Rhabdomyolysis due to rosuvastatin in a patient with ROHHAD syndrome.

We report a 13-year-old female with rapid-onset obesity, hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) syndrome, panhypopituitarism, dyslipidemia, type 2 diabetes mellitus, and nonalcoholic fatty liver disease, who developed rhabdomyolysis and acute kidney injury, two weeks after switching from lovastatin to rosuvastatin. She had been on lovastatin for eight years without any adverse effects.

Attenuation of Cardiac Autonomic Neuropathy by Escin in Diabetic Rats.

Cardiac autonomic neuropathy (CAN) is a least diagnosed complication of diabetes. Inflammation and oxidative stress play a crucial role in the pathophysiology of cardiomyopathy and neuropathy. Escin has anti-inflammatory activity and antioxidant activity. Hence, the present study was designed to evaluate the effect of escin in the management of CAN. Diabetes was induced in Sprague Dawley rats with streptozotocin (STZ). Diabetic animals were randomized in different groups after 6 weeks. Animals in the diabetic control group received no treatment, while animals in other groups received escin at dose 5, 10, and 20 mg/kg for 4 weeks. One group was kept as normal control. Various parameters like basic hemodynamic parameters, heart rate variability (HRV), oxidative stress parameters, and matrix metalloproteinase 9 (MMP-9) were assessed at the end of study. Escin significantly normalized hemodynamic parameters and HRV as compared to diabetic animals. Escin significantly reduced the malondialdehyde level and significantly increased reduced glutathione, catalase and superoxide dismutase levels in diabetic animals. Escin treatment significantly reduced plasma MMP-9 level in diabetic rats. The improvement in the studied parameters was found mainly with administration of higher doses of escin (10 and 20 mg/kg). The escin treatment mitigates CAN in diabetic rats. The results of study indicate that escin can be useful option for management of CAN.

Transdermal opioid patch in treatment of paroxysmal autonomic instability with dystonia with multiple cerebral insults: A case report.

RATIONALE: Paroxysmal autonomic instability with dystonia (PAID) is an underdiagnosed syndrome that describes a collection of symptoms following diverse cerebral insults, such as traumatic brain injury, hydrocephalus, hemorrhagic stroke, or brain anoxia. It is manifested by systemic high blood pressure, hyperthermia, tachycardia, tachypnea, diaphoresis, intermittent agitation, and certain forms of dystonia. PATIENT CONCERNS: A semi-comatose 46-year-old man was transferred from the regional rehabilitation hospital with various complaints involving fluctuating vital signs, including uncontrolled hyperthermia, hypertension, tachycardia, and tachypnea, and dystonia in all extremities. The patient underwent brain surgery for astrocytoma in 1996. The patient also had a history of first ischemic stroke on the basal ganglia in 2008 and a second one in the same area in 2017. DIAGNOSIS: The laboratory, electrocardiography, and radiologic findings were normal. Brain imaging indicated an old infarction on the basal ganglia with hydrocephalus. Tractography using diffusion tensor imaging showed discontinuity of multiple tracts, and electrophysiologic tests, such as evoked potentials, displayed an absent response. Based on the dysautonomic symptoms and brain evaluations, the physiatrist diagnosed the patient with PAID. INTERVENTIONS: Bromocriptine, propranolol, and clonazepam were administered sequentially, but autonomic instability persisted. Then, intravenous opioid was administered, and fluctuations in body temperature, heart rate, and respiratory rate, as well as decerebrate-type dystonia were improved. However, simultaneously, drug-induced severe hypotension developed (systolic blood pressure, 57 mm Hg). Subsequently, a transdermal opioid (fentanyl) patch for PAID was applied once every 3 days. OUTCOMES: Ultimately, all vital signs and dystonia were managed without further complications, and the patient was discharged. LESSONS: A patient diagnosed with PAID following multiple cerebral insults was observed, whose condition was controlled by application of opioid patch rather than by intravenous or oral routes. A transdermal opioid patch, such as fentanyl patch, can thus be effective in the treatment of patients with PAID following multiple cerebral insults.

