Sympathetic Failure Research Articles

Carotid baroreceptor dysfunction after carotid body tumour resections

ObjectiveCarotid body tumours (CBTs) and baroreceptor failure (BRF) are two distinct but interrelated conditions, affecting the carotid body and its regulatory mechanisms. We aim to describe and quantify BRF after unilateral and bilateral CBT resections. MethodsProspective cohort study. We included all patients with unilateral or bilateral CBT undergoing resection from April 2021 to January 2023. Demographics and CBTs characteristics were analysed; baroreceptor sensitivity assessment was conducted using the Composite Autonomic Severity Score (CASS). Statistical analyses were performed using R. Significance level was set at a 2-tailed α = 0.05. ResultsA total of 30 patients with CBT underwent surgical resection, twenty-three were included in the study (18 unilateral and 5 bilateral CBTs). All 23 (100 %) were females, median age of 60 years. Regarding patients with unilateral CBT; preoperatively, 13 had BRF, the most common dysfunction subtype was mixed. Postoperatively, the most common dysfunction subtype was sympathetic failure. With regards to bilateral CBTs; 2 patients did not have autonomic dysfunction preoperatively. After bilateral surgical resection one patient remained without autonomic dysfunction; however, all other patients persisted with BRF. ConclusionBRF was present in 13 patients with unilateral CBT and 3 patients with bilateral tumours preoperatively; most will remain with BRF and will only change the characteristics postoperatively. No associations were found between type, severity of BRF and Shamblin classification or laterality. It is paramount that research in this area continues as many features are yet unknown regarding CBT pathogenesis, hence, BRF may be present yet not affect significantly quality of life.

A Detailed Classification of Neurogenic Orthostatic Hypotension According to the Pattern of Orthostatic Blood Pressure Drop in Patients with Orthostatic Intolerance

Background: To investigate the patterns of blood pressure (BP) decrement during the tilt, to compare the pattern of orthostatic hypotension (OH) and sympathetic index (SI) from the Valsalva maneuver (VM), and to identify whether the pattern of OH can predict the severity of autonomic failure.Methods: From January 2015 to July 2017, 551 consecutive patients with neurogenic OH were enrolled. All patients performed a standardized battery of autonomic tests, including the head-up tilt (HUT) test and VM using Finometer devices for recording beat-to-beat BP. SIs were calculated from the VM. The composite autonomic severity score (CASS) adrenergic subscore was also obtained to evaluate the severity of sympathetic adrenergic failure.Results: We classified OH into nine groups according to the patterns of orthostatic BP decrement during HUT. The two most common patterns of OH were classic stable OH (n=193) and classic OH with delayed normalization (n=102). Patients with classic stable OH and classic OH with delayed worsening had a more severe degree of sympathetic adrenergic failure as assessed with SI 5 and SI 4 from the VM, and a higher CASS adrenergic subscore than patients with other patterns of OH. There were no differences of autonomic parameters between the two delayed OH groups.Conclusions: The different patterns of orthostatic BP decrement may reflect underlying different pathophysiologic mechanisms causing OH. The pattern of orthostatic BP decrement can help to predict the degree of sympathetic adrenergic autonomic failure.

Distribution of Cardiovascular Dysautonomia Pattern across Different Stages of Chronic Kidney Disease

Context: Autonomic dysfunction (AD) brings up cardiovascular morbidity/mortality and has been reported in chronic kidney disease (CKD). Still, the pattern of AD in CKD is elusive. Aim: To evaluate the distribution of cardiovascular dysautonomia in CKD. Material and Methods: This study was conducted on 33 CKD cases and 30 age and sex matched healthy controls. Five standard autonomic function tests were conducted, namely, heart rate response to Valsalva maneuver, deep breathing, and standing, and BP response to standing and sustained handgrip; based on which the patients were classified as normal, or having early parasympathetic, definite parasympathetic and combined damage. The total autonomic function score was also calculated. Results: All cases belonged to CKD stages of 3, 4, and 5; and came up with autonomic failure. The mean total autonomic function score was higher (P < 0.001) in CKD (5.09 ± 2.33) as compared to the control group (0.97 ± 0.24), using the unpaired “t” test. Most of the CKD patients (45.45%) were involved with combined damage. Of the three stages, combined damage struck stage 5 to the maximum extent (63.63%). Sympathetic failure always co occurred with parasympathetic failure. Conclusion: Combined autonomic failure is more conspicuous in late CKD, predominantly occurring in stage 5. The disease course may contort the parasympathetic system before the sympathetic system.

