Clinical manifestations

Presentation and course

The manifestations of hyperventilation syndrome are listed in Table 1. Patients with different symptoms may see different specialists. Cardiologists may see those with complaints of chest pain, palpitations, and shortness of breath. Neurologists frequently see patients describing dizziness and paresthesias (68; 67).

Table 1. Symptoms and Signs of Hyperventilation Syndrome

Hyperventilation syndrome is the most common cause of distal symmetrical paresthesias (57). Although physicians generally recognize bilateral paresthesias of the face, hands, and feet as due to hyperventilation syndrome, many neurologists are not aware that hyperventilation can cause unilateral paresthesias. In two studies of volunteer groups, hyperventilation produced predominantly unilateral paresthesias in 16%, and these involved the left side in over 60% (74; 20; 21). Of those with hand numbness, often only the fourth and fifth fingers are involved. Unusual patterns of numbness reported include one side of the forehead, the shoulders, and one side of the abdomen. Unilateral paresthesias more often involving the left side have also been reported (74; 06; 67; 11; 64).

Patients may report a variety of psychological complaints, commonly including anxiety, nervousness, unreality, disorientation, or feeling "spacy." Impairment of concentration and memory may be described as part of episodes or alternatively as symptoms of an underlying anxiety neurosis or depression. A patient's concern about the cause of the various symptoms of hyperventilation may result in feelings of impending death, fear, or panic, which may accentuate the hyperventilation. Those with chronic hyperventilation have severe impairment of health-related quality of life (13). Patients with hyperventilation syndrome have a mean group profile very similar to patients with pseudoseizures: a neurotic pattern where patients respond to psychological stress with somatic symptoms (11). Other complaints, such as déjà vu or auditory and visual hallucinations, are rare (02; 20; 21).

Prognosis and complications

In a follow-up study of children and adolescents, 40% were still hyperventilating as adults, and many suffered from chronic anxiety (35). One half of patients with acute hyperventilation recover without treatment (37). In 10% of those with chronic hyperventilation, symptoms may persist for more than 3 years (37). With proper management, about 70% to 90% of adults become symptom-free (55; 12).

Clinical vignette

A 47-year-old woman presented with a few-week history of daily episodes of lightheadedness, nervousness, and feelings of weakness, coupled with numbness of the left arm, left leg, and perioral area. The numbness was associated with chest tightness and difficulty inhaling and lasted minutes at a time. She denied any recent stress or depression. She had normal blood and treadmill tests. Past medical history was unremarkable. General physical and neurologic examinations were normal. The hyperventilation test resulted in numbness and tingling periorally and in the left upper and lower extremities. These symptoms were associated with chest tightness.

An MRI scan of the brain with MRA was normal. She was advised to slow her breathing or breathe into a paper bag if additional spells occurred. On follow-up, the episodes had resolved.

Biological basis

Etiology and pathogenesis

Hyperventilation syndrome is frequently associated with anxiety or stress, although some patients have no detectable psychiatric disorder and develop a habit of inappropriately increased ventilatory rate or depth (04).

Common triggers of acute hyperventilation syndrome include anxiety, nausea and vomiting, and fever due to the common cold (37).

In a study of personality traits of 364 patients, only neuroticism was positively linked with self-reported hyperventilation symptoms (17).

Acute hyperventilation reduces arterial pCO2, resulting in alkalosis. Respiratory alkalosis produces the Bohr Effect, a left shift of the oxygen dissociation curve with increased binding of oxygen to hemoglobin and reduced oxygen delivery to the tissues. The alkalosis also causes a reduction in plasma Ca2+ concentration. Hypophosphatemia may be due to intracellular shifts of phosphorus caused by altered glucose metabolism (10). In chronic hyperventilation, bicarbonate and potassium levels may be decreased because of increased renal excretion (66). Finally, stress can produce a hyperadrenergic state that may trigger hyperventilation through beta-adrenergic stimulation (58).

Central and peripheral mechanisms have been postulated to produce neurologic symptoms during hyperventilation (05). Voluntary hyperventilation can reduce cerebral blood flow by 30% to 40% (29; 41). Symptoms and signs such as headache, visual disturbance, dizziness, tinnitus, ataxia, syncope, and various psychological symptoms may be produced by diminished cerebral perfusion.

