Vertical Gaze Palsy Research Articles

Progressive Supranuclear Palsy: an Update.

Progressive supranuclear palsy (PSP) is a 4R tau neuropathologic entity. While historically defined by the presence of a vertical supranuclear gaze palsy and falls in the first symptomatic year, clinicopathologic studies identify alternate presenting phenotypes. This article reviews the new PSP diagnostic criteria, diagnostic approaches, and treatment strategies. The 2017 International Parkinson and Movement Disorder Society PSP criteria outline 14 core clinical features and 4 clinical clues that combine to diagnose one of eight PSP phenotypes with probable, possible, or suggestive certainty. Evidence supports the use of select imaging approaches in the classic PSP-Richardson syndrome phenotype. Recent trials of putative disease-modifying agents showed no benefit. The new PSP diagnostic criteria incorporating the range of presenting phenotypes have important implications for diagnosis and research. More work is needed to understand how diagnostic evaluations inform phenotype assessment and identify expected progression. Current treatment is symptomatic, but tau-based therapeutics are in active clinical trials.

Clinical features and gene mutation analysis of patients with Niemann-Pick disease type C

Objective: To analyze the clinical manifestations, therapeutic efficacy, prognosis and characteristics of NPC1 mutation in Chinese patients with Niemann-Pick disease type C(NPC). Methods: Ten unrelated Chinese NPC patients were diagnosed by NPC1 mutation analysis from July 2013 to February 2017 in Beijing Tian Tan Hospital of Capital Medical University. Clinical data of 10 cases were analyzed retrospectively which included clinical manifestations, laboratory results and NPC1 gene mutation features, and a series of follow-up were carried out about therapeutic efficacy and prognosis. Results: Ten patients suffering from NPC included 5 males and 5 females, aged from 42 days to 14 years when they presented to Tian Tan Hospital. According to their age of neurological onset, 4 were in early infantile period, 2 in late infantile period, 2 in juvenile periods, and the other 2 cases in neonatal period. They all presented with splenomegaly, 5 of 10 accompanied with hepatomegaly. Two cases of neonatal subtype presented mainly with delayed neonatal cholestatic jaundice and hepatosplenomegaly, accompanied with decreased muscle tone and slight psychomotor retardation. The other 8 cases presented with severe neurological involvement, such as progressive encephalopathy, ataxia and language impairment, 4 with dystonia, 3 with decreased muscle tension, 5 with vertical supranuclear gaze palsy, 5 with gelastic cataplexy, and 4 with epilepsy. Eight of 9 cases presented with foam cells in their bone marrow. Head MRI showed diffuse cerebral atrophy in 8 cases, thin corpus callosum in 2 cases, and brain white matter abnormal signals in 2 cases. Among 10 cases, 18 different mutations of NPC1 allelic genes were identified including 11 reported mutations, 3 novel missense mutations: c. 3683T>C (p.Met1128Thr), c.1926G>C (p.Met642Iie) and c. 3006C>G (p.Phe1002Leu), 2 novel nonsense mutation: c. 1142G>A(p.Trp381Ter ) and c. 3229C>T(p.Arg1077Ter), 1 novel minimal deletion mutation: c. 1385-1386del, and 1 novel intron mutation: c. 1757+ 5G>A. In 5 cases, the symptom of gelastic cataplexy was alleviated by imipramine, and the convulsion was relieved by valproate in 2 cases, by carbamazepine in 1 case at the beginning of seizure. During the 25 (3-66) months of follow-up, 4 cases died, the others' neurological symptoms were deteriorated progressively. Conclusions: The NPC1 gene mutation were high heterozygous in this group, and 7 novel mutations enriched the gene mutation spectrum of NPC1. The neurological manifestations were complicated in patients with NPC, and the symptomatology would be different according to their onset age of neurological symptoms. There might be effective symptomatic treatment for gelastic cataplexy by imipramine and for convulsion by valproate or carbamazepine.

Screening for Niemann-Pick Type C Disease in a Memory Clinic Cohort.

