High-pressure nervous syndrome or high-pressure neurological syndrome (HPNS) is characterized by neurological, psychological, and electroencephalographic (EEG) abnormalities during dives deeper than 150 meters with breathing helium-oxygen gas mixtures. The term “neurological” has been used, preferably. Signs and symptoms depend on the speed of compression and the hydrostatic pressure attained. In other words, the faster the compression rate and the higher the pressure, the more severe the clinical presentation will be. Thus, HPNS is one of the significant limitations of deep diving.
HPNS primarily results from the increased atmospheric pressure on the central nervous system (CNS), which leads to hyperexcitability of CNS.
There is no reported epidemiological data about HPNS in the literature.
Although the underlying mechanism has not been proved yet, there are several theories about HPNS pathophysiology.
One of the general assumptions is about the compression effect of pressure, possibly in the lipid component of cell membranes of the CNS. This compression effect may also influence the molecular processes related to volume expansion, such as the role of transmembrane proteins, membrane surface receptors, and ion channels. Likewise, anesthetic gases may ameliorate the clinical manifestation of HPNS by restoring the architecture of the CNS cell membrane into its original form due to the phenomenon of the pressure reversal effect of narcosis. This phenomenon gives rise to studies about breathing mixture modifications, such as using trimix to control HPNS.
The roles of neurotransmitters in the pathogenesis of HPNS have also been studied, for example, gamma-aminobutyric acid (GABA), dopamine, serotonin (5-HT), acetylcholine, and N-methyl-d-aspartate (NMDA).  For instance, sodium valproate, which increases the GABA concentration in the cortex, diminishes the severity of the HPNS signs in a baboon model. Pretreatment with NMDA antagonists in rats exposed to high pressure using helium and oxygen prevented convulsions. On the other hand, serotonin may be related to hyperbaric spinal cord hyperexcitability. Behavioral symptoms in rats under high pressure are similar to the clinical presentation of serotonin syndrome (alteration in mental status, restlessness, myoclonus, hyperreflexia, shivering, tremor) and indicate 5-HT receptor subtype 1A activation. Similarly, it is reported that the increase in striatal dopamine release and the development of enhanced locomotor and motor activity can be partially prevented by 5-HT 1b receptor antagonists in rats exposed to high pressure.
Also, alterations in neuronal calcium ions is another mechanism that has been postulated for HPNS pathophysiology.
On the other hand, intraspecies and interspecies variations of HPNS exist. Some individuals are more susceptible to HPNS than others. A genetic basis may be one of the underlying mechanisms for adaptation to HPNS.
HPNS is mostly characterized by hyperexcitability of the central nervous system (CNS) that involves neurological, psychological abnormalities, and changes in EEG recordings. HPNS should be differentiated from nitrogen narcosis, decompression sickness, and oxygen toxicity.
Tremor, which is the most characteristic symptom of HPNS, occurs at rest and on movement. Tremors begin at distal extremities and may spread to the whole body. The frequency of tremors is 8 to 12 Hz. The amplitude increases with faster compression speed and increasing hydrostatic pressure. Opsoclonus, which is the definition of the spontaneous constant eye oscillations in random directions, is one of the earliest signs of HPNS. A headache, dizziness, fatigue, myoclonic jerking, muscular weakness, and euphoria are possible. Convulsions were reported in animals but not in humans.  Gastrointestinal (GI) symptoms such as nausea, vomiting, stomach cramps, diarrhea, and loss of appetite may occur. Additionally, memory disturbances, cognitive deficits, psychomotor performance impairment, somnolence, sleep disturbances with vivid dreams, or nightmares have been reported.
Clinical presentation may be influenced by breathing gas mixture components, compression rates, and the hydrostatic pressure attained. For instance, adding a certain amount of nitrogen or hydrogen into the helium-oxygen breathing gas mixture ameliorates the signs and symptoms of HPNS. Similarly, a faster compression augments the severity of the clinical manifestation of HPNS and provokes earlier onset of symptoms. Likewise, increasing hydrostatic pressure leads to more severe signs and symptoms. Individual variation in the clinical presentation has been reported.
