Introduction

Hyperbaric Oxygen Therapy (HBOT) involves breathing 100% oxygen under pressure greater than normal atmospheric pressure. It can be conducted in monoplace (or single patient) chambers or in a multiplace chamber, with several individuals together. HBOT enhances the healing of inflammatory and microcirculatory disorders by increasing oxygen availability, antioxidant activity, vasoconstriction, and angiogenesis [1]. Generally considered a safe therapy, HBOT is commonly indicated for a variety of conditions, including diabetic foot ulcers, chronic non-healing wounds, radiation injuries, and necrotizing infections, among others [2]. However, the therapy is not without potential side effects, which can include ear barotrauma, claustrophobia, and, in rare cases, seizures [3].

Seizures during HBOT are a known complication with a relatively low incidence—as low as 0.25 in 10,000 to 6 in 10,000 treatments [4–13]. These seizures are often attributed to oxygen toxicity, where high concentrations of oxygen inhaled at elevated pressures lead to disturbances in the central nervous system [14, 15]. Importantly, even patients without a prior history of seizures can develop oxygen-induced seizures [16]. However, other potential causes that can mimic oxygen-induced seizures, such as hypoglycemia, side effects of medications that lower the seizure threshold, and pre-existing brain pathology, should also be considered [17].

The pathophysiology of oxygen toxicity seizures is not fully understood. One potential mechanism involves elevated levels of oxygen- and nitrogen-derived free radicals with the increase in partial pressure of oxygen during HBOT, which can cause cell membrane lipid peroxidation, enzyme inhibition, and alteration of nucleic acids and protein synthesis [15, 18, 19]. Additionally, increased nitric oxide (NO) production, stimulated by HBOT, may contribute to excess excitatory neurotransmitter (glutamate) activity [20–22]. These antioxidant responses, combined with an imbalance in vaso-modulation, are believed to influence oxygen toxicity seizures [21]. Another possible mechanism is the effect of hyperbaric oxygen on brain glucose transport and metabolism. Hyperoxia decreases AMP (adenosine monophosphate) concentrations in endothelial cells of the blood brain barrier (BBB) and in cells behind the BBB. This suppression reduces the activity of glucose transporters responsible for moving glucose from the blood into cerebrospinal fluid (CSF) and from the CSF to brain cells. The cumulative effect of the diminished glucose concentration in the CSF and reduced glucose transport to the cells beyond the BBB results in local hypoglycemia, hypoglycemic brain syndrome, and seizures [23].

Oxygen induced seizures generally manifest as generalized tonic-clonic convulsions, although focal seizures have also been reported. These seizures may occur suddenly or be preceded by an aura [24, 25]. The risk of seizures is influenced by many factors such as increased treatment pressure, and conditions that could decrease the seizure threshold, such as carbon dioxide retention, brain tumour or brain soft tissue radionecrosis, hypoglycemia, hyperthyroidism, carbon monoxide poisoning, and certain medications [4, 7–9, 16, 26]. While some consider history of seizures as a risk factor for oxygen-induced seizures [16, 27], others suggest no incremental increase in risk [9]. Referrals of patients with a history of seizures to hyperbaric units are not uncommon, especially due to the comorbidity between seizure disorders and conditions typically managed with HBOT, such as diabetic foot ulcers [28]. Excluding these individuals from treatment without robust evidence of heighted risk may inadvertently lead to suboptimal care. Thus, understanding HBOT safety profile in patients with seizure history is essential for guiding clinical decision-making and obtaining informed patient consent for HBOT.

This retrospective cohort study aims to evaluate the application of HBOT in patients with seizure histories who have undergone HBOT for non-emergent indications. The study seeks to provide insights into its safety, which may inform future research and contribute to refining treatment protocols.