Niemann-Pick type C disease (NPC) is a neurovisceral lysosomal storage disorder with a heterogeneous phenotype including ataxia, cognitive impairment, impairment of vertical saccades, and psychiatric symptoms, among many others. Based on clinical, genetic, and biomarker findings, recent guidelines put forward a screening for atypical and oligosymptomatic forms of NPC in clinical niches with an increased risk. Here, we report methods and results of a negative screening study in the niche of a memory clinic. We retrospectively and prospectively identified 83 patients with unclassified cognitive impairment (15 dementia, 46 mild cognitive impairment, and 22 progressive subjective cognitive decline) before 60years of age (82 patients between 41 and 60years). We explored the prevalence of clinical features compatible with NPC and measured plasma levels of chitotriosidase and cholestantriol. The NPC suspicion index indicated high probability for NPC in 3 and moderate probability in 16 patients. Prevalent (>5%) neurological and psychiatric features were depression, seizures, ataxia, dysarthria, and psychotic symptoms. Vertical gaze palsy without parkinsonism was observed in one patient. Cholestantriol levels were only abnormal in one patient. Chitotriosidase levels were susceptible to slight elevations that were reproducible in only two of five patients. Our study does not exclude NPC among memory clinic patients. Instead, we suggest conducting prospective screening studies in younger cohorts that include a focused neurological examination. Excluding minor cognitive impairment and discarding depression as an independent disease symptom probably further improve screening effectivity but may delay or miss therapeutic options in early or mild disease.

Atrophy in Midbrain & Cerebral/Cerebellar Pedunculi is Specific for Progressive Supranuclear Palsy - A Cross-Validation Whole-Brain Meta-Analysis

Objective: Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome characterized by vertical gaze palsy and postural instability. Midbrain atrophy is suggested as a hallmark, but it has not been validated systematically in whole-brain imaging. Methods: We conducted whole-brain meta-analyses identifying disease-specific atrophy in structural MRI. Eighteen studies were identified (N=315 PSP, 393 controls) and separated into gray or white matter analyses (15/12). With overlay analyses, we cross-validated two meta-analytical algorithms: anatomical likelihood estimation and seed-based D mapping. Results: Whole brain meta-analyses revealed consistent gray matter atrophy in bilateral thalamus, anterior insulae, midbrain, and left caudate nucleus. White matter alterations were consistently detected in bilateral superior/middle cerebellar pedunculi, cerebral pedunculi, and midbrain atrophy. Conclusions: Our meta-analyses identify gray matter atrophy of the midbrain and white matter atrophy of the cerebral/cerebellar pedunculi and midbrain as specific to PSP. We support the incorporation of structural MRI data, and particularly these structures, into the revised PSP diagnostic criteria.

Bilateral Vertical Gaze Palsy after Cerebral Digital Subtraction Angiography Due to Unilateral Midbrain Infarction

Bilateral Vertical Gaze Palsy after Cerebral Digital Subtraction Angiography Due to Unilateral Midbrain Infarction

Vertical One-and-a-Half Syndrome Accompanying Contralateral Abduction and Incomplete Depression Palsy Due to Thalamo-Mesencephalic Infarction

Vertical gaze palsy is usually associated with lesions of the rostral midbrain and thalamo-mesencephalic junction. The rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF), the interstitial nucleus of Cajal, and the posterior commissure located in the midbrain are the critical area in supranuclear control of vertical eye movements. We describe a case of vertical one-and-a-half syndrome accompanying contralateral abduction and incomplete depression palsy due to thalamo-mesencephalic infarction. These vertical eye movement abnormalities are presumed to be caused by damage to the ipsilateral riMLF, interstitial nucleus of Cajal, and oculomotor fascicles. Keywords: Gaze palsy; Midbrain; Cerebral infarction 중심 단어: 주시마비, 중뇌, 뇌경색증

Vertical gaze palsy caused by selective unilateral infarction of rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF): A case report

Vertical gaze palsy caused by selective unilateral infarction of rostral interstitial nucleus of the medial longitudinal fasciculus (riMLF): A case report

Brain gray matter abnormalities in progressive supranuclear palsy revisited.

Whole-brain voxel-based morphometry (VBM) studies of progressive supranuclear palsy (PSP) have demonstrated heterogeneous findings regarding gray matter (GM) abnormalities. Here, we used Seed-based d Mapping, a coordinate-based meta-analytic approach to identify consistent regions of GM anomalies across studies of PSP. Totally, 18 original VBM studies, comprising 284 patients with PSP and 367 healthy controls were included. As compared to healthy controls, patients with PSP demonstrated significant GM reductions in both cortical and subcortical regions, including the frontal motor cortices, medial (including anterior cingulate cortex) and lateral frontal cortices, insula, superior temporal gyrus, striatum (putamen and caudate nucleus), thalamus, midbrain, and anterior cerebellum. Our study further suggests that many confounding factors, such as age, male ratio, motor severity, cognitive impairment severity, and illness duration of PSP patients, and scanner field-strength, could contribute to the heterogeneity of GM alterations in PSP across studies. Our comprehensive meta-analysis demonstrates a specific neuroanatomical pattern of GM atrophy in PSP with the involvement of the cortical-subcortical circuitries that mediate vertical supranuclear gaze palsy, motor disabilities (postural instability with falls and parkinsonism), and cognitive-behavioral disturbances. Confounding factors merit attention in future studies.