In the experimental dives, several monitoring tests were applied during compression to subjects to evaluate their neuropsychological, neurophysiological, and performance responses. Vaernes et al.  used static steadiness test for postural tremor in hands, finger oscillation test, a dynamometer for handgrip strength, trails test for visuomotor, and coordination. To evaluate performance, motor, visuomotor, and cognitive tests, a questionnaire was administered at different depths. Key insertion test, visual reaction time tests, arithmetic, reasoning, long-term memory, and visual digit span are some examples of the tests measured.
EEG recordings were also evaluated in several studies. An increase in theta activity and a decrease in alpha waves were demonstrated in the EEG records of divers who suffered from high-pressure neurological syndrome (HPNS). For instance, Rostain et al.  reported a decrease in alpha frequencies from about 100 meters and an increase in theta frequencies in the frontal area at about 200 meters during a dive to 450 meters seawater with the helium-nitrogen-oxygen gas mixture. Sleep EEG also displays specific alterations at high pressure, which were characterized by an increase in stages I and II, a decrease in the duration of stages III and IV, and reduction of REM periods. Similarly, somatosensory evoked potentials may also be influenced by pressure. The shortened latency of peaks following the initial cortical P1 was related with a state of hyperexcitability in the brain.
HPNS is a significant limitation for deep dives. Unfortunately, HPNS cannot be completely prevented. However, there are several existing approaches that may delay HPNS onset or modify its clinical presentation.  These approaches are:
Reduction of the Speed of Compression
Slowing the overall speed of compression or inserting stops during compression to allow for acclimatization can improve or even prevent the symptoms of HPNS. However, the compression speed must be extremely slow and is necessary to allow time for adaptation with staged descent for deeper dives, which is a significant handicap for technical dives. Nevertheless, as the pressure increases, symptoms become more significant and severely limit the diver's performance. Divers may still complain of HPNS symptoms beyond 330 meters regardless of compression speed.
Modification in the Breathing Gas Mixture
Nitrogen has been used to oppose some of the HPNS symptoms due to its narcotic effect. Specific amounts of nitrogen (about 5% to 10%) added to helium-oxygen gas mixture have been reported to reduce some symptoms and signs of HPNS. The advantages of adding nitrogen to helium-oxygen breathing gas mixture are lessened cost, better thermal comfort, reduced speech distortion, and improvement in HPNS. Nevertheless, the diver must be careful about nitrogen narcosis. Similarly, hydrogen has been used for the same aim due to some advantageous properties for deep dives. As hydrogen is less dense than helium, it is better for respiratory mechanics. The gas mixture of hydrogen-helium-oxygen (about 50% hydrogen) provided successful dives up to 500 meters without significant clinical presentation of HPNS. Although EEG changes continued, performance deterioration was minimal. Likewise, a depth of 701 meters has been reached with a reduction in clinical symptoms of HPNS while using helium-hydrogen-oxygen breathing gas mixture. However, it should be noted that hydrogen is explosive in mixtures containing more than 4% oxygen.
Anesthetics, barbiturates, and anticonvulsants have been studied to prevent the clinical manifestations of HPNS. For instance, ketamine has been found to be efficient in controlling HPNS in rats.  Also, barbiturates were effective as an anticonvulsive in HPNS. Similarly, valproate was found to be useful in HPNS in baboon experiments at pressures higher than 40 ATA. Nevertheless, other anticonvulsants have an insufficient effect on HPNS. Common anticonvulsant drugs such as phenytoin, carbamazepine, and diazepam were not useful in the inhibition of tremor, myoclonus, and seizures in rats. This result demonstrates that HPNS related seizures are an unusual type. Thus, the usage of standard anticonvulsant treatment is limited for HPNS in humans. Most of these pharmacological agents cannot be used for HPNS in terms of adverse effects on diving ability. However, studies on 5-HT1A receptor antagonists have promising results.
Selecting the least susceptible diver may be another solution.
Some issues have been discussed in controlling HPNS. First, these approaches may be effective only in some manifestations. This may create a new problem where the first signs of HPNS may be more severe. Secondly, delaying the development of HPNS in baboons may cause new symptoms which can involve brain damage. Finally, there might be a risk of symptom-free development of pressure-related tissue injury, which may cause long-term injuries. Further studies will be beneficial to figure out reliable conclusions.
