Cyclic vomiting syndrome: Pathophysiology, comorbidities, and future research directions.

Cyclic vomiting syndrome (CVS) is characterized by severe episodic emesis in adults and children. Cannabinoid hyperemesis syndrome is an increasingly recognized CVS-like illness that has been associated with chronic cannabis use. There are significant gaps in our understanding of the pathophysiology, clinical features, comorbidities, and effective management options of CVS. Recommendations for treating CVS are based on limited clinical data, as no placebo-controlled, randomized trials have yet been conducted. Diseases associated with CVS, including migraine, mitochondrial disorders, autonomic dysfunction, and psychiatric comorbidities, provide clues about pathophysiologic mechanisms and suggest potential therapies. We review our current understanding of CVS and propose future research directions with the aim of developing effective therapy. Establishing a multicenter, standardized registry of CVS patients could drive research on multiple fronts including developing CVS-specific outcome measures to broaden our understanding of clinical profiles, to serve as treatment end points in clinical trials, and to provide a platform for patient recruitment for randomized clinical trials. Such a robust database would also facilitate conduct of research that aims to determine the underlying pathophysiological mechanisms and genetic basis for CVS, as well as identifying potential biomarkers for the disorder. Soliciting government and industry support is crucial to establishing the necessary infrastructure and achieving these goals. Patient advocacy groups such as the Cyclic Vomiting Syndrome Association (CVSA), which partner with clinicians and researchers to disseminate new information, to promote ongoing interactions between patients, their families, clinicians, investigators, to support ongoing CVS research and education, must be an integral part of this endeavor.

Management of cyclic vomiting syndrome in adults: Evidence review.

BACKGROUND: This evidence review was conducted to inform the accompanying clinical practice guideline on the management of cyclic vomiting syndrome (CVS) in adults. METHODS: We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework and focused on interventions aimed at prophylactic management and abortive treatment of adults with CVS. Specifically, this evidence review addresses the following clinical questions: (a) Should the following pharmacologic agents be used for prophylaxis of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, or mitochondrial supplements? (b) Should the following pharmacologic agents be used for abortive treatment: triptans or aprepitant? RESULTS: We found very low-quality evidence to support the use of the following agents for prophylactic and abortive treatment of CVS: amitriptyline, topiramate, aprepitant, zonisamide/levetiracetam, and mitochondrial supplements. We have moderate certainty of evidence for the use of triptans as abortive therapy. We found limited evidence to support the use of ondansetron and the treatment of co-morbid conditions and complementary therapies. CONCLUSIONS: This evidence review helps inform the accompanying guideline for the management of adults with CVS which is aimed at helping clinicians, patients, and policymakers, and should improve patient outcomes.

Role of chronic cannabis use: Cyclic vomiting syndrome vs cannabinoid hyperemesis syndrome.

Cannabis is commonly used in cyclic vomiting syndrome (CVS) due to its antiemetic and anxiolytic properties. Paradoxically, chronic cannabis use in the context of cyclic vomiting has led to the recognition of a putative new disorder called cannabinoid hyperemesis syndrome (CHS). Since its first description in 2004, numerous case series and case reports have emerged describing this phenomenon. Although not pathognomonic, a patient behavior called "compulsive hot water bathing" has been associated with CHS. There is considerable controversy about how CHS is defined. Most of the data remain heterogenous with limited follow-up, making it difficult to ascertain whether chronic cannabis use is causal, merely a clinical association with CVS, or unmasks or triggers symptoms in patients inherently predisposed to develop CVS. This article will discuss the role of cannabis in the regulation of nausea and vomiting, specifically focusing on both CVS and CHS, in order to address controversies in this context. To this objective, we have collated and analyzed published case series and case reports on CHS in order to determine the number of reported cases that meet current Rome IV criteria for CHS. We have also identified limitations in the existing diagnostic framework and propose revised criteria to diagnose CHS. Future research in this area should improve our understanding of the role of cannabis use in cyclic vomiting and help us better understand and manage this disorder.

Guidelines on management of cyclic vomiting syndrome in adults by the American Neurogastroenterology and Motility Society and the Cyclic Vomiting Syndrome Association.

