The Effects of Deep Brain Stimulation in Patients with Multiple System Atrophy.

The course of patients with multiple system atrophy (MSA) who undergo deep brain stimulation (DBS) is unclear. In a retrospective review of 1,496 patients with MSA evaluated at our institutions from 1998-2021, 12 patients underwent DBS; 9 had a diagnosis of Parkinson's disease at the time of surgery. Nine patients reported initial improvement in at least one symptom and 7 experienced overall worsening following DBS. All patients had at least one red flag sign or symptom suggesting atypical parkinsonism prior to surgery. Considering overall poor outcomes of DBS in MSA, we recommend careful consideration of red flags in patient selection.

Standardized Autonomic Testing in Patients With Probable Radiation-Induced Afferent Baroreflex Failure.

Injury of the afferent limb of the baroreflex from neck radiation causes radiation-induced afferent baroreflex failure (R-ABF). Identification and management of R-ABF is challenging. We aimed to investigate the pattern of autonomic dysfunction on standardized autonomic testing in patients with probable R-ABF. We retrospectively analyzed all autonomic reflex screens performed at Mayo Clinic in Rochester, MN, between 2000 and 2020 in patients with probable R-ABF. Additional tests reviewed included ambulatory blood pressure monitoring, plasma norepinephrine, and thermoregulatory sweat test. We identified 90 patients with probable R-ABF. Median total composite autonomic severity score (range, 0-10) was 7 (interquartile range, 6-7). Cardiovascular adrenergic impairment was seen in 85 patients (94.4%), increased blood pressure recovery time after Valsalva maneuver in 71 patients (78.9%; median 17.4 seconds), and orthostatic hypotension in 68 patients (75.6%). Cardiovagal impairment was demonstrated by abnormal heart rate responses to deep breathing (79.5%), Valsalva ratio (87.2%), and vagal baroreflex sensitivity (57.9%). Plasma norepinephrine was elevated and rose appropriately upon standing (722-1207 pg/mL). Ambulatory blood pressure monitoring revealed hypertension, postural hypotension, hypertensive surges, tachycardia, and absence of nocturnal dipping. Blood pressure lability correlated with impaired vagal baroreflex function. Postganglionic sympathetic sudomotor function was normal in most cases; the most frequent thermoregulatory sweat test finding was focal neck anhidrosis (78.9%). Standardized autonomic testing in R-ABF demonstrates cardiovascular adrenergic impairment with orthostatic hypotension, blood pressure lability, and elevated plasma norepinephrine. Cardiovagal impairment is common, while sudomotor deficits are limited to direct radiation effects.

Natural History of Afferent Baroreflex Failure in Adults.

OBJECTIVE: To describe the natural history of afferent baroreflex failure (ABF) based on systematic review of clinical and laboratory data in patients with a diagnosis of ABF at Mayo Clinic Rochester. METHODS: We performed a retrospective chart review of all patients who underwent standardized autonomic reflex testing between 2000 and 2020 and had confirmation of the diagnosis of ABF by an autonomic disorders specialist. Patients were identified using a data repository of medical records. Variables included demographic, all-cause mortality, medications, ABF manifestations, comorbidities, and laboratory (autonomic testing, blood pressure monitoring, echocardiogram, brain imaging, plasma catecholamines, serum sodium level, and kidney function tests). RESULTS: A total of 104 patients with ABF were identified. Head and neck radiation was the most common etiology (86.5%), followed by neck surgery (5.8%) and other causes (7.7%). The most common findings were hypertension (87.5%), fluctuating blood pressure (78.8%), orthostatic hypotension (91.3%), syncope (58.6%), headache (22.1%), and tachycardia (20.2%). Patients commonly received antihypertensives (66.3%), pressor agents (41.3%), or a combination of both (19.2%). The median latency from completion of radiation to ABF was longer compared to the latency in the surgery group (p < 0.0001). Comorbidities, including complications from neck radiation, were frequently seen and all-cause mortality was 39.4% over a 20-year period. CONCLUSIONS: ABF should be suspected in patients with prior head and neck cancer treated by radiation or surgery who present with labile hypertension and orthostatic hypotension. Management may require both antihypertensive and pressor medications. The morbidity and mortality in ABF are high.

Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society.

INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and above noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, POTS or other forms of dysautonomia. CONCLUSIONS: Certain conditions are prevalent in the same patient populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is insufficient proof of causality.

Human papillomavirus (HPV) vaccine and autonomic disorders: a position statement from the American Autonomic Society.

INTRODUCTION: Human papillomavirus (HPV) vaccination has been anecdotally connected to the development of dysautonomia, chronic fatigue, complex regional pain syndrome and postural tachycardia syndrome. OBJECTIVES: To critically evaluate a potential connection between HPV vaccination and the above-noted conditions. METHODS: We reviewed the literature containing the biology of the virus, pathophysiology of infection, epidemiology of associated cancers, indications of HPV vaccination, safety surveillance data and published reports linking HPV vaccination to autonomic disorders. RESULTS: At this time, the American Autonomic Society finds that there are no data to support a causal relationship between HPV vaccination and CRPS, chronic fatigue, and postural tachycardia syndrome to other forms of dysautonomia. CONCLUSION: Certain conditions are prevalent in the same populations that are vaccinated with the HPV vaccine (peri-pubertal males and females). This association, however, is an insufficient proof of causality.

Utility of the plasma pancreatic polypeptide response to modified sham feeding in diabetic gastroenteropathy and non-ulcer dyspepsia.

BACKGROUND: The relationship between cardiovascular and gastrointestinal (ie, plasma pancreatic polypeptide [PP] response to modified sham feeding [MSF]) indices of vagal function is unclear. Hyperglycemia inhibits PP secretion via vagally mediated mechanisms. Our aims were to (a) compare the PP response, (b) its relationship with glycemia, and (c) the relationship between PP response to MSF, gastric emptying (GE) of solids, and symptoms during GE study in healthy controls, patients with diabetic gastroenteropathy (DM), and non-ulcer dyspepsia (NUD). METHODS: In 24 healthy controls, 40 DM, and 40 NUD patients, we measured plasma PP concentrations during MSF, cardiovagal functions, GE, and symptoms during a GE study. KEY RESULTS: Baseline PP concentrations were higher in DM than in controls and NUD (P = .01), and in type 2 than in type 1 DM patients (P < .01). The PP increment during MSF was normal (≥20 pg/mL) in 70% of controls, 54% of DM, and 47% of NUD patients. Overall, the PP response and cardiovagal tests were concordant (P = .01). Among patients with a reduced PP increment with MSF, 7/10 of T1DM and 1/7 of T2DM patients had moderate or severe cardiovagal dysfunctions (P < .05). The PP response to MSF was not associated with GE. CONCLUSIONS & INFERENCES: Up to 30% of healthy controls have a reduced PP increment during MSF, limiting the utility of this test to detect vagal injury. The PP response is more useful when it is normal than abnormal. A reduced PP response is more likely to be associated with cardiovagal dysfunctions in T1DM than in T2DM.

Earlier age of onset in multiple system atrophy with smoking and heavy alcohol use.

OBJECTIVE: To determine whether smoking or alcohol use impacts the age of onset and disease duration in multiple system atrophy (MSA). METHODS: All patients diagnosed with MSA at Mayo Clinic, Rochester between 1998 and 2012 completed standardized questionnaires surveying smoking and alcohol use at the time of presentation. RESULTS: Of 551 patients with smoking and alcohol use data, 281 were past or present smokers with age of onset of 60.76 years compared to 62.97 years in controls (p = 0.0144). Age of onset in the 87 heavy alcohol users was 56.87 years compared to 62.97 years in controls (p = 0.0133). There was no difference in disease duration for smokers (p = 0.2758) or heavy alcohol users (p = 0.4820) compared to controls. CONCLUSION: Our findings show that smoking history and/or heavy alcohol use is associated with younger age of onset in MSA but do not influence survival.

Intrathecal administration of autologous mesenchymal stem cells in multiple system atrophy.