Approach to the Patient: Perioperative Management of the Patient with Pheochromocytoma or Sympathetic Paraganglioma.

Pheochromocytomas and sympathetic paraganglioma (PPGL) are rare chromaffin cell tumors originating in the adrenal medulla and sympathetic paraganglia, respectively, which share the capacity to synthesize and release catecholamines. The incidence of PPGL has increased in recent years. Surgical resection is the only curative treatment for PPGL. Management of patients with PPGL is complex and should be done by a specialized multidisciplinary team in centers with broad expertise. Surgical resection of a PPGL is a high-risk procedure for which optimal pretreatment with antihypertensive drugs is required in combination with state-of-the-art surgical procedures and anesthesiological techniques. In this article we discuss the underlying evidence and the pros and cons of presurgical medical preparation. Finally, the areas of uncertainty and controversies in this field are addressed.

Behçet's Disease with Severe Autonomic Disorders Developing after Herpes Zoster.

A 58-year-old Japanese woman with herpes zoster developed Behçet's disease (BD) with symptoms including orthostatic intolerance as an autonomic disorder. Multiple immune-suppressive therapies and a ß-blocker successfully controlled both the disease activity of BD and the autonomic disorders. A cytokine multiplex analysis of her serum revealed the elevation of proinflammatory cytokines [interleukin (IL)-1, IL-6, IL-12, tumor necrosis factor alfa (TNFα), and interferon gamma (IFN-γ)] and a low IL-10 concentration. IL-10 production is reported to be important for defense against herpes zoster virus (VZV). Insufficient IL-10 production is reported in BD. The reactivation of VZV with this cytokine profile suggests that BD will develop with various symptoms, including severe autonomic disorders.

Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis.

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, - 7.5; 95% CI: - 11.9, - 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, - 1.1; - 1.8, - 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; - 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, - 0.3; - 0.5, - 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, - 5.3; 95% CI: - 7.9, - 2.7) and individual domains, orthostatic intolerance (- 4.6; - 6.3, - 2.9) and gastrointestinal symptoms (- 0.8; - 1.5, - 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.

Neurogenic Fever in Severe Traumatic Brain Injury Treated with Propranolol: A Case Report.

The causes of intractable fever in severe traumatic brain injury (TBI) patients can be diverse. Neurogenic fever (NF) which is a rare entity can develop due to autonomic dysregulation in the absence of infection or any other cause of fever. It manifests as fever, tachycardia, paroxysmal hypertension, dilated pupils, tachypnea, and extensor posturing in cases of severe TBI, brain neoplasms or brain haemorrhage. We found propranolol to be effective in controlling many of the manifestations of neurogenic fever in our patients with severe TBI. Fever in severe TBI patients is not an uncommon phenomenon, but when intractable with negative fever workup, a central cause should be considered. Propranolol is deemed as one of the most efficacious drugs for managing NF due to dysautonomia. We want to apprise the readers about this entity and its treatment with beta-blockers.

Neurovascular compression syndrome of the brain stem with opsoclonus-myoclonus syndrome combined with vestibular paroxysmia and autonomic symptoms.

We describe a rare case of neurovascular compression syndrome (NVCS) of the brain stem and opsoclonus-myoclonus syndrome (OMS) complicated with vestibular paroxysmia (VP) and autonomic symptoms. Moreover, we discuss the case with respect to the available information in medical literature. A 36-year-old man with vertigo and nausea had difficulty standing, and was transported by an ambulance to our hospital. He had VP, opsoclonus, cervical myoclonus, anxiety, and restless legs syndrome. Magnetic resonance imaging at hospitalization showed that the dolichoectatic vertebral artery was in contact with the postero-lateral side of the pontomedullary junction. He was diagnosed with NVCS of the brain stem (most likely of the input to the vestibular nucleus) associated with contact with the dolichoectatic vertebral artery. Combination therapy using multiple antiepileptic drugs, such as low-dose carbamazepine, clonazepam, and lacosamide, improved his clinical symptoms. He was finally able to walk and was discharged on day 42 after admission. He is being routinely followed-up since then. Further research is needed to confirm the validity of the combination therapy.

