No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Telephone-induced Seizures: A New Type of Reflex Epilepsy
Epilepsia
Abstract
To report a new form of reflex epilepsy in which the seizures are repeatedly and exclusively triggered by answering the telephone.
Three patients with a history of telephone-induced seizures were studied in detail by means of clinical, EEG, and neuroradiologic investigations. Intensive video-EEG monitoring to record the reflex seizures also was performed in all cases.
The patients (two men, one woman, aged 21 to 30 years) had the onset during early adulthood of complex partial and secondarily generalized seizures exclusively triggered by answering the telephone. The seizures were stereotyped, with subjective auditory or vertiginous auras and inability to speak or understand the spoken voices. In one patient, a telephone-induced seizure arising from the dominant temporal lobe was recorded by means of video-EEG technique. In the interictal EEGs, temporal abnormalities were detected in all cases. The patients had a normal neurologic examination and normal magnetic resonance imaging or computed tomography scans.
We suggest that telephone epilepsy is a previously unrecognized form of reflex epilepsy induced by a complex auditory stimulus involving the lateral temporal areas.
... Notably, in ADTLE, seizures can be triggered by auditory or speech stimuli in a number of patients (4,(9)(10)(11)(12). Telephone-induced seizures have recently been described as a specific form of reflex seizures induced by more complex auditory stimuli (13). Precipitation of seizures by answering the phone has been reported in a number of patients (3,9,10,13,14), among them several with proven LGI1 mutations (3,9,10). ...
... Telephone-induced seizures have recently been described as a specific form of reflex seizures induced by more complex auditory stimuli (13). Precipitation of seizures by answering the phone has been reported in a number of patients (3,9,10,13,14), among them several with proven LGI1 mutations (3,9,10). Telephone-triggered seizures never occurred in our patient. ...
Patients with autosomal dominant lateral temporal lobe epilepsy (ADTLE) may have seizures precipitated by sound or speech. We have examined a patient with speech-induced seizures caused by an LGI1 mutation (C46R).
A clinical study and a video-EEG recording using interrogative speech as the activation procedure was performed in a 23-year-old man.
He had experienced short episodes of sensory aphasia in situations in which he was suddenly verbally addressed. Voices became distorted, and he could not comprehend despite hearing words. The day after a late party, his girlfriend unexpectedly spoke to him. Her speech became unintelligible to him. He did not reply and had a generalized tonic-clonic (GTC) seizure. During an EEG, he was suddenly asked for the names of his siblings. He answered, but lost understanding of the further conversation and described how syllables floated together with an echoing character. With a versive movement to the right, another GTC occurred. In the EEG, rhythmic 6-Hz activity built up in the frontotemporal areas starting on the left side with bilateral and posterior spreading. Postictal slowing was symmetrical, and no aphasia was noted on awakening.
To our knowledge, this is the first video-EEG recorded seizure in LGI1-caused ADTLE. This peculiar seizure semiology and precipitating effect of speech may serve as a marker for identifying further individuals with this particular phenotype and genotype and may indicate that the LGI1 gene may have a physiologic function connected to the human capacity for speech and language.
... [3] Sounds or bright lights from electronic phones might be the cause. [4] For patients with Parkinson's disease, seizures are also a possible problem. [5] It is necessary to have a good instruction for patient and cousin on safe and appropriate environmental adjustment when using telemedicine communication. ...
... A second cluster of observations to consider involves another generally recognized feature of many types of epilepsy-the epileptogenic effects of rhythmic stimulations delivered to various sensory systems (see e.g., Kaplan, 2003;Guerrini and Genton, 2004;Hirsch et al., 2004;Michelucci et al., 2004;Wilkins et al., 2004;Parra et al., 2005). Ictal activity provoked by rhythmic exteroceptive stimulation may have similar mechanism to physical resonance systems. ...
... One of three patients with TLE of unknown etiology whose seizures were precipitated by answering the phone [104] likewise was sensitive to the voice of one particular person, her best friend. Her seizures could be documented by video-EEG and occurred within seconds on answering the phone. ...
Introduction: There is growing awareness that reflex epileptic seizures offer unique insight into natural seizure generation in humans. In the last years, focus has mostly been on reflex seizures in generalized epilepsies whereas a comprehensive review of their role in focal epilepsies has been missing.
Areas covered: This paper reviews reflex seizures strictly in focal epilepsies, not including focal reflex seizures in system epilepsies that also exist. They were categorized according to their triggers which can be sensory or cognitive, simple or complex. Numerous diverse conditions exist some of which are much better investigated than others. They required separate individual literature search in PubMed. Where recent review papers exist, it refers to these, but several conditions have never been reviewed, and here it refer to and discusses original reports. Miscellaneous case reports were only exceptionally included when they contributed aspects otherwise missing.
Expert commentary: Research on focal reflex seizures with advanced methods of imaging and neurophysiology to elucidate mechanisms of focal ictogenesis will probably be rapidly increasing and will soon provide much new insight. Sensory and cognitive inhibition, i.e. the counterpart of reflex ictogenesis, is promising but needs more structured and controlled research to establish robust therapeutic approaches.
... Audiogenic seizure precipitation by noises is common in rodents (32) but extremely rare in humans. Complex audiogenic seizure triggers include music (12,33) and answering the phone in familial TLE with aphasic seizures (34), where a chromosome locus has been identified on 10q22-q24. Anecdotal reports exist of seizures precipitated by the voices of specific radio hosts (12). ...
