The startle syndromes: Physiology and treatment

Authors


Address correspondence to Marina A. J. de Koning-Tijssen, Department of Neurology AB 51, University Medical Centre Groningen (UMCG), PO Box 30.001, 9700 RB Groningen, The Netherlands. E-mail: m.a.j.de.koning-tijssen@umcg.nl

Summary

Startle syndromes are paroxysmal and show stimulus sensitivity, placing them in the differential diagnosis of epileptic seizures. Startle syndromes form a heterogeneous group of disorders with three categories: hyperekplexia (HPX), stimulus-induced disorders, and neuropsychiatric syndromes. HPX is characterized by an exaggerated motor startle reflex combined with stiffness and is caused by mutations in different parts of the inhibitory glycine receptor, leading to brainstem pathology. The preserved consciousness distinguishes it from epileptic seizures. Clonazepam is the first-choice therapy. The stimulus-induced disorders cover a broad range of epileptic and nonepileptic disorders, and distinguishing the two can be difficult. Additional information from electroencephalography (EEG) and video registration can help. Many stimulus-induced disorders now have an identified gene defect. Antiepileptic drugs, including benzodiazepines, are frequently mentioned as the best treatment option. Neuropsychiatric syndromes are on the borderland of neurology and psychiatry, and their etiology is poorly understood. These syndromes include startle-induced tics, culture-specific disorders such as Latah, and functional startle syndromes. The electromyography (EMG) startle reflex in these syndromes is characterized by variable recruitment patterns and the presence of a second “orienting” response. Treatment options are limited, but urgently required. In the clinical setting, the patient’s history and a (home) video recording together with genetic and electrophysiologic testing help to classify these challenging disorders.

Paroxysmal movement disorders that are induced by a startling stimulus, also known as startle syndromes, are diverse and can resemble epileptic seizures. Clinically, startle syndromes can be divided into three categories: hyperekplexia (HPX), stimulus-induced disorders, and neuropsychiatric disorders. The normal startle reflex, a common physiologic mechanism, consists of a symmetrical generalized myogenic flexor response with a classic rostrocaudal recruitment activation of different muscles, which can be elicited by unexpected stimuli (Brown et al., 1991).

In this article we discuss the startle reflex and the clinical aspects of the startle syndromes, on the edge of epilepsy. We also discuss the clinical symptoms, (patho)physiology, genetics, and treatment of the different disorders.

Normal Startle Reflex

The startle reflex is present from 6 weeks of age and persists for life (Wilkins et al., 1986). Recordings of the startle reflex reveal two subsequent responses: the “early” response, also known as the “muscular tension reflex” and a second “late” response, also described as the “what-is-it?” or “orienting response” (Gogan, 1970). The early response has been described as “an immediate reflex response which represents innate behavior, unmodified by the various acquired patterns of behavior.” It has been interpreted as the rapid accomplishment of a defensive stance with maximum postural stability (Brown et al., 1991).

There is convincing evidence that this first part of startle reflex originates in the caudal brainstem (Brown et al., 1991). Animal studies support this and have led to the proposal of the following circuit of the acoustic startle reflex: auditory nerve, ventral cochlear nucleus (nuclei of the lateral lemniscus can be bypassed), nucleus reticularis pontis caudalis (nRPC), motor neurons of the brainstem and spinal cord (Dreissen et al., 2012).

This initial reflex is roughly uniform from time to time and between individuals (Pavlov, 1927).

The second “what-is-it?” or “orienting response” occurs after a period of decreased activity following the first response, with a latency of 400–450 msec, lasting three or more seconds. The organism is orienting toward the stimulus source, including postural adjustments with emotional and voluntary behavioral components; the response is therefore more variable (Gogan, 1970; Wilkins et al., 1986).

Many factors modulate the auditory startle reflex, including the presence and intensity of prestimuli, posture, tonic voluntary muscle activity, attentional focus, and general psychological state (Wilkins et al., 1986; Grillon & Baas, 2003). The pathways of many of these modifying influences remain largely elusive.

Startle Syndromes

The differential diagnosis of startle syndromes is extensive and too much to cover in this article (Table 1) (Bakker et al., 2006; Dreissen et al., 2012). We discuss the most relevant groups of syndromes, in particular those resembling forms of epilepsy.

