ABSTRACT | PDF
Seminar IV
Neuropsychiatric aspects of epilepsy
Subhashish Nath
Postgraduate Trainee of Psychiatry, Silchar Medical College and Hospital
Introduction The association between epilepsy and psychiatric disorders has been recognised by clinicians since antiquity. This relation has often been poorly recognised and inadequately investigated. Psychiatric comorbidity has a serious impact on the quality of life and well-being of patients with epilepsy. The genesis of such disabilities is clearly a complex matter, partly psychological, partly social, and partly pathophysiological in origin.
Famous personalities with epilepsy Alexander the Great (“Sacred Disease”), Julius Caesar (“Falling Disease”), Aristotle, Socrates, Napoleon Bonaparte, Leonardo da Vinci, Michaelangelo, President James Madison, Charles Dickens, Dame Agatha Christie, Sir Elton John, Danny Glover.
Epilepsy Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. A seizure (Latin “Sacire”, “to take possession of”) is a paroxysmal event due to abnormal, excessive hypersynchronous discharges from an aggregate of central nervous system (CNS) neurons. Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy.
A historical point of view Epilepsy has afflicted human beings since the dawn of our species and has been recognised since the earliest medical writings. In fact, few medical conditions have attracted so much attention and generated so much controversy as epilepsy.
400 B.C.: The Greek physician Hippocrates writes the first book on epilepsy, On the Sacred Disease. Refuting the idea that epilepsy is a curse or a prophetic power, Hippocrates proves the truth: It's a brain disorder. “It is thus with regard to the disease called Sacred: it appears to me be nowise more divine nor more sacred to than other diseases, but has a natural cause like other affections. . .”
70 A.D.: In the Gospel According to Mark (9:14-29), Jesus Christ casts out a devil from a young man with epilepsy.
1494: A handbook on witch-hunting, Malleus Maleficarum, brings a wave of persecution and torture, leading to the death of more than 200,000 women. Written by two Dominican friars under papal authority, the book identifies the presence of seizures as a characteristic of witches.
1859-1906: Under the leadership of three English neurologists—John Hughlings Jackson, Russell Reynolds, and Sir William Richard Gowers—the modern medical era of epilepsy begins. In a study, Jackson defines a seizure as "an occasional, an excessive, and a disorderly discharge of nerve tissue on muscles."
1904: The term "epileptologist" was first used to describe a person who specialises in epilepsy. William Spratling, the neurologist, who coined the word, is now regarded as North America’s first epileptologist.
1953: Carbamazepine (CBZ) was synthesised by Schindler at Geigy in an attempt to compete with the newly introduced antipsychotic, chlorpromazine.
1958: Ethosuximide (ESM) was introduced as an antiepileptic drug (AED) and has been the drug of choice for children with absence seizures.
1963: Sodium valproate’s (VPA) anticonvulsant property was recognised serendipitously when it was used by Pierre Eymard as a solvent for a number of other compounds.
1968: The Epilepsy Foundation of America is founded.
1970: The Veterans Administration spearheads a movement toward establishing epilepsy centres, launching a new breed of neurologists who began to specialize in the treatment and research of epilepsy.
1993: Felbatol (Felbamate) and Neurontin (Gabapentin) are approved by the United States’ (US) Food and Drug Administration (FDA).
1994: Lamictal (Lamotrigine) is FDA approved.
1996: Topamax (Topiramate) is FDA approved.
1997: Gabitril (Tiagabine) is FDA approved.
1997: FDA approved vagus nerve stimulation in combination with seizure medication for partial epilepsy in adults.
1999: Keppra (Levetiracetam) is FDA approved.
2000: Trileptal (Oxcarbazepine) is FDA approved. A landmark conference, "Curing Epilepsy: The Promise and the Challenge," organized by the Epilepsy Foundation of America, sets bold goals for tomorrow's treatment including prevention and cure of epilepsy.
