Assessment of comorbid symptoms in pediatric autonomic dysfunction.

PURPOSE: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning. METHODS: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains. RESULTS: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI. CONCLUSION: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers.

Introducing the "Temporal Thumb Sign" in Pediatric Patients With New-Onset Idiopathic Seizures With and Without Elevated Cerebrospinal Fluid Opening Pressure.

BACKGROUND: Temporal lobe changes, such as anterior temporal lobe meningoceles or encephaloceles, have been documented as possible epileptogenic foci in a subset of pediatric patients with seizures. In our study, we aim to analyze a different structural change in the temporal lobe, remodeling of the posterior temporal skull base by the inferior temporal gyrus called the "temporal thumb sign" (TTS), in pediatric patients presenting with new-onset seizures with or without elevated opening pressure (OP), patients presenting with confirmed diagnosis of idiopathic intracranial hypertension (IIH) without seizure presentation, and healthy controls. METHODS: Magnetic resonance imaging scans of 163 pediatric patients were studied retrospectively for the presence of TTS. We analyzed the scans of 43 patients with elevated OP and confirmed IIH, 40 patients with elevated OP and new-onset idiopathic seizures, 40 patients with normal OP and new-onset idiopathic seizures, and 40 age- and sex-matched healthy controls. RESULTS: The TTS was detected most frequently in patients with elevated OP and seizures at 72.5% compared with patients with IIH with no seizures and patients with normal OP and seizures (32.6% and 27.5%, respectively). The TTS had a frequency of 12.5% in the control group. The TTS had the highest combination of specificity and sensitivity (72.5% and 72.5%) in patients with seizures and elevated OP compared with patients with seizures and normal OP (P value < 0.001). CONCLUSIONS: Our results suggest the Kamali "temporal thumb sign" is a novel imaging feature that may be used as a sensitive and specific imaging finding associated with seizures and elevated OP in the pediatric population.

Arterial Baroreceptor Physiology: Differences Between Normal Subjects and Pediatric Patients with Postural Tachycardia and Neurocardiogenic Syncope.

The arterial baroreceptor reflex in children and adolescents has not been well studied in the current literature with a lack of agreed upon normal values, particularly in postural orthostatic tachycardia syndrome (POTS) or neurocardiogenic syncope (NCS). We used the sequence method and head-up tilt test (HUTT) to evaluate baroreceptor function in 3 phases: baseline supine position for 10 min, head-up position at 70° for 30 min or until syncope, and post-tilt supine reposition for 10 min. We measured the number of baroreceptor events, baroreceptor effectiveness index (BEI), and the magnitude of sensitivity of the events at each phase of HUTT. We studied 198 individuals (49 normal subjects, 67 POTS, 82 NCS) with age ranges from 8 to 21 years. The data show a statistically significant decrease in slope and BEI in patients with POTS and NCS during the head-up phase, with an increase in activity in the lag 1 and 2 portions of all phases in patients with POTS. This study provides terminology to describe baroreceptor function and identifies the slope and BEI portions of the baroreceptor reflex as the most useful objective measures to differentiate pediatric patients with POTS and NCS from normal subjects.

Neuroimaging Features of Intracranial Hypertension in Pediatric Patients With New-Onset Idiopathic Seizures, a Comparison With Patients with Confirmed Diagnosis of Idiopathic Intracranial Hypertension: A Preliminary Study.

CONCLUSION: A cutoff value of 6.0 mm for optic nerve sheath dilation may be used as a screening imaging marker to suspect elevated opening pressure with specificity of 88% in pediatric patients with new-onset idiopathic seizures.

Orthostatic Headaches Associated With Spontaneous Intracranial Hypotension and Autonomic Dysfunction-A Case Series in Young Patients.

