Complete Horizontal Gaze Paresis Due to Medial Pontine Haemorrhage.

We report a case of bilateral horizontal conjugate gaze palsy due to a dorsal median pontine haemorrhage. The development of horizontal gaze palsy has been attributed to lesions in the pontine tegmentum, and in this case, has occurred in conjunction with other features as part of Foville's syndrome. Complete horizontal gaze palsy is a rare clinical manifestation as bilateral involvement is unusual. Our case provides further insight into the intricacies of the brainstem neuroanatomy through a description of the involved neural pathways and nuclei accounting for complex neurological manifestations in one patient.

How to assess eye movements clinically.

Eye movements serve vision in orienting gaze toward an object of interest in order to place its image simultaneously on both foveas and in stabilizing gaze relative to the environment in order to maintain fixation on the object of interest, even in the case of body displacement. Disorders of eye movements can interfere with ocular alignment and/or monocular motility, and result in diplopia, which is the most common symptom. Eye movement disorders can also interfere with binocular motility without ocular misalignment and result in gaze palsy. Finally, disorders of eye movement can interfere with ocular stability during fixation or body displacement and result in oscillopsia, which is an illusion of an unstable visual world. A systematic examination of eye movements should be part of the neurological exam in order to detect asymptomatic manifestations that can help for the diagnosis of multiple neurological pathologies. In the case of eye movement disorders, the goals of the examination are to precisely characterize the disorder of motility, alignment, or stability, in order to finally localize anatomically the lesion among the peripheral ocular motor system or the more complex central eye movement neural network and suggest mechanisms and etiologies. In this review, we are describing the standard methods of ocular motor examination, including a "general" approach to any ocular motor assessment, and also the specific approaches to evaluating ocular misalignment, difficulty moving both eyes, and finally unstable gaze. This article will include practical tips on how to perform the tests most effectively or how to interpret the clinical signs elicited.

A novel homozygous frameshift mutation in the DCC gene in a Pakistani family with autosomal recessive horizontal gaze palsy with progressive scoliosis-2 with impaired intellectual development.

Horizontal Gaze Palsy with Progressive Scoliosis-2 with Impaired Intellectual Development (HGPPS2) is a rare congenital disorder characterized by absence of conjugate horizontal eye movements, and progressive scoliosis developing in childhood and adolescence. We report three new patients with HGPPS2 in a consanguineous Pakistani family, presenting varying degrees of progressive scoliosis, developmental delays, horizontal gaze palsy, agenesis of corpus callosum, and absence of cerebral commissures. Analysis of genotyping data identified shared loss of heterozygosity (LOH) region on chromosomes 5p15.33-15.31, 6q11.2-12, and 18q21.1-21.3. A hypothesis-free, unbiased exome data analysis detected an insertion of nucleotide A (c.2399dupA) in exon 16 of the DCC gene. The insertion is predicted to cause frameshift p.(Asn800Lysfs*11). Interestingly, DCC gene is present in the LOH region on chromosome 18. Variant (c.2399dupA) in the DCC gene is considered as the most probable candidate variant for HGPPS2 based on the presence of DCC in the LOH region, previously reported role of DCC in HGPPS2, perfect segregation of candidate variant with the disease, prediction of variant pathogenicity, and absence of variant in variation databases. Sanger Sequencing confirmed the presence of the novel homozygous mutation in all three patients; the parents were heterozygous carriers of the mutation, in accordance with an autosomal recessive inheritance pattern. DCC encodes a netrin-1 receptor protein; its role in the development of the CNS has recently been established. Biallelic DCC mutations have previously been shown to cause HGPPS2. A novel homozygous variant in patients of the reported family extend the genotypic and phenotypic spectrum of HGPPS2.

A cross-sectional, prospective ocular motor study in 72 patients with Niemann-Pick disease type C.

