Local anaesthetic-induced seizures: a review

Introduction

Local anaesthetics play a crucial role in modern medicine, serving as indispensable tools for surgical procedures, chronic pain management, and the treatment of cardiac arrhythmias. These versatile drugs act by effectively blocking nerve impulse transmission in both the peripheral and central nervous systems (CNSs), thereby numbing specific areas of the body to facilitate pain-free procedures.

Chemically, local anaesthetics can be classified into amides, esters, or combinations thereof, each with distinct metabolic pathways and differing in the location in which metabolism occurs. While amides undergo hepatic metabolism, esters are broken down in the plasma by plasma cholinesterases (1). Examples of popular amide anaesthetics include mepivacaine, lidocaine and bupivacaine whereas common ester anaesthetics include benzocaine, tetracaine, and procaine. Articaine stands out as a unique local anaesthetic with dual chemical groups, offering a special pharmacological profile.

At the molecular level, local anaesthetics exert their effects by blocking voltage-gated sodium channels, preventing the influx of sodium ions and subsequent neuronal depolarization. This mechanism effectively interrupts nerve action potential signal transmission, leading to temporary numbness and loss of sensation in the targeted area (2).

One of the key aspects of local anaesthetics is their differential susceptibility in blocking nerve types. Autonomic nerves are typically the first to be affected, followed by sensory nerves, and finally motor nerves (3). This variable effect allows for precise control over sensory perception during medical interventions. The duration of action of local anaesthetics is variable and can range from as little as 30 minutes up to 12 hours. It is dependent on a multitude of factors such as the site of administration, the vascularity of the tissue, and the drug’s specific formulation. For instance, regions with robust blood supply tend to experience shorter durations of anaesthesia as the drug is rapidly cleared away by the circulation and metabolized. The drug preparation can also influence the duration of action. For example, liposomal preparations are designed to have an extended-release mechanism leading to a longer duration of action (4).

Despite their efficacy, local anaesthetics are not without risks. Adverse effects can range from cardiovascular complications such as hypotension and dysrhythmias to CNS disturbances like auditory, visual, and taste impairments. Seizures are a rare but serious CNS manifestation associated with local anaesthetic administration and this review outlines the evidence for this association as well as management and methods to minimize the risk of their occurrence (5).

Pathophysiology of seizures

Understanding the intricacies of seizure thresholds sheds light on why seizures occur in some individuals while others remain unaffected. The concept of a seizure threshold elucidates the notion that every individual possesses a certain level of susceptibility to experiencing seizures, influenced by various factors including genetic predisposition, prior injury, infections, stress, and predisposing medical conditions such as hypoglycemia, electrolyte imbalance and hormonal disturbances (6).

At the cellular level, the initiation of seizures is characterized by the hyperexcitability of cerebral neurons, leading to the excessive firing of action potentials. This surge in electrical activity culminates in a seizure occurrence. The delicate balance between excitatory neurotransmitters such as glutamate and inhibitory neurotransmitters like gamma-aminobutyric acid (GABA) plays a pivotal role in modulating seizure activity. When there is an imbalance favouring excessive excitation and/or diminished inhibition, the likelihood of reaching the threshold level for seizure initiation increases (7).

Furthermore, factors such as neurotransmitter receptor abnormalities, ion channel dysregulation, and alterations in synaptic connectivity contribute to the complex interplay modulating seizure threshold. Genetic predispositions can predispose individuals to aberrant neuronal activity, while environmental factors such as head trauma or neuroinflammation can further exacerbate seizure susceptibility (8).

Seizure classification

When classifying seizures, there are three main types: focal seizures, generalized seizures, and status epilepticus (SE) (Figure 1).

Figure 1 Classification of seizures.

Focal seizures

Focal seizures are classified as seizures that are limited to one cerebral hemisphere (9) and are usually broken down into two groups, aware and impaired awareness focal seizures (10). Within these groups, seizures can be broken down even further based on their symptoms and areas of the brain that are affected.

