Clinical manifestations

Presentation and course

Patients with startle epilepsy are mainly children with long-standing static cerebral lesions and learning disabilities (02; 50; 03; 39; 48; Tibussek and Schmidt 2010; 60). Typically, onset is in infancy and childhood or early adolescence (5 months to 16 years) and exceptionally in adulthood (43). Both sexes are equally affected.

Startle seizures are induced by sudden and unexpected stimuli. The startle (unexpected and sudden presentation of the stimulus) is the provoking factor although, rarely, patients may be specifically sensitive to one sensory modality. Sudden noise is the main triggering stimulus, but somatosensory and, less often, visual stimuli also effectively trigger seizures in some patients. The unexpected nature of the stimulus rather than the sensory modality is the distinguishing feature. Habituation to repetitive stimulation occurs. Startle epilepsy associated with gait-induced seizures may occur (49).

The seizures are frequent, usually lasting less than 30 seconds, and consist of a startle response followed by a brief but characteristic tonic phase, which is usually asymmetric (02; 50; 03; 39; 48; Tibussek and Schmidt 2010; 60). A video of a recorded startle seizure can be seen at the following site:https://www.youtube.com/watch?v=mIOt_KCeIHE.

Many subjects fall, and clonic jerks may occur. Injury is common when the seizures occur in patients who are standing or able to fall while seated, or while they are in bathtubs or similar risky locations. In hemiparetic patients, the seizure starts with flexion and abduction of the paretic arm and extension of the ipsilateral leg and rapidly involves the contralateral side. Concurrent symptoms, such as marked autonomic manifestations, automatisms, laughter, and jerks, may occur. Less commonly, startle-induced seizures may be atonic, tonic-myoclonic, or myoclonic, particularly in patients with cerebral anoxia. Seizures are frequent, occurring many times a day, and sometimes progress to status epilepticus.

A unique case of micturition and startle-induced reflex seizures has been reported in a patient with focal cortical dysplasia in the middle frontal gyrus (17). Spontaneous seizures are common (probably all patients) and may precede or follow the startle-induced seizures.

Prognosis and complications

Startle epilepsy usually occurs in patients with severe preexisting encephalopathies, and usually only incomplete or temporary seizure control can be achieved. These patients, with intractable epilepsy, identifiable brain lesions, and neurologic and developmental abnormalities, have significantly increased mortality compared to the general population. Traumatic falls are common. Milder cases may occur in subjects with histories of more subtle neurologic handicap.

Clinical vignette

A 5-year-old boy with a history of neonatal cerebral hemorrhage and infantile hemiplegia developed seizures characterized by stiffening of the paretic side, lateralized jerks, and falling. The first seizure occurred at a party when another child popped a balloon, and his parents noted that sudden and unexpected noises such as a falling wastepaper basket would provoke attacks. Clonazepam controlled the seizures temporarily but also caused agitation and lamotrigine has reduced but not eliminated the seizures.

Biological basis

Etiology and pathogenesis

Startle-induced seizures usually occur in patients with symptomatic epilepsies, but have also been reported in the setting of chromosomal disorders or genetically inherited lysosomal storage diseases (32). Patients usually have evidence of localized or diffuse static encephalopathy, such as hemiparesis or developmental delay of different etiologies, anoxic encephalopathy, and infections (see MRI findings). The insult typically occurs within the first 2 years of life and is often pre- or perinatal. Startle-induced focal seizures are common in children with post-encephalopathic epilepsy after acute encephalopathy with biphasic seizures and late reduced diffusion (33).

Startle epilepsy often occurs with Down syndrome. Startle myoclonus, though not clearly startle epilepsy, has been reported in association with GM2 gangliosidosis (45), and startle epilepsy has been reported with aspartylglucosaminuria (37).

Startle attacks occur in 38% of pediatric patients with epilepsy and KCNQ2 mutations, which opens the possibility to define electroclinical phenotypes associated to KCNQ2 mutations (30). Also, there are case reports of startle epilepsy associated with IL1RAPL1 gene deletion and with cri-du-chat syndrome (19; 44).

The pathophysiology of startle epilepsy is conjectural. The epileptogenic lesion may be in the dorsolateral frontal lobe or in the perirolandic area; for an example with video illustration, see Nolan and colleagues’ work (46). The startle reaction may trigger nearby epileptogenic tissue, but this does not explain patients with diffuse lesions and EEG abnormalities in whom diffuse deficiencies in cortical inhibition have been suggested (03; 27; 54).

Chauvel and associates showed that the seizure starts in the muscles first involved in the startle reflex, propagates to the contralateral limb, and then moves to the ipsilateral side (12). The abnormality is usually frontal or frontoparietal, involving the supplementary motor area and the vicinity of the paracentral lobule (06; 07). The critical discharges take origin in the primary motor cortex. The startle response may be through a feedback mechanism for triggering the epileptogenic focus, but it is assumed that afferent pathways, central organization, and efferent systems are involved in startle reaction and actual fits are different (07).