OBJECTIVE: To characterize ocular motor function in patients with Niemann-Pick disease type C (NPC). METHODS: In a multicontinental, cross-sectional study we characterized ocular-motor function in 72 patients from 12 countries by video-oculography. Interlinking with disease severity, we also searched for ocular motor biomarkers. Our study protocol comprised reflexive and self-paced saccades, smooth pursuit, and gaze-holding in horizontal and vertical planes. Data were compared with those of 158 healthy controls (HC). RESULTS: Some 98.2% of patients generated vertical saccades below the 95% CI of the controls' peak velocity. Only 46.9% of patients had smooth pursuit gain lower than that of 95% CI of HC. The involvement in both downward and upward directions was similar (51°/s (68.9, [32.7-69.3]) downward versus 78.8°/s (65.9, [60.8-96.8]) upward). Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit correlated best to disease severity. Compensating strategies such as blinks to elicit saccades, and head and upper body movements to overcome the gaze palsy, were observed. Vertical reflexive saccades were more impaired and slower than self-paced ones. Gaze-holding was normal. Ocular-motor performance depended on the age of onset and disease duration. CONCLUSIONS: This is the largest cohort of NPC patients investigated for ocular-motor function. Vertical supranuclear saccade palsy is the hallmark of NPC. Vertical upward and downward saccades are equally impaired. Horizontal saccadic peak velocity and latency, vertical saccadic duration and amplitude, and horizontal position smooth pursuit can be used as surrogate parameters for clinical trials. Compensating strategies can contribute to establishing a diagnosis.

Association of Admission NIHSS Score with Infarct Core Volume and Target Mismatch of Infarct Core/Penumbra Volume on CT Perfusion in Acute Ischaemic Stroke.

INTRODUCTION: Neurological impairment is associated with collateral status in acute ischaemic stroke (AIS). We aimed to validate the association between admission National Institutes of Health Stroke Scale (aNIHSS) score and infarct core volume (ICV) and target infarct core/penumbra volume mismatch (TMM) on CT perfusion (CTP) in AIS patients. METHODS: Patients with acute middle cerebral artery or internal carotid artery occlusion from 2011 to 2020 were included. All patients underwent pretreatment CTP at admission. ICV and TMM were analyzed with MIStar software on CTP maps. aNIHSS scores and clinical characteristics of patients were obtained from our prospectively recorded stroke database. RESULTS: We recruited 182 patients with a median age of 69.5 years; 85 (63.7%) were male, and the median aNIHSS score was 14. Of those, 149 (81.8%) had an ICV < 70 mL, and 139 (76.3%) had TMM. Lower aNIHSS was associated with an ICV < 70 mL, with an area under the curve (AUC) of 0.74, and TMM with an AUC of 0.76. Among all 15 items of the aNIHSS, the gaze score was the only item independently associated with an ICV < 70 mL (adjusted odds ratio [OR] = 0.42, 95% confidence interval [CI]: 0.22-0.79, p = 0.008) and TMM (adjusted OR = 0.5, 95% CI: 0.28-0.9, p = 0.021). One or both aNIHSS ≤ 16 and gaze score = 0 predicted TMM with a sensitivity of 0.79 and a specificity of 0.62. CONCLUSION: aNIHSS may be a useful tool to predict an ICV < 70 mL and TMM on CTP in AIS patients.

Upward Gaze Palsy: a Valuable Sign to Distinguish Spinocerebellar Ataxias.

Spinocerebellar ataxias (SCAs) represent a large group of heredodegenerative diseases, with great phenotypic and genotypic heterogeneity. However, in the clinical neurological practice, some symptoms and signs might help differentiate the SCAs. This study's aims were to evaluate the frequency of upward gaze palsy (UGP) and investigate its role in assisting in the clinical differentiation of SCAs. We included 419 patients with SCAs (248 with SCA3, 95 with SCA10, 38 with SCA2, 22 with SCA1, 12 with SCA7, and 4 with SCA6). This study compared UGP with other known markers of disease severity-age of onset, disease duration, SARA score, and size of CAG expansion, and also other semiologic features, as bulging eyes. This sign was significantly more prevalent in SCA3 (64.11%), compared with SCA10 (3.16%; p < 0.001) and other SCAs (SCA1, SCA2, SCA7-11.84%; p < 0.001). UGP showed very high sensibility ins SCA3 (92.9), although lacking of specificity (64.1%). The odds ratio (OR) of UGP were also very high, 23.52 (95% CI 12.38-44.69), and was significantly correlated with larger CAG expansions, age, and disease duration in SCA3 patients, but not with age of onset or severity of the ataxic syndrome. This study showed that UGP is highly suggestive of SCA3 and has high sensitivity for the differential diagnosis among SCAs, and it could be of great value for bedside semiologic tool.

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.

Vertical gaze palsy and intraoral numbness in a patient with neuro-psychiatric systemic lupus erythematosus: A case report and literature review.

