- Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)
- Familial autosomal dominant lateral temporal lobe epilepsy (Autosomal dominant focal epilepsy with auditory features)
- Familial focal epilepsy with variable foci
- Familial mesial temporal lobe epilepsy
Familial (autosomal dominant) focal epilepsies are monogenic (single gene) forms of epilepsy identified in large families with an epileptic trait segregating in the absence of environmental factors. In these families, phenotypes are determined by mutations in susceptibility genes, some of which have been identified or localized. Most of the genes discovered code for either voltage-gated or ligand-gated ion channel subunits, which indicates that, at least in part, familial (autosomal dominant) focal epilepsies are a family of channelopathies. Familial lateral temporal lobe epilepsy was the first non-ion channel disease in this group to be described.
The following familial (autosomal dominant) focal epilepsy syndromes have been recognized:
- Autosomal dominant nocturnal frontal lobe epilepsy
- Benign familial neonatal seizures
- Benign familial infantile seizures
- Familial autosomal dominant lateral temporal lobe epilepsy
- Familial focal epilepsy with variable foci
- Familial mesial temporal lobe epilepsy
The epileptic syndromes and their significance
A major advance in recent epileptology is the recognition of epileptic syndromes that allows an accurate diagnosis and management of seizure disorders.[1-3]
Medical diagnosis is the identification of a disease by investigation of its symptoms and history, which provides a solid basis for the treatment and prognosis of the individual patient. An accurate diagnosis is the golden rule in medicine, and epilepsies should not be an exception to this. Like in any other disease, the recognition of non-fortuitous clustering of symptoms and signs in epilepsies requires the study of detailed clinical and laboratory data.[1-3] However, often in current practice, the diagnosis is limited to either epilepsy or seizures, which is unsatisfactory because this cannot provide guidance on important items such as severity of the disease, prognosis, short- and long-term therapeutic decisions, and genetics (research and counselling), which are all factors that crucially affect personal, family, and social life; education; and career choices of patients. Defining the type of epilepsy should now be considered mandatory as it offers the best guide to both management and prognosis. Most epileptic syndromes and diseases are well defined and easy to diagnose. The benefits of syndromic diagnosis over seizure/symptom diagnosis or an inclusive diagnosis such as epilepsy far outweigh any morbidity from incorrect categorization that may arise in difficult cases.[4]
Important clinical features of a syndrome include the type of seizures, their localization, frequency, sequence of events, circadian distribution, precipitating factors, age at onset, mode of inheritance, physical or mental symptoms and signs, prognosis, and response to treatment.
Epilepsies or epilepsy?
The clinical and practical significance of the syndromic diagnosis of epilepsies is well illustrated by 3 common epileptic disorders. Benign childhood focal epilepsies, juvenile myoclonic epilepsy (JME), and hippocampal epilepsy have nothing in common other than the fact that they may all be complicated by generalized tonic clonic seizures (GTCS), which are primarily GTCS in JME and secondarily GTCS in benign childhood focal epilepsies and hippocampal epilepsy.
Furthermore, the short-and long-term treatment strategies are entirely different for each disorder: benign childhood focal epilepsies may or may not require medication for a few years, appropriate anti-epileptic drug (AED) treatment is lifelong in JME while neurosurgery may be life-saving for patients with hippocampal epilepsy. What may be a life-saving drug such as carbamazepine for hippocampal epilepsy may be ill-advised for JME.
It should not be difficult to distinguish an intelligent child with benign focal seizures or childhood absence epilepsy from a child with Kozhevnikov-Rasmussen, Lennox-Gastaut, Down, or Sturge-Weber syndrome or a child with severe post-traumatic cerebral damage, brain anoxia, or catastrophic progressive myoclonic epilepsy. Describing all these children as simply having epilepsy just because they have seizures offers no more benefit than a diagnosis of febrile illness irrespective of cause, which may be a mild viral illness, a life-threatening acute bacterial meningitis, or a malignancy. Inappropriate generalizations with regard to terminology, diagnosis, and treatment are the single most important factor of mismanagement in epilepsies.[4]
C. P. Panayiotopoulos, MD, PhD, FRCP
Reviewed and revised June 2008 by Steven C. Schachter, MD
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Prevalence
Unknown but with increasing reports of ADNFLE families.
Age at onset
Markedly variable (2 months to 56 years); peak at 11 years; 90% <20 years.
Sex
Males = females.
Neurological and mental state
Normal.
