Involvement Of Autonomic Nervous System Research Articles

Droxidopa for Treatment of Refractory Orthostatic Hypotension in Patients with AL Amyloidosis: A Case Series

BackgroundOrthostatic hypotension due to autonomic dysfunction is a well-known complication of light chain (AL) amyloidosis, which can become progressively debilitating and difficult to manage. Treatment of the underlying plasma cell dyscrasia will eventually decrease further amyloid deposition. Management of orthostatic hypotension secondary to AL amyloidosis improves quality of life and facilitates delivery of plasma cell therapy. Pharmacologic interventions include fludrocortisone, sympathomimetic agents such as midodrine, droxidopa, the acetylcholinesterase inhibitor pyridostigmine or the norepinephrine transporter (NET) inhibitor atomoxetine. Fludrocortisone is often poorly tolerated in amyloid patients because it may exacerbate edema. Droxidopa is a synthetic amino acid analog that is directly metabolized to norepinephrine by dopa-decarboxylase, which increases blood pressure (BP) by inducing peripheral arterial and venous vasoconstriction.AimsTo assess the effectiveness of droxidopa in patients with AL amyloidosis with severe orthostatic hypotension refractory to midodrine. Also, to describe effective dose of droxidopa, duration of therapy, adverse effects and reasons for discontinuation.MethodsA regional retrospective study was done in patients with AL amyloidosis with severe, refractory orthostatic hypotension who received droxidopa. Retrospective data was reviewed from 2018 to 2021 at a single academic center in the United States.ResultsFive patients with AL amyloidosis were included in the study; three patients had lambda-restricted plasma cell dyscrasia and two had multiple myeloma (MM) associated AL amyloidosis (both kappa light chain restricted). Of the five patients, all had cardiac, renal, autonomic nervous system and peripheral nervous system involvement and two of the five had gastrointestinal involvement as well. Given their poor performance status and advanced organ involvement, none of the patients were eligible for high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT), and thus were treated with cyclophosphamide, bortezomib and dexamethasone (CyBorD). All patients achieved very good partial response to complete hematologic response. The main findings are summarized in table 1.All patients had severe, symptomatic orthostatic hypotension that was objectively defined as a decrease in systolic blood pressure by 20 millimeters of mercury (mmHg) or a decrease in diastolic blood pressure of 10 mmHg from supine to either sitting or standing in the clinic or at home (Freeman R consensus statement on the definition of orthostatic hypotension, 2011). Initial treatment for all patients included midodrine, ranging from 5 to 30mg TID based on individual tolerance. Three of the patients also were initially treated with fludrocortisone 0.05 to 0.2mg daily (use limited by fluid retention). Only one patient was on pyridostigmine 30mg TID (case 5). Given persistence of symptoms despite therapy, droxidopa was started at 100mg TID in all patients, and the dose was titrated as tolerated. None required the maximal approved dose of 600mg TID.The indication to start droxidopa was based on refractory, symptomatic orthostatic hypotension in all five patients. After initiation of droxidopa, all except for one patient reported improvement both in symptoms of lightheadedness as well as measurements of orthostatic blood pressure values. By the end of this study, three patients continued treatment with droxidopa (cases 1-3); one was weaned-off after resolution of symptoms (case 5) and one was discontinued due to supine hypertension (case 4).ConclusionData shows that droxidopa is an effective treatment of orthostatic hypotension refractory to midodrine in patients with AL amyloidosis. Slow titration may be important to minimize rapid changes in blood pressure. Further studies are warranted to assess droxidopa's safety and compare with other treatments for orthostatic hypotension. [Display omitted] DisclosuresHughes: Amgen: Speakers Bureau; Rigel: Other: Advisory Board, Research Funding; Abbvie: Speakers Bureau; Karyopharm: Other: Advisory Board, Speakers Bureau. Sanchorawala: Celgene: Research Funding; Takeda: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding; Karyopharm: Research Funding; Sorrento: Research Funding; Pfizer: Honoraria. Sloan: Nuvectis: Consultancy; Abbvie: Consultancy; Stemline: Consultancy; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacosmos: Membership on an entity's Board of Directors or advisory committees.

GUILLAIN-BARRÉ SYNDROME FOLLOWING COVID-19 PNEUMONIA: ARE THEY RELATED?