Background: Orthostatic headaches can be noted in spontaneous intracranial hypotension and orthostatic intolerance. We present a case series of young patients diagnosed with spontaneous intracranial hypotension and were treated for the same but subsequently developed orthostatic intolerance. Methods: We retrospectively reviewed charts for seven young patients with orthostatic headaches related to spontaneous intracranial hypotension and orthostatic intolerance. Results: Patients were diagnosed with spontaneous intracranial hypotension. Diagnosis was confirmed by identifying epidural contrast leakage and three of seven patients were noted to have early renal contrast excretion on computerized tomography myelography. Patients were treated with epidural blood patches. All patients showed persistent symptoms of autonomic dysfunction after treatment of spontaneous intracranial hypotension and orthostatic intolerance was confirmed with head-up tilt table test. Conclusions: Patients with spontaneous intracranial hypotension failing to improve following epidural blood patching should be evaluated for orthostatic intolerance.

Cutaneous manifestations of orthostatic intolerance syndromes.

Dysautonomia refers to a group of autonomic nervous system disorders that affect nearly 70 million people worldwide. One subset of dysautonomia includes syndromes of orthostatic intolerance (OI), which primarily affect adolescents and women of childbearing age. Due to the variability in disease presentation, the average time from symptom onset to diagnosis of dysautonomia is 6 years. In general, there is a paucity of dermatological research articles describing patients with dysautonomia. The objective of this review is to summarize the existing literature on cutaneous manifestations in dysautonomia, with an emphasis on syndromes of OI. A PubMed database of the English-language literature (1970-2020) was searched using the terms "dysautonomia", "orthostatic intolerance", "cutaneous", "skin", "hyperhidrosis", "hypohidrosis", "sweat", and other synonyms. Results showed that cutaneous manifestations of orthostatic intolerance are common and varied, with one paper citing up to 85% of patients with OI having at least one cutaneous symptom. Recognition of dermatological complaints may lead to an earlier diagnosis of orthostatic intolerance, as well as other comorbid conditions.

Mercury-induced autoimmunity: Report of two adolescent siblings with Morvan syndrome "plus" and review of the literature.

Heavy metal toxicity is a global health concern. Mercury intoxication has been implicated in the etiology and pathogenesis of autoimmune disease, including Morvan syndrome. We describe two siblings with overlapping features of distinct autoimmune syndromes following accidental exposure to elemental mercury. Morvan syndrome was the predominant clinical phenotype. In addition to the characteristic anti-leucine-rich glioma-inactivated protein 1 (LGI1) and anti-contactin-associated protein-like 2 (Caspr2) autoantibodies, glutamic acid decarboxylase 65-kilodalton isoform (GAD65), and N-type and P/Q-type voltage-gated calcium channel (VGCC) antibodies were detected. Treatment with chelation therapy, glucocorticoids, and intravenous immunoglobulin was unsuccessful, but complete resolution of symptoms was achieved following treatment with rituximab. Herein, we perform an extensive review of the literature with a focus on the emerging concepts of mercury-induced autoimmunity and the role of mercury in the etiopathogenesis of autoimmune diseases of the nervous system.

Demographic and clinical features of pediatric patients with orthostatic intolerance and an abnormal head-up tilt table test; A retrospective descriptive study.

BACKGROUND: Clinical presentation varies in children with Orthostatic Intolerance. This study aimed to evaluate the epidemiological and clinical characteristics of pediatric patients with orthostatic intolerance (OI) and positive head-up tilt test (HUTT). METHODS: This study was a retrospective review of clinical data from outpatients over 18 months period. RESULTS: We included 112 patients with abnormal HUTT results. Females were 78 (70%). Mean age of presentation was 15.6 years (sd: 3.3). Fifteen percent were overweight, and 14% were obese. A headache and syncope were the most frequent presenting symptoms (46% and 29% respectively). Review of systems identified more patients with headaches (84%), Syncope (61%), presyncope (87%) and abdominal pain (29%). Except for fatigue being more prevalent during a review of systems among patients with severe OI (69%) compared to those with moderate OI (46%, p = 0.02), there was no statistically significant difference in the clinical presentation between investigator-defined moderate and severe OI. Comorbidities identified in this cohort were Chiari malformations (9%), idiopathic intracranial hypertension (9%), electroencephalographic abnormalities (8%) and patent foramen ovale (43%). CONCLUSIONS: Adolescents, mainly females had OI. Patients with OI and abnormal HUTT predominantly had a headache, syncope, and presyncope during the presentation. Eliciting review of systems and using tools such as clinical questionnaire identifies significant clinical presenting features and comorbidities.