Physiological and clinical impact in the carotid baroreceptor function following the surgical management of bilateral carotid body tumors.

The bilateral presentation of Carotid Body Tumors (CBT) is rare; the surgical resection of these masses remains the mainstay management due to the malignant potential. We aim to describe, classify, and quantify baroreceptor failure (BRF) after the surgical management of patients with bilateral CBT to better understand the clinical consequences. Retrospective review of patients that underwent bilateral CBT resection to assess the changes in baroreceptor function. We describe the clinical events associated to BRF after surgery, baseline patient's demographics, characteristics, comorbidities. Additionally, clinical and a quantitative evaluation of baroreceptor sensitivity were conducted using the Composite Autonomic Severity Score (CASS). From 1986 to 2020, a total 146 CBT resections were performed in 132 patients in our institution. Tumors were removed bilaterally in staged procedures in seven patients with a mean age of 61years (Standard Deviation 11), six (85%) were females, and there was no family history of paragangliomas. The clinical presentation were palpable masses in 5 (71%), and odynophagia in 2 (29%) cases; malignant histopathology following surgery was found in one case. BRF occurred in one patient after unilateral CBT resection, consisting of bradycardia and a 40s asystole that was not previously associated to BR sensitivity. Three (43%) patients presented BRF in the immediate postoperative period of the contralateral CBT excision, consisting of volatile hypertensive crisis in two cases, and supraventricular tachycardia in one. All the patients developed (100%) chronic baroreceptor sensitivity symptoms consisting in syncope, vertigo and fatigue in 4 (57%), tachycardia in 2 (28%), and orthostatic headache in one (14%). Autonomic testing showed mixed sympathetic and parasympathetic failure in five (71%), severe sympathetic failure in 1 (14%), and parasympathetic dysfunction in one patient (14%). Postoperative autonomic assessment confirmed BRF in all studied patients that underwent staged bilateral CBT resection with mixed, sympathetic, and parasympathetic dysfunction. Further studies are necessary to evaluate the incidence and physiological mechanisms of these sequelae to anticipate possible complications and offer the appropriate perioperative management.

Autonomic failure: a neglected presentation of Parkinson's disease

Neurogenic orthostatic hypotension is a fall in blood pressure upon standing due to sympathetic autonomic failure, which can cause orthostatic intolerance and syncope. Pure autonomic failure is a sporadic disorder traditionally defined by the presence of idiopathic neurogenic orthostatic hypotension, usually with signs of neurogenic bladder and bowel dysfunction, but no other neurological features. 1 The Consensus Committee of the American Autonomic Society and the American Academy of NeurologyConsensus statement on the definition of orthostatic hypotension, pure autonomic failure, and multiple system atrophy. Neurology. 1996; 461470 Crossref PubMed Scopus (974) Google Scholar Neuropathological findings of α-synuclein aggregates in the brainstem and skin autonomic fibres of affected people led researchers to interpret pure autonomic failure as a peculiar α-synucleinopathy limited to the autonomic nervous system, but studies in the past 5 years provided a substantial paradigm shift in our understanding of this disorder. 2 Kaufmann H Norcliffe-Kaufmann L Palma JA et al. Natural history of pure autonomic failure: a United States prospective cohort. Ann Neurol. 2017; 81: 287-297 Crossref PubMed Scopus (148) Google Scholar , 3 Giannini G Calandra-Buonaura G Asioli GM et al. The natural history of idiopathic autonomic failure: the IAF-BO cohort study. Neurology. 2018; 91: e1245-e1254 Crossref PubMed Scopus (14) Google Scholar , 4 Coon EA Mandrekar JN Berini SE et al. Predicting phenoconversion in pure autonomic failure. Neurology. 2020; 95: e889-e897 Crossref PubMed Scopus (10) Google Scholar Up to a third of people with pure autonomic failure develop another α-synucleinopathy, including Parkinson's disease, suggesting that pure autonomic failure might in fact be a premotor presentation thereof. 2 Kaufmann H Norcliffe-Kaufmann L Palma JA et al. Natural history of pure autonomic failure: a United States prospective cohort. Ann Neurol. 2017; 81: 287-297 Crossref PubMed Scopus (148) Google Scholar , 3 Giannini G Calandra-Buonaura G Asioli GM et al. The natural history of idiopathic autonomic failure: the IAF-BO cohort study. Neurology. 2018; 91: e1245-e1254 Crossref PubMed Scopus (14) Google Scholar , 4 Coon EA Mandrekar JN Berini SE et al. Predicting phenoconversion in pure autonomic failure. Neurology. 2020; 95: e889-e897 Crossref PubMed Scopus (10) Google Scholar Importantly, people with pure autonomic failure who progress to Parkinson's disease show a peripheral pattern of lesions in the autonomic nervous system. 2 Kaufmann H Norcliffe-Kaufmann L Palma JA et al. Natural history of pure autonomic failure: a United States prospective cohort. Ann Neurol. 2017; 81: 287-297 Crossref PubMed Scopus (148) Google Scholar , 4 Coon EA Mandrekar JN Berini SE et al. Predicting phenoconversion in pure autonomic failure. Neurology. 2020; 95: e889-e897 Crossref PubMed Scopus (10) Google Scholar Parkinson's disease outside the brain: targeting the autonomic nervous systemPatients with Parkinson's disease present with signs and symptoms of dysregulation of the peripheral autonomic nervous system that can even precede motor deficits. This dysregulation might reflect early pathology and therefore could be targeted for the development of prodromal or diagnostic biomarkers. Only a few objective clinical tests assess disease progression and are used to evaluate the entire spectrum of autonomic dysregulation in patients with Parkinson's disease. However, results from epidemiological studies and findings from new animal models suggest that the dysfunctional autonomic nervous system is a probable route by which Parkinson's disease pathology can spread both to and from the CNS. Full-Text PDF

