Autonomic Dysfunction and Fatigue

Autonomic Dysfunction and Fatigue – Alan Pocinki MD – notes from a 2015 presentation

These are notes from a 2015 presentation given by Alan Pocinki, a well-known EDS specialist. The format is not pretty, but the information is discernable, so I’ve left it exactly as written.

Cardio Vascular Dysregulation

  • POTS- Postural Tachycardia Syndrome
  • OH- Orthostatic Hypotension
  • NMH- Neurally mediated hypotension (vaso-vagal syncope, neuro-cardiogenic syncope, delayed orthostatic hypotension)
  • OI- Orthostatic Intolerance

What We Know About Cardiovascular Dysregulation 

  • The literature applies primarily to heterogeneous group JHS/hEDS
  • 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)
  • Association of POTS with fatigue- ( Schondorf et al, 1999)
  • In general a 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)

Casual 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
  • Vascular compliance:

Increased aortic wall compliance in 10 of 13 study cases with hEDS (Handler et al, 1985)

OI in hEDS 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.

  • Adrenergic states;
  • In EDS Gazit et al, (2003) identified evidence of alpha-adrenergic and beta-adrenergic hyper-responsiveness
  • In general POTS population
  • Thieben et al. (2007) identified hyperadrenergic states in 29% of cases of POTS from a general cohort.
  • Adrenergic and other neural auto-antiboties found in significant percentage of POTS patients. (Thieben et al, 2007,: Li et al., 2014; Singer et al., 2014; Fedoroski et al., 2015)
  • In the general populations- histamine induces hypotension and tachycardia (Frieri et al., 2013)
  • Mast cell activation identified in hEDS (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 hEDS (Milhorat et al., 2007)

 The Assessment:

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

Diagnostic Criteria / Tests:

  • POTS: increase in HR of  ≥ 30 bpm moving from recumbent to standing (or ≥ 40 bpm in 12 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 min. of standing or head-up tilt ot at lease 60 degree angle.
  • NMH; orthostatic symptom and ≥ 25 mmHg drop in systolic BP during standing or tilt testing.
  • OI; symptoms during 10 min. of upright posture which improve upon lying down and do not meet the above criteria.
  • If  orthostatic signs normal in clinic, but suspicion high or. Signs present but non-pharmacologic treatments not helped then consider:
  • Hematocrit
  • Electrocardiogram and/or Holter monitoring (excluding other dysrhythmias)
  • Blood pressure monitoring and
  • Echocardiogram checking for MVP and aortic root disease
  • 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 and specific potential causation in EDS.
  • In some cases tilt-table testing might be helpful- 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-hr. urine sample to assess sodium balance.


  • 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
  • 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.
  • Hormonal contraceptives can help OI symptoms in women [Boehm et al., 1997]
  • Pyrodostigmine [Raj et al., 200 Singer et al 2006]
  • Clonidine; useful for comorbid anxiety, pain [Robertsonet al., 1983; Nahman-Averbuch et al 2016].
  • Serotonin of 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 IV normal saline infused over 1-2 hours [Burklow et al., 1999, Takenaka
  • et al., 2002] or other forms of sodium loading [Rosen and Cryper 1992]
  • Ruscus aculeatus 9Buthcer’s broom) [Altern, 2000]


  • Pharmacological therapy begins with minimizing of 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.

Chronic Fatigue

What we know about fatigue in hEDS:

  • Fatigue is the principal presenting symptom and disabler in hEDS. [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 hEDS with muscle weakness [Voermans et al., 2011, Celletti et al., 2012] and kinesiophobia [Cellett er al., 2013]
  • No large population case-control randomized trials of the management of fatigue in hEDS.
  • The published advice is based on small cohort studies and expert opinion.
  • Fatigue can be temporally categorized s 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).
  • There is no specific definition for chronic fatigue in hEDS.
  • It is recommended to use 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 activities

Is it CSF or EDS or can it be both?

  • The groups’ opinion- the criteria used for diagnosing CSF and fatigue in hEDS are inadequate, contributing to diagnostic confusion.
  • To meet a diagnosis of CFS, fatigue must be “unexplained by other conditions”.
  • Therefore should a diagnosis of hEDS exclude a diagnosis of CFS?
  • Consensus at International Symposium is:
  • hEDS is likely to be under-diagnosed – some patients diagnosed with CFS may meet the criteria for hEDS.
  • The Risk in missing hEDS? Attention ma be taken away from specific triggering factors and adaptations to management.
  • The literature and diagnostic methods for fatigue in CFS and hEDS are insufficient strength to reliably differentiate between these conditions.

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


  • Simple tools such at the Wood Mental Fatigue inventory can be used in the clinic to explore aspects of fatigue. (Bental 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.
  • 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.


  • Treatment of fatigue in hEDS 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 hEDS.
  • 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.
  • 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.
  • 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 reemployment is generally detrimental to health and wellbeing. The ability to continue in these should be addressed early.
  • 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.
  • Manage any underlying medical (physical/metal health) cause
  • Sleep management
  • Rest
  • Relaxation
  • Pain Management
  • Cognitive Behavioral Therapy
  • Graded Exercise Therapy


  • There is 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 medication 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)
  • 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.


  • Fatigue is commonly reported by hEDS patients
  • 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.
  • 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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