The relations of epilepsy and the sensory systems are bidirectional. Epilepsy may act on sensory systems by producing sensory seizure symptoms, by altering sensory performance, and by epilepsy treatment causing sensory side effects. Sensory system activity may have an important role in both generation and inhibition of seizures.
... The epileptic syndrome displayed by GASH:Sal can be classified within the sensory-elicited human reflex epilepsies as a type of sound-induced epilepsy related to musicogenic epilepsies [106] or telephone-induced seizures [107] appearing in the young adult. Although perhaps GASH:Sal seizures would be closest to the so-called "reflex myoclonic epilepsy of infancy". ...
... In particular, alterations in SCN1A could reduce sodium currents in inhibitory GABAergic interneurons, which are crucial in the control of cortical excitability (Yu et al., 2006). Telephone-induced seizures have been described as a distinct form of idiopathic reflex epilepsy in which seizures are repeatedly and exclusively triggered by answering the telephone (Brodtkorb et al., 2002; Gu et al., 2002; Michelucci et al., 2004). Michelucci et al. (2007) reported a 36-year-old woman with a 11-year history of recurrent complex focal and secondarily generalized seizures evoked by answering the telephone, including mobile phone. ...
... Telephone-induced seizures have been described as a distinct form of idiopathic reflex epilepsy in which seizures are repeatedly and exclusively triggered by answering the telephone Gu et al., 2002;Michelucci et al., 2004). Michelucci et al. (2007) reported a 36-year-old woman with a 11-year history of recurrent complex focal and secondarily generalized seizures evoked by answering the telephone, including mobile phone. ...
Introduction:
Reflex seizures are epileptic events triggered by specific motor, sensory or cognitive stimulation. This comprehensive narrative review focuses on the role of genetic determinants in humans and animal models of reflex seizures and epilepsies.
Methods:
References were mainly identified through MEDLINE searches until August 2015 and backtracking of references in pertinent studies.
Results:
Autosomal dominant inheritance with reduced penetrance was proven in several families with photosensitivity. Molecular genetic studies on EEG photoparoxysmal response identified putative loci on chromosomes 6, 7, 13 and 16 that seem to correlate with peculiar seizure phenotype. No specific mutation has been found in Papio papio baboon, although a genetic etiology is likely. Mutation in synaptic vesicle glycoprotein 2A was found in another animal model of photosensitivity (Fayoumi chickens). Autosomal dominant inheritance with incomplete penetrance overlapping with a genetic background for IGE was proposed for some families with primary reading epilepsy. Musicogenic seizures usually occur in patients with focal symptomatic or cryptogenic epilepsies, but they have been reported in rare genetic epilepsies such as Dravet syndrome. A single LGI1 mutation has been described in a girl with seizures evoked by auditory stimuli. Interestingly, heterozygous knockout (Lgi1(+/-)) mice show susceptibility to sound-triggered seizures. Moreover, in Frings and Black Swiss mice, the spontaneous mutations of MASS1 and JAMS1 genes, respectively, have been linked to audiogenic seizures. Eating seizures usually occur in symptomatic epilepsies but evidences for a genetic susceptibility were mainly provided by family report from Sri Lanka. Eating seizures were also reported in rare patients with MECP2 duplication or mutation. Hot water seizures are genetically heterogeneous but two loci at chromosomes 4 and 10 were identified in families with likely autosomal dominant inheritance. Startle-induced seizures usually occur in patients with symptomatic epilepsies but have also been reported in the setting chromosomal disorders or genetically inherited lysosomal storage diseases.
Discussion:
The genetic background of reflex seizures and epilepsies is heterogeneous and mostly unknown with no major gene identified in humans. The benefits offered by next-generation sequencing technologies should be merged with increasing information on animal models that represent an useful tool to study the mechanism underlying epileptogenesis. Finally, we expect that genetic studies will lead to a better understanding of the multiple factors involved in the pathophysiology of reflex seizures, and eventually to develop preventive strategies focused on seizure control and therapy optimization.
... gered by a wide variety of external or internal stimuli. Triggers such as flashing lights or visual patterns, somatosensory stimulation, reading, eating, listening to music, thinking, playing chess, answering the telephone, brushing teeth, and exposure to hot water have been reported in the literature (Goossens et al., 1990;Wieser et al., 1997;Michelucci et al., 2004;Zifkin and Inoue, 2004;Ferlazzo et al., 2005;Pittau et al., 2008;Striano et al., 2012;Kumada et al., 2013). The majority of RSs have been already identified on the basis of the stimulus that can cause them. ...
Musicogenic seizure is classified as a rare form of complex reflex seizures. We present a patient with musicogenic seizures from whom invasive recordings were obtained using subdural arrays, as well as hippocampal depth electrodes. Interestingly, this patient had both spontaneous seizures and musicogenic seizures, and they originated from different hippocampi. Due to bilateral independent musicogenic seizures and spontaneous seizures, our patient was not eligible for surgery, but vagal nerve stimulation treatment was almost successful. [Published with video sequence].
