Gaze Palsy Research Articles

Beyond Vertical: Unraveling The PSP Enigma

Progressive Supranuclear Palsy (PSP) is an aberrant type of Parkinsonian disorder that cognates with progressive axial rigidity, vertical gaze palsy, dysarthria and dysphagia. It is supposed to affect movement, gait, balance, speech, swallowing, vision, movements, mood, behavior and cognition. PSP increases as per age and its prevalence is 7% per 1 lakh, as reported. PSP is often misdiagnosed with Parkinson’s disease, however, PSP progresses more rapidly than Parkinson’s. people with PSP develop unique eye movement problems with looking up and down, speech and swallowing problems are much more common and severe in PSP than PD, leaning backwards and extend their neck in PSP (axial rigidity) while in PD -bending happens in forward direction than backward. Tremors are rare for PSP but very common in PD. The three most important primary motor symptoms are: tremors, bradykinesia, and rigidity (parkinsonism). Since this disease is termed as tauopathy, 4R-tau isoforms aggregate into straight filaments and appear as a major tau doublet (tau64 & 69). The differential diagnosis is very difficult for PSP because many neurodegenerative disorders have similar symptoms and very less discrimination between PSP and other disorders. The main objective of our study is to create awareness about PSP and its overlapping symptoms with PD as well as other and other neuro-degenerative disorders. However, based upon detailed investigations about, tau and its isoforms, these clinical features may be distinguished. However, it would require abundant knowledge of the molecular functioning and structure of tau proteins. Keywords: tauopathy, parkinsonism, progressive axial rigidity, neuro-degenerative disorders

Asymmetry in Atypical Parkinsonian Syndromes—A Review

Background/Objectives: Atypical parkinsonian syndromes (APSs) are a group of neurodegenerative disorders that differ from idiopathic Parkinson’s disease (IPD) in their clinical presentation, underlying pathology, and response to treatment. APSs include conditions such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), and dementia with Lewy bodies (DLB). These disorders are characterized by a combination of parkinsonian features and additional symptoms, such as autonomic dysfunction, supranuclear gaze palsy, and asymmetric motor symptoms. Many hypotheses attempt to explain the causes of neurodegeneration in APSs, including interactions between environmental toxins, tau or α-synuclein pathology, oxidative stress, microglial activation, and vascular factors. While extensive research has been conducted on APSs, there is a limited understanding of the symmetry in these diseases, particularly in MSA. Neuroimaging studies have revealed metabolic, structural, and functional abnormalities that contribute to the asymmetry in APSs. The asymmetry in CBS is possibly caused by a variable reduction in striatal D2 receptor binding, as demonstrated in single-photon emission computed tomography (SPECT) examinations, which may explain the disease’s asymmetric manifestation and poor response to dopaminergic therapy. In PSP, clinical dysfunction correlates with white matter tract degeneration in the superior cerebellar peduncles and corpus callosum. MSA often involves atrophy in the pons, putamen, and cerebellum, with clinical symmetry potentially depending on the symmetry of the atrophy. The aim of this review is to present the study findings on potential symmetry as a tool for determining potential neuropsychological disturbances and properly diagnosing APSs to lessen the misdiagnosis rate. Methods: A comprehensive review of the academic literature was conducted using the medical literature available in PubMed. Appropriate studies were evaluated and examined based on patient characteristics and clinical and imaging examination outcomes in the context of potential asymmetry. Results: Among over 1000 patients whose data were collected, PSP-RS was symmetrical in approximately 84% ± 3% of cases, with S-CBD showing similar results. PSP-P was symmetrical in about 53–55% of cases, while PSP-CBS was symmetrical in fewer than half of the cases. MSA-C was symmetrical in around 40% of cases. It appears that MSA-P exhibits symmetry in about 15–35% of cases. CBS, according to the criteria, is a disease with an asymmetrical clinical presentation in 90–99% of cases. Similar results were obtained via imaging methods, but transcranial sonography produced different results. Conclusions: Determining neurodegeneration symmetry may help identify functional deficits and improve diagnostic accuracy. Patients with significant asymmetry in neurodegeneration may exhibit different neuropsychological symptoms based on their individual brain lateralization, impacting their cognitive functioning and quality of life.