TOPIC: Chest Infections TYPE: Medical Student/Resident Case Reports INTRODUCTION: Guillain-Barre syndrome (GBS) is an immune-mediated polyneuropathy affecting the peripheral nervous system. Immune system activation in response to a viral or bacterial infection, which cross-reacts with the peripheral nerve components, is GBS's proposed mechanism. Epstein-Barr virus, campylobacter, cytomegalovirus, influenza, and mycoplasma are the most commonly associated infections with GBS development. Since the beginning of the coronavirus 2019 (COVID-19) pandemic, there have been isolated reports of the disease's neurological manifestations and sequelae. In early February 2020 itself, COVID-19 associated GBS has been reported from Italy and China. Here we are reporting the case of a GBS after severe COVID-19 pneumonia. CASE PRESENTATION: A 68-year- old Caucasian male with a history of obstructive sleep apnea, hypertension, and restless leg syndrome came to the hospital with worsening reparatory difficulty. He was diagnosed with COVID-19 pneumonia a week ago and was on remdesivir and dexamethasone therapy at home. At the time of presentation, he was found to be in respiratory failure, which eventually required intubation and mechanical ventilation. After spending 14 days on mechanical ventilation, the patient was extubated. His respiratory status significantly improved, but he was found to have confused mentation on day two after extubation. An MRI scan and EEG showed no significant abnormality. His confusion improved over the next two days, but he gradually developed bilateral upper and lower extremity symmetrical weaknesses with loss of deep tendon reflexes and touch sensation. The patient was also found to have alternating tachycardia and bradycardia around this period. The weakness progressed over the next week. CSF analysis revealed a protein level of 77mg/dL (normal: 8–43 mg/dL) with total nucleated cells of 3 (normal 0-8 ). CSF meningitis/encephalitis PCR panel for the 17 most common pathogens was negative (the panel did not have COVID-19). Nerve conduction studies were not done due to lack of availability. A diagnosis of GBS was made, and the patient was transferred to a higher center for plasmapheresis. DISCUSSION: COVID-19 leading to GBS does not come as a surprise;similar viruses, including Severe acute respiratory syndrome coronavirus and middle east respiratory syndrome coronavirus, had been reported to trigger GBS. If the CSF findings and autonomic nervous system involvement were absent, post-intensive care syndrome and critical care neuropathy might have been close differentials. There are isolated reports of blood transfusions leading to GBS;although unlikely, the patient's reception of convalescent plasma cannot be overlooked. The absence of nerve conduction studies also truncates the confidence of GBS diagnosis here. CONCLUSIONS: GBS may be triggered by COVID-19 infection, although more evidence is needed to establish the causation. REFERENCE #1: Caress JB, Castoro RJ, Simmons Z, Scelsa SN, Lewis RA, Ahlawat A, Narayanaswami P. COVID-19-associated Guillain-Barre syndrome: The early pandemic experience. Muscle Nerve. 2020 Oct;62(4):485-491. doi: 10.1002/mus.27024. Epub 2020 Aug 11. PMID: 32678460;PMCID: PMC7405390. REFERENCE #2: Rajdev K, Victor N, Buckholtz ES, Hariharan P, Saeed MA, Hershberger DM, Bista S. A Case of Guillain-Barre Syndrome Associated With COVID-19. J Investig Med High Impact Case Rep. 2020 Jan-Dec;8:2324709620961198. doi: 10.1177/2324709620961198. PMID: 32981333;PMCID: PMC7545753. REFERENCE #3: Scheidl E, Canseco DD, Hadji-Naumov A, Bereznai B. Guillain-Barre syndrome during SARS-CoV-2 pandemic: A case report and review of recent literature. J Peripher Nerv Syst. 2020 Jun;25(2):204-207. doi: 10.1111/jns.12382. Epub 2020 May 26. PMID: 32388880;PMCID: PMC7273104. DISCLOSURES: No relevant relationships by Arthur Cecchini, source=Web Response No relevant relationships by Bhavesh Gajjar, source=Web Response No relevant relationships by Rasheed Musa, source=Web Response No relevant relati nships by Akesh Thomas, source=Web Response

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Unveiling the relationship between autonomic involvement, fatigue, and cognitive dysfunction in early relapsing-remitting multiple sclerosis.

