Distinct involvement of the cranial and spinal nerves in progressive supranuclear palsy.

The most frequent neurodegenerative proteinopathies include diseases with deposition of misfolded tau or α-synuclein in the brain. Pathological protein aggregates in the PNS are well-recognized in α-synucleinopathies and have recently attracted attention as a diagnostic biomarker. However, there is a paucity of observations in tauopathies. To characterize the involvement of the PNS in tauopathies, we investigated tau pathology in cranial and spinal nerves (PNS-tau) in 54 tauopathy cases [progressive supranuclear palsy (PSP), n = 15; Alzheimer's disease (AD), n = 18; chronic traumatic encephalopathy (CTE), n = 5; and corticobasal degeneration (CBD), n = 6; Pick's disease, n = 9; limbic-predominant neuronal inclusion body 4-repeat tauopathy (LNT), n = 1] using immunohistochemistry, Gallyas silver staining, biochemistry, and seeding assays. Most PSP cases revealed phosphorylated and 4-repeat tau immunoreactive tau deposits in the PNS as follows: (number of tau-positive cases/available cases) cranial nerves III: 7/8 (88%); IX/X: 10/11 (91%); and XII: 6/6 (100%); anterior spinal roots: 10/10 (100%). The tau-positive inclusions in PSP often showed structures with fibrillary (neurofibrillary tangle-like) morphology in the axon that were also recognized with Gallyas silver staining. CBD cases rarely showed fine granular non-argyrophilic tau deposits. In contrast, tau pathology in the PNS was not evident in AD, CTE and Pick's disease cases. The single LNT case also showed tau pathology in the PNS. In PSP, the severity of PNS-tau involvement correlated with that of the corresponding nuclei, although, occasionally, p-tau deposits were present in the cranial nerves but not in the related brainstem nuclei. Not surprisingly, most of the PSP cases presented with eye movement disorder and bulbar symptoms, and some cases also showed lower-motor neuron signs. Using tau biosensor cells, for the first time we demonstrated seeding capacity of tau in the PNS. In conclusion, prominent PNS-tau distinguishes PSP from other tauopathies. The morphological differences of PNS-tau between PSP and CBD suggest that the tau pathology in PNS could reflect that in the central nervous system. The high frequency and early presence of tau lesions in PSP suggest that PNS-tau may have clinical and biomarker relevance.

4R-Tau seeding activity unravels molecular subtypes in patients with Progressive Supranuclear Palsy.

Progressive Supranuclear palsy (PSP) is a 4-repeat (4-R) tauopathy. We hypothesized that the molecular diversity of tau could explain the heterogeneity seen in PSP disease progression. To test this hypothesis, we performed an extensive biochemical characterisation of the high molecular weight tau species (HMW-Tau) in 20 different brain regions of 25 PSP patients. We found a correlation between the HMW-Tau species and tau seeding capacity in the primary motor cortex, where we confirmed that an elevated 4R-Tau seeding activity correlates with a shorter disease duration. To identify factors that contribute to these differences, we performed proteomic and spatial transcriptomic analysis that revealed key mechanistic pathways, in particular those involving the immune system, that defined patients demonstrating high and low tau seeding capacity. These observations suggest that differences in the tau seeding activity may contribute to the considerable heterogeneity seen in disease progression of patients suffering from PSP.

Updated clinical practice recommendations for managing adults with 22q11.2 deletion syndrome.

This review aimed to update the clinical practice guidelines for managing adults with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society recruited expert clinicians worldwide to revise the original clinical practice guidelines for adults in a stepwise process according to best practices: (1) a systematic literature search (1992-2021), (2) study selection and synthesis by clinical experts from 8 countries, covering 24 subspecialties, and (3) formulation of consensus recommendations based on the literature and further shaped by patient advocate survey results. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text review, with 2318 meeting inclusion criteria (clinical care relevance to 22q11.2DS) including 894 with potential relevance to adults. The evidence base remains limited. Thus multidisciplinary recommendations represent statements of current best practice for this evolving field, informed by the available literature. These recommendations provide guidance for the recognition, evaluation, surveillance, and management of the many emerging and chronic 22q11.2DS-associated multisystem morbidities relevant to adults. The recommendations also address key genetic counseling and psychosocial considerations for the increasing numbers of adults with this complex condition.

