Autonomic Dysfunction & Fatigue

Alan J Hakim Consultant Physician &

Rheumatologist, London, UK

On Behalf Of The Working Group

Inge De Wandele, Physiotherapist, Ghent, Belgium Chris O’Calloghan, A/Prof Clinical Pharmacology,Victoria, Australia Alan G Pocinki, Assoc. Prof. of Medicine, Rockville, USA Peter Rowe, Prof. of Pediatrics, Baltimore, USA

With Advice From: Brad Tinkle, Clinical Geneticist, Chicago, USA Lauren Stiles, President, Dysautonomia International

What we know?

Causal associations & evidence for mechanisms

Management and Care Guidelines.

Controversies *

What we need to know?

CONTENT:

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Literature review &

Expert knowledge & opinion

Regular discussion

Several rounds of manuscript productionleading to 2 guideline documents

Peer Review

Response To Peer Review

Manuscripts Version 9 and counting

PROCESS:

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THE ASSESSMENT AND MANAGEMENT OF

CARDIOVASCULAR DYSREGULATION IN

EHLERS-DANLOS SYNDROME – HYPERMOBILITY TYPE.

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Cardiovascular Dysregulation– Postural Tachycardia Syndrome (POTS) – Orthostatic Hypotension (OH) – Neurally mediated hypotension (NMH), (vaso-vagal

syncope, neuro-cardiogenic syncope, delayed orthostatic hypotension)

– Orthostatic Intolerance (OI)

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Cardiovascular Dysregulation

•Term cardiovascular ‘autonomic dysfunction’ or ‘dysautonomia’ is usually applied.

•* Groups’ opinion - ‘cardiovascular dysregulation’ is a more appropriate over-arching term.

•Often inappropriate physiological responses occur without autonomic neuropathy. (clinical and published research)

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Cardiovascular DysregulationWhat We Know

• Literature applies primarily to heterogeneous group JHS / EDS-HT • Symptomatic tachycardia and/or hypotension are observed. [Rowe et al., 1999; Gazit et al., 2003; Hakim & Grahame, 2004; Mathias et al., 2011; Wallman et al., 2014; De Wandele et al., 2014].

• Symptoms can be highly debilitating [Rowe et al., 1999, Hakim & Grahame, 2004; Mathias et al., 2011; De Wandele et al., 2014].

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Cardiovascular DysregulationWhat We Know

• Association of POTS with fatigue [Schondorf et al., 1999]. • In general, reduced quality of life [Benrud-Larsen et al., 2002]. • Greater incidence of migraine and syncope with POTS in patients

with joint hypermobility syndrome. [Kanjwal et al., 2010]. • Poorly controlled, symptoms may restrict other treatment strategies.

(Clinical opinion)10

Cardiovascular DysregulationCausal Associations?

Mechanisms suggested include:

• Peripheral venous dilation and blood pooling • Elevated circulating catecholamines • Auto-immunity - auto-antibodies directed against baroreceptor • Medications e.g. tricyclics • Histamine • Brainstem / upper cervical cord impingement

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Cardiovascular DysregulationCausal Associations – What Do We Know?

Vascular compliance: • Increased aortic wall compliance in 10 of 13 study cases with joint

hypermobility syndrome. [Handler et al.,1985]. • OI in EDS-HT could be attributed to excessive venous distension and

pooling. [Rowe et al., 1999]. • Studies by Mathias et al., [2011] and De Wandele et al., [2014] suggest

neuropathy, connective tissue laxity, and vasoactive medication play a role.

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Cardiovascular DysregulationCausal Associations – What Do We know?

Adrenergic states: In EDS • Gazit et al., [2003] identified evidence of alpha-adrenergic and beta-adrenergic

hyper-responsiveness. In the general POTS population: • Thieben et al. [2007] identified hyperadrenergic states in 29% of cases of POTS

from a general cohort. • Adrenergic and other neural autoantibodies found in a significant percentage of

POTS patients. [Thieben et al., 2007; Li et al., 2014; Singer et al., 2014; Fedoroski et al., 2015]. 13

Cardiovascular DysregulationCausal Associations – What Do We Know?

• In general populations – histamine induces hypotension and tachycardia. [Frieri et al., 2013].

• Mast cell activation identified in EDS-HT [Louisias et al., 2013; Cheung & Vadas, 2015].