• Focal onset (aware) seizures are also known as simple partial seizures (11). People who experience these seizures are aware of themselves and their environment while the seizure occurs. Symptoms vary depending on where in the brain the seizure occurs. If the misfiring of neurons occurs in the temporal lobe, the person may experience an unpleasant smell sensation. If it occurs in the frontal cortex, the person may display uncontrolled motor actions such as kicking or head twitches (10).
• Focal onset (impaired awareness) seizures are also referred to as complex partial seizures (12). This is when a person loses awareness of what is occurring. Usually, the person will lose consciousness, but there are times when they will be conscious but unresponsive or partially responsive (13). Seizures will usually last between one and two minutes and could present with a variety of symptoms, again depending on where the seizure is occurring in the brain. Individuals experiencing this type of seizure can experience cognitive symptoms such as déjà vu, depersonalization, and others. Emotional symptoms can also occur such as aggression, anger, crying, and laughing (14).

Generalized seizures

Generalized seizures take place when the seizure occurs bilaterally in the brain (9). A seizure may begin focally and then become generalized (15). There are six types of generalized seizures.

• Tonic-clonic seizures occur with an instant loss of consciousness. Firstly, in the tonic phase, the person will become stiff and could cry or bite their tongue. Then, in the clonic phase, there will be jerky movements, breathing could be affected as well, and there are times when they may experience a loss of control of bladder and bowel movements. These seizures will usually last anywhere from one to three minutes (16).
• Tonic seizures also happen with an instant loss of consciousness. The person will go stiff and fall to the ground backwards most commonly. These usually last up to a minute (16).
• Clonic seizures refer to the continuous rhythmic jerking of the muscles. The arms, legs, and neck, will be seen twitching in this type of seizure (16).
• Atonic seizures are a type of seizure that usually will not last more than 15 seconds. The muscles will relax, and the person becomes limp which tends to lead them to fall forward (16).
• Myoclonic seizures can occur with a very brief loss of consciousness, and are manifested by one or more limbs jerking uncontrollably. These last for fractions of a second and may happen in bunches (16).
• Absence (or petit mal) seizures are when the person may seem absent from his or her environment. They could appear to just pause and stare for a second during a very short loss of consciousness. It appears that they stop for a few seconds and then continue with what they were doing afterwards. These are more frequently seen in children but can also happen in adults and may be indistinguishable from focal unaware seizures (16).

SE

SE represents the most severe manifestation of epileptic activity, necessitating immediate medical intervention and neurologic evaluation due to its potential to result in irreversible brain damage or death. SE is characterized by either a prolonged convulsive seizure lasting beyond the typical duration of 5 minutes or a series of seizures with incomplete recovery to baseline neurological function, or persistence of focal or absence seizures lasting more than 10 minutes (17,18). It occurs due to a malfunction in the mechanisms involved with ending seizures. At the molecular level, SE induces rapid and profound changes within neuronal networks, including alterations in receptor dynamics and neurotransmitter signalling (18). Early initiation of treatment is paramount in the management of SE, as delayed intervention correlates with increased neuronal damage and heightened mortality rates. Timely administration of anticonvulsant drugs ensuring basic life support (e.g., respiration and blood pressure) is essential in halting the progression of SE and preventing further neurological sequelae. Comprehensive patient monitoring and continuous neurologic assessment are crucial to assess treatment response and ensure optimal outcomes (18).

Epidemiological evidence for an association

Case report evidence for an association between local anaesthetic use and seizures has been published for many years and continues to be found frequently in the literature including several reports published recently.

In 2016, Alsukhni et al. published a case report of a 15-year-old girl who arrived at the emergency department as a result of several tonic-clonic seizures that had occurred in a dental office just prior. She presented to the dentist for endodontic treatment and at the beginning of the procedure, the dentist injected 1.5 mL of 2% lidocaine with 1:100,000 epinephrine to achieve local anaesthesia. The injection lasted for two minutes. Immediately following this injection, the patient experienced several tonic-clonic convulsions, which lasted for about 30 minutes and then the patient fell into a deep coma (19).

