Autonomic Features Research Articles

The Diagnosis and Natural History of Multiple System Atrophy, Cerebellar Type.

The objective of this study was to identify key features differentiating multiple system atrophy cerebellar type (MSA-C) from idiopathic late-onset cerebellar ataxia (ILOCA). We reviewed records of patients seen in the Massachusetts General Hospital Ataxia Unit between 1992 and 2013 with consensus criteria diagnoses of MSA-C or ILOCA. Twelve patients had definite MSA-C, 53 had possible/probable MSA-C, and 12 had ILOCA. Autonomic features, specifically urinary urgency, frequency, and incontinence with erectile dysfunction in males, differentiated MSA-C from ILOCA throughout the disease course (p = 0.005). Orthostatic hypotension developed later and differentiated MSA-C from ILOCA (p < 0.01). REM sleep behavior disorder (RBD) occurred early in possible/probable MSA-C (p < 0.01). Late MSA-C included pathologic laughing and crying (PLC, p < 0.01), bradykinesia (p = 0.01), and corticospinal findings (p = 0.01). MRI distinguished MSA-C from ILOCA by atrophy of the brainstem (p < 0.01) and middle cerebellar peduncles (MCP, p = 0.02). MSA-C progressed faster than ILOCA: by 6years, MSA-C walker dependency was 100% and ILOCA 33%. MSA-C survival was 8.4 ± 2.5years. Mean length of ILOCA illness to date is 15.9 ± 6.4years. A sporadic onset, insidiously developing cerebellar syndrome in midlife, with autonomic features of otherwise unexplained bladder dysfunction with or without erectile dysfunction in males, and atrophy of the cerebellum, brainstem, and MCP points strongly to MSA-C. RBD and postural hypotension confirm the diagnosis. Extrapyramidal findings, corticospinal tract signs, and PLC are helpful but not necessary for diagnosis. Clarity in early MSA-C diagnosis can prevent unnecessary investigations and facilitate therapeutic trials.

Epilepsy is a possible feature in Williams‐Beuren syndrome patients harboring typical deletions of the 7q11.23 critical region

Seizures are rarely reported in Williams-Beuren syndrome (WBS)--a contiguous-gene-deletion disorder caused by a 7q11.23 heterozygous deletion of 1.5-1.8 Mb--and no previous study evaluated electro-clinical features of epilepsy in this syndrome. Furthermore, it has been hypothesized that atypical deletion (e.g., larger than 1.8 Mb) may be responsible for a more pronounced neurological phenotypes, especially including seizures. Our objectives are to describe the electro-clinical features in WBS and to correlate the epileptic phenotype with deletion of the 7q11.23 critical region. We evaluate the electro-clinical features in one case of distal 7q11.23 deletion syndrome and in eight epileptic WBS (eWBS) patients. Additionally, we compare the deletion size-and deleted genes-of four epileptic WBS (eWBS) with that of four non-epileptic WBS (neWBS) patients. Infantile spasms, focal (e.g., motor and dyscognitive with autonomic features) and generalized (e.g., tonic-clonic, tonic, clonic, myoclonic) seizures were encountered. Drug-resistance was observed in one patient. Neuroimaging discovered one case of focal cortical dysplasia, one case of fronto-temporal cortical atrophy and one case of periventricular nodular heterotopia. Comparison of deletion size between eWBS and neWBS patients did not reveal candidate genes potentially underlying epilepsy. This is the largest series describing electro-clinical features of epilepsy in WBS. In WBS, epilepsy should be considered both in case of typical and atypical deletions, which do not involve HIP1, YWHAG or MAGI2.

Hemicrania continua and unilateral headaches: are they still together in the IHS classification?

