Pearls & Oy-sters: CACNA1A-Related Paroxysmal Tonic Upgaze With Ataxia Responsive to Acetazolamide.

A 9-month-old male infant was evaluated for sudden onset of paroxysmal episodes of forced, conjugate upward eye deviation. Extensive in-hospital evaluation including electrophysiology and neuroimaging studies were reassuring against seizures or a structural abnormality. Given the clinical presentation of sudden onset intermittent upward eye deviations, downbeating saccades, associated ataxia, and typical development, a clinical diagnosis of paroxysmal tonic upgaze (PTU) with ataxia was made. Targeted genetic testing of CACNA1A was performed, which revealed a variant of undetermined significance, which was later classified as a de novo pathogenic variant after protein modeling and parental testing performed. Off-label use of oral acetazolamide was prescribed, which led to dose-responsive decrease in the frequency and intensity of eye movement episodes. After 6 months of episode freedom at 2 years of age, acetazolamide was discontinued without return of episodes. Neurodevelopmental assessments revealed continued typical development. This case is presented to describe the diagnostic formulation, etiologic evaluation, and symptomatic treatment of CACNA1A-related PTU with ataxia.

Intraarterial Thrombolytic Treatment for Visual Deficits Caused by Hyaluronic Acid Filler: Efficacy, Safety, and Prognostic Factors.

BACKGROUND: The benefits of intraarterial thrombolytic treatment (IATT) in reversing hyaluronic acid (HA)-related visual deficits remain unclear. This study aimed to report a 5-year experience in the treatment of visual deficits resulting from HA embolization by IATT in a tertiary medical center. METHODS: From December of 2015 to June of 2021, the medical records of consecutive patients with HA-related visual deficits who underwent IATT were reviewed retrospectively. The demographics, clinical features, imaging data, treatment details, and follow-up results of the patients were analyzed. RESULTS: A total of 72 consecutive patients were analyzed, including five men (6.9%) men and 67 women (3.1%), aged 29.3 ± 7.6 years (range, 17 to 50 years). Thirty-two patients (44.4%) showed preserved visual acuity, and 40 (55.6%) exhibited no light perception on admission. Ocular motility disorders were detected in 63 patients (87.5%), ptosis was detected in 61 patients (84.7%), and facial skin changes were detected in 54 patients (75%). The technical success rate of IATT was 100%, with successful recanalization of the occlusive artery. No procedure-related complications were detected, and all skin injuries, ptosis, and ocular motility disorders were healed. Improved visual acuity was detected in 26 cases (36.1%). In the binary logistic regression model, only preoperative preserved visual acuity was independently associated with a good outcome. CONCLUSIONS: IATT for selective patients with HA-related visual deficits is efficient and safe. Preoperative preserved visual acuity was independently associated with a good outcome after IATT. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Botulinum Toxin A Injection for Convergence Insufficiency.

PURPOSE: To evaluate the effects of botulinum toxin A injection in one or both lateral rectus muscles in patients with convergence insufficiency previously managed with non-surgical and/or surgical options other than botulinum toxin A injection. METHODS: All patients with symptomatic convergence insufficiency treated with botulinum toxin A injection to one or both lateral rectus muscles from 2013 to 2018 at the Department of Ophthalmology, Rigshospitalet-Glostrup, Copenhagen University Hospital were retrospectively reviewed. All patients had near symptoms and were previously treated with a combination of convergence exercises, prisms, and/or surgery. Patients with previous botulinum toxin A injection in an extraocular muscle were excluded. Reading symptoms and deviation at near and distance were recorded at baseline and after 1 and 6 months. RESULTS: Twenty-three patients with convergence insufficiency were included (8 men and 15 women). Follow-up was conducted after a median of 47 days (interquartile range [IQR]: 31.5 to 72.5 days) and 174 days (IQR: 139 to 267 days). At baseline, median near angle of deviation was 18 PD of exophoria (IQR: 13 to 21 PD). The near deviation was reduced to 10 PD of exophoria (IQR: 7 to 17 PD) at first follow-up visit and 14 PD of exophoria (IQR: 12 to 18 PD) at last follow-up visit. Thirteen of 23 patients (57%) and 3 of 13 patients (23%) reported improvement in reading symptoms at first and last follow-up visit, respectively, compared to baseline. CONCLUSIONS: Botulinum toxin A injection may be useful in patients with convergence insufficiency. However, some patients may require repeated injections. [J Pediatr Ophthalmol Strabismus. 2023;60(2):108-113.].