Epidemiology Seizure disorders are common and usually have an early onset. Epilepsy affects about 50 million people worldwide. More than 75 percent of patients have their first seizure before 18 years of age, and 12 to 20 percent have a familial incidence of seizures. Among adults, the most common seizures are complex partial and generalised tonic-clonic seizures. The estimated proportion of the general population with active epilepsy is four to ten per 1,000 people. In developing countries, it is six to ten per 1,000. In developed countries, annual new cases are 40 to 70 per 100 000 people in the general population. In developing countries, this figure is often close to twice as high due to the higher risk of experiencing conditions that can lead to permanent brain damage. Close to 90% of epilepsy cases worldwide are found in developing region.
Mechanism of seizure initiation, propagation, and cessation The initiation phase is characterised by two concurrent events –
High frequency bursts of action potentials
Hypersynchronisation
Seizure propagation occurs due to loss of surrounding inhibition.
Seizure cessation is caused by –
Activation of inhibitory neuronal circuits
Reduction of extracellular K+
Elimination of intracellular Ca+2
Activation of locus coeruleus: cortical norepinehrine system, increasing extracellular adenosine, and resulting in decreased excitation.
Neuropathology The common pathological findings in epilepsy are mediobasal temporal lobe lesions. Approximately two-thirds of epileptic adults have a temporal lobe focus, and two-thirds of these have mesial temporal sclerosis with pyramidal cell loss in the hippocampus. Theories about the cause of mesial temporal sclerosis include perinatal insults, dysgenesis, and kindling from reactive seizures. Another 20 to 25 percent of those with temporal lobe lesions have tumours (hamartomas and gangliogliomas).
Classification of epileptic seizures International League Against Epilepsy (1981), based on clinical features and electroencephalographic (EEG) findings, published a modified version of the International Classification of Epileptic Seizures.
Partial seizures
Simple partial (motor, sensory, autonomic or psychic signs)
Complex partial
Partial seizures with secondary generalisation
Primary generalised seizures
Absence (petit mal)
Tonic-clonic (grand mal)
Tonic
Atonic
Myoclonic
Unclassified
Neonatal seizures
Infantile spasms
Neuropsychiatric aspects of epilepsy Epidemiological studies report a 20 to 60 percent prevalence of psychiatric problems among epilepsy patients. Among patients attending epilepsy clinic, approximately 30 percent had a prior psychiatric hospitalisation, and 18 percent were on at least one psychotropic drug. Psychiatric disturbances, particularly psychosis and personality disorders, are two to three times more common in patients with complex partial seizures, most of whom have a temporal focus, compared to those with generalised tonic-clonic seizures.
Proposed relationships of psychiatric disturbances to epilepsy
Common neuropathology, genetics, or developmental disturbance
Ictal or subictal discharges potentiate abnormal behaviour
Absence of function at the seizure focus
Neurochemical
Gonadotrophins and other endocrine hormones
Psychodynamic and psychosocial effects of living with epilepsy
Neurobiological and psychodynamic factors potentiate each other
Sleep disturbance
Antiepileptic drug related
Behavioural disorders in epilepsy in relation to ictal stages
Ictal
Ictal psychic symptoms
Nonconvulsive status: simple partial seizures, complex partial seizures, and periodic lateralising epileptiform discharges
Peri-ictal
Prodomal symptoms: irritability, depression, and headache, etc.
Postictal confusion
Peri-ictal psychoses
Concomitant with increased seizure frequency
Concomitant with decreased seizure frequency
Postictal psychoses
Interictal psychosis and personality disturbances
Behavioural disturbances variably related to ictus
Psychiatric disorders
Psychosis
Depression
Cognitive impairments
Personality disorders
Hyposexuality
Suicide
Interictal mood disorders
Aggression and violence
Other behavioural disorders
Psychosis The lifelong prevalence of all psychotic disorders among epileptic patients ranges from seven to 12%. There is approximately two fold or greater risk for psychosis. Mediobasal temporal focus and left sided focus are having greater risk. A bewildering variety of pictures may be seen: postictal, interictal or post surgery.
