contração do oblíquo superior e do levantador da pálpebra. A literatura foi revisada e especulou-se a possibilidade de classificar essa desordem como um distúrbio da congenital cranial dysinnervation disorder.

MRI findings in Parinaud's syndrome: a closer look at pineal masses.

PURPOSE: The association between MRI findings in patients with pineal lesions and the presence or absence of Parinaud's syndrome (PS) remains poorly described. We sought to better understand what MRI characteristics of a pineal lesion make PS more likely. Can these features predict prognosis for clinical resolution? Based on the anatomical relationship of the pineal gland and midbrain, we hypothesized that the degree of midbrain injury by a pineal mass as assessed by abutment, displacement, or intrinsic midbrain signal abnormality (IMSA) may predict PS. METHODS: We reviewed our institution's databases to find patients with MRI evidence of an intrinsic lesion of the pineal gland. Seventy-seven patients with intrinsic pineal gland lesions, 26 with PS and 51 without PS (NPS), were identified. Data regarding clinical history were collected, and an experienced neuroradiologist reviewed all MRI studies and recorded mass size, midbrain abutment, displacement by the pineal lesion, and presence or absence of IMSA. RESULTS: IMSA occurred with increased frequency in pineal lesions with PS (85%) when compared with NPS (39.2%) (p = 0.0001). Midbrain abutment, compression, and displacement occurred with similar frequencies in both groups, with no statistically significant difference. Hydrocephalus was present in 80.8% of patients with PS and 84% without PS (p = 0.75). CONCLUSION: IMSA in a patient with an intrinsic pineal gland mass is associated with PS. Other findings such as hydrocephalus and midbrain displacement are common in patients with pineal masses both with and without PS and do not have any predictive value.

Trochlear-oculomotor synkinesis: another congenital cranial dysinnervation disorder?

This report documents an unusual phenomenon. A 6-year-old girl with trochlear-oculomotor synkinesis presented with superior oblique and palpebral levator co-contraction. The literature was reviewed and the possibility of classifying this entity as a congenital cranial dysinnervation disorder was speculated.

Infratentorial immature teratoma of congenital origin can be associated with a 20-year survival outcome: a case report and review of literature.

BACKGROUND: Congenital intracranial tumors are very rare and account for less than 2% of all childhood brain tumors. Teratomas constitute about one third to one half of these, predominantly located midline in the supratentorial region. Posterior fossa location rarely occurs and, based on the cases reported in the literature, commonly has a poor prognosis. CASE PRESENTATION: A newborn female, diagnosed prenatally with hydrocephalus, is presented at birth with increasing head circumference and Parinaud's syndrome. Magnetic resonance imaging scans demonstrated a huge posterior fossa tumor with obstructive hydrocephalus. At surgery, through a suboccipital craniotomy, complete excision was achieved of a histological-proven immature teratoma. The infant received adjuvant chemotherapy for 1 year. She had normal neurological development and remained tumor-free through her 20-year follow-up. CONCLUSION: The authors report this rare case of congenital posterior fossa teratoma with long-term outcome, and the literature is reviewed.

Surgical treatment of pineal cysts in non-hydrocephalic and neurologically intact patients: selection of surgical candidates and clinical outcome.

PURPOSE: Management of patients presenting for various nonspecific complaints without clear neurological abnormalities and with normal ventricular size remains highly controversial. We intended to share our rationale for surgical treatment of patients who show symptoms of transient increase of intracranial pressure owing to the presence of the cyst. MATERIALS AND METHODS: We have retrospectively analyzed 28 cases of patients who presented without Parinaud syndrome nor ventricular enlargement and underwent pineal cyst removal in our centre between 2007 and 2015. We analyzed patients' age, sex, symptoms, preoperative cyst size, perioperative course, treatment outcome and neurologic status at discharge and at follow-up visits 4 and 12 months afterwards. RESULTS: Main complaints included paroxysmal headaches, nausea, vomiting, visual disturbances, syncope and transient depression of consciousness. Mean age of patients was 31 years (17-55); there were 24 females and 4 males. Mean cyst diameter was 17 mm (10-26). Decision about surgical treament was based on signs of transient increases of intracranial pressure. All patients underwent complete cyst excision via midline suboccipital craniotomy and infratentorial supracerebellar route. Short-lasting perioperative neurological signs (notably upgaze palsy) were noted in 22 cases and uniformly resolved within the observation period of 12 months. CONCLUSION: Abnormal neurological findings and ventricular enlargement are not indispensable to justify surgical treatment of pineal cysts. Judicious selection of surgical candidates based predominantly on clinical grounds can lead to excellent operative results.

Eye movement deficits in X-linked dystonia-parkinsonism are related to striatal degeneration.