PB 10 Identifying an imaging biomarker for progressive supranuclear palsy – a combined gray & white matter meta-analysis using ALE and SDM

Background Progressive supranuclear palsy (PSP) is an atypical parkinsonian syndrome. PSP is described by clinical features of vertical gaze palsy and postural instability. Even though midbrain atrophy has been suggested as a hallmark of the disease, it has not been validated systematically so far. Methods To identify disease-specific regional atrophy in PSP, we conducted a systematic and quantitative meta-analysis on structural magnetic resonance imaging (MRI) data. Based on strict inclusion criteria 18 studies were identified in PubMed including 315 patients compared with 393 healthy controls. For analysis, the included studies were separated into studies investigating either gray or white matter atrophy. Ensuring consistent results, we used a unique approach by combining two widely used meta-analytical algorithms. The results of anatomical likelihood estimation (ALE) and Seed-basedDMapping (SDM) were superimposed in a conjunction analysis. Results The analysis of gray matter revealed that clusters in the bilateral thalamus, bilateral anterior insulae, midbrain and bilateral caudate nuclei were consistently identified as effected by both methods, SDM and ALE ( Fig. 1 ). White matter analyses revealed consistent atrophy in the bilateral superior cerebellar pedunculi, cerebral pedunculi, and midbrain. Discussion In light of previous meta-analyses investigating neurodegenerative diseases, our meta- analyses identify atrophy in the gray matter in the midbrain and in the white matter in the cerebral/cerebellar pedunculi and midbrain as disease-specific in PSP. Atrophy in these brain regions is suggested to be incorporated into new revised diagnostic criteria for PSP. The study design enabled high validity and statistical power. We combined two meta-analytic techniques, combined analyses in white and gray matter, and included the biggest cohort of PSP patients to date.

Patient with Niemann-Pick disease type C: over 20 years' follow-up

We report a 37-year-old woman with Niemann-Pick disease type C (NPC) 1. At the age of 8 years, she presented slow running followed by both fingers dystonia at the age...

P377 Inappropriate sexual behavior as an initial clinical feature in progressive supranuclear palsy: Case report

Introduction Progressive supranuclear palsy (PSP) is a parkinsonian syndrome that typically affects gait and oculomotor control. Early clinical features of PSP are cognitive impairment and nonspecific affective, behavioral disturbances, personality changes, memory defects, depression, apathy, or euphoria, whereas hypersexuality is rare in PSP. Dopamine agonists are the major risk factor triggering hypersexuality in patients with PSP. In this article, we report a patient presented with hypersexual behavior as an initial symptom before using dopamine agonists as a treatment. Case report A 62-year-old male patient without past psychiatric history, presented to the psychiatric clinic with complaints of slowly progressive cognitive impairment and hypersexuality. He thought his wife cheated on him and frequently attempted to have sex with his partner when awaked from sleep. He showed compulsive sexual behavior harassing a woman in the street with uncontrollable and irrepressible sexual urge. Initially, Mini Mental State Examination (MMSE) score was 24 out of 30 points. An MRI of the brain showed atrophy of the midbrain. One year after his inappropriate sexual behavior was worsen and he started to being treated with L-dopa. At age 64, he showed dysphagia, vertical gaze palsy, growling dysarthria. He was wheelchair-bound at the age of 65. The clinical features and neuroimaging data led to a diagnosis of PSP. Significance Compulsive sexual behavior in patients with PSP before using dopamine replacement therapy reported yet. Conclusion We suggest that inappropriate sexual behavior in PSP can be presented in early course of disease.

Niemann-Pick type C as a cause of progressive intellectual and neurological deterioration in childhood.

