Peripheral Autonomic Nerve Research Articles

Altered connectivity of central autonomic network: effects of dysautonomia in hereditary transthyretin amyloidosis with polyneuropathy

Background Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) is a progressive fatal disorder caused by deposition of mutant transthyretin (TTR) amyloids mainly in the nerves and heart. Autonomic dysfunction is a major disabling manifestation, affecting 90% of patients with late-onset ATTRv-PN. The current study aimed to investigate brain functional alterations associated with dysautonomia due to peripheral autonomic nerve degeneration in ATTRv-PN. Methods Resting-state functional MRI data were acquired from 43 ATTRv-PN patients predominantly of A97S (p.A117S) genotype, and the functional connectivity of central autonomic regions was assessed. Results Compared with age-matched healthy controls, the ATTRv-PN patients exhibited (1) reduced functional connectivity of the central autonomic regions such as hypothalamus, amygdala, anterior insula, and middle cingulate cortex with brain areas of the limbic, frontal, and somatosensory systems, and (2) correlations of reduced functional autonomic connectivity with the severity of autonomic dysfunction especially orthostatic intolerance, decreased heart rate variability, and greater clinical disability. Conclusions Our findings provide evidence linking peripheral autonomic dysfunction with altered connectivity in the central autonomic network in ATTRv-PN.

Sympathetic and parasympathetic central autonomic networks

Abstract The central-autonomic network (CAN) comprises brain regions that are functionally linked to the activity of peripheral autonomic nerves. While parasympathetic CAN (i.e., the CAN projecting onto parasympathetic branches) has recently been investigated and is known to be involved in neurological and neuropsychiatric disorders, sympathetic CAN (i.e., the CAN projecting onto sympathetic nerves) has not been fully characterized. Using functional magnetic resonance imaging (fMRI) data from the Human Connectome Project in conjunction with heartbeat dynamics and its orthonormal autoregressive descriptors as a proxy for sympathetic activity estimation, namely, the sympathetic activity index (SAI), we uncover brain regions belonging to the sympathetic CAN at rest. We uncover a widespread CAN comprising both cortical (in all lobes) and subcortical areas, including the cerebellum and brainstem, which is functionally linked to sympathetic activity and overlaps with brain regions driving parasympathetic activity. These findings may constitute fundamental knowledge linking brain and bodily dynamics, including the link between neurological and psychiatric disorders and autonomic dysfunctions.

Microstates of the cortical brain-heart axis.

Electroencephalographic (EEG) microstates are brain states with quasi-stable scalp topography. Whether such states extend to the body level, that is, the peripheral autonomic nerves, remains unknown. We hypothesized that microstates extend at the brain-heart axis level as a functional state of the central autonomic network. Thus, we combined the EEG and heartbeat dynamics series to estimate the directional information transfer originating in the cortex targeting the sympathovagal and parasympathetic activity oscillations and vice versa for the afferent functional direction. Data were from two groups of participants: 36 healthy volunteers who were subjected to cognitive workload induced by mental arithmetic, and 26 participants who underwent physical stress induced by a cold pressure test. All participants were healthy at the time of the study. Based on statistical testing and goodness-of-fit evaluations, we demonstrated the existence of microstates of the functional brain-heart axis, with emphasis on the cerebral cortex, since the microstates are derived from EEG. Such nervous-system microstates are spatio-temporal quasi-stable states that exclusively refer to the efferent brain-to-heart direction. We demonstrated brain-heart microstates that could be associated with specific experimental conditions as well as brain-heart microstates that are non-specific to tasks.

Clinical, pathological and genetic aspects of laryngeal paralysis in dogs

The review article discusses the main clinical signs of paralysis of the larynx and pathological changes associated with it and other neurological pathologies. These hereditary canine neuropathies form a group of degenerative diseases affecting motor and/or sensory and autonomic peripheral nerves and have similar symptoms.Axonal forms associated with generalized polyneuropathy and paralysis of the larynx have been described in several dog breeds: Dalmatians, Alaskan Malamutes, Rottweilers, Labrador Retrievers, Leonbergers, St. Bernards, Italian Spinols, Pyrenean Mountain Dogs, Podhale Sheepdogs, Cocker Spaniels, Great Danes, American Staffordshire Terriers, Staffordshire Bull Terriers, Bouvier de Flandres, Siberian Huskies and Siberian Husky crosses. Candidate genes for association with the disease are considered: ARHGEF10, RAPGEF6, ADAMTS3, CNTNAP1, DCTN1. The age of onset of the disease can be different, the manifestation of signs of paralysis of the larynx occurs both in young dogs, and the geriatric form also occurs. The prognosis of the complex of paralysis of the larynxpolyneuropathy is from cautious to unfavorable. One case of euthanasia due to intractable regurgitation and aspiration pneumonia has been described. Some authors point to a possible association of the disease with white coat color. Two main types of inheritance of paralysis of the larynx in dogs have been established - autosomal recessive and X -linked recessive. In humans, the dominant type of inheritance of this anomaly is known. Early diagnosis will make it possible to identify the hereditary nature of paralysis of the larynx, reduce the incidence of severe forms of the disease with timely surgical correction of the cartilage of the larynx and symptomatic treatment, as well as the spread of carriers of mutant alleles in dog populations. This is relevant today in connection with the spread of this anomaly in many breeds.

