Cutaneous α-synuclein is correlated with autonomic impairment in isolated rapid eye movement sleep behavior disorder.

STUDY OBJECTIVES: To define the clinical implications of cutaneous phosphorylated α-synuclein (p-syn) and its association with subjective and objective measures of autonomic impairment and clinical features including antidepressant use in isolated rapid eye movement (REM) sleep behavior disorder (iRBD). METHODS: Twenty-five iRBD patients had quantified neurological and cognitive examinations, olfactory testing, questionnaires, autonomic function testing, and 3 punch skin biopsies (distal thigh, proximal thigh, neck). Skin biopsies were stained for the pan-axonal marker PGP 9.5 and co-stained with p-syn, and results were compared to 28 patients with Parkinson's disease (PD) and 18 healthy controls. Equal numbers of iRBD patients on and off antidepressants were recruited. The composite autonomic severity scale (CASS) was calculated for all patients. RESULTS: P-syn was detected in 16/25 (64%) of iRBD patients, compared to 27/28 (96%) of PD and 0/18 controls. The presence of p-syn at any biopsy site was correlated with both sympathetic (CASS adrenergic r = 0.6, p < 0.05) and total autonomic impairment (CASS total r = 0.6, p < 0.05) on autonomic reflex testing in iRBD patients. These results were independent of the density of p-syn at each site. There was no correlation between p-syn and antidepressant use. CONCLUSIONS: In patients with iRBD, the presence of cutaneous p-syn was detected in most patients and was associated with greater autonomic dysfunction on testing. Longitudinal follow-up will aid in defining the predictive role of both skin biopsy and autonomic testing in determining phenoconversion rates and future disease status.

Myasthenia Symptom Burden, Fatigue, and Sleep: Are They Related?

OBJECTIVE: Our aim is to explore the relationship between myasthenia gravis (MG)-related symptom burden, sleep quality, and fatigue in a diverse group of self-identified MG patients. METHODS: Patients provided relevant myasthenia disease data and completed the MG QOL-15, Epworth sleepiness scale, Pittsburgh Sleep Quality Index, and fatigue severity score (FSS) online. MG activities of daily living scale (MG-ADL) was completed on a follow-up telephone interview. RESULTS: One hundred ninety-six patients completed the online survey and 99 provided MG-ADL data. The mean age was 52 ± 15.34 years, 88 were acetylcholine receptor antibody positive, and 21 were muscle specific kinase positive. The mean MG-ADL was 6.81, indicating a moderate MG disease burden. Forty-seven (24%) reported high Epworth sleepiness scale scores, 152 (77%) reported high Pittsburgh Sleep Quality Index scores, and 162 (82%) reported high FSS scores. Correlation analysis correcting for body mass index and sleep apnea revealed a moderate positive correlation between MGQOL-15, MG-ADL, and FSS. CONCLUSIONS: There is a moderate positive correlation between various MG-specific outcome measures and fatigue severity.

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.

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.

Impact of autonomic dysfunction on inflammatory bowel disease.

UNLABELLED: Functional symptoms are common in patients with inflammatory bowel disease (IBD). The autonomic nervous system has been proposed to be involved in the pathogenesis of IBD. Autonomic dysfunction (AD) is associated with systemic manifestations and altered gut motility that may contributed to functional symptoms. AIM: To examine the impact of clinically manifest AD on patients with IBD. METHODS: This was a retrospective case-control study from a single tertiary referral IBD center. The cases comprised 43 IBD patients with AD diagnosed using a standardized battery of tests. Three disease-matched controls were selected for each case. We performed multivariate regression to compare health-related quality of life (SIBDQ), disease activity scores, and healthcare utilization. RESULTS: Female sex (83.7% vs. 53.5%, P<0.001) and psychiatric comorbidity (41.9% vs. 10.9%, P<0.001) were more common among IBD patients with AD than IBD controls. Small bowel transit times were significantly longer in cases (92.7 min) compared with controls (62.9 min, P=0.02). On multivariate analysis, AD was associated with a 7-point lower adjusted SIBDQ score compared with IBD controls [odds ratio (OR)-7.50; 95% confidence interval (CI), -12.0--3.03]. AD was also significantly associated with having more than 3 annual gastroenterology office visits (OR 2.84; 95% CI, 1.09-7.35), and 1 or more IBD-related medical hospitalizations (OR 2.49; 95% CI, 1.09-5.71). CONCLUSIONS: Clinically manifest AD is associated with lower quality of life and higher healthcare utilization in IBD patients. They may represent a cohort at risk for worse outcomes.