A simple division of the clinical picture may be made into –
Psychosis in which confusion and impairment of consciousness are outstanding features.
Admixture of organic and functional manifestations.
In a setting of clear consciousness and take a form characteristics of schizophrenia or affective disorder.
Postictal psychosis: An episode of confusion or psychosis manifested immediately upon a seizure, or emerged within a week of the return of apparently normal mental function. It lasts a minimum duration of 24hrs, and a maximum of three months. There is clouding of consciousness, disorientation or delirium. Delusions, hallucinations occur in clear consciousness. No evidence of antiepileptic drug toxicity, previous history of interictal psychosis, EEG evidence of non convulsive states, recent history of head injury, or alcohol or drug intoxication.
Interictal psychosis: Proposed predisposing factors for the interictal schizophreniform psychosis of epilepsy –
Epilepsy characteristics
Complex partial seizures with secondary generalised tonic-clonic seizures
More auras and automatisms than non psychotic epilepsy patients
Epilepsy present for 11 to 15 years before psychosis
Long interval of poorly controlled seizures
Recently diminished seizure frequency, especially generalised tonic-clonic seizures
Left temporal focus
Mediobasal temporal lesions, especially tumours
Psychosis characteristics
Atypical paranoid psychosis–paranoia with sudden onset
Psychosis alternating with seizures
Preserved affective warmth
Failure of personality deterioration
Less social withdrawal than schizophrenia
Less systematised delusions than schizophrenia
More hallucinations and affective symptoms than schizophrenia
More religiosity than schizophrenia
More positive, as opposed to negative, symptoms
Few schneiderian first-rank symptoms
Post surgery psychosis: More possibility following temporal lobe surgery. Psychosis generally does not improve following surgery. Suicide accounts for 22% of post-operative deaths. Commoner with surgery for gangliogliomas and right sided temporal lobectomy.
Depression Prevalence is 7.5 – 34% of cases. Complex partial seizure and poor seizure control are associated with mood disorders. Patient with complex partial seizures of temporal limbic region have a higher incidence of depression. Left hemisphere focus leads to greater incidence of depression.
Aetiology:
Psychological factors
Stigma
Discrimination
Vocational difficulties
Strains of often unpredictable losses of consciousness
Seizure related factors
Biochemical factors
Limbic seizures (alter functioning of corticotrophin-releasing hormone [CRH] pathways)
Folate depletion
Cognitive impairments Patients with symptomatic epilepsy are more likely to have impaired intellect (Bourgeois et al. 1983). Generalised tonic-clonic seizure is associated with more deficits of attention and concentration. In typical absences, impaired cognitive function is for the duration of the bursts of spike wave discharges. Early age of onset of epilepsy causes poorer prognosis of intellectual abilities. Subclinical focal discharges lead to transient, subtle, cognitive impairments on selective tasks. There can be memory difficulties secondary to problems of attention and concentration. Temporal lobe seizures are most likely to have memory problems. Polytherapy is another reason for more cognitive impairments. Phenytoin and phenobarbitone cause more cognitive impairments, affect learning and behaviour in children. Patients on carbamazepine perform poorer on tests of speed of perception and movement. Generalised tonic-clonic seizure with recurrent head injury and prescription of phenytoin and primidone are associated with cognitive decline.
Epileptic dementia It develops after many years of functioning at a reasonably adequate level coupled with severe personality deterioration, and sometimes with marked behaviour disorder in the form of impulsivity, irritability and outbursts of rage. Neuroimaging reveals cerebral atrophy. Epilepsy secondary to a known brain lesion and when the epilepsy has been severe and of long duration, dementia is more common. It may represent the chronic end-state of a schizophrenia-like psychosis, a depressive disorder or progressive worsening of personality traits that have long been present.
