Clinical manifestations

Presentation and course

Patients with startle epilepsy are mainly children with long-standing static cerebral lesions and intellectual impairment (41; Tibussek and Schmidt 2010; 52). Typically, startle epilepsy arises in infancy and childhood or early adolescence (5 months to 16 years) and exceptionally in adulthood (37). Both sexes are equally affected (41).

Startle seizures are induced by sudden and unexpected stimuli. 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 (ie, sudden noise rather than pure sound) is the distinguishing feature (51).

The seizures usually last less than 30 seconds and consist of a startle response followed by a brief and characteristic tonic phase, which is usually asymmetric. Many subjects fall, and clonic jerks may occur. 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 (41; Tibussek and Schmidt 2010; 52).

Seizures are frequent, occurring many times a day.

Prognosis and complications

Startle seizures have a high rate of injury, due to traumatic falls that may occur during the startle induced tonic contraction. Usually only incomplete or temporary seizure control can be achieved because startle epilepsy typically occurs in patients with severe preexisting encephalopathies. Sometimes, seizures can progress to status epilepticus; therefore, the prognosis is often poor (21). These patients, because of intractable epilepsy due to static neurologic and developmental abnormalities, have significantly increased mortality compared to the general population.

Biological basis

Etiology and pathogenesis

Startle-induced seizures typically occur in patients with structural epilepsy secondary to large static brain lesions, such as perinatal hypoxic injury with congenital hemiparesis, cortical dysplasia, and schizencephaly (25). These lesions could also be related to postnatal causes including central nervous system infection and traumatic brain injury (49).

Startle epilepsies have also been described in certain chromosomal disorders, such as patients with Down syndrome, a peculiar form of Lennox Gastaut syndrome (14), or genetically inherited lysosomal storage diseases (ie, aspartylglucosaminuria, GM1 and GM2 gangliosidosis, and infantile Krabbe disease) (30).

Moreover, startle epilepsy has been associated with peculiar genetically determined conditions. There are many case reports of startle epilepsy associated with KCNQ2 mutations (22), IL1RAPL1 gene deletion, cri-du-chat syndrome (09; 38), and Schuurs-Hoeijmakers syndrome (39).

The pathophysiology of startle epilepsy is conjectural, and functional neuroimaging studies regarding the pathogenic mechanisms underlying startle epilepsy are scarce.

Fernandez and associates performed one of the most comprehensive studies on startle-induced seizures pathways by using a functional neuroimaging approach in four patients with startle epilepsy (15). The study included ictal-single-photon emission computed tomography/subtraction ictal SPECT co-registered to magnetic resonance imaging (MRI) (SPECT/SISCOM), F18-fluorodeoxyglucose–positron emission computed tomography (FDG-PET), and simultaneous electroencephalography–functional MRI (EEG-fMRI). They highlighted the existence of a complex mesial parieto-frontal network involved in the generation of startle-induced seizures; common regions involved were the SMA, the precuneus, and the primary motor and somatosensory area.

Also, Sandhya and associates reported a prominent fronto-parietal network activation pattern on SPECT and EEG-fMRI in startle myoclonus (44).

Job and colleagues reported three cases in which stereotactic EEG recordings demonstrated the prominent involvement of the supplementary motor area (26). Visual analysis was complemented by time-frequency analysis of stereotactic EEG signals using a neuroimaging approach (epileptogenicity maps). 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 MRI lesion (26).

Epidemiology

The prevalence is not known but probably very low. In a report, startle-induced seizures were found in 6.5% of patients with focal epilepsy of unknown cause (01).

Differential diagnosis

Startle syndromes consist of three heterogeneous groups of disorders with abnormal responses to startling events (02; 03; 11; Dreissen and Tijssen 2012):

The diagnosis of startle syndromes depends on clinical history, EEG and EMG studies, neuroimaging, and genetic screening.

Hyperekplexia or Kok disease is characterized by an abnormal and excessive startle response to unexpected stimuli. It could be genetic (hereditary hyperekplexia, mostly associated with GLRA1 gene), idiopathic (sporadic hyperekplexia, when the excessive startle is not associated with any positive family history, a clear genetic basis, or an established neurologic cause), or acquired (symptomatic hyperekplexia, when excessive startle is associated with an underlying cerebral or brainstem damage). The exaggerated startle in hyperekplexia leads to prolonged stiffening, the consciousness is preserved and, in contrast to startle seizures, the motor response is not followed by any generalized or lateralized tonic activity. In case of hyperekplexia, the drug of choice is clonazepam (43).