Infant with protein C deficiency and stroke in the setting of iron deficiency anemia.

We report an 18-month-old infant with ischemic stroke, neurocognitive impairment, and psychomotor retardation in the setting of severe iron deficiency anemia. Although an uncommon outcome in anemic children, stroke is important to consider as a cause for developmental delay in children with iron deficiency anemia.

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models.

Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, the feasibility of these approaches for dominantly inherited diseases - where treatment may require reduction in the expression of a toxic mutant protein resulting from a gain-of-function allele - is unclear. Here we show the efficacy of allele-specific RNAi as a potential therapy for Charcot-Marie-Tooth disease type 2D (CMT2D), caused by dominant mutations in glycyl-tRNA synthetase (GARS). A de novo mutation in GARS was identified in a patient with a severe peripheral neuropathy, and a mouse model precisely recreating the mutation was produced. These mice developed a neuropathy by 3-4 weeks of age, validating the pathogenicity of the mutation. RNAi sequences targeting mutant GARS mRNA, but not wild-type, were optimized and then packaged into AAV9 for in vivo delivery. This almost completely prevented the neuropathy in mice treated at birth. Delaying treatment until after disease onset showed modest benefit, though this effect decreased the longer treatment was delayed. These outcomes were reproduced in a second mouse model of CMT2D using a vector specifically targeting that allele. The effects were dose dependent, and persisted for at least 1 year. Our findings demonstrate the feasibility of AAV9-mediated allele-specific knockdown and provide proof of concept for gene therapy approaches for dominant neuromuscular diseases.

Baroreceptor activity and sensitivity: normal values in children and young adults using the head up tilt test.

BACKGROUND: Baroreceptor function in children and adolescents has not been well studied in the current literature, with a lack of agreed upon normal values. The authors hypothesize that there is a significant increase in the baroreceptor activity with a decrease in the sensitivity during the upright phase in comparison to the supine phases of the head upright tilt test (HUTT) protocol. METHODS: Baroreceptor evaluation was performed using the sequence method in 49 subjects ages 8-21 years, during the 3 phases of HUTT: supine, head up, and post-tilt supine positions. Baroreceptor Effectiveness Index (BEI) and the number and slope of baroreceptor events were recorded. RESULTS: On study of the events and slope values, there was a significant difference between the three phases of the HUTT with regard to the baroreceptor activity and sensitivity. No significant difference was found in BEI. CONCLUSIONS: Our study presents normal values of baroreceptor activity, sensitivity, and BEI in pediatric patients under controlled supine and head up position. We also present new data regarding delayed heart rate responses to pressure changes in the Lag 1 and Lag 2 parameters, which may be beneficial in diagnosis and management of pediatric patients with orthostatic intolerance.

Angiostrongylus cantonensis Meningitis and Myelitis, Texas, USA.

Infection with Angiostrongylus cantonensis roundworms is endemic in Southeast Asia and the Pacific Basin. A. cantonensis meningitis and myelitis occurred in summer 2013 in a child with no history of travel outside of Texas, USA. Angiostrongyliasis is an emerging neurotropic helminthic disease in Texas and warrants increased awareness among healthcare providers.

Autologous Adipose Stem Cell Therapy for Autonomic Nervous System Dysfunction in Two Young Patients.

