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Current Neurology and Neuroscience... Apr 2023To describe the clinical manifestations of Hashimoto's encephalopathy (HE) and discuss its pathogenesis in light of recent research. (Review)
Review
PURPOSE OF REVIEW
To describe the clinical manifestations of Hashimoto's encephalopathy (HE) and discuss its pathogenesis in light of recent research.
RECENT FINDINGS
The pathogenesis of HE is uncertain. Available evidences point towards an autoimmune etiology due to vasculitis or other inflammatory process. Detection of thyroid antibodies - antithyroid peroxidase and anti-thyroglobulin are essential for diagnosis. Autoimmune encephalitis including Anti-IgLON5 disease needs to be excluded in suspected cases with appropriate tests for neuronal surface antibodies. Detection of thyroid autoantibodies is nonspecific, as these can be detected in some normal individuals and in other autoimmune diseases. In recent years, attention has turned to an aggressive form of Hashimoto's thyroiditis accompanied by elevated serum IgG4 levels in younger males with very high levels of thyroid antibodies. The role of the thyroid autoantibodies in the central nervous system (CNS) tissue damage remains unclear and these can act only as markers for diagnosis. Conversely, they have a role to play in determining the thyroid pathology - more glandular fibrosis associated with thyro-peroxidase antibody than with the thyroglobulin antibody. HE is a syndrome characterized by altered mental status, confusion, hallucinations, delusions, and sometimes seizures, in association with high serum anti-thyroid antibody concentration that is usually responsive to glucocorticoid therapy. Diagnosis requires the exclusion of other causes of encephalopathies and encephalitis including autoimmune encephalitis associated with neuronal surface antibodies and paraneoplastic ones. Diagnosis also is dependent on the demonstration of thyroid autoantibodies in serum. Since there is no direct pathophysiologic link between antithyroid antibodies, Hashimoto thyroiditis and the cerebral syndrome, the nomenclature HE could be misleading. The response to steroids led to a renaming of the syndrome to steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), though some cases do not respond to steroids. In recent years, attention has turned to an aggressive form of Hashimoto's thyroiditis accompanied by elevated serum IgG4 levels (IgG4-related disease). This is characterized by a higher incidence in men (5:1) than in women, onset at a younger age, more intense thyroid inflammation and higher antithyroid antibody titters. Such patients have excessive production of IgG4 + plasmacytes, which infiltrate various organs leading to their fibrosis and sclerosis, sometimes resulting in inflammatory tumors. HE is treated with corticosteroids along with treatment of the dysthyroid condition, if any. There are yet no guidelines regarding steroid dose and/or duration.
Topics: Male; Humans; Female; Hashimoto Disease; Encephalitis; Brain Diseases; Autoantibodies; Steroids; Immunoglobulin G; Fibrosis; Autoimmune Diseases of the Nervous System
PubMed: 36853554
DOI: 10.1007/s11910-023-01255-5 -
Nature Reviews. Neurology Jun 2022Rapidly progressive dementias (RPDs) are a group of heterogeneous disorders that include immune-mediated, infectious and metabolic encephalopathies, as well as prion... (Review)
Review
Rapidly progressive dementias (RPDs) are a group of heterogeneous disorders that include immune-mediated, infectious and metabolic encephalopathies, as well as prion diseases and atypically rapid presentations of more common neurodegenerative diseases. Some of these conditions are treatable, and some must be diagnosed promptly because of their potential infectivity. Prion disease is considered to be the prototypical RPD, but over the past two decades, epidemiological reports and the identification of various encephalitis-mediating antibodies have led to a growing recognition of other encephalopathies as potential causes of rapid cognitive decline. Knowledge of RPD aetiologies, syndromes and diagnostic work-up protocols will help clinicians to establish an early, accurate diagnosis, thereby reducing morbidity and mortality, especially in immune-mediated and other potentially reversible dementias. In this Review, we define the syndrome of RPD and shed light on its different aetiologies and on secondary factors that might contribute to rapid cognitive decline. We describe an extended diagnostic procedure in the context of important differential diagnoses, discuss the utility of biomarkers and summarize potential treatment options. In addition, we discuss treatment options such as high-dose steroid therapy in the context of therapy and diagnosis in clinically ambiguous cases.
Topics: Brain Diseases; Dementia; Diagnosis, Differential; Disease Progression; Humans; Neurodegenerative Diseases; Prion Diseases
PubMed: 35508635
DOI: 10.1038/s41582-022-00659-0 -
Neurology Mar 2016To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously... (Review)
Review
OBJECTIVE
To give a comprehensive overview of the phenotypic and genetic spectrum of STXBP1 encephalopathy (STXBP1-E) by systematically reviewing newly diagnosed and previously reported patients.
METHODS
We recruited newly diagnosed patients with STXBP1 mutations through an international network of clinicians and geneticists. Furthermore, we performed a systematic literature search to review the phenotypes of all previously reported patients.
