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Seizures and Epilepsy

J. LucasKoberda, MD, PhD,

Introduction

Seizures are abnormal discharges from the cortex which frequently manifest as jerking movements of the extremities.Seizures may be caused by metabolic problems or by structural dysfunction of the cortex. Epilepsy is diagnosed as reoccurring seizures caused by cortical injury. Seizures may affect only a small, localized portion of the cortical area with out spreading electrical discharge to the whole cortex. This is sometimes associated with symptoms of short-lasting confusion. In such cases, the patient is diagnosed with a partial complex seizure. When the electrical discharge becomes generalized (thus affecting the whole cortex), then the patient is diagnosed with secondary generalized seizures.


Depending on the location of the initial neuronal discharge initiating the seizure, a different type of aura (prodromal symptoms) may be experienced by the patient. Temporal lobe epilepsyis frequently associated with an aura described as a “déjà vu” sensation. Seizures originating in the primary sensory area may produce a strange sensation before seizure onset. Primary generalized epilepsy produces generalized epileptic discharges in all cortical neurons with no definitive primary origin of the seizure. In secondary generalized epilepsy, the grand mal seizure is frequently preceded by focalon set discharges, which in many cases can be detected by conventional EEG.


Case study 1

A 17-year-oldfemale wellknown to my practice for the last 3 years was diagnosed with primary generalized epilepsy resistant to pharmacological therapy. Her seizures consisted of multiple short lasting confusion episodes with intermittent generalization. The patient was previously on multiple medications, including valproid acid, lamotrigine, clonazepam, zonisamide, levetiracetam, and topiramate, frequently in combination.Unfortunately her medications were also producingside effects, including memoryproblems and drowsiness. Despite multiple adjustmentsof medications (lately included lamotrigine and zonisamide)the patient still had intermittent breakthrough seizures.She also reported worsening of her school performancedue to seizures and medications side effects.


Physical Exam

The physicalexamination was grosslyunremarkable. The patient appeared to be a little depressed. She had a normalgeneral appearance. The mental examination too, brought grossly unremarkable findings. No focal weakness ornumbness was noted. Her gait showedno evidence of ataxia.


Clinical Diagnostic Considerations

Primary generalized epilepsy

Secondary generalized epilepsy

Not-epileptogenic seizures

Syncope

Transient ischemic attack

Migraine with aura


Working Diagnosis

Epilepsy

Further Testing Required

The patient’s workup includednormal magnetic resonance imaging of the brain. Electroencephalography showedmultiple generalized electrographic seizures (see Fig 1) in practically every EEG recording(multiple EEG in the past).

Fig 1. EEG of a 17-year-old female with primarygeneralized epilepsy and frequentelectrographic seizures-seegeneralized spike and wave episode which lasted 6seconds followed by normal EEG background.




Subsequent video EEG telemetry completed at the University of Florida epilepsy section confirmed the diagnosis of primary generalized epilepsy. The patient’s computerized neuro psychological testing, showed below, expected results with global cognitive score of 85 (expected score 100) with deficiency in memory,information processing speed as well as other domains (see Fig 2).


Fig 2.  A17- year-old patient with epilepsy and cognitive problems-NeuroTrax is a computerized neuropsychological testing which compared this patient to the age-and education-matched controls with mean-100 and Standard Deviation (SD)-15. In most of the domains tested, this patient scored below expected mean values. Information processing was the weakest, with a poor performance preventing it from being scored.


Plan of Management

Because of her resistance to medications, the patient volunteered to try the Z-score neuro feedback (NFB), focusing on the normalization of grossly abnormal electroencephalogram with multiple spike and wave generalized discharges throughout the recording. NFB, also called EEG-biofeedback, was previously reported to be an effective form of alternative therapy in medication-resistant epilepsy patients (Sterman et al. 2006; Sterman 2010). The Z-score NFB is one of the newest forms of NFB, in which usually 19-electrode (full cap)simultaneous therapy is conducted in order to normalize aberrant EEG with agoal of reaching a Z-score close to 0 (Koberda et al. 2012). Only 8 out of 10 planed sessions were completed due to the fact that the patient decided to withdraw from NFB therapy. The subsequent follow-up visits revealed no more clinical seizures. Two follow-up electroencephalograms were completed which showed complete normalization of EEG with no more evidence of electrographic seizures. In addition, quantitative EEG (QEEG) analysis also showed marked improvement (see Fig 3 A and B) of previously abnormal spectral pattern.