Reticular and propriospinal myoclonus resemble hyperekplexia, but with some differences. Hyperekplexia is characterized by stimulus sensitivity to the nasium, head, face, upper chest, whereas in reticular myoclonus the sensitivity is over the limbs and in propriospinal myoclonus in the abdominal regions (02). The cortical myoclonus is more prominent in the hands and face, it could be focal or multifocal, it is action-induced, and it shows increased sensitivity to tactile stimuli. Subcortical myoclonus affects bilateral arms; it manifests as a generalized synchronous flexor response, both at rest and on action; and it is commonly sensitive to auditory stimuli. The EMG burst is below 70 msec for both cortical and brainstem myoclonus, but the muscle recruitment spreads cephalocaudal in cortical, bidirectional in hyperekplexia. Back averaging of the EEG activity prior to the startle reaction shows a distinct cortical correlate in cortical myoclonus, which is not seen in hyperekplexia (43).

Hyperekplexia-like episodes have been reported in Coffin-Lowry syndrome, a rare 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. Patients present clinically heterogeneous episodes, with some patients exhibiting cataplexy-like events characterized by sudden hypotonia and collapse and others hyperekplexia-like episodes with a startle response (20).

Neuropsychiatric startle syndromes consist of a group of nonhabituating, excessive startle responses followed by a distinct, secondary orientating psychiatric and/or behavioral response such as forced obedience (automatic execution when startled with vigorous commands), violence, humiliation, coprolalia, echolalia, echopraxia, screaming, gesturing, and jumping. They include culture-specific syndromes, anxiety disorders, functional neurologic disorder, tics, and Gilles de la Tourette syndrome (31).

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 (35). Other focal reflex seizures, produced by localized cutaneous or proprioceptive stimulation, should also be distinguished from startle epilepsy (27).

Diagnostic workup

Given the multiple etiologies, patients with startle-induced epileptic seizures require a specific clinical and diagnostic workup.

Brain MRI is mandatory, even in those patients with normal neurologic function, though this is usually abnormal (15). A variety of focal and diffuse, usually atrophic and often large, cerebral abnormalities are found. They usually involve sensorimotor and premotor cortex and white matter (26).

The interictal scalp EEG is usually abnormal, reflecting the underlying structural lesions. The abnormalities may be generalized, multifocal or focal slow waves, or epileptiform discharges. The ictal scalp EEG commonly shows an initial vertex discharge followed by a diffuse electrodecremental pattern (52).

Ictal depth electrodes show an initial high-amplitude response over the region corresponding to vertex scalp activity, followed by epileptic discharge from the motor or premotor lesioned cortex, then spreading to the ipsilateral mesial frontal and parietal regions and the contralateral frontal regions (10; 24).

Finally, functional neuroimaging studies, such as ictal-single-emission computed tomography/subtraction ictal SPECT coregistered to MRI, could be a valid tool not only for research purposes but also for presurgical evaluation (15; 26).

Management

Startle-induced seizures are highly resistant to medication, and polytherapy is usually prescribed, though a complete seizure control is not usually possible.

Carbamazepine may be effective in patients with focal lesions (06). Clonazepam and clobazam have been useful adjuncts (30). Lamotrigine was found effective in all four patients who received it as add-on treatment (13), and in only three of six patients in another study (23). Levetiracetam add-on was effective in 6 of 10 patients (19). Valproic acid was found to suppress auditory startle response, especially in patients using for a long period and in patients using other antiseizure medications together with valproate (Kiziltan al 2018).

Surgery has been widely reported to control startle epilepsy associated with infantile hemiplegia (04; 34) and, in view of the nature of the seizures and their intractability, should perhaps be considered earlier and for more patients. The great majority of patients show a structural lesion, which can be focal or more frequently affecting the whole hemisphere; in such cases, lesionectomy or hemispherotomy can be considered with success.

Indeed, surgery is recognized as a valid option in patients with medically intractable startle epilepsy who have a well-defined unilateral epileptogenic zone (47; 05), but it has been also acknowledged its role in nonlesional seizures.

In a case report of a the patient with nonlesional startle seizures provoked by auditory, somatosensory, and visual stimuli, seizure freedom was achieved through the resection of the cortex around the left supplementary sensorimotor area only (46). Similarly, three patients in whom MRI was negative and stereotactic EEG recordings demonstrated the prominent involvement of the supplementary motor area were seizure free after surgery (26), thus suggesting that surgery could be considered even with a negative MRI. Gomez and colleagues reported a case of a girl suffering with startle-induced seizures since two years of age, with a negative MRI, for whom corpus callosotomy was performed with no seizures after one year from surgery (17). There is also a report of postherpetic anti-NMDAR encephalitis following right hemispherotomy in a patient with intractable startle-induced seizures (12).

A rare case of polymicrogyria combined with drug-resistant startle seizures responded well to multiple stereoelectroencephalography-guided radiofrequency thermocoagulations (32). Miro and associates described two adult patients with longstanding frequent startle-induced seizures who responded well to vagus nerve stimulation (36).

A multidisciplinary approach and psychological support are required in all cases with severe epilepsy (50). A noninvasive treatment method using psychoeducational counseling and sound generators was applied in four children, resulting in a seizure frequency reduction of 50% or more in two of them (29).

Special considerations

Pregnancy

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