In 2018, Cosola et al. published a case report of a 23-year-old female who presented to the dental office for extraction of wisdom teeth. The patient had no prior history of epileptic seizures. The patient developed a seizure 10–20 seconds after the first injection of local anaesthetic. The dentist only injected 0.3 mL of the 1.8 mL vial of anaesthetic. The seizure episode lasted approximately 15 minutes (20).

In 2019, a case report was published by Boparai et al. detailing the events of an eight-year-old, healthy male, also with no known history of epilepsy or drug allergies, who went to the dentist for a tooth extraction. The dentist injected 1.8 mL of 2% lidocaine with 1:200,000 epinephrine. The injection lasted for two minutes and immediately following the nerve block, the patient developed tonic-clonic convulsions (21).

This phenomenon is not only restricted to dental anaesthesia and does not always occur immediately following injection. In 2022, Tüzen et al. published a case report of an 18-year-old male patient who underwent an internal fixation operation for a distal radius fracture. Local anaesthesia was planned with the administration of a brachial plexus block using the infraclavicular technique. There was no known history of epilepsy, smoking, alcohol, or drug use. A local anaesthetic mixture was prepared with 15 mL of 0.5% bupivacaine and 15 mL of 2% prilocaine. A 21-gauge 100-mm Stimuplex A needle was used to accomplish the nerve block. Aspiration was performed prior to injection, and after observing the correct regional distribution in the target area, the injection was started. With repeated aspiration after every 5 mL, the injection continued. The injection was completed with a total of 30 mL of the local anaesthetic. During the injection, full communication was maintained with the patient; his vitals were stable. After the injection was completed, the motor blockade began at the 15th minute, and sufficient anaesthesia for surgery was then provided. Then 2 mg intravenous (IV) midazolam was administered, and he was taken to the operating room. The patient’s vitals were stable throughout the entire surgery and no complications occurred. He was then transferred to the post-operative orthopaedic ward. Three hours later, he began to lose consciousness and experience tonic-clonic convulsions consistent with a delayed local anaesthetic systemic toxicity (LAST) (22).

In another study published in 2022, Li et al. presented a case of local anaesthetic-induced seizures. A 34-year-old woman presented for a bilateral tonsillectomy procedure. This patient did have a history of epilepsy but had not experienced any seizures for 5 years prior. Immediately following administration of 160 mg of lidocaine, the patient developed a tonic-clonic seizure, which lasted approximately 20 minutes (23).

There are as yet no prospective studies of the incidence of LAST including that from the administration of local anaesthetics for dental procedures. There was an extensive review of LAST in published cases from 1979 to 2009, all related to surgical regional anaesthesia which did not include dental procedures (24). Symptoms of CNS toxicity occurred in 83 (89%) of 93 cases with seizures occurring in 63 (68%) of 93 cases. The median time after a single injection was 52.5 seconds, but in 25% of the patients, the symptoms occurred 5 or more minutes after injection. All case reports cited above involving dental procedures manifested seizures within a minute following local anaesthetic injection. What is needed is a prospective population-based study of the incidence of LAST from dental procedures using local anaesthesia.

Biological plausibility

The biological plausibility of local anaesthetic-induced seizures is underpinned by a multifaceted interplay of a variety of factors, each contributing to the intricate mechanisms involved in seizure genesis. A fundamental aspect supporting this plausibility lies in the clear mechanistic understanding of how local anaesthetics could precipitate seizures (Figure 2). Just as these agents exert their analgesic effects by impeding the propagation of pain signals at the intended site of action, they also possess the capability to interfere with signal transmission within the CNS, specifically in the brain. Interestingly, they preferentially block inhibitory synapses in the brain and thus result in unopposed excitatory activity (25), tilting the delicate balance between excitatory and inhibitory neurotransmission towards heightened excitatory activity. This shift in neurotransmitter dynamics creates a conducive environment for the emergence of seizures, as aberrant excitation overwhelms the regulatory mechanisms that maintain neuronal stability and prevent hyperexcitability-induced pathological firing (26).

