Gastrointestinal hypomotility with loss of enteric nicotinic acetylcholine receptors: active immunization model in mice

Background Autoimmune gastrointestinal dysmotility (AGID) is a limited form of dysautonomia. The only proven effector to date is IgG specific for ganglionic nicotinic‐acetylcholine receptors containing α3 subunits [α3*‐ nicotinic acetylcholine receptor (nAChR)]. Rabbits immunized with recombinant α3‐polypeptide produce α3*‐nAChR autoantibodies, and profound AGID ensues. Human and rabbit α3*‐nAChR‐specific‐IgGs induce transient hypomotility when injected into mice. Here, we describe success and problems encountered inducing gastrointestinal hypomotility in mice by active immunization. Methods We repeatedly injected young adult mice of seven different strains susceptible to autoimmunity (spontaneous diabetes or neural antigen immunization‐induced myasthenia gravis or encephalomyelitis) with: (i) α3‐polypeptide, intradermally or (ii) live α3*‐nAChR‐expressing xenogeneic cells, intraperitoneally. We measured serum α3*‐nAChR‐IgG twice monthly, and terminally assessed blue dye gastrointestinal transit, total small intestinal α3*‐nAChR content (radiochemically) and myenteric plexus neuron numbers (immunohistochemically, ileal–jejunal whole‐mount preparations). Key Results Standard cutaneous inoculation with α3‐polypeptide was minimally immunogenic, regardless of dose. Intraperitoneally injected live cells were potently immunogenic. Self‐reactive α3*‐nAChR‐IgG was induced only by rodent immunogen; small intestinal transit slowing and enteric α3*‐nAChR loss required high serum levels. Ganglionic neurons were not lost. Conclusions & Inferences Autoimmune gastrointestinal dysmotility is inducible in mice by active immunization. Accompanying enteric α3*‐nAChR reduction without neuronal death is consistent with an IgG‐mediated rather than T cell‐mediated pathogenesis, as is improvement of symptoms in patients receiving antibody‐depleting therapies.     

Dysautonomia and Headache in the Pediatric Population

Dysautonomia and headache are 2 common diagnoses within pediatric neurology; in the case of dysautonomia, a lack of consideration may lead to misdiagnosis. Despite being common conditions, there is a lot to learn about each individually as well as collectively. Many of the symptoms between headache and dysautonomia patients overlap making the diagnosis difficult. Migraine patients often exhibit symptoms of dysautonomia, namely postural orthostatic tachycardia syndrome (POTS); yet these symptoms are overlooked or lumped in as a part of their migraine diagnosis. The distinction or coexistence between dysautonomia and headache is identified through a thorough history, a full exam, and an open mind. This is crucial for the treatment and outcomes of these patients. Struggles arise when critical treatment differences are overlooked because dysautonomia is not considered. In this review, we will look at the epidemiology of dysautonomia and headache with focus on POTS and migraine. We will then compare the clinical features of both conditions as well as some hypothesized pathophysiology overlaps. We will conclude by summarizing the diagnostic approach and multitiered treatment options for POTS and migraine.     

KIF1A‐related disorders in children: A wide spectrum of central and peripheral nervous system involvement

KIF1A‐related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood‐onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case‐notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent—but sometimes progressive—changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.     

Gallbladder contraction in familial dysautonomia

The impaired function of the autonomic nervous system in patients with familial dysautonomia (FD) is frequently associated with gastrointestinal dysfunction. This study sought to determine whether gallbladder contraction is also affected in these patients. Nine consecutive patients with FD were assessed by real-time ultrasonography for gallbladder volume and calculated percentage of gallbladder contraction before and 45-60 min after a 50 g fatty meal, and compared with nine healthy control patients, matched for age and gender. Gallbladder volume before the fatty meal was found to be larger in healthy controls than in FD patients (25.4 ± 9.5 and 15.4 ± 7.4 ml³, respectively; p = 0.024). No significant difference was demonstrated between the groups after the fatty meal (controls: 12.1 ± 6.0; FD: 9.0 ± 6.6 ml, respectively) and the calculated percentage of gallbladder contraction was similar in both groups (controls: 53.4 ± 16.6; FD: 44.8 ± 18.8%). These results indicate that gallbladder function in FD patients does not differ from the general population and preventive measures for gallstone formation are not required.     

REVERSIBLE PARASYMPATHETIC DYSAUTONOMIA FOLLOWING STINGING ATTRIBUTED TO THE BOX JELLY FISH (CHIRONEX FLECKERI)

Following a box jelly fish sting, a 52 year old Chinese fisherman developed acute abdominal distension, inability to pass urine and failure of erection.
Examination revealed gaseous abdominal distension and a distended urinary bladder. Absence of lachrimation and absence of changes in the R-R interval in the ECG during breathing and carotid sinus massage gave further evidence of parasympathetic dysautonomia. The patient made a complete recovery. The case highlights the occurrence of reversible parasympathetic dysautonomia following box jelly fish sting.     

