Diagnosis
and Management
of Partial Seizures in Children
Edwin Trevathan, M.D., M.P.H.
Associate Professor of Neurology & Pediatrics
Director, Pediatric Epilepsy Center
Washington University School of Medicine
St. Louis Children’s Hospital
One Children’s Place
St. Louis,
email: trevathan_e@kids.wustl.edu
Keywords: epilepsy, management, partial seizures, epilepsy syndromes, epilepsy surgery, anti-epileptic drugs
As a group children with partial epilepsy are relatively common, accounting for up to half of all childhood epilepsy in some population-based studies.1 Yet, children with partial seizures are a very hetereogenous group, and their management varies according to the details of their epilepsy syndrome and associated neurological condition. Furthermore, management of epilepsy varies between developed and developing countries.
Partial seizures may exist as a single predominant seizure type, or one of several different seizure types. Children often experience changes in their seizure types, with changes in the clinical manifestations of their partial seizures occurring as brain maturation and development progresses. Some children seem to initially present with partial seizures with evolution to generalized seizures, while others present with generalized seizures and evolve into partial epilepsy. The first step in managing partial seizures is the mastery of the science and art of seizure diagnosis and classification.
CLASSIFICATION AND DIAGNOSIS OF SEIZURES
The 1981 classification of seizures is now the worldwide standard, and should be used to facilitate communication and identify appropriate therapies (Table 1).2 This seizure classification divides seizures into two groups based upon how the seizure starts; partial seizures start within a single region of cortex, while generalized seizures begin over the entire cortical surface simultaneously. The seizure classification is built upon the concept that partial seizures differ from generalized seizures in their etiologies and management.
TABLE 1
Classification of Seizures and Impairment of
Consciousness
The Diagnosis of Partial Seizures -- General Principles
Partial seizures start in a region of cortex localized to a single part of the brain and are classified further into three sub-types; simple partial, complex partial, and partial with secondary generalization. Simple partial seizures are not associated with impairment of consciousness, while complex partial seizures are associated with clouding of consciousness. Partial seizures with secondary generalization begin within a localized region of the cortex; as the electrical seizure spreads across the cerebral cortex, the seizure clinically changes to a generalized seizure - often a generalized tonic-clonic seizure. Partial seizures are at least as common as generalized seizures in the general population, in spite of the fact that physicians-in-training tend to recognize generalized tonic-clonic seizures more often.1,3
The clinical manifestations of partial seizures depend upon several factors: (1) the region of the cortex where the seizure starts; (2) the pattern of cortical spread of the seizure; (3) the function of the cortex where the seizure starts; (4) the state of the patient at the time of the seizure (i.e., waking or sleep); (5) the underlying neurological disabilities of the patient. Therefore, the possible manifestations of partial seizures are as varied as the different functions of cerebral cortex.
Although the clinical manifestations of partial seizures vary, partial seizures in an individual patient tend to be stereotypic and neuroanatomically plausible. The diagnosis of partial seizures may be quite difficult, especially if the treating physician relies on technology to answer clinical questions. Up to 50% of patients with partial seizures have normal EEGs (between seizures) at the time of first evaluation. Many with partial seizures have normal neurological examinations and normal neuroimaging studies. Diagnosis can not be made by response to AEDs; at least 30% of children with partial seizures do not have an optimal response to AEDs. Some of the most benign partial seizure syndromes are almost always associated with certain abnormalities on EEG (e.g., benign rolandic epilepsy), while the more "malignant" forms of partial epilepsy often have normal EEGs between seizures (e.g., mesial temporal lobe epilepsy).
Although diagnostic tests are often helpful, a good history performed by an experienced clinician will not soon be replaced by sophisticated diagnostic technology.4 The history is the most important tool in making the diagnosis of partial seizures. A normal interictal (between events) EEG never rules out seizures, and an abnormal EEG doesn't necessarily mean that an active seizure disorder is present. Most patients with seizures can be accurately diagnosed with a simple history, physical exam, and routine waking and sleep EEG. A second attempt to clarify the history, especially obtaining history from additional observers, or a second session with the older child to review the history may clarify the diagnosis without further studies.
The Diagnosis of Simple Partial Epilepsy Syndromes
The Classification of Epilepsy Syndromes currently in use refers to partial epilepsy syndromes as ‘Localization-related epilepsies and syndromes’.5 The idiopathic partial epilepsy syndromes include benign childhood epilepsy with centrotemporal spikes (usually referred to as benign rolandic epilepsy), childhood epilepsy with occipital paroxysms, and primary reading epilepsy.