OBJECTIVE: This phase I/II study sought to explore intrathecal administration of mesenchymal stem cells (MSCs) as therapeutic approach to multiple system atrophy (MSA). METHODS: Utilizing a dose-escalation design, we delivered between 10 and 200 million adipose-derived autologous MSCs intrathecally to patients with early MSA. Patients were closely followed with clinical, laboratory, and imaging surveillance. Primary endpoints were frequency and type of adverse events; key secondary endpoint was the rate of disease progression assessed by the Unified MSA Rating Scale (UMSARS). RESULTS: Twenty-four patients received treatment. There were no attributable serious adverse events, and injections were generally well-tolerated. At the highest dose tier, 3 of 4 patients developed low back/posterior leg pain, associated with thickening/enhancement of lumbar nerve roots. Although there were no associated neurologic deficits, we decided that dose-limiting toxicity was reached. A total of 6 of 12 patients in the medium dose tier developed similar, but milder and transient discomfort. Rate of progression (UMSARS total) was markedly lower compared to a matched historical control group (0.40 ± 0.59 vs 1.44 ± 1.42 points/month, p = 0.004) with an apparent dose-dependent effect. CONCLUSIONS: Intrathecal MSC administration in MSA is safe and well-tolerated but can be associated with a painful implantation response at high doses. Compelling dose-dependent efficacy signals are the basis for a planned placebo-controlled trial. CLASSIFICATION OF EVIDENCE: This phase I/II study provides Class IV evidence that for patients with early MSA, intrathecal MSC administration is safe, may result in a painful implantation response at high doses, and is associated with dose-dependent efficacy signals.

Orthostatic heart rate changes in patients with autonomic failure caused by neurodegenerative synucleinopathies.

OBJECTIVE: Blunted tachycardia during hypotension is a characteristic feature of patients with autonomic failure, but the range has not been defined. This study reports the range of orthostatic heart rate (HR) changes in patients with autonomic failure caused by neurodegenerative synucleinopathies. METHODS: Patients evaluated at sites of the U.S. Autonomic Consortium (NCT01799915) underwent standardized autonomic function tests and full neurological evaluation. RESULTS: We identified 402 patients with orthostatic hypotension (OH) who had normal sinus rhythm. Of these, 378 had impaired sympathetic activation (ie, neurogenic OH) and based on their neurological examination were diagnosed with Parkinson disease, dementia with Lewy bodies, pure autonomic failure, or multiple system atrophy. The remaining 24 patients had preserved sympathetic activation and their OH was classified as nonneurogenic, due to volume depletion, anemia, or polypharmacy. Patients with neurogenic OH had twice the fall in systolic blood pressure (SBP; -44 ± 25 vs -21 ± 14 mmHg [mean ± standard deviation], p < 0.0001) but only one-third of the increase in HR of those with nonneurogenic OH (8 ± 8 vs 25 ± 11 beats per minute [bpm], p < 0.0001). A ΔHR/ΔSBP ratio of 0.492 bpm/mmHg had excellent sensitivity (91.3%) and specificity (88.4%) to distinguish between patients with neurogenic from nonneurogenic OH (area under the curve = 0.96, p < 0.0001). Within patients with neurogenic OH, HR increased more in those with multiple system atrophy (p = 0.0003), but there was considerable overlap with patients with Lewy body disorders. INTERPRETATION: A blunted HR increase during hypotension suggests a neurogenic cause. A ΔHR/ΔSBP ratio < 0.5 bpm/mmHg is diagnostic of neurogenic OH. Ann Neurol 2018;83:522-531.

Transthyretin amyloid neuropathy has earlier neural involvement but better prognosis than primary amyloid counterpart: an answer to the paradox?