RESULTS
We describe the phenotypic features of 147 patients with STXBP1-E including 45 previously unreported patients with 33 novel STXBP1 mutations. All patients have intellectual disability (ID), which is mostly severe to profound (88%). Ninety-five percent of patients have epilepsy. While one-third of patients presented with Ohtahara syndrome (21%) or West syndrome (9.5%), the majority has a nonsyndromic early-onset epilepsy and encephalopathy (53%) with epileptic spasms or tonic seizures as main seizure type. We found no correlation between severity of seizures and severity of ID or between mutation type and seizure characteristics or cognitive outcome. Neurologic comorbidities including autistic features and movement disorders are frequent. We also report 2 previously unreported adult patients with prominent extrapyramidal features.
CONCLUSION
De novo STXBP1 mutations are among the most frequent causes of epilepsy and encephalopathy. Most patients have severe to profound ID with little correlation among seizure onset, seizure severity, and the degree of ID. Accordingly, we hypothesize that seizure severity and ID present 2 independent dimensions of the STXBP1-E phenotype. STXBP1-E may be conceptualized as a complex neurodevelopmental disorder rather than a primary epileptic encephalopathy.
Topics: Adolescent; Adult; Brain Diseases; Child; Child, Preschool; Epilepsy; Female; Humans; Infant; Male; Middle Aged; Munc18 Proteins; Mutation; Neurodevelopmental Disorders; Young Adult
PubMed: 26865513
DOI: 10.1212/WNL.0000000000002457 -
Journal of Neurochemistry Apr 2021Mutations in Munc18-1/STXBP1 (syntaxin-binding protein 1) are linked to various severe early epileptic encephalopathies and neurodevelopmental disorders. Heterozygous... (Review)
Review
Mutations in Munc18-1/STXBP1 (syntaxin-binding protein 1) are linked to various severe early epileptic encephalopathies and neurodevelopmental disorders. Heterozygous mutations in the STXBP1 gene include missense, nonsense, frameshift, and splice site mutations, as well as intragenic deletions and duplications and whole-gene deletions. No genotype-phenotype correlation has been identified so far, and patients are treated by anti-epileptic drugs because of the lack of a specific disease-modifying therapy. The molecular disease mechanisms underlying STXBP1-linked disorders are yet to be fully understood, but both haploinsufficiency and dominant-negative mechanisms have been proposed. This review focuses on the current understanding of the phenotypic spectrum of STXBP1-linked disorders, as well as discusses disease mechanisms in the context of the numerous pathways in which STXBP1 functions in the brain. We additionally evaluate the available animal models to study these disorders and highlight potential therapeutic approaches for treating these devastating diseases.
Topics: Animals; Anticonvulsants; Brain; Brain Diseases; Humans; Munc18 Proteins; Mutation; Neurodevelopmental Disorders
PubMed: 32643187
DOI: 10.1111/jnc.15120 -
Revue Neurologique 2021The past two decades have been marked by three epidemics linked to emerging coronaviruses. The COVID-19 pandemic highlighted the existence of neurological manifestations... (Review)
Review
INTRODUCTION
The past two decades have been marked by three epidemics linked to emerging coronaviruses. The COVID-19 pandemic highlighted the existence of neurological manifestations associated with SARS-CoV-2 infection and raised the question of the neuropathogenicity of coronaviruses. The aim of this review was to summarize the current data about neurological manifestations and diseases linked to human coronaviruses.
MATERIAL AND METHODS
Articles have been identified by searches of PubMed and Google scholar up to September 25, 2020, using a combination of coronavirus and neurology search terms and adding relevant references in the articles.
RESULTS
We found five cohorts providing prevalence data of neurological symptoms among a total of 2533 hospitalized COVID-19 patients, and articles focusing on COVID-19 patients with neurological manifestations including a total of 580 patients. Neurological symptoms involved up to 73% of COVID-19 hospitalized patients, and were mostly headache, myalgias and impaired consciousness. Central nervous system (CNS) manifestations reported in COVID-19 were mostly non-specific encephalopathies that represented between 13% and 40% of all neurological manifestations; post-infectious syndromes including acute demyelinating encephalomyelitis (ADEM, n=13), acute necrotizing encephalopathy (ANE, n=4), Bickerstaff's encephalitis (n=5), generalized myoclonus (n=3) and acute transverse myelitis (n=7); other encephalitis including limbic encephalitis (n=9) and miscellaneous encephalitis with variable radiologic findings (n=26); acute cerebrovascular diseases including ischemic strokes (between 1.3% and 4.7% of COVID-19 patients), hemorrhagic strokes (n=17), cerebral venous thrombosis (n=8) and posterior reversible encephalopathy (n=5). Peripheral nervous system (PNS) manifestations reported in COVID-19 were the following: Guillain-Barré syndrome (n=31) and variants including Miller Fisher syndrome (n=3), polyneuritis cranialis (n=2) and facial diplegia (n=2); isolated oculomotor neuropathy (n=6); critical illness myopathy (n=6). Neuropathological studies in COVID-19 patients demonstrated different patterns of CNS damage, mostly ischemic and hemorrhagic changes with few cases of inflammatory injuries. Only one case suggested SARS-CoV-2 infiltration in endothelial and neural cells. We found 10 case reports or case series describing 22 patients with neurological manifestations associated with other human coronaviruses. Among them we found four MERS patients with ADEM or Bickerstaff's encephalitis, two SARS patients with encephalitis who had a positive SARS-CoV PCR in cerebrospinal fluid, five patients with ischemic strokes associated with SARS, eight MERS patients with critical illness neuromyopathy and one MERS patient with Guillain-Barré Syndrome. An autopsy study on SARS-CoV patients demonstrated the presence of the virus in the brain of eight patients.