Benign rolandic epilepsy is not rare, is misdiagnosed often, and has a very good prognosis without AED therapy.6 Benign rolandic epilepsy may be the most common childhood epilepsy syndrome. Children present between 3 and 12 years of age. Almost all children ‘grow out’ of their benign rolandic seizures before the age of 16 years. Children often present with a history of ‘waking’ from sleep in the middle of the night with a gagging/choking noise that wakens the parents. The parents find the child staring, with unilateral facial twitching and drooling. Occasionally there is secondary generalization, but typically the seizures last about 90 seconds to 2 minutes and are simple partial. Although the children are unable to speak, they are often able to comprehend and follow instructions as the ictal discharge is isolated within the rolandic region. The EEG during sleep is always abnormal, with blunted high-voltage central-temporal spikes shifting from side to side. There is often a family history and siblings without a history of seizures may have the typical EEG abnormalities, which are not actual seizures but a marker of lowered rolandic seizure threshold.
I usually do not treat benign rolandic seizures unless children have seizures during the day or prolonged secondarily generalized seizures at night. I usually chose carbamazepine (CBZ) when I treat children with benign rolandic epilepsy. Gabapentin has been shown to reduce frequency of seizures compared to placebo (data on file, Parke-Davis).
Benign occipital epilepsy (or benign childhood epilepsy with occipital paroxysms) is less common than benign rolandic epilepsy, but have a similar benign prognosis. Benign occipital epilepsy has a distinctly visual presentation that consists of simple or complex visual hallucinations and visual distortions. Patients with benign occipital epilepsy often have migraine. The EEG characteristically shows repetitive occipital discharges on eyelid closure. Long-term prognosis is generally excellent with remission by the end of the second decade in most cases; however, some patients with late onset benign occipital epilepsy continue to have partial seizures into adulthood. In my experience, most patients respond to CBZ or sodium valproate (VPA).
The Diagnosis of Complex Partial Epilepsy Syndromes
Complex partial seizures present with a variety of different symptom complexes. Although auras may occur in most children with partial seizures, obtaining the history of auras is often challenging. The symptomatic partial epilepsies are those which are categorized by the lobe in which they arise.
Mesial temporal lobe epilepsy (or hippocampal epilepsy) may be the most common of these syndromes. Patients with mesial temporal lobe epilepsy tend to present months after onset of seizures, because the events are often associated with symptoms not generally believed to be epileptic. Patients often report a vague feeling of dysphoria, impending doom, or de ja vu with a strange epigastric sensation, while others report a stereotypic intrusion of a memory or thought. These initial manifestations are then followed by an alteration of consciousness. Observers note that the patient has a look of fear or confusion, and then stereotypic automatisms such as non-purposeful movement of the hands, feet, and/or mouth. The total duration of the seizure is usually about 90 seconds to 2 minutes. Seizures often cluster with 2-3 seizures per day for a day or two, followed by several seizure-free days. Although the seizures may be very unusual appearing, the stereotypic nature of the progression of clinical seizures may be striking.
Patients with mesial temporal lobe epilepsy often have normal EEGs between seizures, especially early in the course of the disorder. The spikes of mesial temporal lobe epilepsy are often broad-based on scalp EEG recordings with a blunted appearance, and localize to the more anterior-to-mid temporal lobe and are activated by drowsiness and sleep. MRI scans may demonstrated evidence of decreased volume of the mesial temporal lobe structures (hippocampus) on the effected side, with increased T2 signal, especially on the thin coronal images. Occasionally tumors affecting the mesial temporal structures are seen in these patients. Therefore, neuroimaging is indicated even when the patient’s seizures are not intractable. Because some patients with mesial temporal epilepsy do not remember their seizures, patients who experience a decline in memory function should be considered to possibly have experienced an exacerbation in seizure frequency until proven otherwise.
