Nonverbal Cognitive Skills in Children With Aicardi Goutières Syndrome.

BACKGROUND AND OBJECTIVES: Aicardi Goutières syndrome (AGS) is type I interferonopathy characterized by severe neurologic impairment. Although many children with AGS demonstrate motor and expressive language deficits, the magnitude of receptive language impairment is uncharacterized. We sought to characterize cognitive function in AGS-affected children using assessment tools with reduced dependence on motor abilities and compare cognitive testing outcomes with overall severity and parental assessment of adaptive behavior. METHODS: We performed a cross-sectional study. Children were recruited as part of the Myelin Disorders Biorepository Project at the Children's Hospital of Philadelphia. We included individuals with a confirmed diagnosis of AGS. We administered the Leiter International Performance Scale, third edition (Leiter-3), and the Vineland Adaptive Behavior Scale, third edition (VABS-3), in the context of research encounters. Motor skills were categorized by AGS Severity Scale mobility levels. Descriptive statistics and Spearman's rank correlation were used to compare assessments. Mann-Whitney and Kruskal-Wallis tests with correction with Dunn's multiple comparison test were used to compare test performance between mobility groups. RESULTS: Cognitive and adaptive behavior performance was captured in 57 children. The mean age at encounters was 8.51 (SD 5.15) years. The median (IQR) Leiter-3 score was 51 (interquartile range [IQR] 60), with administration failure in 20 of 57 (35%) individuals. On the VABS-3, the Motor Domain (median 29, IQR 36.25) was more impacted than the Communication (median 50, IQR 52), Daily Living Skills (median 52, IQR 31), and Socialization (median 54, IQR 40) Domains (p < 0.0001). The AGS Scale correlated with VABS-3 (r = 0.86, p < 0.0001) and Leiter-3 (r = 0.87, p < 0.0001). There was correlation between VABS-3 Domains and Leiter-3 (r-range 0.83-0.97). Gross motor and fine motor categories, respectively, correlated with VABS-3 (H = 39.37, p < 0.0001; U = 63, p < 0.0001) and Leiter-3 (H = 40.43, p < 0.0001; U = 66, p < 0.0001). Within each gross motor and fine motor category of the AGS Scale, a subset of children scored within normal IQ range. DISCUSSION: Parental assessment of function by the VABS-3 correlated with directly assessed performance measures. Our data underscore the potential value of VABS-3 and Leiter-3 as tools to assess psychometric function in AGS. With a deeper understanding of our patients' abilities, we can better guide clinicians and families to provide appropriate support and personalized interventions to empower children with leukodystrophies to maximize their communication and educational potential.

Cerebrospinal fluid findings in patients with psychotic symptoms-a retrospective analysis.

In current international classification systems (ICD-10, DSM5), the diagnostic criteria for psychotic disorders (e.g. schizophrenia and schizoaffective disorder) are based on symptomatic descriptions since no unambiguous biomarkers are known to date. However, when underlying causes of psychotic symptoms, like inflammation, ischemia, or tumor affecting the neural tissue can be identified, a different classification is used ("psychotic disorder with delusions due to known physiological condition" (ICD-10: F06.2) or psychosis caused by medical factors (DSM5)). While CSF analysis still is considered optional in current diagnostic guidelines for psychotic disorders, CSF biomarkers could help to identify known physiological conditions. In this retrospective, partly descriptive analysis of 144 patients with psychotic symptoms and available CSF data, we analyzed CSF examinations' significance to differentiate patients with specific etiological factors (F06.2) from patients with schizophrenia, schizotypal, delusional, and other non-mood psychotic disorders (F2). In 40.3% of all patients, at least one CSF parameter was out of the reference range. Abnormal CSF-findings were found significantly more often in patients diagnosed with F06.2 (88.2%) as compared to patients diagnosed with F2 (23.8%, p < 0.00001). A total of 17 cases were identified as probably caused by specific etiological factors (F06.2), of which ten cases fulfilled the criteria for a probable autoimmune psychosis linked to the following autoantibodies: amphiphysin, CASPR2, CV2, LGl1, NMDA, zic4, and titin. Two cases presented with anti-thyroid tissue autoantibodies. In four cases, further probable causal factors were identified: COVID-19, a frontal intracranial tumor, multiple sclerosis (n = 2), and neurosyphilis. Twenty-one cases remained with "no reliable diagnostic classification". Age at onset of psychotic symptoms differed between patients diagnosed with F2 and F06.2 (p = 0.014), with the latter group being older (median: 44 vs. 28 years). Various CSF parameters were analyzed in an exploratory analysis, identifying pleocytosis and oligoclonal bands (OCBs) as discriminators (F06.2 vs. F2) with a high specificity of > 96% each. No group differences were found for gender, characteristics of psychotic symptoms, substance dependency, or family history. This study emphasizes the great importance of a detailed diagnostic workup in diagnosing psychotic disorders, including CSF analysis, to detect possible underlying pathologies and improve treatment decisions.