Metronome-Guided Balance Exercises to Aid in Dynamic Balance and Postural Control in a Novel Genetic Presentation of Niemann–Pick Disease Type C: A Case Report

Abstract Niemann–Pick disease type C is a rare progressive lysosomal lipid storage disorder. The disorder is characterized by a range of neurological consequences and complications at different points of its progression including spasticity, incoordination, ataxia, supranuclear gaze palsy, asthenia, and balance impairment, with a higher risk of falls. Among various approaches to managing such a debilitating condition, the role of physical therapy in managing the symptoms of such patients is often limited or underreported in the literature. A combination of spasticity and ataxia leads to impaired timing of agonist–antagonist control. Therefore, balance loss and falls are the most prevalent symptoms. We advocated a 12-week metronome-guided balance training program. Niemann–Pick type C disease is a rare genetic phenomenon that often presents with multi-system changes at structural and functional levels for the patient. Metronome-guided balance training is beneficial for improving dynamic balance variables, including movement velocity, center of gravity sway velocity, and step width.

Dopaminergic neurodegeneration in Gerstmann-Sträussler-Scheinker (P102L) disease: insights from imaging and pathological examination.

Gerstmann-Sträussler-Scheinker (GSS) disease is an inherited prion disease characterized by dementia, cerebellar ataxia, and painful sensory disturbances. GSS is pathologically defined by the presence of amyloid plaques comprised of prion protein predominantly localized in the cerebral cortex, cerebellar cortex, and basal ganglia, resulting from mutations in the prion protein gene. This study investigated five cases of GSS P102L [GSS caused by a leucine (L) substitution of proline (P) at position 102 of the prion protein gene] with L-dopa-resistant extrapyramidal symptoms and reduced dopamine transporter single-photon emission computed tomography (DAT-SPECT) uptake. Clinical findings revealed diverse manifestations, with all cases exhibiting parkinsonism, and four patients had a vertical gaze palsy. Notably, all patients showed reduced striatal DAT-SPECT uptake, indicating neurodegeneration of the nigrostriatal system. Autopsy findings in one case confirmed prion protein plaques and dopaminergic neuron loss in the substantia nigra of a patient with GSS P102L. Additionally, reduced DAT immunostaining was observed in the putamen compared with a control. While previous studies have identified reduced DAT-SPECT and positron emission tomography uptake in Creutzfeldt-Jakob disease and fatal familial insomnia owing to nigrostriatal neurodegeneration induced by abnormal prion protein deposition, similar phenomena in GSS P102L have not been reported. This study provides support for a correlation between abnormal prion protein deposition and nigrostriatal system degeneration in GSS P102L. Our results reveal the importance of considering GSS P102L in cases of atypical Parkinsonism and abnormal DAT-SPECT results, which would serve as a valuable indicator for subsequent prion genetic testing.

POST-STROKE VISUAL FIELD DEFECTS AND OTHER OPHTHALMOLOGICAL ABNORMALITIES: A RETROSPECTIVE STUDY

Objective: The study aimed to estimate prevalence of visual field defects (VFDs) and other ophthalmological abnormalities in post-stroke patients. Methods: This retrospective study, conducted in department of ophthalmology in collaboration of department of neurology of a tertiary care medical institute, analyzed data from 80 adult patients undergoing ophthalmological examination including perimetry for presence of VFDs. Demographic data, including age and gender were extracted. Medical records were reviewed to assess visual disturbances, systemic illnesses, and medications. Gender distribution and presence of risk factors such as diabetes and hypertension were analyzed. Ophthalmological findings and the type and severity of VFDs were noted from perimetry reports. Magnetic resonance imaging and computed tomography scans were analyzed to identify brain lesions causing VFDs. Results: In a study of 80 stroke patients, males were more prevalent (58.8%) than females (41.2%), with the most affected age group being 31– 40 years (33.8%). Hypertension was the most common risk factor (35.0%), and ischemic stroke was the most frequent type (66.3%). The anterior circulation was the predominant site of lesions (85.0%). The most frequent VFDs was complete homonymous hemianopia, observed in 20 patients (25.0%), followed by partial homonymous hemianopia in 6 patients (7.5%). Constriction and inferior quadrantanopia were each noted in 3 patients (3.75%), while superior quadrantanopia was seen in 2 patients (2.5%). Hemianopia combined with quadrantanopia and scotoma were the least common (1.25% each). The other common ophthalmological finding was gaze palsy which was seen in 13 (16.25%) patients. Conclusion: Visual filed defects and other ophthalmological manifestations such as gaze palsies are common in post-stroke patients. Early detection and targeted rehabilitation of these abnormalities enhance recovery, reduce disability and optimize outcomes for stroke survivors.