We report, to the best of our knowledge, the first case of neuropsychiatric systemic lupus erythematosus with clinical presentation of bilateral upward gaze palsy and intraoral numbness. Magnetic resonance imaging of the brain was able to identify the pathogenic lesion at the left side of midbrain, involving the vertical gaze center and sensory pathways for innervating the buccal and hard palate mucosa. A course of aggressive immunosuppressive treatment resulted in prompt resolution of gaze palsy and the midbrain lesion.

The definition of neuronopathic Gaucher disease.

Neuronopathic Gaucher disease (nGD) has a very wide clinical and genotypic spectrum. However, there is no consensus definition of nGD, including no description of how best to diagnostically separate the acute form-Gaucher type 2-from the subacute or chronic form-Gaucher type 3. In this article, we define the various forms of Gaucher disease with particular emphasis on the presence of gaze palsy in all patients with nGD. This consensus definition will help in both clinical diagnosis and appropriate patient recruitment to upcoming clinical trials.

Late-onset Niemann-Pick disease type C overlapping with frontotemporal dementia syndromes: a case report.

The diagnosis of adult-onset Niemann-Pick disease type C (NPC) could be difficult because its primary symptoms [dementia and vertical supranuclear gaze palsy (VSGP)] are mainly seen in neurodegenerative dementias and progressive supranuclear palsy (PSP). Our patient with dementia and asymmetric parkinsonism resembled corticobasal syndrome and after the appearance of VSGP, the criteria of PSP were fulfilled too. Cerebellar symptoms appeared late during the course of the disease, leading to the diagnosis of NPC at the age of 59 years.

Complete horizontal gaze palsy due to bilateral paramedian pontine reticular formation involvement as a presentation of multiple sclerosis: a case report.

BACKGROUND: Demyelinating central nervous system diseases include several disorders that multiple sclerosis (MS) is identified as the most common among them. Ocular movement disturbances are a typical presentation in MS patients where lesions affect the complex and interconnected pathways involved in eye motion. Centers for gaze control are located in the pons primarily; therefore, lesions involving these centers can be presented with abnormalities in gaze. However, bilateral lesions in pontine gaze centers are exceptionally rare. CASE PRESENTATION: A 16-year-old girl with bilateral horizontal gaze palsy was referred to the neurology clinic. Magnetic resonance imaging of the patient indicated bilateral hyperintensities in the pons at the level of the paramedian pontine reticular formation. The patient was diagnosed with multiple sclerosis with respect to clinical and imaging findings and managed. CONCLUSION: Ocular movement abnormalities are a commonly encountered manifestation in patients with multiple sclerosis, however, bilateral gaze palsy is an exceptionally rare sign and should guide the physician to contemplate for anticipated lesions in the pons, and suspect MS, especially in childbearing-aged women. Although an extensive workup should also be done to rule out possible mimickers.

Horizontal Gaze Palsy with Progressive Scoliosis: A Case Report and Literature Review.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive disorder. The ROBO 3 gene mutation is responsible for the disease. We present a boy aged 12 years who was admitted for scoliosis surgery who had also had horizontal gaze palsy since birth. His brainstem abnormalities were compatible with the syndrome of HGPPS. HGPPS is one of the rare congenital diseases of childhood. Horizontal gaze palsy, ametropia, and progressive scoliosis are the main findings of the disease. This syndrome should be kept in mind for both ophthalmologists and orthopaedic surgeons in patients who present with gaze palsy and scoliosis. Early diagnosis of scoliosis makes it possible to treat the disease at an early stage, and early diagnosis of ametropia is important in the prevention of amblyopia.

DCC mutation update: Congenital mirror movements, isolated agenesis of the corpus callosum, and developmental split brain syndrome.

The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).

Oculomotor abnormalities in children with Niemann-Pick type C.

