Generalized Tonic-Clonic Seizure

Etiology

The etiology of most of the generalized tonic-clonic seizures is underlying epilepsy from genetic causes (previously categorized as idiopathic). Besides genetic generalized epilepsy, tonic-clonic seizures can be secondary to epilepsy due to structural, infectious, metabolic, or immune-related pathologies.[1] Acute symptomatic seizures- secondary to ischemic or hemorrhagic strokes, extra-axial hemorrhage, traumatic brain injury, hypoxic-ischemic injury, acute medical illness, metabolic derangements, substance abuse- can manifest as tonic-clonic seizures without the inherent tendency to recurrent seizures, whereas epileptic seizures recur without proximate provocating factors. Common causes of emergency department visits after seizures are alcohol and drugs, head injury, and epilepsy.[2]

Epidemiology

Seizures account for 1 to 2 percent of all emergency visits in the U.S.[3] Seizures are reported to occur about 11% of people in the United States during their lifetime.[4] Acute symptomatic seizures tend to occur more frequently in males than females in a ratio of 1.85 to 1, with a lifetime risk of 5.0% in males and 2.7% in females.[4] Among patients who visit the emergency department, African Americans are overrepresented relative to whites, with an odds ratio of 1.4.[5] Seizures have bimodal age distribution that occurs in infants, secondary to febrile illness, and patients older than 75 years, secondary to structural damage due to stroke or trauma.[4]

Pathophysiology

Seizures are thought to arise secondary to an imbalance between excitation and inhibition of neurons. Imbalance of excitation and inhibition can be the result of alteration in genes or from acquired etiologies. Genetic pathologies can produce dysfunction at the circuit level (e.g., abnormal synaptic connectivity) to the receptor level (imbalance between excitatory glutamate and inhibitory gamma-aminobutyric acid [GABA] receptors) to ionic channel level(example, sodium channel dysfunction in Dravet syndrome). Both monogenic and polygenic mutations can lead to epilepsy, and most adult-onset epilepsies have a complex genetic basis with multiple gene defects playing parts to develop excessive excitability, or diminished inhibition, or both.[6] Acquired cerebral insults such as trauma, strokes, or tumors can alter cerebral neuronal circuits similarly.[4]

History and Physical

The diagnosis of a generalized tonic-clonic seizure is based on the patient's history and physical examination. The patient’s experience, recollection, and awareness of the event should be the initial focus of the history taking. A history of prodrome (auras) should be inquired and often involve subtle changes in mood, cognition, and headache. The auras can be helpful for localization of the seizure origin and indicate focal onset seizure rather than generalized type. Patients after presentation with the first episode of generalized tonic-clonic seizure should be asked about prior staring spells (absence seizures) or early morning myoclonic jerks; the presence of multiple seizure types can help to make a diagnosis of epilepsy or a particular epileptic syndrome. Generalized tonic-clonic seizures begin with an abrupt loss of consciousness without any aura. The tonic phase of seizure can start with a scream with a generalized stiffening of the body with or without cyanosis. After the initial tonic phase, clinical features evolve into clonic jerking followed by postictal sleepiness, confusion, or agitation. A detailed history should also be obtained regarding any environmental or physiologic triggers( example: fever, the menstrual period, lack of sleep, stress, strong emotions, strenuous exercise, loud music, flashing lights, etc.) immediately preceding the seizure.[7]

A detailed physical examination is important in these patients. A postictal state of confusion, somnolence, headache, personality, and mood changes are common and characteristic of generalized tonic-clonic seizures. Examination of oral mucosa can reveal lateral tongue bites, which can be seen in approximately 22% of patients with epileptic seizures. Lateral tongue bites are not seen in patients with psychogenic nonepileptic seizures. Bruises and scrapes over the body can be seen commonly after a seizure. Vertebral compression fracture can manifest as back pain after a fall from the seizure event. Nuchal rigidity from meningeal inflammation from an infection or asterixis from the metabolic disorder can be evident on physical examination that can point towards the etiology of the seizure. Focal weakness or asymmetry on examination can point towards focal seizures evolving into bilateral tonic-clonic seizures rather than generalized seizure onset. Skin examination can reveal signs of neurocutaneous syndromes such as neurofibromatosis, tuberous sclerosis, and Sturge-Weber syndrome, which are associated with epilepsy. Signs of urinary incontinence due to the relaxation of the urinary sphincter can be seen in an immediate postictal phase.[7]