The increasing recognition of cyclic vomiting syndrome (CVS) in adults prompted the development of these evidence-based guidelines on the management of CVS in adults, which was sponsored by the American Neurogastroenterology and Motility Society (ANMS) and the Cyclic Vomiting Syndrome Association (CVSA). GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework was used and a professional librarian performed the literature search. The expert committee included the President of the CVSA who brought a patient perspective into the deliberations. The committee makes recommendations for the prophylaxis of CVS, treatment of acute attacks, diagnosis, and overall management of CVS. The committee strongly  recommends that adults with moderate-to-severe CVS receive a tricyclic antidepressant (TCA), such as amitriptyline, as a first-line prophylactic medication and receive topiramate or aprepitant as alternate prophylactic medications. Zonisamide or levetiracetam and mitochondrial supplements (Coenzyme Q10, L-carnitine, and riboflavin) are conditionally recommended as alternate prophylactic medications, either alone or concurrently with other prophylactic medications. For acute attacks, the committee conditionally recommends using serotonin antagonists, such as ondansetron, and/or triptans, such as sumatriptan or aprepitant to abort symptoms. Emergency department treatment is best achieved with the use of an individualized treatment protocol and shared with the care team (example provided). The committee recommended screening and treatment for comorbid conditions such as anxiety, depression, migraine headache, autonomic dysfunction, sleep disorders, and substance use with referral to appropriate allied health services as indicated. Techniques like meditation, relaxation, and biofeedback may be offered as complementary therapy to improve overall well-being and patient care outcomes.

Lower urinary tract dysfunction in patients with dysautonomia.

OBJECTIVE: With the goal of better defining the types of bladder dysfunction observed in this population, we present the chief urologic complaints, results of urodynamic studies, and treatments of patients with dysautonomia-related urinary symptoms. METHODS: All patients with dysautonomia referred to our neurourology clinic between 2005 and 2015 for management of lower urinary tract dysfunction were retrospectively reviewed. Each patient's chief urologic complaint was recorded and used to initially characterize the bladder storage or voiding symptoms. Patient evaluation included history and physical examination, urinalysis, post void bladder ultrasound, and urodynamic studies. Successful treatment modalities that subjectively or objectively improved symptoms were recorded. RESULTS: Of 815 patients with the diagnosis of dysautonomia, 82 (10 %) were referred for evaluation of lower urinary tract dysfunction. Mean age was 47 years (range 12-83) and 84 % were female. The chief complaint was urinary urgency ± incontinence in 61 % and hesitancy in 23 % of patients. Urodynamic findings demonstrated detrusor overactivity ± incontinence in 50 % of patients, although chief complaint did not reliably predict objective findings. Successful objective and subjective treatments were multimodal and typically non-operative. INTERPRETATION: Lower urinary tract dysfunction may develop in at least 10 % of patients with dysautonomia, predominantly females. Bladder storage or voiding complaints do not reliably predict urodynamic findings. Urodynamically, most patients exhibited detrusor overactivity. The majority of patients were successfully managed with medical or physical therapy.

Cumulative Brain Injury from Motor Vehicle-Induced Whole-Body Vibration and Prevention by Human Apolipoprotein A-I Molecule Mimetic (4F) Peptide (an Apo A-I Mimetic).

BACKGROUND: Insidious cumulative brain injury from motor vehicle-induced whole-body vibration (MV-WBV) has not yet been studied. The objective of the present study is to validate whether whole-body vibration for long periods causes cumulative brain injury and impairment of the cerebral function. We also explored a preventive method for MV-WBV injury. METHODS: A study simulating whole-body vibration was conducted in 72 male Sprague-Dawley rats divided into 9 groups (N = 8): (1) 2-week normal control; (2) 2-week sham control (in the tube without vibration); (3) 2-week vibration (exposed to whole-body vibration at 30 Hz and .5 G acceleration for 4 hours/day, 5 days/week for 2 weeks; vibration parameters in the present study are similar to the most common driving conditions); (4) 4-week sham control; (5) 4-week vibration; (6) 4-week vibration with human apolipoprotein A-I molecule mimetic (4F)-preconditioning; (7) 8-week sham control; (8) 8-week vibration; and (9) 8-week 4F-preconditioning group. All the rats were evaluated by behavioral, physiological, and histological studies of the brain. RESULTS: Brain injury from vibration is a cumulative process starting with cerebral vasoconstriction, squeezing of the endothelial cells, increased free radicals, decreased nitric oxide, insufficient blood supply to the brain, and repeated reperfusion injury to brain neurons. In the 8-week vibration group, which indicated chronic brain edema, shrunken neuron numbers increased and whole neurons atrophied, which strongly correlated with neural functional impairment. There was no prominent brain neuronal injury in the 4F groups. CONCLUSIONS: The present study demonstrated cumulative brain injury from MV-WBV and validated the preventive effects of 4F preconditioning.

