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Febrile Seizures In Children
Febrile seizures (FS) are the most common form of neurological disorders that affect infants and young children under the age of five years old (Millichap, 2022). Febrile seizures have a higher risk of affecting an ill child with the highest age group at risk between six months old to five years old (Xixis et al., 2022). A febrile seizure occurs when there is a spike in body temperature above 38 degrees Celcius without another “seizure provoking” disease (Xixis et al., 2022). When a febrile seizure is diagnosed, it gets categorized one of two ways: a simple febrile seizure or a complex febrile seizure (Xixiset al., 2022).
Clinical and Diagnostic Signs and Symptoms
The clinical signs and symptoms can differ depending on the cause of the fever and the type of seizure the patient has. Diagnostic criteria include: a seizure that is associated with an elevated body temperature higher than 38 degrees Celsius, a child in the age group older than six months old but younger than five years old, absence of a central nervous system (CNS) infection or another cause of CNS inflammation, absence of any other metabolic abnormality that may result in seizure and no previous history of afebrile seizure occurrence (Millichap, 2022).
Simple Febrile Seizure
A simple febrile seizure is the most common of the two and has the following characteristics: the seizures last less than 15 minutes and does not reoccur within 24 hours of the initial seizure, the postictal phase after the seizure ends only last a few minutes (Xixis et al., 2022). Simple seizures are generalized seizures. Generalized seizures begin simultaneously in both cerebral hemispheres of the brain, the patient is unconscious and will have symmetric motor responses (Norris, 2019).
Tonic-Clonic Seizures
Tonic-clonic seizures are the most common of generalized seizures - the patient will have a sharp contraction of their muscles and extension of their extremities with loss of consciousness (Norris, 2019). Patients can often be incontinent of bowel and bladder during a tonic-clonic seizure, and at times they can become cyanotic from contraction of their respiratory muscles and airway (Norris, 2019). This is followed by rhythmic contractions and relaxation of the bilateral extremities. At the end of the seizure, the patient will remain in the postictal phase (unconscious) until Reticular Activating System begins to function again (Norris, 2019).
Other Types of Generalized Seizures
Although tonic-clonic seizures are the most common of generalized seizures, there are numerous other types of seizures that make up generalized seizures. Myoclonic seizures are described as involuntary muscle contractions usually in the face, trunk or extremities (Norris, 2019). Clonic seizures start with a sudden loss of consciousness and then hypotonia of the muscles followed by limb jerking which may or may not be symmetrical (Norris, 2019). Tonic seizures are characterized by a sudden increase in muscular tone in the extensor musclesand atonic seizures are a sudden, rapid loss of muscle tone leading to loosening of jaw, drooping of limbs or falling to the ground (Norris, 2019). Absence seizures are non-convulsive epileptic events which result in a disturbance of consciousness - it can look like a blank stare, motionlessness, and unresponsiveness (Norris, 2019). Absence seizures only last a few seconds and the person will immediately return to normal activity (Norris, 2019). Motion can still occur while someone is having an absent seizure; the motion occurring is called an automatism which usually presents as lip smacking, eyelid fluttering, increase or decrease in postural tone and involuntary reflexes (Norris, 2019).
Complex Febrile Seizures
A diagnosis of complex febrile seizure is made when the patient has one of the following criteria: the duration of the seizure lasts longer than 15 minutes, the patient has a recurring seizure within 24 hours of the initial seizure or they have a focal seizure (Xixis et al., 2022). Focal seizures are differentiated in two ways: without impairment of consciousness and with impairment of consciousness (Fisher et al., 2017).
Focal Seizure Without Loss of Consciousness
A focal seizure without loss of consciousness (simple partial seizure) usually occurs from a stimulus from only one hemisphere of the brain (Norris, 2019). The clinical symptomsof the seizure will depend on which area of the brain is affected. For example, if the motor area of the brain is involved then the seizure may result in a motor response of a muscle on the opposite side of the body (Norris, 2019).
Focal Seizures with Impairment of Consciousness
Focal seizures that lead to impairment of consciousness stim from the temporal lobe of the brain and usually present in automatisms. These types of seizures can present as repetitive, non-purposeful movements such as lip smacking, patting or grimacing. These seizures are very similar to absent seizures but unlike absent seizures, a patient with a focal seizure may be confused during the postictal state (Norris, 2019).
Pathophysiology of Febrile Seizures
The pathophysiology of febrile seizures is complex, and there is still a lot of research being done to better understand the relationship between fevers and convulsions. During an acute infection with a fever, the body’s inflammatory response can play a role in increasing the neuronal excitability of an immature CNS (Han & Han, 2023). Vezzani & Vivani (2015) found there is increasing evidence that the major cytokines that have an impact on neuronal excitability are interleukin-1 beta (IL-1𝛽), tumor necrosis factor alpha (TNF-ɑ), and interleukin-6 (IL-6).