Table 1.   Differential diagnosis of three groups of startle syndromes (modified from Bakker et al., 2006)
HyperekplexiaStimulus-induced disordersNeuropsychiatric disorders
Neonatal stiffness, startle, and stiffness with startleNonepilepticStartle induced tics
Excessive startlingWithout rigidityCulture-specific syndromes
 Cerebral Paroxysmal kinesigenic dyskinesias Latah
  Cerebral palsy Episodic ataxia Jumping Frenchmen of Maine
  Postanoxic encephalopathy Cataplexy (narcolepsy) Myriachit
  Occlusion of posterior thalamic arteries Reflex myoclonusFunctional startle syndromes
  PosttraumaticWith rigidityAnxiety disorders
  Paraneoplastic Stiff-person syndrome Posttraumatic stress syndrome
  Multiple sclerosis and lateral sclerosis Progressive encephalomyelitis with rigidity 
  Cerebral abscess with encephalitis Strychnine poisoning 
 Brainstem Tetanus 
  Brainstem infarctionEpileptic 
  Brainstem hemorrhage Reflex epilepsy 
  Brainstem encephalopathy Progressive myoclonus epilepsy 
  Pontocerebellar hypoplasia Pyridoxine-dependent epilepsy 
  Posterior fossa malformations  
  Medulla compression  
  Multiple system atrophy  

Hyperekplexia

HPX, comprising exaggerated startle reflexes and violent falls due to generalized stiffness, was originally considered partly psychiatric (“emotional stimuli”) and partly epileptic (“drop seizures”) (Kirstein & Silfverskiold, 1958). The mode of inheritance was autosomal dominant. HPX has been identified in >100 pedigrees and in >120 sporadic cases (Bakker et al., 2006; Siren et al., 2006; Doria et al., 2007; Forsyth et al., 2007; Masri & Hamamy, 2007; Gregory et al., 2008; Al-Owain et al., 2011; Zoons et al., 2012). There are three clinical symptoms: generalized stiffness at birth, excessive startle reflexes, and generalized stiffness following startle. Throughout history, all diseases with a form of exaggerated startling, regardless of their cause, have been named HPX (Bakker et al., 2006). However, we strongly argue to keep the term HPX for cases with the three cardinal features. Diseases where an excessive startle reflex is the main clinical symptom but without stiffness should, in our opinion, be described as “excessive startle reflexes.”

In babies with HPX, there is generalized stiffness directly after birth, which normalizes during the first years of life, increases with handling, and disappears with sleep (de Koning-Tijssen & Rees, 2007). Adults with HPX often walk with a stiff-legged, and have a mildly wide-based gait but without signs of ataxia. The excessive startle reflex following unexpected stimuli, particularly auditory, is present from birth and persists throughout life. There is no loss of consciousness during startle responses. The third feature is short-lasting temporary generalized stiffness after being startled, during which voluntary movement is impossible. This phenomenon causes patients to fall forward “as stiff as a stick,” while fully conscious.

On examination, at all ages, there is an exaggerated head-retraction reflex (HRR) (Zoons et al., 2012). Associated symptoms include neonatal tonic cyanotic attacks, periodic limb movements during sleep, and hypnagogic myoclonus. The remaining physical examination is normal; for overview see (Bakker et al., 2006).

Genetic studies in HPX have shown mutations in different parts of the inhibitory glycine receptor (GlyR). The GlyRs are located in the postsynaptic membrane of glycinergic and mixed γ-aminobutyric acid (GABA)ergic/glycinergic neurons; they are ligand-gated chloride channels causing postsynaptic hyperpolarization and consequently synaptic inhibition in the brainstem and spinal cord.

The most common gene affected in HPX concerns the alpha 1 subunit of the glycine receptor (GLRA1). This gene is mutated in about 80% of all HPX pedigrees. Dominant, recessive and compound heterozygote mutations have been identified (Bakker et al., 2006; Chung et al., 2010; Davies et al., 2010).

Missense, nonsense, and frameshift mutations in the GlyT2 (SCL6A5) gene, encoding the presynaptic sodium- and chloride-dependent glycine transporter 2, account for about 20% of HPX cases (Davies et al., 2010). In general, the mode of inheritance in GlyT2 patients is recessive with compound heterozygosity.

In very few sporadic cases, there is genetic heterogeneity with mutations affecting other postsynaptic glycinergic proteins, including the GlyR subunit (GLRB), gephyrin (GPHN), and collybistin (ARHGEF9) (de Koning-Tijssen & Rees, 2007).