Figure 2 Simplified process of local anaesthetic-induced seizure occurrence. CNS, central nervous system.

For local anaesthesia to induce a seizure, it is often thought that the drug must reach the brain. In the realm of dentistry, local anaesthetic can travel to the brain via the blood stream. Therefore, a notable risk factor for this occurrence is accidental intravascular injection. When a local anaesthetic is inadvertently administered into a blood vessel, it initiates a bolus effect wherein a concentrated surge of the drug rapidly reaches the brain before subsequent dilution within the systemic circulation. This bolus effect accentuates the CNS effects of the anaesthetic, significantly amplifying the likelihood of seizure occurrence (27). This bolus effect accounts for the significant potential CNS effects of the anaesthetic.

However, another more likely mechanism in most cases, based on the rapidity of onset in many of the reported events, is a type of reflex epilepsy wherein seizures are precipitated by a sensory stimulus (28). A well-known, but rare epileptic syndrome, is tooth brushing epilepsy (28). We postulate that the effect of local anaesthesia on the nearby dental nerves causing acute local anaesthesia and very rapid deafferentation of the innervated part of the CNS which could then create a reflex epilepsy without significant concentrations of local anaesthetic in the brain parenchyma. This concept is supported by the rapidity of seizure onset following local anaesthetic injection.

Prevention and management

Preventing complications associated with the administration of local anaesthetics, such as seizures, constitutes the best form of management in clinical practice. Central to this is a comprehensive understanding of the key risk factors implicated in adverse effect development, thus enabling healthcare providers to proactively mitigate potential hazards. Since the adverse effects of local anaesthetics are generally concentration-dependent, minimizing the amount of local anaesthetic used is a good way to decrease the risk. This approach not only serves to mitigate the risk of complications but also aligns with the principles of prudent prescribing and evidence-based practice.

Furthermore, consistent aspiration practices prior to injection constitute a critical safeguard against intravascular administration, a recognized risk factor for adverse events such as seizures. By meticulously aspirating to verify needle placement and ensure extravascular deposition, healthcare providers can effectively avert inadvertent intravascular injection and mitigate the associated risks. Reducing the risk of systemic absorption and subsequent CNS effects is essential to safeguard patient well-being.

Since seizures are caused by an imbalance in brain conduction signals favouring excitatory pathways, drugs that increase inhibition should assist in the prevention of seizures. A variety of drugs have been assessed for their ability to prevent local anaesthetic-induced seizures such as carbamazepine, and benzodiazepines (29,30).

Benzodiazepines have been well-studied for their ability to prevent local anaesthetic-induced seizures. Diazepam is commonly used to treat seizures and thus it is logical that it has utility in their prevention. In 1971, De Jong and Heavner conducted a study assessing the ability of diazepam to prevent local anaesthetic-induced seizures in cats. Intramuscular diazepam injection prevented seizures in 8/10 cats given an IV bolus of lidocaine (31). Munson and Wagman continued investigating this in 1972 by studying the ability of diazepam to arrest seizures caused by injection of lidocaine, mepivacaine, and bupivacaine. Their study showed that not only was diazepam an effective drug to prevent seizures, but also that it could be used to abort local anaesthetic-induced seizures in rhesus monkeys. They gave an IV infusion of each local anaesthetic type until a seizure occurred. They then injected a 0.1 mg/kg bolus of diazepam, which successfully stopped the seizures in each case (32). Another study conducted in 1976 by Ausinsch et al. showed that diazepam prophylaxis of 0.05–0.025 mg/kg could increase the dose of lidocaine required to cause seizures by 24–34% (33). Although diazepam is used prophylactically for certain conditions, it remains questionable whether it should be considered for local anaesthetic-induced seizures. Since this is a relatively rare adverse effect, it may be better reserved as a rescue treatment measure if a seizure is to occur and does not stop on its own. Another approach to abort a local anesthetic seizure is to administer midazolam, which can be delivered in three ways: buccal, intranasal via a spray, or systemically via IV or intramuscular injection. Intramuscular injection is most convenient and as effective as IV administration (34). In addition to preventive measures, being equipped with the knowledge and skills to effectively manage seizures in the dental office is paramount. Non-pharmacological interventions play a crucial role in ensuring the safety and well-being of patients experiencing seizures within the dental setting. Non-pharmacological management includes promptly removing any objects or instruments from the patient’s mouth to prevent aspiration and mitigate the risk of airway obstruction. Clearing the oral cavity of debris or dental equipment helps maintain unimpeded airflow and reduces the likelihood of respiratory compromise during the seizure episode. Furthermore, it is imperative to remove sharp objects or hazardous materials from the patient’s vicinity to prevent accidental injuries or harm to themselves or others.