Genetics
Autosomal dominant with 70% penetrance. Linkage to chromosomes 20q and 15q. Mutations have been identified in the CHRNA4 gene encoding the neuronal nicotinic acetylcholine receptor (nACHR) alpha 4 subunit protein and CHRNB2 encoding the nACHR beta 2 subunit protein. The clinical phenotypes appear markedly homogeneous.
Clinical manifestations
Hypermotor seizures (identical to those originating from the supplementary somatosensory area) are frequent (nearly every night), occur in clusters, and are brief (20 to 50 sec). Sudden, hyperkinetic movements and dystonic posturing or tonic stiffening of the limbs and the body occur, often with superimposed clonic components. Patients may be thrown out of bed or find themselves prone in a crawling position. Injuries may occur. Sleep is abruptly interrupted but immediately resumes with the end of the seizure. Post-ictal state is normal.
2/3 of patients experience a non-specific aura of somatosensory, sensory, psychic, and autonomic symptoms.
Consciousness is usually preserved.
Secondarily generalized tonic-clonic seizures, occurring in 2/3, are infrequent, mainly in untreated patients.
Timing
Nearly exclusive in sleep (hypnagogic state or shortly before awakening).
Diagnostic procedures
Brain imaging is normal.
Inter-ictal EEG
Usually normal but 12% to 65% have frontal lobe epileptiform abnormalities, mainly in sleep.
Ictal EEG
Usually normal. In 40% to 88%, repetitive frontal sharp waves are intermixed with spikes or rhythmic theta (unilateral frontal or bifrontal).
Prognosis
Seizures are lifelong, with spontaneous remissions and relapses. Attacks become milder after ages 50 to 60. Severity varies from mild (seizures appearing only in brief periods) to severe (frequent and intractable seizures).
Differential diagnosis
Usually misdiagnosed as benign nocturnal parasomnias, night terrors, nightmares, obstructive sleep apnea syndrome, psychiatric and medical disorders. ‘Nocturnal paroxysmal dystonia’ and ‘hypnic tonic postural seizures of frontal lobe origin’ are certainly frontal lobe seizures and most patients probably have ADNFLE.
Management options*
As for focal seizures; 1/3 of patients are resistant to carbamazepine. Newer drugs licensed for focal epilepsies may be effective.
*Expert opinion, please check FDA-approved indications and prescribing information
This page was adapted from:
The educational kit on epilepsies
The epileptic syndromes
By C. P. Panayiotopoulos
Originally published by MEDICINAE
21 Cave Street, Oxford OX4 1BA
First published 2006 and reprinted in 2007
Reviewed and revised June 2008 by Steven C. Schachter, MD
Prevalence
Unknown but may be rare.
Age at onset
Typically in teenage years or early adult life; may start earlier, 5 to 10 years or later.
Sex
Males = females.
Neurological and mental state
Normal.
Genetics
Autosomal dominant inheritance with high (~80%) penetrance. It is the first non-ion channel idiopathic focal epilepsy to be described. Mutations of the leucine-rich, glioma-inacivated 1 (LGI1/Epitempin gene) on chromosome 10q are responsible for this disorder.
Clinical manifestations
Simple focal seizures that are the most common consist mainly of simple auditory hallucinations such as ringing, humming, clicking, or unspecified noises. These may infrequently progress to complex focal seizures and generalized tonic-clonic seizures (GTCS). Other sensory symptoms such as visual (lights, colors, and simple figures), olfactory, vertiginous, or cephalic are frequent with simple focal seizures while autonomic, mental, and motor symptoms are less common. Families with brief aphasic seizures have been described.
Secondarily GTCS are rare.
Timing
GTCS predominantly nocturnal.
Seizure-precipitating factors
Sleep.
Diagnostic procedures
MRI is normal.
Inter-ictal EEG
Often normal; epileptiform abnormalities rarely occur.
Prognosis
Excellent. Patients are neurologically and mentally normal, and the condition does not appear to affect their otherwise normal life, particularly when on medication. Seizures are generally mild, infrequent, and well controlled with anti-epileptic medication.
Differential diagnosis
Symptomatic lateral temporal lobe epilepsy that lacks a similar family history and that is markedly different from hippocampal epilepsy and familial mesial temporal lobe epilepsy.
Management options*
AEDs indicated for focal seizures. Response to carbamazepine is excellent.