Personality disorders Among epileptic patients, there is a high prevalence of personality disorders, including borderline, atypical or mixed, histrionic, and dependent disorders. Patients with personality disorders tend to show dependent and avoidant personality traits. The most common personality disorder in epilepsy is a borderline personality. Psychosocial difficulties, along with any associated mental retardation, contribute to the overall borderline personality traits.
Sexuality Patients with epilepsy tend to be hyposexual. Men and women experience disturbances of sexual arousal and a lower sexual drive. Men have an increased risk of erectile dysfunction, suggesting a neurophysiological component, and studies of sex hormones suggest the possibility of a subclinical hypogonadotropic hypogonadism.
Suicide The risk of completed suicide in epilepsy patients is four to five times greater than that among the nonepileptic population, and those with complex partial seizures of temporal lobe origin have a particularly high risk, as much as 25 times greater. Death by suicide occurs in three to seven percent of epilepsy patients. Contributors to successful suicides include paranoid hallucinations, agitated compunction to kill themselves, occasional ictal command hallucinations to commit suicide.
Inter ictal mood disorders Patients with epilepsy may suffer from specific mood disorders that are paroxysmal, relatively short lasting and often unrecognised. Intermittent affective somatoform symptoms are frequently present in chronic epilepsy. Occur at various intervals and tend to last from hours to two/three days.
Aggression and violence Temporal lobe seizure foci score higher on hostile feelings. They are usually associated with psychosis or intermittent explosive disorder. It correlates with subnormal intelligence, lower socioeconomic status, childhood behaviour problems, prior head injuries, and possible orbital frontal damage. Simple violent automatisms such as spitting or flailing the arms can occur at the onset of complex partial seizure. Secondary violent automatisms can be seen as a response to an unpleasant or emotional aura or periictal sensation.
Other behavioural disorders
Anxiety disorders including panic disorders and posttraumatic stress disorder (PTSD)
Intermittent explosive disorders characterised by a prodromal mounting tension and irritability, postictal remorse and increased temporal spikes on EEG
Adjustment disorders
Subtle cognition effects of seizure
Dissociative identity disorder
Depersonalisation disorders
Possession states including fugue states
Psychogenic amnesia
Conversion disorder
Potential behavioural effects of anticonvulsant medications
Pathology and laboratory examination
Routine laboratory data and toxicology screens
Neurodiagnostic Tests
EEG
Closed-circuit television video-EEG (CCTV-EEG) telemetry
Computed tomography (CT) scans and magnetic resonance imaging (MRI)
Quantitative EEG
Single photon emission computed tomography (SPECT) scans
Positron emission tomography (PET) scans
Neuropsychological examinations, particularly during a Wada’s test, further help in localising and lateralising memory and language before surgery.
Treatment
Anticonvulsant drugs
Psychotropic drugs
Drug interaction
Surgery
Seizure control
Anticonvulsant drugs Carbamazepine, valproate, lamotrigine, and gabapentine have significant antimanic and modest antidepressant properties.
Carbamazepine and valproate may also ameliorate some dyscontrolled, aggressive behaviour in brain injured patients.
Clonazepam, in addition to its anxiolytic properties, can serve as a supplement to other antimanic therapies.
Carbamazepine and ethosuximide may have value for borderline personality disorders.
Encephalopathic changes may occur at toxic levels of all anticonvulsant drugs.
Psychotropic medication Psychosis – Antipsychotics are mainstay treatment. Psychotropic drugs are most convulsive with rapid introduction of the drug and in high doses. Haloperidol is safest drug to be used in epilepsy. Clozapine induces seizures in 1.0 to 4.4 percent of patients. Quetiapine is the only antipsychotic not causing EEG changes. Clobazam 10mg six hourly for a few days and then tapered slowly and stopped over seven to ten days may be used prevention of post ictal psychosis.
Depression and anxiety – selective serotonin reuptake inhibitors (SSRIs) e.g. paroxetine, citalopram, escitalopram.