Sjaastad & Spierings described “Hemicrania continua” (HC) in 1984[1]. In 2001, succinct criteria were presented[2]: permanent hemicrania, pain intensity: mild-moderate, (but occasionally - severe) and indomethacin dosage < 150 mg daily. In addition, relative shortage of “local” autonomic phenomena, relative lack of “migraine symptoms” and of “cervicogenic” features. Such patients generally had tried legion drugs, with little effect. Such trials equal the usage of placebo. These guidelines seemed to function close to optimally. Then, criteria of the International Headache Society (IHS) (ICHD-III beta classification) came along. Surprisingly, they were transferred from a recent review article by Goadsby[3], almost word by word, despite the existence of a committee of intelligent and knowledgeable colleagues. There is an abundance of failures in the actual scheme. It is unacceptable to include as mandatory criteria, facial/forehead autonomic features. In this way, e.g. sweating becomes prominent - 33%, against a subjective feeling of sweating in only 6% of our series (ratio: 5.5). Objectively, by quantitative evaporimetry, there was no facial asymmetry in all our 8 cases. There were 12 autonomic phenomena in this category[3], with a mean ratio between Goadsby's/our figures of 4.4. When made mandatory, autonomic features will create bogus cases. Bogus cases necessitate ultra-high indomethacin dosages; such dosages have an unspecific, analgesic effect, on various headaches. Our mean indomethacin continuation dosage was: 83 mg (range: 50-150), while in Goadsby's series it was 176 mg (25-500). HC is the unilateral headache with the least “local” autonomic features, “migrainous” and “vascular” components. It is a rather “pure” headache. The present classification brings HC nearer to other unilateral headaches with local autonomic symptoms, a misunderstood policy. CPH is exceptional with clinical similarities; the absolute indomethacin effect suggests a shared, core pathogenesis.

O073. Proposal guidelines for epilepsy and headache.

Background Headache and epilepsy are two paroxysmal disorders with epidemiological and clinical comorbidity. Among the primary headaches, migraine, and in particular the subtype with aura (MA) has a significant correlation with epilepsy. Like epilepsy MA is a chronic condition characterized by recurrent focal neurological attacks that are variously accompanied by headache and inconstant autonomic features. Interictal electroencephalogram (EEG) findings are usually normal although several abnormalities, especially diffuse slowings, have been reported in migraineurs. EEG is not useful in MA with the exception of situations where seizure disorders are to be excluded. The relationship between headaches and epilepsy is covered in the International Classification of Headache Disorders in chapters 1 and 7 where migraine-triggered seizure (1.4.4), hemicrania epileptica (7.6.1) and post-ictal headache (7.6.2) are collocated. An interictal headache was defined as headache starting not earlier than three hours after a seizure or a headache never proceeding directly into an epileptic fit. Headache caused by an epileptic seizure, occurring during and/or after the seizure and remitting spontaneously within hours or up to 3 days [1,2]. The classification of the International League against Epilepsy does not refer to this type of disorder. In the last decade other terms for this association have been proposed (epileptic headache or ictal epileptic headache) and some Authors have proposed to abandon or modify some terms (hemicrania epileptica and migralepsy) [3-5].

Clinical features and autonomic testing predict survival in multiple system atrophy.

Multiple system atrophy is characterized by autonomic failure along with motor symptoms of parkinsonism and/or cerebellar ataxia. There are differing reports on the influence of certain clinical features, including motor subtype (multiple system atrophy-parkinsonism versus multiple system atrophy-cerebellar ataxia), age of onset, gender, and early autonomic symptoms, on the survival in patients with multiple system atrophy. We sought to evaluate overall survival and predictors of survival in a large cohort of patients with multiple system atrophy seen at a single referral centre where objective autonomic testing is routinely performed for this indication. All cases of multiple system atrophy evaluated at Mayo Clinic, Rochester and assessed with an autonomic reflex screen between January 1998 and December 2012 were retrospectively reviewed. A total of 685 patients were identified; 594 met criteria for probable multiple system atrophy, and 91 for possible multiple system atrophy. Multiple system atrophy-parkinsonism was the predominant subtype in 430 patients (63%). Average age of onset was earlier in multiple system atrophy-cerebellar ataxia (58.4 years) compared to multiple system atrophy-parkinsonism (62.3 years; P < 0.001). Median disease duration from symptom onset to death was 7.51 years (95% confidence interval 7.18-7.78) while time from diagnosis to death was 3.33 years (95% confidence interval 2.92-3.59). There was no difference in survival between motor subtypes of multiple system atrophy (P = 0.232). An initial motor symptom was most common (61%) followed by autonomic onset (28%) and combined motor and autonomic symptoms (11%). The initial onset of either motor or autonomic symptoms did not influence length of survival. However, a number of clinical and autonomic laboratory features predicted unfavourable survival in a univariate analysis. A multivariate model retained the following unfavourable predictors of survival: (i) falls within 3 years of onset (hazard ratio 2.31, P < 0.0001); (ii) bladder symptoms (hazard ratio 1.96, P < 0.0001); (iii) urinary catheterization within 3 years of symptom onset (hazard ratio 1.67, P < 0.003); (iv) orthostatic intolerance within 1 year of symptom onset (hazard ratio 1.28, P < 0.014); (v) older age of onset (hazard ratio 1.02, P = 0.001); and (vi) degree of autonomic failure as measured by a validated composite autonomic severity score (hazard ratio 1.07, P < 0.0023). We conclude that carefully selected clinical features can be used to predict survival in patients with multiple system atrophy. Autonomic testing adds an additional, independent predictor of survival, demonstrating its value not only in the diagnosis of multiple system atrophy but also as prognostic marker.