To describe the cases of Niemann-Pick type C (NP-C) disease in a United Kingdom epidemiological study of progressive intellectual and neurological deterioration in childhood. Paediatricians notified cases via the British Paediatric Surveillance Unit between 1997 and 2015. Fifty-three NP-C patients were identified: 29 females, 24 males. Fifteen cases had a systemic presentation (neonatal jaundice and/or hepatosplenomegaly). Thirty-eight had a neurological onset, the commonest presenting symptom being gait disturbance/ataxia (29 cases, 76%). Forty-nine cases eventually had neurological problems, the commonest were school/cognitive difficulties (40, 82%), seizures (33, 67%), dysphagia (20, 41%), dysarthria (18, 37%), cataplexy (17, 35%), and visual deterioration (8, 16%); their commonest abnormal physical signs were vertical supranuclear gaze palsy (35, 71%), hypotonia (19, 39%) and hepatosplenomegaly (19, 39%). The median diagnostic delay in the 38 neurological onset cases was 3 years (range 0.3-12.8). Confirmatory investigations included filipin staining of skin fibroblasts (42 cases), bone marrow examination in 30 (the last in 2011), and increasingly DNA studies, mutations in NP-C1 being found in 20 cases. NP-C should be considered in children with progressive neurological deterioration. Subtle neurological problems combined with a history of prolonged neonatal jaundice and/or hepatosplenomegaly may provide early evidence of the disease.

Artery of percheron occlusion: a rare cause of coma

Objectives To present a case of artery of Percheron (AOP) occlusion and discuss the neuroimaging and clinical differential diagnosis. Case A 40-year-old male with no past medical history was found unconscious by his work colleagues. On presentation, he had a GCS of 7 (E3, V1, M3) and a left dilated unreactive pupil. He had no witnessed seizure activity and displayed no focal neurological deficits. Immediate brain imaging showed no evidence of intracranial haemorrhage or basilar artery occlusion. He was intubated and treated empirically for seizures and encephalitis. Lumbar puncture was negative and an EEG performed 24 hours later revealed no seizure activity. An MRI done 72 hours after the event revealed bi-thalamic infarction, suggestive of AOP occlusion. He was extubated 4 days after presentation. He displayed intermittent drowsiness throughout the day, as well as a vertical gaze palsy. Mobility was significantly impaired secondary to reduced dynamic balance but he had no sensory or motor deficits and no cerebellar signs. MRI scans revealed an associated small left cerebellar hemisphere infarct, suggesting an embolic aetiology. The patient underwent a full young stroke work-up, including vasculitic and thrombophilia screen, which were unremarkable. Transoesophageal echocardiography identified no cardiac source of embolus and no patent foramen ovale. The decision was made to commence anti-coagulation with apixaban. Three-weeks post onset, the patient had an ongoing vertical gaze palsy but improved levels of alertness, and is awaiting in-patient rehabilitation to improve mobility. Conclusions AOP occlusion is a rare cause of coma and should be suspected in patients who present with acute loss of consciousness, once other common aetiologies are excluded. This case raises pertinent questions regarding the indications and benefits of thrombolysis and/or clot retrieval in such patients.

Acute Bilateral Supranuclear Vertical Gaze Palsy: Vertical One-and-a-one Syndrome - Report of Three Cases.

Acute Bilateral Supranuclear Vertical Gaze Palsy: Vertical One-and-a-one Syndrome - Report of Three Cases.

Isolated Vertical Ophtalmoplegia and Mydriasis Due to Bilateral Midbrain Infarction

Partial fascicular oculomotor palsy, the combination of bilateral midriasis with loss of vertical gaze movements, is rarely a consequence of midbrain infarction. We describe a patient with acute ischemic infarcts involving both upper most part of the midbrain, presenting with marked vertical gaze palsy and mydriasis bilaterally as the only neurological abnormality. These features are suggestive of partial fascicular oculomotor palsies involving the pupil, inferior rectus(IR), superior rectus(SR), inferior oblique(IO) muscles and sparing medial rectus(ML), levator palpebrae(LP) muscles. These neuro-ophthalmological and radiological findings in our case support the model that the fibers to medial rectus and levator palpebrae muscles might be located in the more caudal portion of the oculomotor fascicles.

Efficacy of repetitive transcranial magnetic stimulation (rTMS) for progressive supranuclear palsy (PSP).

Progressive supranuclear palsy (PSP) is clinically characterized by vertical gaze palsy, postural instability with falls and poor response to dopaminergic drugs. We evaluated the efficacy of repetitive transcranial magnetic stimulation (rTMS) with open-label 5 Hz 5000 pulses for ten days over the supplementary motor area in seven PSP cases. Progressive Supranuclear Palsy Rating Scale (PSPRS) is improved by 7 points compared to the baseline (pre=48, post=41, p<0.05). rTMS might be a therapeutic tool to treat neurological sign of PSP.