Temporal lobe epilepsy in infants and children may appear clinically different than the same entity in adults. The concept of complex partial seizures is often difficult to apply to infants, since it may be difficult to assess impairment of consciousness in that age group. Infantile temporal lobe seizures tend to be different from older children and adults in that they; (1) tend to have behavioral arrest with more discrete automatisms, (2)more frequent secondary generalized seizures, (3) and longer duration of seizures.7
Sedative drugs such as primidone and phenobarbital may exacerbate the memory and depression problems associated with mesial temporal lobe epilepsy, and I typically use these drugs only as a last option. The outcome after temporal lobe epilepsy surgery is good, with as many as 80% of patients rendered seizure free in our series. Quality of life and seizure frequency outcomes may be better if surgery is performed soon after intractability is established. Patients who have seizures of mesial temporal lobe origin who fail to respond to three drugs have little chance of being seizure free with medication, and should therefore be referred to a Comprehensive Epilepsy Center for evaluation of possible epilepsy surgery.
Frontal lobe seizures are more varied than those of temporal lobe origin, as the frontal lobe is a large structure with a heterogeneous mixture of executive, processing, language and motor functions. Yet, any of these following features should suggest frontal lobe seizures; (1) frequent short attacks (20 seconds in duration) with impairment of consciousness upon arousal from sleep, (2) minimal or no post-ictal confusion, (3) frequent secondary generalization, with status epilepticus, (4) motor manifestations common, (5) automatisms are complex, sometime bizarre, and often gestural, (6) urinary incontinence common, (7) frequent drop attacks.
Supplementary motor seizures are short, often occur out of sleep, and are associated with sudden vocalization with a fencing posture, along with other features such as forced head turning. These seizures have been previously mis-diagnosed as paroxysmal nocturnal dystonia. Interictal EEGs are often normal, and ictal recordings are often difficult to interpret. Patients with supplementary motor seizures often have multiple seizures per night, and may be mis-diagnosed as having non-epileptic seizures. EEG-video monitoring may be necessary to distinguish supplementary motor seizures from non-epileptic seizures. In the absence of EEG-video, a good history is usually the most valuable diagnostic tool.
Anterior frontopolar seizures are associated with initial loss of eye contact, versive head and eye movement to the contralateral side, and axial clonic jerks of the arms and legs associated with falls. Secondary generalization is typical, and therefore diagnosis is usually not delayed. However, most of these patients are initially diagnosed as having "generalized tonic-clonic seizures, " when in reality they have partial seizures. Therefore, patients with ‘intractable generalize d tonic-clonic’ seizures may be candidates for epilepsy surgery because many actually have anterior frontopolar seizures with secondary generalization.
Orbitofrontal seizures are often heralded by an olfactory hallucination aura, followed by autonomic signs and subsequent motor and gestural automatisms. Electrically they may be confused with mesial temporal seizures on EEG-video monitoring. Seizures also often cluster and last over one minute, typical of the mesial temporal lobe seizures. Patients with ‘atypical’ mesial temporal lobe seizures without MRI evidence of hippocampal atrophy or T2 signal change on MRI may have orbitofrontal epilepsy.
Parietal lobe seizures are associated with positive sensory phenomena consisting of tingling, feelings of electricity, or discomfort which usually then secondarily generalize. Muscle tone may be lost, and those parts most frequently involved are those with the largest cortical representation: the legs, hands, and face. Rarely, pain may be the manifestation of seizures. 8 9 Negative phenomena include numbness, feeling as if a body part were absent and a loss of awareness of a part or half of the whole body may occur. Dominant parietal seizures result in a variety of receptive or conductive language disturbances. Intractable partial seizures of parietal lobe origin may be treatable surgically, especially if there is a lesion in the area of the epileptogenic region of the non-dominant parietal lobe. Non-lesional parietal lobe epilepsy surgery is usually associated with disappointing results.
Occipital lobe seizures often begin with a sensation of an elementary visual phenomena or disturbance, with subsequent spread of the seizure determining the manifestations. Often the discharge spreads to the temporal lobe, producing seizure manifestations of either lateral posterior temporal or hippocampal seizures. Our experience and reports in the literature suggest that surgical therapy of partial epilepsy, while possible, usually does not produce optimal results (seizure free without clinically significant neurological defects) is not likely unless there is a structural lesion that correlates with the epileptogenic zone. Our patients with intractable occipital seizures with focal cortical dysplasias in the epileptogenic region have had especially good surgical outcomes.
