Postural orthostatic tachycardia syndrome (POTS) and headache

Epidemiology

The current epidemiology of this condition is not known but there is spreading awareness of this condition. POTS is the most common form of orthostatic intolerance in the premenopausal age. It has an estimated prevalence of about 1%. It predominantly affects women (ratio of 4:1) between the ages of 13–50 years. There is a suspected predilection for whites, although referral bias may be at play. The symptoms in this condition may be so disabling that about 25% are reported to be unable to work and there are strong correlates of having associated depression.

Pathophysiology

The underlying mechanisms associated with this disorder include the impairment in the ability in having efficient venous return when assuming a recumbent position. Several theories exist as to the mechanisms involved but overall these are very poorly understood. These varied mechanisms provide for a varied clinical phenotype. There are no specific laboratory studies that are pathognomonic of this syndrome. Understanding the underlying mechanisms may be helpful in directing the treatment plan. Here are some of the proposed mechanisms:

• 1.
  

  Abnormal autonomic regulation due to increased or decreased sympathetic tone with poor peripheral sympathetic tone due to a neuropathy of the autonomic nerves.

  
  
• 2.
  

  Hypovolemic state is seen in about 70% of patients with POTS. Some of these patients have been shown to have low levels of plasma renin and aldosterone which may suggest a neuroendocrine dysfunction within the kidney.

  
  
• 3.
  

  Autoimmune mechanism is supported by the clinical history that may suggest the onset of symptoms after a febrile illness or vaccination. A few studies have shown the presence of various autoantibodies against cholinergic and adrenergic receptors. The resolution of symptoms with some immune therapies may support this theory.

  
  
• 4.
  

  Mast cell disorders – a subgroup of patients have facial flushing and face or extremity erythema in association with orthostatic intolerance. Elevation of methylhistamine has been documented in some of these patients. The mechanism is unclear but perhaps the sympathetic activation leads to mast cell degranulation.

  
  
• 5.
  

  Hyperadrenergic state is seen in about half of the patients with a more gradual onset. These patients may have elevation in norepinephrine levels and may have clinical signs that support heightened adrenergic activation such as tremor, excessive sweating, and anxiety. It is thought that 50% of patients have this hyperadrenergic subtype of POTS. These patients may have elevation in their systolic blood pressure. Some of these patients have a loss of function mutation with resultant norepinephrine transporter (NET) deficiency.

  
  
• 6.
  

  Connective tissue disorders and joint hypermobility is yet another mechanism. Ehlers-Danlos syndrome (EDS) is an inherited connective tissue disorder with subtypes with fragile connective tissue and skin and joint hypermobility. The joint hypermobility subtype has high association with POTS. About 18% of patients with POTS are thought to meet criteria for EDS. The laxity is thought to contribute to increased venous pooling and associated orthostatic intolerance. The hypermobile joints predispose to frequent subluxations, chronic injury, and chronic pain.

Clinical features common to headache disorders and POTS

There is significant overlap in clinical features of POTS and various primary and secondary headache disorders ( Table 1 ). The majority of pediatric patients with POTS are adolescents but some have been diagnosed as young as 5 years old. Greater than 80% are female. Among adolescent patients presenting with headache and lightheadedness in a pediatric headache clinic, 53% had POTS. Conversely among patients with POTS, 27.6%–95.8% report headache. By definition, patients with POTS should have symptoms of chronic orthostatic intolerance combined with excessive upright tachycardia in the absence of postural hypotension. Symptoms of orthostatic intolerance can include those relating to cerebral hypoperfusion (lightheadedness, dizziness, presyncope, blurred vision, generalized weakness, and cognitive difficulties) or sympathoexcitation (palpitations, chest pain, shortness of breath, tremulousness, nausea, diarrhea, pallor, sweating, and coldness of the extremities); these symptoms can worsen when upright and resolve or improve with recumbency. Patients with POTS can also have many non-orthostatic symptoms.

Evaluation

Clarifying the extent to which autonomic conditions, such as POTS, have the potential to contribute to symptom burden in headache disorders is critical, especially in patients with chronic headache disorders or those refractory to standard headache therapies. This requires considering the possibility that a patient may have POTS. Unfortunately, misdiagnosis or delayed diagnosis of POTS is common.