Pure Autonomic Failure: A Case Report of Recurrent Orthostatic Hypotension

Pure autonomic failure is a neurodegenerative disorder affecting the autonomic nervous system which clinically presents with orthostatic hypotension. It is a diagnosis of exclusion after detailed clinical examinations and relevant investigations. Here, we discuss a case of 68 years old male who had complaints of multiple episodes of loss of consciousness on standing from a sitting position for the last 3 years. The diagnosis was considered by clinical examinations revealing autonomic dysfunctions with normal appropriate investigations. The patient was treated successfully with midodrine, fludrocortisone, and other non-pharmacological interventions. We focused on doing various autonomic dysfunction tests in the evaluation of a patient with recurrent orthostatic hypotension. We suspect that pure autonomic failure might not have been considered in the differential diagnosis of recurrent orthostatic hypotension and suggest that it is to be kept as a differential in such a scenario. Midodrine has an effective role in syncope due to sympathetic vasoconstrictor failure.

Multimodal Biomarkers Quantify Recovery in Autoimmune Autonomic Ganglionopathy.

The objective of this study was to evaluate patients with ganglionic acetylcholine receptor antibody (gAChR-Ab) positive autoimmune autonomic ganglionopathy using a multimodal testing protocol to characterize their full clinical phenotype and explore biomarkers to quantify immunotherapy response. We conducted a cohort study of 13 individuals (7 women, 21-69 years of age) with autonomic failure and gAChR-Ab >100 pM identified between 2005 and 2019. From 2018, all patients were longitudinally assessed with cardiovascular, pupillary, urinary, sudomotor, lacrimal and salivary testing, and Composite Autonomic Symptom Score (COMPASS-31) autonomic symptom questionnaires. The orthostatic intolerance ratio was calculated by dividing change in systolic blood pressure over time tolerated on head-up tilt. Eleven patients received immunotherapy. At first assessment, all 13 patients had cardiovascular and pupillary impairments, 7 of 8 had postganglionic sudomotor dysfunction, 9 of 11 had urinary retention and xeropthalmia, and 6 of 8 had xerostomia. After immunotherapy, there were significant improvements in orthostatic intolerance ratio (33.3 [17.8-61.3] to 5.2 [1.4-8.2], p = 0.007), heart rate response to deep breathing (1.5 [0.0-3.3] to 4.5 [3.0-6.3], p = 0.02), pupillary constriction to light (12.0 [5.5-18.0] to 19.0 [10.6-23.8]%, p = 0.02), saliva production (0.01 [0.01-0.05] to 0.08 [0.02-0.20] g/min, p = 0.03), and COMPASS-31 scores (52 to 17, p = 0.03). Orthostatic intolerance ratio correlated with autonomic symptoms at baseline (r = 0.841, p = 0.01) and following immunotherapy (r = 0.889, p = 0.02). Immunofluorescence analyses of skin samples from a patient 32 years after disease onset showed loss of nerve fibers supplying the dermal autonomic adnexa and epidermis, with clear improvements following immunotherapy. Patients with autoimmune autonomic ganglionopathy demonstrated objective evidence of widespread sympathetic and parasympathetic autonomic failure, with significant improvements after immunotherapy. Quantitative autonomic biomarkers should be used to define initial deficits, guide therapeutic decisions, and document treatment response. ANN NEUROL 2021;89:753-768.