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.

Cricopharyngeal electromyography: patterns of injury based on etiology.

OBJECTIVE: Although cricopharyngeal electromyography (CP-EMG) is recognized as a diagnostic tool for dysphagia assessment, few reports in the literature characterize CP-EMG abnormalities in relation to clinical presentation. The aim of this study was to review a large series of CP-EMG studies, and compare the CP-EMG results with the patients' diagnoses. METHODS: A retrospective review of all CP-EMG performed at our institution over a 10-year period was executed. CP-EMG findings were then compared with the patients' clinical history, focusing on potential etiologies of neurogenic injury. RESULTS: Seventy CP-EMGs were reviewed, with 47 (67%) demonstrating neural injury. Of those cases with neural injury on EMG, 29 (60%) had known vagal injuries, 13 (28%) had idiopathic nerve palsies, and 5 (11%) had central etiologies, such as stroke. Each of these three neurogenic subgroups revealed a distinct pattern of EMG abnormalities. CONCLUSION: This study suggests there is an association between patterns of CP-EMG abnormalities and underlying etiology based on clinical history.

Comparative neuromuscular histopathology of cricopharyngeal achalasia patients with and without previous botulinum toxin treatment.

OBJECTIVES: Botulinum toxin injection (BTX) and cricopharyngeal (CP) myotomy are performed in the treatment of CP achalasia (CA). The objective of this study was to examine the effects of BTX on neuromuscular histopathologic findings and to make direct comparisons between specimens of muscle from CA patients who had received BTX to the upper esophageal sphincter and from CA patients who had no previous exposure to BTX. METHODS: We performed a retrospective review (2001 to 2005) of CP muscle specimens from all patients who underwent myotomy for CA. Cases of Zenker's diverticulum were excluded. Patient demographics, clinical course, and neuromuscular pathology findings were noted from the chart. RESULTS: Nineteen patients with CA were identified: 10 male and 9 female, with a mean age of 57 years. Eleven had no prior BTX (6 male and 5 female; mean age, 62 years); 8 had previous treatment with BTX (4 male and 4 female; mean age, 51 years). Eight of the 11 BTX-naive patients revealed predominantly myopathic changes on histology. Those with previous BTX tended to be younger; 6 of the 8 had a clinical benefit from their BTX and ultimately went on to myotomy. The CP muscle specimens featured both mixed and neurogenic pathologic changes in 5 of the 8 patients with BTX. Although these findings suggest some impact of BTX on the CP muscle, the difference between the groups was not statistically significant (p < .20, chi2 test). CONCLUSIONS: Treatment with BTX may have some clinical and histopathologic impact on the upper esophageal sphincter of patients with CA. Although neuropathic changes were noted in the CP muscle of previously injected patients at the time of their CP myotomy, the neuromuscular pathologic findings overall were not significantly different from those of BTX-naive patients.

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.

Association of autonomic dysfunction and mild obstructive sleep apnea.

BACKGROUND: Autonomic dysfunction (AD) has been independently associated with obstructive sleep apnea (OSA). Autonomic abnormalities are generally considered to be secondary to OSA. Autonomic dysfunction may also contribute to OSA. If AD contributes to OSA, we postulated that abnormalities may be present in mild OSA where the confounding causal effects of hypoxemia and sleep disruption are reduced. OBJECTIVE: We evaluated autonomic function tests and sleep studies in a cohort of subjects with no known diagnosis of OSA. METHODS: We prospectively enrolled a cohort without diagnosed OSA who were part of an ongoing study of vasomotor rhinitis (VMR) for testing. A battery of autonomic nervous system tests (sudomotor and cardiovagal), nonattended polysomnography, and three-site esophageal/pharyngeal pH monitoring were performed. RESULTS: Twenty of 22 patients completed the test battery and 12 (60%) met criteria for OSA (Apnea/Hypopnea Index "AHI" >5 events/hour). AHI correlated to mean tilt table blood pressure decrease (R = 0.58, P = 0.007) and the Valsalva-mediated phase 2 mean blood pressure decrease (R = 0.52, P = 0.017). OSA severity was related to sympathetic but not parasympathetic abnormalities. No differences in blood pressure responses were related to age, oxygen desaturation nadir, gastroesophageal reflux, VMR, or sleepiness. CONCLUSION: Autonomic abnormalities suggestive of decreased adrenergic tone are associated with mild OSA. These abnormalities may potentially be secondary but may also precede development of OSA.