Neurobiology and sleep disorders in cluster headache.

Cluster headache is characterized by unilateral attacks of severe pain accompanied by cranial autonomic features. Apart from these there are also sleep-related complaints and strong chronobiological features. The interaction between sleep and headache is complex at any level and evidence suggests that it may be of critical importance in our understanding of primary headache disorders. In cluster headache several interactions between sleep and the severe pain attacks have already been proposed. Supported by endocrinological and radiological findings as well as the chronobiological features, predominant theories revolve around central pathology of the hypothalamus. We aimed to investigate the clinical presentation of chronobiological features, the presence of concurrent sleep disorders and the relationship with particular sleep phases or phenomena, the possible role of hypocretin as well as the possible involvement of cardiac autonomic control. We conducted a questionnaire survey on 275 cluster headache patients and 145 controls as well an in-patient sleep study including 40 CH-patients and 25 healthy controls. The findings include: A distinct circannual connection between cluster occurrence and the amount of daylight, substantially poorer sleep quality in patients compared to controls which was present not only inside the clusters but also outside, affected REM-sleep in patients without a particular temporal connection to nocturnal attacks, equal prevalence of sleep apnea in both patient and control groups, reduced levels of hypocretin-1 in the cerebrospinal fluid of patients and finally a blunted response to the change from supine to tilted position in the head-up tilt table test indicating a weakened sympathoexcitatory or stronger parasympathetic drive. Overall, these findings support a theory of involvement of dysregulation in hypothalamic and brainstem nuclei in cluster headache pathology. Further, it is made plausible that the headache attacks are but one aspect of a more complex syndrome of central dysregulation manifesting as sleep-related complaints, sub-clinical autonomic dysregulation and of course the severe attacks of unilateral headache. Future endeavors should focus on pathological changes which persist in the attack-free periods but also heed the possibility of long-lived, cluster-induced pathology.

Trigeminal Autonomic Cephalalgias in Children and Adolescents: Cluster Headache and Related Conditions

Cluster headache is a primary headache disorder that can occur in children and adolescents, and is a member of the broader diagnostic group of trigeminal autonomic cephalalgias. It is characterized by repeated attacks typically lasting between 15 and 180 minutes of severe unilateral side-locked headache with cranial autonomic features. Acute treatment of the cluster attack can include the use of triptans or high-flow oxygen. Preventive measures typically start with the use of verapamil. The other trigeminal autonomic cephalalgias, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT), and short-lasting unilateral neuralgiform headache with cranial autonomic features (SUNAA), have also been reported in children, and should be considered when the clinical presentation is at all unusual.

AVOCLOUDY: a simulator of volunteer clouds

SummaryThe increasing demand of computational and storage resources is shifting users toward the adoption of cloud technologies. Cloud computing is based on the vision of computing as utility, where users no more need to buy machines but simply access remote resources made available on‐demand by cloud providers. The relationship between users and providers is defined by a service‐level agreement, where the non‐fulfillment of its terms is regulated by the associated penalty fees. Therefore, it is important that the providers adopt proper monitoring and managing strategies. Despite their reduced application, intelligent agents constitute a feasible technology to add autonomic features to cloud operations. Furthermore, the volunteer computing paradigm—one of the Information and Communications Technology (ICT) trends of the last decade—can be pulled alongside traditional cloud approaches, with the purpose to ‘green’ them. Indeed, the combination of data center and volunteer resources, managed by agents, allows one to obtain a more robust and scalable cloud computing platform. The increased challenges in designing such a complex system can benefit from a simulation‐based approach, to test autonomic management solutions before their deployment in the production environment. However, currently available simulators of cloud platforms are not suitable to model and analyze such heterogeneous, large‐scale, and highly dynamic systems. We propose the AVOCLOUDY simulator to fill this gap. This paper presents the internal architecture of the simulator, provides implementation details, summarizes several notable applications, and provides experimental results that measure the simulator performance and its accuracy. The latter experiments are based on real‐world worldwide distributed computations on top of the PlanetLab platform. Copyright © 2015 John Wiley &amp; Sons, Ltd.