Cardiovascular Disorders Mediated by Autonomic Nervous System Dysfunction.

Cardiovascular disorders, such as orthostatic hypotension and supine hypertension, are common in patients with neurodegenerative synucleinopathies such as Parkinson disease (PD), and may also occur in other conditions, such as peripheral neuropathies, that result in autonomic nervous system (ANS) dysfunction. Dysfunction and degeneration of the ANS are implicated in the development of orthostatic and postprandial hypotension and impaired thermoregulation. Neurogenic orthostatic hypotension (nOH) results from sympathetic failure and is a common autonomic disorder in PD. Supine hypertension may also occur as a result of both sympathetic and parasympathetic dysfunction in conjunction with nOH in the majority of patients with PD. Management of supine hypertension in the setting of nOH can be counterintuitive and challenging. Additionally, the presence of other noncardiovascular comorbidities, such as diabetes mellitus and peripheral edema, may further contribute to the burden of disease. ANS dysfunction thus presents major healthcare implications and challenges for neurology and cardiovascular practices, necessitating an integrated neurology and cardiology management approach.

2784 Steroid Responsive Gastric Dysmotility - Seronegative Autoimmune Autonomic Neuropathy

INTRODUCTION: Gastrointestinal motility disorders are complex conditions manifesting with a wide array of symptoms. In recent years, the increasing discovery of autoantibodies targeting the nervous system has led to the recognition of new neurologic autoimmune disorders (NAD) which present with the subacute development of profound neurological impairment and gastrointestinal motility disorders which when promptly treated with immunotherapy, may show dramatic improvement. CASE DESCRIPTION/METHODS: A 32 year old woman with a history of undifferentiated connective tissue disease presented to establish care for known gastroparesis Her symptoms started following an upper respiratory infection the age of 15 years, which was followed by development of arthralgia, rash, raynaud's, tonic pupils, and distal sensory symptoms. She also developed orthostatic intolerance and was diagnosed with severe gastroparesis with over 40 lb weight loss. Her medications included Plaquenil and methotrexate, as well as Zofran. She underwent extensive testing with autonomic function testing showing moderate sympathetic adrenergic dysfunction and distal sudomotor impairment which indicated a limited autonomic neuropathy and skin biopsy showed small fiber neuropathy. Paraneoplastic antibody testing, GAD antibody and ganglionic Acetylcholine receptor (gAChR ab) was negative. A trial of IVIg was started for suspected autoimmune GI dysmotility but this was complicated with pancytopenia. On exam she was malnourished with a BMI of 15, normal reflexes, and decreased distal sensations. She underwent repeat autonomic function testing which was normal. A 4 hour solid gastric emptying was performed which showed delayed emptying at 4 hr of 80%. She was underwent a 5 day infusion of IV Solumedrol at 1000 mg daily for suspected autoimmune dysmotility. A daily GCSI-DD ( gastroparesis cardinal symptom index- daily diary) score showed a >50% improvement in scores on Day 0 to Day 5 and normalization of 4 hour solid GES and was then started on IV Rituximab. DISCUSSION: This case highlights that importance of considering a diagnosis of neurologic autoimmune disorders which can present with as solitary GI dysmotility. Seronegative autoimmune autonomic neuropathy is a clinical entity which shows prominent sympathetic failure, sensory symptoms and is steroid responsive.