Internuclear Ophthalmoplegia as an Isolated Symptom of Brainstem Wake-up Stroke Responsive to Intravenous Thrombolysis: Evidence from MRI.

BACKGROUND: Internuclear ophthalmoplegia (INO) is a disorder of eye movements caused by a lesion involving the medial longitudinal fasciculus (MLF) within the brainstem, and it is characterized by adduction impairment combined with contralateral dissociated abduction nystagmus. The frequency of acute ischemic stroke (AIS) presenting with INO as a predominant symptom is very low, and many patients suffering from this brainstem AIS are precluded from intravenous thrombolysis (IVT). OBJECTIVE: To provide for the first time a magnetic resonance imaging (MRI) evidence of response to the IVT in brainstem wake-up stroke presenting with INO as an isolated symptom. METHODS: Here, we described a rare case of pons AIS presenting with INO as a unique symptom of awakening. In order to differentiate an ischemic stroke from other stroke mimics, and to determine whether the patient was within the therapeutic window for IVT (wake-up stroke), brain MRI including DWI and FLAIR sequences was acquired. RESULTS: A left paramedian pontine DWI/FLAIR mismatch was detected and the patient was considered eligible for IVT. After IVT, the patient made a full recovery with complete resolution of INO. Follow-up MRI at 1 month demonstrates the absence of ischemic lesions. CONCLUSION: Our case provides neuroradiological evidence of IVT efficacy in brainstem stroke, and it should prompt clinicians to rapidly perform MRI in wake-up onset INO and to just as quickly administer IVT, since INO is a functionally disabling deficit. Finally, this case demonstrates the value of MRI in diagnostic, prognostic, and therapeutic workup of posterior circulation wake-up stroke.

Postinfectious SARS-CoV-2 Opsoclonus-Myoclonus-Ataxia Syndrome.

BACKGROUND: The opsoclonus-myoclonus-ataxia syndrome (OMAS) represents a pathophysiology and diagnostic challenge. Although the diverse etiologies likely share a common mechanism to generate ocular, trunk, and limb movements, the underlying cause may be a paraneoplastic syndrome, as the first sign of cancer, or may be a postinfectious complication, and thus, the outcome depends on identifying the trigger mechanism. A recent hypothesis suggests increased GABAA receptor sensitivity in the olivary-oculomotor vermis-fastigial nucleus-premotor saccade burst neuron circuit in the brainstem. Therefore, OMAS management will focus on immunosuppression and modulation of GABAA hypersensitivity with benzodiazepines. METHODS: We serially video recorded the eye movements at the bedside of 1 patient with SARS-CoV-2-specific Immunoglobulin G (IgG) serum antibodies, but twice-negative nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR). We tested cerebrospinal fluid (CSF), serum, and nasopharyngeal samples. After brain MRI and chest, abdomen, and pelvis CT scans, we treated our patient with clonazepam and high-dose Solu-MEDROL, followed by a rituximab infusion after her formal eye movement analysis 10 days later. RESULTS: The recordings throughout her acute illness demonstrated different eye movement abnormalities. While on high-dose steroids and clonazepam, she initially had macrosaccadic oscillations, followed by brief ocular flutter during convergence the next day; after 10 days, she had bursts of opsoclonus during scotopic conditions with fixation block but otherwise normal eye movements. Concern for a suboptimal response to high-dose Solu-MEDROL motivated an infusion of rituximab, which induced remission. An investigation for a paraneoplastic etiology was negative. CSF testing showed elevated neuron-specific enolase. Serum IgG to Serum SARS-CoV2 IgG was elevated with negative RT-PCR nasopharyngeal testing. CONCLUSION: A recent simulation model of macrosaccadic oscillations and OMAS proposes a combined pathology of brainstem and cerebellar because of increased GABAA receptor sensitivity. In this case report, we report 1 patient with elevated CSF neuronal specific enolase, macrosaccadic oscillations, ocular flutter, and OMAS as a SARS-CoV-2 postinfectious complication. Opsoclonus emerged predominantly with fixation block and suppressed with fixation, providing support to modern theories on the mechanism responsible for these ocular oscillations involving cerebellar-brainstem pathogenesis.