Fernandez and associates performed one of the most comprehensive studies in 4 patients with startle-induced seizures (24). All 4 patients underwent a presurgical evaluation including ictal-single-emission computed tomography/subtraction and ictal SPECT coregistered to MRI. They searched for areas with ictal changes of perfusion higher than 2 standard deviations above the reference. In 1 patient, a fluorodeoxyglucose-positron emission tomography and an ictal EEG-functional MRI (EEG-fMRI) were also performed. All the patients had their typical startle-induced seizures, consistent with bilateral asymmetric tonic seizures. Ictal-EEG pattern was located over the mesial centroparietal region in all of them. In 3 of 4 patients, a significant hyperperfusion over the mesial frontocentral region was seen, involving the supplementary motor area, the perirolandic region, and the precuneus. In 1 patient, who had a congenital bilateral perisylvian polymicrogyria, the pattern was located over the lateral perirolandic region. 18F-FDG-PET results in the patient in whom it was done, were concordant with ictal SPECT coregistered to MRI findings. Ictal EEG-fMRI showed an initial activation located over the precuneus, supplementary motor area, cingulate gyrus, and the precentral/perirolandic area. The authors concluded that startle-induced seizures could be generated by the interaction of a frontoparietal network located over the mesial surface of the brain (24). Also, Sandhya and associates reported a 17-year-old boy with startle myoclonus in association with increased delta and theta activity with a spike-and-slow-wave pattern of interictal epileptiform discharges on EEG and a fronto-parietal network activation pattern on SPECT and EEG-fMRI (51). However, in another study, Job and colleagues (34) reported 3 cases in which stereotactic EEG recordings demonstrated the prominent involvement of the supplementary motor area. Visual analysis was complemented by time-frequency analysis of stereotactic EEG signals using a neuroimaging approach (epileptogenicity maps), which showed at seizure onset a significant increase of high frequency oscillations (60-100 Hz) over the premotor and prefrontal areas. Critically, in all cases, the supplementary motor area showed ictal high frequency oscillations at seizure onset and was included in the surgical resection. All patients became seizure-free after surgery, and histopathological examinations showed no specific lesion. According to the authors, these cases suggest the prominent but not exclusive role of the supplementary motor area in startle seizures, and highlight the fact that surgery can be considered even in the absence of any magnetic resonance imaging lesion (34).

In a previously reported case of startle epilepsy associated with gait-induced seizures, interictal EEG revealed abundant spike-wave activity at the centroparietal midline areas, and ictal EEG of post-startle and gait-induced seizures revealed initial voltage attenuation followed by recruitment of vertex activity, which preceded a tonic or myoclonic-atonic phase (49). MRI was normal, but magnetoencephalography and positron emission tomography suggested the presence of an extensive epileptogenic zone in the bilateral pericentral gyri and the bilateral paracentral and left precuneus lobules, including the primary motor, supplementary motor, and supplementary sensory areas.

Epidemiology

The prevalence is not known but probably very low. In a report, startle-induced seizures were found in 2% of patients with focal epilepsy of unknown cause (04).

Differential diagnosis

Startle epilepsy should not be confused with hyperekplexia (also called startle disease) and other startle disorders and should be distinguishable on clinical, EEG, and radiologic grounds especially because the seizures of startle epilepsy can usually be easily induced for study during routine EEG recording (03). Occasionally, startle epilepsy may be more difficult to distinguish from hyperekplexia (14).

Startle syndromes consist of 3 heterogeneous groups of disorders with abnormal responses to startling events (05; 10; 20; 21):

The diagnosis of startle syndromes depends on clinical history, EEG, EMG studies, neuroimaging, and genetic screening. Neuropsychiatric startle syndromes demonstrate a variable response pattern and abnormal behavioral features.

Stimulus-induced drop episodes have also been described in Coffin-Lowry syndrome, a rare but well-defined X-linked semi-dominant syndrome characterized by psychomotor and growth retardation and progressive skeletal changes caused by loss of function mutations in the Rps6ka3 gene encoding the ribosomal S6 kinase 2 protein. These are nonepileptic, and they are clinically heterogeneous, with some patients exhibiting cataplexy-like events characterized by sudden hypotonia and collapse and others hyperekplexia-like episodes with a startle response (29).

Touch-evoked or tap seizures in children (18; 61) may have a startle component, but are not startle epilepsy as currently defined. In these infants and young children, generalized epileptiform EEG activity and myoclonic seizures are evoked without clinical, radiologic, or EEG evidence of lateralized lesions. Infants and children with touch-evoked seizures usually are developmentally normal, with normal EEG background activity. Touch-evoked seizures are rare, and though usually relatively benign, age-related, and often not requiring long-term treatment, they also have been reported with diffuse degenerative encephalopathies (18).

Seizures induced by sudden dousing with hot water may also have a startle component at some time in their course but are not to be confused with startle epilepsy (52; 08; 41). Other focal reflex seizures, produced by localized cutaneous or proprioceptive stimulation, should also be distinguished from startle epilepsy (59; 35).

Diagnostic workup

In view of multiple etiologies, patients with startle-induced epileptic seizures require a thorough clinical and diagnostic workup.