PO-01-168 PREVALENCE OF ATRIAL FIBRILLATION IN PATIENTS WITH PRIMARY AUTONOMIC FAILURE

The autonomic nervous system plays a central role in the initiation and maintenance of atrial fibrillation (AFib). Primary autonomic failure is characterized by impaired cardiovascular autonomic reflexes due to α-synuclein deposition in central or peripheral autonomic nerves causing absence of norepinephrine secretion during orthostatic stress in neurodegenerative conditions such as Parkinson disease (PD), multiple system atrophy (MSA), dementia with Lewy body (DLB) and pure autonomic failure. We hypothesized that primary autonomic failure would lead to decrease risk of AFib This was a retrospective analysis that included patients diagnosed with primary autonomic failure based on autonomic reflex testing at Vanderbilt Autonomic Dysfunction Center between 2015-2022. An age and sex-matched cohort of patients without a diagnosis of primary autonomic failure were used as a control population. Logistic regression analysis was used to identify factors associated with AFib. A total of 114 patients with primary autonomic failure were included (age 72.7±8.3, 64% males); of whom 52 (45.6%) had PD, 37 (32.5%) had MSA, 2 (1.8%) had DLB and 23 (20.2%) had pure autonomic failure. Patients with primary autonomic failure had elevated supine BP 155±26/86±14 mmHg and orthostatic hypotension (standing BP decreased to 104±28/65±16 mmHg). Impaired sympathetic reflexes were evident by a reduced sinus arrythmia ratio 1.09±0.09, profound BP decreased during phase II of the Valsalva maneuver 89±28/59±18 mmHg and no BP recovery during phase IV of Valsalva 131±28/59±16 mmHg. Compared to age (72.7±8.1 years) and sex-matched (65.1% males) controls, patients with primary autonomic failure had lower prevalence of diabetes, hypertension, heart failure, coronary artery diseases, and chronic kidney disease. The prevalence of AFib was significantly lower in patients with primary autonomic failure compared to the control population (4.4% vs 32.1%; p <0.001). In a multivariate regression model adjusting for hypertension, chronic kidney disease and heart failure, the only independent predictors of AFib were older age (OR 1.07, 95% CI 1.01-1.13; p 0.01) and presence of primary autonomic failure (OR 0.05, 95% CI 0.01-0.22; p <0.001), which was protective. AFib is significantly less prevalent in patients with primary autonomic failure compared to age and sex-matched controls. The etiology is possibly related to the autonomic failure. Further prospective studies are warranted.

A Case of Mononeuopathy Multiplex in the Setting of Durvalumab Therapy (P13-8.002)

