HISTORICAL NOTE AND NOMENCLATURE
Genetic factors in the causation of epilepsy have been recognized since the time of Hippocrates. However, until the second half of the 20th century, generalized epilepsies were thought to be genetic in origin, whereas focal or partial epilepsies were largely attributed to environmental factors, such as birth injuries, infections, postnatal head trauma, and brain lesions such as tumors and vascular insults.

In a series of publications (Andermann and Metrakos 1969; Andermann 1980; 1982; 1985) based on patients operated for partial epilepsy at the Montreal Neurological Hospital, Eva Andermann was able to demonstrate that genetic factors were important in patients with partial epilepsy, particularly temporal lobe epilepsy, and that both generalized and partial epilepsies fit a model of multifactorial inheritance (now termed complex inheritance), with interaction of one or more genes and environmental factors.

It was only in the 1990s that several autosomal dominant forms of partial epilepsy were described by the group of Berkovic and colleagues (Berkovic and Steinlein 1999). These included: autosomal dominant nocturnal frontal lobe epilepsy, familial temporal lobe epilepsy, familial partial epilepsy with variable foci, and autosomal dominant rolandic epilepsy with speech dyspraxia.

Recently, familial temporal lobe epilepsy was included in the new proposal for classification of epileptic syndromes by the International League Against Epilepsy, supporting it as a well-defined syndrome (Engel 2001).

The first description of familial lateral temporal lobe epilepsy was in 1995 by Ottman and colleagues, who reported an autosomal dominant partial epilepsy syndrome with auditory features (Ottman et al 1995). Autosomal dominant partial epilepsy syndrome with auditory features corresponds to a neocortical or lateral temporal lobe epilepsy.

After detailed descriptions of many families, it has been possible to define two groups of familial temporal lobe epilepsy based on clinical and molecular characteristics (Vadlamudi et al 2003): familial mesial temporal lobe epilepsy, with clinical features of mesial temporal onset and no clear-cut molecular definitions to date (Kobayashi et al 2001; 2004); and familial lateral temporal lobe epilepsy associated with LGI-1 gene mutations in chromosome 10q (Kalachikov et al 2002; Morante-Redolat 2002).

It is important to recognize that it is impossible to distinguish familial and nonfamilial temporal lobe epilepsy patients based solely on the clinical presentation, for both mesial and lateral forms. As the family history is not always accurately documented, many so-called “sporadic” or “isolated” patients may actually have a familial epilepsy syndrome.

CLINICAL MANIFESTATIONS

Familial lateral temporal lobe epilepsy is a benign epilepsy syndrome characterized by auditory auras (buzzing, roaring, radio- or motor-like sounds, distortions in sounds and words). Although other manifestations such as psychic, cephalic and other sensory and motor phenomena can occur, the auditory auras are a landmark for this syndrome. Sometimes ictal aphasia and visual misperceptions can occur, and in some families, secondarily generalized tonic-clonic seizures are frequent (Poza et al 1999; Winawer et al 2000; 2002; Brodtkorb et al 2002; Gu et al 2002; Kobayashi et al 2003; Michelucci et al 2003). The pattern of inheritance observed is autosomal dominant with incomplete penetrance.

Age of onset is variable, usually in the second or third decades of life, and seizures are easily controlled with anti-epileptic drugs. EEGs may show posterior temporal epileptiform discharges, but are frequently normal. No signs of HA are seen in MRI studies, but a lateral temporal malformation pattern has been observed in 45% of individuals, including one asymptomatic carrier of the mutation (Kobayashi et al 2003). The left temporal lobes of these individuals seemed enlarged and sometimes there was a protrusion of the brain parenchyma laterally, with an “encephalocele-like” appearance. Anterior temporal lobe volumetry showed a significant global increase in volumes in only two individuals. The epileptogenic significance of these structural abnormalities is unknown.

CLINICAL VIGNETTE
No information was provided by the author.

ETIOLOGY
The identification of a positive family history of seizures in patients with lateral temporal lobe epilepsy is not sufficient for a diagnosis of familial lateral temporal lobe epilepsy. The best definition of familial lateral temporal lobe epilepsy is based on the familial recurrence of lateral temporal lobe epilepsy, which is defined by clinical-EEG criteria according to the International League Against Epilepsy recommendations (Anonymous 1989), in the absence of any suggestion of other partial or generalized epilepsy syndromes in other affected family members. Thus, the observation of at least two lateral temporal lobe epilepsy patients in one family is suggestive of familial lateral temporal lobe epilepsy. The observation of an autosomal dominant inheritance pattern with incomplete penetrance implies the presence of asymptomatic carriers of the genetic abnormalities, who can transmit the disease to their offspring. Therefore, we should consider inclusion of families not only with affected first-degree relatives, but also with affected second and third degree relatives.