ANTI-EPILEPTIC DRUG THERAPY
Carbamazepine (CBZ), phenytoin (PHT), phenobarbital (PB), and sodium valproate (VPA) are currently the first-line drugs for treatment of partial seizures. PB has been shown to have significantly more sedative and cognitive side effects than PHT, CBZ, or VPA in comparative trials, while the efficacy of these drugs has been similar.10-12 In developed countries, PHT is used less frequently as a first -line AED for newly diagnosed partial seizures in children because of problems with gingival hypertrophy. PHT’s zero-order kinetics make PHT less attractive in growing, young children in whom dose adjustments are frequently required. In the U.S.A. most neurologists probably use CBZ as the first-line AED for newly diagnosed partial seizures. In western Europe, where newly diagnosed patients are less likely to be evaluated by a neurologist, VPA is the most frequently used drug – probably because of the efficacy of VPA against both partial and generalized seizures.
Several new AEDs have been introduced for use in the treatment of partial seizures, including lamotrigine (LTG), topiramate (TPM), gabapentin (GBP), vigabatrin (VGB), and tiagabine(TGB). VGB is marketed in much of the world for partial seizures and infantile spasms. It is not likely to be a first-line AED because of lack of efficacy against some generalized seizures and associated retinal cone system dysfunction in humans after long-term use.13 TGB has a mechanism of action that is similar to VGB, and is effective against partial seizures.14,15 However, TGB exacerbates some generalized seizures.16 TGB has less post-marketing experience than the other newer AEDs, and some clinicians are questioning whether the retinal cone system dysfunction seen with VGB occurs with TGB as well.
GBP probably has the best safety profile of the newer AEDs and is effective as an add-on drug as well as in monotherapy against partial seizures, but exacerbates some generalized seizures and has a very short half-life requiring t.i.d. to q.i.d. dosing.17 FBM is not a first line AED, because of increased risk of both aplastic anemia and hepatic failure. However, FBM is a very potent AED and is still useful in refractory patients.18
TPM is probably effective against both generalized and partial seizures, but requires slow dose-escalation schedules in order to avoid cognitive slowing and language problems.19 LTG has demonstrated efficacy against partial seizures (as monotherapy and as an add-on drug), generalized seizures associated with Lennox-Gastaut syndrome, absence seizures, and probably JME. LTG was superior to CBZ in a comparative monotherapy trial of newly diagnosed partial seizures.20 LTG may be safer in pregnancy than CBZ and VPA, but the risk of rash with rapid dose escalation or when the drug is combined with VPA has recently caused many investigators to resist the use of LTG as a first-line AED.
Proposed Protocols for Partial Seizure Treatment
Proposed protocols for treatment of partial seizures in developed countries and in developing Latin American countries are considered separately. The proposed protocol for developed countries is not controversial among epileptologists in the United States, as it is consistent with current practice in 1998 (figure 1). However this developed country protocol assumes easy access to neurologists and comprehensive epilepsy centers, as well as reduced utilization of anti-parasitic agents such as praziquantel and albendazole. Therefore, the developed country protocol (figure 1) may not be appropriate in developing countries.
Figure 1. Clinical Protocol for Treatment of Partial Seizures in Developed Countries. Benign syndromes, such as benign rolandic epilepsy, and single symptomatic seizures may not require treatment.. New onset partial seizures are treated with carbamazepine (CBZ). Those who fail CBZ monotherapy may next receive either sodium valproate (VPA) monotherapy or CBZ + gabapentin (GBP). Patients who fail three drugs are evaluated at an Epilepsy Center for diagnostic and therapeutic evaluation. Those who are excellent candidates for epilepsy surgery (e.g., temporal lobe epilepsy or extratemporal epilepsy with a developmental malformation) may elect surgery, while others are treated with either lamotrigine (LTG), topiramate (TPM), tiagabine (TGB), vigabatrin (VGB), felbamate (FBM), or barbiturates. Continued failure to respond to medication should prompt a second consideration for epilepsy surgery and/or vagus nerve stimulation.
The WHO currently recommends PB for all with epilepsy in developing countries, primarily because of the low cost of PB and its availability.21 We agree that PB is probably a reasonable choice in situations of almost complete poverty. However, we and others have argued that PB is inappropriate as a first-line AED in most Latin American developing countries. PB is not effective against all major seizure types, has significant cognitive and sedative side effects, and probably reduces the bioavailability of praziquantel and other frequently used anti-parasitic drugs.22,23
Recently we have proposed that under certain conditions a broad-spectrum AED might be a better first-line AED in developing Latin America than PB.23 We propose that once identified the best drug for developing Latin America can be bought at a deep discount in very large quantities at a price that rivals PB. Then, that better AED could be distributed to epilepsy treatment programs in developing Latin America. The best first-line AED for developing Latin America should not reduce the bioavailability of anti-parasitic drugs, have fewer cognitive side effects and addictive potential than PB (e.g., VPA), and be effective against all major seizure types. A broad-spectrum AED is needed as a first-line drug in developing Latin America because most with epilepsy do not have access to neurologists or EEG, and accurate classification of seizure types (required for use of drugs like CBZ) is not currently feasible in many areas of developing Latin America.