Paroxysmal affective-somatoform symptoms – antidepressent.
Low potency antipsychotics (sulpiride) can be used in bouts of aggression, outburst of anger, inter ictal psychosis.
Drug interaction Most commonly an anticonvulsant drug increases the metabolism of a psychotropic drug thus decreasing therapeutic efficiency. Withdrawal of anticonvulsant drug can precipitate rebound elevation in psychotropic levels. Initiation of a psychotropic drug may result in competitive inhibition of anticonvulsant metabolism with elevation of anticonvulsant levels to toxicity. New anticonvulsant drugs like gabapentin, lamotrigine, vigabatrin, and tiagabine are relatively free of enzyme-inducing or -inhibiting properties.
Surgery It is the fourth treatment consideration which is indicated for medically intractable seizures. Resection of epileptogenic tissue is done by removal of four to six cm of the anterior temporal lobe. Temporal lobectomy results in some reduction in 80% cases while 50% are totally seizure free. Anomia or verbal memory deficit may occur after resection of the dominant hemisphere. There is reduction in postictal psychosis, depression, hyposexuality. Epileptic patients may continue to develop interictal psychosis, personality changes, and suicidal behaviour.
Seizure management In treating the neuropsychiatric disorder of epilepsy, a final consideration is altering the seizure management itself. In addition to the occasional behaviour alleviated by strict seizure control, allowing seizures under carefully controlled conditions, much like electroconvulsive therapy (ECT), relieves some cases of periictal psychosis, depression, or other behaviours.
Recent advances Cellular and gene therapy for refractory seizures – The recent development of experimental cell and gene therapies may offer several advantages compared to conventional systemic pharmacotherapy: (i) Specificity to underlying pathogenetic mechanisms by rational design; (ii) specificity to epileptogenic networks by focal delivery; and (iii) avoidance of side effects.
A new field of cell and gene-based neuropharmacology has emerged, aimed at either delivering endogenous anticonvulsant compounds by focal intracerebral transplantation of bioengineered cells (ex vivo gene therapy), or by inducing epileptogenic brain areas to produce these compounds in situ (in vivo gene therapy).
Neuroimaging in paediatric epilepsy – Recent advances in neuroimaging with a multimodality imaging approach that combines fluorine 18 fluorodeoxyglucose positron emission tomography, magnetoencephalography, diffusion tensor imaging, and magnetic source imaging with conventional magnetic resonance imaging continue to improve diagnosis and treatment in affected patients.
Corpus callostomy.
Functional hemispheroctomy.
Molecular targets for antiepileptic drug therapy – Recently, α2–δ voltage-gated Ca2+channel subunits and the SV2A synaptic vesicle protein have been recognised as likely targets. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as gamma aminobutyric acid type B receptor (GABA-B) and metabotropic glutamate receptors; hyperpolarisation-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarisation-activated current; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate.
Apart from dysfunction of neuronal networks the role of astrocytes in epileptogenesis is becoming more and more recognised.
Diet therapy – Ketogenic diet: The diet consists of very large amounts of fat, one g per kg per day of protein and minimal amounts of carbohydrates. A typical fat to carbohydrate ratio is 4:1 or 3:1. A recent popular interest in this treatment modality, the diet is initiated with starvation until ketones are present in the urine.
Vagus nerve stimulation – It does not require craniotomy. The mechanism of action is unclear, but it is likely mediated by the widespread afferent connections of the vagal nerve (which terminates in the nucleus of the solitary tract).
The NeuroCybernetic Prosthesis: Adjunct treatment of partial epilepsy – It consists of two components: an electrode attached to the left vagus nerve through an incision in the neck and a generator, similar to a pacemaker that is surgically implanted in the chest wall. A mean seizure frequency reduction of 25 to 35 percent and a seizure frequency reduction of at least 50 percent in 40 percent of patients is observed.
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