CONCLUSION
The wide range of neurological manifestations and diseases associated with SARS-CoV-2 is consistent with multiple pathogenic pathways including post-infectious mechanisms, septic-associated encephalopathies, coagulopathy or endothelitis. There was no definite evidence to support direct neuropathogenicity of SARS-CoV-2.
Topics: Brain Diseases; COVID-19; Coronavirus Infections; Coronavirus OC43, Human; Female; Guillain-Barre Syndrome; Humans; Male; Middle East Respiratory Syndrome Coronavirus; Myelitis; Nervous System Diseases; SARS-CoV-2; Severe Acute Respiratory Syndrome; Stroke
PubMed: 33446327
DOI: 10.1016/j.neurol.2020.10.001 -
Critical Care (London, England) Jul 2021Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious... (Review)
Review
Infectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood-brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation.
Topics: Blood-Brain Barrier; Brain Diseases; COVID-19; Cytokines; Humans; Influenza, Human; Malaria; Sepsis
PubMed: 34229735
DOI: 10.1186/s13054-021-03659-6 -
Brain : a Journal of Neurology Sep 2017Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were...
Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype-phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype-phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.
Topics: Animals; Brain Diseases; Epilepsy; Genetic Association Studies; Kv1.2 Potassium Channel; Mutation; Oocytes; Phenotype; Xenopus
PubMed: 29050392
DOI: 10.1093/brain/awx184 -
Revista Espanola de Enfermedades... Jan 2022We report the case of a 79-year-old male who had undergone surgery for a mucus-secreting, stage-III pancreatic adenocarcinoma 2 years previously, who was recently...
We report the case of a 79-year-old male who had undergone surgery for a mucus-secreting, stage-III pancreatic adenocarcinoma 2 years previously, who was recently started on capecitabine monotherapy for radiographic local progression. He developed disorientation, asterixis, nausea and elevated serum ammonia (221 μmol/L) 48-72 hours after treatment onset with preserved liver function. After ruling out potential causes of encephalopathy and tumor progression by abdominal and brain CT scans, his symptoms were related by exclusion to the recently initiated treatment with capecitabine. Capecitabine discontinuation, onset of standard anti-encephalopathy measures, and intravenous hydration led to a rapid, complete resolution of symptoms with serum ammonia normalization.
Topics: Adenocarcinoma; Aged; Ammonia; Brain Diseases; Capecitabine; Humans; Hyperammonemia; Male; Pancreatic Neoplasms
PubMed: 34154371
DOI: 10.17235/reed.2021.8129/2021 -
Journal of Child Neurology Mar 2017
Topics: Brain Diseases; Epilepsy; Humans
PubMed: 28192032
DOI: 10.1177/0883073816680886 -
International Journal of Gynaecology... Jan 2023Neonatal encephalopathy (NE) is an important cause of neonatal morbidity and mortality worldwide; however, there remain gaps in our knowledge about its pathogenesis. The... (Review)
Review
Neonatal encephalopathy (NE) is an important cause of neonatal morbidity and mortality worldwide; however, there remain gaps in our knowledge about its pathogenesis. The placenta has been implicated in the pathogenesis of this disease but conclusive evidence related to the placental factors that influence it is sparse. This review aims to outline the current knowledge on the role of the placenta with particular attention to its role in NE as a consequence of hypoxia-ischemia. A total of 26 original articles/review papers were used to compile this review. Three themes were identified from these publications: fetal vascular malperfusion including umbilical cord pathology, inflammatory changes in the placenta, and maternal vascular malperfusion including placental weight. These features were identified as being significant in the development of NE. Advancing our understanding of this relationship between placental pathology and NE may facilitate the development of additional antenatal screening to better identify at-risk fetuses. We highlight areas for further research through antenatal screening and placental histology.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Placenta; Infant, Newborn, Diseases; Brain Diseases; Umbilical Cord
PubMed: 35694848
DOI: 10.1002/ijgo.14301