Abstract P2063: Isolated Noradrenergic Failure Due Tocongenital Cyb561 Deficiency

CYB561 generates ascorbic acid, a cofactor for the function of dopamine-beta-hydroxylase (DBH), the enzyme that converts dopamine to norepinephrine. We report a novel genetic defect in the CYB561 gene and provide the clinical characteristics of CYB561 deficiency. We evaluated 4 patients referred for life-long disabling orthostatic hypotension and performed whole genome sequencing of the CYB561 gene. Patients had disabling orthostatic hypotension (OH) since infancy and impaired blood pressure response to the Valsalva maneuver (VM) with exaggerated phase 2 hypotension and absence of phase 2 late recovery and phase 4 blood pressure overshoot consistent with sympathetic failure. Heart rate ratio to sinus arrhythmia and the VM, however, were normal. Plasma norepinephrine and metabolites were undetectable, and plasma dopamine and metabolites were normal. Droxidopa restored norepinephrine and improved orthostatic hypotension. Patients 1 and 2 were sisters and were homozygous for a nonsense mutation in Exon 2, c.131G>A, p.Trp44 (Circ Res 2018). Their brother (patient 3) died at age 16 and his DNA was not available. Patient 4 was compound heterozygous; one allele had a mutation in Exon 2, c157C>T, p.His.53Tyr, and the other had an Exon 2 deletion. In conclusion, CYB561 deficiency is characterized by isolated sympathetic noradrenergic failure with disabling orthostatic hypotension since infancy, but with normal sympathetic cholinergic (sweating) and parasympathetic (heart rate regulation) functions. The genetic defect differed between patients; we report a novel case of CYB561 deficiency due to compound heterozygosity, with a gene deletion in one allele, and a missense mutation in the other. These patients highlight the critical role of CYB561 in sympathetic function and cardiovascular regulation.

Abstract P176: Familial Autonomic Ganglionopathy Caused by Rare CHRNA3 Genetic Variants. Novel Genetic Cause of Neurogenic Orthostatic Hypotension

Patients with autonomic failure developed severe neurogenic orthostatic hypotension (nOH). There are only two reported genetic conditions that cause nOH, dopamine β-hydroxylase deficiency, and CYB561 deficiency; both affect norepinephrine synthesis resulting in an isolated sympathetic failure. Objective: To determine molecular basis of a new Mendelian cause of familial nOH with impaired cardiovagal function, and miosis associated with sympathetic (SNS) and parasympathetic (PNS) failure. Method and Results: The proband developed disabling nOH with poor compensatory increase in heart rate at 39 yrs of age. Plasma norepinephrine levels were abnormally low. His sister had onset of nOH in her late teens. Their parents and brother were healthy. Whole exome sequencing of DNAs from the proband and his affected sister showed that both were compound heterozygotes for c.907_908delCT (p.L303Dfs*115) /c.688G>A (p.D230N) variants in the acetylcholine receptor, neuronal nicotinic, alpha 3 subunit (CHRNA3) gene. CHRNA3 is a subunit of nicotinic acetylcholine receptors (nAChRs) that regulates blood pressure through modulation of synaptic transmission in the autonomic ganglia. The autonomic ganglia regulates both SNS and PNS activity. The frameshift (fs) and missense CHRNA3 variants were inherited from the sibs’ mother and father, respectively, and their non-affected brother was a nl/p.D230N heterozygote. The fs variant is obviously pathogenic and the p.D230N variant is predicted to be damaging (SIFT)/probably damaging (PolyPhen2). Furthermore, we predict from structural modeling that the p.D230N variant lies on the interface between CHRNA3 and other nAChR subunits and that it would destabilize the nAChR pentameric complex. In humans, the presence of acquired nAChR autoantibodies against the alpha 3 subunit is associated with nOH and non-reactive pupils. Conclusions: We report sibs affected with NOH and miosis who are compound heterozygotes forCHRNA3 variants that co-segregate with and have predicted effects on nAChR structure that suggest they likely cause this family’s SNS and PNS failure.

Neurogenic Orthostatic Hypotension in Parkinson Disease: A Primer.

