Clinical manifestations

Presentation and course

Clinical features of high-pressure neurologic syndrome vary according to the depth and the gas mixture used. Those encountered with the commonly used helium-oxygen mixture can be summarized as follows (18):

Symptoms

Signs

Neurologic

Neuropsychiatric

Tremor. In humans, tremor may appear at 16 absolute atmospheric pressure (150 m) and progressively intensifies with an increase of pressure. Both hyperlocomotor activity and tremor are more sensitive to increasing pressure in experimental animals. The following types of tremor are seen in high-pressure neurologic syndrome: at rest, postural, and on intentional movement. The tremor frequency is 8 to 12 Hz and does not change with increasing pressure; only the amplitude increases. It is more severe with faster compression.

Postural sway. Increased ambient pressure causes an increase in postural sway as demonstrated in a simulated saturation dive to 240 meters of sea water (2.5 MPa) and seems to be related to absolute pressure (16). It may be due to an effect on the vestibulo-ocular reflex.

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.

Myoclonus. Myoclonus is seen in humans at 50 to 60 absolute atmospheric pressure, whereas in rats it appears at 70 to 80 absolute atmospheric pressure.

Reflex disturbances. The existence of hyperbaric hyperreflexia is well established and may occur after compression at 25 absolute atmospheric pressure or more. 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.

Convulsions. These are seen in experimental animals but not in humans.

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. Mild to moderate neuropsychological changes have been seen in some divers.

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, but repeated episodes of high-pressure neurologic syndrome in a diver may lead to long-term neuropsychological sequelae. This topic has not been studied thoroughly, but 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.

Biological basis

Etiology and pathogenesis

Excessive atmospheric pressure. High-pressure neurologic syndrome is primarily a result of excessive atmospheric pressure on different structures in the central nervous system, 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 risk factor predisposing to this syndrome. The rate of compression influences the manifestations of high-pressure neurologic syndrome. 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 on for days. In some cases, complaints such as memory disturbances take several months to resolve. Eventually, all divers who experience only high-pressure neurologic syndrome recover. 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.

Genetic factors. Intraspecies and interspecies variations of high-pressure neurologic syndrome exist. There appears to be a genetic basis for adaptation to high-pressure neurologic syndrome. Some individuals are more susceptible than others to development of the full syndrome, or manifest various symptoms at different pressures. A single mutation in 3'UTR (untranslated region) of vacuolar protein sorting gene 52 (Vps52) is associated with greater than 60% of the seizure risk difference between the high- and low-risk seizure susceptibility strains of mice (22). By gene homology with human VPS52, this mutation may be considered a risk factor for seizures on exposure to high pressure.

Inappropriate breathing gas mixtures. Contributing factors to development of high-pressure neurologic syndrome include the following:

Cellular mechanisms. The cellular mechanisms responsible for high-pressure neurologic syndrome are difficult to study using classic in vitro electrophysiological methods due to the physical barrier imposed by the sealed pressure chamber and mechanical disturbances during tissue compression. Immersion to depth brings about an increase in pressure of 0.1 MPa for each 10 m of seawater, and signs of high-pressure neurologic syndrome appear at a depth of 120 m and pressure of 1.3 MPa (12 atm); its effects intensify at greater depths. Moderate pressure stimulates certain solitary complex neurons by a mechanism that possibly involves an increased cation conductance, but that does not involve free radicals. Sensitivity of the nervous system to high pressures may be compensated by a physiological adaptive response.

Role of neurotransmitters in the pathogenesis of high-pressure neurologic syndrome. Reserpine, a monoamine-depleting alkaloid, lowers the convulsive-onset hyperbaric pressure. Since this observation, various neurotransmitters and amino acids have been implicated in the pathogenesis of high-pressure neurologic syndrome: GABA, dopamine, serotonin (5-HT), acetylcholine, and glutamate. Conclusions from various studies on this subject are:

Dopamine. In divers exposed to hyperbaric experiments, psychotic symptoms appear that are the result of dopamine hyperactivity. Increase in striatal dopamine induced by hyperbaric pressure has been attributed to release of both newly synthesized and vesicular dopamine. Depletion of dopamine in Parkinson disease leads to resting tremor, but the frequency is 3 to 8 Hz, whereas in high-pressure neurologic syndrome it is 8 to 12 Hz.

Exposure to helium under hyperbaric conditions leads to activation of 5-HT(2A) receptors and depression of 5-HT(2C) receptors. Therefore, HT(2A) receptor antagonists and 5-HT(2C) receptor agonists can reduce dopamine hyperactivity.