Fig 3 A shows QEEG maps which are color-coded (Before NFB). The patient’s EEG was compared to normal controls. The areas in green are between 0-1 Standard Deviation (SD); the area in yellow between 1-2 SD; and in red between 2-3 SD from the norm. Marked increases in Delta, Theta and frontal Beta power was recorded.


Fig 3 B shows marked improvement of the Delta and Theta power over expression. There is still an elevation of the frontal Beta power most likely related to the frontal muscle artifact.


The patient also reported an improvement in her cognitive function and a school performance.Currently, the patient has been seizure-free for more than 8 months. She continues being on lamotrigine and zonisamide.


Case study 2


A 40-year-old male noticed his first seizure after experiencing several episodes of the left upper extremity numbness associated with a headache. Generalized seizure was preceded by jerking movements of the left upper extremity. The patient subsequently noted several more seizures with an identical pattern. He reported that on a few occasions he had developed an incontinence and tongue biting during a generalized seizure. The patient never experienced similar episodes in the past. Thepatient reported no other medical problems. He denies excessive alcohol consumption or smoking.


Physical Exam


The physical examination was quite unremarkable with apparent normal mental condition and general appearance. No evidence of weakness in the extremities was noted. His gait showed no evidence of ataxia.


Clinical Diagnostic Considerations


Secondarygeneralized epilepsy due to:

Focal lesionin the cortex (brain tumor, stroke, vascular formation, infection, corticaldysplasia or trauma).

Non-epileptogenic seizures


Working Diagnosis

Secondarygeneralized seizures


Further testing required


1.   Magnetic resonance of the brainrevealed the left frontal central contrast enhancing lesion-likely meningioma.

2.   Electroencephalography showed the left frontal sharp appearing discharges.

3.   Blood work was grossly unremarkable.


Plan of Management


The patient was started on levetiracetam for seizure prevention. The neurosurgical consultation was requested at the Johns Hopkins University. The neurosurgical consultation indicated high likelihood of meningioma. The subsequent surgery included frontal craniotomy and tumor resection, which confirmed the diagnosis of meningioma. Unfortunately, despite being on levetiracetam, the patient still experienced breakthrough seizure, most likely due to the residual scar tissue,which developed after the surgery. The subsequent electroencephalogram showed the left frontal central breach rhythm with a sharp contoured activity (see Fig 4).

Fig 4. A 40-year-old patient with partial complex epilepsy with frequent generalization-EEG shows a breach rhythm with epileptiform activity including sharp contoured waves with frequent phase reversals at C4 location.

The subsequent Z-score NFB (10 sessions) resulted in clinical remission with no further clinical seizures.