... Apart from being a more classical reflex type of response, patients and physicians easily recognize the triggering mechanism. However, sensory stimuli such as listening to music (musicogenic epilepsy) or to a telephone ringing (telephone epilepsy) evoke complex partial seizures with or without secondary generalization, and the time between stimulus and seizure is longer (Wieser et al., 1997, Michelucci et al., 2004. Due to the long time lag and loss of consciousness with amnesia of preceding events, these kinds of reflex seizures are less well recognized. ...
Most patients with epilepsy report that seizures are sometimes, or exclusively, provoked by general internal precipitants (such as stress, fatigue, fever, sleep, and menstrual cycle) and by external precipitants (such as excess alcohol, heat, bathing, eating, reading, and flashing lights). Some patients describe very exotic and precise triggers, like tooth brushing or listening to a particular melody. Nevertheless, the most commonly noticed seizure increasers by far are stress, lack of sleep, and fatigue. Recognized reflex seizure triggers are usually sensory and visual, such as television, discotheques, and video games. Visually evoked seizures comprise 5% of the total of 6% reflex seizures. The distinction between provocative and reflex factors and seizures seems artificial, and in many patients, maybe all, there is a combination of these. It seems plausible that all of the above-mentioned factors can misbalance the actual brain network; at times, accumulation of factors leads then to primary generalized, partial, or secondarily generalized seizures. If the provoking factors are too exotic, patients may be sent to the psychiatrist. Conversely, if the seizure-provoking fluctuating mechanisms include common habits and environmental factors, these may hardly be considered as provocative factors. Awareness of precipitating factors and its possible interactions might help us to unravel the pathophysiology of epilepsy and to change the notion that seizure occurrence is unpredictable. This article provides an overview of the epidemiology, classification, diagnosis, treatment, and especially similarities in the variety of provocative and reflex factors with resulting general hypotheses.
... This process was shown to be inhibited in mice either overexpressing mutant Lgi1 or with heterozygous LGI1 deletion, resulting in persistence of immature retinal axons and aberrant sensory processing [106••]. It was hypothesized that a similar impairment of postnatal maturation of auditory sensory axons may also occur in LGI1-mutated ADLTE patients, providing an explanation to the observation that seizures are triggered by acoustic stimuli in about 25 % of ADLTE cases [82,107]. Overall, the above studies suggest that a localized defect of postnatal development may underlie ADLTE, which is currently the best studied paradigm on non-ion channel genetic epilepsies. ...
Genetic factors are likely to play a major role in many epileptic conditions, spanning from classical idiopathic (genetic) generalized epilepsies to epileptic encephalopathies and focal epilepsies. In this review we describe the genetic advances in progressive myoclonus epilepsies, which are strictly monogenic disorders, genetic generalized epilepsies, mostly exhibiting complex genetic inheritance, and SCN1A-related phenotypes, namely genetic generalized epilepsy with febrile seizure plus and Dravet syndrome. Particular attention is devoted to a form of familial focal epilepsies, autosomal-dominant lateral temporal epilepsy, which is a model of non-ion genetic epilepsies. This condition is associated with mutations of the LGI1 gene, whose protein is secreted from the neurons and exerts its action on a number of targets, influencing cortical development and neuronal maturation.
... Additionally, many types of stimuli have been reported to provoke or aggravate seizures. This heterogeneous group, called the reflex epilepsies, has been reported by a wide variety of seizure-inducing modalities, including music or other auditory stimuli, visual stimuli, and somatosensory stimuli [72][73][74][75][76][77][78][79][80][81]. Even AEDs themselves have been reported to aggravate seizures [82,83]. ...
This study was a prospective, randomized, single-blinded, crossover, placebo-controlled, pilot clinical trial investigating the effect of Mozart's Sonata for Two Pianos (K448) on the frequency of interictal epileptiform discharges (IEDs) from the EEGs of children with benign childhood epilepsy with centrotemporal spikes, or "rolandic" epilepsy. The goal was to demonstrate decreased frequency of IEDs with exposure to K448. Four subjects were recruited and 4-hour awake EEG recordings performed. IED frequency per minute was averaged over each of three epochs per hour. Mean IED count per epoch, standard deviations, and variance were calculated. Only complete waking epochs were analyzed. Two subjects demonstrated sufficient waking IEDs for statistical analysis, consisting of three epochs of K448-related effects. Significant decreases in IEDs per minute (33.7, 50.6, and 33.9%) were demonstrated comparing baseline with exposure to K448, but not to control music (Beethoven's Für Elise).
Reflex epilepsy is a relatively rare form of epilepsy, occurring only in five percent of all cases of this disease. The genetic factors of reflex epilepsy are diverse and, in general, poorly studied. This review examines the main results obtained in recent years in the study of molecular genetic factors of reflex epilepsy, including new data on the mechanisms of genetic regulation in reflex epilepsy caused by triggers such as audio and video stimulation, food consumption, reading, contact with water and hypoxia. The results obtained in studies on animal models and patients using next-generation sequencing technology are presented.