The electromyography (EMG) startle reflex in HPX is exaggerated but uses the common afferent and efferent system as in the normal startle reflex, involving the generator in the lower brainstem (Tijssen et al., 1997). An increased psychogalvanic response indicates that the startle reflex is not restricted to a sole motor response (Tijssen et al., 1997).

The exaggerated startle reflex in HPX is probably caused by brainstem pathology. This is supported by the concentration of glycine receptors in the brainstem and spinal cord (Rousseau et al., 2008). In addition, symptomatic excessive startling is usually caused by brainstem damage (Bakker et al., 2006).

Together with the discovery of HPX, the term “minor” HPX has been introduced. This phenotype was observed in relatives of patients with HPX and originally considered hereditary. However, HPX “minor” lacks stiffness and consists exclusively of excessive startling (Suhren et al., 1966). Patients with the minor form do not have the same gene defect as those with HPX cases; this has been a topic of much discussion (Tijssen et al., 1996). In view of the prolonged latencies in the “minor” form it is possible that psychological factors are important in the origin of the exaggerated startle reflex (Bakker et al., 2006).

Although there is little evidence to guide treatment in HPX, clonazepam is probably the most effective therapy in gene-positive cases—(Dijk & Tijssen, 2010)—both GLRA1 positive and GlyT2 positive. The initial dose is 0.5 mg daily, and up to 6 mg daily.

Stimulus-Induced Disorders

Stimulus-induced disorders show excessive responses other than just an excessive startle reflexes due to a startling stimulus (Table 2). They can be divided into nonepileptic, comprising paroxysmal kinesigenic dyskinesias, episodic ataxia, cataplexy (narcolepsy), and reflex myoclonias, and epileptic, comprising reflex epilepsy and progressive myoclonus epilepsy. We discuss the most relevant disorders and their clinical, genetic, (patho)physiologic, and therapeutic features.

Table 2.   Clinical, genetic, (patho)physiologic, and therapeutic features of startle syndromes
 HPXPKDEA1CataplexyCortical reflex myoclonusReticular reflex myoclonusStartle epilepsyStartle-induced ticsCulture-specificFunctional myoclonus
  1. HPX, hyperekplexia; PKD, paroxysmal kinesigenic dyskinesia; EA1, episodic ataxia type 1; EEG, electroencephalography; EMG, electromyography; g-SEPP, giant somatosensory evoked potential; REM, rapid eye movement; 5-HTP, 5-hydroxytryptophan; GLRA1, encodes alpha 1 subunit of the glycine receptor; SCL6A5, encodes presynaptic sodium- and chloride-dependent glycine transporter 2; GLRB, encodes postsynaptic glycinergic protein GlyR subunit; GPHN, encodes postsynaptic glycinergic protein gephyrin; ARHGEF9, encodes postsynaptic glycinergic protein collybistin, PR.

Movement disorder↑ StartleUnilateral dystoniaAtaxiaBilateral weaknessDistal and facial jerksGeneralized jerkUnilateral tonic posturingVocal/motor tic↑ StartleReflex jerks
Attack durationStiffness with startle (seconds)<1 minSeconds–minutesSecondsSecondsSecondsSeconds–minutesSecondsSeconds–minutesSeconds
Additional featuresStiffness at birth Myotonia↓ Tendon reflexes Relation to posthypoxic episode  Echo-phenomenaIncongruent inconsistent distractible suggestible
Main triggerStartleSudden movementSudden movementLaughingTouchStartleStartleStartleStartleStartle
Age of onsetAt birth7–15 yearsEarly childhoodTeenageAll agesAll agesChildhoodAll agesMiddle ageAll ages
Loss of consciousnessNoNoNoNoNoNoYesNoNoNo
EMG startle reflex↑ Motor reflex
Short latencies
Lack of habituation
Normal↑ Motor reflexSimilar to startle reflex
Shorter intervals
↑ Motor reflex
Long latencies
Variable pattern
↑ Motor reflex
↑ Orienting response
Long latencies
Variable pattern
ElectrophysiologyIctal/interictal EEG abnormalities rare EMG pattern similar to tonic REM sleepEMG burst <50 msec EEG-EMG correlation g-SSEP C-reflex Ictal discharge at vertex with spreading interictal EEG abnormalities of focal lesionsBereitschafts potential
Genetic mutationGLRA1, SCL6A5
GLRB, GPHN
ARHGEF9
PRRT2KCNA1
First choice treatmentClonazepamCarbamazepineAcetazolamideSodium oxybateLevetiracetam
Valproic acid
Clonazepam
Clonazepam
5-HTP
AntiepilepticsAlpha-2 agonists habit reversal trainingMultimodal