Further Discussion


The Etiology of Epilepsy


The prevalence of epilepsy is estimated at 1 in 200 persons. An epileptic seizure is a result of the dysfunction of the brain caused by abnormal electrical dis charge of cortical neurons. The dysregulation between the cortical and thalamic connections may be a contributing factor in the epileptic seizure formation. Thalamocortical cells have excitatory (predominantly glutamatergic) projections to the cortex.Cortical neurons, in turn, are reciprocally connected by excitatory  connections with the thalamus. Inhibitory GABAergic neurons are located throughout the cortex as well as the thalamus, but a layer of almost pure GABAergic neurons is located in the lateral parts of the thalamus. This is the thalamic reticularnucleus (nRT), a special portion of the thalamus that receives collaterals of the thalamocortical and corticothalamic axons. These collaterals excite the cells of the nRT. The GABAergic cells in the nRT project back to the thalamusand also connect with other nRT cells via inhibitory synapses (Blumenfeld, 2003). An enhanced burst firing in corticothalamic neurons may increase γ-aminobutyric acid-B (GABAB)receptor activation in the thalamus, leading to the slower, more synchronous oscillations seen in spike-and-wave seizures (Blumenfeld, 2003). In addition, other subcortical structures may contribute to epileptic seizures control. For instance, the GABAergic projections from substantia nigra pars reticulata (SNR) to thalamocortical neurons of the ventral medial (VM) thalamic nucleus were reported to provide a potent network for the control of seizures by basal ganglia (Paz, 2007). The hippocampus is particularly susceptible to epileptogenic activity, and is frequently the source of epileptic seizures. Seizures activate NMDA receptors and strengthen connections between the exited neurons. Long-Term Potentiation (LTP) may contribute to promotion of ongoing epileptic activity, and could explain why seizure activity at particular site often spreads to involve other synaptically connected cortical regions. The repetitive cortical activation potentiates excitatory transmission and depresses inhibitory transmission, creating a self-perpetuating excitatory circuit and facilitating excitation of neighboring neurons. The abnormal electrical activity generated by a seizure spreads throughout the brain to other regions utilizing various connector structures, including corpus callosum. The brain damage producing seizure activity may be related to prior trauma. The head injury frequently produces neuronal damage with scar tissue formation and subsequent abnormal electrical discharge generation. Most of seizures initiate within one-year since a head injury, however, remote seizures occurring many years after a brain trauma were also reported. A vascular malformation which may be prone to blood extravasation and cortical irritation may also be responsible for epileptic seizures. A venous angiomas or arteriovenous malformations are frequently inborn abnormalities which may produce periodical seizures. An ischemic or hemorrhagic stroke may also be generating seizures by producing neuronal damage and aberrant neuronal electric potential.


Cortical developmental abnormalities or hereditary disorders, like tuberous sclerosis, frequently contribute to epilepsy (Jones, 2012). Brain tumors either primary or metastatic also may produce recurrent seizures due to the vasogenic edema and neuronal damage. Brain infections, including encephalitis, may be producing mesial temporal sclerosis, which often manifests itself as a temporal type of epilepsy.


The Clinical Picture of Epilepsy.


Depending on the location of the initial seizure onset, the beginning of the seizure may manifest itself as tingling or other type of somatosensory phenomena. The patient may experience a visual or auditory aura. Focal motor tonic-clonic extremity movements, facial grimacing or autonomic symptoms like epigastricsensation, may be also present (Rowland, 2010). In partial complex seizures, bydefinition, an alteration of consciousness needs to be present. Psychomotorphenomenon, such as chewing movements, or an automatism described as picking atclothing, is frequently experienced by the patient. In a primary-generalizedepilepsy or a secondary-generalized epilepsy, the development of tonic andclonic phase is typical with postictal confusion. Unless there is a majorstructural lesion in the brain present, a neurological examination betweenseizures is frequently unremarkable. Absence seizures, also called Petit Malseizures, are mostly seen in the pediatric population, when children becomeconfused and inattentive for short periods of time. Eye fluttering is often notedduring these episodes. The EEG provides the best diagnostic confirmation andtypically demonstrates brief generalized bilaterally synchronous 3 Hz spike andwave discharges. Hyperventilation may precipitate absence seizures. Juvenile Myoclonicepilepsy is a primary-generalized epilepsy that usually begins during theteenage years and is associated with the morning myoclonic jerks that appear soonafter awakening. Many of the patients have intermittent generalized seizures. TheEEG frequently shows bilaterally synchronous spike and wave or polyspikedischarges at variable frequency.