Manifestations and impact of the COVID-19 pandemic in neuroinflammatory diseases.

OBJECTIVE: To report initial results of a planned multicenter year-long prospective study examining the risk and impact of COVID-19 among persons with neuroinflammatory disorders (NID), particularly multiple sclerosis (MS). METHODS: In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID-19 in persons with NID (PwNID) and change in their neurological care. RESULTS: Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (ORadj  = 1.45, 1.17-1.84). INTERPRETATIONS: Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID-19 similar to the reference population.

Exploratory investigation on antibodies to GluN1 and cognitive dysfunction in patients with chronic autoimmune psychosis.

INTRODUCTION: Mild cognitive dysfunction has been implicated in a number of psychiatric diseases and affects social functioning. Although clinical criteria were recently proposed for autoimmune psychosis (AP), biomarkers have not yet been established for the severity and prognosis of cognitive dysfunction. We herein investigated the relationships between 3 types of serum antibodies and cognitive dysfunction in chronic psychiatric patients suspected of AP. METHODS: We included 31 patients suspected of AP and obtained information on their clinical characteristics. Three types of autoantibodies (the anti-N-methyl-D-aspartate receptor (anti-NMDAR Ab), anti-N-terminal of GluN1 (anti-GluN1-NT Ab), and anti-thyroid antibodies) were evaluated in serum. Cognitive function was assessed using Wechsler Adult Intelligence Scale-III. We examined the relationships between serum autoantibodies and cognitive dysfunction in patients using multiple regression models. RESULTS: Serum titers of anti-GluN1-NT Ab significantly contributed to the estimated score of working memory (B= -55.85, ß= -0.46, p= 0.01), while no correlation was observed between the other 2 types of antibodies and cognitive function. CONCLUSIONS: The present results indicate the potential of serum anti-GluN1-NT Ab as a biomarker for the severity and prognosis of cognitive dysfunction underlying various psychiatric symptoms in patients with AP. The pathological significance of anti-GluN1-NT Ab needs to be verified in future studies.

Complex syndromes of chronic pain, fatigue and cognitive impairment linked to autoimmune dysautonomia and small fiber neuropathy.

Chronic fatigue syndrome, postural orthostatic tachycardia syndrome, complex regional pain syndrome and silicone implant incompatibility syndrome are a subject of debate among clinicians and researchers. Both the pathogenesis and treatment of these disorders require further study. In this paper we summarize the evidence regarding the role of autoimmunity in these four syndromes with respect to immunogenetics, autoimmune co-morbidities, alteration in immune cell subsets, production of autoantibodies and presentation in animal models. These syndromes could be incorporated in a new concept of autoimmune neurosensory dysautonomia with the common denominators of autoantibodies against G-protein coupled receptors and small fiber neuropathy. Sjogren's syndrome, which is a classical autoimmune disease, could serve as a disease model, illustrating the concept. Development of this concept aims to identify an apparently autoimmune subgroup of the disputable disorders, addressed in the review, which may most benefit from the immunotherapy.

