Focal (Partial) Epilepsy Differential Diagnoses

Updated: Mar 14, 2022
  • Author: Muhammad H Jaffer, MD; Chief Editor: Helmi L Lutsep, MD  more...
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Diagnostic Considerations

Understanding the conceptual difference between seizure and epilepsy is important, as the latter carries important prognostic and management considerations. A seizure is defined as a transient neurologic dysfunction resulting from an excessive abnormal electrical discharge of cerebral neurons. In contrast, epilepsy is a disorder characterized by chronic, recurrent seizures caused by abnormalities in electrical activity of the brain. As defined in the 2017 International League of Epilepsy consensus guidelines, epilepsy is diagnosed when either: a) an individual has had at least two unprovoked seizures more than 24 hours apart; b) when an individual has had one seizure with a 60% probability of having another seizure within the next 10 years; or c) diagnosis of an epilepsy syndrome. Unprovoked implies a clearly identifiable acute and transient factor that lowers the seizure threshold. Factors that increase the risk of seizure recurrence include abnormal brain imaging, nocturnal seizures, an EEG with epileptiform abnormalities, or seizures related to a prior brain injury. [21]

Epileptic syndromes

In addition to the above differentiation, there is a recognition of “epilepsy syndromes,” or epileptic conditions in which there are shared common characteristics. Although a full characterization of epileptic syndromes is beyond the scope of this article, we will summarize a number of common epileptic syndromes as below: [22, 23]

Focal epilepsies are the most common type of epilepsy of adult onset, and and again most are of unknown cause (ie, normal MRI). For practical reasons, they can be divided into two categories: mesial temporal epilepsies and neocortical epilepsies.

Mesial temporal epilepsies

Mesial temporal epilepsies are seen in cases where the epileptic focus is located in the hippocampus, amygdala, or parahippocampal gyrus. The most common cause in adults is hippocampal sclerosis. Mesial temporal lobe epilepsies are characterized by focal seizures with impaired awareness, often preceded by an autonomic (commonly epigastric sensation and/or tachycardia), cognitive (déjà-vu or jamais-vu), or sensory (olfactory or gustatory) aura that is recalled by the patient. Hand and mouth automatisms as well as emotional manifestations, specifically fear or laughter, can also be seen. Lateralizing features include the following:

  1. Unilateral automatisms are often ipsilateral to the seizure focus.
  2. Dystonic posturing usually occurs on the contralateral side.
  3. Head deviation at seizure onset is usually ipsilateral to the seizure, while late “versive” head turning is contralateral.
  4. Nose-wiping may be performed by the hand ipsilateral to the seizure focus.
  5. Post-ictal hemiparesis can occur contralateral to the seizure focus.

Mesial temporal epilepsy often manifests by adolescence and there is a statistically significant association with febrile seizures in childhood. A younger age at onset and a history of febrile seizures are associated with an increased risk of drug resistance, and therefore timely surgical management is essential. [24, 25] Diagnosis of mesial temporal lobe epilepsy is supported by temporal sharp waves at the anterior or middle temporal electrodes (F7/F8, T1/T2, T3/T4) as well as temporal intermittent rhythmic theta activity (TIRDA). Bitemporal independent discharges can be observed in up to 40% of patients. Hippocampal atrophy confirmed on high-resolution MRI is usually a highly sensitive localizing feature. [26]

Neocortical focal epilepsies

This term is used to refer to seizures arising from the temporal neocortex as well as extratemporal epilepsies. Seizures may be focal with preserved or impaired awareness, usually with other aspects of semiology governed by the area of affected cortex. In general, neocortical extratemporal epilepsies may be difficult to localize precisely as surface EEG is usually less reliable, especially when the focus is in the deep cortex.

Neocortical temporal lobe epilepsy often overlaps in many clinical characteristics with mesial temporal lobe epilepsy. Auras of auditory hallucinations or complex visual hallucinations without an epigastric aura often suggest a temporal neocortical origin. Congenital malformations and early clonic activity after automatisms are also associated features. On EEG, predominant discharges are seen in the lateral temporal electrodes and MRI usually demonstrates neocortical temporal lesions with a lack of associated mesial temporal pathology. [27]

Frontal lobe epilepsies are usually characterized by short duration (< 30 seconds), nocturnal predilection, a non-specific aura, and complex motor behaviors that may be mistaken for psychogenic non-epileptic events (bicycling, pelvic thrusting, gestural automatisms, asymmetric tonic extension of proximal extremities, and complex vocalizations). Awareness may be spared, even for bilateral motor seizures. Focal motor seizures involving the primary motor cortex will produce contralateral hemiclonic activity that usually spreads across the motor homunculus in a “Jacksonian march.” Supplementary motor area seizures may manifest in the “fencing posture,” whereby the head and eye deviate to the contralateral side with extension of the contralateral arm and flexion of the ipsilateral arm. Medial frontal seizures can manifest in behavioral arrest states lasting for several minutes to hours. Up to one-third of patients do not have a diagnostic ictal EEG during a frontal lobe seizure and an MRI may also fail to disclose the lesion. [28]