Fatigue is a common, yet disabling, symptom in patients with multiple sclerosis (PwMS). Fatigue has shown to be associated with self-reported autonomic nervous system (ANS) symptoms, particularly for cognitive fatigue; however, the question whether ANS involvement is related to cognitive impairment has never been addressed. We performed a study to unveil the complex relationship between fatigue, ANS symptoms, and cognitive impairment. We prospectively recruited early PwMS that were tested with Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS), State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), Modified Fatigue Impact Scale (MFIS) and Composite Autonomic Symptoms Scale-31 (COMPASS-31) scale. We performed a comparison between fatigued and non-fatigued patients and between cognitive unimpaired and impaired patients. We evaluated the association of COMPASS-31, MFIS, BDI, STAI, and BICAMS scores, and the analysis was repeated for each scale's sub-scores. A multivariable analysis was performed to elucidate predictors of fatigue. Forty-four patients were recruited. Fatigued patients had higher COMPASS-31 total, orthostatic intolerance, secretomotor, and pupillomotor scores. No differences in fatigue and ANS symptoms were found between cognitive impaired and unimpaired patients. MFIS total score correlated with STAI state (p = 0.002) and trait (p < 0.001), BDI (p < 0.001), COMPASS-31 total (p < 0.001), orthostatic intolerance (p < 0.001), pupillomotor scores (p = 0.006). Multivariable analysis showed that BDI (p < 0.001) and COMPASS-31 (p = 0.021) predicted MFIS score. Sub-scores analysis showed that orthostatic intolerance has a relevant role in fatigue. ANS symptoms are closely related with fatigue. Orthostatic intolerance may have a predominant role. Cognitive impairment seems not to be associated with ANS symptoms.

Peripheral nervous system in multiple sclerosis-understanding the involvement via autonomic nervous system.

The aim of this review is to summarize the clinical and paraclinical findings that demonstrate that multiple sclerosis (MS) affects theperipheral nervous system (PNS) as well as the central nervous system (CNS).Methods: Narrative review. MS is traditionally defined as a chronic demyelinating immune-mediated disease of the CNS. However, there is emerging evidence that MS is adisease that does not solely affect the CNS but can manifest with PNS involvement as well. Several pathology studies have reported on signs ofdemyelination in the PNS, as well as on structural and functional involvement of the PNS in persons with MS (pwMS). From the functional aspect, severalstudies have shown autonomic nervous system (ANS) involvement in the form of sudomotor dysfunction measured with quantitative sudomotor axon reflextest (QSART) in different stages of MS, adding to the growing body of evidence that indicate PNS involvement in MS. In this review the clinical,pathological, neurophysiological, and imaging findings that demonstrate that MS affects the PNS as well as the CNS are summarized, with the emphasis onthe ANS abnormalities. Further large-scale research is needed in order to fully understand the frequency and importance of PNS affection in MS.

HYPERTENSION, AUTONOMIC DYSFUNCTION AND SUDDEN DEATH RISK IN CADASIL DISEASE: NOVEL DATA

Objective: Sudden death (SD) is the first cause of mortality in CADASIL disease (CD)(Cerebral Autosomic Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy). An early development of cardiac autonomic neuropathy (CAN) in the pathogenesis of CD was demonstrated by others. As we detected hypertension in members of 4 families of this rare condition we decided to explore the imbalance of the autonomic nervous system as a potential tool for the prediction of SD risk. Aims: to explore the relationship between hypertension and CAN in CD. Design and method: We included 10 hypertensive (officce and 24 hs ABPM) patients with CD. Autonomic function was evaluated by the study of heart rate variability (HRV) and Ewing test (handgrip, inspiration/espiration, valsalva manouver and orthostatism). CAN stages were determined as as subclinical, early and advanced. Results: CD patients were classified as hypertensives (n:5), or normotensives. Table 1 showed hypertensives subjects characteristics and the distribution of CAN. The control group was constituted with patients with CD and arterial normotension (n:5), the study of HRV and Ewing Test being normal in them. No association was observed between the number and extent of brain lessions, location, impact of white matter with the presence of hypertension. The prevalence of CVRF was similar between both groups. Conclusions: Autonomous alterationwas identified in 80% of hypertensive patients with CADASIL disease in our population sample. This association would be independent of traditional CVRF, and the evolutionary characteristics of brain lesions. Although hypertension has not been reported elsewhere as associated with CD, its identification could indicate the risk of autonomic nervous system involvement in these patients. The relevance of their suspicion would reside in the risk re-stratification of cardiovascular events with a focus on the risk of sudden death, linked to the NAC. The limitation of the reduced number of subjects requires the analysis of this hypothesis in a larger population sample, the present being a proof of concept that could justify the development of a survey work in other centers that report cases of this rare disease.