In a healthy person, cytokine levels are typically low at baseline, but it has been found that cytokine levels take a rapid increase shortly after infection, seizures, or injuries (Vezzani & Vivani, 2015). Usually, when cytokines fight infection they stay localized to the infected area of the body. But, at times if levels are high enough the cytokines can spill over into the extracellular circulation resulting in elevated cytokine levels in the blood (Mosili et al., 2020). Extracellular changes in cytokine levels can change the way the glio-neuronal and vascular levels communicate (Vezzani & Vivani, 2015). The cytokines along with the pathogen-associated molecular patterns (PAMPS) that are expressed on the lipopolysaccharide of the pathogen affect the blood brain barriers (BBB) ability to maintain homeostasis.The BBB’s inability to maintain homeostasis results in a leaky blood brain barrier and allows cytokines and lipopolysaccharides to enter the central nervous system (Mosiliet al., 2020). Waruiru et al. (as cited in Mosili et al., 2020) found that once across the blood brain barrier, cytokines activate the cyclooxygenase-2(COX-2) and microglia. COX-2 stimulates the formation of prostaglandin-E2 (PGE2) which acts on the hypothalamus to induce a fever. The microglia releases more IL-1𝛽, TNF-ɑ, and IL-6 into the central nervous system. Further release of these cytokines into the CNS lead to modification of voltage-gated channels and receptor-coupled channels leading to presynaptic changes in neurotransmission of the neurons resulting in increased excitability and seizures (Vezzani & Vivani, 2015).
IL-1𝛽 and IL-1R1
IL-1𝛽 and interleukin 1 receptor type I (IL-1R1) act on the receptor-operated ion channel (ROC) called the N-methyl-D-aspartate receptor subtype 2B (NMDAR-NR2B), which is a glutamate receptor. When the NMDAR-NR2B is acted on by IL-1𝛽 and IL-1R1, it signals sphingomyelinase/Src activation which causes an abnormal influx of Ca2+ into the axon terminal resulting in hyperexcitability and increased susceptibility to seizures (Vezzani & Vivani, 2015).
TNFR1
Like IL-1𝛽, excess TNFR1 will similarly cause an abnormalinflux of Ca2+ into the axon terminal resulting in hyperexcitability and increased susceptibility to seizures. The TNFR1 acts on multiple ROC channels such as the AMPAR-GLU1/GLU2, NMDAR-NR1, and GABA-A R𝛽2/𝛽 3 subunits. When acted on, these ROC channels signal PI3K/Akt and PP1 leading to influx of Ca2+ into the axon terminal, a reduction in glutamatergic drive, decrease inhibitory synaptic strength and ultimately increased susceptibility to seizure (Vezzani & Vivani, 2015).
IL-6
Another significant cytokine when discussing cause of febrile seizures is IL-6. IL-6 acts on multiple ROC channelssuch as mGLUR2/3, NMDAR-NR and GABA-A R. When these channels are opened by IL-6 it causes STAT3 and PI3K-AKt to be signaled resulting in dysregulation of presynaptic glutamate release, changes in synaptic network functions, and decreased GABA current (Vezzani & Vivani, 2015). GABAs function as a synaptic inhibitor in the CNS (Norris, 2019). A decrease in the GABA current, reducation in glutamatergic drive, along with dysregulation of synaptic networks allow for the dysregulation to continue without any inhibitatory mechanisms resulting in a seizure.
Risk Factors For Febrile Seizure
There are a number of factors which can place a patient at higher risk for having a febrile seizure. The highest risk age group is children between the ages of six months to five years old (Xixis et al., 2022). In addition to age, other risk factors include family history of parents or siblings with febrile seizures, infection, fever and recent immunization (Millichap, 2022). Some social determinants of health that impact a patient with the diagnosis of febrile seizures are family history, if the child has siblings, if the child attends day care/school, and the child’s immunization history. A patient having a sibling or attending day care puts them at increased risk for infection which puts them at risk for developing a fever.
Fever
Febrile seizure can occur with any body temperature above 38C (Xixis et al., 2022). Any cause of a fever places the patient at higher risk for developing a febrile seizure (Febrile Seizure, 2023). Sometimes, receiving vaccinations such as diphtheria, tetanus and pertussis vaccine and the measles-mumps-rubella vaccine can place patients at a higher risk for febrile seizure due to the body’s fever response to the vaccine (Febrile Seizure, 2023). The fever can leave the child at higher risk of developing a seizure not the vaccine.