The precise cause of generalized slowing of brain waves during hyperventilation is uncertain. This response is most common and pronounced in children and teenagers, diminishes in young adults, and is rare in the elderly. A brainstem-mediated response to hypocarbia has been proposed (65). The response may be due to metabolic rather than just hemodynamic factors (45). Hypoglycemia can accentuate the generalized slowing or buildup.

There have been additional postulates to explain the manifestations of hyperventilation. Muscle spasms and tetany may be due to respiratory alkalosis and hypocalcemia. The finding that there is no relationship between the rate of fall of pCO2 and the onset of dizziness and paresthesias suggests that symptoms may be due to hypophosphatemia (69). Hypophosphatemia can result in symptoms such as tiredness, dizziness, poor concentration, disorientation, and paresthesias. A hyperadrenergic state may result in tremors, tachycardia, anxiety, and sweating. Hypokalemia can cause muscle weakness and lethargy.

The cause of bilateral and unilateral paresthesias is not certain; evidence exists for both a central and peripheral mechanism. A reduction in the concentration of extracellular Ca2+ may increase peripheral nerve axonal excitability, resulting in spontaneous bursting activity of cutaneous axons, perceived as paresthesias (57). Lateralization of symptoms might be explained by anatomic differences in the peripheral nerves and their nutrient vessels (23).

Alternatively, symmetrically decreased cerebral perfusion could account for bilateral paresthesias and asymmetrically decreased perfusion for unilateral paresthesias. O'Sullivan and colleagues reported nonspecific, asymmetric slowing of brain waves in the hemisphere opposite to the side of unilateral paresthesias in hyperventilators and normal bilateral somatosensory evoked potentials (64). Although anatomic differences in the cerebral vasculature might explain the unilateral paresthesias, normal magnetic resonance angiographic findings in two cases argue against this (20). Additionally, there is a single report of asymmetrically decreased cerebral blood flow with decreased flow in the right parietal area with left-sided symptoms (20).

It is not known why unilateral paresthesias occur more often on the left side of the face and body. One hypothesis is that psychosomatic symptoms are associated with right hemisphere psychic processes. During stress and emotional arousal, the right hemisphere is activated more than the left (79). Symptoms of conversion or hyperventilation are more likely to occur on the left side of the face and body (23; 64). However, this hypothesis does not explain the increased frequency of left-sided paresthesias in normal subjects who are asked to hyperventilate.

Epidemiology

Hyperventilation syndrome occurs in about 6% to 11% of the general patient population (08). In a clinic that evaluated patients with dizziness, hyperventilation syndrome accounted for 24% of the cases (18). Most studies have reported hyperventilation syndrome occurring two to seven times more frequently in women than in men, with most patients ranging in age between 15 and 55 years (25). One large study reported that patients with acute hyperventilation syndrome ranged in age from 5 to 85 years and was particularly prevalent in women in their late teens (37). Hyperventilation syndrome may have a high incidence after COVID-19 infection (77).

Using a questionnaire, a French study found a prevalence of chronic hyperventilation syndrome in 24.7% of girls and 16.2% of boys among children ages 1 to 17 years (31). The prevalence of chronic hyperventilation is highest in middle-aged women (37). In studies of patients with neurologic symptoms of hyperventilation syndrome, the percentage of females ranges from 50% (06) to 67% (67; 11; 64) to 87% (68).

Prevention

For psychogenic cases of hyperventilation syndrome, avoidance of triggers is a preventative measure.

Differential diagnosis

Hyperventilation syndrome has organic and physiological as well as emotional and habitual causes. Less than 5% of hyperventilation has a solely organic cause, 60% has a psychogenic (emotional and habitual) basis, and the remainder has varying combinations (09). The variety of organic disorders that can result in hyperventilation include: (1) effects of salicylate, caffeine, topiramate (47), and other drugs; (2) cirrhosis and hepatic coma; (3) acute pain such as that accompanying a myocardial infarction; (4) splenic flexure syndrome, cholecystitis, fever, and sepsis; and (5) dissecting aortic aneurysm, respiratory dyskinesia, pulmonary embolism, pneumothorax, interstitial lung disease, asthma, and heat and altitude acclimatization (08; 07).

