Epilepsia, 53(Suppl. 7):3–11, 2012
doi: 10.1111/j.1528-1167.2012.03709.x
THE BORDERLAND OF EPILEPSY
The startle syndromes: Physiology and treatment
*Yasmine E. M. Dreissen and yMarina A. J. Tijssen
*Department of Neurology and Clinical Neurophysiology, Academic Medical Center, University of Amsterdam,
Amsterdam, The Netherlands; and yDepartment of Neurology, University Medical Center Groningen,
University Groningen, Groningen, The Netherlands
orders 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.
KEY WORDS: Hyperekplexia, Epilepsy, Culturespecific startle, Tics, Functional movement disorders.
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 stimulusinduced 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 dis-
(patho)physiology, genetics, and treatment of the different
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,
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 ‘‘whatis-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
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
Wiley Periodicals, Inc.
ª 2012 International League Against Epilepsy
3
Y. E. M. Dreissen and M. A. J. Tijssen
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.
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
Table 1. Differential diagnosis of three groups of startle syndromes
(modified from Bakker et al., 2006)
Hyperekplexia
Neonatal stiffness, startle, and stiffness with startle
Excessive startling
Cerebral
Cerebral palsy
Postanoxic encephalopathy
Occlusion of posterior thalamic arteries
Posttraumatic
Paraneoplastic
Multiple sclerosis and lateral sclerosis
Cerebral abscess with encephalitis
Brainstem
Brainstem infarction
Brainstem hemorrhage
Brainstem encephalopathy
Pontocerebellar hypoplasia
Posterior fossa malformations
Medulla compression
Multiple system atrophy
Epilepsia, 53(Suppl. 7):3–11, 2012
doi: 10.1111/j.1528-1167.2012.03709.x
Stimulus-induced disorders
Neuropsychiatric disorders
Nonepileptic
Without rigidity
Paroxysmal kinesigenic dyskinesias
Episodic ataxia
Cataplexy (narcolepsy)
Reflex myoclonus
With rigidity
Stiff-person syndrome
Progressive encephalomyelitis with rigidity
Strychnine poisoning
Tetanus
Epileptic
Reflex epilepsy
Progressive myoclonus epilepsy
Pyridoxine-dependent epilepsy
Startle induced tics
Culture-specific syndromes
Latah
Jumping Frenchmen of Maine
Myriachit
Functional startle syndromes
Anxiety disorders
Posttraumatic stress syndrome
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4
Physiology and Treatment of Startle Syndromes
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 c-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 sodiumand 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.
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
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doi: 10.1111/j.1528-1167.2012.03709.x
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5
Epilepsia, 53(Suppl. 7):3–11, 2012
doi: 10.1111/j.1528-1167.2012.03709.x
Stiffness with
startle (seconds)
Stiffness at birth
Startle
At birth
Attack duration
Additional features
Main trigger
Age of onset
Sudden
movement
7–15 years
Unilateral
dystonia
<1 min
PKD
GLRA1, SCL6A5
GLRB, GPHN
ARHGEF9
Clonazepam
Genetic mutation
KCNA1
All ages
Touch
Distal and
facial jerks
Seconds
Cortical reflex
myoclonus
–
EMG pattern
similar to
tonic REM
sleep
Levetiracetam
Valproic acid
Clonazepam
–
EMG burst
<50 msec
EEG-EMG
correlation
g-SSEP C-reflex
No
No
› Motor reflex –
Teenage
Laughing
fl Tendon
reflexes
Bilateral
weakness
Seconds
Cataplexy
Carbamazepine Acetazolamide Sodium
oxybate
PRRT2
Ictal/interictal
EEG
abnormalities
rare
Sudden
movement
Early
childhood
No
–
Seconds–
minutes
Myotonia
Ataxia
EA1
Clonazepam
5-HTP
–
No
Similar to
startle reflex
Shorter
intervals
All ages
Startle
Relation to
posthypoxic
episode
Generalized
jerk
Seconds
Startleinduced tics
Culturespecific
Antiepileptics
Ictal discharge
at vertex with
spreading
interictal EEG
abnormalities
of focal
lesions
–
Yes
–
Childhood
Startle
Alpha-2
agonists
habit
reversal
training
–
No
› Motor reflex
Long latencies
Variable
pattern
–
All ages
Startle
All ages
Incongruent
inconsistent
distractible
suggestible
Startle
Seconds
Reflex jerks
Functional
myoclonus
–
–
–
Multimodal
–
Bereitschafts
potential
No
No
› Motor reflex Long latencies
› Orienting
Variable
response
pattern
Middle age
Startle
Unilateral tonic Vocal/motor tic › Startle
posturing
Seconds–
Seconds
Seconds–
minutes
minutes
Echophenomena
Reticular
reflex myoclonus Startle epilepsy
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.
First choice
treatment
–
Electrophysiology
Loss of consciousness No
No
EMG startle reflex
› Motor reflex
Normal
Short latencies
Lack of habituation
› Startle
Movement disorder
HPX
Table 2. Clinical, genetic, (patho)physiologic, and therapeutic features of startle syndromes
Y. E. M. Dreissen and M. A. J. Tijssen
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6
Physiology and Treatment of Startle Syndromes
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
(c-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.
Epilepsia, 53(Suppl. 7):3–11, 2012
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7
Y. E. M. Dreissen and M. A. J. Tijssen
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).
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).
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
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
Epilepsia, 53(Suppl. 7):3–11, 2012
doi: 10.1111/j.1528-1167.2012.03709.x
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 startleinduced 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.
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8
Physiology and Treatment of Startle Syndromes
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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