Infection
Aside from age, one of the largest risk factors of febrile seizure is infection. Carman et al. (2019) conducted a prospective multicenter study in eight different cities in Turkey between 3/1/2016 and 4/1/2017. They took nasopharyngeal swabs from all children who presented to the ED with febrile seizure to test them for an active viral infection. Of the 174 children studied, 82.7% of children were found to test positive for a viral infection. 55.5% of the children with viruses were found to have adenovirus and 47.2% were found to have influenza. 36.2% out of the 174 children reported to have a family history of febrile seizures. This data is statistically significant because it supports the claim that infection (especially viral infections) and family history of febrile seizures put a patient at higher risk for developing a febrile seizure.
Risk for Recurrence of Febrile Seizure
Up to 30% of children who have had previous febrile seizures remain at risk for recurrent febrile seizures (Xixis et al., 2022). Kubota et al. (2021) conducted a prospective study at Atsugi City Hospital in Kanagawa, Japan with patients with febrile seizure who visited the ED between March 1, 2019 and February 29, 2020. Of the 109 participants, 13 had a recurrent febrile seizure (11.9%) and all participants had their second seizure within 24 hours of their first seizure. Kubota et al. (2021) found that lower body temperature upon arrival to the ED had a significant association with recurrent febrile seizure. Children with a lower body temperature at the initial onset of febrile seizure have a lower threshold for febrile seizures to occur and therefore are at higher risk to experience another seizure if they spike another fever.
Linking the Signs and Symptoms to the Pathophysiology
The process of developing a febrile seizure typically begins when a child is in an incubation period after being exposed to a pathogen. Mike being in pre-kindergarten is at higher risk for developing a number of illnesses. Mike likely caught an infection while at school. The pathogen entered his body and started creating cytokine levels to increase due to the body’s immune response to the pathogen. Together, the cytokines work synergistically with the PAMPS that are expressed on the lipopolysaccharide of the pathogen to cause a leaky blood brain barrier and allowing cytokines and lipopolysaccharides to enter the central nervous system (Mosili et al., 2020). Once across the blood brain barrier, the cytokines stimulate the COX-2 to form PGE2 which acts on the hypothalamus to induce a fever (Vezzani & Vivani, 2015). Mike was found to have a temperature of 39.1C upon presenting to the urgent care, so it is very likely he had a fever this morning during the time of his convulsion.
Mike’s stimuli from the cerebrum of his brain was likely a result of the hyperexcitability of the neurotransmitters in his central nervous system. Mike’s cytokines and lipopolysaccharide of the pathogen entering his CNS through the leaking BBB stimulated his microglia in his CNS to release more IL-1𝛽, TNF-ɑ, and IL-6 to help protect his body against the pathogen (Mosili et al., 2020). The excess IL-1𝛽 and IL-1R1 are acting on his NMDAR-NR2B glutamate receptor activating sphingomyelinase/Src and allowing an abnormal influx of Ca2+ into the axon terminal of his neurotransmitter (Vezzani & Vivani, 2015). Similarly, his TNFR1 was acting on a multitude of ROC channels such as AMPAR-GLU1/GLU2, NMDAR-NR1, and GABA-A R𝛽2/𝛽 3 subunits which signals PI3K/Akt and PP. This also results in an abnormal influx of Ca2+ into the axon terminal but also causes a reduction in glutamatergic drive resulting in a decrease in inhibitory synaptic strength (Vezzani & Vivani, 2015).
Lastly, his IL-6 is working on multiple ROC channels such as mGLUR2/3, NMDAR-NR and GABA-A R. Opening these channels signal STAT3 and PI3K-AKt resulting in dysregulation of presynaptic glutamate release, changes in synaptic network functions, and decreased GABA current (Vezzani & Vivani, 2015). This is significant because the GABA functions as a synaptic inhibitor (Norris, 2019) and when it is dysregulated, it cannot inhibit the abnormal synapses/hyperexcitability occurring in the neurotransmitters as a result of the abnormal influx of Ca2+. Homeostasis between excitability of neurotransmitters and the inhibitory processes is essential for avoiding seizure activity. The abnormal influx of Ca2+ into the axon and the dysregulation of the GABA and glutamatergic inhibitory drive causes Mike’s cerebrum of his brain to be hyperexcitable leading to his seizure activity.
Mike’s Mother reports that initially, Mike’s eyelids were fluttering; this is a symptom of either a myoclonic seizure which is described as involuntary muscle contractions usually in the face, trunk or extremities or an absent seizure which can present as eye fluttering (Norris, 2019). The seizure then progressed to “shaking” of his body. The shaking of Mike’s body that his mother described was sharp contractions of his muscles and tensions of his extremities which are the characteristics of a tonic-clonic seizure (Norris, 2019). Mike was also incontinent of urine at the time of the shaking which is another indicator that the episode was a tonic-clonic seizure - his muscles were contracting which includes his bladder leading to urinary incontinence.