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.

Videofluoroscopic swallow studies in unilateral cricopharyngeal dysfunction.

OBJECTIVES/HYPOTHESIS: Although the cricopharyngeus muscle is a ring-like structure, unilateral cricopharyngeal dysfunction can produce significant dysphagia. This entity has not been well described in the literature. The aims of the study were to identify the characteristic findings on videofluoroscopic swallow studies in patients with dysphagia secondary to unilateral cricopharyngeal dysfunction, to note the associated vagal nerve injury, and to evaluate patient outcomes following ipsilateral cricopharyngeal myotomy. STUDY DESIGN: Retrospective clinical investigation. METHODS: The clinic charts, electromyographic tests, videostroboscopic examinations, and videofluoroscopic swallow studies were reviewed from a series of patients who presented to our institution from 1993 to 2001 with dysphagia and findings on videofluoroscopic swallow studies suggestive of unilateral cricopharyngeal dysfunction on posterior-anterior view. In patients treated with ipsilateral cricopharyngeal myotomy, postoperative findings on swallow studies and patient outcomes were also reviewed. RESULTS: Eighteen patients demonstrated findings characteristic of unilateral cricopharyngeal muscle dysfunction on videofluoroscopic swallow study. The common feature was a unilateral shelf-like barrier at the cricopharyngeus on the posterior-anterior view with pooling of liquid bolus in the ipsilateral pyriform sinus and episodic shunting to the contralateral side. Eight patients did not have evidence of cricopharyngeal dysfunction (ie, cricopharyngeal bar) on lateral films. Of the 18 patients, 14 had histories consistent with vagal injury secondary to trauma (n = 2), neoplastic involvement (n = 7), iatrogenic injury (n = 2), or central nervous system disease (n = 3). Results of videostroboscopic examinations demonstrated vocal fold motion impairment in 14 patients, and electromyographic test results confirmed unilateral vagal injuries in those who underwent electromyographic testing (n = 6). In the remaining 4 of 18 patients, videostroboscopic examinations demonstrated normal vocal fold abduction but impaired lengthening with a posterior glottic gap, and electromyographic test results (n = 4) indicated unilateral superior laryngeal nerve involvement. Of the 15 patients treated with ipsilateral cricopharyngeal myotomy, 1 patient required postoperative esophageal dilations for an esophageal stricture distal to the cricopharyngeus, whereas the remaining 14 patients had functional resolution of their dysphagia. CONCLUSION: In patients presenting with dysphagia and evidence of unilateral vagal injury, careful assessment of posterior-anterior view on videofluoroscopic swallow study should be included to evaluate for unilateral cricopharyngeal dysfunction.

Morphology of the cricopharyngeal muscle in Zenker and control specimens.

The cricopharyngeal muscle (CPM) is essential for normal deglutition. Pharyngeal dysphagia commonly results from impaired or uncoordinated CPM dilation. Dysfunction of the CPM has also been implicated in the genesis of Zenker's (pharyngoesophageal) diverticulum. Despite the CPM's significance, little is understood about its morphology. We studied CPM biopsy specimens from 20 patients with Zenker's diverticulum and from 5 fresh cadaver patients with detailed histologic techniques to include fiber size and shape and adenosine triphosphatase, reduced nicotinamide adenine dinucleotide, trichrome, succinate dehydrogenase, cytochrome C oxidase, periodic acid-Schiff reaction, oil red O, acid phosphatase, Congo red, crystal violet, and monoadenylate deaminase stains. The normal CPM has unique morphological characteristics, with some myofibers having staining properties that are a hybrid between striated muscle and muscle spindle. The variable orientation of the muscle fibers is also different from that of most other striated musculature. Of the 20 Zenker CPM specimens, 4 specimens did not reveal any significant differences from controls (2 of which had insufficient amounts of tissue for complete analysis). In the remaining 16 specimens, several abnormalities existed, including excessive size variation (16/16), grouping of atrophic fibers (9/16), target or targetoid formations (4/16), cores (2/16), and ragged red fibers (2/16). The final pathological pattern of the 16 specimens was neurogenic in 7, myopathic in 4, and mixed (with neurogenic predominance) in the remaining 5. Two specimens contained significant lymphocytic inflammatory infiltrates. We conclude that the unique neuromuscular function of the CPM in deglutition is likely due to its fiber orientation and the hybrid nature of some of the myofibers. Morphological disturbances of the CPM impair its dilation and may account for the development of Zenker's diverticulum. This disturbance is most often due to progressive denervation of the CPM.