Development of the clinical assessment scale in autoimmune encephalitis.

OBJECTIVE: There is no scale for rating the severity of autoimmune encephalitis (AE). In this study, we aimed to develop a novel scale for rating severity in patients with diverse AE syndromes and to verify the reliability and validity of the developed scale. METHODS: The key items were generated by a panel of experts and selected according to content validity ratios. The developed scale was initially applied to 50 patients with AE (development cohort) to evaluate its acceptability, reproducibility, internal consistency, and construct validity. Then, the scale was applied to another independent cohort (validation cohort, n = 38). RESULTS: A new scale consisting of 9 items (seizure, memory dysfunction, psychiatric symptoms, consciousness, language problems, dyskinesia/dystonia, gait instability and ataxia, brainstem dysfunction, and weakness) was developed. Each item was assigned a value of up to 3 points. The total score could therefore range from 0 to 27. We named the scale the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). The new scale showed excellent interobserver (intraclass correlation coefficient [ICC] = 0.97) and intraobserver (ICC = 0.96) reliability for total scores, was highly correlated with modified Rankin scale (r = 0.86, p < 0.001), and had acceptable internal consistency (Cronbach α = 0.88). Additionally, in the validation cohort, the scale showed high interobserver reliability (ICC = 0.99) and internal consistency (Cronbach α = 0.92). INTERPRETATION: CASE is a novel clinical scale for AE with a high level of clinimetric properties. It would be suitable for application in clinical practice and might help overcome the limitations of current outcome scales for AE. ANN NEUROL 2019;85:352-358.

The impact of motivational interviewing on self-perceived burden in patients receiving therapeutic plasma exchange.

BACKGROUND: Autoimmune disorders and neurodegenerative disorders take a physical and emotional toll on patients that undergo therapeutic plasma exchange (TPE) treatments. Previous literature has shown that these patients may feel a greater sense of self-burden. Motivational Interviewing (MI) is a technique used in various settings that has the potential to decrease feelings of self-burden. MI for patients who receive TPE has not been tested. The purpose of this study was to examine the impact of MI in patients with a neurodegenerative diagnosis (eg, transverse myelitis, myasthenia gravis, multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy) that are undergoing TPE treatments. METHODS: This was a prospective, non-randomized, longitudinal study of the impact of MI with patients at high risk of sense of self-burden who underwent apheresis treatments. Consented patients underwent three to six MI sessions with a trained clinician. Patients completed a self-report baseline and post-test of self-perceived burden. RESULTS: Thirty participants consented to the study; 27 were included in the analysis. The Self-Perceived Burden Scale scores were significantly higher at baseline (m = 26.2) when compared to scores post MI sessions (m = 21.48, P < .05). The number of MI sessions (3, 4, 5, 6 sessions) did not significantly impact the outcome score (r2 = 0.001; P = .901). CONCLUSION: MI is a straightforward technique that is feasible and shown to be effective to be used by bedside clinicians while working with patients who receive TPE to decrease levels of self-perceived burden.

[Timely consideration of future care; advance care planning for people with intellectual disabilities]. / Tijdig nadenken over toekomstige zorg.

People with intellectual disabilities (IDs) are often unable to decide for themselves regarding complex medical decisions, and need assistance from representatives, often next-of-kin. People with IDs are often frail. This frailty is characterized on the one hand by health problems, on the other hand by significant limitations in both intellectual functioning and in adaptive behaviour. In this group of people, when compared to the general population, the principles of palliative care are applicable more often and over a longer period. Advance care planning should be considered not only at the end of life, but at each stage where decisions have to be made that may affect quality of life. In this article, we present three patient cases to illustrate the complexity of the process and the commitment of representatives and other key stakeholders.

Neuropsychological assessment as an objective tool to monitor treatment response in anti-N-methyl-D-aspartate receptor encephalitis.