Postural orthostatic tachycardia syndrome and neurocardiogenic syncope are clinical manifestations of autonomic nervous system dysfunction (dysautonomia) that can lead to impaired daily functions. We report two young patients presenting with dysautonomia and autoimmune disease who both received autologous adipose stem cells (ASCs) infusions. This report is the first description of ASCs therapy for patients with combined dysautonomia and autoimmune disease. Case 1: A 21-year-old female presented at 12 years of age with escalating severe dysautonomia with weight loss and gastrointestinal symptoms. She had elevated autoantibodies and cytokines and received multiple immune modulation therapies. Her dysautonomia was treated by volume expanders, vasoconstrictors, and beta blockers with mild improvement. She received ASCs about 2 years before this report with dramatic improvement in her dysautonomia and autoimmune symptoms with a 10 kg weight gain. Case 2: A 7-year-old boy presented at 2 years of age with polyarthritis. At 5 years of age, he manifested orthostatic intolerance. He received immune modulatory therapies with mild improvement. He received ASCs and showed marked improvement of his dysautonomia and immune symptoms. Dysautonomia symptoms of these two patients improved significantly after modulation of autoimmune components by ASC therapy. Favorable clinical responses of these two cases warrant further case-control studies.

Dominant Transmission Observed in Adolescents and Families With Orthostatic Intolerance.

BACKGROUND: Orthostatic intolerance is typically thought to be sporadic and attributed to cerebral autonomic dysfunction. We sought to identify families with inherited autonomic dysfunction manifest as symptomatic orthostatic intolerance to characterize mode of inheritance and clinical features. METHODS: Sixteen families with two or more first- or second-degree relatives with autonomic dysfunction and orthostatic intolerance were enrolled. A clinical diagnosis of autonomic dysfunction defined by symptomatic orthostatic intolerance diagnosed by head-up tilt table testing was confirmed for each proband. Clinical features and evaluation were obtained from each proband using a standardized intake questionnaire, and family history information was obtained from probands and available relatives. RESULTS: Comprehensive pedigree analysis of 16 families (39 individuals with orthostatic intolerance and 40 individuals suspected of having orthostatic intolerance) demonstrated dominant transmission of autonomic dysfunction with incomplete penetrance. Affected individuals were predominantly female (71.8%, 28/39; F:M, 2.5:1). Male-to-male transmission, although less common, was observed and demonstrated to transmit through unaffected males with an affected parent. Similar to sporadic orthostatic intolerance, probands report a range of symptoms across multiple organ systems, with headaches and neuromuscular features being most common. CONCLUSIONS: Familial occurrence and vertical transmission of autonomic dysfunction in 16 families suggest a novel genetic syndrome with dominant transmission, incomplete penetrance, and skewing of the sex ratio. Elucidation of potential genetic contributions to orthostatic intolerance may inform therapeutic management and identification of individuals at risk. Adolescent evaluation should include identification and treatment of potential at-risk relatives.

Cerebral blood flow during HUTT in young patients with orthostatic intolerance.

PURPOSE: To investigate patterns of change in cerebral perfusion during head-up tilt testing (HUTT) in children and young adults with autonomic dysfunction. METHODS: We utilized near-infrared spectroscopy (NIRS) to estimate bilateral cerebral perfusion patterns during HUTT in 71 adolescents and young adults with a diagnosis of autonomic dysfunction. In addition, we used transthoracic impedance to measure cardiac stroke volume and thus infer autonomic tone, heart rate, and blood pressure during the test. Cerebral blood-flow wave-patterns were then visually analyzed and associated with clinical symptoms and measures of cardiovascular and autonomic function. RESULTS: Visual analysis of contour changes in head NIRS values during phases of HUTT revealed variable patterns of cerebral blood flow, some specifically associated with severe symptomatology (i.e., syncope). We also observed an inequality in blood flow of the cerebral hemispheres in many patients. Finally, we observed changes in cardiac stroke volume during HUTT, as previously reported, that related to changes in head NIRS. CONCLUSION: These results confirm a decrease in cerebral blood flow during HUTT as assessed by head NIRS in patients with autonomic dysfunction. Specifically, we have profiled the cerebral blood flow contours throughout the phases of HUTT, which add insight into the clinical spectrum of the disorder and may correlate with clinical severity.

Oculomotor executive function abnormalities with increased tic severity in Tourette syndrome.