Paroxysmal kinesigenic dyskinesia

Paroxysmal kinesigenic dyskinesia (PKD) is defined as being triggered by a sudden movement; there are short (<1 min) attacks of involuntary movements, mainly dystonia but also chorea, ballismus, or a combination of these. Startle can also trigger an attack (Houser et al., 1999; Bruno et al., 2004). The attacks usually occur in the limbs of one side, but some patients also have facial involvement. Patients can report an aura-like sensation preceding an attack. There is no loss of consciousness and no postictal phase (Houser et al., 1999; Bruno et al., 2004). The age of onset is usually 7–15 years, and there is a male preponderance (4:1 up to 8:1). Attacks can occur frequently, up to 100 per day. About 70% of patients with PKD have a positive family history with an autosomal dominant inheritance pattern and incomplete penetrance (Bhatia, 2011). The prognosis is good; the attack frequency usually decreases with age.

Recently, there was a major breakthrough in genetic studies. The proline-rich transmembrane protein 2 (PRRT2) was identified as a major causative gene for PKD, located on chromosome 16 (Wang et al., 2011). There have been different mutations identified so far in several families, including insertion, nonsense, frameshift, and missense mutations. Some of these mutations were in patients or families with other phenotypes such as infantile convulsion chorea athetosis syndrome (ICCA), paroxysmal nonkinesiogenic dyskinesia (PNKD), and paroxysmal exertion-induced dyskinesia (PED), suggesting that this gene mutation causes a spectrum of phenotypes (Liu et al., 2012). PRRT2 is mainly expressed in the basal ganglia (http://human.brain-map.org). We do not yet know the exact underlying molecular mechanism causing PKD.

The pathophysiology of PKD is poorly understood; it is still debated whether PKD is an epileptic or nonepileptic disorder, or whether it has a cortical or subcortical origin. The paroxysmal nature of the attacks and the excellent response to antiepileptic drugs (AEDs) argues for an epileptic origin, whereas the attacks with dystonic posturing and choreiform movements, general normal (inter)ictal electroencephalography (EEG) studies (Bhatia, 2011), and preserved consciousness argue for a subcortical etiology. The startle response is normal in PKD (Mir et al., 2005).

PKD is usually treated with AEDs, carbamazepine being the first choice (Bruno et al., 2004; Bhatia, 2011). The doses for adults are phenytoin 5 mg/kg/day and carbamazepine 7–15 mg/kg/day (Houser et al., 1999). Other suggested drugs include acetazolamide, hydantoin, topiramate, barbiturates, or benzodiazepines, with variable effects.

Episodic ataxia

Episodic ataxia (EA) is usually an autosomal dominantly inherited disorder, characterized by intermittent attacks of ataxia with normal cerebellar function between (Bhatia et al., 2000). Although it is clinically and genetically heterogeneous, the main symptoms relate to cerebellar dysfunction. There are different forms of primary EA syndromes. It is rare, with an incidence probably less than 1:100,000 (Jen et al., 2007). The attacks in EA type1 (EA1), as in PKD, may be triggered by sudden movements, physical and emotional stress, and also by startle. Patients with EA1 have varying degrees of neuromyotonia and brief attacks (seconds to minutes) of ataxia up to 30 times a day (Bhatia et al., 2000), with an onset in early childhood. Aura-like symptoms may precede attacks (Jen et al., 2007). EA1 is an autosomal dominantly inherited channelopathy of the central nervous system (CNS) caused by a mutation in the KCNA1 gene, encoding the potassium channel Kv1.1 on chromosome 12p13 (Browne et al., 1995). The potassium ion channel is abundantly expressed in the cerebellum and the neuromuscular junction; its dysfunction appears to lead to neuronal hyperexcitability (Jen et al., 2007). Brain imaging is usually normal (Tomlinson et al., 2009).

Acetazolamide, a carbonic anhydrase inhibitor, is the first choice for treating EA (Jen et al., 2007; Strupp et al., 2011). The starting dose is 125–250 mg, which can be increased to 1,000 mg/day (Strupp et al., 2011), although side effects may limit their use. Carbamazepine and valproic acid are other possible effective drugs.