Familial dysautonomia

Familial dysautonomia (FD) is a neurodevelopmental genetic disorder within the larger classification of hereditary sensory and autonomic neuropathies, each caused by a different genetic error. The FD gene has been identified as IKBKAP. Mutations result in tissue-specific expression of mutant IkappaB kinase-associated protein (IKAP). The genetic error probably affects development, as well as maintenance, of neurons because there is neuropathological and clinical progression. Pathological alterations consist of decreased unmyelinated and small-fiber neurons. Clinical features reflect widespread involvement of sensory and autonomic neurons. Sensory loss includes impaired pain and temperature appreciation. Autonomic features include dysphagia, vomiting crises, blood pressure lability, and sudomotor dysfunction. Central dysfunction includes emotional lability and ataxia. With supportive treatment, prognosis has improved greatly. About 40% of patients are over age 20 years. The cause of death is usually pulmonary failure, unexplained sudden deaths, or renal failure. With the discovery of the genetic defect, definitive treatments are anticipated.     

Urinary incontinence in familial dysautonomia

The aim of this study was to determine the prevalence of urinary incontinence in women with familial dysautonomia (FD). A telephone survey was conducted on 68 known surviving female FD patients over 13 years of age registered with the Dysautonomia Centers in the USA and Israel. The mean age of the surveyed group was 27.1+/-9.8 years and 99% of the patients were nulliparous. The overall reported prevalence of urinary incontinence was 82% (n=56). Of the patients with incontinence, 59% (n=33) reported stress incontinence, 11% (n=6) reported urge incontinence, and 30% (n=17) reported symptoms of both, or mixed incontinence. In most women urinary loss was both small and infrequent, but 36% of women (n=20) with incontinence experienced a loss sufficient to necessitate the use of protection (panty liners, pads or diapers); in 7% (n=4) such loss occurred daily. Twelve per cent of all women with FD surveyed experienced primary nocturnal enuresis and 26% experienced nocturia. The prevalence of urinary incontinence is high in young female patients with familial dysautonomia. Neurophysiologic testing in this population may provide a better understanding of the role of the autonomic nervous system in urinary incontinence.Abbreviations FD familial dysautonomia - MI mixed incontinence - MRI magnetic resonance imaging - SI stress incontinence - UI urge incontinence Editorial Comment: The authors report the prevalence of urinary incontinence in familial dysautonomia. This is fertile area for investigation, given the paucity of information currently available. The subtypes of incontinence bear further comparison to populations without dysautonomia. Additional investigators may wish to study this fascinating area further.     

A new sign of sympathetic neurocirculatory failure: premature ventricular contraction as a “one-beat Valsalva maneuver”

Sympathetic neurocirculatory failure (SNF) features orthostatic hypotension and abnormal beat-to-beat blood pressure (BP) responses to the Valsalva maneuver. This article describes a new sign of SNF, based on changes in BP after premature ventricular contractions (PVCs). Records of supine beat-to-beat BP at rest were reviewed from 22 patients with SNF and 52 control subjects. Records were also taken during intravenous infusion of the ganglion blocker trimethaphan from 38 control subjects. In all 10 control subjects who had PVCs, after the postextrasystolic beat, mean arterial pressure increased progressively to levels higher than before the PVC, peaking at about the eighth beat. In contrast, in all 13 patients with SNF who had PVCs, after the postextrasystolic beat, BP decreased to less than baseline and then increased gradually back to baseline. In all 3 control subjects who had at least one PVC before trimethaphan infusion and another during trimethaphan infusion, the post-PVC pressure pattern during trimethaphan infusion resembled that in SNF patients. Because of a brief increase in sympathetic cardiovascular outflows, after a PVC, BP increases progressively to greater than pre-PVC values, mimicking the pressure overshoot after release of the Valsalva maneuver. Just as the absence of the overshoot of BP after release of the Valsalva maneuver supports a diagnosis of SNF, so does the absence of the overshoot after a PVC.     

Evaluation of Synaptophysin as an Immunohistochemical Marker for Equine Grass Sickness

It has been proposed that synaptophysin, an abundant integral membrane protein of synaptic vesicles, is an immunohistochemical marker for degenerating neurons in equine grass sickness (GS). In the present study, a statistically generated decision tree based on assessment of synaptophysin-immunolabelled ileal sections facilitated correct differentiation of all 20 cases of GS and 24 cases of non-GS disease (comprising eight horses with colic, six with neuroparalytic botulism and 10 controls). This technique also facilitated correct diagnosis of GS in all three cases that had been erroneously classified as having non-GS disease based on conventional interpretation of haematoxylin and eosin-stained cryostat sections of ileal surgical biopsies. Further prospective studies involving larger numbers of horses are required to fully validate this decision tree. In contrast to GS, botulism did not alter ileal neuron density or synaptophysin labelling, indicating that different mechanisms cause neuronal damage and/or dysfunction in GS and botulism.     

Painful and involuntary multiple sclerosis

Introduction: Pain, dysphagia, respiratory problems, sexual and cardiovascular dysfunctions may occur in patients with MS.

Areas covered: In the present review, we attempt to summarize the current knowledge on the impact pain, dysphagia, respiratory problems, sexual and cardiovascular dysfunctions have in patients with MS.

Expert opinion: To effectively manage MS, it is essential that these symptoms are recognized as early as possible and treated by a rehabilitative multidisciplinary approach, based on proven scientific evidence.