Using nitrous oxide as a narcotic gas in experimental animals, the measurements of the extracellular dopamine in the striatum reflect an opposing effect of pressure because the decrease in dopamine release is lower with increasing pressure. Changes in dopamine release and metabolism during high-pressure helium exposure reflect the effect of the pressure per se, whereas the intrinsic effects of narcotic gases, although sensitive to pressure, is revealed by hyperbaric nitrogen exposure.

Gamma amino butyric acid (GABA). The main evidence for the involvement of GABA is that drugs such as valproic acid, which are GABA enhancers, prevent the changes associated with this syndrome. Valproic acid not only increases GABA levels, but also simultaneously decreases the excitatory transmitter aspartate in the brain. The latter appears to be a more significant effect. The GABA antagonist picrotoxin is a convulsant, but baclofen (a GABA analog) and muscimol (a GABA agonist) do not provide any protection against high-pressure neurologic syndrome. Therefore, GABA may not be the primary neurotransmitter and excitatory amino acids may contribute to the appearance of behavioral symptoms. GABA enhancers may reduce the excitability of the central nervous system and tendency for seizures, but drugs that decrease the excitatory neurotransmission might be more beneficial.

N-methyl-D-aspartate. Enhanced glutamate release in various subcortical structures has been shown to contribute to myoclonic activity observed at 85 absolute atmospheric pressure. Cholinergic agents can induce epileptic seizures as acetylcholine potentiates response to N-methyl-D-aspartate. Intracerebroventricular injection in the rat of beta-D-aspartyl aminomethylphosphonate or Y-D-glutamylaminomethylsulfonate has been shown to increase the onset pressure for the initial tremor phase in high-pressure neurologic syndrome.

Development of hyperlocomotor activity after exposure to hyperbaric environment requires N-methyl-D-aspartate activity at both the striatal and pallidal levels. In contrast, myoclonus mainly requires N-methyl-D-aspartate activity at the pallidal level. Therefore, N-methyl-D-aspartate activity neurotransmission in the striatopallidal pathway plays variable roles in the movement disorders induced by high atmospheric pressures while breathing helium-oxygen mixtures.

N-methyl-D-aspartate receptor or reduced GABAergic inhibition may be involved in neuronal hyperexcitability observed at high pressure. Significant hyperexcitability is attained at pressure only when the normal fast field excitatory postsynaptic potentials are intact.

Under hyperbaric conditions, more than double Mg2+ and by dl-2-Amino-5-phosphonopentanoic acid are required to block N-methyl-D-aspartate receptors as compared to normobaric conditions, indicating that hyperbaric pressure reduces the efficacy of these receptor blockers (23). Thus, high pressure modification of N-methyl-D-aspartate receptors activity significantly contributes to CNS hyperexcitability in high-pressure neurologic syndrome.

Potentiation by pressure of the N-methyl-D-aspartate-sensitive glutamate receptor can lead to increased excitability within the cerebellum and excessive calcium entry into neurons and neuronal cell death within the cerebellum, which may give rise to delayed motor and cognitive dysfunction depending on the extent of hyperbaric exposure, but this remains to be proven.

High pressure differentially affects ionic currents of 8 specific N-methyl-D-aspartate receptor subtypes generated by the co-expression of GluN1-1a or GluN1-1b with 1 of the 4 GluN2(A-D) subunits. A further study reports that 8 GluN1 splice variants, when co-expressed with GluN2A, mediate different ionic currents at normal and high pressure of 45 atm, indicating that both GluN1 and GluN2 subunits play a critical role in determining N-methyl-D-aspartate receptor currents under normal and high pressure conditions (08). Because of the differential spatial distribution of various N-methyl-D-aspartate receptor subtypes in the CNS, these data explain the mechanism governing the complex signs and symptoms of high-pressure neurologic syndrome as well as for the long-term health sequelae of repetitive deep dives by professional divers. These investigators now report that the N-methyl-D-aspartate receptor subtype that contains GluN1-4a/b splice variants exhibits "dichotomic" (either increased or decreased) responses at high pressure, which can be used as a model for studying reduced response in N-methyl-D-aspartate receptor at high pressure (08). Successful reversal of other N-methyl-D-aspartate receptor subtype responses by current reduction may enable the elimination of the reversible malfunctioning short-term effects, or even deleterious long-term effects, induced by increased N-methyl-D-aspartate receptor function during exposure to high pressure. Molecular dynamics simulations of the N-methyl-D-aspartate receptor structure, embedded in a dioleoylphosphatidylcholine lipid bilayer, dissolved in water at 1 bar, under hydrostatic pressure at 25 bar, and in helium at 25 bar (09). Further analysis of important regions of the N-methyl-D-aspartate receptor protein revealed that high pressure helium, not hydrostatic pressure per se, alters the receptor tertiary structure via protein-lipid interactions, indicating that helium in divers' breathing mixtures may partially contribute to symptoms of high-pressure neurologic syndrome. Results of a further study indicate that there is no increase in surface expression of N-methyl-D-aspartate receptors in the cell membrane under high pressure conditions (10). In contrast, consistent increase in glyceraldehyde-3-phosphate dehydrogenase and β-actin, cytosolic proteins involved in various cellular control processes, was discovered, suggesting a general cellular stress response to high pressure. Understanding the precise hyperexcitation mechanism(s) of N-methyl-D-aspartate receptor R subtypes and other possible neurotoxic processes during high pressure exposure may provide the key for eliminating the adverse, yet reversible, short-term effects of high-pressure neurologic syndrome.