The diagnostic evaluation of suspected POTS starts with confirming the presence of postural symptoms and excessive postural tachycardia. For individuals aged 12–18 years, a heart rate increment of at least 40 beats per minute must be demonstrated. Diagnostic criteria have not been established for younger children. Because POTS is a syndrome, it is also important to evaluate for conditions that have the potential to cause, be associated with, exacerbate or mimic disorders of the autonomic nervous system. Conditions within the differential of POTS include mastocytosis, spontaneous intracranial hypotension or CSF leak, adrenal insufficiency, anemia, pheochromocytoma, paraganglioma, carcinoid, thyroid disease, deconditioning, cardiomyopathy, inappropriate sinus tachycardia, mitochondrial disorders, median arcuate ligament syndrome, Chiari malformation, tethered cord syndrome, narcolepsy with cataplexy, vertebral artery dissection, cerebral venous sinus thrombosis, and anxiety disorder. Table 2 outlines the components of POTS evaluation including history, clinical examination, and diagnostics. Note there is not a single test that is exclusively diagnostic of POTS.

Table 2

Evaluation of POTS: History, clinical examination and diagnostics.

History
Presenting Symptoms	Documentation of symptoms of chronic orthostatic intolerance is required. Refer to Table 1 for a list of commonly reported multi-system symptoms of POTS
Timing of symptoms	Acute (< 1 month), Subacute (1–3 months), Insidious (> 3 month)
Mechanism of symptom onset	Antecedent symptoms suggestive of a viral infection with a prolonged course (ex. infectious mononucleosis) are noted in up to 50% of cases. Previous stressors, such as pregnancy, immunization, head trauma, or surgery, have also been reported; the remainder of patients develop symptoms insidiously. Inflammatory or autoimmune mechanisms may also be responsible
Autonomic review of symptoms	A careful review of symptoms is necessary to establish the extent of autonomic system involvement: • Adrenergic (Postural lightheadedness, Near-syncope, Syncope) • Gastrointestinal (Dysphagia, Early satiety, Abdominal bloating, Nausea, Vomiting, Abdominal pain, Constipation, Diarrhea) • Genitourinary (Increased frequency, Difficulty initiating urination, Nocturnal enuresis, Incomplete bladder emptying) • Pupillomotor (Sensitivity to bright light, Trouble focusing vision) • Sudomotor (Hyperhidrosis, Hypohidrosis, Anhidrosis, Heat/Cold intolerance, Limb color changes) • Secretomotor (Dry eyes, Dry mouth)
Conditions that may be associated with POTS **Note comorbidity does not denote causation**	Joint Hypermobility/Ehlers Danlos Syndrome (EDS) • Inquire about hypermobile joints, “double-jointedness,” joint dislocations, and clicking joints. Hypermobility 5-point questionnaire Autoimmune • Celiac disease, Hashimoto’s thyroiditis, Sjögren syndrome, Systemic lupus erythematosus, Antiphospholipid antibody syndrome Headache • Refer to Table 1 Gastrointestinal • Gastroparesis, Gastrointestinal dysmotility, Irritable Bowel Syndrome Gynecologic • Dysmenorrhea, Menorrhagia, Metrorrhagia, Polycystic ovarian syndrome Mast cell activation syndrome (MCAS) • Inquire about flushing, hives, diarrhea, itchy skin, and urinary irritability Psychiatric • Anxiety, Depression, Brain fog
Exacerbating factors	Dehydration, heat, food ingestion, menses, physical exertion, alcohol, insomnia, deconditioning
Medication History	Medications that might mimic or exacerbate POTS include : • Angiotensin-converting enzyme inhibitors, stimulant medications, α and β blockers, calcium channel blockers, diuretics, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and phenothiazines
Family History	A family history of orthostatic intolerance has been reported in 12.5%

 

Clinical examination
Vitals	Supine and standing heart rate and blood pressure Note: Validation of a standing test for POTS exists for adults but not yet for children, for whom the tilt table is standard
Cardiac	To exclude structural heart disease or dysrhythmia
MSK	Joint hypermobility may be quantified by calculating a Beighton score
Dermatologic	Sweat Output • Excessive resting sweat on the palms and feet may suggest hyperhidrosis or excessive sympathetic activation • Dry skin and dry oral mucosa may indicate secretomotor impairment from medication effect or with Sjögren syndrome Vasomotor instability • Blotchy, marbled, mauve or purple skin MCAS • Flushing of the face and upper chest and hives Antiphospholipid syndrome • Livedo reticularis EDS • Soft or velvety skin, mild skin hyperextensibility, unexplained striae, bilateral piezogenic papules of the heel, and atrophic scarring of at least two sites
Neurologic	Neurologic exam in patients with POTS should generally be normal. Special considerations: • Pupillary response-if absent or sluggish, consider autonomic neuropathy • Sensory exam – if diminished pinprick or temperature sensation in the extremities, consider small fiber neuropathy

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