Alzheimer's Disease-Related Cerebrospinal Fluid Biomarkers in Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is the most common four-repeat tauopathy. PSP cases are typically characterized by vertical gaze palsy and postural instability; however, various phenotypes have been reported, making antemortem diagnosis based on clinical symptoms challenging. The development of biomarkers reflecting brain pathology and the ability to diagnose patients based on these biomarkers are essential for developing future intervention strategies, including disease-modifying therapies. However, despite many dedicated efforts, no highly specific fluid biomarker for PSP has yet been established. Conversely, several cerebrospinal fluid (CSF) biomarkers of Alzheimer's Disease (AD) have been established, and an AT(N) classification system has been proposed. Typically, among patients with AD, CSF amyloid β42 (Aβ42), but not Aβ40, is decreased, resulting in a reduction in the Aβ42/Aβ40 ratio, while tau phosphorylated at threonine 181 (p-tau181) and total tau (t-tau) are increased. Interestingly, the core CSF AD biomarkers show unique patterns in patients with PSP. Furthermore, reports have indicated that the CSF levels of both Aβ42 and Aβ40 are decreased independently of Aβ accumulation in PSP. Therefore, the Aβ42/Aβ40 ratio could potentially be used to differentiate PSP from AD. Additionally, studies have reported that CSF p-tau and t-tau are reduced in PSP, and that the neurofilament light chain is remarkably increased compared to healthy controls and patients with AD, even though PSP is a neurodegenerative disease associated with tau accumulation. These PSP-specific changes in AD-related core biomarkers may reflect the pathology of PSP and contribute to its diagnosis. As such, elucidating the mechanisms underlying the observed decreases in Aβ and tau levels could facilitate a better understanding of the pathogenesis of PSP.

Through their eyes: Navigating life with limited eyelid closure in patients with Moebius syndrome

Moebius syndrome (MoS), a rare congenital condition caused by the underdevelopment of the sixth and seventh cranial nerves, presents with uni- or bilateral facial paralysis and lateral gaze palsy. Those with MoS often have incomplete eyelid closure (lagophthalmos). This study aimed to investigate the experiences of individuals living with incomplete eyelid closure due to MoS. Participants shared their experiences in semi-structured open-ended focus groups during the 2023 MoS Foundation Conference. Data were analyzed thematically using Nvivo. The Terzis and Bruno scoring system was used to grade participant eyelid closure (range: 1 being no eyelid closure with full scleral show to 5 being complete eyelid closure with no scleral show) and blink (from 1 being no blink to 5 being synchronous and complete blink present). Marginal reflex distances 1 and 2 (MRD1 and MRD2) were measured to grade for ptosis and lid retraction, respectively. Fifteen participants participated in two focus groups, comprising adults (n=12) and adolescents (n=3). All participants had lagophthalmos with some scleral show, ptosis, and lid retraction. The median eyelid closure score was 3 (incomplete eye closure with 1/3 scleral showing). Five key themes were identified: social stigma and misunderstanding, daily life impacts, seasonal exacerbations, different attitudes toward surgical intervention between adults and adolescents, and a prevailing sense of self-acceptance regarding their condition. Incomplete eyelid closure poses significant social challenges for individuals with MoS, especially around social encounters. Our findings show the importance of developing tailored communication tools to support those living with this facial difference.