The presence of family members with episodes of either generalized tonic-clonic seizures only with no witnessed onset, or with febrile seizures alone, does not exclude the diagnosis of familial lateral temporal lobe epilepsy, since these do not fulfill criteria for other epilepsy syndromes. Families with individuals who have such clinical manifestations should also be considered to have familial lateral temporal lobe epilepsy, as long as there are at least two affected individuals who fulfill the clinical and EEG criteria for lateral temporal lobe epilepsy.

It is now possible to provide a molecular diagnosis of familial lateral temporal lobe epilepsy, through identification of mutations in the LGI-1 gene. However, it is known that the absence of these mutations does not exclude the syndrome, since not all families manifest mutations in the LGI-1 gene.

PATHOGENESIS AND PATHOPHYSIOLOGY
The pathogenesis and pathophysiology of familial epilepsies must be determined first by the genetic basis that indicates an inherited disease, and second by the structural/functional abnormalities that are associated with this genetic background.

Although mutations in the LGI-1 gene have been found in familial lateral temporal lobe epilepsy, the role of the gene in the pathophysiology of the epilepsy is still unknown. LGI-1 codes for a putative membrane-anchored protein of unknown function. The LGI-1 gene is characterized by a central leucine-rich repeat region, which is involved in regulation of cell growth, adhesion, and migration (Hocking et al 1998). It was cloned from a glioblastoma cell line and possibly represents a tumor suppressor gene (Chernova et al 1998). It is mutated in approximately 50% of families with familial lateral temporal lobe epilepsy (Berkovic et al 2004a; Ottman et al 2004), and the association of lateral temporal malformation patterns in some families may be indicative of a probable role of LGI-1 in the development of the temporal lobes (Kobayashi et al 2003).

LGI-1 mutations seem to be specific for familial lateral temporal lobe epilepsy, but the identification of LGI-1 mutations in only one-half of families presenting the typical phenotype (Berkovic et al 2004a; Ottman et al 2004) suggests genetic heterogeneity.

EPIDEMIOLOGY
There is no predominance of familial lateral temporal lobe epilepsy in any particular ethnic group. Familial lateral temporal lobe epilepsy has been studied in the USA, Brazil, Japan, Germany, France, Italy and Australia. There is probably an underestimate of the real prevalence of familial lateral temporal lobe epilepsy worldwide, especially because of the usually mild phenotypes and predominantly good outcomes.

PREVENTION

Although amniocentesis and mutation detection is possible in offspring of known LGI-1 mutation carriers, prenatal diagnosis is not likely to be routinely practiced, since the usually mild phenotype of lateral temporal lobe epilepsy would not warrant termination of pregnancy.

DIFFERENTIAL DIAGNOSIS

The two main differential diagnoses for familial lateral temporal lobe epilepsy are sporadic lateral temporal lobe epilepsy and familial mesial temporal lobe epilepsy, which can be clarified most of the time with a detailed history and seizure description.

Recently, the presence of patients with lateral temporal lobe epilepsy but without a positive family history was highlighted by Bisulli and colleagues (Bisulli et al 2004). The authors termed this syndrome idiopathic partial epilepsy with auditory features, and performed a clinical and genetic study in 53 sporadic cases. Mutations in LGI-1 were excluded in all idiopathic partial epilepsy with auditory features patients although, except for the absence of family history, these patients had identical clinical manifestations as those seen in familial lateral temporal lobe epilepsy, including the always-good prognosis (Bisulli et al 2004).

To date, no families with familial mesial temporal lobe epilepsy were found to have an LGI-1 mutation, even though some had affected family members with both mesial symptoms and auditory features (Santos et al 2002; Badhwar et al 2004; Berkovic et al 2004a). This further supports the fact that familial lateral temporal lobe epilepsy and familial mesial temporal lobe epilepsy constitute separate genetic syndromes.

In addition, there are other familial epilepsy syndromes in which patients with temporal lobe epilepsy are found. In familial partial epilepsy with variable foci (Scheffer et al 1998; Xiong et al 1999; Xiong 2002; Callenbach et al 2003; Berkovic et al 2004b), most reported families mapped to chromosome 22q, but the gene has not yet been identified. Affected family members may present with various forms of partial epilepsy, including temporal lobe epilepsy.