Dystonia with myoclonus and vertical supranuclear gaze palsy associated with a rare GNB1 variant.

GNB1 encephalopathy (OMIM: 616973), caused by pathogenic variants in the GNB1 gene, is a rare neurodevelopmental syndrome characterized by global developmental delay (GDD) variably co-occurring with movement disorders. For the latter, dystonia, although the most frequent, remains uncommon. Other phenomenologies including myoclonus, tics, chorea, and ataxia, as well as oculomotor abnormalities are rare [1]. Most pathogenic variants in GNBI occur in exons 6 and 7, which are considered to be mutational hotspots [2]. Here, we report a case of GNB1 encephalopathy arising from a de novo mutation in a gene region with few reported pathogenic variants (i.e., exon 11) presenting with a unique phenotype consisting of dystonia with myoclonus and vertical supranuclear gaze palsy.

Newly Approved and Investigational Drugs for Motor Symptom Control in Parkinson's Disease.

Motor symptoms are a core feature of Parkinson's disease (PD) and cause a significant burden on patients' quality of life. Oral levodopa is still the most effective treatment, however, the motor benefits are countered by inherent pharmacologic limitations of the drug. Additionally, with disease progression, chronic levodopa leads to the appearance of motor complications including motor fluctuations and dyskinesia. Furthermore, several motor abnormalities of posture, balance, and gait may become less responsive to levodopa. With these unmet needs and our evolving understanding of the neuroanatomic and pathophysiologic underpinnings of PD, several advances have been made in defining new therapies for motor symptoms. These include newer levodopa formulations and drug delivery systems, refinements in adjunctive medications, and non-dopaminergic treatment strategies. Although some are in early stages of development, these novel treatments potentially widen the available options for the management of motor symptoms allowing clinicians to provide an individually tailored care for PD patients. Here, we review the existing and emerging interventions for PD with focus on newly approved and investigational drugs for motor symptoms, motor fluctuations, dyskinesia, and balance and gait dysfunction.

Body mass index and its association with COVID-19 clinical outcomes: Findings from the Philippine CORONA study.

BACKGROUND AND AIMS: To explore the association between body mass index (BMI) and adverse outcomes in a large cohort of patients with coronavirus disease 2019 (COVID-19). METHODS: This is a secondary analysis of a 37-site, nationwide, multicenter, retrospective cohort study that investigated the clinical and neurological outcomes of adult patients with confirmed COVID-19 admitted from February to December 15, 2020. RESULTS: We analyzed 4,463 patients with BMI and outcome data. A total of 790 (17.7%) and 710 (15.9%) had the primary outcome of in-hospital mortality and need for invasive mechanical ventilation (IMV), respectively. There was no significant association between WHO BMI groups and these outcomes. Using Asia-Pacific cutoffs showed a significant association between obesity and in-hospital mortality risk (P = 0.012). Being underweight was an independent predictor of prolonged IMV requirement regardless of BMI criteria used (P < 0.01). Obesity correlated with the need for intensive care unit admission using Asia-Pacific cutoffs (P = 0.029). There was a significant association between any BMI abnormality and odds of severe/critical COVID-19 (P < 0.05). Obese patients with concomitant acute neurological presentation/diagnosis during their COVID-19 admission were shown to have lower odds of neurologic recovery (P < 0.05). CONCLUSIONS: We found BMI abnormalities to be associated with several adverse clinical and neurologic outcomes, although such associations may be more evident with the use of race-specific BMI criteria.