A Case of Anti-IgLON5 Disease with Aplastic Anemia and review of the literature

Anti-IgLON5 is a neurological condition with neurodegenerative and autoimmune etiology. A 64-year-old man with a 2-year history of aplastic anemia presented with symmetrical parkinsonism, fluctuating consciousness, supranuclear gaze palsy, mild fasciculation, and muscular atrophy. He had disturbances in his sleep cycle and brain MRI. CSF analysis was positive for the IgLON5 antibody. We initiated immunotherapy with high-dose methylprednisolone, intravenous immunoglobulin, and rituximab. The patient showed a mild to moderate response to treatment. We reviewed 29 published case reports regarding anti-Iglon-5 and examined the clinical manifestation. None of the cases showed aplastic anemia, which was the main presentation in our case. All of the patients experienced sleep disturbances, while other symptoms were heterogeneous. Anti-Iglon-5 is usually diagnosed late, leading to a weak prognosis. This study helped us establish a better understanding of the correlation between antiIglon5 disease and other autoimmune disorders like anemia.

Generation and characterization of human-derived induced pluripotent stem cell line (IGIBi010-A) from a patient with neurodegenerative disease phenotype carrying mutation in SQSTM1/p62 gene

SQSTM1 (Sequestosome 1) also known as p62, plays several important physiological roles in the cell. It regulates autophagy and mitochondrial homeostasis and can further lead to metabolic reprogramming. Pathogenic variants in SQSTM1 gene are known to cause Neurodegeneration with ataxia, dystonia, and gaze palsy in autosomal recessive inheritance fashion. We report here, the generation of induced pluripotent stem cell (iPSC) line (IGIBi010-A) carrying a novel homozygous frameshift variant in SQSTM1 i.e. p.Leu251SerfsTer4. In future, this iPSC line will be used as a resource to elucidate the molecular pathway, targeting strategies for disease biology derived by variation in SQSTM1 gene.

New-Onset Gaze Palsy in a Sports-Related Concussion.

Concussions are a common injury in pediatric sports medicine clinics. Occasionally, a patient presenting for concussion will demonstrate abnormal neurologic findings, but in this case, a gaze palsy was witnessed during the initial 2 weeks following closed head injury with subsequent complete resolution of symptoms. There are limited available studies or case reports demonstrating this atypical presentation; thus, this case study aims to provide sports medicine physicians a reference for future similar atypical presentations.

Horizontal gaze palsy with progressive scoliosis: Further expanding the ROBO3 spectrum.

Horizontal gaze palsy with progressive scoliosis (HGPPS) is a rare, autosomal recessive disorder resulting from axonal midline crossing defect due to variants in ROBO3. We retrospectively evaluated demographics, clinical phenotype, course of spinal deformities, and neuroimaging findings of six Turkish patients with HGPPS. We performed targeted gene testing by next-generation sequencing. The median age at symptom onset and diagnosis was 1.5 years (0.5-4), and 11 years (2-16), respectively. Oculomotor signs were the most common presenting symptom (n = 4), followed by scoliosis (n = 2). The course of scoliosis was progressive and accompanied by kyphosis, showed intrafamilial variability, and was corrected surgically in three of the patients. Intellectual disability (n = 4), hypergonadotropic hypogonadism (n = 2), hearing loss (n = 2), and tranisent movement disorders (n = 1) were additional features. Targeted gene sequencing revealed five distinct homozygous variants. Of the four novel variants, two of them were located in the acceptor site of the noncoding region of the gene, remaining two were missense and frameshift variants, located in immunoglobulin-like domain-2, and cytoplasmic signaling motif 2, respectively. Structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) showed the absence of decussation of superior cerebellar peduncle and dorsal transverse pontine fibers. Spectrum of HGPPS is further expanded with novel variants in the ROBO3 with clinical and radiological fingerprints. Spinal deformities require close orthopedic screening and individualized approach. Intellectual disability and hearing loss emerge as additional features. Hypogonadism and transient subtle movement disorders require further attention and confirmation from other series.

Kufor-Rakeb syndrome-associated psychosis: a novel loss-of-function ATP13A2 variant and response to antipsychotic therapy.

Biallelic (autosomal recessive) pathogenic variants in ATP13A2 cause a form of juvenile-onset parkinsonism, termed Kufor-Rakeb syndrome. In addition to motor symptoms, a variety of other neurological and psychiatric symptoms may occur in affected individuals, including supranuclear gaze palsy and cognitive decline. Although psychotic symptoms are often reported, response to antipsychotic therapy is not well described in previous case reports/series. As such, we describe treatment response in an individual with Kufor-Rakeb syndrome-associated psychosis. His disease was caused by a homozygous novel loss-of-function ATP13A2 variant (NM_022089.4, c.1970_1975del) that was characterized in this study. Our patient exhibited a good response to quetiapine monotherapy, which he has so far tolerated well. We also reviewed the literature and summarized all previous descriptions of antipsychotic treatment response. Although its use has infrequently been described in Kufor-Rakeb syndrome, quetiapine is commonly used in other degenerative parkinsonian disorders, given its lower propensity to cause extrapyramidal symptoms. As such, quetiapine should be considered in the treatment of Kufor-Rakeb syndrome-associated psychosis when antipsychotic therapy is deemed necessary.

