Clinical manifestations

Presentation and course

Clinical features of high-pressure neurologic syndrome vary according to the depth and the gas mixture used. Motor signs are often the initial manifestations of high-pressure neurologic syndrome (01).

Clinical features encountered with the commonly used helium-oxygen mixture in humans include the following (01; 02; 52; 13; 40; 32; 33; 44):

Vertigo. Vertigo is not ameliorated by nitrogen (01). The common symptoms of vertigo and nausea with high-pressure neurologic syndrome have been attributed to a pressure-related decrease in the normal cerebellar inhibitory modulation of the vestibular nuclei (12).

Opsoclonus. This is an involuntary, constant jitter of the eyes that is random in direction. It is the earliest sign of high-pressure neurologic syndrome and is seen at about 160 meters (32).

Tremor. In humans, tremor may appear at depths corresponding to 16 times atmospheric pressure (150 m), and it progressively intensifies with further increases of pressure. Rest, postural, and intention tremors may be seen in high-pressure neurologic syndrome (01; 32).

Many divers develop a rhythmic 5 to 8 Hz tremor in the arms, trunk, and even lower jaw (01). The most common form of tremor, which mainly occurs during active movements, mimics the intention tremor seen in cerebellar disorders and mainly appears from approximately 200 msw. Meter sea water (msw) is a metric unit of pressure that is used in underwater diving and is defined as one tenth of a bar. A rest tremor may also be seen, but this tremor is more inconstant and less disabling. It is also more rapid than the resting tremor seen in parkinsonism. These involuntary movements are enhanced by compression and will, therefore, become worse with increasing depth but then disappear when the pressure is stabilized.

Such tremors can be incapacitating for some divers, whereas other divers are not significantly affected (01). High-pressure tremors can be ameliorated by adding some nitrogen to the breathing mixture (01).

Myoclonus. Myoclonus is seen in humans at 50 to 60 absolute atmospheric pressure. In animal studies (eg, in mice), myoclonus has been a harbinger of seizures, but seizures have never been reported in man in association with high-pressure neurologic syndrome (01; 32).

Postural sway. Increased ambient pressure causes an increase in postural sway as demonstrated in simulated saturation dives to 240 meters of sea water (2.5 MPa) (29).

Reflex disturbances. Hyperbaric hyperreflexia may occur after compression at 25 absolute atmospheric pressure or more. The Hoffmann reflex has been recorded at 43 absolute atmospheric pressure.

Sleep disorders. Sleep is disrupted at 30 absolute atmospheric pressure; awake periods and sleep stages 1 and 2 are increased, and REM periods are decreased. In deeper diving, stage 1 sleep increases, but stage 4 sleep tends to decrease.

Cognitive and memory disturbances. Disturbances of long-term memory and a decrease of psychomotor performance have been reported following high-pressure neurologic syndrome. However, no residual memory deficits have been shown in monkeys following high-pressure neurologic syndrome. In some cases, the reported memory disturbances are attributable to stress (31; 01). Mild to moderate neuropsychological changes have been seen in some divers.

Psychiatric symptoms. In divers exposed to hyperbaric experiments, psychosis and anxiety have been reported, mostly in anecdotal case reports (48). Diving anxiety among professional and military divers is relatively transient and, when present, personality factors (eg, low self-control and emotional instability) are important contributors (03).

Prognosis and complications

Most of the signs and symptoms of high-pressure neurologic syndrome are reversible on gradual ascent to the surface, and usually no long-term sequelae are seen. There are no recognized complications. No evidence for neuropsychological impairment was reported in various long-term follow-up studies of United States Navy divers who had experienced repeated exposures to high pressure.