• In general populations - Arnold Chiari malformation may trigger cardiovascular dysregulation . [Ireland et al., 1996].

• Association between Arnold Chiari and EDS-HT. [Milhorat et al., 2007]

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Cardiovascular DysregulationWhat We Need To Know

• Is cardiovascular dysregulation (or certain mechanisms that cause it) truly associated with EDS-HT? – The incidence, prevalence, and natural history of cardiovascular

dysregulation in the EDS-HT population – Distribution and types of mechanisms.

• What are the risk factors, and the natural history? – Age of onset and evolution throughout life, etc., – Influence of anxiety disorders / mental health factors.

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Cardiovascular DysregulationWhat We Need To Know

• By subgroup (mechanism of disorder) what is optimal treatment?

• Clinical trials of efficacy and safety of treatments: – To move beyond case study and expert opinion evidence. – Assess effect of treatment on quality of life, fatigue etc., also.

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Cardiovascular DysregulationWhat We Know - Management

• Evidence for management in EDS-HT is lacking; there are no published clinical trials.

• Level IV evidence arises from small cohort studies, case reports, and expert opinion.

• Confounding by imprecision in definitions and diagnostic methods.

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Cardiovascular DysregulationWhat We Know - Management

• In general - Level I to III evidence of effectiveness of treatment strategies.

• Pragmatic approach - guidance in EDS is based on expert opinion, but drawing on Level I to III data published by international groups on management dysautonomia per se

[Grubb et al., 2006; Lahrmann et al., 2006; Sheldon et al., 2015].

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Cardiovascular DysregulationAssessment

• Recognize that patients often have complex co-morbidities

• Recognize that there are many causes beyond EDS • Thorough history and physical examination, considering

– Broadly the causes – Specific potential causation in EDS

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Cardiovascular Dysregulation AssessmentDiagnostic Criteria / Tests :

– POTS: increase in HR of ≥ 30 bpm moving from recumbent to standing (or ≥ 40 bpm in12 to 19 years of age); [in the absence of orthostatic hypotension (≥ 20 mm Hg drop)].

– OH: sustained reduction ≥ 20 mmHg systolic or diastolic ≥ 10 mmHg within 3 minutes of standing or head-up tilt to at least 60˚ angle.

– NMH: orthostatic symptoms and ≥ 25 mm Hg drop in systolic BP during standing or tilt testing.

– OI: symptoms during 10 minutes of upright posture which improve upon lying down and do not meet the above criteria. 20

Cardiovascular DysregulationAssessment

• Orthostatic signs normal in clinic, but suspicion high. Or, Signs present but non-pharmacologic treatments not helped. • Consider:

– hematocrit, – Electrocardiogram and/or Holter monitoring,(excluding other

dysrhythmia) – Blood pressure monitoring, and – Echocardiogram* (screening for MVP and Aortic Root Disease)21

Cardiovascular DysregulationAssessment

• Some cases tilt-table testing might be helpful - more prolonged period than a standing test.

• More extensive evaluation by an expert Autonomic Unit might be required and might include: – Thermoregulatory sweat test or QSART testing to detect autonomic

neuropathy – Supine and upright plasma epinephrine and norepinephrine level

tests, – 24-hour urine sample to assess sodium balance

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Cardiovascular DysregulationTreatment

• Several treatments, used together, are likely to be needed. • Education, advice and non-pharmacologic treatments should be

offered first in all patients, and include education on: – Avoid / Reducing exposure to triggering factors – Adjust / remove medications that might worsen symptoms – Maintaining good hydration and electrolyte balance – Reduce venous pooling with abdominal and lower limb

compression garments – Graduated exercise program*

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Cardiovascular DysregulationTreatment

• For moderate-severe impairment of daily function, pharmacologic treatments include:

[Grubb et al., 2006; Lahrmann et al., 2006; Sheldon et al, 2015] include:

– Fludrocortisone – Midodrine – Ivabradine – Beta blockers. Lower doses tend to be better tolerated, but

inter-individual variability. 24

Cardiovascular Dysregulation Treatment[Sheldon et al, 2015] include:

– Hormonal contraceptives can help OI symptoms in women. [Boehm et al., 1997]. – Pyridostigmine [Raj et al., 2005; Singer et al., 2006]. – Clonidine; useful for comorbid anxiety, pain [Robertson et al., 1983; Nahman-

Averbuch et a., 2016 ]. – Serotonin or serotonin-norepinephrine reuptake inhibitors in some patients with

OI; also for co-morbid pain, anxiety, or depression [Di Girolamo et al., 1999]. – Methylphenidate [Grubb et al., 1996] – Desmopressin – Octreotide – 1-2L of intravenous normal saline infused over 1-2 hour [Burklow et al., 1999;

Takenaka et al., 2002], or other forms of sodium loading [Rosen and Cryper, 1992].