<h3>Objective:</h3> NA <h3>Background:</h3> As immune checkpoint inhibitors (ICIs) become a mainstay of treatment for several malignancies, neurological complications associated with their use have been increasingly recognized. We present a case of mononeuropathy multiplex (MM) in the setting of durvalumab (PD-L1 inhibitor) use. <h3>Design/Methods:</h3> NA <h3>Results:</h3> A 68-year-old man with stage III non-small cell lung cancer (NSCLC) was seen for the evaluation of asymmetric, painful bilateral upper extremity weakness of 2 months’ duration. He had pre-existing painless glove-and-stocking sensory loss, attributed to cisplatin-induced peripheral neuropathy. Following 4 cycles of cisplatin-based chemotherapy, the patient was started on durvalumab 4 months prior to presentation. Key exam findings included weakness affecting right digit I flexion, wrist and finger extension as well as left interphalangeal joint flexion affecting digits II–V, glove-and-stocking sensory loss, and diffuse areflexia. Upper extremity EMG findings were notable for active denervation changes restricted to multiple bilateral radial- and median-innervated muscles. Following initial assessment, the right wrist drop continued to progress, and a decision was taken to discontinue durvalumab given the concern for peripheral neurotoxicity. The left arm weakness resolved over 3–4 weeks, while the right wrist drop had improved only partially at last assessment 5 months later. The patient had declined a trial of steroids or IVIG. <h3>Conclusions:</h3> The clinical and EMG findings were consistent with MM and bore a temporal relation to durvalumab use. No alternate etiology was identified. ICI-mediated toxicity can result in sensory, motor and autonomic peripheral nerve involvement with a myriad of clinical presentations. In the existing literature, MM has been described with both ipilimumab and nivolumab, but to our knowledge, this is the first reported case of MM with durvalumab use. Early identification of often severe neurological adverse events is crucial due to implications for treatment and decisions regarding continued immune checkpoint therapy. <b>Disclosure:</b> Miss Scurfield has nothing to disclose. Miss Kelly has nothing to disclose. Dr. Desai has nothing to disclose. Dr. Dhanjal has nothing to disclose.

Cutaneous α-Synuclein Signatures in Patients With Multiple System Atrophy and Parkinson Disease.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder caused by the abnormal accumulation of α-synuclein in the nervous system. Clinical features include autonomic and motor dysfunction, which overlap with those of Parkinson disease (PD), particularly at early disease stages. There is an unmet need for accurate diagnostic and prognostic biomarkers for MSA and, specifically, a critical need to distinguish MSA from other synucleinopathies, particularly PD. The purpose of the study was to develop a unique cutaneous pathologic signature of phosphorylated α-synuclein that could distinguish patients with MSA from patients with PD and healthy controls. We studied 31 patients with MSA and 54 patients with PD diagnosed according to current clinical consensus criteria. We also included 24 matched controls. All participants underwent neurologic examinations, autonomic testing, and skin biopsies at 3 locations. The density of intraepidermal, sudomotor, and pilomotor nerve fibers was measured. The deposition of phosphorylated α-synuclein was quantified. Results were compared with clinical rating assessments and autonomic function test results. Patients with PD had reduced nerve fiber densities compared with patients with MSA (p < 0.05, all fiber types). All patients with MSA and 51/54 with PD had evidence of phosphorylated α-synuclein in at least one skin biopsy. No phosphorylated α-synuclein was detected in controls. Patients with MSA had greater phosphorylated α-synuclein deposition (p < 0.0001) and more widespread peripheral distribution (p < 0.0001) than patients with PD. These results provided >90% sensitivity and specificity in distinguishing between the 2 disorders. α-synuclein is present in the peripheral autonomic nerves of patients with MSA and when combined with synuclein distribution accurately distinguishes MSA from PD. This study provides Class II evidence that measurement of phosphorylated α-synuclein in skin biopsies can differentiate patients with MSA from those with PD.

A review of the hybrid description of diabetes mellitus

Elevated blood sugar levels, which are either brought on by inadequate insulin synthesis by the pancreas or byincorrect insulin usage by the body, characterize diabetes mellitus, a chronic metabolic disease. Diabetes mellituscan cause renal failure, and those with the condition are at least 10 times more likely to have to amputate a foot dueto diabetes than those without it. High blood sugar levels are thought to contribute to kidney and heart problems.A rapid rate of beta cell malfunction and sequences resulting from an absolute lack of insulin hormone secretionmay be used to describe type 1 diabetes mellitus. Type 1 diabetes mellitus often manifests itself in young patients,although it may also affect adults. Diabetic neuropathy, one of the most severe microvascular complications ofdiabetes mellitus, is characterized by a metabolic-vascular disorder that compromises the structure and functionof peripheral somatic or autonomic nerves without inducing inflammation. Dehydration brought on by osmoticdiuresis, which impacts hyperviscosity and a hypercoagulable condition, and elevated blood glucose levels aretypical symptoms of a hyperosmolar hyperglycemic state. People with type 1 diabetes are 12 times more likelythan those with type 2 diabetes to develop diabetic nephropathy.