Methods

Results

Clinical data

Of the 43 patients referred to HBOT, 21 patients did not receive HBOT due to refusal to participate in HBOT (n = 11); poorly controlled seizure disorder, defined as an episode of seizures in the last three months despite anti-seizure therapy (n = 3); palliative state (n = 3); severe confinement anxiety (n = 1); multiorgan dysfunction (n = 1); inability to commute to the treatment centre (n = 1); or referral to another center (n = 1). Twenty-two patients with a documented seizure history (Table 1) were included in the final analysis.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 1. Patient baseline demographics, co-morbidities, and medications.

https://doi.org/10.1371/journal.pone.0317586.t001

The mean patient age was 58 ± 15 years, and nine (41%) were female (Table 1). The most common comorbid conditions included hypertension (8; 36%), history of substance use (5; 23%), and chronic obstructive pulmonary disease/asthma/interstitial lung disease (4; 18%). Fifteen (68%) patients were on antiseizure medications, five (23%) were on opioid therapy, and four (18%) were on steroid medications.

Most patients had a documented etiology for the seizures: five patients (23%) had seizures related to structural abnormalities such as intracranial tumour and brain radiation necrosis; four patients (18%) had substance withdrawal/abuse-related seizures; and three patients (14%) had seizures related to infection and metabolic derangements. The remaining 10 patients (45%) had a seizure history of unknown etiology (Table 2). Indications for HBOT were most commonly for complex wounds (6; 27%), idiopathic sensorineural hearing loss (4; 18%), and osteomyelitis (3; 14%). Other indications for HBOT included diabetic foot ulcers (2; 9%), osteoradionecrosis (2; 9%), radiation cystitis (2; 9%), and soft tissue radiation injury (radiation-induced brain necrosis) (2; 9%). Two patients with brain radiation necrosis (#20, 22, Table 2) had seizures three months prior to HBOT including the patient (#22, Table 2) with ongoing focal aware seizures. Both patients underwent HBOT uneventfully.

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 2. History of seizures and HBOT protocol.

https://doi.org/10.1371/journal.pone.0317586.t002

Discussion

This study examined the safety profile of HBOT in a cohort of patients with a history of prior seizures. Over the course of 634 HBOT sessions among 22 patients, only one seizure was recorded, yielding an incidence of one in 634 treatments.

In the literature, there is considerable variability in the incidence of seizure during HBOT, ranging from 0.25 in 10,000 to 6 per 10,000 [4–13]. The variability of the rate could be explained by the clinical profile of patients included in the analysis and the differences in the treatment protocols.

Although a history of seizures is recognized by some authors as a risk factor for oxygen-induced seizures, the safety of HBOT in these patients has not been extensively evaluated (Table 3). Some studies did not specify whether patients with seizure histories were eligible for HBOT or included in the analyses [4–6, 8, 11]. Costa et al. excluded such patients from their analyses [13]. Yilidz et al. included data from centres that decline patients with seizures for HBOT [7]. Hadanny et al. treated only patients with a seizure-free interval of six months and a normalized EEG [10]. Sherlock et al. and Plafki et al., did not provide clinical data on patients with seizure histories [5, 12]. Heyboer et al. and Hadanny et al. offered limited information, reporting that at 2.0 ATA, the seizure risk may be negligible even in those with seizure histories [9, 10].

Download:

• PPT
  PowerPoint slide
• PNG
  larger image
• TIFF
  original image

Table 3. Incidence of HBOT related seizures, treatment pressures, and inclusion of patients with the history of seizure for data analysis.

https://doi.org/10.1371/journal.pone.0317586.t003

To address the gaps in the existing literature and provide new insights into the safety of HBOT in patients with a history of seizures, our study included patients with a shorter seizure-free interval of three months, and one patient with ongoing focal aware seizures. This is in contrast with Hadanny et al. who only treated patients with a seizure-free period of six months. The Heyboer’s trial lacked detailed safety data [9, 10].

Most patients in our cohort tolerated HBOT without complications, with only one patient experiencing a seizure during treatment (#14, Table 2). Differential diagnosis in this case includes underlying epilepsy that was worsening by poor compliance with antiseizure medications or oxygen induced seizure. While the exact cause of her seizure cannot be definitively determined, seizures were rare in this cohort of patients with a history of prior seizures.

The safety and low incidence of seizures during HBOT can be ascribed to several factors. Firstly, patient selection for HBOT in those with a history of seizures requires a comprehensive assessment. Stabilization and appropriate management of seizure disorders and comorbidities are important to minimizing risks during the therapy. Hadanny et al. found that the incidence of seizures is low when patients have a normalised EEG and a six months seizure-free period prior to HBOT [10]. In our study, patients with poorly controlled seizure disorders were not approved for HBOT, however, those with a 3-month seizure-free period were considered safe to initiate the therapy. One patient (#22, Table 2) with poorly controlled ongoing focal aware seizures due to radiation-induced brain necrosis was approved for HBOT following multidisciplinary discussion with the radiation oncologist and neurologist. The patient’s condition improved after 30 uneventful HBOT sessions at 1.8 ATA. This case highlights the importance of understanding each patient’s underlying seizure disorder and tailoring the HBOT protocol accordingly.