We present two different approaches to managing Latin American patients with seizures who are not managed by neurologists and who do not have easy access to EEG. The first is the protocol implied by the current WHO recommendation (figure 2). The second is a protocol that assumes that VPA, which is effective against all major seizure types, is purchased in very large quantities at a very deep discount and distributed to epilepsy treatment programs in developing Latin America (figure 3). There are no data that prove the use of either of these protocols is superior to the other. Although currently controversial in some circles, we do not believe PHT is a reasonable alternative to PB as a first-line AED in developing countries.23,24 PHT exacerbates some primary generalized epilepsies, causes gingival hypertrophy in countries with limited dental resources, has zero-order kinetics, and reduces the bioavailability of commonly used anti-parasitic drugs.25
Figure 2. Management of seizures in developing Latin America according to WHO recommendations. Newly diagnosed patients with seizures of all types are treated with PB, which is titrated to effect (usually without use of plasma blood levels). Those who fail PB are usually treated with PHT monotherapy or with PHT added to PB. Some patients who fail these therapies might have access to a neurologist. Under this protocol, virtually all with primary generalized seizures would fail to respond and/or their seizures would be exacerbated by PHT.
Figure 3. Proposed alternative management of seizures in developing Latin America. VPA, which is effective against all major seizure types, would be administered to all with new onset seizures requiring treatment over the age of 2 years (those under 2 years of age would receive PB). VPA would be co-administered with folic acid. All females of child-bearing age would receive contraception or be given the option of PB if contraception is refused. If VPA therapy fails, then either VPA + PB or PB monotherapy would be used. Then if both VPA and PB fail, patients could be evaluated by a neurologist.
We hypothesize that the protocol outlined in figure 3 should offer better seizure control with fewer cognitive side effects than the WHO recommendation (figure 2). However, the protocol in figures 3 has not been tested in developing Latin America. The risk of VPA-associated hepatic failure in children under 2 years (the highest risk group) is approximately 1 per 500, making VPA a poor choice in the youngest children. The risk of VPA-associated neural tube defects makes this approach unattractive in females of child-bearing age who do not practice birth control and do not take supplemental folic acid.
LTG may be safer in pregancy than VPA or the other broad-spectrum AEDs, and like VPA probably does not reduce the bioavailability of major anti-parasitic drugs. In the future, then LTG may be a more attractive broad-spectrum drug for the developing world than VPA if the following occur: (1) lower initial dosing and slower dose-titration schedules reduce the incidence of serious rash in children associated with LTG26; and, (2) LTG can also be bought at a deep discount in large quantities. TPM may be proven to be safe and effective against all major seizure types, but post-marketing surveillance adverse event data and clinical trial data are not yet sufficient to know if this new AED could be a future first-line drug. (At the time of this writing, there have been about 2 million people worldwide exposed to LTG and about 200,000 exposed to TPM.)
The future role of epilepsy surgery in developing countries remains unclear. While a few centers will perform epilepsy surgery on a small percentage of those who could benefit from these therapies, considerable resources in terms of equipment and trained personnel will be required to transfer epilepsy surgery technologies to developing countries on a large scale.
The therapy of partial seizures in children throughout the world will improve during the 21st Century. Treatment protocols and health care policies will need to be frequently updated to take advantage of new emerging therapies. The most exciting new area of therapy in the 21st Century will probably be gene therapy27 – an area of clinical research virtually untouched today.
7. Bourgeois BF. Temporal lobe epilepsy in infants and children. Brain Dev 1998; 20:135-141.
14. Leach JP, Brodie MJ. Tiagabine. Lancet 1998; 351:203-207.
18. Pellock JM, Brodie MJ. Felbamate: 1997 Update. Epilepsia 1997; 38:1261-1264.
19. Glauser TA. Topiramate use in pediatric patients. Can J Neurol Sci 1998; 25:S8-S12.
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