Autoimmune encephalitis in a tertiary hospital in the Philippines.

BACKGROUND: Autoimmune encephalitis (AE) is an emerging disorder in adults and children. Due to its potentially reversible nature, prompt recognition and intervention are of utmost importance. OBJECTIVE: To describe the clinical and paraclinical features, as well as treatment outcomes of patients with AE admitted in a Philippine tertiary hospital. METHODS: Retrospective case series of patients with definite AE. RESULTS: Eighteen (18) patients were included (12 adults, 6 children), majority of whom had anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. The median age of onset was 32 (IQR: 10.8) years old and 13 (IQR: 4.8) years old in the adult and pediatric population, respectively. In both age groups, most presented with psychiatric symptoms and normal imaging findings. Cerebrospinal fluid (CSF) pleocytosis was detected in 8/12 (66.7%) adults and 2/6 (33.3%) children, while CSF protein elevation was only seen in 6/12 (50%) adults. Most patients presented with seizures, and the most frequent electroencephalography (EEG) abnormality detected was slow activity (70.5%). A high proportion of patients received high dose steroids, alone (35.3%) or in combination with intravenous immunoglobulin (IVIG, 52.9%). Overall, 66.7% had improved outcomes, mostly seen in the pediatric population. CONCLUSION: This study highlighted the broad clinical phenotype, as well as the similarities and differences of AE manifestations in adults and children. It demonstrated the limited but supportive role of laboratory investigations in the diagnosis of AE. It also underscored the importance of early intervention in AE and highlighted factors influencing treatment practices and discharge outcomes in the local setting.

Malnutrition and related factors in Filipino patients with Parkinson's disease: results from a pilot study.

Aim: Emerging evidence demonstrates a bidirectional relationship between nutritional status and Parkinson's disease (PD). Our aim was to determine the local prevalence of malnutrition and associated factors among Filipino PD patients. Materials & methods: We assessed the nutritional status of 95 PD patients using the body mass index (BMI) and Subjective Global Assessment (SGA) and identified malnutrition-associated factors. Results & conclusion: In our sample, the mean BMI was 24.5 ± 4.2 kg/m2. Consistent with published estimates, five (5.3%) patients were classified as underweight and 57 (60%) patients were classified as overweight/obese. A total of 30 (31.6%) patients had abnormal nutritional status based on SGA. Weight-adjusted levodopa equivalent daily dose was a significant factor (p = 0.032) for BMI, while dysphagia and higher weight-adjusted levodopa equivalent daily dose were found to be predictive of abnormal nutritional status using SGA (adjusted odds ratio of 8.85 [95% CI: 1.59-49.17; p = 0.015] and 1.10 [95% CI: 1.02-1.20; p = 0.021], respectively).

Cerebellar ataxia as a primary manifestation of neuropsychiatric systemic lupus erythematosus.

Acute cerebellar ataxia is a rare primary manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE). We report a case of a 22-year-old woman who presented with gait instability, behavioural changes and new-onset seizures. The tempo of disease progression was explained by an autoimmune cause, eventually fulfilling the criteria for systemic lupus erythematosus. The patient's neurological symptoms improved markedly following administration of steroids and immunomodulators. A review of literature on cerebellar ataxia in NPSLE and a summary of all reported cases to date are also presented.

Hemichorea-Hemiballismus as a Presentation of Cerebritis from Intracranial Toxoplasmosis and Tuberculosis.

