Postural orthostatic tachycardia syndrome

Abstract

Postural orthostatic tachycardia syndrome (POTS) is characterised by the development of excessive tachycardia on standing with maintained blood pressure. We report a case of POTS in a 20-year-old girl with type 1 diabetes who presented with a 3-week history of lethargy, fatigue and orthostatic intolerance. Examination revealed a postural rise in heart rate of over 50 bpm with maintained blood pressure. This was associated with symptoms of light-headedness. Cardiac structure and function as assessed by ECG and ECHO were normal as was thyroid and adrenal function. POTS was confirmed with tilt table testing. Treatment was initiated with increased fluid intake, fludrocortisone and bisoprolol with improvement. POTS is a disabling condition which can significantly limit a patient’s activities and working capacity and should be considered in a young, otherwise well patient who presents with orthostatic intolerance and a postural rise in heart rate.

BACKGROUND

Postural orthostatic tachycardia syndrome is a common condition in centres specialising in diseases of the autonomic nervous system. It typically affects young, otherwise well patients. It can therefore be very disabling and cause much distress to the patient and their family. Further distress can be caused when symptoms are prolonged with no apparent diagnosis. On admission our patient was unwell with genuine postural symptoms. By following a systematic approach to investigation, we were able to quickly rule out non-neurological causes such as cardiac, adrenal or thyroid disease.

Making the diagnosis of postural orthostatic tachycardia syndrome (POTS) is straightforward with head tilt table testing, however an awareness of the condition is necessary to ensure appropriate investigations are arranged. Prompt diagnosis is important as treatment does improve symptoms and enables the patient to return to functional activities and employment. In addition, it is very reassuring and helpful for patients to be informed that, in the majority of cases, they should return to baseline function.

Therefore, this case is important in reminding medical practitioners of this relatively common condition affecting young, healthy patients. Without an awareness of this condition, patients may be misdiagnosed with similar conditions such as chronic fatigue syndrome. thus delaying treatment and causing further distress and frustration.

CASE PRESENTATION

A 20-year-old girl was admitted with a 3-week history of generalised lethargy, weakness and fatigue. During this time she had intermittent episodes of light-headedness associated with shortness of breath. These were postural in nature. She had no recent illnesses prior to this presentation.

The patient had a 6-year history of type 1 diabetes managed with a basal bolus regimen of insulin glulisine and glargine. Glycaemic control was suboptimal with a HbA1c of 8.5%. There was no other significant past medical history and she was not taking any other medication. She was a university student living with her parents at home. She did not report any smoking or alcohol use. There was no history of illness in the family.

On examination she weighed 54.4 kg and was 1.67 m in height (BMI 19.5 kg/m²). Full examination was normal with the exception of a postural rise in heart rate. This increased from 80 bpm on lying to 136 bpm on standing for 5 min. Blood pressure was 105/63 mm Hg on lying flat and remained at 100/80 mm Hg after standing for 5 min.

INVESTIGATIONS

Initial blood biochemistry and full blood picture were normal. Glucose was 14.6 mmol/l on admission and inpatient monitoring of capillary glucose did not reveal a glycaemic cause for these episodes. Urinalysis was positive for glucose only.

Electrocardiogram performed during an episode showed sinus tachycardia. A cardiac monitor was attached and confirmed intermittent episodes of sinus tachycardia typically associated with posture or activity.

Given the patient’s history of type 1 diabetes, a 250 μg short synacthen test was performed which demonstrated an adequate cortisol rise from 847 to 1248 nmol/l after 30 min. Adrenal function was further assessed with aldosterone 351 pmol/l and plasma renin activity 0.69 ng/ml/h. Three 24 h urine collections were tested for catecholamines, all of which were normal. Thyroid function was also normal.

An echocardiogram did not show any structural abnormality with normal left ventricular systolic function.

A tilt table test was performed. On tilting to 60°, the patient developed sinus tachycardia. This was associated with light-headedness. Heart rate increased to a maximum of 195 bpm during the test. Blood pressure fell after 4 min of tilting from 109/90 to 86/74 mm Hg. After 8 min, the patient felt increasingly weak and the test was stopped. When the patient lay flat, the heart rate instantly returned to normal sinus rhythm at a rate of 99 bpm and blood pressure returned to 104/82 mm Hg. The heart rate and systolic blood pressure response to tilting are shown in fig 1.

Figure 1.

Heart rate and systolic blood pressure response to 60° tilt table testing. HR, heart rate; SBP, systolic blood pressure.

DIFFERENTIAL DIAGNOSIS

Orthostatic intolerance in a young female with diabetes is suggestive of either autonomic failure as a complication of her condition or indeed a related autoimmune disease such as adrenal failure. Other conditions unrelated to diabetes also need to be considered, such as chronic fatigue syndrome and POTS.