Surface-evoked laryngeal sensory action potential evaluation in neurogenic chronic cough.

OBJECTIVES: Neurogenic chronic cough is currently a diagnosis of exclusion. We hypothesized that surface-evoked laryngeal sensory action potential (SELSAP) testing could be used to help establish a diagnosis of laryngeal sensory neuropathy as a cause of chronic cough, based on altered SELSAP waveform morphology. STUDY DESIGN: Retrospective cohort study. METHODS: Laryngeal electromyographic (EMG) data including SELSAP waveform testing from patients with chronic cough were directly compared with a control population without significant laryngeal symptoms, and statistical analysis of unilateral and bilateral neuropathy injury subgroups was performed. RESULTS: Thirty patients with a chief complaint of chronic cough underwent laryngeal EMG testing since January 2000 with needle EMG and surface nerve conduction studies. SELSAP waveform analysis of unilateral and bilateral laryngeal neuropathy demonstrated significantly lowered median SELSAP peak amplitude compared with controls (P < 0.01). CONCLUSIONS: Patients with suspected neurogenic chronic cough demonstrate statistically significant alterations in SELSAP waveform that can support a diagnosis of laryngeal sensory neuropathy.

The correlation between calcium intensity and histopathological changes in brachial plexus nerve injuries.

BACKGROUND: After nerve injury, an influx of calcium exceeds the homeostatic capacity, which damages peripheral nerves. Previous studies identified that following nerve crush, function improves as calcium levels normalize. METHODS: Electrophysiological analysis was performed to measure the compound muscle action potential of 15 patients' damaged nerves. These samples were evaluated for calcium level and also stained with a Luxol fast blue and neurofilament antibodies to evaluate the myelin sheath and neurofilaments of the nerves. Based on the Sunderland scale, we identified three exclusive types of peripheral nerve injury groups. RESULTS: There was a correlation between histopathological damage and calcium levels of 0.81 (p < 0.005). The average relative fluorescence units (RFUs) was 235.28 ± 19, which corresponds to 5.3 × 10⁻7 M of calcium, five times the normal value. CONCLUSION: Our study shows promising clinical implications via faster pathology results by the RFU technique. This approach of calcium staining, though still in clinical trials, offers significant clinical application, allowing physicians to get the clinically diagnostic nerve injury degree faster and will also facilitate better strategies for further treatment or future surgeries.

Wilms tumor presenting with Lambert-Eaton myasthenic syndrome.

Paraneoplastic syndromes may affect the central and peripheral nervous system of adults and children with cancer. Neurological symptoms may resolve with treatment of the underlying neoplasm. We report the case of a child with Wilms tumor who presented with generalized weakness, fatigue, ptosis, hypokinesis, dysarthria, urinary retention, facial diplegia, ophthalmoplegia, and autonomic dysfunction. Routine electrodiagnostic testing, including repetitive nerve stimulation, was normal. Clinical features and stimulation single-fiber electromyogram were consistent with a neuromuscular junction transmission disorder, likely Lambert-Eaton myasthenic syndrome. The child's neurological status returned to normal with successful treatment of the tumor.

Botulinum toxin injection for the treatment of upper esophageal sphincter dysfunction.

OBJECTIVES: We sought to review the dysphagia-related outcomes and quality of life in a series of patients with upper esophageal sphincter (UES) dysfunction treated with cricopharyngeal (CP) botulinum toxin (BTX) injection, and to identify patient characteristics or CP muscle histologic features that predict efficacy of BTX injection. METHODS: A retrospective chart review was performed on patients with UES dysfunction who underwent CP BTX injection. Dysphagia-related quality-of-life questionnaires based on the Eating Assessment Tool (EAT-10) were mailed to patients. RESULTS: Forty-nine patients (30 female, 19 male; average age, 59 +/- 16 years) with UES dysfunction have been treated at our institution with CP BTX injection since 2000. Seventeen of these patients also underwent CP myotomy. Injections of BTX were occasionally repeated after the treatment effect subsided, and the BTX dose varied widely (average, 39 +/- 19 units). Improvement in symptoms was noted by 65% of patients. The overall complication rate was minimal, although many patients complained of transient worsening of dysphagia after CP BTX injection. Biopsy specimens of the CP muscle were evaluated in the subset of patients with CP BTX injection who proceeded to myotomy, with results of neuropathic, myopathic, and mixed histologic subtypes. The EAT-10 scores demonstrated a general trend toward improved swallowing outcomes after CP BTX injection. CONCLUSIONS: This study reviewed findings from the largest published series of BTX treatment of UES dysfunction and evaluated the efficacy, patient satisfaction, and complications of this procedure. Dysphagia-related quality-of-life outcomes appear to be improved after CP BTX injection.