AI Communications track on agreement technologies

The area of agreement technologies is receiving increased attention within the Artificial Intelligence research community. This is because current intelligent software applications are often based on components that are autonomous, capable of sophisticated ways of interacting, massively distributed, and quite often embedded in all sorts of appliances and sensors. These autonomous components, usually termed agents, need to be socially-aware in order to successfully achieve their goals. The important research question is how can we build software systems as collections of these components and guarantee that they interoperate correctly, and are thus reliable, especially when the components are complex, with autonomic and adaptive features, and open? One of the basic assumptions in the development of agreement technologies is that the components are independently developed and thus no a priori assumptions on their workings can be made. Correct interoperability needs to be based on a two step process: first, the establishment of explicit agreements among the entities and then the execution of those agreements. The generation of agreements requires techniques that cover the two fundamental aspects of potential disagreement: semantics and co-ordinated action, for instance, semantic alignment techniques to allow compo-

&lt;i&gt;PLA2G6&lt;/i&gt;-associated Dystonia–Parkinsonism: Case Report and Literature Review

<strong>Background:</strong> Phospholipase-associated neurodegeneration (PLAN) caused by <em>PLA2G6</em> mutations is a recessively inherited disorder with three known phenotypes: the typical infantile onset neuroaxonal dystrophy (INAD); an atypical later onset form (atypical NAD); and the more recently recognized young-onset dystonia– parkinsonism (PLAN-DP). <strong>Case Report:</strong> We report the clinical, radiological, and genetic findings of a young Pakistani male with PLAN-DP. We review 11 previously published case reports cited in PubMed, and summarize the demographic, clinical, genetic, and radiological data of the 23 patients described in those articles. <strong>Discussion:</strong> PLAN-DP presents with diverse motor, autonomic, and neuropsychiatric features and should be considered in the differential diagnosis of patients with young-onset neurodegenerative disorders.

PLA2G6-associated Dystonia-Parkinsonism: Case Report and Literature Review.

BackgroundPhospholipase-associated neurodegeneration (PLAN) caused by PLA2G6 mutations is a recessively inherited disorder with three known phenotypes: the typical infantile onset neuroaxonal dystrophy (INAD); an atypical later onset form (atypical NAD); and the more recently recognized young-onset dystonia–parkinsonism (PLAN-DP).Case ReportWe report the clinical, radiological, and genetic findings of a young Pakistani male with PLAN-DP. We review 11 previously published case reports cited in PubMed, and summarize the demographic, clinical, genetic, and radiological data of the 23 patients described in those articles.DiscussionPLAN-DP presents with diverse motor, autonomic, and neuropsychiatric features and should be considered in the differential diagnosis of patients with young-onset neurodegenerative disorders.

SUNCT/SUNA: A Review.

Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting neuralgiform headache attacks with cranial autonomic features (SUNA) are rare headache disorders characterized by severe, short-lasting headaches. These headache disorders are often refractory to treatment and can be secondary phenomena. This article reviews the history, pathophysiology, and treatment of these disorders. Both pharmacotherapy and procedural interventions are discussed in context of historical and more recent reports.

Episodic paroxysmal hemicrania with an atypical clinical presentation: a case report and review of the literature

71 Paroxysmal hemicrania (PH) is characterized by frequent, short-lasting, severe, unilateral headaches that occur in association with cranial autonomic features. The hallmarks of this syndrome are relatively short attacks and a complete therapeutic response to indomethacin. Although PH has been classified as strictly unilateral headache in association with cranial autonomic features, a few cases have been reported that suggest bilateral PH. We report a case of PH with bilateral distribution and bilateral autonomic features. PH may actually represent a clinical spectrum including different phenotypes. (Turkish Journal of Neurology 2015; 21:71-3)

Reduced Baroreflex Sensitivity in Cluster Headache Patients.