A Review of the Hybrid Description of Diabetes Mellitus

Elevated blood sugar levels, which are either brought on by inadequate insulin synthesis by the pancreas or by incorrect insulin usage by the body, characterize diabetes mellitus, a chronic metabolic disease. Diabetes mellitus can cause renal failure, and those with the condition are at least 10 times more likely to have to amputate a foot due to diabetes than those without it. High blood sugar levels are thought to contribute to kidney and heart problems. A rapid rate of beta cell malfunction and sequences resulting from an absolute lack of insulin hormone secretion may be used to describe type 1 diabetes mellitus. Type 1 diabetes mellitus often manifests itself in young patients, although it may also affect adults. Diabetic neuropathy, one of the most severe microvascular complications of diabetes mellitus, is characterized by a metabolic-vascular disorder that compromises the structure and function of peripheral somatic or autonomic nerves without inducing inflammation. Dehydration brought on by osmotic diuresis, which impacts hyperviscosity and a hypercoagulable condition, and elevated blood glucose levels are typical symptoms of a hyperosmolar hyperglycemic state. People with type 1 diabetes are 12 times more likely than those with type 2 diabetes to develop diabetic nephropathy.

Emx1-Cre Is Expressed in Peripheral Autonomic Ganglia That Regulate Central Cardiorespiratory Functions.

The Emx1-IRES-Cre transgenic mouse is commonly used to direct genetic recombination in forebrain excitatory neurons. However, the original study reported that Emx1-Cre is also expressed embryonically in peripheral autonomic ganglia, which could potentially affect the interpretation of targeted circuitry contributing to systemic phenotypes. Here, we report that Emx1-Cre is expressed in the afferent vagus nerve system involved in autonomic cardiorespiratory regulatory pathways. Our imaging studies revealed expression of Emx1-Cre driven tdtomato fluorescence in the afferent vagus nerve innervating the dorsal medulla of brainstem, cell bodies in the nodose ganglion, and their potential target structures at the carotid bifurcation such as the carotid sinus and the superior cervical ganglion (SCG). Photostimulation of the afferent terminals in the nucleus tractus solitarius (NTS) in vitro using Emx1-Cre driven ChR2 reliably evoked EPSCs in the postsynaptic neurons with electrophysiological characteristics consistent with the vagus afferent nerves. In addition, optogenetic stimulation targeting the Emx1-Cre expressing structures identified in this study, such as vagus nerve, carotid bifurcation, and the dorsal medulla surface transiently depressed cardiorespiratory rate in urethane anesthetized mice in vivo. Together, our study demonstrates that Emx1-IRES-Cre is expressed in the key peripheral autonomic nerve system and can modulate cardiorespiratory function independently of forebrain expression. These results raise caution when interpreting systemic phenotypes of Emx1-IRES-Cre conditional recombinant mice, and also suggest the utility of this line to investigate modulators of the afferent vagal system.

Renal Transplantation in Pure Autonomic Failure.

Renal Transplantation in Pure Autonomic Failure.

Pathological Study of Pure Autonomic Failure

Pure autonomic failure (PAF) is a subtype of Lewy body disease whose main target is the peripheral autonomic nervous system. The differential diagnosis includes multiple system atrophy and small fiber neuropathy like amyloidosis. Low uptake of 123I- metaiodebenzyl guanidine (MIBG) cardiac scintigraphy is of diagnosis use. Biopsy of skins affected with decreased sweating could prove Lewy pathology in the peripheral autonomic nerves. Among more than 10,000 autopsy cases in BBAR (Brain Bank for Aging Research), representing an aging cohort in Tokyo metropolitan suburban area, only two cases had clinical diagnosis of PAF. Orthostatic hypotension without parkinsonism is common clinical features. Both presented with diffuse Lewy body pathology involving the peripheral autonomic nervous system, brain stem, limbic system and neocortex with mild loss of pigmented neurons in substantia nigra. Other senile changes like Alzheimer pathology, argyrophlic grains and TDP43 (TAR DNA- binding protein of 43kDa) proteinopathy were mild. Neuropathological features fulfilled morphological criteria of dementia with Lewy bodies (DLB) pure neocortical form, suggesting dementia as one of the late clinical complications. About one third of autopsy cases registered to BBAR contained Lewy pathology in the body, among whom, 5% had Lewy pathology only in the peripheral autonomic nervous system. These cases may be the earliest stage of PAF.

Autonomic Dysfunction in Lewy Body Disease

Lewy body disease is a clinicopathological entity that includes Parkinson's disease, dementia with Lewy bodies, and pure autonomic failure with Lewy bodies, all of which are characterized by varied degrees of autonomic dysfunction. Research in animal models has shown transmission of α-synuclein from peripheral autonomic nerves to the central nervous system via the autonomic nervous system, and the autonomic nervous system plays an important role in the study of Lewy body disease. This paper outlines the pathophysiology, characteristics, and treatment of typical autonomic dysfunction in patients with Lewy body disease.