Some divers experience pressure-induced brain dysfunction, which persists for a transient post-dive period. Focal neurologic findings that were not present before apparently uncomplicated dives may be found after the dives (01; 02; 52). Findings have included asymmetrical plantar responses, unilateral weak abdominal reflexes, and asymmetries in the distal perception of vibration sense (01; 52). Occasionally, subjective or objective neurologic symptoms may persist for weeks after an accomplished dive. EEG changes have been reported up to 3 weeks post-dive (01; 02). Transitory neurologic signs indicating focal cerebral dysfunction are found immediately post-dive in less than 20% of divers and presumably reflect the unmasking of preexisting subclinical minimal CNS lesions (eg, from prior subclinical decompression sickness) (02; 52).

Aarli and colleagues studied a group of 23 professional divers before and after dives to 300 and 350 msw; 12 of these divers were also studied during the actual dive (02). All of the divers developed neurologic symptoms and signs during compression. Vertigo, nausea, intention tremor, ataxia, motor weakness, sensory symptoms, and reduced memory were the most prominent features. There were considerable individual differences. Neuropsychological and neurophysiological investigations performed after one dive showed no significant changes in any of the divers, but there was evident impairment in six divers who had performed two dives 3 months apart. The post-dive neuropsychological tests showed that an open-sea dive is more strenuous than a chamber dive and that both subjective and objective neurologic disturbances may persist for a long period after a 300 msw dive.

Todnem and colleagues studied 18 divers breathing heliox on a simulated dive to a depth of 360 msw (52). Two divers had mild ataxic signs and EEG changes after the dive, and one had impaired vibration sense in one lower extremity. Two divers had abnormal EEGs with slow waves and sharp potentials, primarily in the temporal regions. Cranial MRIs showed no changes. Divers with evidence of previous central nervous system injury, or a history of unconsciousness or previous decompression sickness, were more likely to develop neurologic signs.

Biological basis

Etiology and pathogenesis

The air we breathe is comprised of 20.9% oxygen, 79% nitrogen, and 0.1% inert gases. Atmospheric pressure at sea level is 14.7 pounds per square inch (psi). The standard atmosphere pressure unit (atm) is often used to relate a pressure value at depth to multiples of atmospheric pressure. Immersion to depth brings about an increase in pressure of 0.1 MPa, or approximately 1 atm for each 10 m of seawater, so at a depth of 10 m (approximately 33 feet), the pressure is approximately 2 atm. The megapascal (MPa) is a basic unit of pressure or tension measurement in the International System of Weights and Measures. For reference, 1 MPa equals 145 psi or approximately 10 atm. More precisely, 1 atm equals 101325 Pa, or equivalently 0.101325 MPa. Another pressure unit sometimes applied to underwater physiology and medicine is the bar, which is typically used for weather, aviation, and industrial purposes: 1 bar = 100,000 Pa. A now mostly obsolete unit is the "at" technical pressure unit, sometimes written "ata," which is short for “at absolute.”

Excessive atmospheric pressure. Signs of high-pressure neurologic syndrome appear at a depth of 120 meters and pressure of 1.3 MPa (12 atm). Its effects intensify at greater depths.

High-pressure neurologic syndrome is primarily a result of excessive atmospheric pressure on different structures in the CNS, particularly on the lipid component of cell membranes. Carbon dioxide retention due to restriction of lung ventilation caused by the high density of breathing gas mixture at great depths may be an additional etiologic factor. A faster rate of compression increases the intensity of high-pressure neurologic syndrome and decreases the pressure threshold for the onset of symptoms. The manifestations persist during a stay at a constant depth and decrease during decompression. The symptoms usually subside after the pressure is normalized, but some of these, such as lethargy, may linger for days. In some cases, memory disturbances take several months to resolve. There is no evidence of permanent neurologic sequelae or histopathologic changes in the brain resulting from high-pressure neurologic syndrome.

Various neurologic manifestations appear at different depths: tremor is seen at 200 to 300 meters, myoclonus at 300 to 500 meters, and EEG abnormalities are noted at 200 to 400 meters.

Inappropriate breathing gas mixtures. Contributing factors to the development of high-pressure neurologic syndrome include malfunction of the regulator controlling the gas mixture during diving, contamination of the air supply with exhaled gases, and overexertion with an inadequate increase in respiratory rate leading to carbon dioxide retention.