Treatment pressure and duration should be tailored to each patient. For patients with a history of seizures, lower pressures, such as 1.8 to 2.0 ATA, are generally recommended as they are associated with lower incidences of seizures compared to higher pressures (≥2.4 ATA) [9, 10]. In this study, hyperbaric pressures were mostly at 2.0 ATA or lower (21; 95%).

Air breaks during treatment were another critical factor, as they help lower oxygen partial pressure and reduce the risk of oxygen toxicity [13]. Costa et al. previously demonstrated across over 180,000 HBOT sessions that introducing even a single 5-minute air break during a session could significantly reduce seizure frequency [13]. In this study, all patients received at least one 5-minute air break per session, with the majority receiving two to three air breaks (18; 82%). The frequency and duration of these breaks were adjusted based on each patient’s needs. Additionally, the duration and number of HBOT sessions should be periodically reassessed, particularly in patients with chronic conditions, to minimize the risk of cumulative oxygen exposure increasing seizure susceptibility.

The method of oxygen delivery during HBOT is also important. It has been suggested that using a hood, as opposed to a mask, to deliver oxygen in multiplace chambers may increase the risk of seizures due to the higher partial pressure of oxygen and accumulation of carbon dioxide [7, 20]. The incidence of oxygen toxicity with hoods have previously been reported as 3 in 10,000 [7]. Inadequate removal of carbon dioxide can lead to hypercapnia, raising the risk of oxygen toxicity seizures [13, 16, 29]. All patients in the current study were treated in monoplace chambers pressurized with oxygen, minimizing the risk of carbon dioxide accumulation and potentially contributing to the low incidence of seizures.

In addition to these factors, individual physiological differences, such as age, comorbidities, and medications, may influence the oxygen toxicity seizures incidence [13]. In our patients’ cohort, a total of 68% of the patients treated with HBOT were on antiseizure medications. Although, antiseizure medications do not entirely eliminate the risk of seizures, they have been shown to reduce seizure onset, even under high treatment pressures [30]. This underscores the importance of optimizing antiseizure therapy before initiating HBOT.

Beyond seizure control, conditions that may lower the seizure threshold, such as hypoglycemia, electrolyte imbalances, and alcohol dependence, should be managed to further reduce the oxygen toxicity risk during treatment [4, 16, 31]. For instance, the incidence of seizures in general population has been shown to increase with age [32, 33]. This may be due to reduced resilience to oxidative stress and age-associated accumulation of reactive oxygen and nitrogen species [34]. Comorbid conditions are also influential in determining seizure risk. For example, patients with diabetes mellitus may experience hypoglycemic events during HBOT, which is a documented risk factor for seizures [35–37].

Patient safety can be further enhanced by educating hyperbaric staff for possible early signs of oxygen toxicity, such as vision changes, auditory changes, nausea, tingling, twitching, dizziness or vertigo, irritability, pallor, which can precede seizure onset [10]. Additionally, certain medications, such as antidepressants, tramadol, disulfiram, and cephalosporins, can lower the seizure threshold during HBOT [16]. Selective serotonin reuptake inhibitors, for example, can elevate serotonin levels in the brain, heightening neuronal excitability and reducing the seizure threshold [38–40]. Similarly, tramadol inhibits the reuptake of serotonin and norepinephrine, lowering the seizure threshold, especially in patients with a history of seizures [41–43]. These considerations emphasize the importance of individualized treatment plans that account for medication profiles and potential adverse interactions during HBOT.

Conclusion

Although patients with a history of seizures can experience oxygen toxicity-induced seizures despite ongoing antiseizure therapy, its incidence remains very low. Given the relatively low incidence of seizures among patients with a history of seizures receiving HBOT, it may be considered in cases where the indication is strong, with close monitoring and assessment of seizure-related relative contraindications.