Brentuximab-Induced Peripheral Neurotoxicity: A Multidisciplinary Approach to Manage an Emerging Challenge in Hodgkin Lymphoma Therapy.

Simple SummaryThis article highlights the importance of monitoring peripheral neurotoxicity in patients with Hodgkin lymphoma (HL) who receive brentuximab vedotin, with a particular focus on early recognition and multidisciplinary management of this type of toxicity. Brentuximab vedotin-induced neurotoxicity (BVIN) is the most common non-haematological complication and cause of dose-delay or early discontinuation of BV treatment. An accurate and prompt diagnosis in patients with HL is essential to optimise management of this potentially disabling complication.Brentuximab vedotin (BV) is an anti-CD30 antibody–drug conjugate approved to treat classical Hodgkin lymphoma (HL). BV-induced peripheral neurotoxicity (BVIN) is one of the greatest concerns for haematologists treating HL for several reasons. First, BVIN is highly frequent. Most patients receiving BV will experience some degree of BVIN, resulting in the primary reason for dose modification or discontinuation of HL therapy. Second, BV produces sensory, motor, and/or autonomic peripheral nerve dysfunction, which can present as severe, disabling forms of BVIN—predominantly motor—in some patients. Third, although largely reversible, BVIN may persist months or years after treatment and thereby become a major issue in HL survivorship. BVIN may, therefore, negatively affect the quality of life and work-life of often young patients with HL, in whom long-term survival is expected. Currently, the only strategy for BVIN includes dose adjustments and treatment discontinuation; however, this could interfere with LH therapy efficacy. In this setting, early recognition and adequate management of BVIN are critical in improving clinical outcomes. Careful neurologic monitoring may allow accurate diagnoses and gradation of ongoing forms of BVIN presentation. This review analysed current, available data on epidemiology, pathophysiology, patient- and treatment-related risk factors, clinical and neurophysiologic phenotypes, and management in patients with HL. Furthermore, this review specifically addresses limitations posed by BVIN assessments in clinical practice and provides skills and tools to improve neurologic assessments in these patients. Integrating this neurotoxic drug in clinical practice requires a multidisciplinary approach to avoid or minimise neurotoxicity burden in survivors of HL.

“Micro Botulinum Toxin” for the Treatment of a Deep Dermal Burn After Single IPL and a Second Combined IPL/Nd: YAG Laser Treatment for Skin Rejuvenation and Discoloration

Botulinum toxin (BTX) is a neurotoxin derived from the Clostridium botulinum bacterium that inhibits the release of acetylcholine at the neuromuscular junction. Botox is not new, and it has been used for many years to treat a variety of muscular/neuromuscular conditions and now more popularly for cosmetic use. Botulinum toxins use has been experimented in some dermatological conditions, which include Rosacea and facial flushing treatment with positive outcomes. The complex mechanism underlying those results is not completely understood but was proposed that a release inhibition of acetylcholine from peripheral autonomic nerves of the cutaneous vasodilatory system combined with the blockade of substance P and calcitonin gene-related peptide (CGRP), thus modulating vasodilatation of blood vessels as the likely mechanism of action. In cosmetic and aesthetic medicine, thermal burns from laser-type treatments are the number 1 lawsuit in this field. However, seldom are reports shared on management of these patient’s burns. This is a case report of such a patient who had a deep dermal burn after 2 consecutive treatments for the goal of correcting skin discoloration and sun damage.

Acute sensory inflammatory demyelinating polyneuropathy and central diabetes insipidus

Guillain-Barre syndrome (GBS) is characterized by acute, progressive monophasic course with a predominance of motor disorders in typical cases; it develops due to an aberrant immune response in some viral and bacterial infections. As ganglioside complexes are the direct cause of acute dysimmune neuropathy, it is assumed that the combined damage of peripheral nerves structure, and neurohypophysis and hypothalamus, may be based on similar immunopathogenetic mechanisms. Here we present the first case of a patient with diabetes insipidus and acute inflammatory dysimmune damage to sensory and autonomic peripheral nerve fibers due to secondary hypothalamic-pituitary system lesion. Due to the long-term persistence of arthralgias, accompanied by a low-grade fever and a single positive denatured DNA IgG antibodies test, atypical variant of GBS, hypophysitis, we differentiated the patient's condition with systemic rheumatic diseases, primary and secondary vasculitis. Those nosologies were not confirmed during the examination and observation; porphyrias and thyroid gland damage as etiological factors of nervous system damage were also excluded. This case report demonstrates the need for a prompt determination of the nature of the pathological process that causes damage to peripheral nerves' fibers and the neuroendocrine system to select an adequate treatment strategy.

Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats.

Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson’s disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson’s disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson’s disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson’s disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson’s disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.

Adult-onset neuronal intranuclear inclusion disease, with both stroke-like onset and encephalitic attacks: a case report

BackgroundNeuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease, the clinical manifestations of which are complex and easily misdiagnosed. NIID clinical characteristics are varied, affecting the central and peripheral nervous systems and autonomic nerves. In this study, we present an NIID case with both stroke-like onset and encephalitic attacks, which is a rare case report.Case presentationA 68-year-old Chinese female presented with sudden aphasia and limb hemiplegia as the first symptoms, as well as fever, cognitive impairment and mental irritability from encephalitic attacks. During hospitalization, a brain magnetic resonance imaging (MRI) examination detected high signal intensity from diffusion-weighted imaging (DWI) of the bilateral frontal grey matter-white matter junction. Electrophysiological tests revealed the main site of injury was at the myelin sheath in the motor nerves. A skin biopsy revealed eosinophilic spherical inclusion bodies in the nuclei of small sweat gland cells, fibroblasts and fat cells, whilst immunohistochemistry revealed that p62 and ubiquitin antibodies were positive. From genetic analyses, the patient was not a carrier of the fragile X mental retardation 1 (FMR1) permutation, but repeated GGC sequences in the NOTCH2NLC gene confirmed an NIID diagnosis. Through antipsychotic and nutritional support therapy, the patient’s symptoms were completely relieved within 3 weeks.ConclusionsThis report of an NIID case with both stroke-like onset and encephalitic attacks provides new information for NIID diagnoses, and a comprehensive classification of clinical characteristics.

Gastrointestinal motility disorders in neurologic disease.

The extrinsic and autonomic nervous system intricately controls the major functions of the gastrointestinal tract through the enteric nervous system; these include motor, secretory, sensory, storage, and excretory functions. Disorders of the nervous system affecting gastrointestinal tract function manifest primarily as abnormalities in motor (rather than secretory) functions. Common gastrointestinal symptoms in neurologic disorders include sialorrhea, dysphagia, gastroparesis, intestinal pseudo-obstruction, constipation, diarrhea, and fecal incontinence. Diseases of the entire neural axis ranging from the cerebral hemispheres to the peripheral autonomic nerves can result in gastrointestinal motility disorders. The most common neurologic diseases affecting gastrointestinal function are stroke, parkinsonism, multiple sclerosis, and diabetic neuropathy. Diagnosis involves identification of the neurologic disease and its distribution, and documentation of segmental gut dysfunction, typically using noninvasive imaging, transit measurements, or intraluminal measurements of pressure activity and coordination of motility. Apart from treatment of the underlying neurologic disease, management focuses on restoration of normal hydration and nutrition and pharmacologic treatment of the gut neuromuscular disorder.

Cutaneous sensory and autonomic denervation in progressive supranuclear palsy.

Progressive Supranuclear Palsy (PSP) is a progressive neurodegenerative tauopathy characterised by motor, behavioural and cognitive dysfunction. While in the last decade, sensory and autonomic disturbances as well as peripheral nerve involvement are well-recognised in Parkinson's Disease (PD), little is known in this regard for PSP. Herein, we aim to assess peripheral sensory and autonomic nerve involvement in PSP and to characterise possible differences in morpho-functional pattern compared to PD patients. We studied 27 PSP and 33 PD patients without electrophysiological signs of neuropathy, and 33 healthy controls (HC). In addition to motor impairment, evaluated by means of UPDRS-III and the PSP rating scale, all patients underwent clinical, functional and morphological assessment of sensory-autonomic nerves through dedicated questionnaires, sympathetic skin response, dynamic sweat test and skin biopsies. The analysis of cutaneous sensory and autonomic innervation was performed using indirect immunofluorescence and confocal microscopy. PSP patients displayed a length-dependent loss of sensory and autonomic nerve fibres associated with functional impairment compared to HC and, overall, a more severe picture than in PD patients. The disease severity correlated with the loss of intraepidermal nerve fibre density in the leg of PSP patients (p<0.05). We demonstrated a length-dependent small fibre pathology in PSP, more severe compared to PD, and paralleling disease severity. Our findings suggest the morphological and functional study of cutaneous nerves as possible biomarkers to monitor disease progression and response to new treatments.