Pathophysiology

Tremor. Tremor may result, in part, from an exaggeration of physiological tremor by high-pressure stress. The mixed tremor types suggest that more than one mechanism is involved.

Psychiatric symptoms. Psychotic symptoms in divers exposed to hyperbaric experiments may appear in anecdotal case reports (48). Such cases have been attributed to either high-pressure neurologic syndrome, confinement in pressure chamber, the subject's personality, or the addition of nitrogen or hydrogen to the basic helium-oxygen breathing mixture used for deep diving. Alternatively, these disorders may be paroxysmal narcotic symptoms that result from the sum of the individual narcotic potencies of each inert gas in the breathing mixture.

EEG. The EEG may remain normal in divers who do not develop symptoms of high-pressure neurologic syndrome (01). Although there are considerable differences in the threshold for appearance of EEG anomalies, EEG changes commonly appear around depths of 200 msw (39; 01; 02). The EEG changes during compression are typically diffuse and symmetrical, but interhemispheric differences may appear (02). The first change observed is an increase of 5 to 6 Hz activity with gradual disruption of the alpha-rhythm. The EEG disturbances increase in severity with increasing pressure and are inevitably associated with intermittent bouts of somnolence (27). The EEG often normalizes when a stable pressure is obtained, but in some cases a delayed effect occurs with the appearance of symptoms of high-pressure neurologic syndrome (01; 02).

Somatosensory-evoked potential studies. Somatosensory-evoked potential studies show shorter latencies of all peaks following the initial cortical P1 at depth than in surface control recordings, which is consistent with a state of CNS hyperexcitability that characterizes high-pressure neurologic syndrome.

Animal studies. Many experiments have attempted to elucidate the mechanism(s) of high-pressure neurologic syndrome.

Reserpine, a monoamine-depleting alkaloid, lowers the hyperbaric pressure associated with convulsive-onset in mice (36). (Convulsions are not a part of the human high-pressure neurological syndrome.) Since this observation, various neurotransmitters and amino acids have been implicated in the pathogenesis of high-pressure neurologic syndrome in animal models: GABA, dopamine, serotonin (5-HT), acetylcholine, and glutamate (15; 16; 07; 28; 25; 47; 38; 41; 42; 17; 18; 19; 35). Inhibition of GABA transmission and augmented excitation of N-methyl-D-aspartate receptors (NMDA) are important components of experimental high-pressure neurologic syndrome, both of which bring about a net increase in CNS excitability (45; 55; 40; 18). However, it is not entirely clear whether the studies in rats, frogs or frog oocytes, or other animals have a direct bearing on the human syndrome even though they have often been portrayed as having a direct bearing, even on such uncommon manifestations as psychosis (04; 49; 35).

Modulation of different voltage-dependent calcium channels may also contribute (10; 09).

High pressure reduces cerebellar climbing fiber synaptic responses but does not affect its paired-pulse depression, suggesting that it is not linked to synaptic depletion (26). This phenomenon is mimicked by Ca(2+) channel blockers, supporting the concept that high pressure is involved in synaptic release mechanism(s).

An experimental study on rat hippocampal slices found that medial perforant path synapses, connecting entorhinal cortex with the hippocampal formation, can be modulated and may be able to conserve their dynamic properties under exposure to high pressure (50). This may help explain the ability of beaked whales to dive to 1000 meters for an hour to forage, apparently without neurologic problems (53). Pressure and extracellular calcium ions produce an inverse modulation on synaptic input strength and network excitability, suggesting that networks adjust gain as an inverse function of the strength of synaptic inputs (51).

Prevention

High-pressure neurologic syndrome was previously only a problem in deep professional diving, but some recreational divers are now going beyond the depth of 200 meters.

There are individual variations in tolerance for deep diving and susceptibility to the development of high-pressure neurologic syndrome. An obvious means of preventing high-pressure neurologic syndrome is to select the least susceptible divers based on their responses to simulated dives in hyperbaric chambers and then to initial performance in deep-diving environments (01; 44).