Background: There is limited literature documenting hemichorea-hemiballism (HCHB) resulting from co-infection of toxoplasmosis and tuberculosis (TB) in acquired immunodeficiency syndrome (AIDS). Toxoplasmic abscess is the most common cause while TB is a rare etiology. Case Description: We describe a 24-year-old male with AIDS-related HCHB as the presentation of cerebritis on the right subthalamic nucleus and cerebral peduncle from intracranial toxoplasma and TB co-infection. Antimicrobials and symptomatic therapy were given. Marked improvement was seen on follow-up. Discussion: HCHB may be the initial presentation of intracranial involvement of this co-infection in the setting of AIDS and is potentially reversible with timely management. Highlights: Hemichorea-hemiballismus (HCHB) may be an initial presentation of intracranial involvement of concomitant toxoplasmosis and tuberculosis causing focal cerebritis in the contralateral subthalamic nucleus and cerebral peduncle, particularly in the setting of human immunodeficiency virus infection.Acquired immunodeficiency syndrome-related HCHB is potentially reversible with timely diagnosis and treatment.

Acute hemorrhagic leukoencephalitis of Weston Hurst secondary to herpes encephalitis presenting as status epilepticus: A case report and review of literature.

Acute hemorrhagic leukoencephalitis (AHL) is a rare and mostly fatal fulminant demyelinating disease. This case describes a 63-year old male in status epilepticus associated with an intracerebral hemorrhage following a one week viral prodrome with rapid decline to coma. He exhibited peripheral leukocytosis, neutrophilic pleocytosis with normal glucose and high protein in cerebrospinal fluid (CSF). Additionally, CSF was positive for herpes simplex virus (HSV) polymerase chain reaction (PCR). Medical decompression, low-dose dexamethasone, antibiotics and acyclovir were initially given. Magnetic resonance imaging (MRI) was suggestive of AHL, thus he was treated with methylprednisolone 1 g/day for 5 days. The patient improved and was discharged with significant neurologic morbidity. This is the first reported case of AHL in the Philippines presenting as a diagnostic dilemma with a protracted clinical course who responded to high dose intravenous steroids.

Neuromyelitis optica spectrum disorder in a tertiary hospital in the Philippines: a case series.

Neuromyelitis optica spectrum disorder (NMOSD) is a rare disease that commonly presents with optic nerve and spinal cord inflammation, and it is associated with the presence of aquaporin-4 immunoglobulin G antibody (AQP4-IgG). Information on the clinical profile and occurrence of NMOSD among Filipino patients, however, is not sufficiently documented. In this series, we presented eighteen (18) patients with NMOSD consecutively seen in the Philippine General Hospital, a major tertiary referral center. Demographic data showed a female-to-male ratio of 2.6:1. Median age of onset of symptoms was 26 years. Eight patients (53.3%) were positive for AQP4-IgG. Most patients initially presented with myelitis (56.6%) and followed by optic neuritis (16.7%) and area postrema syndrome (16.7%). All patients had longitudinally extensive transverse myelitis on magnetic resonance imaging (MRI). Cranial MRI rarely demonstrated lesions in the optic nerves (18.2%). CSF pleocytosis (33%) and increased protein (8.3%) were infrequent. These results demonstrated that the profile of Filipino patients with NMOSD seen in our institution strengthens those described in other populations with this disorder. Large scale cross-sectional studies are necessary to fully define the profile of these patients and to determine with accuracy the prevalence and incidence of this disorder in the Philippines. Further investigation regarding the utility of ancillary tests as diagnostic and prognostic indicators in patients with NMOSD are also suggested by the authors.

Efficacy of sertraline in post-traumatic brain injury (post-TBI) depression and quality of life: A systematic review and meta-analysis of randomized controlled trials.