Niemann-Pick type C (NP-C) is a rare recessive disorder associated with progressive supranuclear gaze palsy. Degeneration occurs initially for vertical saccades and later for horizontal saccades. There are studies of oculomotor degeneration in adult NP-C patients [1, 2] but no comparable studies in children. We used high-resolution video-based eye tracking to record monocular vertical and horizontal eye movements in 2 neurological NP-C patients (children with clinically observable oculomotor abnormalities) and 3 pre-neurological NP-C patients (children without clinically observable oculomotor abnormalities). Saccade onset latency, saccade peak velocity and saccade curvature were compared to healthy controls (N=77). NP-C patients had selective impairments of vertical saccade peak velocity and vertical saccade curvature, with slower peak velocities and greater curvature. Changes were more pronounced in neurological than pre-neurological patients, showing that these measures are sensitive to disease progress, but abnormal curvature and slowed downward saccades were present in both groups, showing that eye-tracking can register disease-related changes before these are evident in a clinical exam. Both slowing, curvature and the detailed characteristics of the curvature we observed are predicted by the detailed characteristics of RIMLF population codes. Onset latencies were not different from healthy controls. High-resolution video-based eye tracking is a promising sensitive and objective method to measure NP-C disease severity and neurological onset. It may also help evaluate responses to therapeutic interventions.

Horizontal gaze palsy with progressive scoliosis: a case report with magnetic resonance tractography and electrophysiological study.

BACKGROUND: Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare autosomal recessive congenital anomaly characterized by horizontal gaze limitation and progressive scoliosis. We investigated the underlying pathogenesis by incorporating diffusion tensor imaging and an electrophysiological study. CASE PRESENTATION: A 55-year-old female patient presented to our clinic due to a chronic history of eye movement limitation since childhood. Her eye problem was followed by a progressive scoliotic change in her torso during junior high school. Neurological examinations revealed remarkable conjugate horizontal but not vertical gaze palsy. Her pupils were isocoric, with a prompt response to light reflex and convergence. Her vision, including visual acuity and field, were normal. No pathological signs of muscle tone, muscle power, deep tendon reflex or coordination were revealed. There was no associated family history, and no diseases involving other systems were noted. On reviewing her past medical history, X-rays revealed scoliotic changes of her thoracic and lumbar spine. Brain magnetic resonance imaging showed a midline cleavage at the tegmentum (split pons sign) and butterfly configuration of the medulla, consistent with HGPPS. Color-coded diffusion tensor imaging in our patient revealed absence of decussation of the superior cerebellar peduncle. In tractography, the pontocerebellar tracts and fibers within the inferior cerebellar peduncle, deemed to be primarily dorsal spinocerebellar and vestibulocerebellar tracts, appeared to be agenetic. The tegmentum was compromised secondary to dorsal displacement of the corticospinal tracts. Of note, the bilateral corticospinal tracts remained uncrossed at the level presumed to be the pyramidal decussation. A somatosensory evoked potential study also revealed predominantly ipsilateral cortical sensory responses. CONCLUSIONS: Our study confirmed that a compromised tegmentum secondary to dorsal displacement of the corticospinal tracts and poorly-developed afferent fibers within the pontocerebellar tracts and inferior cerebellar peduncle to be the main neuroanatomical anomalies responsible for the clinical presentations of HGPPS. In addition, the uncrossed nature of the majority of pyramidal and proprioceptive sensory systems was confirmed.

Identification of characteristic features of pineal germinoma that enhance accuracy of preoperative differentiation in pineal region tumors: its significance on optimum surgical treatment.

The aim of the study is to identify characteristic features of pineal germinoma that enhance preoperative accuracy in differentiating germinoma from other pineal region tumors. Twenty-one consecutive patients with pineal region tumors were enrolled. In all patients, tumor resection was performed to verify the histology. Clinical records including upward gaze palsy of Parinaud's syndrome and neuroimaging were analyzed. In addition, we evaluated the relationship between magnetic resonance imaging (MRI) findings and tumor progression patterns in pineal germinoma. Among 21 patients, 15 patients were diagnosed with germ cell tumor, 4 with pineal parenchymal cell tumor, and 2 with meningioma. Upward gaze palsy was seen in 11 patients; nine had pure germinomas and two had mixed germ cell tumors. These tumors occupied the pineal region with extension to the area of the mesodiencephalic junction (MDJ) and the bi-epithalamic area between the bilateral pulvinar and the third ventricle. Tumor involvement of the former area could cause upward gaze palsy by insulting the rostral interstitial nucleus of the medial longitudinal fasciculus located in the MDJ area. Tumor invasion into the latter area is commonly seen as a cardioid-shaped tumor as the tumor image on the axial MRI view. Upward gaze palsy and a cardioid-shaped tumor image on the axial MRI views were demonstrated to be specific features of pineal pure germinoma. It is suggested that combination of both features may become useful tools to preoperatively differentiate germinoma from other pineal tumors, resulting in achievement of the optimum treatment of pineal region tumors.