In general, the incidence and severity of high-pressure neurologic syndrome can be lowered by reducing the speed of compression in both humans and animals (01; 23).

The introduction of heloix extended the limits of diving without nitrogen narcosis, which then allowed exposures to depths where high-pressure neurologic syndrome is possible. The addition of 5% to 10% nitrogen to the heliox mixture ("trimix" can considerably reduce the occurrence and severity of high-pressure neurologic syndrome (Bennett and Rostain 1993). The use of narcotic gas (nitrogen or hydrogen) added to a helium-oxygen mixture reduces some symptoms of high-pressure neurologic syndrome but may aggravate others due to an additional effect of the narcotic potency of the gas. Nitrogen can diminish tremor significantly but has no effect on the EEG abnormalities, and, indeed, may exacerbate them. The addition of hydrogen has been successfully used as a preventive measure for decreasing the density of the breathing gas mixture, and it can also be used for amelioration of signs and symptoms of high-pressure neurologic syndrome (37).

Based on previous data and the critical volume model of inert gas narcosis as well as the development of new saturation deep diving programs, the ultimate depth for saturation diving could be around 1000 meters (05). Extending the present limits of deep diving by pharmacological means may induce yet unforeseen neurologic problems in the same way as did the emergence of high-pressure neurologic syndrome after the introduction of special gas mixtures to extend diving beyond 100 meters. The possible neurologic consequences and other health risks associated with deep diving should be weighed against any potential advantages of manned explorations versus those done with robotic devices.

A systematic review of human and animal studies of medications in the hyperbaric environment found no evidence of significant risks due to changes in pharmacologic mechanisms at depth (30). However, the potential of pharmacological prevention of high-pressure neurologic syndrome is inherently limited because most of the compounds identified as potentially protective in animals would impair the ability of humans to safely dive and work in that environment.

Pharmacological prevention studies in animals. Heliox selectively affects distinct neurochemical reactions associated with the effects of some, but not all, anticonvulsant drugs (06). Most anticonvulsants have a limited effect on high-pressure neurologic syndrome in experimental animals, and diphenylhydantoin has no effect. Only primidone, valproic acid, diazepam, and clonazepam are somewhat effective, possibly because they have an anesthetic effect at high doses. Although lamotrigine is protective in several models of neuronal excitation, it is ineffective in protecting against behavioral signs associated with high-pressure neurologic syndrome.

Some drugs with anticonvulsant properties against seizures induced under pressure show marked dependence on the chemical structure of various isomers, suggesting that pressure acts not by some general perturbation of the membranes of excitable cells but, rather, by a specific interaction (21).

Nonanesthetic compounds related to the steroid anesthetic alphaxalone have been found to ameliorate the tremor of high-pressure neurologic syndrome in rats. Nonanesthetic barbituric acid has some dose-dependent, anti-high-pressure neurologic syndrome activity in rats, suggesting that the targeting of sites other than those involved in anesthetic activity can be effective against high-pressure neurologic syndrome.

The finding that high pressure and strychnine (which acts by inhibiting postsynaptic glycine receptors, mostly in the spinal cord, to causing painful, involuntary skeletal muscle spasms) have additive effects has led to a hypothesis that pressure and strychnine may share a common mechanism in the production of convulsions and, specifically, that the hyperexcitability associated with pressure might arise from an action on glycine-mediated inhibitory processes (21). However, some drugs that are effective against high-pressure neurologic syndrome in animals act via an effect on excitatory NMDA receptor-mediated transmission rather than on inhibitory glycine-mediated transmission (47).