OBJECTIVE: To systematically compare transthyretin with primary amyloid neuropathy to define their natural history and the underlying mechanisms for differences in phenotype and natural history. METHODS: All patients with defined amyloid subtype and peripheral neuropathy who completed autonomic testing and electromyography at Mayo Clinic Rochester between 1993 and 2013 were included. Medical records were reviewed for time of onset of defined clinical features. The degree of autonomic impairment was quantified using the composite autonomic severity scale. Comparisons were made between acquired and inherited forms of amyloidosis. RESULTS: One hundred one cases of amyloidosis with peripheral neuropathy were identified, 60 primary and 41 transthyretin. Twenty transthyretin cases were found to have Val30Met mutations; 21 had other mutations. Compared to primary cases, transthyretin cases had longer survival, longer time to diagnosis, higher composite autonomic severity scale scores, greater reduction of upper limb nerve conduction study amplitudes, more frequent occurrence of weakness, and later non-neuronal systemic involvement. Four systemic markers (cardiac involvement by echocardiogram, weight loss > 10 pounds, orthostatic intolerance, fatigue) in combination were highly predictive of poor survival in both groups. INTERPRETATION: These findings suggest that transthyretin has earlier and greater predilection for neural involvement and more delayed systemic involvement. The degree and rate of systemic involvement is most closely related to prognosis. Ann Neurol 2016;80:401-411.

Patients With Fibromyalgia Have Significant Autonomic Symptoms But Modest Autonomic Dysfunction.

BACKGROUND: Research suggests that disordered autonomic function may be one contributor to deconditioning reported in fibromyalgia; however, no study to date has assessed these variables simultaneously with comprehensive measures. OBJECTIVE: To characterize physical fitness and autonomic function with the use of clinically validated measures and subjective questionnaires between patients with fibromyalgia and healthy controls. DESIGN: Cross-sectional, observational, controlled study. SETTING: Community sample of patients with fibromyalgia and healthy controls. PARTICIPANTS: Thirty patients with fibromyalgia and 30 pain and fatigue-free controls. METHODS: Participants completed a battery of self-report questionnaires and physiological measures, including clinically validated measures of physical fitness and autonomic function. MAIN OUTCOME MEASUREMENTS: Six-Minute Walk Test total distance, maximal oxygen consumption as assessed by cardiopulmonary exercise testing, total steps using activity monitor, Composite Autonomic Scoring Scale as assessed by Autonomic Reflex Screen, total metabolic equivalents per week using the International Physical Activity Questionnaire, and self-reported autonomic symptoms via the 31-item Composite Autonomic Symptom Score questionnaire. RESULTS: Autonomic function, as assessed by self-report, was significantly different between patients and controls (P < .0001); in contrast, the only difference between patients and controls on the Autonomic Reflex Screen was in the adrenergic domain (P = .022), and these abnormalities were mild. Self-reported physical activity was not significantly different between patients and controls (P = .99), but levels of moderate and vigorous physical activity as measured by actigraphy were significantly lower in patients (P = .012 and P = .047, respectively). Exercise capacity (6-Minute Walk) was poorer in patients (P = .0006), but there was no significant difference in maximal volume of oxygen consumption (P = .07). CONCLUSIONS: Patients with fibromyalgia report more severe symptoms across all domains, including physical activity and autonomic symptoms, compared with controls, but the objective assessments only showed modest differences. Our results suggest that patients with widespread subjective impairment of function have only modest objective measures of autonomic dysfunction. We recommend that the primary treatment goal should be focused on restoration of function, which may also ameliorate symptoms.

Relationship between glycemic control and gastric emptying in poorly controlled type 2 diabetes.

BACKGROUND & AIMS: Acute hyperglycemia delays gastric emptying in patients with diabetes. However, it is not clear whether improved control of glycemia affects gastric emptying in these patients. We investigated whether overnight and short-term (6 mo) improvements in control of glycemia affect gastric emptying. METHODS: We studied 30 patients with poorly controlled type 2 diabetes (level of glycosylated hemoglobin, >9%). We measured gastric emptying using the [(13)C]-Spirulina platensis breath test on the patients' first visit (visit 1), after overnight administration of insulin or saline, 1 week later (visit 2), and 6 months after intensive therapy for diabetes. We also measured fasting and postprandial plasma levels of C-peptide, glucagon-like peptide 1, and amylin, as well as autonomic functions. RESULTS: At visit 1, gastric emptying was normal in 10 patients, delayed in 14, and accelerated in 6; 6 patients had gastrointestinal symptoms; vagal dysfunction was associated with delayed gastric emptying (P < .05). Higher fasting blood levels of glucose were associated with shorter half-times of gastric emptying (thalf) at visits 1 (r = -0.46; P = .01) and 2 (r = -0.43; P = .02). Although blood levels of glucose were lower after administration of insulin (132 ± 7 mg/dL) than saline (211 ± 15 mg/dL; P = .0002), gastric emptying thalf was not lower after administration of insulin, compared with saline. After 6 months of intensive therapy, levels of glycosylated hemoglobin decreased from 10.6% ± 0.3% to 9% ± 0.4% (P = .0003), but gastric emptying thalf did not change (92 ± 8 min before, 92 ± 7 min after). Gastric emptying did not correlate with plasma levels of glucagon-like peptide 1 and amylin. CONCLUSIONS: Two-thirds of patients with poorly controlled type 2 diabetes have mostly asymptomatic yet abnormal gastric emptying. Higher fasting blood levels of glucose are associated with faster gastric emptying. Overnight and sustained (6 mo) improvements in glycemic control do not affect gastric emptying.