Serotonin. Decreased serotonergic activity in striatal neurons probably contributes to hyperexcitability associated with high-pressure neurologic syndrome. Motor symptoms of high-pressure neurologic syndrome are attributed to changes in neural excitability at spinal and midbrain levels. Serotonin may be implicated in hyperbaric spinal cord hyperexcitability. Quinolinic acid and kynurenine are metabolites of 5-HT that are endogenous convulsants. Precise balance between these 2 metabolites may be an important determinant of onset of high-pressure neurologic syndrome.

Multiple pathomechanisms. Synaptic depression that requires less transmitter turnover may serve as an energy-saving mechanism when enzymes and membrane pumps activity are slowed down at pressure. Lethargy and fatigue, as well as reduction in cognitive and memory functions, are compatible with this state. Maladaptation to high pressure may lead to a pathophysiological response, ie, high-pressure neurologic syndrome. Clinical manifestations with multiple pathomechanisms are:

Tremor. This may be considered an exaggeration of physiological tremor by high-pressure stress. The tremor differs from that of Parkinson disease (3 to 8 Hz). Pathogenic mechanism may involve activation of neuronal noradrenergic circuits activated through beta-receptors by an increased amount of noradrenaline.

Tremor is a manifestation of hyperexcitability of the central nervous system and is central rather than peripheral in origin. High pressure may reduce the threshold for tremor-associated activity by altering the balance between excitation and inhibition. High pressure, despite its general depressant effect on the synaptic transmission, might increase excitability in neurons wherein excitatory input is strongly facilitating and tonic inhibition is desensitizing.

Convulsions. These are subcortical in origin. Pressure has no effect on the cerebral cortex, but it provides a substantial measure of inhibition to counteract the convulsive activity arising in the subcortical region. Convulsions are an expression of hyperexcitability arising as a perturbation of strychnine-sensitive mechanisms. Paroxysmal EEG discharge accompanying epileptic seizures is not seen in convulsions of high-pressure neurologic syndrome in experimental animals. Although it has been noted that clonic high-pressure neurologic syndrome convulsions are like uremia-induced myoclonic seizures, no evidence has been produced that a metabolic encephalopathy is associated with high-pressure neurologic syndrome.

Memory impairment. The perforant (temporoammonic) path transfer of cortical information to the hippocampal formation is important for memory acquisition. High pressure may alter information transfer in this connection.

Psychiatric symptoms. Psychotic-like episodes in divers exposed to high pressure 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, it is suggested that these disorders are in fact paroxysmal narcotic symptoms that result from the sum of the individual narcotic potencies of each inert gas in the breathing mixture. There are cellular interactions between inert gases at raised pressure and pressure itself.

Rats subjected to hyperbaric pressure show behavioral changes during pressure and minimal neuropathologic alterations, but no lasting sequelae are noted. Findings in this animal model of high-pressure neurologic syndrome may explain psychoses seen in deep divers.

Relation of high-pressure neurologic syndrome to serotonin syndrome. Clinical features of serotonin syndrome are changes in mental status, restlessness, myoclonus, hyperreflexia, shivering, and tremors. Behavioral changes in rats exposed to pressure resemble serotonin syndrome and are consistent with activation of 5-HT receptor subtype 1A. Sensorimotor hyper-reactivity to acoustic startle observed in rats subjected to rise of pressure from 0 to 50 barometric pressure can be included as a component of serotonin syndrome.