There is an association between hyperventilation syndrome diagnosis and a history of patients who were not hospitalized with COVID-19 (01). Hyperventilation syndrome was common in a prospective study of long COVID-19 patients with dysfunctional breathing without underlying disease to explain the symptoms (26).

Neurologic disorders that may cause hyperventilation include Rett syndrome, Joubert syndrome, Reye syndrome, pyruvate dehydrogenase deficiency, biotin-dependent multiple carboxylase deficiency, malignant hyperthermia, brainstem tumor, primary cerebral lymphoma, encephalitis, brainstem strokes, thalamic hemorrhage, syringobulbia, and neurogenic pulmonary edema due to intracranial hypertension (05). Severe hyperventilation can occur in the absence of psychiatric, respiratory, neurologic, or other organic abnormalities (04).

In patients diagnosed with hyperventilation syndrome by neurologists, the misdiagnoses of referring physicians have included epilepsy, migraine, multiple sclerosis, arteriovenous malformation, cerebrovascular disease, vertebrobasilar insufficiency, brachial neuritis, angina, malingering, vasovagal attacks, functional illness, hypoglycemia, and cerebral tumor (06; 67). Hyperventilation might also contribute to some of the manifestations of migraine, such as syncope.

Cardiac abnormalities should certainly be considered in those patients with chest pain. The distinction between angina and hyperventilation syndrome at times is difficult because hyperventilation can produce electrocardiogram changes, including T-wave inversions, systolic time-segment depression, and systolic time-segment elevation in patients without coronary artery disease (34; 16). Some patients with angina may hyperventilate in response to their pain and anxiety. The symptoms of mitral valve prolapse and hyperventilation syndrome overlap. Some patients may have symptoms due to hyperventilation (76).

The symptoms of panic attacks greatly overlap with hyperventilation syndrome, and the differential diagnosis is quite similar (78; 72). The pathophysiology of panic attacks is controversial; hyperventilation syndrome has been suggested as a cause (52; 63; 22) and as an inducer of panic attacks (61). Patients diagnosed with panic attacks that report brief episodic unilateral paresthesias or weakness may have the neurologic symptoms reproduced with the hyperventilation test (14).

Tonic spasms (paroxysmal dystonia) of multiple sclerosis can be somewhat similar to the muscle spasms, tetany, and paresthesias of hyperventilation syndrome. The episodes consist of brief, recurrent, often painful, abnormal posturing of one or more extremities without alteration of consciousness, loss of sphincter control, or clonic movements. They last for 10 seconds to 3 minutes and recur as often as 30 times daily. Some patients may experience brief sensory disturbances in the involved extremity before or during the attack. Because the episodes can be the initial presentation of multiple sclerosis (33) and can be triggered by hyperventilation (71), diagnostic confusion might result.

Diagnostic workup

The acute form of hyperventilation syndrome is easily recognized. However, the chronic form is less easily recognized because the breathing rate is not reported as rapid or does not appear rapid and because the symptoms may appear atypical. For example, a respiration rate of 18 per minute combined with an increased tidal volume of 750 mL per minute may lead to overbreathing that is not easily detectable. Because the chronic disorder is intermittent, spot arterial pCO2 or end tidal volume pCO2 results can be normal. The diagnosis depends on reproducing some or all of the symptoms with the hyperventilation provocation test and excluding other possible causes by either clinical reasoning or laboratory testing when indicated. Patients frequently report only one or two symptoms but, on performing the hyperventilation provocation test, report other symptoms that appear during their typical episodes that they had forgotten.

The hyperventilation provocation test can be performed with either an increased ventilation rate of up to 60 per minute or simply deep breathing for 3 minutes (56). Based on a study of healthy subjects, a minimum duration of 3 minutes and end-tidal pCO2 decreasing to at least 1.9 kPa or dropping well over 50% of baseline should elicit symptoms in most people (38). Dizziness, unsteadiness, and blurred vision commonly develop within 20 to 30 seconds, especially with the patient in the standing position; paresthesias start later (56). Chest pain is reported by 50% of patients after 3 minutes of hyperventilation and by all by 20 minutes (19). For clinical purposes, measurement of end tidal volume pCO2 is not necessary. In addition, there is no clear correlation between paCO2 and neurologic signs (73). The hyperventilation provocation test should not be performed in patients with ischemic heart disease, cerebrovascular disease, pulmonary insufficiency, hyperviscosity states, significant anemia, sickle cell disease, or uncontrolled hypertension (08).