A rare case of pineoblastoma – Case report

Pineoblastoma is a very rare and aggressive malignant tumor of pineal gland. We report a case of 12-year-old male patient presented to S.V.P. tertiary care hospital with complain of progressive loss of vision in both eyes with nausea and headache. On examination bilateral upward gaze palsy was present. The magnetic resonance imaging report revealed possibility of pineal Germinoma. The patient underwent ventriculoperitoneal shunt insertion surgery for obstructive hydrocephalus and suboccipital craniectomy for tumor resection. The Histopathological examination report stated the tumor as Pineoblastoma, Grade IV. Immunohistochemistry studies were positive for synaptophysin and Integrase interactor-1 (INI-1) markers with high ki-67 labelling index and negative for CD-117 and Glial fibrillary acid protein (GFAP) markers. Microscopic and Immuno histochemisty findings are important to differentiate pineoblastoma from other pineal region tumors.

Clinical and genetic analysis of Niemann-Pick disease type C with a novel NPC1 variant

BackgroundNiemann-Pick disease type C poses a significant challenge within the landscape of rare genetic disorders, marked by its connection to variants in the NPC1 or NPC2 genes. This autosomal recessive lipid storage disorder unfolds with a relentless progression of neurological deterioration and a distinctive hallmark of hepatosplenomegaly.Case presentationThis case report delves into the intricate presentation of a 9-year-old Iraqi boy exhibiting heightened walking instability and speech slurring. His medical history unfolds a series of challenges, including neonatal hyperbilirubinemia, hepatosplenomegaly, and recurrent nasal bleeding. A comprehensive physical examination reveals motor and neurological abnormalities such as an inability to squat and rise, vertical gaze palsy, and dysdiadochokinesia. Further investigations, encompassing laboratory tests and imaging studies, coupled with the identification of foamy cells in bone marrow smears, raise significant concerns about Niemann-Pick disease type C. By utilizing whole exome sequencing, we pinpointed a previously unreported homozygous variant—c.2925_2928delCTGC; p.Cys976PhefsTer6—found within exon 20 (NM_000271.5) of the proband’s NPC1 gene.ConclusionsThis study significantly advances our understanding of the c.2925_2928del (C976Ffs*6) variant in the NPC1 gene, shedding light on the complexities of Niemann-Pick disease type C. Beyond its scientific significance, the findings provide crucial insights for familial genetic counseling and prenatal diagnoses. This research expands our knowledge of the variant’s genetic landscape, making it a valuable resource in both academic and clinical settings, particularly for families dealing with Niemann-Pick disease type C.

Patterns of brain volume and metabolism predict clinical features in the progressive supranuclear palsy spectrum.