We report a 1-year follow-up of a young woman with anti-N-methyl-D-aspartate receptor encephalitis. Management of autoimmune encephalitis remains challenging as objective and clinically relevant biomarkers are sought, which allow for the monitoring of treatment response. While further investigation is required, we believe that this case highlights the importance of following a comprehensive neuropsychological profile as a clinically relevant biomarker to guide therapeutic decision-making. By relying on the neuropsychological assessment of the patient, treatment with more toxic medications was avoided and her antiepileptic drug regimen was simplified.

A clinical approach to new-onset psychosis associated with immune dysregulation: the concept of autoimmune psychosis.

Growing data point to the overlap between psychosis and pathological processes associated with immunological dysregulation as well as inflammation. Notably, the recent discovery of antibodies against synaptic and neuronal cell membrane proteins such as anti-N-methyl-D-aspartate receptor provides more direct evidence of the etiological connection between autoimmunity and subsequent hazard of psychosis. Here, we advocate the use of term "autoimmune psychosis," as this term suggests that autoimmune disorders can masquerade as drug-resistant primary psychosis, and this subtype of psychosis has anatomical and immunological footprints in the brain, despite the frequent absence of structural abnormalities on conventional brain MRI. Furthermore, this term might serve as a reminder not to overlook appropriate neurological workup such as neuroimaging and EEG testing, as well as CSF analysis, for cases with acute or subacute atypical onset of neuropsychiatric presentations including those dominated by acute psychotic symptoms. We propose etiologically and serologically oriented subclassification as well as multi-modal diagnostic approach to address some of the challenges inherent to early diagnosis of patients presenting with atypical and refractory new-onset psychotic symptoms of autoimmune origin. This is particularly relevant to the diagnosis of seronegative but probable autoimmune psychosis (SPAP) that might masquerade as antipsychotic drug-resistant primary psychotic disorder. This distinction is therapeutically important as autoimmune-related psychotic symptomatology can frequently respond well to timely treatment with proper immune modulatory therapies.

Autoimmune Encephalopathy for Psychiatrists: When to Suspect Autoimmunity and What to Do Next.

OBJECTIVE: To provide a critical review of autoimmune encephalopathy-broadly defined as neuropsychiatric features directly related to an autoimmune process-relevant for psychiatric practice. METHODS: We consulted rheumatology textbooks to define the scope of autoimmune conditions and identified recent reviews of rheumatic conditions, autoimmune vasculitis, and autoimmune encephalitis. We integrated these with primary reports to provide a clinically relevant overview of autoimmune encephalopathy. We focus on clinical features that should raise suspicion for autoimmunity. RESULTS: Despite outlying conditions, 2 categories of autoimmune encephalopathy are described: (1) neuropsychiatric symptoms associated with rheumatic conditions and (2) antibody-associated autoimmune encephalitis. Rheumatic conditions principally include connective tissue disease and other vasculitides. These may present variously such as with unexplained delirium, cognitive decline, or depression. Autoimmune encephalitis may be diffuse or localized as in limbic, brainstem, or basal ganglia encephalitis. Unexplained delirium, psychosis, catatonia, strokes, and seizures are among common presenting symptoms. CONCLUSIONS: Prompt identification and management of autoimmunity are critical for optimal outcomes. The fact that undiagnosed and, therefore, untreated autoimmunity leads to debilitation demands vigilance for these conditions. Close attention to the unusual nature and course of neuropsychiatric symptoms, associated neurological features, and review of systems as reviewed here should guide the skillful clinician.

Voltage-gated Potassium Channel Antibody Autoimmune Encephalopathy Presenting With Isolated Psychosis in an Adolescent.