A modified end-to-side method for peripheral nerve repair: large epineurial window helicoid technique versus small epineurial window standard end-to-side technique.

This study evaluated 2 end-to-side nerve repair techniques for ability to induce nerve sprouting and muscular recovery. Twenty-four rats underwent identical surgeries. The helicoid method of neurorrhaphy was used on the left (large epineurial window) side and the standard end-to-side (small epineurial window) repair on the right side of each rat to repair the peroneal nerve. The helicoid configuration markedly increases the area from which axons can sprout into the recipient nerve. At 11 months after surgery, axons were counted in donor and recipient nerves, and muscle moist weight of the extensor digitorum longus (EDL) and tetanic force were measured. Muscle volume, tetanic force, and moist weight of EDL muscles were significantly higher on the left side (helicoid) than on the right (end-to-side). Histologic analysis and nerve axon counting of the recipient peroneal nerve showed significantly more regenerative nerves on the left than on the right. There were no significant differences between sites above and below the repair site in the donor tibial nerve in regard to mean number of nerve fibers. Helicoid nerve repair can entice more nerve fiber sprouts from the intact donor nerve, improve muscular recovery, and maintain donor nerve health.

Autonomic dysfunction, vasomotor rhinitis, and extraesophageal manifestations of gastroesophageal reflux.

OBJECTIVE: Several recent reports suggest there may be a relationship between chronic rhinitis and extraesophageal manifestations of gastroesophageal reflux (EER). It is hypothesized that this relationship is a result of autonomic nervous system (ANS) dysfunction. STUDY DESIGN: Patients with isolated vasomotor rhinitis (VR), both VR and EER, and a control group were studied by a battery of tests designed to objectively evaluate ANS function. In addition all 3 groups underwent barium esophagogram and 4-site (proximal pharynx, distal pharynx, proximal esophagus, and distal esophagus) ambulatory pH monitoring. Adult patients fulfilling diagnostic criteria for VR, and with both VR and EER underwent objective ANS testing in a recently developed ANS testing laboratory. The control group consisted of age- and sex-matched adults without diagnostic criteria for VR or EER. RESULTS: In patients with VR only (n = 9), 2 patients had a positive esophagogram, whereas a positive pharyngeal reflux probe was found in 1 and an abnormal composite autonomic scoring scale (CASS) was found in 8 (mean VR CASS = 1.750 vs control CASS 0.556, P =.02). The group with VR and EER (n = 12) had a positive esophagogram in 10 patients, positive pharyngeal reflux by probe in 9, and all 12 had an abnormal CASS (mean CASS VR/EER = 2.909 vs CASS control = 0.556, P =.001 and vs VR CASS = 1.750, P =.05). The control patients (n = 9) had normal transesophageal gastroduodenoscopy in 8, 1 had a positive pharyngeal probe study, and all 9 had a normal CASS. In addition ANS testing in patients with diagnostic criteria for both VR/EER revealed statistically significant evidence of an adrenergic deficit as compared with control patients on the basis of mean phase II blood pressure response to Valsalva maneuver (mean phase II VR/EER = -16.730 vs control = -7.780, P =.05). In the VR only group, the phase II blood pressure decrease was greater than in control patients, but did not reach statistical significance (mean phase II VR = -9.370 vs control = -7.780, P = 0.672). CONCLUSION: Patients with VR and VR/EER have objective evidence of ANS dysfunction when compared with a group of age- and sex-matched control patients. Patients with both VR/EER demonstrate a significantly greater degree of ANS dysfunction than patients with isolated VR. The mechanism by which VR and EER interact is not entirely clear, but ANS dysfunction is objectively associated with both disorders. In addition, patients with VR/EER seem to demonstrate hypofunction of the adrenergic component of the ANS, in contrast to the generally held hypothesis that VR results from increased cholinergic activity. Further characterization of the type of ANS abnormality may allow the development of novel pharmacologic therapies for these disorders.