– Ruscus aculeatus (butcher’s broom) [Altern, 2000].25

Summary

• Cardiovascular dysregulation is found in some patients with EDS-HT. • Mechanisms exist that may explain in some cases the association with EDS-

HT. • The diagnosis is predominantly based upon taking a detailed history and

examination for general causes and specific complications of EDS. • Simple clinic room tests can provide support for the diagnosis and other tests

may be useful to exclude other diseases that can present in a similar manner.

• Although pharmacological therapies may be required, non-drug treatments should always be considered first.

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Summary• Pharmacological therapy begins with minimizing or removing

medications that are either ineffective or producing deleterious effects.

• Drug treatments include volume expansion, vasoconstriction, and modulators of autonomic tone.

• Prognosis remains uncertain. • Substantial epidemiological and therapeutics questions remain.

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THE ASSESSMENT AND MANAGEMENT OF

CHRONIC FATIGUE IN

EHLERS-DANLOS SYNDROME – HYPERMOBILITY TYPE.

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Chronic Fatigue What We Know – in EDS-HT

• Principal presenting symptom and disabler in Ehlers-Danlos syndrome – hypermobility type (EDS-HT).

[Rowe et al., 1999; Hakim and Grahame, 2004; Voermans et al., 2010; Voermans and Knoop, 2011; Castori et al., 2011; Murray et al., 2013].

• Associated in EDS-HT with muscle weakness [Voermans et al., 2011; Celletti et al., 2012], and kinesiophobia [Celletti et al., 2013].

• No large population case-control randomized trials of the management of fatigue in EDS.

• The published advice is based on small cohort studies and expert opinion.29

Chronic Fatigue What We Know

• Fatigue can be temporally categorized as recent, prolonged, or chronic i.e. – less than one month, – 1-6 months, and – more than 6 months respectively.

• Persistence and impact on quality of life are recognized in descriptors of Chronic Fatigue Syndrome (CFS) / Myalgic Encephalomyelitis (ME).

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Chronic Fatigue What We Know

• There is no specific definition for chronic fatigue in EDS-HT. Recommend using the Institute of Medicine [2015] definition:

– persistent and/or recurrent fatigue – been present for more than 6 months unexplained by other

conditions – not the result of ongoing exertion – not substantially alleviated by rest – results in a substantial reduction or impairment in the ability to

engage in normal levels of activities31

Chronic Fatigue Is it CFS or EDS or can it be both? *

• Groups’ opinion - the criteria used for diagnosing CFS and fatigue in EDS-HT are inadequate, contributing to diagnostic confusion.

• To meet a diagnosis of CFS, fatigue must be “unexplained by other conditions”.

• Therefore should a diagnosis of EDS-HT exclude a diagnosis of CFS?

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Chronic Fatigue CFS or EDS? *

Groups’ opinion:

•EDS-HT is likely to be under-diagnosed - some patients diagnosed with CFS may meet the criteria for EDS-HT. •The risk in missing EDS-HT? Attention may be taken away from specific triggering factors and adaptations to management. •The literature and diagnostic methods for fatigue in CFS and EDS-HT are of insufficient strength to reliably differentiate between these conditions.

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Chronic Fatigue Common Reported Triggers

• Poor sleep quality –initiation, maintenance and restoration disturbed by pain, nocturnal tachycardia, or sleep disordered breathing.

• Daytime napping may in some cases lead to either a shift or reversal of the day-night sleep cycle.

• Chronic pain. • Physical deconditioning. • Cardiovascular dysregulation. • Bowel dysfunction. • Bladder dysfunction. • Anxiety and depression. • Headaches and migraines. 34

Chronic Fatigue in EDS-HT What We Need To Know

• The incidence, prevalence, and natural history of fatigue in the EDS-HT population is unknown, so therefore also the distribution and types of (co-associated) mechanisms that trigger this phenomenon.

• How many patients diagnosed with CFS actually really have EDS, not CFS?