Parkinson disease (PD) is associated with a variety of motor and non-motor clinical manifestations, including cardiovascular autonomic dysfunction. Neurogenic orthostatic hypotension (nOH) is a potentially serious manifestation of cardiovascular sympathetic failure that occurs in approximately 30% of patients with PD. Here we review the pathophysiology and effects of the condition as well as treatment considerations for patients with PD and nOH. Screening for nOH using orthostatic symptom questionnaires, orthostatic blood pressure measurements, and specialized autonomic testing is beneficial for the identification of symptomatic and asymptomatic cases because cardiac sympathetic denervation and nOH can occur even at early (premotor) stages of PD. Symptoms of nOH, such as orthostatic lightheadedness, in patients with PD, have been shown to adversely affect patient safety (with increased risk of falls) and quality of life and should prompt treatment with non-pharmacologic and, occasionally, pharmacologic measures. Patients with nOH are also at increased risk of supine hypertension, which requires balancing various management strategies.FundingLundbeck (Deerfield, IL).Electronic supplementary materialThe online version of this article (10.1007/s40120-019-00152-9) contains supplementary material, which is available to authorized users.

Association of small fiber neuropathy and post treatment Lyme disease syndrome.

ObjectivesTo examine whether post-treatment Lyme disease syndrome (PTLDS) defined by fatigue, cognitive complaints and widespread pain following the treatment of Lyme disease is associated with small fiber neuropathy (SFN) manifesting as autonomic and sensory dysfunction.MethodsThis single center, retrospective study evaluated subjects with PTLDS. Skin biopsies for assessment of epidermal nerve fiber density (ENFD), sweat gland nerve fiber density (SGNFD) and functional autonomic testing (deep breathing, Valsalva maneuver and tilt test) were performed to assess SFN, severity of dysautonomia and cerebral blood flow abnormalities. Heart rate, end tidal CO2, blood pressure, and cerebral blood flow velocity (CBFv) from middle cerebral artery using transcranial Doppler were monitored.Results10 participants, 5/5 women/men, age 51.3 ± 14.7 years, BMI 27.6 ± 7.3 were analyzed. All participants were positive for Lyme infection by CDC criteria. At least one skin biopsy was abnormal in all ten participants. Abnormal ENFD was found in 9 participants, abnormal SGNFD in 5 participants, and both abnormal ENFD and SGNFD were detected in 4 participants. Parasympathetic failure was found in 7 participants and mild or moderate sympathetic adrenergic failure in all participants. Abnormal total CBFv score was found in all ten participants. Low orthostatic CBFv was found in 7 participants, three additional participants had abnormally reduced supine CBFv.ConclusionsSFN appears to be associated with PTLDS and may be responsible for certain sensory symptoms. In addition, dysautonomia related to SFN and abnormal CBFv also seem to be linked to PTLDS. Reduced orthostatic CBFv can be associated with cerebral hypoperfusion and may lead to cognitive dysfunction. Autonomic failure detected in PTLDS is mild to moderate. SFN evaluation may be useful in PTLDS.

Integrated treatment for autonomic paraneoplastic syndrome improves performance status in a patient with small lung cell carcinoma: a case report

BackgroundParaneoplastic neurological syndromes (PNS) are rare disorders associated with cancer and are believed to be immune mediated. Patients with autonomic PNS suffer from variable combinations of parasympathetic and sympathetic failure. Autonomic PNS are usually associated with other PNS, such as encephalomyelitis and sensory neuropathy; however, autonomic symptoms may rarely manifest as PNS symptoms. Autonomic symptoms, therefore, may be overlooked in patients with cancer.Case presentationWe described a 65-year-old Japanese man who was diagnosed with autonomic PNS due to small-cell lung carcinoma (SCLC) with Eastern Cooperative Oncology Group (ECOG) performance status 3, who suffered from orthostatic hypotension, and urinary retention needing a urethral balloon. Laboratory studies showed decreased levels of noradrenaline, and were positive for anti-ganglionic acetylcholine receptor antibody, type 1 antineuronal nuclear antibody, and sry-like high mobility group box 1 antibody. Nerve conduction evaluations and 123I-metaiodobenzylguanidine myocardial scintigraphy showed no abnormalities. Abdominal contrast-enhanced computed tomography revealed marked colonic distention. The patient’s autonomic symptoms resolved following integrated treatment (symptomatic treatment, immunotherapy, and additional chemotherapy) enabling the patient to walk, remove the urethral balloon, and endure further chemotherapy. ECOG performance status remained at 1, 10 months after admission.ConclusionsIntegrated treatment for autonomic PNS may improve autonomic symptoms and ECOG performance status of patients with cancer.