Antibody-mediated encephalopathies associated with serum or cerebrospinal fluid antibodies directed against neuronal structures may present with a multitude of neuropsychiatric syndromes. Although some of the antibody-driven conditions are now well recognized in adults (eg, N-methyl-D-aspartate receptor antibody encephalitis), the spectrum of neuropsychiatric manifestations in the pediatric population is less clear. Psychosis, confusion, catatonia, and additional behavioral changes, along with seizures, encephalopathy, and movement disorders, may be initial manifestations or concurrent features in all age groups. Psychosis, when present, is often part of a broader spectrum of neurological and neuropsychiatric symptoms for which the diagnosis of autoimmune encephalitis is considered. The authors present the case of an adolescent with an acute and isolated psychotic presentation of voltage-gated potassium channel antibody encephalitis, further expanding the phenotypic spectrum of this specific antibody-mediated disease and raising the possibility that specific immune-mediated processes may define a biological subgroup of psychoses.

[Neurological appraisal of children and adolescents with psychotic symptoms]. / Valoracion neurologica de niños y adolescentes con sintomas psicoticos.

INTRODUCTION: Psychotic manifestations in childhood are not infrequent, yet the existing literature dealing with the neurological appraisal of children and adolescents with a clinical picture of psychosis is very scant. AIM: To conduct a non-systematic review of the literature that provides an answer to these three questions: When must a neurological appraisal be performed in a child with psychotic traits? What medical conditions can include signs and symptoms of psychosis in their development? And, what diagnostic procedure should be followed? DEVELOPMENT: The diseases that can present psychotic symptoms at onset or during their course are reviewed and grouped by pathologies: inborn errors of metabolism, genetic diseases, autoimmune and infectious diseases, malformations of the central nervous system, epilepsy, vascular pathology, rheumatologic processes, brain tumours, and psychoactive substances and drugs. A diagnostic regimen is proposed in which both the information obtained from the anamnesis and examination and the findings from each of the diagnostic tests are evaluated. CONCLUSIONS: A huge number of processes can display psychotic symptoms during their course and the key information offered by the anamnesis and examination must be taken into account. This review can help neuropaediatricians and other specialists perform a more systematised appraisal of children and adolescents with psychotic signs and symptoms.

TITLE: Valoracion neurologica de niños y adolescentes con sintomas psicoticos.Introduccion. Las manifestaciones psicoticas en la infancia no son infrecuentes; sin embargo, la bibliografia existente acerca de la valoracion neurologica de niños y adolescentes con cuadros psicoticos es muy escasa. Objetivo. Realizar una revision bibliografica no sistematica que permita responder a estas tres cuestiones: cuando debe llevarse a cabo una valoracion neurologica en un niño con rasgos psicoticos?, cuales son las condiciones medicas que pueden incluir un cuadro psicotico en su evolucion? y cual debe ser el procedimiento diagnostico? Desarrollo. Se revisan las enfermedades que pueden presentar sintomatologia psicotica al inicio o durante la evolucion, y se agrupan por patologias: errores congenitos del metabolismo, enfermedades geneticas, enfermedades autoinmunes e infecciosas, malformaciones del sistema nervioso central, epilepsia, patologia vascular, procesos reumatologicos, tumores cerebrales, y farmacos y sustancias psicoactivas. Se propone una pauta diagnostica en la que se valora la informacion obtenida a partir de la anamnesis y la exploracion y la aportacion de cada prueba diagnostica. Conclusiones. El numero de procesos que pueden manifestar sintomatologia psicotica a lo largo de su evolucion es muy elevado, y hay que considerar las claves que ofrecen la anamnesis y la exploracion. Esta revision puede ayudar a neuropediatras y otros especialistas a realizar una valoracion mas sistematizada de niños y adolescentes con cuadros psicoticos.

Psychiatric manifestations in patients with dysautonomy associated with systemic lupus erythematosus.

The psychiatric manifestations of three patients with systemic lupus erythematosus (SLE) and neuropathic dysautonomic processes are described. All patients had a severe form of SLE with neurological, renal, articular, pulmonary or haematological manifestations. All three have two types of psychiatric manifestations: (1) a chronic and progressive depression and (2) a complex dissociative disorder during the acute episodes of postural hypotension. A provocative test with SPECT with 99mTc-HmPAO to be done during the episode of orthostatic hypotension may contribute to clinical assessment of complex changes in cerebral regional perfusion.