High pressure–induced locomotor hyperactivity, but not myoclonus, correlates with pressure-induced striatal dopamine increase and is reduced by intracerebroventricular or intrastriatal administration of dopaminergic receptor antagonists as well as N-methyl-D-aspartate antagonists, possibly mediated by the reduction of glutamate-evoked activity. The N-methyl-D-aspartate receptor has been repeatedly implicated in the generation of high-pressure neurologic syndrome, with increasing response as the pressure increases (43). Because N-methyl-D-aspartate transmission in the substantia nigra and globus pallidus plays a major role in the development of helium pressure-induced hyperlocomotor activity, manipulation of the excitatory amino acid (amino-methyl propionic acid and kainate) receptors may have therapeutic potential. Protective effects of dopamine (D1 and D2) receptor antagonists against locomotor and motor hyperactivity are probably independent of the processes involved in the striatal glutamate increase evoked by pressure as these compounds do not prevent the pressure-induced glutamate increase.

Differential diagnosis

Confusing conditions

High-pressure neurologic syndrome should be differentiated from the following conditions:

Inert gas narcosis. This is seen with air-breathing dives up to 100 meters and is characterized by euphoria, impairment of intellectual function, and impairment of neuromuscular coordination. Loss of consciousness may occur in later stages. It is attributed to nitrogen narcosis and resembles initial effects of some anesthetics. Breathing compressed air while at atmospheric pressures greater than 1 atmosphere causes absolute increases in the partial pressures of nitrogen and oxygen in the blood. The nitrogen atoms inhaled in the compressed air remain chemically unchanged in the blood, indicating that there may be a physical component to the involvement of nitrogen in causing narcosis. The effects may start at a depth of 70 meters and symptoms progress as a diver descends deeper to greater pressures (34). The narcotic symptoms observed are quickly reversible upon ascent.

In contrast to nitrogen narcosis, high-pressure neurologic syndrome involves hyperexcitability of the central nervous system, and although euphoria may be seen in early stages, intellectual impairment occurs only in later stages.

Decompression sickness. This is associated with release of nitrogen bubbles in the body following rapid decompression and can be easily differentiated from high-pressure neurologic syndrome. Some of the neurologic complications of decompression sickness, such as convulsions and intellectual deficits, are severe and persistent.

Oxygen poisoning. This may occur when diving to a depth beyond 20 meters and includes effects such as muscle twitching and seizures.

Divers who use closed-circuit breathing apparatus face the risk of hyperbaric oxygen neurotoxicity, which resembles high-pressure neurologic syndrome, and both are characterized by reversible CNS hyperexcitability, accompanied by cognitive and motor deficits.

Previous studies in animals found that the hyperexcitability of high-pressure neurologic syndrome is induced mainly by NMDA receptors (NMDARs). The response of NMDARs containing GluN1 + GluN2A subunits is increased by up to 50% at high-pressure helium whereas GluN1 + GluN2B NMDARs response was not affected under similar conditions (20).

Associated or underlying disorders

Some neurologic signs presented by those with high-pressure neurologic syndrome may be an unmasking of previous silent brain lesions due to decompression sickness.

Diagnostic workup

Patients with high-pressure neurologic syndrome should have a thorough neurologic examination with emphasis on detection of changes in tendon reflexes and any abnormal movements.

Neuropsychological examination of deep divers is an important supplement to the neurologic examination. The following five tests are employed for neuropsychological testing of U.S. Navy divers:

Another study showed there is no association between subjective measurements and neuropsychometric test results, and the study confirmed the feasibility of using the computerized test battery to monitor saturation divers at work. The high-pressure neurologic syndrome battery and Physiopad software could be an important tool for monitoring diver's health in the future (14).

A computerized test battery to monitor saturation divers at work is feasible (14).

Management

The symptoms of high-pressure neurologic syndrome usually ease after decompression, but lethargy may continue for a while. Eventually, all of the divers who experience only high-pressure neurologic syndrome recover with no relevant permanent neurologic sequelae or histopathological lesions in the brain.

Special considerations

Pregnancy

No information is available, as pregnant women usually do not engage in deep diving.

Anesthesia

Antagonism between pressure and anesthesia is known, but the mechanism is not clear. General anesthetics have been used to protect animals and humans from central nervous system disturbances induced by pressure.