Autonomic and Motor Involvement among the Patients Presented with Prolapse Lumbar Intervertebral Disc

Background: Involvement of autonomic and motor nervous system are very crucial for the patients suffering from prolapse lumbar intervertebral disc.&#x0D; Objective: The purpose of the present study was to see the involvement of autonomic and motor nervous system of the patients suffering from prolapse lumbar intervertebral disc.&#x0D; Methodology: This cross-sectional study was carried out in the department of Neurosurgery at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from March 2006 to October 2007 for a period of one and half year. Prolapse lumbar intervertebral disc (PLID) patients who were admitted in the Department Neurosurgery at BSMMU, Dhaka, Bangladesh after clinical and radiological evaluation were selected as study population. The involvement of autonomic and motor nervous system were examined among the patients suffering from prolapse lumbar intervertebral disc.&#x0D; Result: A total of 59 hospital-admitted cases of PLID were included in the study. The mean age of the patients was 40.8±11.9 years and the lowest and highest ages were 21 and 65 years respectively. Majority of the patients had intact bladder function which was 57(94.9%) cases and the remaining 2(3.4%) cases had incontinence of urine. More than half (54.2%) of the subjects exhibited weak extensor hallucis longus test, while 30.5% had weak flexor digitalis longus test.&#x0D; Conclusion: In conclusion motor dysfunction is very high, but low rate of autonomic abnormalities are found among the patients suffering from prolapse lumbar intervertebral disc.&#x0D; Journal of Science Foundation, January 2020;18(1):3-6

Autonomic nervous system involvement in COVID 19 and risk of sudden cardiac death

The acute SARS CoV 2 infection causes increased metabolic demand with reduced cardiac reserve, tachypnoea, acidosis, hypoxia causing deleterious effects on cardiac myocytes. Since its heightened sympathetic state these patients are more prone for malignant arrhythmias. The central nervous system involvement of MERS-CoV is mostly caused by the autoimmune reaction against viral antigens rather than viral infection itself. Although coronaviruses can infect the autonomic center in the brainstem, potentially contributing to cardiovascular and respiratory failure, the direct effect of SARS-CoV2 on the autonomic nervous system is not well known yet. The purpose of this review is to emphasise the involvement of autonomic nervous system (ANS) which is an integral part of our human body to adapt for the stressful environment like COVID 19 infection.

Post-Acute Sequelae of SARS-Cov-2 Infection Associating Peripheral, Autonomic and Central Nervous System Disturbances: Case Report and Review of the Literature

Aim: To describe post-infectious neurological aspects of COVID-19 in a patient with progressive post-infectious peripheral (PNS), autonomic (ANS) and central nervous system (CNS) involvement due to SARS-CoV-2 infection. Background and Purpose: A variety of neurological manifestations have been described in association with Covid-19, however, progressive multisystem neurological aspects have not been described. Methods: A case report detailing the history, examination, and infectious serology associated with SARS-CoV-2, and subsequent neurodiagnostic laboratory testing and treatment. Results: Neurodiagnostic laboratory studies showed large-fiber demyelinating sensorimotor and painful small fiber sensory polyneuropathy, orthostatic hypotension, and hypometabolism of bilateral anterior and mesial temporal lobes with a possible frontal seizure focus. Treatment was initiated with high-dose immune globulin therapy. Conclusions: The combination of PNS, ANS and CNS involvement in this patient was associated with post-infectious acquired immunity to SARS-CoV-2.

Electrocardiographic changes predate Parkinson\u2019s disease onset

Autonomic nervous system involvement precedes the motor features of Parkinson’s disease (PD). Our goal was to develop a proof-of-concept model for identifying subjects at high risk of developing PD by analysis of cardiac electrical activity. We used standard 10-s electrocardiogram (ECG) recordings of 60 subjects from the Honolulu Asia Aging Study including 10 with prevalent PD, 25 with prodromal PD, and 25 controls who never developed PD. Various methods were implemented to extract features from ECGs including simple heart rate variability (HRV) metrics, commonly used signal processing methods, and a Probabilistic Symbolic Pattern Recognition (PSPR) method. Extracted features were analyzed via stepwise logistic regression to distinguish between prodromal cases and controls. Stepwise logistic regression selected four features from PSPR as predictors of PD. The final regression model built on the entire dataset provided an area under receiver operating characteristics curve (AUC) with 95% confidence interval of 0.90 [0.80, 0.99]. The five-fold cross-validation process produced an average AUC of 0.835 [0.831, 0.839]. We conclude that cardiac electrical activity provides important information about the likelihood of future PD not captured by classical HRV metrics. Machine learning applied to ECGs may help identify subjects at high risk of having prodromal PD.

Dysautonomia in Alzheimer's Disease.