Occipital lobe epilepsies may be the product of the benign focal epilepsies of childhood or an underlying structural etiology. Visual auras are well characterized and may include elementary (flashing lights) or complex visual hallucinations, visual distortions (macropsia, micropsia, metamorphosia, dyschromatopsia), or ictal blindness. The visual aura usually manifests in the contralateral visual field. Awareness may be spared. Usually, interictal EEG reveals localized occipital spikes. [29]

Parietal lobe epilepsies are poorly characterized and do not have any specific or sensitive features; contralateral somatosensory and emotional auras have been reported. Asymmetrical tonic-clonic activity and automatisms may also be seen with a post-ictal “Todd paralysis.” EEG is often not reliable in localization and MRI usually discloses structural pathologies in the parietal region. [30]

Less common focal epilepsies

Panayiotopoulos syndrome

This syndrome presents around 3 to 6 years of age and is characterized by prominent autonomic seizures (nausea/vomiting, salivation, tachypnea) that may evolve into focal clonic activity. Awareness is usually preserved during the seizure; two-thirds of the seizures tend to occur out of sleep. There is a presumed genetic basis although it is yet to be elucidated. On EEG, multifocal occipital spikes are seen in approximately 75% of cases, usually elicited by closing the eyes. Most patients suffer from less than five total seizures and the condition usually remits on its own 1 to 2 years after onset without treatment.

Late-onset childhood occipital epilepsy (Gastaut-type)

This syndrome presents between 8 and 11 years of age. It is characterized by focal non-motor sensory visual seizures (hallucinations, hemianopia, visual illusions) with preserved awareness, lasting 3–20 minutes in duration often with post-ictal headaches. Some patients will have ictal blindness lasting up to 3–5 minutes afterwards. Seizure frequency is about 1 to 2 per month and responds dramatically to carbamazepine. A genetic etiology is presumed but has not yet been discovered. Findings on EEG are nearly identical to Panayiotopoulos syndrome. In the majority of cases, seizures remit within 2 to 7 years after onset.

Childhood epilepsy with centrotemporal spikes

This syndrome was formerly known as benign childhood epilepsy with centrotemporal spikes (BCECTS) or Rolandic epilepsy. It accounts for up to 25% of childhood epilepsy and many children with Panayiotopoulos syndrome will evolve into this epilepsy syndrome. The onset peaks around 7 to 10 years of age. It is often nocturnal out of non-REM sleep and is characterized by brief hemifacial clonic focal seizures with preserved awareness. Semiological features may also include oropharyngeal paresthesias, drooling, guttural vocalizations, dysarthria, and/or aphasia. Seizure frequency is approximately 10 lifetime seizures and it does not require treatment. Findings on EEG consist of high-amplitude centrotemporal sharp waves. It is considered to be on the spectrum of epilepsy-aphasia syndromes and has been linked to heterozygous mutations on the GRIN2A gene. In the majority of cases seizures remit 2 to 4 years after onset, although extremely rarely cases may progress to the more severe epilepsy-aphasia diseases such as Landau-Kleffner syndrome.

Autosomal-dominant lateral temporal epilepsy

This syndrome is also referred to as “autosomal dominant epilepsy with auditory features” and presents in the second or third decade of life. Patients present with focal seizures with preserved awareness and distinct auditory hallucinations or receptive aphasia; this may evolve into bilateral tonic-clonic seizures. Interictal EEG may disclose temporo-occipital sharp waves. It is associated with LGI11 and RELN gene mutations. It responds well to anti-seizure medications and the prognosis is good.

Autosomal-dominant nocturnal frontal lobe epilepsy

This genetic epilepsy syndrome usually presents between early childhood and adulthood. Patients present with clusters of focal nocturnal tonic or hypermotor seizures, often preceded by a non-specific aura. Interictal EEG may show rare frontal sharps but is often normal. Several mutations have been implicated, but neuronal nicotinic acetylcholine receptor mutations (CHRNA2, CHRNA4) are particularly common. While most patients will respond well with anti-seizure medications, up to 30% are drug resistant.