High pressure is the most challenging part for human physiology during deep diving. Nevertheless, the high concentration of gases, increased density of the matter, alteration of the regular properties of heat, sound, and others may also cause neurological signs without being properly HPNS . Deep diving-related conditions are oxygen toxicity, intoxication with polluted breathing gases, nitrogen narcosis, HPNS, decompression illness, and carbon dioxide retention due to increased gas density. The symptoms, the depth of the symptoms arise and subside, the diving protocol (the rate of the ascend and descend, decompression stops), and the breathing gas mixture are significant differentiating points.
The clinical manifestations persist but tend to ameliorate at constant pressure with time. Rostain et al. stated that the changes in the sleep pattern of divers began to improve after the first week under pressure. However, healthy sleep patterns values were recorded only during the decompression at depths below 200 meters. The symptoms usually ease after decompression, but some of the symptoms, such as lethargy, may continue for a while. In the end, all of the divers who experience only HPNS heal. No permanent neurological sequelae or histopathological lesions in the brain have been identified related to HPNS.
A professional diver education should include diving related diseases, preventive measures, and breathing gas properties. Divers should choose the safest diving protocol, such as a slow compression rate and appropriate breathing gas mixture. The safety rules are the golden prevention methods for diving-related diseases. Thus, medical professionals should also be careful during fitness to dive examinations of the professional divers in terms of psychological eligibility. Safe diving requires educated divers who obey the rules strictly.
HPNS is one of the major limitations of deep diving. Unfortunately, no drug has been used successfully to prevent HPNS in humans. In general, modifications on breathing gas mixtures and compression profiles and selecting less susceptible diver may be partially beneficial for controlling HPNS. However, these methods are still inadequate for extremely deep dives regarding HPNS. Further studies about HPNS pathophysiology, prevention, and adaptation mechanisms should be performed to widen borders in modern diving for humans.
HPNS is a significant consequence of modern deep diving. There are several preventive approaches. These approaches should be considered carefully by divers and diving supervisors. In this regard, diving protocols may be designed in tandem with diving experts. Diving supervisors should record any abnormal symptoms or signs during deep dives and consult with a diving expert. The symptoms usually ease after decompression, but some of the symptoms, such as lethargy, may continue for a while.  These divers should be examined detailed by a diving physician and may be consulted to neurology for further examinations. [Level 2]
An interprofessional team, including neurologists, undersea specialists, hyperbaric nurses, and occupational medicine physicians and nurses, are best suited to caring for and preventing HPNS. Initial evaluation by emergency department personnel is crucial. Intensive care and neuroscience nurses care for patients, educate families about the condition, and relay updates to the rest of the team. [Level 5]
|||Jain KK, High-pressure neurological syndrome (HPNS). Acta neurologica Scandinavica. 1994 Jul [PubMed PMID: 7941956]|
|||Extremely deep recreational dives: the risk for carbon dioxide (CO(2)) retention and high pressure neurological syndrome (HPNS)., Kot J,, International maritime health, 2012 [PubMed PMID: 22669812]|
|||Buzzacott P,Schiller D,Crain J,Denoble PJ, Epidemiology of morbidity and mortality in US and Canadian recreational scuba diving. Public health. 2018 Feb [PubMed PMID: 29306625]|
|||Talpalar AE, [High pressure neurological syndrome]. Revista de neurologia. 2007 Nov 16-30 [PubMed PMID: 18008270]|
|||Aviner B,Gradwohl G,Bliznyuk A,Grossman Y, Selective pressure modulation of synaptic voltage-dependent calcium channels-involvement in HPNS mechanism. Journal of cellular and molecular medicine. 2016 Oct [PubMed PMID: 27273194]|
