doi:10.1684/epd.2011.0475
forms, lack a molecular diagnosis. Autonomic dys- Proprioception-induced seizures are usually brief function, hand stereotypies, and scoliosis often tonic seizures or simple partial attacks induced by appear, and up to 75% of RTT patients present active or passive repetitive limb movements. Self- seizures, which influences social interaction and induced seizures may be associated with compulsive motor skills. Epilepsy patterns are different among proprioceptive self-provocation in cases of brain patients with the same mutations, and may change lesions, non-ketotic hyperglycaemia and Rasmussen’s during their follow-up. In classic RTT patients, as encephalitis. in other similarly disabled children, it is sometimes We report three Rett patients with reflex seizures. difficult to differentiate epileptic seizures from other abnormal movements (such as stereotypies), vacant spells caused by breathing disturbances (apnoeas or Case reports Valsalva contraction), or “voluntary” loss of social contact, which may lead to treatment of non-epileptic For Patient 1 (an 18-year-old girl), the clinical cri- paroxysms with antiepileptics. Furthermore, electro- teria for the congenital form of RTT (Neul et al., graphic status epilepticus in these patients is some- 2010) were fulfilled, without pathogenic mutations in times only manifested as a change of mood, or as Rett-related genes (MECP2, CDKL5 and FOXG1). Par- a slight worsening of their apraxic gait, and can tial motor seizures and infantile spasms started at remain unidentified unless parents or physicians seven months. Interictal EEG showed bursts of dif- consider this possibility. It is therefore very important fuse slow waves and multifocal sharp waves, without to identify epileptic seizures in order to undertake the hypsarrhythmia. Seizures were controlled with val- most suitable therapy to prevent clinical deterioration. proate (discontinued after 12 months). Despite severe To the authors’ knowledge, no pressure or eating- global delay, she acquired autonomous apraxic gait by triggered seizures have previously been described in three years of age. Brain magnetic resonance imaging Rett, although myoclonic reflex seizures have been (MRI) was normal. Hand stereotypes appeared at eight reported in one patient with a mutation in FOXG1 years of age. She remained seizure-free until 10 years (Bahi-Buisson et al., 2010). Other types of reflex old, but subsequently presented frequent generalised seizures have been described in different disabling tonic-clonic seizures and absences, with occasional disorders, such as startle reflex epilepsy in Down akinetic seizures. Interictal EEG showed subconti- Syndrome and hemiparetic patients (Panayiotopoulos, nuous high-voltage bilateral frontal sharp waves. 2005). Epilepsy was controlled at 11 years old with val- Reflex seizures were first described by Boudouresques proate and ethosuximide. Five years later, eating reflex and Gastaut (1953) and may accompany focal or seizures appeared. Upon the fourth spoonful, a clus- generalised epileptic syndromes. In reflex epilepsy, ter of seizures occurred, consisting of breakdown of every seizure is precipitated by a trigger, which social contact, sometimes followed by axial tone loss may involve vision, proprioception, eating, or other (recurrent head falls). Other episodes included upper stimuli. Although the physiopathology is not yet well limb recurrent tonic extension with neck flexion. Once understood, stimuli seem to activate the recruitment the cluster had finished, the patient continued eat- of an epileptogenic group of neurons, which may ing normally. Initially, this occurred at the beginning be registered as a seizure on EEG. Diffuse corti- of some meals, but became more frequent over time cal hyperexcitability is frequently present, such that and was not modified by the type of spoon, food, focal seizures often become secondarily generalised plate, caregiver or tablecloth, or by emotional stress. (Rémillard et al., 1998). Interictal EEG showed brief discharges over the central Eating-triggered seizures, with a prevalence of 1/1,000- and frontal areas (figure 1); reflex tonic seizures were 2,000 epileptic patients (Ganga et al., 1988), may be confirmed using video-EEG and polygraphy record- related to one or several different parts of the meal; ings when the patient was asked to eat in a seated the trigger is stereotyped for each patient and leads to position (figure 2). Levetiracetam did not improve partial motor seizures or automatisms. Symptomatic reflex seizures. Low doses of diazepam before meals epilepsy may coexist and EEG may show epilep- did not reduce frequency or intensity. At 17 years tic activity in the temporo-limbic or suprasylvian old, after an upper respiratory tract infection treated areas. Seizures can be triggered by combinations of with amoxicillin/clavulanic acid, levetiracetam dose stimuli and can sometimes be aborted by sudden was reduced and the patient’s reflex seizures (both manoeuvres, probably related to subcortical involve- atonic and tonic) disappeared. At present, her genera- ment. Brain tumours, dysplasias and opercular lised epilepsy remains under control with valproate, syndrome must be ruled out when confronting eating levetiracetam and ethosuximide, and reflex seizures reflex seizures (Loreto et al., 2000). have not reappeared in the last six months.