Oftalmoplejía internuclear bilateral (WEBINO) en un paciente pediátrico con Lupus Eritematoso Sistémico / Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) in a pediatric patient with Systemic Lupus Erythematosus

Resumen El síndrome de WEBINO (wall-eyed bilateral internuclear ophthalmoplegia), se presenta por una lesión del tegmento pontino (incluye área pontina paramediana, fascículo longitudinal medial y núcleo del abducens). Presenta limitación bilateral en la aducción y exotropía en la posición de la mirada primaria, nistagmo del ojo que abduce e incapacidad para la convergencia. Reporte de caso: Presentamos el caso de una paciente de 14 años con antecedente de Lupus Eritematoso Sistémico que debutó con diplopía horizontal de inicio súbito. El diagnóstico de WEBINO fue clínico y asociado con hallazgos de lesión isquémico pontomesencefálica en Resonancia Nuclear Magnética y angioresonancia cerebral. Se administró tratamiento con Metilprednisolona y presentó resolución gradual de los síntomas, sin embargo una semana después falleció por criptococosis sistémica. Conclusiones: Hacer el diagnostico de WEBINO se hace desafiante por su rareza y por la precisión de su localización neuroanatómica. Se debe realizar una exploración detallada para definir la causa probable y establecer el tratamiento oportuno que favorezca el pronóstico neurológico.

Background: Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is presented by a lesion of the pontine tegment (includes paramedian pontine area, medial longitudinal fascicle and nuclei of the abducens). It presents bilateral limitation in adduction and exotropia in the position of the primary gaze, abducting eye nystagmus and inability to converge. Case report: We present the case of a 14-year-old patient with a history of Systemic Lupus Erythematosus who debuted with sudden onset horizontal diplopia. WEBINO's diagnosis was clinical and associated with findings of ponto-mesencephalic ischemic injury in magnetic resonance imaging and magnetic resonance angiography. Treatment with Methylprednisolone was administered and she presented gradual resolution of the symptoms, however, one week later she died of systemic cryptococcosis. Conclusions: Making the WEBINO diagnosis is challenging due to its rarity and the precision of its neuroanatomical location. A detailed examination should be performed to define the probable cause and establish the appropriate treatment that favors the neurological prognosis.

Paroxysmal tonic upgaze accompanied by occipital discharge on electroencephalography: a case report and literature review.

BACKGROUND: Paroxysmal tonic upgaze (PTU) is an infantile-onset paroxysmal neurological disorder that is characterized by episodes of sustained conjugate upward eye deviation. The paroxysmal abnormal eye movements need to be differentiated from seizures. We report a case of PTU with occipital discharge on electroencephalography (EEG), which made the diagnosis more complicated. CASE PRESENTATION: A 6-month-old girl presented with paroxysmal upward deviation or left strabismus of the eyes, with a bowed head, lowered jaw, raised eyebrows, closed lips, and slight grin. Each episode lasted for a few seconds, and episodes occurred multiple times per day. EEG showed spike waves in the right occipital region, and the girl was initially misdiagnosed with epilepsy. After further analysis using video EEG, we corrected her diagnosis as PTU and stopped the administration of an antiepileptic drug. CONCLUSION: PTU accompanied by discharge on EEG may lead to a misdiagnosis. Video EEG monitoring, and especially the analysis of EEG traces synchronized with attacks, can provide evidence to distinguish between seizures and non-epileptic events.