Role of neuronal calcium. High-pressure neurologic syndrome, encountered by divers breathing helium-oxygen mixtures at high pressures, and its known antagonism by nitrogen may be due in part to effects on neuronal [Ca2+]i levels because an increase in these would most likely result in an excitatory response. High-pressure depresses single synaptic release by reducing [Ca2+]i entry, whereas slowing of synaptic frequency response is independent of [Ca2+]i. These findings increase our understanding of high-pressure neurologic syndrome experienced by deep divers.

Role of calcium ion channels. Modulation of various voltage-dependent calcium channels by high pressure is a part of the mechanisms of high-pressure neurologic syndrome and may explain some of its signs and symptoms. Changes in the response to depolarization influence these channels' functionality in neurons. Pressure selectivity augmented the current in CaV1.2 and depressed it in CaV3.2 channels (04). Decrease in locomotor activity, myoclonus, tremors, changes in EEG, and sleep disorders may be the manifestation of these changes. Further studies of high-pressure neurologic syndrome mechanism by examining the effect of high pressure on Ca(2+) currents in neuronal voltage-dependent calcium channels showed that high pressure augmented the CaV 2.2 current amplitude, much less so in a channel variation containing an additional modulatory subunit, and had almost no effect on the CaV 2.1 currents (03). The differential effects on channel kinetics indicate that signs and symptoms of high-pressure neurologic syndrome result, at least partially, from pressure modulation of different voltage-dependent calcium channels.

Pressure effects on CNS synapses. In high-pressure neurologic syndrome, synaptic transmission is usually depressed at all synapses. Studies show that pressure effects may be selective for various types of synapses in the CNS. 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 (15). This phenomenon is mimicked by Ca(2+) channel blockers, supporting the concept that high pressure is involved in synaptic release mechanism(s).

Adaptation to high pressure. An experimental study on rat hippocampal slices has shown that medial perforant path synapses, connecting entorhinal cortex with the hippocampal formation, can be modulated and may have the ability to conserve their dynamic properties under different conditions, including exposure to high pressure high pressure (26). Such a mechanism may also explain adaptability and regular performance of diving mammals such as whales, which can dive to 1000 meters, apparently without neurologic problems. Further studies of activation of medial perforant path with single and 50 Hz frequency stimuli that simulated physiologic and deleterious conditions reveal that the pressure and [Ca2+]o produce an inverse modulation on synaptic input strength and network excitability, suggesting that networks adjust gain as an inverse function of synaptic inputs' strength (27). This mechanism indicates adaptation to variable pressure and other physiological as well as pathological conditions and may explain the increased sensitivity to strong sensory stimulation suffered by human deep-divers.

Role of TREK-1 channel. TREK-1 knockout mice have a higher threshold of resistance to the narcotic effects of nitrogen as well as death following recurrent epileptic seizure induced by high pressure (28). Manipulation of TREK-1 potassium channels may have a key role in neuroprotection in high-pressure neurologic syndrome.

Comparison of the effects of anesthetics and high-pressure nitrogen. Conventional anesthetics, including inhalational agents and inert gases, such as xenon and nitrous oxide, interact directly with ion channel neurotransmitter receptors. The research performed at the level of basal ganglia of the rat brain, and particularly the nigrostriatal pathway involved in the control of the motor, locomotor, and cognitive functions, disrupted either by nitrogen narcosis or high pressure, have indicated that GABAergic neurotransmission is implicated via GABA receptors in both cases.

Role of breathing gas mixtures. Further research of a correlation between individual sensitivity to nitrogen narcosis and protection by nitrogen against central nervous system oxygen toxicity may lead to a personal oxygen limit in mixed-gas diving based on the diver’s sensitivity to nitrogen narcosis.

Prevention

High-pressure neurologic syndrome was previously a problem of deep professional diving, but currently, some recreational divers are going beyond the depth of 200 meters, and preventive measures should be considered for them as well.

Reduction of the speed of compression. The incidence and severity of high-pressure neurologic syndrome can be lowered by reducing the speed of compression.

Modification of gas mixtures. The introduction of heliox extended the limits of diving without nitrogen narcosis and made the onset of high-pressure neurologic syndrome possible. Nitrogen addition to the breathing mixture has been suggested for reversal of high-pressure neurologic syndrome by its narcotic effect. Nitrogen can diminish tremor significantly but has no effect on the EEG abnormalities. Addition of 6% to 8% nitrogen between 600 to 700 meters does not prevent convulsions in baboons if the compression speed is fast and nonexponential. Trimix (He + N2 + O2) has been shown to prevent neurotransmitter turnover under hyperbaric pressure in some brain regions studied in experimental animals. Symptoms of high-pressure neurologic syndrome can be prevented by addition of hydrogen to the heliox mixture.