Treatment of Febrile Seizure
History and Physical
The provider should obtain a thorough history and physical for Mike. It is important to obtain information regarding the exact appearance of their seizure presentation and how long the seizure lasted for (Xixis et al., 2022). The provider will want to do a full neurological exam on Mike as well, to rule out other central nervous system infection, structural abnormalities (such as a head injury), or any other neurological disorder that could be a potential cause for the seizure (Xixis et al., 2022). Lastly, the provider would want to ask Mike’s Mother if there is a known family history of febrile seizures, if he is up to date on immunizations, the date he received his immunizations, if Mike has had any known sick contacts in the last 2 weeks and if Mike has been displaying any other signs or symptoms of an infectious process (such as fever, sore throat, cough, congestion).
Fever
Based on Mike’s stemperature of 39.1C and the reports from his Mother, he would be diagnosed with generalized febrile seizures. Mike should be treated first with a dose of oral Acetaminophen 15mg/kg/dose to treat his fever and prevent the fever from getting higher. This dose of Tylenol can be repeated every 6 hours as needed for fever or pain with a maximum dose of 75mg/kg/day (Lexicomp Online, n.d.).
PCR Testing
Mike’s Mom reports that there have been illnesses spreading around his pre-kindergarten class since the start of the school year. He also presented to urgent care with mildly swollen tonsils and a reddened and inflamed oropharynx. The provider should consider obtaining a Viral PCR test and a Strep test to determine the cause of Mike’s fever and swollen tonsils/oropharynx and if Mike will need to be treated with antibiotics.
Admission to the Hospital
Witnessing your child have a seizure is a very traumatic experience for parents. 30% of children with previous febrile seizures remain at risk for developing a recurrent febrile seizure so the provider should recommend Mike’s Mom take him to the emergency department (ED) for further workup and observation. Mike should be admitted to the hospital for 24hr observation due to the risk of recurrence of the febrile seizure (Xixis et al., 2022). Admission to the hospital will ensure that Mike has immediate access to medical attention in the event that he seizes again and help reduce Mom’s stress of having to monitor him 24/7 for a recurring febrile seizure at home. Because Mike was alert and oriented x3 upon presenting to urgent care and rapidly returned to his baseline at the end of the seizure, no medication treatment or EEG monitoring would be required for Mike at this time (Millichap, 2022). Because Mike was so well appearing at presentation, he had full mobility of his head and neck and had no neurological deficits there is no need for a lumbar puncture at this time. The provider should have nursing place intravenous (IV) access in case there is recurrence of seizure activity and a need for IV seizure rescue medication. While placing IV access, the provider should obtain blood cultures, a complete blood count (CBC) and Basic Metabolic Panel (BMP) to rule out sepsis, evaluate Mike’s white blood cell count and ensure his electrolytes are within normal limits. The provider should place Mike on continuous pulse oximetry monitoring in the event that Mike has another seizure.There is a risk for him becoming hypoxic during a tonic-clonicseizure if his respiratory muscles contract and restrict air movement through his trachea. There should also be an as needed order placed for administration of an IV Benzodiazepine (IV Diazepam 0.1 to 0.2mg/kr OR IV Lorazepam 0.05 to0.1mg/kg) for a recurring seizure that lasts five minutes or longer (Millichap, 2022).
Recurring Febrile Seizure
Like stated above, in the event that a recurrent febrile seizure occurs, Mike should have a rescue IV Benzodiazepine order placed in his electronic medical record for nursing to administer for a seizure that lasts longer than five minutes (Millichap, 2022). In the event that the seizure persists after administration of the IV Benzodiazepine or the patient has repetitive seizures then an additional dose of IVBenzodiazepine (IV Diazepam 0.1 to 0.2mg/kr OR IV Lorazepam 0.05 to 0.1mg/kg) may be required to be given and antiseizure medications such as Fosphenytoin (20mg phenytoin equivalents/kg IV) to stop the seizure activity (Millichap, 2022).
At The Time of Discharge
When a child has a febrile seizure, there is an increased risk of them having febrile seizures in the future or even developing afebrile seizures (Millichap, 2022). Mike should be prescribed a rescue medication at the time of discharge and Mom should be instructed to give Mike the rescue medication if he has another seizure in the future that lasts longer than fiveminutes. The prescription should be buccal Midazolam (0.2mg/kg and a max dose of 10mg) (Millichap, 2022). Mom should also be reminded to start a timer as soon as she notices seizure activity starting make sure Mike is in a safe area, that his head remains protected, and to call 911.