Cataplexy

Cataplexy is a sudden transient (3–50 s) bilateral muscle weakness with preserved consciousness. The attacks manifest as a sudden partial or total loss of muscle tone, with loss of tendon reflexes. They are usually triggered by emotions, particularly laughing and startle (Vetrugno et al., 2010). Cataplexy is considered an abnormal expression of the atonia that would normally present during REM (rapid eye movement) sleep (Hishikawa & Shimizu, 1995), and is almost always part of—and therefore a diagnostic criterion for—narcolepsy (American Academy of Sleep Medicine, 2005).The age of onset is usually during teenage and young adulthood. Narcolepsy–cataplexy is rarely familial (Mignot, 1998). The prevalence of narcolepsy is about 0.02–0.05% (Ohayon et al., 2002).

Video-polygraphy (EMG, EEG, and heart rate) together with humorous movies and/or jokes in seven narcolepsy–cataplexy patients showed an EMG pattern similar to that of tonic REM sleep (Vetrugno et al., 2010). Patients considered the body falling phase to be similar to that of startle response following an auditory stimulus. Furthermore, the autonomic changes during these attacks, namely heart rate deceleration, differ from that of classic REM sleep and are characteristic of the orienting second phase of the startle response. Of interest, the first part of the startle reflex may be exaggerated in patients with narcolepsy–cataplexy (Lammers et al., 2000).

In narcolepsy with cataplexy, there is a loss of hypocretin-producing neurons in the posterolateral hypothalamus (Thannickal et al., 2000). Hypocretin-producing neurons are widely expressed through the CNS and play a crucial role in the regulation of sleep and wakefulness (Saper et al., 2005). More recent studies suggest that the loss of hypocretin neurons has an autoimmune cause. Like other autoimmune diseases, narcolepsy is strongly associated with a specific human leukocyte antigen (HLA) allele, namely (HLA)-DQB1*0602 (Hor et al., 2010). Linkage studies so far have identified chromosome 4p13-q21 in a Japanese family and 21q in a large French family with narcolepsy–cataplexy (Nakayama et al., 2000; Dauvilliers et al., 2004).

Cataplexic attacks respond well to sodium oxybate (γ-hydroxybutyrate, GHB), a natural metabolite of GABA that acts on GABAB receptors (Maitre, 1997). The proven effective dose is 4–9 g at night (Anonymous, 2002; U.S. Xyrem Multicenter Study Group, 2004; Black & Houghton, 2006); for overview treatment of narcolepsy see Dauvilliers et al. (2007).

Reflex myoclonus

Myoclonus manifests as brief, quick involuntary jerks (positive myoclonus) or interruptions of tonic muscle activity (negative myoclonus) and can be classified in different ways; one is by anatomic origin (Dijk & Tijssen, 2010). Two forms of myoclonus—cortical and subcortical (especially reticular)—are characterized by their stimulus sensitivity.

Cortical myoclonus manifests as (multi)focal, distally located myoclonic jerks, affecting particularly those body parts that have a large cortical presentation. A common trigger is muscle stretching of the affected limb. There is often reflex myoclonus (Caviness, 2009). Cortical myoclonus may develop with focal lesions of the sensorimotor cortex, may follow a posthypoxic episode, or can occur as part of a syndrome such as progressive myoclonus epilepsy or neurodegenerative disorders (Hallett, 2000; Caviness, 2009).

Neurophysiologic measures show that the recruitment of muscle activation occurs in a rostrocaudal order. Typically EMG bursts are of short duration (<50 msec) (Shibasaki & Hallett, 2005). Further neurophysiologic signs include a cortical spike preceding the jerk, or coherence between EEG and EMG activity in continuously present jerks (van Rootselaar et al., 2006). Furthermore, there may be evidence of increased cortical hyperexcitability, including a giant somatosensory evoked potential (g-SSEP) and the presence of a C reflex (Mima et al., 1998).

Cortical myoclonus probably results from abnormal firing of the sensorimotor cortex, giving activity that travels through the fast corticospinal pathways. It is often related to epilepsy and associated with generalized convulsions; continuous isolated cortical muscle jerks may also occur and present as epilepsia partialis continua (Cockerell et al., 1996).