Evaluation

A patient seeking care in the emergency department should have a chemistry panel done to rule out hypoglycemia, hyponatremia, uremia, and drug intoxication. Emergency neuroimaging is recommended for patients with suspected serious brain lesions, persistent neurological deficits, recent trauma, and headache. Computed tomography (CT) is the first imaging modality of choice in the emergency department. Advanced imaging such as magnetic resonance imaging (MRI) needs to be done, if high suspicion of focal abnormality, despite a negative CT scan.[8][9] Emergency electroencephalography is recommended for a patient who does not return to baseline after 30 to 60 minutes after a seizure, fluctuating mental status, or focal neurological deficits not explained by structural abnormality. A lumbar puncture should be part of the diagnostic evaluation if there is a concern for meningitis, encephalitis, or subarachnoid hemorrhage.[7]

Treatment / Management

A person experiencing tonic-clonic seizures should be rolled over to the recovery position to decrease the risk of asphyxiation and aspiration. Most generalized tonic-clonic seizures resolve spontaneously, and antiseizure medications are not usually required. Patients presenting with seizures are recommended to have intravenous access, in case of prolonged seizures. Metabolic and infectious etiologies should be investigated and treated. Seizures lasting more than 5 minutes or recurrent seizures without return to baseline consciousness meets the definition of status epilepticus. During the first 5 minutes of seizure(stabilization Phase), several interventions are necessary: maintenance of airway, breathing, and circulation; neurological examination, initiation of EEG monitoring if available; maintenance of normoglycemia; procurement of IV access; and completion of necessary laboratory work-up (electrolytes, hematology, toxicology screen, anticonvulsant levels if appropriate). Patients who are critically ill with ongoing seizures should have antiseizure medication administered intravenously to achieve therapeutic plasma levels. A benzodiazepine (intramuscular midazolam, intravenous lorazepam, intravenous diazepam, intranasal midazolam, or rectal diazepam) is the initial therapy of choice. If seizures continue for more than 20 minutes, second-line therapy should be initiated. There is no evidence-based preferred second-line therapy, but one of these three antiepileptic drugs- intravenous fosphenytoin, valproic acid, or levetiracetam, can be given as a single bolus dose.

The decision to start chronic, prophylactic antiseizure medications is individualized based on numerous factors, including the chance of event being a seizure, confirmation of seizure based on history and physical examination, patient stability, and risk of recurrent seizures. Curative epilepsy surgery is an option for patients with focal onset seizures that are refractory to medical therapy but usually not a consideration for generalized seizures.[10][11](A1)

Differential Diagnosis

Accurate diagnosis of seizure requires differentiating from seizure mimics. In patients presenting with generalized tonic-clonic movements, the following diagnosis needs to be ruled out.[12]

• Syncope (cardiac or non-cardiac)
• Transient ischemic attack
• Psychogenic non-epileptic seizure
• Paroxysmal movement disorders
• Sleep disorders
• Migraine

Treatment Planning

A person experiencing tonic-clonic seizures should be rolled over to the recovery position to decrease the risk of asphyxiation and aspiration. Most generalized tonic-clonic seizures resolve spontaneously, and antiseizure medications are not usually required. Patients presenting with seizure it is recommended to have intravenous access, in case if seizures are prolonged or recur. Metabolic and infectious etiologies should be investigated and treated. Seizures lasting more than 5 minutes or recurrent seizures without return to baseline consciousness meets the definition of status epilepticus. Patients who are critically ill with ongoing seizures should have antiseizure medication administered intravenously to achieve therapeutic plasma levels. The decision to start antiseizure medications is individualized based on numerous factors, including the chance of event being seizure, confirmation of seizure based on history and physical examination, patient stability, and risk of recurrent seizures. Epilepsy surgery is an option for patients with focal onset seizures that are refractory to medical therapy.[11][12]