Effects of multiple injections of hypertonic dextrose in the rabbit carpal tunnel: a potential model of carpal tunnel syndrome development.

BACKGROUND: This study investigated the effects of a series of four hypertonic dextrose injections on the subsynovial connective tissue (SSCT) and median nerve within the carpal tunnel of a rabbit model. METHODS: Twenty New Zealand white rabbits were used. One forepaw carpal tunnel was randomly injected with 0.1 ml of 10 % dextrose solution. The contralateral forepaw was injected with a similar amount of saline. This injection was made once per week for 4 weeks. The animals were killed at 16 weeks after the initial injection and were evaluated by electrophysiology (EP), SSCT mechanical testing, and histology. RESULTS: Mechanical testing revealed significantly greater ultimate load and energy absorption in the dextrose injection group compared to the saline injection group (P < 0.05). Histological evaluation revealed SSCT fibrosis and thickening and edema in the median nerve bundles in the dextrose injection group. There was a prolongation in the latency of the EP test in the dextrose injection group (P = 0.08). CONCLUSIONS: Previous studies had shown that one or two injections of 10 % dextrose could induce moderate SSCT fibrosis and mild EP changes without nerve histology changes. In this study, we have shown that higher doses create more severe fibrosis and, most importantly, more severe neuropathy, suggesting a dose-response effect, and confirming this as a potentially useful animal model for researching the etiology and treatment of carpal tunnel syndrome.

Autonomic function tests: some clinical applications.

Modern autonomic function tests can non-invasively evaluate the severity and distribution of autonomic failure. They have sufficient sensitivity to detect even subclinical dysautonomia. Standard laboratory testing evaluates cardiovagal, sudomotor and adrenergic autonomic functions. Cardiovagal function is typically evaluated by testing heart rate response to deep breathing at a defined rate and to the Valsalva maneuver. Sudomotor function can be evaluated with the quantitative sudomotor axon reflex test and the thermoregulatory sweat test. Adrenergic function is evaluated by the blood pressure and heart rate responses to the Valsalva maneuver and to head-up tilt. Tests are useful in defining the presence of autonomic failure, their natural history, and response to treatment. They can also define patterns of dysautonomia that are useful in helping the clinician diagnose certain autonomic conditions. For example, the tests are useful in the diagnosis of the autonomic neuropathies and distal small fiber neuropathy. The autonomic neuropathies (such as those due to diabetes or amyloidosis) are characterized by severe generalized autonomic failure. Distal small fiber neuropathy is characterized by an absence of autonomic failure except for distal sudomotor failure. Selective autonomic failure (which only one system is affected) can be diagnosed by autonomic testing. An example is chronic idiopathic anhidrosis, where only sudomotor function is affected. Among the synucleinopathies, autonomic function tests can distinguish Parkinson's disease (PD) from multiple system atrophy (MSA). There is a gradation of autonomic failure. PD is characterized by mild autonomic failure and a length-dependent pattern of sudomotor involvement. MSA and pure autonomic failure have severe generalized autonomic failure while DLB is intermediate.

Infrequent SCN9A mutations in congenital insensitivity to pain and erythromelalgia.

OBJECTIVE: Mutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia. METHODS: We sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes. RESULTS: In erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations. CONCLUSIONS: Two novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.