Mutations in the gene encoding syntaxin binding protein 1 (STXBP1) have been implicated in a wide variety of epileptic encephalopathies. Although the recognized phenotypes of patients with STXBP1 encephalopathies have broadened in recent years, no case of reflex seizures, particularly musicogenic seizures, has been reported in the literature. We present an 18‐year‐old woman with STXBP1 encephalopathy and seizures that are stereotypically reproducible in response to a variety of audible stimuli. An 18‐year‐old woman with a history of profound intellectual disability, confirmed STXBP1 genetic defect via genetic testing, and seizures beginning as infantile spasms during childhood, who presented to the epilepsy monitoring unit for seizure characterization. Her mother reported reproducible seizures triggered by a particular cell phone ringtone, music from a certain automobile television commercial and certain beeping alarm sounds. In response, the patient had clinically stereotyped seizures associated with staring, behavioral arrest, followed by eye deviation to the left, tonic stiffening in upper and lower extremities, and labored breathing lasting between 30 s and 2 min. These seizures were reliably reproducible within a few seconds of exposure to the auditory stimulus. During hospitalization, mother played one of the cell phone ringtones known to trigger seizures for the patient, which resulted in induction of a seizure characterized by diffuse electrodecrement, subsequent emergence of frontal‐predominant theta which was followed by progressive diffuse attenuation and semi‐rhythmic slowing over the right posterior quadrant. This is the first case to describe musicogenic or other reflex seizures in a patient with STXBP1 encephalopathy.
Introduction
Aphasic and other language disturbances occur in patients with epilepsy during and after epileptic seizures. Moreover, the interictal language profile in these patients is heterogeneous, varying from normal language profile to impairment in different language functions. The aim of this paper was to critically review the terms and concepts of ictal language alterations.
Material and method
For this review we performed an extensive literature search on the term “epileptic aphasia” and analyzed the semiology and terminology indicating language-associated seizure symptoms. In addition, we give an overview on EEG, etiology, and brain imaging findings and ictal language disorders.
Results
In the literature, a plethora of terms indicates language-associated seizure symptoms. Simultaneous Video-EEG monitoring represents the gold standard to correctly classify ictal versus postictal language disturbances and to differentiate aphasic symptoms from speech automatisms. Different rhythmic and periodic EEG patterns associated with ictal language disturbances are recognized. Cerebral magnetic resonance imaging (cMRI) is essential in the diagnosis of seizures and epilepsy. Brain tumors and acute or remote cerebrovascular lesions are the most frequently reported structural etiologies underlying ictal language alterations. However, it has to be recognized that brain imaging may show alterations being the consequence of seizures itself rather than its cause. Functional brain imaging might be informative in patients with inconclusive EEG and MRI findings. Overall, seizure-associated aphasia is reported to have good lateralizing significance.
Conclusion
Various language disturbances are caused by different types of seizures, epilepsies and underlying etiologies. In the clinical context, simultaneous Video-EEG monitoring facilitates precise classification of ictal versus postictal language alterations and differentiation of aphasic symptoms from speech automatisms.
Reflex seizures represent the 4–7% of all epileptic seizures. Most of these are visually induced seizures (about 1/4000 of the population and about 5% of people with epileptic seizures, with higher prevalence in females and in the adolescence. However, rate widely differs among studies, between 1 and 10%). The multiplication of artificial light stimulations in the modern environment has greatly increased the possibility of clinical expression of this phenomenon [1].
The fact that seizures can be “provoked” has of course been long recognized. The precipitation by light was recorded by Pliny and by Apuleius, and by the nineteenth century, cases of epilepsy induced by stress, startle, sensory stimulation, shock, noise, sexual activity and masturbation, eating, reading, and music, for instance, were well recorded. Following Tissot (1770), most authorities for the next hundred years at least tended to divide the causes of epilepsy into two categories: (a) underlying causes (syn. predisposing causes), and (b) “exciting” or provoking causes (see Chapter 2). Exciting causes were often described in relation to reflex action, and these were systematically explored by Marshall Hall (who coined the term) (Hall 1850), Brown-Séquard, and Hughlings Jackson amongst others. Jackson described a number of provoked seizures, including one case in which seizures were induced by a tap on the head. Gowers (1885) described cases of epileptic seizures induced by “light, voluntary movement and sudden muscular tension.” In experimental animals, seizure provocation by touch was first demonstrated by Amantea (1921), by light by Clementi (1929), and by noise by Morgan and Morgan (1939). Pavlov's demonstration on conditional reflexes stimulated further research and Gastaut described conditioned-reflex epilepsy in 1956. Gastaut and his colleagues also made early studies of photic-induced seizures, and the first experiments in the photosensitive baboon, Papio papio, were made by Naquet in Gastaut's unit in 1956 (Beaumanoir 1995). In any book dealing with etiology, the provoking causes of seizures are important.
Definitions Auditory-induced epilepsy is a particular clinical condition in which epileptic seizures are induced by an acoustic stimulus, which is often unexpected and varies from a simple noise to more structured sounds. From a nosological point of view, these conditions usually encompass several different entities; consequently the term “auditory-induced epilepsy” is used to refer not to a specific epileptic syndrome, but to those clinical contexts in which seizures evoked by any acoustic trigger recur as the predominant epileptic manifestation. Some of these conditions, such as those rare syndromes in which seizures are precipitated by specific sensory stimulations, may be included in the general chapter on reflex epilepsy (Zifkin and Zatorre 1998; Engel 2001). As in other forms of reflex epilepsy, any attempt to classify auditory-induced seizures on the basis of the stimulus type is likely to be unsatisfactory and questionable. Indeed, a “pure” acoustic trigger does not exist in the majority of cases, seizures usually being elicited by a complex and highly elaborate stimulus that involves not only the acoustic system, but also other components (e.g., somatosensory, vegetative, psychic–cognitive) as well as their related underlying structures. In a highly simplified, functional classification, auditory-induced (or audiogenic) reflex epilepsy may be subdivided in two different subtypes (Avanzini 2003) The first, more “simple” subtype, is “startle epilepsy,” a condition in which seizures are related to a normal startle reflex that evokes a secondary pathological abnormality; the second, more “complex” subtype, is a condition in which seizures are usually related to more integrated stimuli (such as music) that induce an ictal cortical response.