The treatment of cortical myoclonus, with exception of epileptic myoclonus, is based mainly upon small observational studies and expert opinion—for overview see (Dijk & Tijssen, 2010). Piracetam 24 g/day has proven effective in cortical myoclonus in several trials. An alternative is levetiracetam, at a lower daily dose of 2–3 g/day and with fewer side effects. Other agents include valproic acid and clonazepam.

Brainstem or reticular myoclonus is marked by a more generalized, synchronized muscle activation pattern that is axially localized; there is particular stimulus sensitivity over the limbs. It closely resembles the startle reflex. Brainstem and reticular myoclonus usually occurs after a postanoxic event (Hallett, 2000). The generator is the reticular formation of the brainstem. The signal is transmitted down the spinal cord to the upper and lower limbs and up to the brainstem, lasting 10–30 msec. The jerks are usually generalized due to the bilateral pathway, and so focal forms are rare (Hallett, 2000). Reticular reflex myoclonus can be distinguished from startle syndromes by shorter intervals between bursts (Brown et al., 1991).

There is little evidence to support the various treatment options in reticular myoclonus. Clonazepam and 5-HTP (5-hydroxytryptophan) may be effective—for overview see (Dijk & Tijssen, 2010).

Reflex epilepsy

Reflex epilepsy is epilepsy that is induced by a specific afferent stimulus or activity of the patient (Engel, 2001). It is classified into three categories: pure reflex epilepsies, reflex seizures as part of focal or generalized epilepsy syndromes, and isolated reflex seizures without a necessary diagnosis of epilepsy (Xue & Ritaccio, 2006).

Startle epilepsy is discussed here because of its resemblance with startle syndromes. Startle epilepsy is a rare form of epilepsy comprising seizures that occur both spontaneously and induced by an unexpected mainly auditory stimulus (Panayiotopoulos, 2005). Patients with startle epilepsy are typically young and have preexisting brain disease such as infantile cerebral hemiplegia or diffuse or localized static brain encephalopathy from different causes (Yang et al., 2010). Startle seizures are brief (up to 30 s), symmetrical, and include axial tonic posturing, which frequently results in traumatic falls. In hemiparetic patients, the seizures typically start with flexion of the affected arm and extension of the ipsilateral leg, rapidly followed by involvement of the other side. Additional features include autonomic signs, automatisms, laughter, and jerks. Seizures may occur many times a day. The ictal EEG usually starts with a discharge over the vertex, followed by low-voltage rhythmic or diffuse flattening, which starts in the premotor or motor cortex lesion and spreads to the frontal and parietal regions (Panayiotopoulos, 2005). The interictal EEG shows diffuse or focal abnormalities, depending on the underlying brain lesion. The EEG may also be normal, or show features that are not related to the clinical symptoms (Xue & Ritaccio, 2006; Yang et al., 2010). Neuroimaging can be normal or may show lateralized lesions in the sensorimotor and premotor cortex and white matter. There may also be focal or generalized atrophy (Manford et al., 1996).

The treatment of startle epilepsy is usually difficult; it is nearly impossible to obtain total seizure control and the prognosis is usually poor. Several AEDs may help, including carbamazepine, valproic acid, and levetiracetam (Saenz et al., 1984; Gurses et al., 2008). Lamotrigine may be an effective adjunctive therapy, especially through preventing falls (Ikeda et al., 2011).

Neuropsychiatric Startle Syndromes

Neuropsychiatric startle syndromes are marked by a combination of neurologic and psychiatric symptoms, and they often develop later in life. Disorders include startle-induced tics, culture-specific syndromes, hysterical jumps or functional startle syndromes, and anxiety disorders (posttraumatic stress syndrome) (Bakker et al., 2006). We do discuss anxiety disorders here because of its lack of resemblance with epilepsy.

Startle-induced tics

Startle-induced or reflex tics may occur as part of Tourette’s syndrome as well as an independent phenomenon (Commander et al., 1991; Eapen et al., 1994; Tijssen et al., 1999). Tics are characterized by feelings or sensations preceding the tic, suggestibility, suppressibility, an increase with stress, and typical waxing and waning through time. Tics are typically provoked by internal, but occasionally by external stimuli, such as startle. It is still debatable whether the startle reflex in Tourette’s syndrome is exaggerated, with an exaggerated response in one (Gironell et al., 2000), but not in all studies (Stell et al., 1995; Sachdev et al., 1997). Three cases of late-onset startle-induced tics showed abnormally long latencies and variable muscle activation patterns after auditory stimulation (Tijssen et al., 1999). This could be interpreted as voluntary stimulus-induced movement in healthy subjects. It can be difficult to distinguish stimulus-induced psychogenic jumps or jerks from startle-induced tics. Finding a premovement potential, often present in psychogenic movement disorders, can help to differentiate these (Hallett, 2010).