Tafamidis for autonomic neuropathy in hereditary transthyretin (ATTR) amyloidosis: a review.

PURPOSE: Autonomic dysfunction is a very common, early and distressing aspect of hereditary transthyretin (ATTR) amyloidosis leading to significant loss of quality of life and morbidity for patients. Although the clinical variability of ATTR has been well characterized as neuropathic, cardiac or mixed phenotype, the extent of autonomic involvement remains poorly understood. Despite the fact that the autonomic nervous system has not been specifically evaluated in any of the clinical trials of tafamidis, and that, for some primary and secondary endpoints used in these trials, the behavior cannot be separated from non-autonomic items, an attempt was made to use published material to indirectly access the efficacy of tafamidis in treating dysautonomia. METHODS: Literature review summarizing the results of primary and secondary endpoints related to the autonomic features used in the original tafamidis trials, the post hoc publications, and real-world data, on the effect of tafamidis on autonomic dysfunction in patients with ATTR amyloidosis. RESULTS: There is some evidence that indirectly demonstrates that tafamidis is safe and could slow or arrest the progression of autonomic neuropathy in patients with ATTR amyloidosis, in addition to its well-described effects to ameliorate sensory-motor peripheral neuropathy. CONCLUSION: Although the current evidence is scarce, tafamidis might be effective in arresting the progression of autonomic neuropathy in patients with ATTR amyloidosis. Tafamidis might be more effective at the early stage of the disease; however, individual responses must be monitored.

Novel RNA-targeted therapies for hereditary ATTR amyloidosis and their impact on the autonomic nervous system.

PURPOSE: Transthyretin-mediated hereditary amyloidosis (hATTR amyloidosis) is a multisystemic disease with heterogeneous clinical presentation. Hallmarks of the disease are sensory-motor and autonomic neuropathy and cardiomyopathy. Two disease-modifying drugs, inotersen (an antisense oligonucleotide) and patisiran (a small interfering RNA agent), were recently approved for the treatment of hATTR polyneuropathy. We here review the results of the RNA-targeted therapy clinical trials with special emphasis on the endpoints measuring autonomic symptoms and function. METHODS: Literature review. We used the terms "autonomic neuropathy", "dysautonomia", "autonomic symptoms", "oligonucleotides", "inotersen" and "patisiran" in patients with hATTR amyloidosis. RESULTS: In the NEURO-TTR (inotersen) clinical trial, the modified NIS+7 score (mNIS+7) remained stable in 36% of the patients in the inotersen arm (defined as a change of less than 2 points), and 50% of patients had improved quality of life (Norfolk-QOL-DN score) after 15 months. In the APOLLO patisiran trial, 74% of the patients showed stabilization of the neuropathy, defined as a < 10 points increase on mNIS+7, and 51% of patients showed an improvement of quality of life (Norfolk QOL-DN), favoring patisiran at 18 months. Patients on patisiran had a reduced burden of autonomic dysfunction as measured by the COMPASS-31, and a stabilization of nutritional status, suggesting an effect on gastrointestinal autonomic function. CONCLUSIONS: Clinical trials of inotersen and patisiran showed that these agents were able to halt the progression of the disease, with some patients even reducing the burden of polyneuropathy, and improving qualify of life. The information on their impact on autonomic parameters is limited, warranting further dedicated studies.

Treatment of Menopausal Vasomotor Symptoms With Fezolinetant, a Neurokinin 3 Receptor Antagonist: A Phase 2a Trial.