In 1989 the International Classification of Epileptic Syndromes recognized only three established forms (BECTS, CEOP and PRE) of Idiopathic Focal Epilepsies (IFE). Less than 15 years later, many other familial (monogenic, usually autosomal dominant) and non-familial (sporadic) forms of IFE have been identified, and other syndromes are in development. Panayiotopoulos suggests an unified view for benign childhood focal seizures (the BCSSS concept); the "splitter's approach" of this report searches for differences rather than similitudes among IFE. A special emphasis is dedicated to reflex seizures in this chapter.
Recent changes in the understanding and classification of reflex seizures have fuelled a debate on triggering mechanisms of seizures and their conceptual organization. Previous studies and patient reports have listed extrinsic and intrinsic triggers, albeit their multifactorial and dynamic nature is poorly understood. This paper aims to review literature on extrinsic and intrinsic seizure triggers and to discuss common mechanisms among them. Among self-reported seizure triggers, emotional stress is most frequently named. Reflex seizures are typically associated with extrinsic sensory triggers; however, intrinsic cognitive or proprioceptive triggers have also been assessed. The identification of a trigger underlying a seizure may be more difficult if it is intrinsic and complex, and if triggering mechanisms are multifactorial. Therefore, since observability of triggers varies and triggers are also found in non-reflex seizures, the present concept of reflex seizures may be questioned. We suggest the possibility of a conceptual continuum between reflex and spontaneous seizures rather than a dichotomy and discuss evidence to the notion that to some extent most seizures might be triggered.
Epileptic seizures can arise in a’ spontaneous’ unpredictable fashion with no detectable precipitating factors, or they can
be provoked by certain recognisable stimuli.
The term reflex epilepsy is commonly used when seizures are triggered reproducibly and instantaneously by some well-defined sensory or cognitive stimulus. In a stricter sense it signifies that a patient has seizures exclusively in response to such triggers. The many varieties of reflex epilepsies can be divided roughly into precipitation by simple versus complex stimuli. Reflex seizures occur in both idiopathic and symptomatic epilepsies, but more frequently in the former. Therapeutically, patients can use awareness of sensitivity to a specific trigger for self-control or avoidance of seizures. Scientifically, through clinical analysis, EEG, and functional imaging, these phenomena provide unique insights into ictogenesis in human epilepsies. At present, the best studied variants are photosensitivity, language-induced orofacial reflex myocloni, and musicogenic seizures. The findings indicate that reflex epileptic mechanisms involve complex neuronal networks that, at least in the idiopathic epilepsies, seem to use pre-existing functional-anatomical networks that normally subserve physiological functions. Intriguingly, triggers of reflex seizures in some instances can also inhibit seizures, even in the same patient, depending on the timing of the stimulation. In consequence, the concept of reflex epilepsies is about to evolve into a broader concept of epilepsies with external modification of ictogenesis.
Reflex seizures and epilepsies represent an ancient human model to understand basic mechanisms of epilepsy. The increase of light stimulation makes this issue extremely actual and interesting. In addition, a lot of observations show the frequent occurrence of provoked seizures in malformations of cortical development and in recently defined conditions such as familial or sporadic lateral temporal epilepsy. Advances in morphological and functional neuroimaging techniques, and the possibility of their fusion with EEG (e.g., fMRI-EEG co-registration) offer a unique non-invasive opportunity to investigate cortical areas and brain networks involved in cerebral functions and in epileptic discharges.
To describe the clinical and genetic findings of four families with autosomal dominant lateral temporal epilepsy.
A personal and family history was obtained from each affected and unaffected subject along with a physical and neurologic examination. Routine electroencephalography and magnetic resonance imaging (MRI) studies were performed in almost all patients. DNAs from family members were screened for LGI1 mutations. The effects of mutations on Lgi1 protein secretion were determined in transfected culture cells.
The four families included a total of 11 patients (two deceased), six of whom had lateral temporal epilepsy with auditory aura. Age at onset was in the second decade of life; seizures were well controlled by antiepileptic treatment and MRI studies were normal. We found two pathogenic LGI1 mutations with uncommonly low penetrance: the R136W mutation, previously detected in a sporadic case with telephone-induced partial seizures, gave rise to the epileptic phenotype in three of nine mutation carriers in one family; the novel C179R mutation caused epilepsy in an isolated patient from a family where the mutation segregated. Another novel pathogenic mutation, I122T, and a nonsynonymous variant, I359V, were found in the two other families. Protein secretion tests showed that the R136W and I122T mutations inhibited secretion of the mutant proteins, whereas I359V had no effect on protein secretion; C179R was not tested, because of its predictable effect on protein folding.
These findings suggest that some LGI1 mutations may have a weak penetrance in families with complex inheritance pattern, or isolated patients, and that the protein secretion test, together with other predictive criteria, may help recognize pathogenic LGI1 mutations.