Progressive supranuclear palsy (PSP) is a neurodegenerative tauopathy that presents with highly heterogenous clinical syndromes. We perform cross-sectional data-driven discovery of independent patterns of brain atrophy and hypometabolism across the entire PSP spectrum. We then use these patterns to predict specific clinical features and to assess their relationship to phenotypic heterogeneity. We included 111 patients with PSP (60 with Richardson syndrome and 51 with cortical and subcortical variant subtypes). Ninety-one were used as the training set and 20 as a test set. The presence and severity of granular clinical variables such as postural instability, parkinsonism, apraxia and supranuclear gaze palsy were noted. Domains of akinesia, ocular motor impairment, postural instability and cognitive dysfunction as defined by the Movement Disorders Society criteria for PSP were also recorded. Non-negative matrix factorization was used on cross-sectional MRI and fluorodeoxyglucose-positron emission tomography (FDG-PET) scans. Independent models for each as well as a combined model for MRI and FDG-PET were developed and used to predict the granular clinical variables. Both MRI and FDG-PET were better at predicting presence of a symptom than severity, suggesting identification of disease state may be more robust than disease stage. FDG-PET predicted predominantly cortical abnormalities better than MRI such as ideomotor apraxia, apraxia of speech and frontal dysexecutive syndrome. MRI demonstrated prediction of cortical and more so sub-cortical abnormalities, such as parkinsonism. Distinct neuroanatomical foci were predictive in MRI- and FDG-PET-based models. For example, vertical gaze palsy was predicted by midbrain atrophy on MRI, but frontal eye field hypometabolism on FDG-PET. Findings also differed by scale or instrument used. For example, prediction of ocular motor abnormalities using the PSP Saccadic Impairment Scale was stronger than with the Movement Disorders Society Diagnostic criteria for PSP oculomotor impairment designation. Combination of MRI and FDG-PET demonstrated enhanced detection of parkinsonism and frontal syndrome presence and apraxia, cognitive impairment and bradykinesia severity. Both MRI and FDG-PET patterns were able to predict some measures in the test set; however, prediction of global cognition measured by Montreal Cognitive Assessment was the strongest. MRI predictions generalized more robustly to the test set. PSP leads to neurodegeneration in motor, cognitive and ocular motor networks at cortical and subcortical foci, leading to diverse yet overlapping clinical syndromes. To advance understanding of phenotypic heterogeneity in PSP, it is essential to consider data-driven approaches to clinical neuroimaging analyses.

Qualitative Study of the Patient Experience with Venglustat for Gaucher Disease Type3 in a Phase2 Open-Label, Multicenter, Multinational Study (LEAP).

Gaucher disease type3 (GD3) is a genetic, progressive lysosomal storage disorder characterized by visceral manifestations and chronic neurologic symptoms (e.g., horizontal ophthalmoplegia/supranuclear gaze palsy, ataxia, dystonia). The investigational agent venglustat is being studied in combination with imiglucerase as potential treatment for systemic and neuronopathic manifestations of GD3 in a single-arm, open-label, phase2 trial (LEAP; N = 11). To understand perceived changes in GD3 symptoms from the perspectives of patients, caregivers, and clinicians, we conducted a qualitative case study of selected LEAP participants. Four patients in LEAP (age range, 20-28years), four of their caregivers, and three clinicians involved in LEAP were interviewed individually by moderators using semi-structured guides. Clinicians' perceptions were based on observation of interviewed patients and those in LEAP who were not interviewed, as well as information provided by other staff involved in LEAP, patients, and caregivers. Reported changes in GD3 symptoms varied among patients and among reporters. Only eye movement was spontaneously mentioned as improved by at least one patient, caregiver, and clinical expert. Symptom improvement also varied in terms of time to improvement. Within the first weeks, improvements were seen in understanding new information or complex instructions, remembering the weekday, eye movement, tremor, and seizures. Changes in alertness, engagement and responsiveness, memory, and concentration appeared after months or a year. Most caregivers and all clinical experts reported greater patient independence (e.g., increased ability to perform activities of daily living or travel independently during the trial) as a perceived treatment effect on a GD3 impact. For one patient who perceived benefits from venglustat therapy, pharmacokinetic analyses during LEAP found low to undetectable venglustat levels in their plasma and cerebrospinal fluid. Outcomes from this study provide insights into GD3 symptoms and the early signaling of changes reported during venglustat therapy. ClinicalTrials.gov identifier, NCT02843035.

Artery of Percheron infarct – An ophthalmologist’s perspective

Thalamus is an important relay station in diencephalon which receives its blood supply mostly from the posterior cerebral artery. The Artery of Percheron (AOP) arises from the posterior cerebral artery and bifurcates to supply paramedian thalami. AOP infarction, though rare, presents with a triad of clinical features including altered mental status, memory impairment, and supranuclear vertical gaze palsy. Our patient had concurrent manifestation of vertical gaze palsy (both upward and downward) and third cranial nerve palsy in the left eye, which is an interesting clinical amalgamation. Our case report elucidates the quick recognition of the abnormalities in ocular motility through a simple, yet effective nine gaze ocular motility evaluation and thereby enhancing clinical recognition of this entity among the practicing general Ophthalmologists.