Ophthalmologic manifestations in myasthenia gravis: presentation and prognosis.

We investigated the ophthalmologic manifestations and factors that influence outcomes in patients with myasthenia gravis (MG). We retrospectively analyzed the prevalence of neuro-ophthalmologic findings and clinical and outcome measures of 100 consecutive patients (53 males, 47 females), aged 55.7 ± 17.5 (range 15-85) years with an established diagnosis of MG. Forty-eight patients had purely ocular symptoms at the onset of disease (OMG) and 52 patients presented with generalized symptoms (GMG). Overall, 21 patients presented with extraocular muscle (EOM) weakness. Bilateral EOM weakness was seen in 12 patients, and unilateral EOM weakness was seen in nine patients. Diplopia responded partially to immunosuppressive treatments in 60% of patients with ophthalmoparesis. Twenty-five (52.1%) patients with ocular-onset MG converted to secondary GMG at a mean time of 14.5 months. Patients who developed secondary GMG were younger and had an earlier age of disease onset when compared with patients with pure OMG (p < 0.05). Patients with secondary GMG presented more frequently with ptosis and diplopia (72% vs. 28%) compared with patients with pure ocular MG who presented more frequently with isolated ptosis (66.7% vs. 33.3%) (p = 0.02). Remission and minimal manifestation status were achieved in 50 (79.3%) of all patients with a clinical follow-up ≥ 3 years. Poor outcome was associated with the presence of thymoma (p < 0.05). Myasthenic ophthalmoparesis is bilateral and heterogeneous and partly responds to treatment with immunotherapy. Younger patients with ptosis and diplopia at disease onset had an increased risk of secondary GMG. The presence of thymoma increases the risk for poor prognosis.

Status Dystonicus, Oculogyric Crisis and Paroxysmal Dyskinesia in a 25 Year-Old Woman with a Novel KCNMA1 Variant, K457E.

The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous episodes of dystonic spasms. A 25 year old woman with chronic ataxia and paroxysmal dyskinesia presented with facial twitching, writhing of arms, oculogyric crisis and visual and auditory hallucinations. She developed respiratory failure and was ventilated. No cause was found so whole exome sequencing was performed and this revealed a novel, non-synonymous heterozygous variant in exon 11 of the KCNMA1 gene, K457E (c 1369A>G) in the patient but not her parents. This variant has not been previously reported in gnomAD or ClinVar. The finding of a de novo variant in a potassium channel gene guided a trial of the potassium channel antagonist 3,4 diaminopyridine resulting in significant improvement, discharge from the intensive care unit and ultimately home.

Isolated opsoclonus heralding neuromyelitis optica spectrum disorder.

Opsoclonus is an ocular motility disorder characterized by spontaneous, arrhythmic conjugate saccades of varying amplitude occurring in all directions of gaze without normal intersaccadic interval. Etiological spectrum of opsoclonus encompasses paraneoplastic and neoplastic conditions, infectious and para-infectious encephalitis, autoimmune, metabolic and toxic encephalopathies, drugs, motor neuron diseases, multiple sclerosis and rarely neuromyelitis optica spectrum disorder (NMOSD). Opsoclonus has never been reported as a presenting manifestation heralding NMOSD. We herein report a previously healthy 37-year-old Asian Indian woman who presented with oscillopsia and opsoclonus, followed, 12 h later, by right-sided hemiparesis, right-sided appendicular ataxia, and left-sided lower motor neuron type facial palsy and dysarthria. Brain magnetic resonance imaging revealed hyperintense lesions in brainstem and thalamus in T2-weighted and fluid attenuated inversion recovery-weighted images, quite suggestive of NMOSD. Serum and cerebrospinal fluid samples were positive for anti-aquaporin-4 antibodies, which clinched the diagnosis of seropositive NMOSD. After completion of a course of intravenous methylprednisolone 1 g/day for 5 days, her opsoclonus disappeared completely. There was significant improvement in her speech and weakness within the first week of therapy and no objective deficit after day 20 of admission. After one-and-a-half-year follow-up, the patient was maintaining well on rituximab as secondary prophylaxis without any further attack. Our case highlights that isolated opsoclonus can be the presenting feature of NMOSD.