Assessment of the penetrance of disease-causing mutations is extremely important for developing clinical applications of gene discovery, such as genetic testing and counseling. Mutations in the leucine-rich, glioma inactivated 1 gene (LGI1) have been identified in about 50% of families with autosomal dominant partial epilepsy with auditory features (ADPEAF), but estimates of LGI1 mutation penetrance have ranged widely, from 50 to 85%. The current study aimed to provide a more precise estimate of LGI1 mutation penetrance.
We analyzed data from all 24 previously published ADPEAF families with mutations in LGI1. To estimate penetrance, we used the information from the published pedigree figures to determine the proportion of obligate carriers who were affected. We assessed whether penetrance was associated with the total number of affected individuals in each family, or mutation type (truncating or missense) or location within the gene. We also compared penetrance in males and females, and among different generations within the families.
Overall penetrance was 67% (95% CI 55-77%), and did not vary according to mutation type or location within the gene. Penetrance was greater in families with more affected individuals, but this trend was not significant. Penetrance did not differ by gender but increased with advancing generation, probably because of limited information about early generations.
Our results suggest that about two-thirds of individuals who inherit a mutation in LGI1 will develop epilepsy. This probably overestimates the true penetrance in the population because it is based on data from families containing multiple affected individuals.
Epilepsy can affect perception. Ictal perceptual experiences are common, but interictal perceptual function may also be affected. This article reviews the English-language literature on interictal perceptual disturbances in epilepsy. Although most studies report impaired perceptual ability, heightened sensitivity has also been described. There is a compelling, though not absolute, correlation between affected sensory modality and underlying epilepsy syndrome. Olfaction is clearly affected in temporal lobe epilepsy, while visual information processing is disturbed in occipital lobe epilepsy. The cause of interictal perceptual dysfunction is unknown, but propagating epileptiform discharges may play a role. The presence of specific perceptual disturbances in focal epilepsy syndromes is consistent with the view that epilepsy is a network disease, with the potential to affect neural circuits distant from the seizure focus. The use of thoughtfully selected psychophysical perceptual tasks may provide additional insight into the cognitive impact of different epilepsy syndromes and of ablative epilepsy surgery.
Reflex seizures are evoked by a specific afferent stimulus or by activity of the patient and are divided into those characterized by generalized seizures and those principally manifested by focal seizures. Reflex epilepsies are syndromes in which all epileptic seizures are precipitated by sensory stimuli. Three categories of reflex seizures encountered clinically include pure reflex epilepsies, reflex seizures that occur in generalized or focal epilepsy syndromes that are also associated with spontaneous seizures, and isolated reflex seizures occurring in situations that do not necessarily require a diagnosis of epilepsy. Generalized reflex seizures are precipitated by visual light stimulation, thinking, and decision making. These seizures usually respond to valproate treatment. Numerous triggers can induce focal reflex seizures. The triggers include reading, writing, other language functions, startle, somatosensory stimulation, proprioception, auditory stimuli, immersion in hot water, eating, and vestibular stimulation. The classification and characteristics of reflex seizures and epilepsies are described in this review. Findings on EEG and advanced neuroimaging in the reflex seizures and epilepsies, treatment and preventive options, and animal models and mechanisms are also discussed.
Lafora disease (LD) can be diagnosed by skin biopsy, but this approach has both false negatives and false positives. Biopsies of other organs can also be diagnostic but are more invasive. Genetic diagnosis is also possible but can be inconclusive, for example, in patients with only one heterozygous EPM2A mutation and patients with apparently homozygous EPM2B mutations where one parent is not a carrier of the mutation. We sought to identify occult mutations and clarify the genotypes and confirm the diagnosis of LD in patients with apparent nonrecessive disease inheritance. We used single nucleotide polymorphism, quantitative PCR, and fluorescent in situ hybridization analyses. We identified large EPM2A and EPM2B deletions undetectable by PCR in the heterozygous state and describe simple methods for their routine detection. We report a coding sequence change in several patients and describe why the pathogenic role of this change remains unclear. We confirm that adult-onset LD is due to EPM2B mutations. Finally, we report major intrafamilial heterogeneity in age at onset in LD.
The most frequent precipitants of photic- or pattern-induced seizures are television and discotheque lighting effects. Seizure induction by reflection of bright sunlight on water surfaces has also been reported. We report a patient with seizures induced by the sight of moving water in the absence of bright sunlight. [Published with video sequences].
This PET study has revealed the neural system involved in implicit face, proper-name and object name processing during an explicit visual 'same' versus 'different' matching task. Within the identified system, some areas were equally active irrespective of modality (faces or names) or type of stimuli (famous and non-famous) while other areas exhibited differential effects. Our findings support the hypothesis that faces and names involve differential pre-semantic processing prior to accessing a common neural system of stored knowledge of personal identity which overlaps with the one associated with object knowledge. The areas specialized for the perceptual analysis of faces (irrespective of whether they are famous or non-famous) are the right lingual and bilateral fusiform gyri, while the areas specialized for famous stimuli (irrespective of whether they are faces or names) spread from the left anterior temporal to the left temporoparietal regions. One specific area, the more lateral portion of the left anterior middle temporal gyrus, showed increased activation for famous faces relative to famous proper names and for famous proper names relative to common names. The differential responsiveness of this region when processing familiar people suggests functional segregation of either personal attributes or, more likely, the demands placed on processes that retrieve stored knowledge when stimuli have highly similar visual features but unique semantic associations.