Important elements of cluster headache (CH) pathophysiology may be seated in the posterior hypothalamus. Cranial autonomic features are inherent, but involvement of systemic autonomic control is still debated. We aimed to characterize autonomic function as investigated by baroreflex sensitivity (BRS) in CH patients. Twenty-six active CH patients and an equal number of age-, sex-, and BMI-matched controls underwent head-up tilt table test and BRS was determined by the sequence method. Compared with controls, patients exhibited a blunted reactivity of RR intervals in response to falls and increases in systolic blood pressure (SBP) (15.3 vs. 20.0 ms/mmHg, P = .0041) in the supine position. Also, compared with controls, BRS was lower in patients having suffered an attack within the past 12 hours (n = 13, 12.5 vs. 22.3 ms/mmHg, P = .0091), opposed to those patients who had not (n = 13, 16.0 ms/mmHg, P = .1523). In the tilted position, the drop in SBP at the carotid sinuses was higher in patients who had recently suffered an attack. Despite this, they exhibited a less marked shortening of RR intervals when compared with patients who had been attack free for longer. CH patients exhibit a subclinical blunting of BRS that may be affected by the attacks themselves. The fast RR interval fluctuations used in this method reflects cardiovagal responses, thus the blunted responses are suggestive of dysfunction in the parasympathetic division of the autonomic nervous system or in the central relay of impulses from the baroreceptors.

Cluster headache and trigeminal autonomic cephalgias

The trigeminal autonomic cephalgias (TACs) consist of a group of primary headache disorders that share the features of relatively short-duration, unilateral headache associated with cranial autonomic features. Cranial autonomic features include signs of parasympathetic activation including lacrimation, rhinorrhea, nasal congestion, eye lid edema, and sympathetic hypofunction, ptosis and miosis. As a group, they are much less common than the other primary headache disorders, migraine and tension headache, but they are important to recognize due to the severity of the pain, frequency of attacks, and in most cases, specific treatment options are available. The group consists of cluster headache, paroxysmal hemicranias, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT).

OnabotulinumtoxinA for hemicrania continua: open label experience in 9 patients.

BackgroundHemicrania continua is a strictly unilateral, continuous headache, typically mild to moderate in severity, with severe exacerbations commonly accompanied by cranial autonomic features and migrainous symptoms. It is exquisitely responsive to Indomethacin. However, some patients cannot tolerate treatment, often due to gastrointestinal side effects. Therapeutic alternatives are limited and controlled evidence lacking.MethodsWe present our experience of nine patients treated with OnabotulinumtoxinA for hemicrania continua. All patients were injected using the PREEMPT (Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy) protocol for migraine.ResultsFive of nine patients demonstrated a 50% or more reduction in moderate to severe headache days with OnabotulinumtoxinA with a median reduction in moderate to severe headache days of 80%. Patient estimate of response was 80% or more in five subjects. The median and mean duration of response in the five responders was 11 and 12 weeks (range 6–20 weeks). Improvements were also seen in headache-associated disabilityConclusionsOnabotulinumtoxinA adds a potential option to the limited therapeutic alternatives available in hemicrania continua.

Ring 17 syndrome: first clinical report without intellectual disability.

Ring chromosomes are rare abnormalities caused by the fusion of the telomeric regions. Three-ring chromosome syndromes (Cr 20, Cr 17 and Cr 14) cause epilepsy with variable phenotypes. In ring 17 patients with mild phenotype, some authors have shown an epilepsy syndrome similar to that of ring 20. We report the first case of a girl with ring chromosome 17 and a normal neurological and general cognitive profile. She had had, from 9 years old, focal pharmacoresistant epilepsy associated with episodes of non-convulsive status epilepticus with mainly autonomic features. Cytogenetic analysis revealed an abnormal karyotype characterised by the presence of de novo ring chromosome 17 in 19% of metaphases. The array CGH (100KB) did not show any genetic deletion. The clinical and epilepsy phenotype was, to a certain degree, similar to that of ring 20 syndrome.

Myovascular innervation: axon loss in small-fiber neuropathies.

Vascular denervation occurs in some neuropathies, but measurement of small perivascular axons has been difficult. We evaluated 31 consecutive patients who had both muscle and skin biopsies. We quantitated myovascular innervation by staining unmyelinated axons with peripherin and non-myelinating Schwann cells with neural cell adhesion molecule and comparing their areas. Perivascular unmyelinated axon-Schwann (UAS) ratios correlated with axon density in skin (r = 0.679; P < 0.0001). Low UAS ratios (≤0.25) had a sensitivity of 90% and specificity of 91% for a clinical diagnosis of small-fiber neuropathy (P < 0.0001). Autonomic features were more common in patients with low perivascular UAS ratios (P = 0.002). A patient subgroup with myovascular, but not skin, denervation commonly had muscle discomfort and autonomic features. UAS ratio measurements, comparing axons and associated non-myelinating Schwann cells, can quantitate perivascular innervation. Small-fiber neuropathies are often associated with myovascular denervation. Some patients with muscle discomfort have selective myovascular denervation.