BACKGROUND: Reports conflict as to whether Tourette syndrome (TS) confers deficits in executive function. This study's aim was to evaluate executive function in youths with TS using oculomotor tasks while controlling for confounds of tic severity, age, medication, and severity of comorbid disorders. METHOD: Four saccade tasks requiring the executive functions of response generation, response inhibition, and working memory (prosaccade, antisaccade, 0-back, and 1-back) were administered. Twenty youths with TS and low tic severity (TS-low), nineteen with TS and moderate tic severity (TS-moderate), and 29 typically developing control subjects (Controls) completed the oculomotor tasks. RESULTS: There were small differences across groups in the prosaccade task. Controlling for any small sensorimotor differences, TS-moderate subjects had significantly higher error rates than Controls and TS-low subjects in the 0-back and 1-back tasks. In the 1-back task, these patients also took longer to respond than Controls or TS-low subjects. CONCLUSIONS: In a highly controlled design, the findings demonstrate for the first time that increased tic severity in TS is associated with impaired response inhibition and impaired working memory and that these executive function deficits cannot be accounted for by differences in age, medication or comorbid symptom severity.

Biogenic amine metabolism in juvenile neurocardiogenic syncope with dysautonomia.

OBJECTIVE: Biogenic amine brain levels and their cerebral metabolism are frequently studied by quantitation of biogenic amine metabolites in cerebrospinal fluid (CSF) compared to age-matched controls. There is a paucity of studies in adolescents and young adults investigating the potential role of disordered cerebral biogenic amine metabolism in young patients who have dysautonomia based on abnormal head-up tilt table (HUTT). METHODS: In a cohort of juvenile patients with neurocardiogenic syncope and dysautonomia documented by abnormal HUTT, biogenic amine metabolites of dopamine and serotonin were quantitated in 18 patients (15 females). HUTT testing is an effective clinical method to evaluate posturally induced physiological events in patients suspected of neurocardiogenic syncope with dysautonomia. RESULTS: Levels of the dopamine metabolite (homovanillic acid: HVA) and/or the serotonin metabolite (5-hydroxyindoleacetic acid: 5HIAA) were significantly reduced in 13 patients compared to age-matched controls. INTERPRETATION: Peripheral biogenic amines and their metabolites have been extensively studied in adults with dysautonomia due to various neurodegenerative disorders (Parkinson disease, multiple system atrophy, primary autonomic failure). Our findings indicate that more than two-thirds of this cohort of young patients with dysautonomia of variable severity have a defect in cerebral biogenic amines, particularly in dopamine and serotonin metabolism.

Neurologic manifestations of achondroplasia.

Achondroplasia is the best described and most common form of the congenital short-limbed dwarfing conditions. Achondroplasia is apparent at birth and has a birth prevalence of 1 in 20000-30000 live-born infants. Achondroplasia is inherited as an autosomal dominant condition, although 80% of cases occur sporadically as new events in their families. Achondroplasia is caused, in virtually all of the cases, by a G380R mutation in fibroblast growth factor receptor 3 (FGFR3). Patients with achondroplasia should be evaluated by a multidisciplinary team of clinicians including geneticists, neurologists, and orthopedists, since there are numerous bony and neurological complications. The most severe complication results from craniocervical stenosis and medullary and upper spinal cord compression, which can have devastating and even lethal sequelae during early childhood. In subsequent decades, including adolescence, spinal cord and nerve compression are more prominent. The neurological complications of achondroplasia have been recognized in adults for more than a century and are attributed to bony defects, connective tissue structures, or both. Similar neurological complications are now appreciated in infants, young children, and teenagers with achondroplasia. Defective connective tissue elements in achondroplasia frequently lead to ligamentous laxity, which can aggravate the complications associated with bony stenosis. Bony abnormalities are known to cause neurological morbidity and lead to a shortened lifespan. Neurological complications associated with achondroplasia are reviewed, including recommendations for the evaluation and management of these clinical problems.

Severe narrowing of left cavernous carotid artery associated with Fusobacterium necrophorum infection.

Severe oropharyngeal infection can result in Lemierre's disease, a syndrome with high mortality secondary to inflammation and thrombosis of cervical and intracranial veins with involvement of contiguous structures; however arterial involvement is rare. We report a case of Lemierre's disease in a 12 year old boy with severe narrowing of the left cavernous carotid artery.