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Chronic Fatigue in EDS-HT What We Need To Know

• Subgroup clinical trials of efficacy and safety of treatments are required to move beyond the limitations of case study and expert opinion evidence.

• The influence of anxiety disorders / mental health factors on presentation and response to treatment are not clear.

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Chronic Fatigue Assessment

• Simple tools such as the Wood Mental Fatigue Inventory can be used in the clinic to explore aspects of fatigue

[Bentall et al., 1993].

• Multidimensional Fatigue Inventory – Short Form (MFI-SF) - a 30-item self-report tool. The full MFI is 83 questions [Smets et al 1995].

• Patient self-record of daily activities, general function, and degree of disability perceived.

• Personal electronic devices measure activity – useful monitoring physical exertion pre/post therapeutic programs. 37

Chronic Fatigue Assessment

• Thorough history and physical examination: Fatigue is a common symptom in many systemic illnesses.

• History should include exacerbating and alleviating factors, sleep disturbance and stressors, and impact on wellbeing.

• Include assessment of psychological wellbeing both as a cause and an impact.

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Chronic Fatigue Treatment

• Treatment of fatigue in EDS-HT is based on guidance from the general literature on management of chronic fatigue, and expert opinion.

• There is no specific evidence for use of pharmacological or non-pharmacological therapies in EDS-HT.

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Chronic Fatigue Treatment

General key principles:

• To facilitate effective management the clinician needs to establish a collaborative relationship with the patient and their caregivers.

• Engagement with the family is particularly important for children and young people, and for people with severe fatigue.

• The patient and their clinician should share decision making both in identifying the causes of, recognizing the impact of, and developing a treatment plan for fatigue.

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Chronic Fatigue Treatment

General key principles:

• People with severe fatigue may need support from a multidisciplinary team e.g., nursing, occupational therapy, dietetics, psychology, physiotherapy, and pain management.

• This should be coordinated by a named healthcare professional, and usually their general practitioner / general physician.

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Chronic Fatigue Treatment

General key principles:

• An individualized, patient-centered program should be offered.

• Objectives: gradually extend and sustain the person's physical, emotional and cognitive capacity.

• Treatment is based on addressing the underlying issues.

• Disruption of education or employment is generally detrimental to health and wellbeing. The ability to continue in these should be addressed early.42

Chronic Fatigue Treatment *

• Manage any underlying medical (physical/mental health) cause

• Sleep management • Rest • Relaxation • Pain management • Cognitive Behavioural Therapy • Graded Exercise Therapy

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Chronic Fatigue Treatment

MEDICATIONS:

• No known pharmacological treatment or cure for fatigue per se.

• Large systematic reviews have not identified consistently effective medications for CFS symptoms • In the general population, medications are effective for specific symptoms (e.g. pain, depression) and

co-morbid conditions that result in fatigue [Smith et al., 2014].

• Unless an underlying medical disorder, the following medications should be avoided as they may cause harm:

– Glucocorticoids (in the absence of other indications) – Thyroxine (in the absence of hypothyroidism) – Antiviral agents (in the absence of confirmed active viral infection)

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Chronic Fatigue Treatment

MEDICATIONS:

• Insufficient evidence to recommend complementary therapies and supplements. Some patients choose to use these therapies and find them helpful.

• These include: co-enzyme Q10, magnesium, nicotinamide adenine dinucleotide (NADH), and multivitamins and minerals.

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Chronic Fatigue Treatment*

Medications To Assist Sleep: •Melatonin •Doxepin •Cyproheptadine •Diphenhydramine •Trazodone •Propranolol •Clonazepam •Zolpidem

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Summary

• Fatigue is a commonly reported by EDS –HT patients presenting to clinic.

• It clinically presents in a manner that appears indistinguishable ‘definition-wise’ from CFS.

• The initial approach to fatigue in EDS is to exclude or identify other

conditions that may produce fatigue.

• Conditions which are commonly seen in EDS and which may manifest as or exacerbate fatigue include sleep disorder, chronic pain, deconditioning, cardiovascular dysregulation, and psychological concerns.

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Summary

•Treatment should focus on improving symptoms, maintaining function and providing social, physical and psychological support.

•Substantial epidemiological, diagnostic, and therapeutics questions remain.

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Thank You

Alan J Hakim Consultant Physician & Rheumatologist, London, UK

For the Working Group

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