Toxicity and Adverse Effect Management

Antiepileptic drug (AED) medications are the mainstay of treatment for most patients with seizures.  First-line medications are valproic acid, lamotrigine, and topiramate.[13] Each of these drugs has side effects of which treating clinicians should be aware. Valproic acid has a risk of hepatotoxicity, teratogenicity, and pancreatitis.[13] Valproate is contraindicated in patients with suspected mitochondrial disorders due to the high risk of hepatic failure. Valproate can cause neural tube defects and decreased IQ scores and autism following in utero exposure. Therefore, valproate should not be administered to women of childbearing potential unless seizures refractory to other AEDs. If valproate is used in women of childbearing potential, folic acid supplementation and effective contraception should be used. Lamotrigine has a boxed warning that it can cause severe skin rashes. The incidence of these rashes, including Stevens-Johnson syndrome, is approximately 0.08% to 0.3% in the adult population. The incidence of skin rash is higher in pediatric patients. These life-threatening rashes usually occur 2 to 8 weeks after starting the medication.[13] Coadministration of lamotrigine with valproate, higher than the recommended initial dose of lamotrigine, or faster dose escalation of lamotrigine can increase the risk of skin rash. Lamotrigine should be discontinued at the first sign of rash unless the rash is clearly not drug-related. There is a new safety warning of potentially life-threatening immune reaction called hemophagocytic lymphohistiocytosis (HLH) in association with lamotrigine. Common features of HLH are fever and rash, enlarged spleen, cytopenias, elevated triglycerides or low levels of fibrinogen, high levels of ferritin, hemophagocytosis identified through bone marrow, spleen or lymph node biopsy, absent or denatured natural killer (NK) cell activity or elevated CD25 levels showing prolonged immune cell activation.

Topiramate has the risk of causing acute myopia and secondary closed-angle glaucoma. Common adverse effects are paresthesia, memory impairment, anorexia, dysgeusia, renal calculus, and oligohydrosis. In addition, it can lead to a hyperchloremic, non-anion gap, metabolic acidosis, and hyperammonemia and encephalopathy. Hyperammonemia is more commonly seen in patients with inborn errors of metabolism or hepatic dysfunction.[14] Patients on these medications should be followed closely by their neurologists. Moreover, all AEDs carry a warning about an increased risk of suicidal thoughts and behaviors. 

Prognosis

The prognosis for generalized tonic-clonic seizures is dependent on the cause of the seizure and risk factors for the patient. On average, the risk of recurrent seizures is about 40% based on observational studies. The risk of recurrent seizure is highest during the period immediately after the initial seizure and decreases with increasing time from the event. Studies have shown that seizure risk reduction of approximately 30% to 60% after initiating treatment with medications. Three factors consistently shown to have increased risk of seizure recurrence are the number of seizures, neurological disorder, and an abnormal electroencephalogram.[15]

Complications

Patients with generalized tonic-clonic seizures are at increased risk of psychiatric disorders, cognitive impairment, sleep disorders, cardiovascular disease, bone disease, physical injuries, and even premature mortality. The most significant risk factor for sudden unexpected death in epilepsy (SUDEP) is frequent generalized tonic-clonic seizures. The etiology of SUDEP is unknown; however, different pathophysiologic factors have been postulated to be involved, including cardiac arrhythmia, seizure-induced apnea, and pulmonary dysfunction, and neurogenic cardiorespiratory depression. Although there are no definitive strategies to reduce the risk of SUDEP, better seizure control, and nocturnal supervision can be useful.