Enfermedades autoinmunitarias sistémicas y trastornos depresivos / Systemic autoimmune diseases and depressive disorders

Introducción. La incidencia de trastornos depresivos acompañando a patologías médicas es elevada y tienen importancia pronostica en su evolución. Objetivo. Determinar la frecuencia de depresión en pacientes con enfermedades autoinmunitarias sistémicas (EAS) y su relación con el dolor, fatiga, trastornos del sueño. Material y métodos. Se realizó un estudio prospectivo descriptivo en 88 pacientes con EAS. Se aplicó cuestionario de depresión CES-D, cuestionario de fatiga FSS y calidad del sueño de Pittsburgh. Resultados. El 69% (n=61) de los pacientes se encontraba deprimido. El dolor se halló en 97% (59/61) de los pacientes deprimidos y en el 62% (17/27) de los no deprimidos (p=0,0006), trastornos del sueño en 95% (58/61) de los pacientes deprimidos, y en el 60% (15/27) de los no deprimidos (p=0,00008). La depresión se asoció a la fatiga: 80% (49/61) para deprimidos y 44% (12/27) para no deprimidos (p=0,001). Discusión. La prevalencia de depresión en las EAS hallada fue muy elevada, 69%, siendo la comorbilidad más frecuente. La depresión se asoció significativamente al dolor, la fatiga y los trastornos del sueño (AU)

Introduction. The incidence of depression accompanying medical pathologies is elevated and have prognostic importance. Objective. To determine the frequency of depression in patients with systemic autoimmune diseases (SAD), as well as to determine the frequency of pain, fatigue and sleep disorders in these patients and their relation with depression. Material and methods. We performed a descriptive, prospective study on 88 patients with AID. The CES-D depression questionnaire, FSS fatigue questionnaire and the Pittsburgh sleep quality index were administered. Results. 69% (n=61) of patients were depressed. Pain was found in 97% (59/61) of depressed patients and in 62% (17/27) of non-depressed patients (P=.0006). Sleep disorders were found in 95% of depressed patients, whereas 60% of non-depressed patients presented them (P=.00008). Depression was associated with fatigue: 80% (49/61) for depressed and 44% for non-depressed (p=0,001) persons. Discussion. A very elevated prevalence of depression was found in SAD: 69%; constituting the most frequent comorbidity. Depression was significantly associated with pain, fatigue and sleep disorders (AU)

Post-streptococcal 'complex' movement disorders: unusual concurrence of psychogenic and organic symptoms.

Post-streptococcal neuropsychiatric disorders encompass a broad spectrum of movement disorders, including tics, stereotypies, dystonia and tremor. We report the case of a 15-year-old boy who presented with a relapsing-remitting combination of psychogenic and organic movement disorders. Both relapses occurred after an episode of streptococcal pharyngitis and consisted in motor and phonic tics, an atypical gait disorder, and severe worsening of a pre-existing psychogenic tremor of the right hand. After each relapse, both psychogenic and 'organic' symptoms concomitantly remitted after the administration of an association of oral steroids and antibiotics. The peculiarity of this case consists in the coexistence of psychogenic and organic symptoms subsequent to streptococcal infection, and broadens the clinical spectrum of post-streptococcal neuropsychiatric disorders.

A Japanese case of autoimmune autonomic ganglionopathy (AAG) and a review of AAG cases in Japan.

A 29-year-old woman presented with acute, pure autonomic (both sympathetic and parasympathetic) failure and positive antibody to ganglionic nicotinic acetylcholine receptor; the diagnosis was autoimmune autonomic ganglionopathy (AAG). She had typical symptoms of AAG, although the patient also had coughing episodes and psychiatric symptoms, which are not typical of AAG in Western countries but are common in AAG cases in Japan. In a review of the Japanese literature, 29 cases of AAG had been reported. AAG patients in Japan were younger and more male predominant than in Western countries. Of the patients in these 29 cases, 10 (34.5%) had coughing episodes and 12 (41.4%) had psychiatric symptoms.