During a seizure, it is essential to closely monitor the patient’s condition. Generally, seizures will resolve on their own within a few minutes. Once the seizure subsides, patients may benefit from receiving supplemental oxygen to support respiratory function and aid in recovery. Allowing the patient to rest in a comfortable position can help facilitate post-seizure recovery. If the seizure does not self-terminate within a few minutes, prompt activation of emergency services should be initiated and consideration should be given to the administration of an anticonvulsant such as midazolam, as mentioned above.

Importantly, patients who experience a seizure episode in the dental office should undergo medical assessment if they have not been previously diagnosed with a seizure disorder. A comprehensive evaluation by a healthcare professional can help elucidate the underlying cause of the seizure and guide appropriate management and follow-up care. Additionally, documentation of the seizure episode and communication with the patient’s primary care provider or neurologist can facilitate continuity of care and ensure that any underlying medical conditions are addressed effectively.

Conclusions

The correlation between local anaesthetic injection and the occurrence of seizures is supported by a wealth of evidence gleaned from both epidemiological data and biologically plausible mechanisms. While such occurrences are relatively rare, the potential consequences of seizures cannot be understated, as they can pose significant risks to patient safety and even prove life-threatening in certain circumstances. Consequently, it is imperative for dental offices to implement stringent preventive measures aimed at minimizing the risk of seizure incidence following the administration of local anaesthetics.

Given the gravity of this issue, dental professionals must undergo comprehensive and regularly updated training to effectively manage seizures should they arise during dental procedures. Such training ensures that dental practitioners are equipped with the necessary knowledge and skills to promptly and appropriately respond to seizure events, thereby safeguarding the well-being of their patients.

In addition to training, dental offices should also prioritize the implementation of robust safety protocols and risk mitigation strategies to further mitigate the likelihood of seizure occurrence. This may include meticulous patient assessment to identify individuals at higher risk of experiencing seizures, as well as the utilization of alternative anaesthetic techniques or adjunctive medications when appropriate.

Furthermore, fostering open communication with patients regarding their medical history, including any history of seizures or related conditions, is essential for tailoring treatment plans and optimizing patient safety. By maintaining a proactive and vigilant approach to seizure prevention and management, dental professionals can uphold the highest standards of care and ensure the well-being of their patients throughout the entirety of dental procedures involving local anaesthetic administration.

It is imperative to acknowledge that there are inherent limitations in this review paper. It is important to emphasize that the conclusions drawn are based on the currently available evidence, which mostly includes case reports and retrospective analyses. The absence of prospective, large-scale studies in this area means that our understanding of the incidence and mechanisms of local-anaesthetic induced seizures remains incomplete. Additionally, the variability in patient responses and the differing methodologies across reported cases introduce further uncertainty. Therefore, while we highlight significant associations and potential biological mechanisms, we must be careful not to overstate these findings. Our aim is to provide a balanced perspective, acknowledging the need for more rigorous research to confirm these associations and clarify the underlying pathophysiology. We encourage practitioners to consider these limitations when interpreting the findings and to remain vigilant in their clinical practice, applying the recommended prevention and management strategies to ensure patient safety.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-28/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-24-28/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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