CONTEXT: The thermoregulatory center in the hypothalamus is stimulated by neurokinin 3 receptor (NK3R) activation and inhibited by estrogen-negative feedback. This balance is disrupted in menopause, producing vasomotor symptoms (VMSs). OBJECTIVE: To evaluate safety and efficacy of the NK3R antagonist fezolinetant in menopausal VMSs. DESIGN: Twelve-week, double-blind, randomized, placebo-controlled study. SETTING: Eight Belgian centers from September 2015 to October 2016. PARTICIPANTS: Generally healthy menopausal women aged 40 to 65 years with moderate/severe VMSs. INTERVENTIONS: Subjects were randomized (1:1) to 90 mg of fezolinetant twice daily or placebo for 12 weeks. MAIN OUTCOME MEASURES: Subjects captured VMS severity and frequency using an electronic diary. The primary outcome was change from baseline to week 12 in total VMS score with fezolinetant vs placebo. Secondary outcomes included timing of changes in frequency and severity of moderate/severe VMSs and quality-of-life assessments at weeks 4, 8, and 12. Pharmacodynamic and pharmacokinetic effects were assessed, as were safety and tolerability. RESULTS: Of 122 subjects screened, 87 were randomized and 80 (92%) completed the study. At week 12, fezolinetant significantly reduced total VMS score vs placebo (-26.5 vs -12.2, P < 0.001) and decreased mean frequency of moderate/severe VMSs by five episodes per day vs placebo. Severity and frequency of moderate/severe VMSs were reduced from the first day of treatment. Improvements were achieved in all quality-of-life measures. Fezolinetant was well tolerated. The most common fezolinetant-related adverse event was gastrointestinal disorder (n = 6). CONCLUSIONS: Fezolinetant rapidly and significantly reduced moderate/severe VMSs, supporting its potential as an effective nonhormonal treatment option for menopausal women.

Neurological autoimmune disorders with prominent gastrointestinal manifestations: A review of presentation, evaluation, and treatment.

BACKGROUND: The identification of autoantibodies directed against neuronal antigens has led to the recognition of a wide spectrum of neurological autoimmune disorders (NAD). With timely recognition and treatment, many patients with NAD see rapid improvement. Symptoms associated with NAD can be diverse and are determined by the regions of the nervous system affected. In addition to neurological symptoms, a number of these disorders present with prominent gastrointestinal (GI) manifestations such as nausea, diarrhea, weight loss, and gastroparesis prompting an initial evaluation by gastroenterologists. PURPOSE: This review provides a general overview of autoantibodies within the nervous system, focusing on three scenarios in which nervous system autoimmunity may initially present with gut symptoms. A general approach to evaluation and treatment, including antibody testing, will be reviewed.

Clinical Problem Solving: A Tobacco Merchant Who Can't Spit.

BACKGROUND: A 47 year old man presented with a combination of dry mouth and lightheadedness while standing. His medical background was unremarkable except for cigarette smoking and hyperlipidemia. Sjögren's syndrome was ruled out, and he was referred for evaluation of orthostatic hypotension, which by then included syncopal episodes and injuries. Additional symptoms included dry eyes, constipation, reduced sweating, and erectile dysfunction. After excluding medications and structural cardiac abnormalities as causes of orthostatic hypotension, a clinical autonomic evaluation was performed. The pattern of beat-to-beat blood pressure associated with performance of the Valsalva maneuver, and a low plasma norepinephrine level that did not increase in response to standing, established that the orthostatic hypotension was neurogenic. Treatment with an alpha-adrenoceptor agonist and fludrocortisone yielded partial improvement. After systemic diseases involving autonomic failure were excluded, cardiac sympathetic neuroimaging was performed by 123I-metaliodobenzylguanidine (MIBG) scanning. The normal uptake seen in the heart indicated intact post ganglionic sympathetic innervation. There were no signs of central neurodegeneration or peripheral neuropathy. Because of symptoms and signs of both parasympathetic and sympathetic failure without denervation, an autonomic ganglionopathy was considered. A high titer of antibody to the neuronal nicotinic receptor, which mediates ganglionic neurotransmission, was obtained. The diagnosis of autoimmune autonomic ganglionopathy (AAG) was made, and the management strategy shifted to first lowering the antibody burden by plasma exchanges and then instituting chronic anti-autoimmune treatment with rituximab and a low dose of cortiosteroid. The patient showed remarkable improvement.

Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study.

OBJECTIVE: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45 mg (n = 230) or transdermal estradiol (t-E2) 50 µg (n = 225; both with micronized progesterone 200 mg for 12 d each mo), or placebos (PBOs; n = 275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P < 0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P = 0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P = 0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

Improved Behavior and Neuropsychological Function in Children With ROHHAD After High-Dose Cyclophosphamide.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation.

A Chinese Decoction, Kuan-Sin-Yin, Improves Autonomic Function and Cancer-Related Symptoms of Metastatic Colon Cancer.

BACKGROUND: Kuan-Sin-Yin (KSY) is a traditional Chinese medicine (TCM) decoction, which has been shown to have cytostatic effects on cancer cells and involved in the TCM theory of promoting yin-yang balance.Sonce many cancer patients suffer from autonomic dysfunction (AD), which correspond to yin-yang imbalance in TCM. The aim of this study is to evaluate the possible effect of KSY in metastatic colon cancer (mCRC) patients with AD. METHODS: We conducted a single-group experiment. Total 52 qualified patients were enrolled. Participants took the KSY daily for 2 weeks. The primary outcome was KSY efficacy as reflected in the heart rate variability (HRV) and electrical conductivity (µA) over 12 meridian points. Autonomic function was examined before and after the KSY intervention. The vagal and sympathetic tone were recorded by HRV; 12 meridian energies were measured using a meridian energy analysis device. Secondary outcomes were cancer-related symptoms and patient quality of life (QoL). RESULTS: The results showed that the KSY intervention improved AD via increasing the vagal tone (HF: P = .041), but not the sympathetic tone (LF: P = .154); total autonomic activity was significantly enhanced (HRV activity: P = .013). Intriguingly, energy increased more over the yin meridian (P = .010) than over the yang meridian (P = .015). Cancer-related symptoms and QoL were significantly improved (P < .05). CONCLUSION: The safety and effectiveness of KSY in improving AD in mCRC patients are through regulating the vagal-sympathetic dynamic balance, which correspond to the TCM yin-yang concept of energy.

Catecholamine excess: pseudopheochromocytoma and beyond.

Symptoms of catecholamine excess or pseudopheochromocytoma can be clinically indistinguishable from pheochromocytoma. Patients usually present with paroxysmal or episodic hypertension and have a negative evaluation for pheochromocytoma. It is important to exclude other causes of catecholamine excess that can be induced by stress, autonomic dysfunction due to baroreflex failure, medications, and drugs. Patients with pseudopheochromocytoma appear to have an amplified cardiovascular responsiveness to catecholamines with enhanced sympathetic nervous stimulation. The exact mechanism is not well understood and increased secretion of dopamine, epinephrine, and norepinephrine, and their metabolites have been identified as potentiating this clinical scenario leading to differing hemodynamic presentations depending on which catecholamine is elevated. Management of this condition is often difficult and frustrating for both the physician and the patient. Most patients respond reasonably well to medications that reduce sympathetic nervous system activity. Anxiolytics, antidepressants, and psychotherapy also play an important role in managing these patients' symptoms.

Exacerbation of SUNCT and SUNA syndromes during intravenous dihydroergotamine treatment: A case series.