In generalized epilepsy with febrile seizure plus (GEFS+), related to mutations in genes SCN1A, SCN2A, SCN1B and GABRG2 (Wallace et al 1998; 2001; 2002; Escayg et al 2000; Lopes-Cendes et al 2000; Sugawara et al 2001; Harkin et al 2002), patients may present heterogeneous epilepsy phenotypes. Febrile seizures are the most common phenotype, followed by febrile seizures plus (FS+), where individuals have seizures with fever that may persist beyond the age of 6 years and may be associated with afebrile generalized tonic-clonic seizures (Scheffer and Berkovic 1997; Singh et al 1999). Less frequent phenotypes seen in generalized epilepsy with febrile seizure plus involve other generalized and partial seizure types, including temporal lobe epilepsy (Scheffer and Berkovic 1997; Singh et al 1999; Wallace et al 2002).

It is essential to evaluate the phenotype of all possibly affected individuals before classifying the family to have a specific familial syndrome. In addition, because phenotypes may vary, we can never be absolutely sure that an “isolated” or “sporadic” lateral temporal lobe epilepsy patient does not have familial lateral temporal lobe epilepsy. Molecular studies with testing of the LGI-1 mutation and other genes related to other familial epilepsies can be helpful.

DIAGNOSTIC WORKUP
As it is impossible to distinguish, so far, familial from nonfamilial temporal lobe epilepsy in a single individual, it is necessary to obtain a detailed family history with the mother or the grandmother of each patient to exclude familial recurrence (which is often hidden in families). All family members with suggestive symptoms of epilepsy should be interviewed personally or by telephone, and medical records should be obtained whenever possible.

Familial lateral temporal lobe epilepsy patients should have the same investigations as nonfamilial patients. Routine EEG and MRI should be performed, to rule out the presence of any treatable lesion.

Molecular studies can now be performed for the LGI-1 mutation in suspected cases of familial lateral temporal lobe epilepsy. If other familial epilepsy syndromes are suspected, specific molecular testing for these syndromes can also be performed.

PROGNOSIS AND COMPLICATIONS

Familial lateral temporal lobe epilepsy has a benign clinical course with no refractory patients reported to date (Ottman et al 1995; Poza et al 1999; Winawer et al 2000; 2002; Brodtkorb et al 2002; Michelucci et al 2003). Many patients may present only a few episodes, and then have spontaneous remission. No neurologic disabilities are known in this syndrome.



MANAGEMENT

Treatment should be based on the patient’s response to anti-epileptic drugs and the rationale is similar to that in nonfamilial patients. Usually, familial lateral temporal lobe epilepsy patients are well controlled with small doses of anti-epileptic drugs indicated in partial epilepsies.

PREGNANCY

No information was provided by the author.

ANESTHESIA

No information was provided by the author.


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ABBREVIATIONS

EEG:electroencephalogram
GTCS:generalized tonic-clonic seizure
MRI:magnetic resonance imaging

SYNONYMS

Autosomal dominant lateral temporal lobe epilepsy
Autosomal dominant partial epilepsy with auditory features
Familial lateral temporal lobe epilepsy
Familial neocortical temporal lobe epilepsy
Familial partial epilepsy with aphasic seizures

SUBTOPICS

Autosomal dominant nocturnal frontal lobe epilepsy
Autosomal dominant rolandic epilepsy with speech dyspraxia
Familial partial epilepsy with variable foci

MAJOR KEYWORD DESCRIPTORS

auditory auras
familial epilepsies
familial temporal lobe epilepsy
LGI1
LGI-1 gene
temporal lobe epilepsy
temporal lobe seizures

MINOR KEYWORD DESCRIPTORS

epilepsy
seizures

AGE OF PRESENTATION

06-12 years
13-18 years
19-44 years

AGE OF TYPICAL PRESENTATION

06-12 years
13-18 years

POPULATION GROUP(s) PREFERENTIALLY AFFECTED
none selectively affected

POPULATION GROUP(s) EXCLUSIVELY AFFECTED Population group(s) exclusively affected
none

OCCUPATION GROUP(s) PREFERENTIALLY AFFECTED
none

OCCUPATION GROUP(s) EXCLUSIVELY AFFECTED
none

SEX

FAMILY HISTORY
may be obtained

HEREDITY
heredity may be a factor

PERMUTATIONS
Familial lateral temporal lobe epilepsy
lateral temporal lobe epilepsy, Familial
temporal lobe epilepsy, Familial lateral
lobe epilepsy, Familial lateral temporal
epilepsy, Familial lateral temporal lobe

RELATED TOPICS
Epilepsy
Mesial temporal lobe epilepsy
Neocortical temporal lobe seizures

DIFFERENTIAL DIAGNOSIS
familial mesial temporal lobe epilepsy
familial partial epilepsy with variable foci
generalized epilepsy with febrile seizures plus
idiopathic partial epilepsy with auditory features
isolated lateral temporal lobe epilepsy
nonfamilial temporal lobe epilepsy
sporadic lateral temporal lobe epilepsy