Helicoid end-to-side and oblique attachment technique in repair of the musculocutaneous nerve injury with the phrenic nerve as a donor: an experimental study in rats.

The purpose of this study was to identify if a modified end-to-side repair can achieve equal results of nerve regeneration compared to an end-to-end repair using donor phrenic nerves in repair of the musculocutaneous nerve and also pulmonary protection. Eighteen rats were divided into three groups of six each comparing two nerve graft techniques: helicoid end-to-side plus distal oblique repair vs. traditional end-to-end repair, using a donor phrenic nerve. The saphenous nerve was used as a graft between the phrenic nerve and the musculocutaneous nerve. The third group was used as control; the musculocutaneous nerve was transected without any repair. Three months postoperatively, electrophysiology, tetanic force, moist muscle weight, histology, nerve fiber counting, and chest X-ray were evaluated. All results have shown that this modified end-to-side repair was superior to the end-to-end repair. The former did not compromise the diaphragm function, but the latter showed an elevation of the diaphragm. Little recovery was seen in the third group. The conclusion is that this modified end-to-side repair can replace the traditional end-to-end repair using donor phrenic nerves with better results of nerve regeneration without diaphragm compromise.

A new noninvasive method for determination of laryngeal sensory function.

OBJECTIVES/HYPOTHESIS: We report a new surface technique for studying sensory conduction in the superior laryngeal nerve (SLN). STUDY DESIGN: Prospective controlled cohort study at an academic tertiary care hospital. METHODS: Surface stimulation of the vagus nerve 7-10 cm proximal to a surface electrode placed over the cricothyroid muscle was performed in controls and in subjects with needle electromyographic-confirmed laryngeal neuropathy. Cathodal stimulation was applied below the mastoid process behind the sternocleidomastoid muscle. Nerve conduction parameters were determined. RESULTS: Noninvasive SLN evoked potential studies were performed on healthy volunteers (n = 28) as well as neuropathic subjects (n = 27). Compared to controls, the neuropathic subjects had statistically significant differences in baseline-to-peak amplitude, conduction velocity, and intrasubject side-to-side amplitude ratio (P <.01) of their surface evoked laryngeal sensory action potential (SELSAP). CONCLUSIONS: Laryngeal sensory nerve conduction can be determined noninvasively by evaluating SELSAP waveform. This study provides a reproducible method for electrophysiologic evaluation of a sensory branch of the SLN.

The correlation between calcium absorption and electrophysiological recovery in crushed rat peripheral nerves.

The correlation between calcium ion (Ca2+) concentration and electrophysiological recovery in crushed peripheral nerves has not been studied. Observing and quantifying the Ca2+ intensity in live normal and crushed peripheral nerves was performed using a novel microfine tearing technique and Calcium Green-1 Acetoxymethyl ester stain, a fluorescent Ca2+ indicator. Ca2+ was shown to be homogeneously distributed in the myelinated sheaths. After a crush injury, there was significant stasis in the injured zone and the portion distal to the injury. The Ca2+ has been almost completely absorbed after 24 weeks in the injured nerve to be similar to the controls. The process of the calcium absorption was correlated with the Compound Muscle Action Potential recovery process of the injured nerves. This correlation was statistically significant (r = -0.81, P < 0.05). The better understanding of this process will help us to improve nerve regeneration after peripheral nerve injury.

Cortical brain mapping of peripheral nerves using functional magnetic resonance imaging in a rodent model.

The regions of the body have cortical and subcortical representation in proportion to their degree of innervation. The rat forepaw has been studied extensively in recent years using functional magnetic resonance imaging (fMRI), typically by stimulation using electrodes directly inserted into the skin of the forepaw. Here we stimulate the nerve directly using surgically implanted electrodes. A major distinction is that stimulation of the skin of the forepaw is mostly sensory, whereas direct nerve stimulation reveals not only the sensory system but also deep brain structures associated with motor activity. In this article, we seek to define both the motor and sensory cortical and subcortical representations associated with the four major nerves of the rodent upper extremity. We electrically stimulated each nerve (median, ulnar, radial, and musculocutaneous) during fMRI acquisition using a 9.4-T Bruker scanner (Bruker BioSpin, Billerica, MA). A current level of 0.5 to 1.0 mA and a frequency of 5 Hz were used while keeping the duration constant. A distinct pattern of cortical activation was found for each nerve that can be correlated with known sensorimotor afferent and efferent pathways to the rat forepaw. This direct nerve stimulation rat model can provide insight into peripheral nerve injury.