Alzheimer's disease is the most common neurodegenerative disorder, and its prevalence increases with age. Although there is a large amount of scientific literature focusing on Alzheimer's disease cardinal cognitive features, autonomic nervous system dysfunction remains understudied despite being common in the elderly. In this article, we reviewed the evidence for autonomic nervous system involvement in Alzheimer's disease. We identified four major potential causes for dysautonomia in Alzheimer's disease, out of which two are well-studied (comorbidities and medication) and two are rather hypothetical (Alzheimer's pathology and brain co-pathology). Although there appears to be some evidence linking Alzheimer's disease pathology to autonomic nervous system dysfunction, there is an important gap between two types of studies; histopathologic studies do not address dysautonomia manifestations, whereas clinical studies do not employ histopathologic diagnostic confirmation. Moreover, brain co-pathology is emerging as an important confounding factor. Therefore, we consider the correlation between dysautonomia and Alzheimer's disease to be an open question that needs further study. Nevertheless, given its impact on morbidity and mortality, we emphasize the importance of assessing autonomic dysfunction in patients with Alzheimer clinical syndrome.

Involvement of Autonomic Nervous System in New-Onset Atrial Fibrillation during Acute Myocardial Infarction.

Background: Atrial fibrillation (AF) is common after acute myocardial infarction (AMI) and associated with in-hospital and long-term mortality. However, the pathophysiology of AF in AMI is poorly understood. Heart rate variability (HRV), measured by Holter-ECG, reflects cardiovascular response to the autonomic nervous system and altered (reduced or enhanced) HRV may have a major role in the onset of AF in AMI patients. Objective: We investigated the relationship between autonomic dysregulation and new-onset AF during AMI. Methods: As part of the RICO survey, all consecutive patients hospitalized for AMI at Dijon (France) university hospital between June 2001 and November 2014 were analyzed by Holter-ECG <24 h following admission. HRV was measured using temporal and spectral analysis. Results: Among the 2040 included patients, 168 (8.2%) developed AF during AMI. Compared to the sinus-rhythm (SR) group, AF patients were older, had more frequent hypertension and lower left ventricular ejection fraction LVEF. On the Holter parameters, AF patients had higher pNN50 values (11% vs. 4%, p < 0.001) and median LH/HF ratio, a reflection of sympathovagal balance, was significantly lower in the AF group (0.88 vs 2.75 p < 0.001). The optimal LF/HF cut-off for AF prediction was 1.735. In multivariate analyses, low LF/HF <1.735 (OR(95%CI) = 3.377 (2.047–5.572)) was strongly associated with AF, ahead of age (OR(95%CI) = 1.04(1.01–1.06)), mean sinus-rhythm rate (OR(95%CI) = 1.03(1.02–1.05)) and log NT-proBNP (OR(95%CI) = 1.38(1.01–1.90). Conclusion: Our study strongly suggests that new-onset AF in AMI mainly occurs in a dysregulated autonomic nervous system, as suggested by low LF/HF, and higher PNN50 and RMSSD values.

Correlation between benign joint hypermobility syndrome and primary focal hyperhidrosis in children: a novel concept

BackgroundBenign joint hypermobility syndrome (BJHS) is one of the most common hereditary connective tissue disorders in children in which autonomic nervous system involvement has been reported. This study aimed to evaluate the frequency of primary focal hyperhidrosis in children with BJHS.MethodsThis observational-analytical study was conducted in a case-control setting on children aged 3 to 15 years in 2018 at Mofid Children’s Hospital, Tehran, Iran. Benign joint hypermobility syndrome was diagnosed according to the Brighton criteria; then, the patients referred to a dermatologist for evaluation of hyperhidrosis.ResultsIn total, 130 eligible patients with confirmed BJHS and 160 age- and sex-matched healthy subjects were enrolled in this study. Primary focal hyperhidrosis (PFH) was seen in 56.2 and 16.3% of the cases and controls, respectively, indicating a significant difference (P < 0.05). The severity of hyperhidrosis did not differ between the two groups.ConclusionAlthough the results of the study showed a significant correlation between BJHS and PFH, more comprehensive studies are needed to confirm these findings.