Adrenal function was evaluated early in the course of the patient’s admission and was normal as demonstrated by a short synacthen test.

Autonomic neuropathy is found to be present in over 20% of patients with type 1 diabetes when assessed 7 years after diagnosis.¹ In healthy subjects, there is a rapid early rise in heart rate upon standing which falls over approximately 30 beats to relative bradycardia. In patients with diabetic autonomic neuropathy, there is only a gradual rise in heart rate on standing, which was not found in our patient.² Autonomic neuropathy is also typically associated with postural hypotension. This is defined as a reduction in systolic blood pressure of at least 20 mm Hg or a reduction in diastolic blood pressure of at least 10 mm Hg after 3 min of standing. This was not demonstrated on clinical assessment of our patient.

Chronic fatigue syndrome (or myalgic encephalomyelitis) is associated with orthostatic tachycardia and autonomic abnormalities. The US Centers for Disease Control and Prevention (CDC) set criteria for the diagnosis of chronic fatigue syndrome. They include chronic activity limiting fatigue lasting for 6 months or more with associated cognitive difficulties, pharyngitis, muscle pain, joint pain, headache, sleep disturbance and post-exercise malaise that is unexplained by other illness and did not predate fatigue.³ Although our patient did describe fatigue at presentation, she did not meet the criteria for chronic fatigue syndrome.

POTS is a clinical syndrome of orthostatic intolerance characterised by the development of excessive tachycardia and symptoms of cerebral hypoperfusion on standing without significant hypotension.⁴ This describes the features found in our patient and a tilt table test was arranged to confirm our clinical suspicion. The excessive tachycardia found during tilting, which was associated with the patient’s described symptoms and preceded any change in blood pressure, confirmed the diagnosis of POTS.

TREATMENT

Treatment for POTS is based upon the suspected aetiology of the condition. Therapies therefore focus on increasing salt and fluid intake, increasing venous return and limiting the hyperadrenergic state found in this condition. Our patient was advised on a number of compensatory mechanisms and treatment was initiated during her inpatient stay.

Non-pharmacological treatment

The patient was advised to increase her intake of salt and fluid. It was also advised that she should drink a glass of cold water at the time of an episode. She was provided with compression stockings and advised to wear them during daily activities.

Pharmacological treatment

Treatment with fludrocortisone was commenced at 100 μg daily and after 48 h when tilt table testing had been performed, bisoprolol 2.5 mg was added.

OUTCOME AND FOLLOW-UP

Upon commencement of fludrocortisone and bisoprolol, symptoms improved enabling the patient to sit in bed without experiencing light-headedness. At the time of discharge, her heart rate was well controlled and she was able to move slowly around the ward with improved confidence. She was reviewed at the outpatient clinic 8 weeks after discharge. At this time there was no postural change in blood pressure or heart rate. Although she was unable to complete her academic year, her mobility had improved significantly from pre-admission enabling her to leave the house and carry out day-to-day activities. She plans to return to university to complete her studies at the start of the next academic year.

DISCUSSION

POTS is the most common disorder amongst patients referred to centres specialising in the autonomic nervous system disease. It is thought to affect 500 000 people in the United States.⁵ It is defined as an excessive increase in heart rate of greater than 30 bpm on standing, associated with orthostatic symptoms in the absence of orthostatic hypotension.⁶ POTS typically presents in the 12–50-year-old age group and affects females more frequently with a female:male ratio of 5:1.⁷

POTS was first described in 1940 and since then much research has been dedicated to understanding the pathophysiology of this important and disabling condition. In normal subjects plasma noradrenaline increases on standing. This increase occurs over the first 5 min of upright posture. In patients with POTS it continues to rise for over 30 min. This has been attributed to reduced clearance of noradrenaline in these patients.⁸ A suggested mechanism for reduced clearance is a decreased cardiac output secondary to hypovolaemia or reduced venous return. Patients with POTS have been found to have a volume deficit of greater than 20% of their ideal plasma volume.⁶ Despite being hypovolaemic, patients were also found to have relatively reduced renin and aldosterone levels which typically should be elevated in the presence of hypovolaemia. This suggests that the renin–angiotensin axis is involved in the pathogenesis of this condition, however the cause of its reduced responsiveness to hypovolemia is uncertain.

Another important causative mechanism for this condition is impaired sympathetic function of the lower limbs with subsequent dependent venous pooling and reduced venous return to the heart.⁹ This has been attributed both to hypovolaemia and impaired noradrenergic function of the lower limbs. Other mechanisms implicated in this condition include an autoimmune association after the discovery of acetylcholine receptor (AChR) antibodies in 10% of patients with POTS.¹⁰ In addition, reduced red cell volume has also been found in these patients.⁶ Erythropoietin deficiency has been postulated as a cause of this. It has been reported that diabetic autonomic neuropathy can cause anaemia due to erythropoietin deficiency. This is due to the rich sympathetic innervation of the kidney which modulates erythropoietin production.¹¹ The relationship of reduced red cell volume to symptoms found in patients with POTS is unclear but likely is attributed to reduced plasma volume.