390 Epileptic Disord, Vol. 13, No. 4, December 2011 Eating and proprioception reflex seizures
40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 Fp1-F3
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Figure 1. Interictal EEG of Patient 1 showing discharges over the midline (Cz), central, and frontal electrodes.
For Patient 2 (a 14-year-old girl), the clinical diagnostic computerised tomography (CT) was normal. Gene- criteria for classic RTT were met, with severe cognitive ralised tonic-clonic seizures started at four years disability and without mutations in Rett-related genes. and six months of age, followed shortly by partial Social withdrawal appeared at 13 months, hand stereo- motor seizures. Interictal EEG showed diffuse slow types at two years and six months, and loss of acquired background activity and multifocal independent spike- language by three years. Her hand skills worsened, and-wave complexes, and epilepsy was controlled but did not disappear. Brain MRI was normal. She pre- with carbamazepine. At seven years and six months, sented partial motor seizures at five years old, followed partial epilepsy relapsed and after various combi- by absences, which were controlled with valproate. nations of drugs, seizures were finally controlled Four years later, she presented with proprioceptive with carbamazepine alone. Eight years later, she pre- reflex seizures, self-triggered by rhythmic pressure sented proprioception reflex seizures, self-provoked on her left hand, which led to loss of social contact by rhythmic pressure on her hands; atonic seizures and tone, and backward falls. She self-provoked the were triggered while holding onto the table and falling attacks, taking someone’s hand or holding onto a table. laterally. Anxiety or stress increased their frequency. The episodes were influenced by stress, and she could Various EEG records were obtained, but the patient prevent them at the beginning if she was asked to. Her did not reproduce the seizures while monitored. She reflex seizures were modified over the years: from the did self-induce a seizure during consultation, after age of 13, before going to sleep, she would sit on the firmly holding the table, as described above. Her partial edge of the bed and rub the top of the bed in order epilepsy remained under control with carbamazepine to trigger a loss of social contact and fall onto a mat- and reflex seizures persisted, although these were tress. Interictal EEG showed diffuse slow background infrequent into adulthood. activity,multifocal spike-and-wave complexes and gen- eralised spike-and-wave discharges. Although several EEG records were obtained, the patient never repro- Discussion duced the reflex seizures while monitored. However, during both home videos and neurology consultation, Epilepsy is frequent in RTT patients and affects 75% of she presented the above-described episodes. the patients of the Spanish RTT database. Only 1% of Patient 3 (a 22-year-old woman) with classic Rett, epileptic Rett patients present reflex seizures, less than with MECP2 mutation c.880C>T/ p.Arg294Stop and the 4-7% reported among the general epileptic popu- X-chromosome inactivation pattern 59:41, presented lation (Panayiotopoulos, 2005), but it is possible that a slight psychomotor delay during the first year of some patients remain undiagnosed. Reflex seizures life with social withdrawal by 20 months, followed in our patients appeared after both generalised and by instauration of severe cognitive disability. Brain partial epilepsy.
Epileptic Disord, Vol. 13, No. 4, December 2011 391 A. Roche Martínez, et al.
Export mark EEG - VIDEO 19 20 21 22 23 CRISIS 25 26 27 28 29 30 31 32 33 34 35 36 37 Fp1-F3
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Export mark EEG - VIDEO CRISIS 40 42 44 46 CRISIS 50 52 54 56 58 0 CRISIS 4 6 8 10 12CRISIS 14 16 18 20 CRISIS 24 26 28 30 3
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Figure 2. Ictal EEG of Patient 1. Polygraphic electrodes placed at para-vertebral cervical muscles showing the disappearance of the previous interictal epileptiform abnormalities immediately at the beginning of food intake. Ictal EEG shows a generalised high-voltage slow wave component, which was sometimes preceded by epileptiform abnormalities. Cephalic and axial loss of tone was associated with a peak of this slow component, followed by an event with rhythmic sharp waves of low or medium amplitude. Polygraph recording revealed sudden interruption of the electromyographic (EMG) potentials; this EMG silencing was more evident when the seizures were more prolonged (400 msec). A total of 12 seizures were registered; generalised high-voltage slow-wave activity was observed on the EEG following each seizure.