'Twenty syndrome' in neuromyelitis optica spectrum disorder.

A 30-year-old woman presented with recurrent hiccups, vomiting and painful diminution of vision and gait instability for 1 day. She had one-and-a-half syndrome, bilateral seventh cranial nerve paresis with bilateral symptomatic optic neuritis and left-sided ataxic haemiparesis. We described her disorder as the 'twenty syndrome' (11/2+7+7+2+2+½=20). MRI of her brain revealed demyelination predominantly in right posterolateral aspect of pons, medulla and bilateral optic nerves. Serum antiaquaporin-4 antibody came out positive. Thus, she was diagnosed as neuromyelitis optica spectrum disorder (NMOSD). She responded brilliantly to immunosuppressive therapy. This is the first ever reported case of the 'twenty syndrome' secondary to cerebral NMOSD.

A case of acquired Brown syndrome treated with adalimumab.

We present the case of a 4-year-old boy with acquired Brown syndrome of inflammatory origin. Without evidence of systemic inflammation, the disease typically resolves with oral steroids or nonsteroidal anti-inflammatory drugs. Refractory cases can be treated with local steroid injections or surgery. The present case of inflammatory Brown syndrome did not respond to conservative therapy, and parental concerns and wishes precluded more invasive treatments. Adalimumab was initiated and led to complete resolution of the disease.

Paroxysmal tonic upgaze: A heterogeneous clinical condition responsive to carbonic anhydrase inhibition.

BACKGROUND: Paroxysmal tonic upgaze (PTU), defined as an involuntary upward movement of the eyes, has been considered as a benign phenomenon but may also be associated with ataxia and developmental delay. METHODS: We report eight children with PTU; six of them also exhibiting symptoms of ataxia and/or developmental delay. Treatment with carbonic anhydrase inhibition was offered to children with persisting and/or severe forms. RESULTS: Whole-exome sequencing and genome-wide array analysis (n = 7) did not reveal mutations in the three known genes associated with PTU (CACNA1A, GRID2, SEPSECS), whereas by MLPA a heterozygous deletion of exon 31 of the CACNA1A gene could be detected in one patient, her mother and two further family members. Further exome and array analysis showed no recurrent variants in potentially novel PTU-related genes in more than one patient. A de novo variant at a highly conserved position in the SIM1 gene was detected in one patient, for which a pathogenic effect could be speculated. Carbonic anhydrase inhibition was started in five children and proved at least partially effective in all of them. CONCLUSION: Irrespective of the clinical background and the molecular basic mechanism of PTU, therapeutic carbonic anhydrase inhibition was effective in all five children (acetazolamide, n = 3; sultiame, n = 2) who received this treatment.

Atypical "nine" syndrome in bilateral pontine infarction: A case report.