Multiple system atrophy: the case for an international collaborative effort.

“United we stand divided we fall.” — Alexandre Dumas, The Three Musketeers Multiple system atrophy (MSA) is a rare neurodegenerative disease that affects both men and women and has no clear ethnic or racial susceptibilities. Cases are geographically spread throughout the world. Age of onset is typically in the mid-50s. Based on MSA prevalence rates [6] and 32% of Americans being over 50, estimates suggest there are around 5,200 Americans suffering from MSA. The rarity of the disease in combination with the geographical spread of the cases is the biggest obstacle when it comes to enrolling patients in clinical trials. It is thought that with so few cases, no single treatment center -and probably no single country- has enough patients to perform well-powered translational research. MSA is an orphan disease – because it affects less than 200,000 Americans. Orphan diseases are surprisingly common, with an estimated 7,000 different orphan diseases affecting around 30 million Americans. Awareness of rare diseases is growing fast. The National Institutes of Health (NIH) released a position piece recommending that each rare disease has a dedicated global registry and data repository. They emphasized the importance of collecting de-identified clinical data in a standardized fashion overtime and making this information linkable to tissue stored in bio-specimen banks [2]. Gathering specific information from a large pool of patients has obvious advantages when it comes to defining true rates of disease progression as well as the impact of common treatment interventions. Well-defined patient cohorts also lay the foundation for future biomarker research. This strength in numbers approach requires an international collaborative effort that brings together clinical centers conducting research on MSA. Fortunately, in the case of MSA, these collaborative consortia working on the disease already exist. MSA is a central focus of the North American Autonomic Disorders Consortium, created in 2009, as part of the Rare Diseases Clinical Research Network (RDCRN) – a partnership between several NIH Programs [3]. The Consortium has an ongoing prospective natural history study of MSA. The Consortium recently completed a controlled trial to test the neuroprotective potential of the old antibiotic rifampicin. Although the trial ultimately proved negative, the undertaking showed that it was possible to enroll 100 early MSA patients in little under a year [4]. The European counterpart is the European MSA Study Group (EMSA-SG), founded in 1999, from sites in Austria, Denmark, France, Germany, Italy, Portugal, Sweden, Spain and Great Britain. The European MSA Study Group published a report of it’s prospective MSA cohort that had been followed for 2-years [5], which defines much of what we know about the motor progression rates in MSA. They have also completed several clinical trials. In 2013, the MSA Coalition, a patient and caregiver advocacy group, provided support for an initiative to form a transatlantic alliance that would unite US and European MSA Centers. The organization and structure are now in place and a standardized dataset has been agreed upon. Sites in Europe, the US and South America have signed agreements to contribute the standardized data set that will be used to follow the motor and autonomic features of MSA overtime (Figure). Figure Collaborating sites in the Global MSA Natural History Study include: New York University Medical Center (Coordinating site: Horacio Kaufmann), Vanderbilt University Medical Center (PI Autonomic RDCRC: David Robertson & Italo Biaggioni), Beth Israel ... On a day-to-day basis, natural history studies are not the most exciting and require endless hours pouring through case report forms and entering data, but the efforts pay off in the long-term. Large and well-thought natural history studies can provide valuable information for drug development. They are the only way to understand the variability in disease severity amongst patients and reliably estimate the sample size necessary to sufficiently power a study with a clinically meaningful endpoint [1]. They also define rates of progression of affected patients outside a clinical trial. By describing the natural course of the disease, an international prospective study in MSA should help to also define guidelines for clinical care. The argument for an international registry and natural history study is convincing, Sharing data across academic institutions and international boundary lines requires understanding of local rules and regulations, but is possible. The continued support of the MSA Coalition and the NIH’s Rare Diseases Clinical Research Network will make the project feasible.

Cardiac arrest from tramadol and fentanyl combination.