Mutations in MECP2, CDKL5 or FOXG1 genes have diagnostic criteria), only one had a molecular diag- been identified in 70% of the Spanish database nosis. Reflex epilepsy among Spanish Rett patients patients. Although the three patients were clinically without mutations (2/123) is more prevalent than in characterised as RTT patients (one congenital variant those with mutations in any of the Rett-related genes and two classic forms, following the recently revised (1/423), with a ratio of almost 7:1. The molecular and
392 Epileptic Disord, Vol. 13, No. 4, December 2011 Eating and proprioception reflex seizures
biochemical pathways involved in neuronal migration duce in severely disabled or uncooperative children. and maturation are currently under study in these RTT Video recording (at home or at consultation) can be a patients. useful tool to identify reflex seizures. Eating-triggered seizures are rare. They can be sim- Response to antiepileptics is poor in reflex seizures, ple or complex partial seizures, with or without although non-reflex epilepsy was controlled in our secondary generalisation. Physiopathological mecha- patients. Both patients with self-provoked seizures nisms involve oral proprioception, emotional and were controlled with one antiepileptic drug (valproate digestive organ stimuli, as well as psychological infe- or carbamazepine), but the patient with eating reflex rences. Clinical control is difficult because avoidance epilepsy remains under triple therapy. of stimulus is not always possible. Some patients Risperidone reduced our patients’ anxiety levels with may improve by changing the context of food, or partial or good response and may thus help to reduce administrating benzodiazepines (Ganga et al., 1988) or self-provoked attacks related to stress. However, avoid- clobazam before meals (which was of no use in our ing the trigger remains the best treatment, although patient). Other patients have shown some improve- this is not always possible. ment after vagal nerve stimulation (Cukiert et al., 2010). Our patient presented “akinetic-tonic seizures”, con- Disclosure. firmed by video-EEG recording, while other groups This study was supported by a pre-doctoral grant from the Sant observed a series of tonic spasms and both generalised Joan de Dèu Foundation (PR004) for Rett Syndrome. and focal seizures. Previous non-reflex epilepsy could influence this variability. References Afferent information in an “abnormal” sensorimo- tor cortex may provoke an epileptic discharge and Ahuja GK, Pauranik A, Behari M, Prasad K. Eating epilepsy.J either a focal or generalised seizure. Our patients with Neurol 1988; 235: 444-7. proprioception reflex seizures presented with spon- Bahi-Buisson N, Nectoux J, Girard B, et al. Revisiting the phe- taneous seizures at around five years old (the typical notype associated with FOXG1 mutations: two novel cases of age for epilepsy onset in RTT); reflex seizures appeared congenital Rett variant. Neurogenetics 2010; 11: 241-9. between four and eight years afterwards. A delay of Boudouresques J, Gastaut H. Épilepsie temporale réflexe five years was also previously observed (Ahuja et al., chez un jeune enfant. Rev Neurol (Paris) 1953; 89: 155-7. 1988), which reinforces the hypothesis of reflex seizure development in a “hyperexcitable” brain, such as in Cukiert A, Mariani PP, Burattini JA, et al. Vagus nerve stimu- lation might have a unique effect in reflex eating seizures. RTT patients. Epilepsia 2010; 51: 301-3. It remains intriguing why some patients with proprio- ception reflex seizures provoke an attack. This may Ganga A, Sechi GP, Porcella V, Traccis S, Rosati G, Agnetti V. Eating seizures and distraction-arousal functions. Eur Neurol bring secondary benefits or induce a seizure-free pos- 1988; 28: 167-70. tictal period. Our two patients appeared happy before self-provocation and upset when asked not to do so. Guerrini R, Genton P, Dravet C, et al. Compulsive somatosen- They were able to abort seizures at the beginning sory self-stimulation inducing epileptic seizures. Epilepsia 1992; 33: 509-16. of their self-provocation. Guerrini’s group observed stereotyped behaviour, as in Rett patients (eg. rocking, Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syn- limb rotation, tapping, etc), in three grown-up males, drome of autism, dementia, ataxia and loss of purposeful some years before the onset of reflex propriocep- hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol 1983; 14: 471-9. tive seizures (Guerrini et al., 1992). This co-occurrence of stereotypies and self-induced seizures could be Loreto V, Nocerino C, Striano P, D’Aulos F, Boccelia P, Striano explained as a relief of tension and anxiety, and escape S. Eating epilepsy. Heterogeneity of ictal semiology: the role from a disturbing or an overexciting situation. of video-EEG monitoring. Epileptic Disord 2000; 2: 93-8. Reactions of patients with severe mental disability are Neul JL, Kaufmann WE, Glaze DG, et al. RettSearch often difficult to interpret and epileptic Rett children Consortium. Rett syndrome: revised diagnostic criteria and are sometimes misdiagnosed: respiratory or stereo- nomenclature. Ann Neurol 2010; 68: 944-50. typed events may mimic seizures and seizures may be Panayiotopoulos CP. The Epilepsies: Seizures, Syndromes described as vacant spells. EEG with video and poly- and Management. Chipping Norton (Oxfordshire, UK): graph recording with the suspected trigger is very Bladon Medical Publishing, 2005. http://www.ncbi.nlm.nih. useful to confirm the diagnosis of reflex seizures. How- gov/books/NBK2596/. ever, self-induced seizures depend on the patient’s Rémillard GM, Zifkin BG, Andermann F. Seizures induced by mood and cooperation and can be difficult to repro- eating. Adv Neurol 1998; 75: 227-40.
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