Brain MRI is necessary even in those patients with normal neurologic function (39), though this is usually abnormal. A variety of focal and diffuse, usually atrophic and often large, cerebral abnormalities are found (01; 27). The lateralized lesions usually involve sensorimotor and premotor cortex and white matter, but normal scans have been reported without neurologic deficit (39). Such patients have precentral or perisylvian dysplastic lesions on MRI. Schizencephaly has also been found.

The interictal EEG is usually abnormal, reflecting the underlying structural lesions. The abnormalities may be generalized, multifocal or focal slow waves, or epileptiform discharges. Frontal spikes are the most common (01).

Ictal scalp EEG commonly shows an initial vertex discharge followed by diffuse relative flattening or low-voltage rhythm at about 10 Hz.

Diffuse electrodecremental pattern is probably the most common ictal EEG pattern (60).

Ictal depth electrode recordings have shown an initial high amplitude evoked response over motor areas corresponding to the vertex scalp activity, followed by ictal EEG discharge, which begins in lesioned motor or premotor cortex and spreads to mesial frontal, parietal, and contralateral frontal regions (06; 07; 59). Subdural recordings in a patient with a small lesion next to the right supplementary sensorimotor area showed seizure onset in the right dorsolateral premotor cortex and the right supplementary sensorimotor area (54).

See also cases reported in the pathogenesis and pathophysiology section of this article.

Management

Prophylactic treatment is entirely empirical. Because startle-induced seizures are highly resistant to medication, polytherapy is usually prescribed though complete or lasting seizure control is not usually possible.

Clonazepam and clobazam have been useful adjuncts (01; 50; 37), and carbamazepine may be effective in patients with focal lesions (14). Lamotrigine was found effective in all 4 patients who received it as add-on treatment (23) and only 3 of 6 patients in another study (31). Levetiracetam add-on was effective in 6 of 10 patients (28).

Surgery has been reported to control startle epilepsy associated with infantile hemiplegia (47; 11; 40) and, in view of the nature of the seizures and their intractability, should perhaps be considered earlier and for more patients.

In a case report, the patient had nonlesional startle seizures provoked by auditory, somatosensory, and visual stimuli during video-electrocorticography recording (55). All types of seizures triggered by the 3 kinds of stimuli showed that seizure onset originated from the left supplementary sensorimotor area. The patient has been seizure-free since resection of the cortex around the left supplementary sensorimotor area only. Therefore, the authors speculated that the left supplementary sensorimotor area is the epileptogenic zone of startle epilepsy in this patient and perhaps the primary cortex to modulate the startle reflex in healthy persons. Similarly, seizure freedom was achieved in 3 patients in whom stereotactic EEG recordings demonstrated the prominent involvement of the supplementary motor area (34) as detailed in the pathogenesis and pathophysiology section of this article.

Also, excellent results were achieved with neurosurgery in another patient with medically intractable startle epilepsy (56). The ictal onset zone was localized to a part of the premotor cortex on the basis of intracranial electroencephalography recording, and surgical resection of the epileptogenic zone was done. The motor area close to the epileptogenic focus was localized using electrical cortical stimulation and, thus, preserved. The patient has been seizure-free postoperatively (Engel Class I) during the 18-month follow-up. The patient illustrates that surgery can be an option in patients with medically intractable startle epilepsy who have a well-defined unilateral epileptogenic zone. Another patient with type IB focal cortical dysplasia of the frontal lobe and startle seizures became seizure free after appropriate neurosurgery (13).

In another case report, the patient became seizure-free after corpus callosotomy (26). This was a girl who had been suffering with startle-induced seizures since 2 years of age. She had focal, tonic, and tonic-clonic seizures, refractory to antiepileptic treatment. Daily tonic seizures led to frequent falls and morbidity. Neurologically, she had no deficit. Interictal EEG showed slow waves and epileptiform discharges in central and fronto-central regions. Video-polygraphic recordings of seizures, triggered by stimuli, showed generalized symmetric tonic posturing with ictal EEG, characterized by an abrupt and diffuse electrodecremental pattern of fast activity, followed by alpha-theta rhythm superimposed by epileptic discharges predominantly over the vertex and anterior regions. Magnetic resonance imaging showed no abnormalities. Corpus callosotomy was performed when the patient was 17. Since surgery, the patient (one year follow-up) has remained seizure-free. The authors proposed that corpus callosotomy may be considered in patients with startle epilepsy and tonic seizures, in the absence of focal lesions amenable to surgery (26). There is a report of postherpetic anti-NMDAR encephalitis following right hemispherotomy in a patient with intractable startle-induced seizures (22).

A rare case of polymicrogyria combined with drug-resistant startle seizures responded well to multiple stereoelectroencephalography-guided radiofrequency thermocoagulations (38). Miro and associates described 2 adult patients with longstanding frequent startle-induced seizures who responded well to vagus nerve stimulation (42).

A multidisciplinary approach and psychological support is required as in all cases with severe epilepsy (58). A noninvasive treatment method using psychoeducational counseling and sound generators was applied in 4 children, resulting in a seizure frequency reduction of 50% or more in 2 of them (36).

Special considerations

Pregnancy

Although no information is available that is specific to this syndrome and pregnancy, information is available on epilepsy and pregnancy.