Progressive supranuclear palsy: Neuropathology, clinical presentation, diagnostic challenges, management, and emerging therapies

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized by the accumulation of 4R-tau protein aggregates in various brain regions. PSP leads to neuronal loss, gliosis, and tau-positive inclusions, such as neurofibrillary tangles, tufted astrocytes, and coiled bodies. These pathological changes mainly affect the brainstem and the basal ganglia, resulting in distinctive MRI features, such as the hummingbird and morning glory signs. PSP shows clinical heterogeneity and presents as different phenotypes, the most classical of which is Richardson's syndrome (PSP-RS). The region of involvement and the mode of atrophy spread can further distinguish subtypes of PSP. PSP patients can experience various signs and symptoms, such as postural instability, supranuclear ophthalmoplegia, low amplitude fast finger tapping, and irregular sleep patterns. The most common symptoms of PSP are postural instability, falls, vertical gaze palsy, bradykinesia, and cognitive impairment. These features often overlap with those of Parkinson's disease (PD) and other Parkinsonian syndromes, making the diagnosis challenging. PSP is an essential clinical topic to research because it is a devastating and incurable disease. However, there are still many gaps in knowledge about its pathophysiology, diagnosis, and treatment. Several clinical trials are underway to test noveltherapies that target tau in various ways, such as modulating its post-translational modifications, stabilizing its interaction with microtubules, or enhancing its clearance by immunotherapy. These approaches may offer new hope for slowing down the progression of PSP. In this review, we aim to provide an overview of the current knowledge on PSP, from its pathogenesis to its management. We also discuss the latest advances and future directions in PSP research.

Progressive Thrombocytopenia, Splenomegaly, and Abnormal Tone in an Infant With Growth Faltering.

A 4-month-old full-term female presented with growth faltering associated with progressive feeding difficulty, rash, abdominal distension, and developmental delays. She was found to have disconjugate gaze, abnormal visual tracking, mixed tone, bruising, and splenomegaly on examination. Initial workup was notable for thrombocytopenia and positive cytomegalovirus (CMV) immunoglobulin G and immunoglobulin M antibodies. She initially presented to the infectious diseases CMV clinic, where she was noted to have severe malnutrition, prompting referral to the emergency department for hospital admission to optimize nutrition with nasogastric tube feeding and facilitate additional evaluation. An active CMV infection with viruria and viremia was confirmed, but elements of her presentation and workup including brain magnetic resonance imaging were not consistent with isolated CMV infection. To avoid premature diagnostic closure, a multidisciplinary workup was initiated and ultimately established her diagnosis.

Comparing classic-onset corticobasal syndrome to speech/language-onset corticobasal syndrome

IntroductionPatients with classic-onset corticobasal syndrome (CBS) present with asymmetric limb apraxia and parkinsonism. We have, however, observed patients who initially present with speech and/or language (SL) problems and several years later develop CBS (i.e., SL-onset CBS). We aimed to compare clinical, neuroimaging and pathological characteristics of classic-onset CBS with SL-onset CBS. MethodsWe conducted a retrospective cohort study of 62 patients who met criteria for CBS (17 presented with classic-onset CBS and 45 had SL-onset CBS). We compared demographics, clinical characteristics, and grey and white matter volume loss with SPM12 between groups and assessed pathology and corticobasal degeneration (CBD) pathological lesion counts in patients who had died and undergone autopsy. ResultsMedian age at CBS diagnosis was 66.4 years in classic-onset CBS and 73.6 years in SL-onset CBS. Classic-onset CBS had higher frequencies of dystonia, myoclonus, and alien limb phenomenon, while SL-onset CBS had a higher frequency of vertical supranuclear gaze palsy. Both groups showed smaller frontoparietal volumes than controls, with SL-onset CBS having greater volume loss in the left supplementary motor area than classic-onset CBS. All three classic-onset CBS cases with autopsy (100 %) had CBD pathology while 8/21 of SL-onset CBS cases (38 %) had CBD. Pathological lesion burden (including astrocytic plaques) did not differ between classic-onset and SL-onset CBS. ConclusionClassic-onset and SL-onset CBS appear to be different syndromes, with the former being a more profuse motor syndrome. The more widespread volume loss in SL-onset CBS likely reflects longer disease course.