Efficiency of neuromultivit in complex therapy of patients with rheumatoid arthritis associated with diabetes mellitus

To examine the dysregulation of the autonomic nervous system and manifestations of pain syndrome in patients with rheumatoid arthritis combined with diabetes mellitus and the possibility of their correction in patients who receive complex therapy including neurotropic vitamins (neuromultivitis). One hundred and forty-six patients with rheumatoid disease were examined including 59 patients with diabetes mellitus. When testing for the presence of neuropathic pain syndrome using the diagnostic questionnaire of neuropathic pain (DN4), a greater prevalence of these features was revealed, with a high correlation with the duration of rheumatoid arthritis (r=0,56) and duration of diabetes mellitus (r=0,82). A positive effect of combined therapy with neuromultivitis on the daily rhythm of arterial pressure with its normalization and correction of autonomic disorders was noted. There were a more pronounced decrease in the frequency and severity of parasympathetic and sympathetic failure, as well as an improvement in the adaptation of the peripheral vascular system to orthostatic changes. Improvement of quality of life is, to some extent, due to the more pronounced positive effect of combined therapy with neuromultivitis on such autonomic disorders as palpitations, heart rhythm disturbances, manifestations of lipotymic disorders and even panic attacks.

Seronegative autoimmune autonomic neuropathy: a distinct clinical entity.

Autoimmune autonomic ganglionopathy (AAG) is associated with ganglionic acetylcholine receptor (gAChR) antibodies. We describe a similar but distinct series of patients with autoimmune autonomic failure lacking this antibody. Retrospective chart review. Six patients presented with subacute autonomic failure, seronegative for gAChR antibodies. Orthostatic hypotension and gastrointestinal complaints were common. Autonomic testing revealed predominant sympathetic failure and no premature pupillary redilation. All patients had sensory symptoms and/or pain, which was severe in three. Immunotherapy with plasma exchange, intravenous immunoglobulin, and rituximab was ineffective. Three patients responded to intravenous steroids. In these cases of autoimmune autonomic failure, key differences from seropositive AAG emerge. Testing showed prominent sympathetic (rather than cholinergic) failure, specific pupillary findings of AAG were absent, and sensory symptoms were prominent. AAG responds to antibody-targeted immunotherapy, while these patients responded best to steroids. This seronegative autoimmune autonomic neuropathy is a distinct clinical entity requiring a different treatment approach from AAG.

Beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver

Measurement of beat-to-beat blood pressure and heart rate responses to the Valsalva maneuver is the basis for a highly informative autonomic function test. Whereas in the past this measurement required intra-arterial cannulation, the development of finger cuff devices that acquire arterial pressure waveforms indistinguishable from those recorded intra-arterially has made it possible to obtain accurate measurements noninvasively. In a patient with orthostatic hypotension, the pattern of blood pressure responses during and after the release of the maneuver can identify a neurogenic basis: sympathetic neurocirculatory failure. The quantifiable change in cardiac interbeat interval per unit change in systolic pressure during the maneuver can identify baroreflex-cardiovagal failure.

Abstract 92: Cardiac Bridging Integrator 1 Gene Transfer Improves Left Ventricular Lusitropy in Mice With Continuous Infusion of Isoproterenol

Background: Cardiac bridging integrator 1(cBIN1) is a membrane scaffolding protein, which organizes t-tubule dyad microdomains critical for normal calcium transient development. BIN1 is transcriptionally reduced in heart failure, and reduced BIN1 diminishes calcium transients, limiting excitation-contraction coupling and impairing contractility. Furthermore, cBIN1-microdomains organize with acute β-adrenergic activation. It remains unclear whether over-expression of cBIN1 improves myocardial function in mice with chronic sympathetic overdrive. Methods: Adult male C57BL/6 mice received retro-orbital injections of adeno-associate virus 9 (AAV9) transducing either control GFP, sBIN1 (small BIN1), BIN1+13, BIN1+17, or cBIN1 (BIN1+13+17). Three weeks after virus injection, mice were subjected to subcutaneous implantation of micro osmotic pumps continuously releasing isoproterenol at 30mg /kg/day for four weeks. Left ventricular (LV) geometry and function were evaluated by echocardiography before and weekly after isoproterenol infusion. Results: In the control GFP group, isoproterenol infusion significantly increased LV mass and relative wall thickness (RWT), consistent with concentric hypertrophy. Over-expression of any of the four BIN1 isoforms attenuated left ventricular hypertrophy (n=5 per group). However, only cBIN1 over-expressing mice became more efficient. Their hearts had improved left ventricular relaxation, and were able to preserve ejection fraction yet with increased end systolic and diastolic volumes. As a result of improved relaxation, cBIN1 over-expression increased stroke volume and cardiac output without their hearts becoming hyperdynamic. Thus cBIN1 conveys a general BIN1 protection against isoproterenol induced hypertrophy together with a cBIN1 specific improvement in lusitropy. Conclusions: In mice with chronic sympathetic overdrive, over-expression of cBIN1 increases LV compliance, preserves heart lusitropy, and improves cardiac function. This athletic heart like phenotype induced by cBin1 gene therapy indicates that exogenous cBIN1 can reverse the diastolic dysfunction associated with sympathetic overdrive and heart failure progression.