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 (20). 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. Repetitive breath-hold diving, seen in Ama divers of Japan, can lead to the accumulation of nitrogen in blood and tissues, which may give rise to decompression illness.

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

Hyperbaric oxygen neurotoxicity. 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 have demonstrated that the hyperexcitability of high-pressure neurologic syndrome is induced mainly by NMDA receptors (NMDARs). Studies have demonstrated that 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 (11).

Associated or underlying disorders

Some of the 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

Neurologic examination. 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.

Electroencephalographic changes. Visual analysis of EEG records during hyperbaric exposure of divers usually reveals increased theta activity that occurs at the depth of 60 meters while breathing air. Frontal midline theta activity has been noted to be associated with features of high-pressure neurologic syndrome such as euphoria and laughter at pressures greater than 21 absolute atmospheric pressure.

Human somatosensory-evoked potential studies have shown that latencies of all peaks following the initial cortical P1 were shorter at depth than in surface control recording. This is consistent with a state of hyperexcitability in the brain that characterizes high-pressure neurologic syndrome.

Neuropsychological evaluation. Neuropsychological examination of deep divers is an important supplement to the neurologic examination. The following 5 tests are employed most frequently and consistently for neuropsychological testing of the divers in the United States Navy:

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 (06).

Management

Helium. The noble gas helium has many applications owing to its distinct physical and chemical characteristics, ie, its low density, low solubility, and high thermal conductivity. It can be used as a neuroprotective in several neurologic disorders that include high-pressure neurologic syndrome (07). Because of its reduced solubility, little helium is taken into cell membranes at high pressures with lack of narcotic effect (14).

Hydrogen. 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 (21).

Anesthetics. 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. The use of narcotic gas (nitrogen or hydrogen) added to a helium-oxygen mixture reduces some symptoms of the high-pressure neurologic syndrome but may aggravate others due to an additional effect of the narcotic potency of the gas.

Barbiturates. These have been investigated and found to have an anticonvulsive effect over a wide range of pressures. Phenobarbital is the most effective compound in this group.

Anticonvulsants. 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 notably effective as 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.

Nonanesthetic compounds. Nonanesthetic compounds related to 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 the rat, suggesting that targeting of sites other than those involved in anesthetic activity can be effective against high-pressure neurologic syndrome.

Dopaminergic receptor antagonists. High pressure-induced locomotor hyperactivities, but not myoclonus, correlate with pressure-induced striatal dopamine increase and are reduced by intracerebroventricular or intrastriatal administration of dopaminergic receptor antagonists as well as N-methyl-D-aspartate antagonists in experimental animals. The proposed mechanism of this effect is by reduction of glutamate-evoked activity. The N-methyl-D-aspartate receptor has been repeatedly implicated in generation of high-pressure neurologic syndrome, with increasing response as the pressure increases. This, along with differential response at 8 different subtypes of N-methyl-D-aspartate receptor in different brain regions, is one of the key elements in causing long-term irreversible CNS impairment (24).

Because the 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.

Limitations of pharmacological approaches. Most of the compounds listed above cannot be used in divers as they would impair the ability to dive.

The pharmacological approach is based on the resemblance of high-pressure neurologic syndrome to serotonin syndrome. 5-HT1A receptor antagonists may provide a promising approach to prevent high-pressure neurologic syndrome.

A systematic review of human and animal studies of medications in the hyperbaric environment has not revealed any evidence of significant risks due to changes in pharmacologic mechanisms, and use of most medications is not a contraindication to diving (17). Finally, a note of caution is warranted about agents that delay the onset of high-pressure neurologic syndrome, as they may also reduce acclimatization to the stimulus that causes the condition.

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. Man will always aspire to dive deeper in the ocean, but the possible neurologic consequences should be weighed against any potential advantages of manned explorations versus those done with robotic devices. Based on previous data and the critical volume model of inert gas narcosis as well as development of new saturation deep diving programs, it is estimated that the ultimate depth for saturation diving could be around 1000 meters (01).

Hyperbaric oxygen. This can be considered for delayed neurologic sequelae, but precautions must be taken to avoid oxygen toxicity and control seizures (19).

Selection of suitable low risk individuals for deep diving. There are individual variations in tolerance for deep diving and susceptibility to development of high-pressure neurologic syndrome. The genetic basis for this variation has not been studied. Based on a study of CNS barosensitivity in mice by brainstem auditory-evoked potentials, the method has been suggested for selection of suitable individuals for deep sea diving to reduce the occurrence of high-pressure neurologic syndrome (13). Another suggestion for prevention of high-pressure neurologic syndrome is selection of least susceptible divers (25).

Outcomes

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.