The first-choice pharmacologic treatment for tics is an alpha-2-agonist (Scahill et al., 2006). Antipsychotics have proven very effective for tics in several randomized controlled trials (Scahill et al., 2006) but are second line because of their unfavorable side effects. Behavioral therapy also gives significant results for tics: habit reversal training is the first choice (Piacentini et al., 2010).

Culture-specific syndromes

Tourette’s syndrome was historically linked to the culture-bound startle syndromes: “Latah” in Indonesia and Malaysia, the “Jumping Frenchmen of Maine,” and the less known “Myriachit” in Siberia (Thompson, 2006). The feature common to all these syndromes is a clinically, nonhabituating exaggerated startle response triggered by, for instance, sound. Following being startled, there may be various behavioral responses, including “forced obedience,” echolalia, echopraxia, and coprolalia.

Because there have been no detailed physiologic studies of these culture-specific startle-matching syndromes, their etiology and classification remains debatable. Our group found increased early motor startle reflexes and also increased “late” orienting responses in a group of 12 Latah patients compared to 12 healthy volunteers in Indonesia (Bakker MJ, van Dijk JG, Pramono A, Sutarni S, Tijssen MAJ, unpublished data). Increased early motor startle reflexes point to increased activity of the startle generator in the brainstem, as occurs in HPX. However, Latah patients do not have the cardinal stiffness features of HPX. Motor startle reflexes can be increased in anxiety disorders (Bakker et al., 2009). The movements are paroxysmal and bizarre, and therefore these disorders may resemble psychogenic movement disorders (Hinson & Haren, 2006). Other characteristic features as echo phenomena, palilalia, coprolalia, and sensitivity to stimuli, resembling those in a tic disorder and especially reflex tics. Latah patients do not show other characteristics of tic disorders, such as the ability to suppress responses, relief, and sensory warning. Latah is likely to have important cultural influences. There is little literature on the treatment of these disorders, because of its rarity.

Functional startle syndromes

Functional movement disorders can mimic the whole range of organic abnormal movements, but tremor and myoclonus are the most common (Hinson & Haren, 2006). It begins at any age. The phenomenology is diverse and often involves several body parts with complex movements. Other symptoms suggesting a functional origin are sudden onset, inconsistency, incongruity, suggestibility, lessening of symptoms with distraction and disappearance of symptoms if unobserved. There may be stimulus-sensitivity or reflex jerks, mimicking other startle syndromes (Thompson et al., 1992; Brown & Thompson, 2001). Functional reflex myoclonus can be distinguished from organic reflex myoclonus by measuring the latencies following visual or somatosensory stimulation; in functional myoclonus the latencies are ≥100 msec (Thompson et al., 1992; Brown & Thompson, 2001). Furthermore, the muscle recruitment pattern is variable.

Because the patient’s acceptance of the diagnosis is essential, treatment can be difficult. The gold standard treatment is multimodal, combining psychotherapy, rehabilitation, physical therapy, hypnosis, and antidepressants (Hinson & Haren, 2006; Hinson et al., 2006; Ness, 2007). However, we urgently need randomized controlled trials and new treatment options.

Conclusion

Startle syndromes are a diverse and heterogeneous group of syndromes. Their paroxysmal nature places them in the differential diagnosis of epileptic seizures. Startle syndromes are classified into HPX, stimulus-induced disorders, and neuropsychiatric disorders. HPX is well defined. The retained consciousness distinguishes it from epileptic seizures. In the stiff neonatal period an EEG during a startle reflex or genetic testing might be required if the family history is negative. The stimulus-induced disorders and neuropsychiatric startle syndromes are diverse. They form a clinical heterogeneous group whose overlapping features are their paroxysmal nature and by their frequent provocation by an external stimulus. Some of these disorders are a form of epilepsy and in others their epileptic nature remains debatable. The patient’s history and a (home) video recording together with genetic and electrophysiological testing help to classify these challenging disorders.

Disclosure

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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