Refining the sensory and motor ratunculus of the rat upper extremity using fMRI and direct nerve stimulation.

It is well understood that the different regions of the body have cortical representations in proportion to the degree of innervation. Our current understanding of the rat upper extremity has been enhanced using functional MRI (fMRI), but these studies are often limited to the rat forepaw. The purpose of this study is to describe a new technique that allows us to refine the sensory and motor representations in the cerebral cortex by surgically implanting electrodes on the major nerves of the rat upper extremity and providing direct electrical nerve stimulation while acquiring fMRI images. This technique was used to stimulate the ulnar, median, radial, and musculocutaneous nerves in the rat upper extremity using four different stimulation sequences that varied in frequency (5 Hz vs. 10 Hz) and current (0.5 mA vs. 1.0 mA). A distinct pattern of cortical activation was found for each nerve. The higher stimulation current resulted in a dramatic increase in the level of cortical activation. The higher stimulation frequency resulted in both increases and attenuation of cortical activation in different regions of the brain, depending on which nerve was stimulated.

Myosin heavy chain composition and fiber size of the cricopharyngeus muscle in patients with achalasia and normal subjects.

OBJECTIVES: Cricopharyngeal achalasia (CA) can be defined as inadequate opening of the cricopharyngeus muscle (CPM) resulting in dysphagia. Myosin heavy chain (MHC) isoform fiber type composition and size are key determinants of muscle function. These parameters have not been described in CA. It is hypothesized that there is a difference between the MHC isoform composition of the CPM in patients with the clinical diagnosis of CA and that in normal subjects. METHODS: Patients who had received prior botulinum were excluded. The MHC fiber type composition and size in patients and cadaveric controls were determined by adenosine triphosphatase staining and image analysis. RESULTS: The CPMs of 12 CA patients (6 male, 6 female; mean age, 61 years) and 5 control cadaveric subjects (3 male, 2 female; mean age, 67 years) were analyzed. There were relatively fewer type I fibers (67%) in patients with CA than in controls (81%), but the difference was not significant (p = .18). Type I fibers were slightly smaller in CA patients (38.7 microm) than in controls (47.2 microm), but this was not significantly different (p > .05). Of the 12 CA patients, 3 had type II predominance, a feature not seen in normal subjects. CONCLUSIONS: Patients with CA had relatively fewer type I fibers, although the difference was not statistically significant. The MHC isoform composition and fiber size were not different between CA patients and normal subjects. This is the first report to characterize the CPM in patients with CA.

Autonomic nervous system evaluation in allergic rhinitis.

OBJECTIVES: To evaluate the relationship between allergic rhinitis (AR) and autonomic nervous system (ANS) dysfunction. METHODS: Quantitative ANS testing was completed in 10 patients with AR confirmed by clinical findings and allergy testing. This data was compared to 16 age-matched controls. RESULTS: ANS scores were significantly abnormal in AR patients when compared to normal controls. The composite autonomic scale score for the AR group was significantly impaired when compared to controls (1.6 vs 0.63, P < 0.0001). Additionally, subscore values quantifying the level of dysfunction within the sympathetic nervous system (1.0 for sudomotor and 0.5 adrenergic) were found to be significantly different (P < 0.0001 and 0.018). The mean subscore value quantifying the level of dysfunction within the parasympathetic system (cardiovagal) was not found to be significantly different from controls (P = 0.38). CONCLUSIONS: ANS dysfunction, specifically sympathetic hypofunction, was identified in all of the allergic rhinitis patients studied. Further characterization of the type of ANS abnormality may allow the development of novel pharmacologic therapies for these disorders.

Muscle, nerve, and skin biopsy.

The diagnostic approach to neuromuscular disorders begins with clinical evaluation and electromyographic examination. The histology of the muscle, nerve, and skin are the subsequent essential steps in establishing the diagnosis.

Evaluation of the autonomic nervous system.

This article has reviewed the laboratory evaluation of autonomic disorders. Autonomic testing can be divided into the assessment of three functional domains: sudomotor (assessed best by the thermoregulatory sweat test or QSART), cardiovagal (assessed by the Valsalva ratio and heart rate response to deep breathing or standing up), and adrenergic (assessed by the blood pressure response to the Valsalva maneuver or head-upright tilt). Tables 2 and 3 summarize the test findings in a variety of clinical disorders affecting autonomic nervous system function.