Familial mesial temporal lobe epilepsy

These are generally autosomal-dominantly inherited conditions that may be associated with hippocampal sclerosis. Onset is usually in early adulthood with focal cognitive seizures that can evolve to automatisms, focal tonic, and/or bilateral tonic-clonic seizures. Interictal EEG will often show temporal sharp waves. The underlying genetic causes are yet to be discovered. Most cases are well controlled with medications with intractable cases responding to surgical management.

Familial focal epilepsy with variable foci

This entity is highly heterogeneous with an onset at any point from infancy to late adulthood, often with long periods of remission. Although the epileptic focus varies between family members, every individual usually has a single focus. It is characterized by focal motor seizures with preserved awareness, although evolution to bilateral tonic-clonic seizures is sometimes seen. Interictal EEG may reveal focal epileptiform abnormalities in the epileptic focus. Mutations in GATOR complex genes have been implicated.

Special diagnostic considerations in neonates and children

Given their limited language development, neonates and children often cannot properly verbalize their level of awareness and may have difficulties describing their semiology. When possible, caregivers are encouraged to obtain a video recording of the semiology, which is rendered highly possible with current smartphone technology. It has been noted that owing to immaturity of the early brain, children less than 6 years of age will often exhibit very limited ictal behaviors. Clinical seizures often consist of behavioral arrest, atonic or tonic posturing with head or eye version, and myoclonic seizures; the localization value is often highly questionable. [31]

Additionally, there are important differential diagnoses for epileptic seizures in these populations.

In the neonatal population, the differential should include:

  1. Jitteriness
  2. Sleep-related rhythmic movement disorders (body rocking, head banging, etc.)
  3. Self-gratification behaviors
  4. Benign neonatal sleep myoclonus ad benign myoclonus of infancy
  5. Benign paroxysmal torticollis
  6. Spasmus nutans
  7. Opsoclonus-myoclonus syndrome
  8. Hyperekplexia
  9. Alternating hemiplegia
  10. Breath-holding attacks
  11. Pallid syncope
  12. Non-epileptic head drops

In children, the differential should include:

  1. Stereotypies
  2. Tic disorders
  3. Paroxysmal dyskinesias
  4. Episodic ataxias
  5. Benign paroxysmal vertigo
  6. Sandifer syndrome
  7. Narcolepsy or cataplexy
  8. Tantrums or rage reactions
  9. Factitious illness
  10. Daydreaming/eidetic imagery
  11. Cyclical vomiting/abdominal migraine
  12. Panic attacks
  13. Dissociative states

Differential diagnosis

The misdiagnosis of seizures is common, with up to one-third of patients referred for “difficult seizures” having been misdiagnosed. Among the common differential diagnoses one should consider are the following: [32]

Psychogenic non-epileptic events are by far the most common condition misdiagnosed as epilepsy, at least in patients seen at referral centers. These are events that have no electrophysiological correlate or clinical evidence for epilepsy and are psychological in origin. Motor features that distinguish these attacks from seizures include truncal movements, back-arching, asynchronous movements, variable rate and direction of movements, stuttering, eye closure with resistance to passive eye opening, and horizontal movements of the head. Preserved awareness during bilateral motor activity is also characteristic, although rarely supplementary sensorimotor area seizures can also result in bilateral limb involvement with preserved consciousness. The etiology is heterogeneous although psychiatric factors may play a prominent role. Video EEG monitoring and detailed psychological evaluation is recommended to render the diagnosis. 

Syncope refers to a transient loss of consciousness secondary to an abrupt reduction of blood flow to the brain; sometimes there may be associated convulsive movements due to cortical disinhibition of the brainstem. An evidence-based criteria has been developed to differentiate syncope from seizures with very high specificity and sensitivity. [33]

Parasomnias are unusual behaviors that occur while asleep (REM or NREM) or during arousal and are an important differential to consider in patients who present with purported nocturnal seizures. They may easily be confused for frontal lobe seizures. Parasomnias are distinguished by the fact that events are non-stereotyped, clustering is rare, and events are usually long in duration (> 10 min).

Transient ischemic attacks are due to temporary interruption of the blood supply to a cerebral vessel. They may have a stuttering course and typically always present with rapid onset of negative symptoms (numbness, weakness, aphasia) without stiffness or jerking. This should be on the differential of a focal seizure, especially when a patient has several cardiovascular risk factors.

Migraine headaches may present with a visual aura, unilateral headache, nausea, and vomiting. They are characteristically slowly progressive over several hours; in some cases, an aura may be present without any headache, termed an acephalgic migraine. Confusion/inattention in the setting of severe pain can sometimes be seen, however awareness is nearly always preserved. A personal and family history of migraines should always be elicited. Familial hemiplegic migraine is a subtype that can present with focal weakness, dysphasia, and paresthesias prior to the headache.

Differential Diagnoses