RATIONALE: "Nine" syndrome, that is "eight-and-a-half" syndrome associated with hemiplegia and hemidysesthesia, is a rare disorder. This study aimed to report a Chinese patient with acute bilateral pontine infarction manifesting as eight-and-a-half syndrome plus hemiplegia (atypical nine syndrome), and also the clinical and neuroimaging findings were explained and discussed with review of the literature. PATIENT CONCERNS: A 79-year-old woman experienced sudden vertigo, nausea, vomiting, and weakness at her left arm and leg. The neurological examination disclosed her right horizontal gaze palsy, internuclear ophtalmoplegia (INO), and right-sided peripheral facial paralysis combined with slight left-sided hemiplegia, which were consistent with atypical nine syndrome. DIAGNOSES: Cranial magnetic resonance imaging (MRI) displayed acute multiple ischemic infarction, involving bilateral pontine tegmentum, basilar part of right paramedian pontine, and left cerebellar hemisphere. Intracranial MR angiography (MRA) revealed right middle cerebral artery occlusion, no clear visualization of bilateral vertebral arteries, and basilar artery hypoplasia with stenotic segments. INTERVENTIONS: Thrombolysis could not be performed due to the time window. The patient was given low molecular weight heparin for anticoagulation because of posterior circulation and progressive stroke. OUTCOMES: The vertigo disappeared, and a notable improvement with minimal restriction in the right horizontal gaze and partial relief of her facial paralysis were found at discharge, while her left hemiparesis was fully resolved. No recurrence of cerebral infarction was observed during follow-up as well. LESSONS: This case report with atypical nine syndrome is fairly rare. Nine syndrome may refer to the lesion located in unilateral tegmentum of the caudal pontine plus paramedian pontine, with an important localization value.

Oculomotor effects of medical and surgical treatments of Parkinson's disease.

Oculomotor abnormalities are fast becoming a proxy for disease diagnosis and progression. Saccades-ballistic eye movements-are known to be affected by dopaminergic cell loss in the basal ganglia, caused by Parkinson's disease. Pharmaceutical and neurosurgical interventions such as deep brain stimulation and functional neurosurgery have both been noted to have an effect on saccades. Comparing and contrasting these effects may yield insights into Parkinson's disease pathophysiology, and the mechanisms of pharmacological and neurosurgical treatments. Computational models of saccadic control, such as the LATER model, can help to interpret the distribution of saccadic latencies, providing a framework for objectively comparing the effects of pharmaceutical interventions and deep brain stimulation.

Treatment of acquired Brown syndrome in a child with a single intramuscular systemic depot steroid injection.

A 10-year-old girl presented with a complaint of diplopia and mild superomedial orbital pain in the left eye of 2 weeks' duration. She had limited elevation of the left eye, especially in adduction, moderate limitation of elevation in the primary position, mild limitation of elevation in abduction, downshoot in adduction, mild hypotropia in the primary position, and normal abduction. There was mild swelling and tenderness in the superomedial aspect of her left orbit. Fundus examination revealed intorsion of the left fundus on upgaze. She was diagnosed with acquired Brown syndrome, due presumably to a local inflammatory cause, and treated with a single intramuscular depot injection of betamethasone in her deltoid muscle. One week later, her symptoms were resolving, and there was marked improvement of elevation of the left eye in adduction, with near normal elevation in the primary position and in abduction. There was no recurrence 3 months later.

Advances in pharmacotherapy of vestibular and ocular motor disorders.

INTRODUCTION: Vertigo and dizziness are common chief complaints of vestibular and ocular motor disorders (lifetime prevalence 30%). Treatment relies on physical, pharmacological, psychological and rarely surgical approaches. Eight groups of drugs are currently used in vestibular and ocular motor disorders, namely anti-vertiginous, anti-inflammatory, anti-menière's, anti-migrainous medications, anti-depressants, anti-convulsants, aminopyridines and agents that enhance vestibular plasticity. AREAS COVERED: The purpose of this review is to summarize the pharmacological characteristics and clinical applications of medications that are used for peripheral, central and functional vestibular and ocular motor disorders. The level of evidence for the respective drugs is described alongside the pathophysiological premises supporting their use. The authors place particular focus on translation and back-translation in vestibular pharmacological research and the repurposing of known drugs for new indications and rare disorders. EXPERT OPINION: The use of drugs in vestibular and ocular motor disorders is often based on open-label, non-controlled studies and expert opinion. In the future, strong evidence derived from RCTs is needed to support the effectiveness and tolerability of these therapies in well-defined vestibular and ocular motor disorders. Vestibular pharmacological research must be guided by a better understanding of the molecular targets relevant in the pathophysiology of vestibular and ocular motor disorders.