Knowledge, Perception and Seroprevalence of HIV/STIS among Young Adults in Brazilian Amazon Region: A Population-Based Study

Background: Neurological complications involving central and peripheral nervous system are well described but there is paucity of literature on involvement of autonomic nervous system. HIV patients on ART have a higher prevalence of symptoms due to dysautonomia in comparison to normal individuals. Aims and objectives: To study the prevalence of cardiac autonomic dysfunction in PLHA (People living with HIV/ AIDS) with and without antiretroviral treatment. Methodology: It is a cross sectional study. The subjects are broadly divided into 3 categories with 25 patients in each group. PLHA on ART, PLHA not on ART and healthy controls. Observation and results: Three patients from ART group two from ART naive group had symptoms of syncope. There was a significant difference between the autonomic parameters in the control population as compared to that of PLHA, but no difference between those on ART and not on ART. The resting heart rate was significantly higher in PLHA compared to controls. On testing for sympathetic response, there was no notable difference between the median values of fall in systolic blood pressure between PLHA patients and control population. Respiratory sinus arrhythmia, expiration to inspiration ratio, in the controls was higher when compared to PLHA There is a significant difference in fall in systolic blood pressure between the HIV on ART and not on ART, however there was no significant difference in other autonomic parameters. Conclusion: This study shows that deterioration of parasympathetic function is more common than sympathetic function decline in HIV infected subjects as compared to normal population.

Involvement of small nerve fibres and autonomic nervous system in AL amyloidosis: comprehensive characteristics and clinical implications

Peripheral nerve involvement in immunoglobulin light chain (AL) amyloidosis is common, characterised by severe progressive mixed neuropathy with autonomic dysfunction but there is limited data on the implications and the characteristics of small nerve fibres dysfunction (SNFD). The aim of our prospective study was to evaluate SNFD and its clinical implications in newly diagnosed AL patients. Twenty-three consecutive patients (10 male, mean age 61.78 years) and 21 age- and gender-matched healthy controls (8 male, mean age 61.28 years) underwent clinical evaluation and standard nerve conduction studies (NCS), baroreflex sensitivity (BRS) test, quantitative sensory testing (QST) and skin biopsy at the lower leg for measuring the density of the nerve fibres innervating the epidermis (IENFD). Axonal degeneration of the large nerve fibres was revealed in 15 out of 23 patients while SNFD was indicated by QST and skin biopsy in 56% and 61% of the patients respectively. BRS index significantly correlated with the IENFD and the QST results while low IENFD was associated with significantly poorer survival. Our study provides new insights and also an initial evaluation of new tools for assessment of the involvement of autonomic and small nerve fibres in AL amyloidosis. These findings also appear to have prognostic implications.

Cardiovascular and sudomotor dysfunction in Hirayama disease.

Hirayama disease is a disease of young males causing atrophy of small muscles of the affected hand and forearm. Localized autonomic dysfunction of the affected upper limb such as cold skin and excessive sweating has been described in some patients. In this study, we looked for local as well as systemic involvement of autonomic nervous system in patients with Hirayama disease. Forty-four patients with a median duration of illness of 3years were included in the study. Assessment of symptom profile and evaluation of autonomic nervous system were done at the time of enrolment. The mean age at presentation was 21.9 (10-32) years, with a delay in seeking medical attention of around 3 (1-11) years. Localized clinical autonomic dysfunction was present in 39 (88.6%) patients, while objective generalized autonomic dysfunction was present in 33 (75%) patients. Cold skin and excessive sweating showed good correlation with the presence of objective autonomic dysfunction (P < 0.05). In three patients, sympathetic skin response (SSR) could not be recorded in one of the four limbs. Compared to controls, the SSR results in patients with Hirayama disease showed increased latency (1.64 ± 0.21 vs. 1.57 ± 0.14, P 0.04) and decreased amplitude in upper limbs (0.65 ± 0.19 vs. 0.86 ± 0.40, P 0.01). Hirayama disease has both localized and systemic dysautonomia. Careful longitudinal evaluation during the progressive phase of the disease may help in diagnosing subtle systemic autonomic dysfunction.

Immunoglobulin Variable Gene Region (IGVL) Usage Correlates with Distinct Clinical Presentation in IgM Versus Non-IgM Light Chain Amyloidosis