Sir, Tramadol is a centrally acting atypical opioid analgesic commonly used in the treatment of moderate to severe pain. It has a low affinity to μ opioid receptors and also inhibits the reuptake of serotonin and norepinephrine. Fentanyl is a potent, synthetic opioid with a rapid onset of action and strong affinity to μ receptor. Both the drugs are considered to have a high safety profile and used widely in anaesthesia. Fentanyl and tramadol impair presynaptic reuptake of serotonin and in combination with other serotonergic medications can cause serotonin syndrome. We report a case where premedication with the two drugs in therapeutic doses led to serotonin syndrome with severe life-threatening cardiac arrhythmia. A 43-year-old male American Society of Anaesthesiologists physical status1 patient, with radicular pain was scheduled for C5–6 anterior cervical discectomy. He was on gabapentin 150 mg tid and ibuprofen 200 mg bid for pain relief since 1 month. Preanaesthetic evaluation had been insignificant, and and so was the examination prior to shifting into the theatre. After connecting standard monitors and preoxygenation, intravenous (i.v.) fentanyl 50 μg (0.83 μg/kg, in dilution of 1 ml = 50 μg) was administered. Patient was agitating, and pain was thought to be the cause of his agitation. For the fear of developing chest wall, rigidity another agent was considered instead of higher doses of fentanyl. I.v. tramadol 75 mg (1.25 mg/kg, in dilution of 1 ml = 20 mg) was administered slowly over 2–3 min. Immediately a supraventricular rhythm (SVT) with a rate of 180/min and ventricular ectopics were noted on the monitor. It soon deteriorated to ventricular tachycardia (VT) and then into ventricular fibrillation (VF). Cardiopulmonary resuscitation (CPR) was initiated, and airway was secured with endotracheal intubation. Defibrillation with biphasic mode (200 J) was administered thrice during the CPR cycle without sustained sinus rhythm. Injection amiodarone 300 mg bolus was administered after 3rd shock after which sustained sinus rhythm was achieved. After initiating maintenance amiodarone infusion (0.5 mg/kg/h for 24 h) and vasoactive support (noradrenaline and adrenaline infusion at 20 mcg/min) patient was shifted to the intensive care unit (ICU). In the ICU, ventilation was continued for a day with midazolam and morphine for sedation and analgesia. A bedside echocardiogram revealed a good cardiac contractility and output. Induced hypothermia at 34°C was maintained for the day. The next day vasoactive drugs were weaned off, and the patient was awake and successfully extubated. Amiodarone was changed to oral mode of administration and patient was discharged to the ward on 2nd day. The combination of tramadol and fentanyl for premedication is seldom used. The combination has improved tolerance for awake endotracheal intubation[1] and has reduced the incidence of supraventricular arrhythmia in patients undergoing pulmonary resection.[2] Fentanyl associated fatalities have been primarily due to respiratory depression as even low concentrations lead to it.[3] Life-threatening central nervous system (CNS) and cardiac complications are generally found after tramadol ingestion at high doses with unintentional or intentional suicidal attempts. Ahmadi et al., after analysing the cases of tramadol intoxication found mortality rate of 0.97%. Most of the cases have been reported in conjunction with other drugs such as CNS depressants.[4] However, Shadnia et al., reported two fatalities with tramadol intoxication without any co-ingestions.[5] In therapeutic doses, both tramadol and fentanyl have been implicated in serotonin toxicity though tramadol is more notorious for severe toxicity.[6] Serotonin toxicity is marked by the triad of neuromuscular excitation, autonomic stimulation and changes in mental state. Based on the clinical profile we suspected serotonin syndrome to be causative for the complication in our patient. The features of toxicity from drug combination develop rapidly after onset of effective blood levels of the second drug. The autonomic features such as tachycardia and tachypnea are not usually severe.[6] In our patient, the administration of i.v. fentanyl initiated the toxicity features (agitation) which became more pronounced with tramadol dose. However, the cardiac signs erstwhile considered not to be of serious consequence, in our patient caused near fatal arrhythmia. The rhythm quickly transformed from SVT to VT and then to VF [Figure 1]. No role of use of gabapentin preoperatively in this peroperative drug interaction between fentanyl and tramadol could be explained. Figure 1 Electrocardiogram tracing of the rhythm during cardiopulmonary resuscitation To our knowledge and belief, this is the first report of serotonin toxicity with tramadol and fentanyl combination, in therapeutic doses without any other serotonergic medication. The inability to monitor serum drug level has been a limitation, but the absence of any other drug administered prior to fentanyl and tramadol effectively establishes the aetiology. This case report highlights the dangers of combining two drugs with potential of serotonin toxicity and the severity of cardiac complication that can even be near fatal.