Autosomal dominant lateral temporal epilepsy (EPT; OMIM 600512) is a form of epilepsy characterized by partial seizures, usually preceded by auditory signs. The gene for this disorder has been mapped by linkage studies to chromosomal region 10q24. Here we show that mutations in the LGI1 gene segregate with EPT in two families affected by this disorder. Both mutations introduce premature stop codons and thus prevent the production of the full-length protein from the affected allele. By immunohistochemical studies, we demonstrate that the LGI1 protein, which contains several leucine-rich repeats, is expressed ubiquitously in the neuronal cell compartment of the brain. Moreover, we provide evidence for genetic heterogeneity within this disorder, since several other families with a phenotype consistent with this type of epilepsy lack mutations in the LGI1 gene.
We examined the modality of EEG activation by various kinds of acoustic stimulation in a middle‐aged Japanese female with epilepsy. Paroxysmal discharges were triggered in the right frontal area (F4) by verbal stimulation. For the activation of EEG, concentration of attention on the stimulation was essential; therefore paroxysmal discharges were triggered most easily by verbal stimuli when someone spoke to the patient directly. Stronger responses than usual were triggered by specific words, and apparently reflected the interest and concern of the patient. The latency from stimulation to paroxysmal discharges ranged from 230 to 1,300 msec, suggesting that the responses may have been a function of the perception and recognition of acoustic stimuli. “Heard‐word epilepsy” or “Anges‐prochene Epilepsie” is suggested in this case.
RÉSUMÉ
Les auteurs ont étudié les modalites d'activation de L'EEG par différentes sortes de stimulations acousti‐ques chez une femme épileptique japonaise d'âge moyen. Les paroxysmes étaient provoqués sur L'aire frontale droite (F4) par la stimulation verbale, mais 1'activation de L'EEG dépendait essentiellement de la concentration de L'attention sur le stimulus. C'est pourquoi les paroxysmes étaient plus aisément provo‐qués par les stimuli verbaux lorsque quelqu'un parlait directement à la malade. Des réponses plus impor‐tantes que la moyenne étaient déclenchées par des mots spécifiques concernant plus particulièrement la malade. La latence entre le stimulus et la réponse paroxystique se situait entre 230 msec et 1,300 msec. Les réponses survenaient probablement au niveau de perception et de reconnaissance des stimuli acousti‐ques. Les auteurs suggeGrent d'accorder le nom d'épilepsie des mots entendus“à des cas de ce type.
RESUMEN
En una mujer japonesa de edad media, que padecia epilepsia se ha examinado el modo de activación del EEG con varios tipos de estimulos acusticos. La estimulación verbal produjo descargas paroxisticas en la región frontal derecha (F4), siendo esencial la con‐centración de la atención en el estimulo para que se produjera la activación del EEG. Por esta razón las descargas paroxísticas se consiguen más facilmente si el estimulo verbal se realiza hablando directamente al paciente. Palabras especificas desencadenaron respuestas más claras y éstas coincidieron con un mayor interés y preocupación del paciente. Las latencias entre el estimulo y las descargas paroxísticas oscilaron entre los 230 y los 1,300 milisegundos. Las respuestas probablemente ocurren a nivel de las percepción y reconocimiento de los estímulos acústicos. En este caso se sugiere el término de “epilepsía de la palabra oida.”
ZUSAMMENFASSUNG
Wir untersuchten an japanischen Frauen mittleren Alters mit Epilepsie die durch verschiedene Arten akustischer Stimulation hervorgerufenen EEG‐Aktivi‐erungen. Verbale Stimulation triggerte paroxysmale Entladungen im Frontalbereich rechts (F4). Für die Aktivierung des EEG war Konzentration auf den Stimulus erforderlich; daher wurden paroxysmale Entladungen am ehesten ausgelöst durch unmittelbare Ansprache der Patienten. Deutlichere EEG‐Antwor‐ten als gewöhnlich konnten durch jeweils bestimmte Worte und solche, die für die Patientin von Interesse oder Wichtigkeit waren, ausgelöst werden. Die Latenz zwischen Stimulation und Paroxysmus lag zwischen 230 und 1,300 msec. Wahrscheinlich resultierten die EEG‐Antworten aus der Ebene der Perzeption und Erkennung der akustischen Stimuli. Fur diese Fälle sind die Begriffe “Heard‐word epilepsy” oder “Angesprochene Epilepsie” als zutreffend vorzusch‐lagen.
Cerebral metabolic responses to verbal and nonverbal auditory stimuli were examined, using 18F-fluorodeoxyglucose and positron CT. Twenty right-handed subjects were studied in both control and stimulated states. Monaural verbal stimuli produced diffuse metabolic changes in the left hemisphere and bilateral activation of the transverse and posterior temporal lobes. Monaural nonverbal stimulation with chords demonstrated bilateral parietotemporal activations and diffuse right greater than left frontotemporal asymmetries. Tone sequence pairs presented monaurally produced asymmetries that differed by the subject's analysis strategy. Nonanalytical, musically naive subjects had right greater than left frontotemporal asymmetries, whereas analytic or musically sophisticated subjects had an absence of right greater than left relative hypermetabolism and demonstrated left greater than right temporal asymmetries. Binaural presentation of a factual story and music produced diffuse bilateral activations of the temporal and frontal cortex. Known anatomic asymmetries of the perisylvian cortex were revealed by high-resolution tomography. These results demonstrate that metabolic responses to auditory stimuli are determined by the content of the stimulus and the analysis strategy of the subject rather than the side of stimulation. The results also demonstrate the capacity of functional imaging techniques to study the physiologic cerebral mechanisms underlying auditory processing.