*Expert opinion, please check FDA-approved indications and prescribing information
This page was adapted from:
The educational kit on epilepsies
The epileptic syndromes
By C. P. Panayiotopoulos
Originally published by MEDICINAE
21 Cave Street, Oxford OX4 1BA
First published 2006 and reprinted in 2007
Reviewed and revised June 2008 by Steven C. Schachter, MD
Prevalence
Small; <10 unrelated families have been reported.
Age at onset
Markedly varies. Range is 2 months to 43 years; median 10 years.
Sex
Males = females.
Neurological and mental state
Normal.
Genetics
Autosomal dominant inheritance with ~60% penetrance. Genetic heterogeneity. Mapped to chromosome 22q11-q12 and there may be possible linkage to chromosome 2q.
Clinical manifestations
Different family members have focal seizures emanating from different cortical locations that include temporal, frontal, centroparietal, or occipital lobe regions. Each individual patient has the same electro-clinical pattern of single location focal epilepsy.
Secondarily generalized tonic-clonic seizures (GTCS) in 60% to 86%.
Timing
Seizures often occur in sleep.
Diagnostic procedures
Neuroimaging usually normal.
Inter-ictal EEG
Focal epileptiform abnormalities in most patients. Location varies within family members in the temporal, frontal, centroparietal, or occipital regions, but for each individual a single focus remains constant over time. They are facilitated or brought up in sleep EEG. Clinical seizures are concordant with EEG localization. EEG severity varies significantly in different individuals and does not correlate with seizure frequency. Normal family members may also have an EEG epileptiform focus, thus indicating that this is likely to be a marker for this disorder.
Ictal EEG
Focal seizure discharges.
Prognosis
Great intra-familial variability. Severity varies among family members; some may be intractable to medication but usually these are infrequent, easily controlled, or even asymptomatic, manifesting only with EEG foci.
Differential diagnosis
Symptomatic focal epilepsies.
Management options
AEDs indicated for focal seizures.
This page was adapted from:
The educational kit on epilepsies
The epileptic syndromes
By C. P. Panayiotopoulos
Originally published by MEDICINAE
21 Cave Street, Oxford OX4 1BA
First published 2006 and reprinted in 2007
Reviewed and revised June 2008 by Steven C. Schachter, MD
Prevalence
Unknown but may be more common than diagnosed.
Age at onset
Teenage or early adult life; median 25 years. Not before 10 years of age.
Sex
Females (58%) > males.
Neurological and mental state
Normal.
Genetics
Autosomal dominant inheritance with reduced 60% penetrance. Genetically heterogeneous.
Clinical manifestations
Simple focal seizures (90%) manifest with a galaxy of déjà vu and other subjective complex internal sensations (nearly all) alone or together with autonomic disturbances. Other symptoms include fear and panic, visual and auditory illusions of distortions of light and sound, and somatosensory sensations of diffuse, not localized, numbness and tingling. These may progress to complex focal seizures (66%). Generalized tonic-clonic seizures (GTCS; 2/3 of patients) are infrequent (<1/year) and usually prior to medication.
Rising epigastric sensation does not occur.
Diagnostic procedures
MRI is normal but severe cases may show hippocampal atrophy, including rare examples of familial hippocampal sclerosis. Diffuse small high signal areas on T2-weighted images may be seen. Ipsilateral temporal hypometabolism in inter-ictal 18F fluoro-deoxyglucose (FDG)-PET.
Inter-ictal EEG
Usually normal (half the cases) or with mild focal slow waves (28%) or sparse sharp- and slow-wave complexes localized in the temporal region and usually unilateral (22%). Sleep may activate epileptiform abnormalities.
Ictal EEG
Temporal lobe seizure discharge but occasionally no EEG change.
Prognosis
Usually excellent; 16% with mild simple focal seizures alone would never know that this is epilepsy if other family members were not affected. Of those with overt seizures, 66% have complex focal seizures and GTCS, which are infrequent and respond well to anti-epileptic medication. For seizures to continue after drug treatment is rare (10% to 20%). Long remissions, with or without therapy, are common. A more severe clinical spectrum may exist.
Differential diagnosis
Very mild and infrequent seizures with predominantly déjà vu from normal phenomena and hippocampal epilepsy.
Management options
Easily controlled with AEDs indicated for focal seizures.
This page was adapted from:
The educational kit on epilepsies
The epileptic syndromes
By C. P. Panayiotopoulos
Originally published by MEDICINAE
21 Cave Street, Oxford OX4 1BA
First published 2006 and reprinted in 2007
Reviewed and revised June 2008 by Steven C. Schachter, MD
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