For some patients with hyperventilation syndrome, symptoms cannot be reliably reproduced during the hyperventilation provocation test or even on consecutive tests (37). In some cases, the hyperventilation provocation test lacks test-retest reliability (53). For others, antecedent anxiety and stress, not present during the test, may predispose to symptom formation, perhaps because of a hyperadrenergic state (58; 67). Different patterns of hyperventilation with different respiratory rates, tidal volumes, and durations may induce different symptoms (32; 38). Finally, as a response to a change in body position from supine to standing, patients with hyperventilation syndrome have an accentuated increase in ventilation that can be calculated with noninvasive measurements of pulmonary gas exchange, and that distinguishes them from healthy subjects (59).

Interestingly, in a study of 50 patients with electrophysiologically proven carpal tunnel syndrome who presented to outpatient surgery for decompression, 86% had their symptoms of carpal tunnel reproduced by hyperventilation with no false positives (03).

A double-blind, placebo-controlled study found the hyperventilation provocation test invalid (39). Because hyperventilation seemed a negligible factor in the experience of spontaneous symptoms, Hornsveld and colleagues even recommended avoiding the term "hyperventilation syndrome." However, the study may be flawed because of the method of patient selection. Patients were referred because of a suspicion of hyperventilation syndrome and not based on reproduction of symptoms on a hyperventilation provocation test. Moreover, the presenting symptoms of subjects were not provided. Because the symptoms of hyperventilation syndrome can indeed be vague and nonspecific and because symptoms sometimes occur only with certain types of anxiety or stress, their conclusion may not apply to different population subsets (62). The subjects' symptoms may have been due to chest wall pain or panic attacks.

Alternatively, the Nijmegen questionnaire (a list of 16 symptoms rated on a 5-point scale from never to very often) can screen for hyperventilation syndrome. The efficacy of this questionnaire has been evaluated, revealing the sensitivity to be 91% and the specificity to be 95% (when using the clinical diagnosis based on the pattern of complaints as the gold standard) (80). In a consecutive series of 100 patients in a neuro-otology practice, 23% of patients seen for vestibular assessment were diagnosed with hyperventilation syndrome; 74% of these would have potentially remained undetected had the Nijmegen questionnaire not been used (40).

From my experience with patients with predominantly neurologic complaints, the concept of hyperventilation syndrome is valuable and the hyperventilation provocation test, despite its recognized shortcomings (24), is useful. In the individual case, if the hyperventilation provocation test fails to reproduce the symptoms but clinical suspicion persists, treatment such as breath holding, slow breathing, or breathing into a paper bag can certainly be suggested on a trial basis.

Management

The various treatments for hyperventilation that have been proposed include patient reassurance and education, instructions to hold the breath, breathe more slowly, or breathe into a paper bag, along with breathing exercises and diaphragmatic retraining, biofeedback, hypnosis, psychological and psychiatric treatment, and medications such as beta-blockers, benzodiazepines, and antidepressants (05). A study of nonpharmacologic treatments found efficacy for educational sessions, breathing techniques and retraining, and progressive relaxation; the greatest improvement occurred in the group given an explanation and eight sessions of breathing retraining (60). A small study found benefit from “grounding therapy,” a physical exercise inspired by African dance (70). A small pilot study found benefit from acupuncture (27). There is a lack of well-controlled treatment trials comparing these approaches, including breathing exercises (36; 42).

In my experience, most patients respond to reassurance, education, and instructions to hold their breath, breathe more slowly, or breathe into a paper bag. Providing the patient with written materials such as those used by Lance may be worthwhile (46). If significant symptoms of stress, anxiety, or depression are present, use of appropriate medication and psychological or psychiatric referral may be helpful.

Special considerations

Pregnancy

Although hyperventilation syndrome has often been seen during pregnancy, studies on the incidence are not available.