|||Bennett PB, Physiological limitations to underwater exploration and work. Comparative biochemistry and physiology. A, Comparative physiology. 1989 [PubMed PMID: 2568233]|
|||Pearce PC,Clarke D,Doré CJ,Halsey MJ,Luff NP,Maclean CJ, Sodium valproate interactions with the HPNS: EEG and behavioral observations. Undersea biomedical research. 1989 Mar [PubMed PMID: 2499971]|
|||Pearce PC,Halsey MJ,MacLean CJ,Ward EM,Webster MT,Luff NP,Pearson J,Charlett A,Meldrum BS, The effects of the competitive NMDA receptor antagonist CPP on the high pressure neurological syndrome in a primate model. Neuropharmacology. 1991 Jul [PubMed PMID: 1833661]|
|||Kriem B,Abraini JH,Rostain JC, Role of 5-HT1b receptor in the pressure-induced behavioral and neurochemical disorders in rats. Pharmacology, biochemistry, and behavior. 1996 Feb [PubMed PMID: 8808129]|
|||Philp RB,Kalogeros G,McIver DJ,Dixon SJ, Effects of elevated pressures of inert gases on cytosolic free Ca2+ of cultured human neuroblastoma cells stimulated with carbachol: relevance to high pressure neurological syndrome. Cell calcium. 1994 Feb [PubMed PMID: 8149411]|
|||McCall RD, HPNS seizure risk: a role for the Golgi-associated retrograde protein complex? Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc. 2011 Jan-Feb [PubMed PMID: 21384758]|
|||Aarli JA,Vaernes R,Brubakk AO,Nyland H,Skeidsvoll H,Tønjum S, Central nervous dysfunction associated with deep-sea diving. Acta neurologica Scandinavica. 1985 Jan [PubMed PMID: 3976349]|
|||Rostain JC,Gardette-Chauffour MC,Lemaire C,Naquet R, Effects of a H2-He-O2 mixture on the HPNS up to 450 msw. Undersea biomedical research. 1988 Jul [PubMed PMID: 3212843]|
|||Vaernes R,Hammerborg D,Ellertsen B,Peterson R,Tønjum S, CNS reactions at 51 ATA on trimix and heliox and during decompression. Undersea biomedical research. 1985 Mar [PubMed PMID: 3839948]|
|||Abraini JH,David HN,Vallée N,Risso JJ, Theoretical considerations on the ultimate depth that could be reached by saturation human divers. Medical gas research. 2016 Apr-Jun [PubMed PMID: 27867478]|
|||HPNS effects among 18 divers during compression to 360 msw on heliox., Vaernes RJ,Bergan T,Warncke M,, Undersea biomedical research, 1988 Jul [PubMed PMID: 3212842]|
|||Rostain JC,Gardette-Chauffour MC,Naquet R, EEG and sleep disturbances during dives at 450 msw in helium-nitrogen-oxygen mixture. Journal of applied physiology (Bethesda, Md. : 1985). 1997 Aug [PubMed PMID: 9262455]|
|||Seo Y,Matsumoto K,Park YM,Mohri M,Matsuoka S,Park KP, Changes in sleep patterns during He-O2 saturation dives. Psychiatry and clinical neurosciences. 1998 Apr [PubMed PMID: 9628116]|
|||Bennett PB,Coggin R,McLeod M, Effect of compression rate on use of trimix to ameliorate HPNS in man to 686 m (2250 ft). Undersea biomedical research. 1982 Dec [PubMed PMID: 7168098]|
|||Bennett PB,Coggin R,Roby J, Control of HPNS in humans during rapid compression with trimix to 650 m (2131 ft). Undersea biomedical research. 1981 Jun [PubMed PMID: 7268942]|
|||Rostain JC,Balon N, Recent neurochemical basis of inert gas narcosis and pressure effects. Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc. 2006 May-Jun [PubMed PMID: 16869533]|
|||Levett DZ,Millar IL, Bubble trouble: a review of diving physiology and disease. Postgraduate medical journal. 2008 Nov [PubMed PMID: 19103814]|
|||Abraini JH,Gardette-Chauffour MC,Martinez E,Rostain JC,Lemaire C, Psychophysiological reactions in humans during an open sea dive to 500 m with a hydrogen-helium-oxygen mixture. Journal of applied physiology (Bethesda, Md. : 1985). 1994 Mar [PubMed PMID: 8005852]|
|||Wardley-Smith B,Wann KT, The effects of non-competitive NMDA receptor antagonists on rats exposed to hyperbaric pressure. European journal of pharmacology. 1989 Jun 8 [PubMed PMID: 2548878]|
|||Wardley-Smith B,Doré C,Hudson S,Wann K, Effects of four common anticonvulsants on the high pressure nervous syndrome in the rat. Undersea biomedical research. 1992 Jan [PubMed PMID: 1536060]|
|||Brauer RW, Hydrostatic pressure effects on the central nervous system: perspectives and outlook. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 1984 Jan 7 [PubMed PMID: 6142475]|