Diagnostic Considerations


Other multipleneurological conditions may mimic epileptogenic seizures. The most commonneurologic spell that may be confused with seizure is a syncope. Postictal confusion,tongue biting and generalized tonic-clonic movements are suggestive of seizureor epilepsy. Another condition frequently difficult to distinguish fromepilepsy is a psychogenic non-epileptogenic seizure. Many patients with thiscondition have combined epileptic and nonepileptic seizures. In case of a normalinterictal EEG, ambulatory 24 hours of EEG or video-EEG-telemetry is needed inmany cases to provide the final diagnosis. In cases of non-epileptogenicseizures, a video EEG telemetry shows no epileptogenic abnormalities despitetypical clinical manifestation of the symptoms. Sometimes sleep disordersdescribed as parasomnia, including night terrors, may resemble a seizure-likeactivity. Less frequently, migrainous events may be mistaken for seizures,especially when associated with lethargy and a loss of the consciousness. Thistype of symptoms may be associated with a basilar type of migraine. A similarsituation may be noticed during a transient ischemic attack when the patientmay experience altered consciousness or focal weakness leading to a fall, whichmay be mistaken for epilepsy. Psychiatric manifestations like anxiety withpanic attacks and hyperventilation may also be mistaken for a seizure. Additionaltesting may be needed, including the standard electroencephalography orambulatory EEG. Brain imaging, including magnetic resonance imaging (in orderto rule out focal abnormalities), is usually recommended. Supplementary testing,if needed, may include video- EEG telemetry, where the patient is observed for24 hours or even longer, with a continuous EEG and video guidance. Nuclear andfunctional imaging with the Position Emission Tomography (PET) and SinglePhoton Emission Tomography (SPECT), Functional Magnetic Resonance Imaging (fMRI)may be of benefit in more complex cases. Functional MRI is able to demonstrateabnormalities in blood oxygenation in different areas of the brain. PET showsabnormalities in glucose metabolism in the areas affected by neuronal damageresponsible for the seizure. Ictal SPECT shows increased blood flow in theepileptic region of the brain.


Treatment of Epilepsy


Currently, amainstay of therapy in epilepsy is pharmacotherapy. Multiple medications areavailable on the market for different types of epilepsy. Some of them arebroad-spectrum medications which cover both primary generalized and secondary generalized epilepsy. Other relatively narrow-spectrum medications areeffective mostly in certain type of seizures. Phenobarbital, which is one ofthe oldest anti-seizure medications, binds with GABA receptor which hasneuronal inhibitory activity. Carbamazepine, another anti-seizure agent iseffective by blocking the sodium channels and inhibiting depolarization ofseizure foci in the brain without affecting the normal function. The ValproicAcid, in addition to the inhibition of the sodium ion influx through the voltagegated sodium channels, inhibits the calcium ion influx through T-type calciumchannels. Topiramate blocks the voltage gated sodium channels, enhancesGABA-mediated synaptic inhibition, and antagonizes the excitatory effect ofNMDA receptors. Unfortunately, approximately 30% of patients with epilepsy do notrespond to pharmacological treatment. These patients are classified asmedically refractory and require other forms of treatment in order to reduce thefrequency of seizures. In the pediatric population, the ketogenic diet has beenfound effective in a seizure numbers reduction in selected patients. Surgicaloptions include minor surgery, such as the vagus nerve stimulator implantation,or major surgery, such as the lesion resection, or even lobectomy. NFB has beenfound to be an effective treatment modality in patients who do not respond topharmacological treatment. Dr. Sterman from UCLA initiated the NFB experiments,which have proven effectiveness of Sensory Motor Rhythm (SMR) entrainment inepilepsy treatment. Approximately 60% seizure frequency reduction was noted inclinical studies with SMR entrainment. Currently, newer NFB protocols are beingtested for effectiveness in the treatment of epilepsy, including the Z-scoreNFB.


References:

1.  B. HBlumenfeld, 2003. From Molecules to Networks: Cortical/Subcortical Interactionsin the Pathophysiology of Idiopathic Generalized Epilepsy. Epilepsia 44 suppl.7-15.

2.   HR Jones, 2012. Netter’s Neurology.Elsevier, Philadelphia.

3.   JL Koberda et al. 2012. Cognitiveenhancement using 19-electrode Z-score Neurofeedback. J. Neurotherapy 3.

4.  JL Koberda, 2012. Comparison of theeffectiveness of Z-score Surface/LORETA 19-electrode Neurofeedback to standard1-electrode Neurofeedback-ISNR meeting-Orlando, FL.

5.  A-JT Paz etal. 2007. Activity of Ventral Medial Thalamic Neurons during Absence Seizuresand Modulation of Cortical Paroxysms by the Nigrothalamic Pathway . J.Neuroscience, 27 929-941.

6.   LP Rowland and TA Pedley, 2010.Merritt’s Neurology. Lippincott, Philadelphia

7.   MB Sterman, T Egner, 2006. Foundation and practice of neurofeedback for the treatment ofepilepsy. ApplPsychophysiol Biofeedback. 31(1):21-35. Review.

8.   MB Sterman, 2010, Biofeedback in the treatment of epilepsy.

Cleve Clin J Med. 77 Suppl 3:S60-7. Review.