BACKGROUND: X-linked dystonia-parkinsonism (XDP) is characterized by the unique transition of dystonia to parkinsonism and striatal degeneration. Slowing of saccades on clinical examination has been taken as suggestive of a progressive supranuclear palsy (PSP) phenotype. OBJECTIVES: To elucidate whether eye movement abnormalities in XDP patients reflect striatonigral impairment or deficits in the brainstem saccade generator as present in PSP. METHODS: Eye movements of 18 male XDP patients from the Philippines and 16 ethnically and age-matched, healthy control participants were analyzed and the results related to morphometric frontostriatal changes. RESULTS: There was moderate saccade hypometria in XDP but velocity of visually guided saccades was normal. XDP patients showed an increased antisaccade error rate which correlated with the reduction of (i) the volume of the pallidum and putamen as well as (ii) the volume and cortical thickness in dorsolateral prefrontal cortex. Amplitude of memory-guided saccades was smaller and latency prolonged. Horizontal smooth pursuit eye movements were impaired. CONCLUSIONS: Oculomotor abnormalities in XDP resemble those of patients with the Parkinsonian type of multiple system atrophy and - to a lesser degree - Parkinson's disease, but are not compatible with PSP. They indicate striatal impairment and may represent preclinical signs of the parkinsonian stage of XDP. The increasing failure of response inhibition in the antisaccade task with increasing striatal atrophy may indicate an endophenotype for striatal degeneration. Dorsolateral prefrontal degeneration can be inferred from the failure in initiating antisaccades, prolonged latency of memory-guided saccades and the reduction of dorsolateral prefrontal volume and cortical thickness.

Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments.

Christianson syndrome (CS) is a recently described rare neurogenetic disorder presenting early in life with a broad range of neurological symptoms, including severe intellectual disability with nonverbal status, hyperactivity, epilepsy, and progressive ataxia due to cerebellar atrophy. CS is due to loss-of-function mutations in SLC9A6, encoding NHE6, a sodium-hydrogen exchanger involved in the regulation of early endosomal pH. Here we review what is currently known about the neuropathogenesis of CS, based on insights from experimental models, which to date have focused on mechanisms that affect the CNS, specifically the brain. In addition, parental reports of sensory disturbances in their children with CS, including an apparent insensitivity to pain, led us to explore sensory function and related neuropathology in Slc9a6 KO mice. We present new data showing sensory deficits in Slc9a6 KO mice, which had reduced behavioral responses to noxious thermal and mechanical stimuli (Hargreaves and Von Frey assays, respectively) compared to wild type (WT) littermates. Immunohistochemical and ultrastructural analysis of the spinal cord and peripheral nervous system revealed intracellular accumulation of the glycosphingolipid GM2 ganglioside in KO but not WT mice. This cellular storage phenotype was most abundant in neurons of lamina I-II of the dorsal horn, a major relay site in the processing of painful stimuli. Spinal cords of KO mice also exhibited changes in astroglial and microglial populations throughout the gray matter suggestive of a neuroinflammatory process. Our findings establish the Slc9a6 KO mouse as a relevant tool for studying the sensory deficits in CS, and highlight selective vulnerabilities in relevant cell populations that may contribute to this phenotype. How NHE6 loss of function leads to such a multifaceted neurological syndrome is still undefined, and it is likely that NHE6 is involved with many cellular processes critical to normal nervous system development and function. In addition, the sensory issues exhibited by Slc9a6 KO mice, in combination with our neuropathological findings, are consistent with NHE6 loss of function impacting the entire nervous system. Sensory dysfunction in intellectually disabled individuals is challenging to assess and may impair patient safety and quality of life. Further mechanistic studies of the neurological impairments underlying CS and other genetic intellectual disability disorders must also take into account mechanisms affecting broader nervous system function in order to understand the full range of associated disabilities.

A potential gain-of-function variant of SLC9A6 leads to endosomal alkalinization and neuronal atrophy associated with Christianson Syndrome.

Loss-of-function mutations in the recycling endosomal (Na+,K+)/H+ exchanger gene SLC9A6/NHE6 result in overacidification and dysfunction of endosomal-lysosomal compartments, and cause a neurodevelopmental and degenerative form of X-linked intellectual disability called Christianson Syndrome (CS). However, knowledge of the disease heterogeneity of CS is limited. Here, we describe the clinical features and underlying molecular and cellular mechanisms associated with a CS patient carrying a de novo missense variant (p.Gly218Arg; G218R) of a conserved residue in its ion translocation domain that results in a potential gain-of-function. The patient manifested several core symptoms typical of CS, including pronounced cognitive impairment, mutism, epilepsy, ataxia and microcephaly; however, deterioration of motor function often observed after the first decade of life in CS children with total loss of SLC9A6/NHE6 function was not evident. In transfected non-neuronal cells, complex glycosylation and half-life of the G218R were significantly decreased compared to the wild-type transporter. This correlated with elevated ubiquitination and partial proteasomal-mediated proteolysis of G218R. However, a major fraction was delivered to the plasma membrane and endocytic pathways. Compared to wild-type, G218R-containing endosomes were atypically alkaline and showed impaired uptake of recycling endosomal cargo. Moreover, instead of accumulating in recycling endosomes, G218R was redirected to multivesicular bodies/late endosomes and ejected extracellularly in exosomes rather than progressing to lysosomes for degradation. Attenuated acidification and trafficking of G218R-containing endosomes were also observed in transfected hippocampal neurons, and correlated with diminished dendritic branching and density of mature mushroom-shaped spines and increased appearance of filopodia-like protrusions. Collectively, these findings expand our understanding of the genetic diversity of CS and further elucidate a critical role for SLC9A6/NHE6 in fine-tuning recycling endosomal pH and cargo trafficking, processes crucial for the maintenance of neuronal polarity and mature synaptic structures.