Introduction: The clinical presentation and frequency of organ involvement are quite distinct in patients with IgM amyloidosis compared to patients with non-IgM amyloidosis, with less heart involvement and more nerve, soft tissue and lung involvement in IgM patients. It has been observed that immunoglobulin light chain variable region (IGVL) gene and gene family of the plasma cell clone impact phenotypic manifestations in AL amyloidosis, particularly organ tropism. (Kourelis et al. Blood. 2017;129). Given the variability in clinical features amongst patients with IgM vs. non IgM AL amyloidosis, we hypothesized that IGVL gene usage would be different between these two groups. Methods: Patients with newly diagnosed IgM and non-IgM amyloidosis seen at our institution from 01/2006 to 12/2015 were identified. IGVL gene usage was assessed by liquid chromatography tandem mass spectrometry (LC/MS/MS) as previously described. (Vrana et al Blood 2009;Dasari et al J of Proteome Res; Kourelis et al. Blood. 2017). Mass spectrometry data for IGVL analysis was obtained from clinically available data. LC/MS/MS was performed on available archival specimens when such data was not available clinically. Results: Patients with newly diagnosed amyloidosis who had sufficient mass spectrometry data on fat aspirate or tissue biopsy for IGVL gene usage identification were included (IgM AL, N=44 and Non-IgM AL, N=391). Clinical Features: As expected, differences were noted in baseline characteristics of patients with IgM vs. non-IgM AL amyloidosis. Patients with IgM amyloidosis were older (68 vs. 64 years, p=0.04) and more likely to have kappa as the involved light chain (34% vs. 25%, p=0.2), though the difference did not reach statistical significance. IgM amyloidosis patients had lower difference in involved and uninvolved free light chains (dFLC) (15.5 vs. 25.8 mg/dL, p=0.01) and lower NTProBNP levels (median: 1987 vs. 2655 pg/mL, p=0.02) compared with non-IgM amyloid patients. Presence of t(11;14) was less common by FISH (30% vs. 48%, p=0.1), though the difference did not reach statistical significance. Patterns of organ involvement were different, with heart involvement being less frequent in IgM patients (64% vs. 76%), while peripheral nerve (30% vs. 18%, p=0.05), soft tissue (41% vs. 21%, p=0.005) and lung involvement (7% vs. 3%, p=0.1) were more common in patients with IgM vs. non-IgM AL amyloidosis. There was no difference in liver (9% vs. 15%), kidney (50% vs. 51%) GI (23% vs. 25%) or autonomic nervous system involvement (18% vs. 14%). IGVL Gene Usage: As shown in Figure 1, IGVL usage differed across the two groups. In the lambda group, LV2-08 (14% vs. 2%, p&lt;0.001) and LV2-14 (36% vs. 10%, p&lt;0.001) were more common in IgM amyloid patients, while LV1-44 (0% vs. 10%, p=0.02) and LV6-57 (2% vs. 18%, p=0.004) were less common in the IgM group. There was also a trend towards less frequent involvement of LV3-01 (2% vs. 12%, p=0.07) in IgM amyloid patients. In the kappa group, KV4-01 (11% vs. 4%, p=0.04) was more common in patients with IgM amyloidosis. Correlation Between IGVL Gene usage and Clinical Features: IGVL gene usage correlated with disease characteristics and differences in the clinical presentation of patients across the two groups. LV2-14 was more commonly seen in IgM amyloid patients (above). It has been previously associated with a higher frequency of peripheral nerve involvement (Kourelis et al. Blood 2017), which was more frequent in IgM group. LV2-14 is also associated with low dFLC levels, which were noted to be lower in the IgM AL cohort. LV1-44 has been associated with higher likelihood of cardiac involvement. LV1-44 was seen less frequently in the IgM amyloid patients, who also had lower rates of cardiac involvement. LV6-57 has been historically associated with higher rates of t(11;14). It was less common in IgM AL patients, who also had lower rates of t(11;14). Conclusions: IGVL gene usage differed significantly in patients with IgM vs. non-IgM amyloidosis, correlating with differences in disease characteristics and organ involvement. This is the first study to our knowledge to report IGVL gene usage differences in IgM vs. non-IgM AL amyloidosis. Differences in IGVL gene usage may explain the distinct clinical presentation seen in IgM amyloidosis, the biology of which has so far remained poorly understood. *SS and SD contributed equally Disclosures Dasari: The Binding Site: Patents &amp; Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Dispenzieri:Alnylam: Research Funding; Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Akcea: Consultancy; Intellia: Consultancy. Murray:The Binding Site: Patents &amp; Royalties: US Patent Rights on Mass Spectroscopy Licensing agreement with The Binding Site, Research Funding. Kumar:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Research Funding. Gertz:Prothena: Honoraria; Alnylam: Honoraria; Ionis: Honoraria; Janssen: Honoraria; Spectrum: Honoraria, Research Funding; Celgene: Honoraria.

Cardiac biomarkers are prognostic in systemic light chain amyloidosis with no cardiac involvement by standard criteria.