The symptom complex of POTS can be divided into orthostatic and non-orthostatic symptoms (table 1).⁴ The most common features which are present in over 75% of patients include light-headedness, weakness, disequilibrium, tachycardia, shakiness, dry eyes and gastrointestinal upset. Symptoms are typically aggravated by heat, meals and exertion.⁴ On clinical examination, patients may demonstrate venous pooling with leg oedema on standing.

Table 1.

POTS symptoms

Orthostatic symptoms	Non-orthostatic symptoms
Light-headedness	Heat intolerance
Weakness	Dry eyes
Disequilibrium	Dry mouth
Visual symptoms	Bloating
Palpitations	Nausea
Tremor	Early satiety
Anxiety	Vomiting
Shortness of breath	Diarrhoea
Nausea	Constipation
Pallor	Weight changes
Clammy skin

The diagnosis of POTS is made with head tilt table testing. A positive result is a sustained heart rate increase of greater than 30 bpm or an increase to 120 bpm or greater within the first 10 min of tilt.¹² It may, as in this case, be associated with relative hypotension. In addition to tilt table testing, other investigations include catecholamine levels (blood and urine) along with tests for alternative causes such as thyroid function, cortisol, electrolytes and electrocardiogram.⁷

Treatment of POTS is based on an understanding of the pathogenesis of the condition. There are a number of non-pharmacological interventions which focus on both correcting hypovolaemia and improving venous return. These include rapidly increasing plasma volume with intravenous saline (1 litre over 1 h) or drinking 480 ml of tap water. Both interventions have been found to significantly reduce standing heart rate in patients with POTS.^13,14 In patients with autonomic dysfunction, this response is sustained for up to 1 h.¹⁵ Treatments which are beneficial in patients with orthostatic hypotension are also used in POTS. These include compressive stockings extending to the waist to reduce pooling of blood in the lower limbs and splanchnic circulation.¹⁶ In addition, increased dietary sodium intake sufficient to give a urinary sodium excretion of 170 mmol over 24 h is helpful in patients with orthostatic hypotension.¹⁷ Increased sodium intake is also beneficial in patients with POTS.⁴

Drug therapy is used with some success in POTS and combination treatment is often required. Fludrocortisone, a mineralocorticoid agonist, results in symptomatic improvement which parallels improvements in haemodynamic measurements.¹⁷ This helps in retaining sodium and water, thus boosting plasma volume. Adrenoreceptor agonists have vasoconstrictor effects and are also of benefit in these patients with midodrine demonstrating an improvement in postural heart rate and intravenous phenylephrine also improving orthostatic symptoms and heart rate.^13,18 As POTS is a hyperadrenergic state, beta blockers are beneficial in limiting this and have been found to reduce both symptoms and heart rate in patients.¹⁷ Drug studies in this syndrome are all of short duration and not placebo randomised. Therefore, prolonged benefit of long term treatment is uncertain. In a follow-up study of patients with POTS of at least 18 months’ duration, the majority of patients benefited from salt supplementation with beta blockade as the second most useful treatment intervention.⁴

Other treatment options for POTS include selective serotonin reuptake inhibitors which reduce venous pooling through stimulation of the standing vasoconstriction reflex.⁷ Other potential therapies include pyridostigmine (an acethycholine esterase inhibitor) and as discussed earlier, erythropoietin.¹⁹

POTS is a disabling condition which typically affects young, otherwise healthy women. It can often be mistaken for similar conditions such as vasovagal syncope or chronic fatigue syndrome. Delays in diagnosis or indeed inaccuracies in diagnosis can cause considerable distress to the patient and their family. It is therefore important that it is diagnosed quickly with appropriate initiation of treatment. Patients will also benefit from the reassurance that the condition improves or resolves in the majority of cases. In a follow-up study of more than 18 months, 80% of patients improved with 60% back to normal and 90% able to return to work at the end of the follow-up.⁴ This is reassuring for patients who should be counselled about this favourable long term outcome at diagnosis.

LEARNING POINTS

1. Although postural orthostatic tachycardia syndrome is common in specialist centres, its prevalence in the general population is much lower and therefore it may be overlooked in general practice or medical clinics in patients with orthostatic symptoms and maintained blood pressure.

2. This highlights the importance of checking postural heart rate alongside blood pressure in patients with orthostatic intolerance.

3. Diagnosis of this condition is relatively straightforward with tilt table testing.

4. The value of diagnosis lies with the initiation of appropriate treatment and symptom limiting therapy. In addition, a well researched diagnosis with a good long term outlook should provide reassurance for the patient.