Human Bacterial Artificial Chromosome (BAC) Transgenesis Fully Rescues Noradrenergic Function in Dopamine β-Hydroxylase Knockout Mice.

Dopamine β-hydroxylase (DBH) converts dopamine (DA) to norepinephrine (NE) in noradrenergic/adrenergic cells. DBH deficiency prevents NE production and causes sympathetic failure, hypotension and ptosis in humans and mice; DBH knockout (Dbh -/-) mice reveal other NE deficiency phenotypes including embryonic lethality, delayed growth, and behavioral defects. Furthermore, a single nucleotide polymorphism (SNP) in the human DBH gene promoter (-970C>T; rs1611115) is associated with variation in serum DBH activity and with several neurological- and neuropsychiatric-related disorders, although its impact on DBH expression is controversial. Phenotypes associated with DBH deficiency are typically treated with L-3,4-dihydroxyphenylserine (DOPS), which can be converted to NE by aromatic acid decarboxylase (AADC) in the absence of DBH. In this study, we generated transgenic mice carrying a human bacterial artificial chromosome (BAC) encompassing the DBH coding locus as well as ~45 kb of upstream and ~107 kb of downstream sequence to address two issues. First, we characterized the neuroanatomical, neurochemical, physiological, and behavioral transgenic rescue of DBH deficiency by crossing the BAC onto a Dbh -/- background. Second, we compared human DBH mRNA abundance between transgenic lines carrying either a “C” or a “T” at position -970. The BAC transgene drove human DBH mRNA expression in a pattern indistinguishable from the endogenous gene, restored normal catecholamine levels to the peripheral organs and brain of Dbh -/- mice, and fully rescued embryonic lethality, delayed growth, ptosis, reduced exploratory activity, and seizure susceptibility. In some cases, transgenic rescue was superior to DOPS. However, allelic variation at the rs1611115 SNP had no impact on mRNA levels in any tissue. These results indicate that the human BAC contains all of the genetic information required for tissue-specific, functional expression of DBH and can rescue all measured Dbh deficiency phenotypes, but did not reveal an impact of the rs11115 variant on DBH expression in mice.

Pathophysiology and Treatment of Orthostatic Hypotension in Parkinsonian Disorders.

Orthostatic hypotension (OH) is defined as a sustained pathological reduction in blood pressure within 3min after orthostatic stress such as tilt-table testing or active standing. Non-neurogenic OH is caused by either decreased cardiac output or impaired vasoconstriction without a primary autonomic disorder whereas neurogenic OH results from inadequate release of norepinephrine in the vasomotor sympathetic system. Once non-neurogenic causes of OH such as medications and cardiac problems are ruled out, neurogenic OH can be considered. Neurogenic OH can accompany parkinsonian diseases in different stages and is associated with increased risk of morbidity and mortality. The pathophysiology of neurogenic OH in parkinsonian diseases includes sympathetic neurocirculatory failure and impaired cardiovagal activity. The inadequate release of peripheral norepinephrine upon orthostatic stress is a final pathologic pathway for neurogenic OH and is important for many therapeutic interventions. With mild or early autonomic failure, OH that occurs beyond 3min of standing (defined as delayed OH) can result in orthostatic intolerance. Supine hypertension and postprandial hypotension are frequent comorbidities and may exacerbate orthostatic hypotension. The non-pharmacologic therapies should be tried initially, followed by pharmacologic treatments. Common medications used in the treatment of OH include fludrocortisone, midodrine, pyridostigmine, and droxidopa. Only midodrine and droxidopa have received FDA approval for the treatment of orthostatic hypotension.