Lateral Familial (Autosomal Dominant) Temporal Lobe Epilepsy (LFTLE)

• Overview:

  • Also known as "autosomal dominant focal epilepsy with auditory features."
  • Caused by defects in the same gene.
  • First non-ion channel familial epilepsy discovered.
  • Previously discovered genes for idiopathic epilepsies were associated with ion channels.

• Demographic Data:

  • Onset typically in teenage or early adult life.
  • Can occur as early as 5-10 years of age or later.

• Clinical Manifestations:

  • Seizure Characteristics:
    • Mild seizures with mainly auditory hallucinations.
    • Mainly nocturnal and infrequent generalized tonic-clonic seizures (GTCS).
    • Excellent response to treatment with antiepileptic drugs (AEDs).
  • Seizure Types:
    • Simple focal seizures are most common.
      • Auditory hallucinations (ringing, humming, clicking, unspecified noises).
      • Other sensory symptoms (visual, olfactory, vertiginous, cephalic).
    • Autonomic, experiential, and motor symptoms are less common.
    • Simple focal seizures may progress to complex focal seizures.
    • Brief aphasic seizures have been described.
  • GTCS:
    • Rare and predominantly nocturnal.

• Aetiology:

  • Autosomal dominant inheritance with high penetrance (~80%).
  • Linked to chromosome 10q, localizing a gene in a common overlapping region of 3-cM at 10q24 (LGI1/Epitempin gene).
  • LGI1 mutations cause protein truncation, leading to loss of function.
  • LFTLE is genetically heterogeneous; LGI2, LGI3, or LGI4 mutations do not account for all cases.

• Diagnostic Procedures:

  • EEG and MRI are often normal or show mild, non-specific abnormalities.
  • Interictal EEG epileptiform abnormalities are rare.

• Prognosis:

  • Excellent prognosis.
  • Patients are neurologically and mentally normal.
  • The condition does not significantly affect normal life, especially with medication.

• Differential Diagnosis:

  • Differentiated from other structural causes of lateral temporal lobe epilepsy.
  • Different from hippocampal and other types of mesial familial temporal lobe epilepsy (MFTLE).
    • Main ictal symptom of LFTLE: auditory hallucinations.
    • Main ictal symptoms of MFTLE: déjà vu and other experiential phenomena.

• Management:

  • Excellent response to carbamazepine.

Familial Focal Epilepsy with Variable Foci

• Overview:

  • Familial partial epilepsy with variable foci is an autosomal dominant syndrome.
  • Characterized by focal seizures originating from different brain regions in different family members.
  • Occurs in the absence of detectable structural abnormalities.

• Demographic Data:

  • Age at onset varies widely (from months to 43 years).
  • Mean age at onset of seizures is 13 years.
  • Reported in eight unrelated families to date.

• Clinical Manifestations:

  • Different family members have focal seizures from different cortical locations:
    • Temporal
    • Frontal
    • Centroparietal
    • Occipital
  • Each patient has a consistent electroclinical pattern of single-location focal epilepsy.
  • Seizures are often nocturnal.
  • Great intrafamilial variability in severity:
    • Some are asymptomatic with only an EEG spike-focus.
    • Most are easily controlled with AEDs.
    • A few may be intractable to medication.
  • Identification is challenging in small families due to insufficient individuals to establish a specific pattern.

• Aetiology:

  • Rare inherited syndrome with autosomal dominant inheritance.
  • Penetrance of about 60%.
  • In two families, mapped to a locus on chromosome 22q11-q12.
  • Genetic heterogeneity indicated by non-linkage to chromosome 22 in the original Australian family and a suggestion of linkage on chromosome 2q.