BACKGROUND: The management of short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and with short-lasting unilateral neuralgiform headache attacks with autonomic symptoms (SUNA) remains challenging in view of the limited understanding of their pathophysiological mechanisms. METHODS: An initial observation that patients with both chronic migraine (CM) or cluster headache (CH) and SUNCT/SUNA receiving intravenous dihydroergotamine (IV DHE) had complained of dramatic worsening of the latter led to review of the case notes of patients with CM or CH and co-existent SUNCT/SUNA seen between 2008 and 2013 and who had a trial of IV DHE. RESULTS: Twenty-four patients were identified. IV DHE was ineffective for SUNCT/SUNA in 16 patients, while one patient reported a marginal improvement. Five patients reported dramatic worsening of the SUNCT/SUNA. Moreover, two patients developed new-onset SUNA during their first IV DHE infusion. Out of these seven patients, those requiring repeated courses of IV DHE consistently experienced exacerbations of SUNCT/SUNA which were suppressed with IV lidocaine. CONCLUSIONS: DHE is an ineffective treatment option for SUNCT and SUNA. Physicians who intend to offer IV DHE to CH or CM patients should warn them that IV DHE could exacerbate and possibly even lead to a de novo onset of SUNCT/SUNA. In view of the reported worsening or new onset of SUNCT/SUNA in patients using dopamine agonists for the treatment of pituitary prolactinomas, we speculate that DHE might worsen or induce SUNCT and SUNA, at least in a sub-group of patients, through a perturbation in the dopaminergic system.

Interleukin-6 blockade improves autonomic dysfunction in rheumatoid arthritis.

Autonomic nervous system (ANS) involvement in rheumatoid arthritis (RA) is well recognised and contributes to arrhythmia and sudden death. However, there is no study documented the therapeutic efficacy on autonomic neuropathy (AN) in RA. This is the first reported observation of improvement in AN with interleukin-6 (IL-6) blockade with tocilizumab in RA. We report a case of 61-year old female with seropositive RA with severe disease activity, investigated for autonomic neuropathy. A battery of non invasive tests was used for accurate assessment of AN function based on assessment of peripheral sympathetic autonomic function and cardiovascular reflex tests. Tocilizumab 8 mg/kg intravenous infusion at weeks 0, 4 and 8 was added to her treatment regimen. Cardiovascular autonomic function tests at baseline showed marked abnormalities of parasympathetic cardiovascular reflexes. After the first dose of tocilizumab there was a rapid improvement with normalization of parasympathetic autonomic activity with subsequent doses. IL-6 blockade with tocilizumab seems to have the potential to improve the vagus nerve mediated parasympathetic neuropathy and hence has the potential to restore cholinergic anti-inflammatory pathway.

Efficacy of diflunisal on autonomic dysfunction of late-onset familial amyloid polyneuropathy (TTR Val30Met) in a Japanese endemic area.

OBJECTIVE: To evaluate the long-term efficacy and safety of diflunisal in late-onset familial amyloid polyneuropathy (FAP) in a Japanese endemic area. METHODS: Consecutive six FAP patients (mean age: 65.8 ± 7.3 years) with a transthyretin (TTR) Val30Met mutation from an endemic area of late-onset FAP were prospectively recruited to an open label study with oral diflunisal (250 mg twice a day). We evaluated clinical symptoms, Kumamoto FAP score, modified body mass index (mBMI), Medical Research Council sum score, nerve conduction studies (NCS), electrocardiogram (ECG), ECG Holter monitor test, echocardiography, and (123)iodine-metaiodobenzylguanidine ((123)I-MIBG) myocardial scintigraphy. RESULTS: One patient ceased to take diflunisal because of hematuria which was reversible. The other five patients were treated with diflunisal for 3-5 (4.4 ± 0.9 years) years. Autonomic symptoms (orthostatic hypotension and gastrointestinal symptoms) disappeared after treatment in two of the four patients with the symptoms. Delayed heart to mediastinum ratio on (123)I-MIBG imaging, a marker of cardiac postganglionic sympathetic nerve function, increased during the three-year treatment. mBMI was maintained through observation period. While, motor and sensory symptoms, Kumamoto FAP scores, and data on NCS gradually deteriorated. CONCLUSION: Diflunisal might be effective especially for autonomic dysfunction in late-onset FAP with a TTR Val30Met mutation.