Twenty-Four Syndrome: An Untold Presentation of Pontine Hemorrhage.

Pontine hemorrhages are relatively uncommon. Various atypical manifestations of pontine stroke like eight-and-a-half syndrome, fifteen-and-a-half syndrome, and sixteen syndrome have been described in the past. We came across a case of pontine bleed that presented with bilateral facial palsy, bilateral horizontal gaze palsy, and contralateral sensorineural hearing loss accounting to the hitherto not described "twenty-four syndrome" with Horner's syndrome and left hemiparesis.

Vertical Gaze Palsy Caused by Selective Unilateral Rostral Midbrain Infarction.

Vertical gaze palsy is rarely a neurological symptom, although it has been observed in some cases. Here, we report the case of a patient presenting with complete upward and downward gaze palsy. In this case, a small lesion in the left rostral midbrain was observed on diffusion-weighted magnetic resonance (MR) images, and the lesion was considered to cause the ocular symptom. We consider that vertical gaze palsy is an important clue to an accurate topical diagnosis of a brain lesion.

Facial Dystonia with Facial Grimacing and Vertical Gaze Palsy with "Round the Houses" Sign in a 29-Year-Old Woman.

A 29-year-old woman developed progressive dysarthria and coordination problems from the age of 15. Examination showed dysarthria, facial dystonia, bibrachial dystonia, hyperreflexia, ataxia, and emotional incontinence. Downward supranuclear gaze palsy was prominent with a "Round the Houses" sign. Magnetic resonance imaging of the brain and medulla, electroneurography, and cerebrospinal fluid were normal. A computed tomography scan showed hepatosplenomegaly. This combination of progressive neurological symptoms together with hepatosplenomegaly was suggestive of inborn error of metabolism. A bone marrow biopsy showed an increased number of macrophages with foamy content, highly suggestive of lysosomal disease. Plasmatic chitotriosidase activity and CCL18 were increased. Genetic testing showed heterozygosis for the variation c.1070C→T (p.Ser357Leu) and c.1843→T (Arg615Cys), confirming the diagnosis of Niemann-Pick type C (NPC). The "Round the Houses" sign has only been described in patients with progressive supranuclear palsy (PSP). This sign is described as an inability to produce pure vertical saccades along the midline and instead moving the eyes in a lateral arc to accomplish the movement. The observation of this sign in a patient with NPC indicates that this bedside finding is not specific for PSP, but a sign of medial longitudinal fasciculus dysfunction. The presence of facial dystonia with facial grimacing together with supranuclear gaze palsy is highly characteristic and useful for the diagnosis of NPC. NPC is an important underdiagnosed condition, given the availability of treatment and a mean diagnostic delay of 6 years.

Unilateral thalamic infarction causing downward gaze palsy in a patient with uncorrected tetralogy of fallot: a case report.

Introduction - Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD). Adults with surgically uncorrected forms of this condition are extremely rare, since operation is recommended in childhood to prevent cyanosis. Cyanotic CHD increases the risk of thromboembolic events. An endothelial dysfunction caused by chronic hypoxia and shear stress due to rheological alterations with a platelet dysfunction appear to be the explanation behind this finding. Paramedian thalamic infarction causing vertical gaze palsy without midbrain involvement is an infrequent finding. We report here a rare case of a patient with untreated TOF, who suffered a left-sided unilateral thalamic infarction presenting as downward gaze palsy and diplopia. Case presentation - A 44-year-old women complained of sudden onset diplopia and vertigo. Neurological examination revealed a downward gaze palsy with other symptoms related to a vertebrobasilar territory circulatory disturbance. The MRI scan revealed an acute infarction, 8 mm in diameter in the left medial thalamic region without midbrain involvement. Discussion - Adults with uncorrected forms of TOF are extremely uncommon, and descriptions of stroke in these patients are therefore rarities. We set out to give a concise survey of the literature regarding TOF patients with stroke. Conclusion - We present a rare case of unilateral thalamic infarction causing downward gaze palsy in an adult patient with uncorrected TOF. Cyanotic CHD is regarded as one of the risk factors of stroke. Besides other pathologic conditions, ischaemic stroke at an early age should raise the suspicion of a cardioembolic origin and, in rare cases, might result from cyanotic CHD.