• Diagnostic Procedures:

  • Neuroimaging:
    • Usually normal.
  • Electroencephalography (EEG):
    • Interictal focal epileptiform abnormalities occur in most patients.
    • Locations vary between family members but remain constant for each individual over time.
    • Abnormalities often facilitated or brought on by sleep.
    • Clinical seizures align with EEG localization.
    • EEG severity varies among individuals and does not correlate with seizure frequency.
    • Normal family members may also exhibit an EEG spike focus, indicating it as a marker for the syndrome.

• Prognosis:

  • Development is usually normal.

• Management:

  • Effects of new AEDs not directly evaluated.
  • Carbamazepine and phenytoin appear to be effective.

Autosomal Dominant Rolandic Epilepsy and Speech Dyspraxia

• Overview:

  • Described as a rare hereditary condition by the Australian team of Berkovic, Scheffer, and associates.
  • Characterized by nocturnal oro-facio-brachial focal seizures, secondarily generalized tonic-clonic seizures (GTCS), and centrotemporal epileptiform discharges.
  • Associated with oral and speech dyspraxia and cognitive impairment.
  • The speech disorder differs from that in Landau-Kleffner syndrome and epilepsy with continuous spike and wave during slow-wave sleep.

• Demographic Data:

  • Studied in a family of nine affected individuals across three generations.
  • Patients in previous generations were less severely affected but also had neurological deficits, mainly oral and speech dyspraxia without evidence of dysarthria.

• Clinical Manifestations:

  • Seizure Characteristics:
    • Nocturnal oro-facio-brachial focal seizures.
    • Secondarily generalized tonic-clonic seizures (GTCS).
    • Centrotemporal epileptiform discharges.
  • Neurological Deficits:
    • Prominent oral and speech dyspraxia.
    • Cognitive impairment.
    • In some cases, neurological deficits precede seizures.

• Aetiology:

  • Autosomal dominant inheritance.
  • Clinical anticipation observed in seizure disorder, oral and speech dyspraxia, and cognitive dysfunction.
  • Genetic mechanism could involve expansion of an unstable triplet repeat.

• Prognosis:

  • The condition shows clinical anticipation, meaning symptoms may worsen or appear earlier in successive generations.
  • Permanent neurological deficits make it distinct from benign rolandic epilepsy.

• Clinical Significance:

  • Resembles benign rolandic epilepsy in some electroclinical features but differs due to permanent neurological deficits and anticipation.
  • Molecular studies on this syndrome may help identify a gene for benign rolandic epilepsy, where anticipation does not occur and the mode of inheritance is uncertain.

• Management:

  • Specific management strategies not detailed; implications for treatment and genetic counseling need further research.

Focal Epilepsy with Pericentral Spikes

• Overview:

  • Based on the study of a family with a variety of seizure types.
  • Seizure types include hemiclonic, hemitonic, generalized tonic-clonic seizures (GTCS), simple focal (stereotyped episodes of epigastric pain), and complex focal seizures with temporal lobe semiology.
  • The syndrome is benign, requiring no treatment or responding well to a single antiepileptic drug (AED).

• Demographic Data:

  • Seizure onset typically occurs in the first or second decades of life.
  • Seizures can persist up to 71 years of age.
  • EEG changes have been documented up to the age of 30 years.

• Clinical Manifestations:

  • Seizure Types:
    • Hemiclonic
    • Hemitonic
    • Generalized tonic-clonic seizures (GTCS)
    • Simple focal seizures (stereotyped episodes of epigastric pain)
    • Complex focal seizures consistent with temporal lobe semiology
  • EEG Abnormalities:
    • Characteristic spikes or sharp waves in the pericentral region:
      • Centroparietal
      • Centrofrontal
      • Centrotemporal
  • Variability:
    • The syndrome may be overlooked due to variability in penetrance and seizure types among affected family members.

• Aetiology:

  • Evidence for linkage to chromosome 4p15.

• Prognosis:

  • The syndrome is benign.
  • Seizures are either self-limiting or respond well to a single AED.

• Management:

  • Treatment is often not required.
  • When needed, seizures respond well to a single AED.