Sudden Onset Altered Sensorium: Artery of Percheron Infarct

Acute onset Altered mental status is a common but clinically challenging emergency due to numerous possibilities with little clinical window and time to treat. The numerous causes include stroke, encephalitis, organ dysfunction, metabolic, endocrine and intoxication. Amongst the vascular causes, one rare but peculiar cause being artery of percheron infarct. Blood supply to the thalamus and brainstem have various anatomic variations. Artery of Percheron is one such variation in which a single arterial trunk arises from proximal segment of one of the posterior cerebral artery (PCA) and bifurcates to supply bilateral paramedian thalami. Occlusion of this artery, although uncommon results in characteristics pattern of symmetric infarction in bilateral medial thalami with or without mesencephalic infarction. We here describe a case of a gentleman who presented with sudden onset altered mental status and skew deviation. After improvement in sensorium characteristic vertical gaze palsy was noted with subtle confusion which recovered. MRI brain revealed characteristic Para median bithalamic infarcts with normal intracranial angiogram. Patient showed a slow and incomplete clinical recovery to conservative management.

Progressive Supranuclear Palsy-Like Syndrome after Surgical Repair of Chronic Ascending Aorta Dissection

A 70-year-old woman underwent cardiopulmonary bypass surgery for aorta dissection. After 10 days she developed a vertical gaze palsy, and 2 months later she presented with dysarthria, bradykinesia, postural instability, blepharospasm, and truncal tilt to the left. Brain imaging indicated old lacunes in the bilateral thalamus. Her symptoms remained unchanged during a 4-year follow-up, which seems to be incompatible with progressive supranuclear palsy (PSP). However, the clinical features of this case were suggestive of PSP-like syndrome after cardiopulmonary bypass surgery. Key Words: Parkinsonism, Progressive supranuclear palsy, Cardiopulmonary bypass

Mystery Case: Acute clot within P1 segment mimicking cisternal hemorrhage in Percheron infarction

A 72-year-old man was admitted after sudden onset of coma (Glasgow Coma Scale score 6/15). At clinical examination he had tetraparesis, bilateral Babinski signs, bilateral unresponsive miosis, and vertical gaze palsy. Head CT scan demonstrated a linear hyperdensity outlining the interpeduncular cistern (figure, A). Additional MRI examination was performed promptly to rule out blood extravasation since thrombolysis was considered. Bilateral Percheron artery type II infarction was demonstrated on diffusion-weighted imaging (figure, B). Magnetic resonance (MR) angiogram demonstrated complete occlusion of right P1 segment (figure, C), the abnormal hyperintensity seen on CT image corresponding to the occluding fresh clot. Comparison of CT and MRI data appeared mandatory to reach an appropriate therapeutic option in this peculiar condition. Follow-up MR angiogram demonstrated complete recanalization (figure, D).

The clinical spectrum and natural history of pure akinesia with gait freezing.

Gait freezing as a presenting and relatively restricted condition is uncommon but a distinctive disorder. This entity was initially defined as "pure akinesia with gait freezing", and later a neuropathological substrate of progressive supranuclear palsy has been recognized. Limited studies have reported the clinical evolution after presentation, which is important for patient counseling. The objective of this study was to assess the demographic and clinical features, treatment-response, neuroimaging, and evolution of pure akinesia with gait freezing. A retrospective review of patients with this phenotype as previously defined was performed. Patients included had no or minimal limb rigidity and/or bradykinesia and no resting tremor, and all underwent neuroimaging of the brain after onset. Inclusion criteria were met by 30 patients, who were followed up to 21years after symptom onset. During their course, 28 patients had falls (93%), 12 patients had dysarthria (40%), and 13 had handwriting changes (43%). All patients had progression of their gait disorder over time, but with a variable interval until falls occurred. None of the patients developed vertical gaze palsy or met diagnostic criteria for an alternative parkinsonian disorder. Pure akinesia with gait freezing is a distinctive disorder that can be recognized in the clinic. Despite the previously reported progressive supranuclear palsy-like neuropathology, the clinical course is much less aggressive and disabling than classic Richardson syndrome, although fall risk eventually develops in nearly all patients. Bradykinesia, tremor, and rigidity do not develop, distinguishing pure akinesia with gait freezing from Parkinson's disease and other parkinsonian disorders.