The relative paucity of robust studies on pharmacological treatments for depression following traumatic brain injury precludes establishment of firm recommendations for its routine use in this population. The purpose of this study is to determine the efficacy and tolerability of sertraline in the treatment of post-TBI depression and improvement in quality of life. Randomized controlled trials (RCT) were identified by electronic search through PubMed, Scopus, CINAHL (Cumulative Index to Nursing and Allied Health Literature), LILACS (Literatura Latino-Americana e do Caribe em Ciencas da Saude), Cochrane Library, Clinicaltrials.gov, and HERDIN (Health Research and Development Information Network database). Random effects meta-analysis of data for depression scale scores, treatment response, and quality of life scale scores was conducted. Four RCTs were included with a total of 224 patients. There were no significant mean differences in the Hamilton Depression Rating Scale (HAM-D17) scores (MD = 2.63, 95% CI [-1.32,6.57], p = 0.19), Maier subscale scores (MD = 0.88, 95% CI [-2.26, 4.01], p = 0.58), odds ratio of treatment response (OR = 1.04, 95% CI [0.13, 8.43], p = 0.97) and quality of life scale scores (SMD = -1.52, 95% CI [-5.65, 2.61], p = 0.47) between sertraline and placebo. The pooled evidence from four RCTs shows that sertraline is not superior to placebo in terms of improving depression and quality of life of patients with post-TBI depression. There is also insufficient evidence regarding its safety in this subset of patients.

Hemilingual Angioedema after Thrombolysis in a Patient on an Angiotensin II Receptor Blocker.

Orolingual angioedema (OLAE) is a rare adverse effect of alteplase. Previous studies have associated the occurrence of OLAE with thrombolysed patients maintained on angiotensin converting enzyme inhibitors. We report a case of a 60-year-old male presenting with hyperacute ischemic stroke developing hemilingual edema after thrombolysis. He was previously maintained on an angiotensin II receptor blocker (ARB), losartan. The swelling resolved over 2 days with immediate administration of intravenous steroids and antihistamine drugs. Our case is the third documented case of OLAE occurring in a thrombolysed patient concurrently taking an ARB. The presence of hemilingual edema in a post-thrombolysis patient maintained on losartan suggests a possible association between OLAE and ARBs.

Autoimmune encephalitis associated with two antibodies.

•In patients presenting with clinical manifestations of encephalitis without clinical or laboratory signs of infection, an autoimmune etiology should be suspected.•Antibodies for various neural antigens may coexist, thus a complete and clinically-guided autoimmune panel must be done in suspected cases of autoimmune encephalitis.•Tumor resection, if applicable, combined with high dose steroids and immunotherapy are effective treatment strategies for autoimmune encephalitis with coexisting antibodies.

Development and Validation of a Questionnaire Evaluating Impaired Hypoglycemia Awareness among Adult Filipino Patients with Type 2 Diabetes Mellitus.

INTRODUCTION: Hazards of hypoglycemia include accidents, cardiovascular events, neurologic damage, and impaired hypoglycemia awareness (IHA) which presents as inability to perceive and respond to hypoglycemic warning symptoms. OBJECTIVE: This study aimed to develop the first questionnaire evaluating IHA adapted from Clarke Hypoglycemia Index (CHI) and validated among adult Filipino patients with Type 2 Diabetes Mellitus (T2DM). METHODOLOGY: A questionnaire development study was conducted involving CHI linguistic translation, its modification through literature review and focus group discussions, panel synthesis, and content validity. A cross-sectional analytic study followed by administration of the questionnaire to 117 adult Filipinos with T2DM, advanced age, long-standing T2DM, insulin or sulfonylurea, polypharmacy, comorbidities and/or prior hypoglycemia. There were 9 participants in pilot testing, 69 in criterion validity against continuous glucose monitoring (CGM), and 108 in construct validity. RESULTS: IHA domains in the concept map included Elusive Euglycemia Model, Developmental Model, and Cognitive Model. The Filipino-CHI formulated had 8 questions with content validity scores ranging from 87.5-93.75%. Owing to brevity, its internal consistency Cronbach's alpha was 0.45. Criterion validity against CGM yielded 21 patients with biochemical hypoglycemic events, of which 2 had clinical hypoglycemic events and 19 were positive monitor-identified IHA. A questionnaire IHA cutoff score of ≥4 had sensitivity of 89.47%, and area under the curve of 0.55. CONCLUSION: An 8-item questionnaire evaluating IHA among adult Filipino T2DM patients was developed and validated.