Magnetic resonance imaging methods recently demonstrated regional cerebral signal changes in response to limb movement and visual stimulation, attributed to blood flow enhancement. We studied 5 normal subjects scanned while listening to auditory stimuli including nonspeech noise, meaningless speech sounds, single words, and narrative text. Imaged regions included the lateral aspects of both hemispheres. Signal changes in the superior temporal gyrus and superior temporal sulcus were observed bilaterally in all subjects. Speech stimuli were associated with significantly more widespread signal changes than was the noise stimulus, while no consistent differences were observed between responses to different speech stimuli. Considerable intersubject variability in the topography of signal changes was observed. These observations confirm the utility of magnetic resonance imaging in the study of human brain structure-function relationships and emphasize the role of the superior temporal gyrus in perception of acoustic-phonetic features of speech, rather than processing of semantic features.
Autosomal dominant partial epilepsy with auditory features (ADPEAF) has been identified as a distinct genetic syndrome. Several families have been described linked to chromosome 10q24, which carries mutations in the LGI1 gene. We report a small new pedigree with partial epilepsy with auditory symptoms. We performed a detailed clinical study of the family, constructed an extended pedigree comprising 106 individuals, and obtained blood samples for genetic analysis. Individuals with seizures also underwent neurophysiological and neuroradiological investigations. Genetic analysis was performed with six microsatellite markers spanning to the critical region of chromosome 10q24. Mutation analysis of the coding sequence of LGI1 was performed in two patients. Five members of the family in generation IV had seizures. Three individuals had auditory auras, followed by generalised seizures in two and brief loss of contact in one, one had nocturnal tonic-clonic seizures with an EEG suggestive of right temporal lobe onset, and one only had febrile seizures. In addition, a deceased woman was said to have had seizures. Haplotype analysis of this region of chromosome 10q24 failed to disclose a common haplotype in affected family members and no disease-associated mutations were detected in the LGI1 gene, suggesting that this locus is not associated with the disease in our family. Our small sample with partial epilepsy with auditory symptoms, clinically resembles previously described ADPEAF families. However, the low number of patients is compatible with either autosomal dominant or other inheritance patterns. In the case of the former, the lack of segregation with 10q24 suggests that a second locus is involved in the aetiology of ADPEAF; in the latter, an epileptic syndrome also characterized by auditory features, but distinct from ADPEAF, could be transmitted in this family.
[corrected] To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE).
A personal and family history was obtained from each affected and unaffected member, along with a physical and neurologic examination. Routine and sleep EEGs, computed tomography (CT), or magnetic resonance imaging (MRI) were performed in almost all the patients. DNAs from family members were typed with several microsatellite markers localized on either side of LGI1 at 10q24 and screened for LGI1 mutations.
The seven families included a total of 34 affected individuals (10 deceased). The age at onset ranged between 8 and 50 years (average, 22 years). Twenty-six patients had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Less frequent ictal symptoms were visual, psychic, or aphasic seizures, the latter occurring in isolation in one family. The attacks were rare and well controlled by antiepileptic drug treatment but recurred after drug discontinuation. Interictal EEGs were usually unrevealing. MRI or CT scans were negative. Analysis of LGI1/Epitempin exons failed to show mutations in three pedigrees. Linkage analysis strongly suggested exclusion of linkage in one of these families. We found two novel missense mutations, a T-->C substitution in exon 6 at position 598, and a T-->A transition in exon 8 at position 1295, the latter being detected in a family with aphasic seizures.
Our data confirm the inclusion of aphasic seizures within the ADLTE clinical spectrum, suggest the existence of locus heterogeneity in ADLTE, and provide new familial cases with LGI1 missense mutations associated with the disease.
Functional magnetic reso-nance imaging of human auditory cortex
- Rao Binder Jr
- Sm
- Ta Hammeke
Binder JR, Rao SM, Hammeke TA, et al. Functional magnetic reso-nance imaging of human auditory cortex. Ann Neurol 1994;35:662– 72.
Reflex epilepsies and reflex seizures: advances in neurology. Philadelphia: Lippincott-Raven
- Zifkin Bg
- F Andermann
- A Beaumanoir
In: Zifkin BG, Andermann F, Beaumanoir A, et al., eds. Reflex epilepsies and reflex seizures: advances in neurology. Philadelphia: Lippincott-Raven, 1998:75:5–13.
Hearing-induced seizures Epileptic seizures: pathophysiology and clinical semiology
- Rosenow F Luders
- Ho
Rosenow F, Luders HO. Hearing-induced seizures. In: Luders HO, Noachtar S, eds. Epileptic seizures: pathophysiology and clinical semiology. New York: Churchill Livingstone, 2000:580– 4.
Epileptic seizures: pathophysiology and clinical semiology
- F Rosenow
- H O Luders
Rosenow F, Luders HO. Hearing-induced seizures. In: Luders
HO, Noachtar S, eds. Epileptic seizures: pathophysiology and
clinical semiology. New York: Churchill Livingstone, 2000:580-4.