Patients with systemic immunoglobulin light chain amyloidosis (AL) with no evidence of cardiac involvement by consensus criteria have excellent survival, but 20% will die within 5 years of diagnosis and prognostic factors remain poorly characterised. We report the outcomes of 378 prospectively followed Mayo stage I patients (N-terminal pro b-type natriuretic peptide <332 ng/L, high sensitivity cardiac troponin <55 ng/L). The median presenting N-terminal pro b-type natriuretic peptide was 161 ng/L, high sensitivity cardiac troponin 10 ng/L, creatinine 76 μmol/L and mean left ventricular septal wall thickness, 10 mm. Median follow up was 42 (1-117 months), with 71 deaths; median overall survival was not reached (78% survival at 5 years). Although no patients had cardiac involvement by echocardiogram, a proportion (n=25/90, 28%) had cardiac involvement by cardiac magnetic resonance imaging. Age, autonomic nervous system involvement, N-terminal pro b-type natriuretic peptide >152 ng/L, high sensitivity cardiac troponin >10 ng/L and cardiac involvement by magnetic resonance imaging were predictive for survival; on multivariate analysis only N-terminal pro b-type natriuretic peptide >152 ng/L (P<0.008, hazard ratio [HR] 3.180, confidence interval [CI]: 1.349-7.495) and cardiac involvement on magnetic resonance imaging (P=0.026, HR=5.360, CI: 1.219-23.574) were prognostic. At 5 years, 70% of patients with N-terminal pro b-type natriuretic peptide >152 ng/L were alive. In conclusion, N-terminal pro b-type natriuretic peptide is prognostic for survival in patients with no cardiac involvement by consensus criteria and cardiac involvement is detected by magnetic resonance imaging in such cases. This suggests that N-terminal pro b-type natriuretic peptide thresholds for cardiac involvement in AL may need to be redefined.

Assessing severity of involvement of autonomic functions in iron-deficiency anemia patients

Background: Iron-deficiency anemia (IDA) is one of the most frequently found anemias in all countries. In India itself, 60–70% of population has IDA. Autonomic dysfunctions are common in anemias so also in IDAs. The present study was conducted to categorize these autonomic dysfunctions according to severity. Aims and Objective: The objective of the present study was to find if there are any autonomic dysfunctions in IDA patients and to assess the severity of autonomic dysfunction in IDA patients. Materials and Methods: A total of 60 patients of IDA were selected from hematology OPD and included in the study. The patients were subjected to autonomic function tests, and the results of the test were compared with age and socioeconomically matched healthy subjects. Results: Comparing the pattern of involvement of autonomic nervous system in IDA patients and the severity of autonomic dysfunction, it was seen that 13 (22%) had normal functions, early involvement was seen in 17 (28%) IDA patients, definite involvement is seen in 22 (37%) patients, and 5 (8%) had severe involvement, while remaining 3 (5%) had atypical involvement. Conclusion: Autonomic dysfunction manifests in IDA patients. This autonomic dysfunction may vary from early involvement to severe involvement. Severe autonomic dysfunction may even cause death in some cases.

Heart rate variability in juvenile systemic lupus erythematosus patients.

Başaran Ö, Çetin İİ, Aydın F, Uncu N, Çakar N, Ekici F, Çelikel Acar B. Heart rate variability in juvenile systemic lupus erythematosus patients. Turk J Pediatr 2019; 61: 733-740. Although neurological involvement has been well recognized in patients with systemic lupus erythematosus (SLE), autonomic nervous system (ANS) involvement has rarely been studied, and has shown conflicting results. The aim of this study was to evaluate the ANS functions by using heart rate variability (HRV) in juvenile patients with SLE. Sixteen juvenile-onset SLE patients and 16 healthy controls were enrolled in the study. All participants underwent 24-hour Holter electrocardiogram monitoring and HRV indices were assessed. The SLE disease activity index (SLEDAI) score was used to assess the disease activity. We analyzed the correlation between disease duration, the SLEDAI score, and the HRV domains. Overall HRV was diminished in patients with SLE compared to controls. There were negative correlations between day and night RMSSD (root-mean-square of the successive normal sinus NN interval differences) and PNN50 (percentage of successive normal sinus NN intervals > 50 ms) values, and SLEDAI (r= -0.588 p=0.017; r= - 0.607 p= 0.013; r= -0.498 p=0.049; r= -0.597 p=0.015, respectively). There were positive correlations between both day and night LF/HF values and SLEDAI (r=0.766 p=0.001; r=0.635 p=0.008, respectively). The results suggest that autonomic dysfunction exists in juvenile patients with SLE. As these children are at increased risk for cardiovascular disease, they need to be assessed for the development of autonomic dysfunction.