The Startle Syndrome

Peter Brown, MD*

Sobell Department of Neurophysiology, Institute of Neurology, London, United Kingdom

The normal human startle response consists of a briefflexion response, most marked in the face and upper halfof the body, elicited by an unexpected auditory, or some-times somaesthetic, visual, or vestibular stimulus. Som-aesthetic stimuli are most effective when applied to themantle area. Activity is most prominent in orbicularisoculi and sternocleidomastoid. Habituation of the normalgeneralised startle response is rapid, although the blinkreflex tends to persist.

Hyperekplexia consists of a pathologically exagger-ated response to unexpected stimuli, particularly sounds.It is distinguished from the normal startle reflex by itslower threshold, greater extent, and resistance tohabituation.1–3 Specifically, the normal startle responserarely involves the lower limbs in a sitting subject,whereas this is almost always the case in hyperekplexia.The normal startle response habituates within one to fivetrials of auditory stimulation repeated every 20 secondsor so, leaving only an auditory blink reflex, whereas inhyperekplexia extensive jerks persist. Like the normalstartle response, somaesthetic stimuli are most effectivewhen applied to the mantle area, particularly the face,when the response that results is sometimes termed ahead retraction reflex.

Physiology of the Normal Startle Reflexand Hyperekplexia

Studies in animals suggest that the normal startle re-sponse originates in the lower brainstem. The short la-tency startle response to sound persists after decerebra-tion. Lesioning experiments in the rat have implicatedthe medial bulbopontine reticular formation, particularlythe nucleus reticularis pontis caudalis, as the primarycentre subserving the acoustic startle reflex. Thus, elec-trical stimulation of the nucleus reticularis pontis cauda-lis elicits short latency startle-like responses. The recruit-

ment order of cranial nerve-innervated muscles in thehuman startle would be consistent with a bulbospinalorigin, if the early response in orbicularis oculi were aseparate, but simultaneously elicited, blink reflex.5 Inaddition, the startle response after auditory or somaes-thetic stimulation is absent in progressive supranuclearpalsy, a condition in which there is degeneration of thenuclei of the pontine reticular formation.

The startle response in hyperekplexia has variouslybeen considered to have a cortical or brainstem origin,with most current evidence favouring the latter. Twolines of evidence have been used to support a corticalorigin for the startle response, the presence of giant cor-tical evoked potentials and the presence of cortical neu-ronal loss on magnetic resonance spectroscopy.6 How-ever, giant evoked potentials are only present in the mi-nority of patients, and the study that demonstratedcortical neuronal loss did so in patients with epilepsy andwithout a known mutation.6 Magnetic resonance spec-troscopy has been repeated in patients with a mutation inthe alpha1 subunit of the glycine receptor and has beenfound to be normal (Tijssen and Brown, personal obser-vation). The same patients were also tested with trans-cutaneous stimulation of the motor cortex and found tohave normal stimulus response curves, cortical inhibi-tion, and facilitation.

On the other hand, there are several lines of evidencepointing to a brainstem origin for the startle response inhyperekplexia: (1) Pathology in symptomatic cases isoften confined to the brainstem1; (2) familial cases aredue to mutations in the alpha1 subunit of the inhibitoryglycine receptor, and glycine receptors are particularlyconcentrated in the brainstem (and spinal cord) of themammalian central nervous system7; (3) the latency ofelectromyographic (EMG) responses to taps to the head/face is often <20 msec (Fig. 1) and is in these cases onlycompatible with relay within the brainstem1,3; and (4) therecruitment of cranial nerve-innervated muscles is cau-dorostral in the startle, as in brainstem reticular reflexmyoclonus.1

The caudorostral recruitment of cranial nerve inner-

Key words: hyperekplexia; startle response; familial hyperekplexia;brainstem

*Correspondence to: Peter Brown, Sobell Department of Neuro-physiology, Institute of Neurology, London WC1N 3BG, United King-dom. E-mail: p.brown@ion.ucl.ac.uk

Movement DisordersVol. 17, Suppl. 2, 2002, pp. S79–S82© 2002 Movement Disorder SocietyPublished by Wiley-Liss, Inc.DOI 10.1002/mds.10065

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vated muscles in the startle is the most contentious ob-servation supporting a brainstem origin for the hyperek-plectic startle response. There is little doubt that theshortest latency responses to taps to the face may followthis rule, so that the earliest muscle activity is recorded insternocleidomastoid and later in orbicularis oculi andmasseter (Fig. 1). However, the picture is more compli-cated in the startles of longer latency that follow auditorystimulation (or responses to taps in some patients). Here,the earliest EMG activity is orbicularis oculi, with ster-nocleidomastoid then masseter following (Fig. 2). Butthis early response in orbicularis oculi may be due to asimultaneously induced physiological blink reflex andseparate from the true generalised startle response in thismuscle, as may be the case in the physiological startleresponse. Certainly two components in the EMG re-sponse in this muscle are common, one perhaps due tothe blink reflex and a later one due to the pathologicalstartle reflex.1,3

There are other features in the recruitment order of

muscles in the startle of hyperekplexia that merit com-ment. EMG activity in trunk and limb muscles followsthat in sternocleidomastoid, usually at intervals that are afew milliseconds longer than those seen after synchro-nous activation of muscles through the pyramidal tract,either as in cortical myoclonus or as follows transcuta-neous stimulation of the motor cortex.1 The responsesrecorded in the intrinsic hand and foot muscles (Figs. 1and 2) are particularly delayed relative to more proximallimb muscles.1,3 This finding is also a feature of thephysiological human startle reflex.

Studies of the recruitment order of muscles in thestartle response must be carefully controlled, as stimulusparameters such as intensity, repetition rate, and site mayall have an influence on the absolute latency of the re-

FIG. 2. Electromyographic (EMG) activity in the abnormal startleresponse elicited by auditory stimulation in a patient with symptomatichyperekplexia. The unrectified EMG activity in three single trials issuperimposed. Each trial was started at the point of presentation of a124-dB tone. After the normal auditory blink reflex, EMG activity wasrecorded first in sternocleidomastoid (SCM), then later in masseter andtrunk and limb muscles. The latencies to the intrinsic hand muscles ofthe hand and foot were disproportionately long. The upper verticalcalibration line refers to the upper three channels, and the lower cali-bration line refers to the lower five channels. 1DI, first dorsal interos-seus; Rect abdominis, rectus abdominis; Tib anterior, tibialis anterior;Abd hal brevis, abductor hallucis brevis. Reprinted from Brown et al.with permission.1

FIG. 1. Electromyographic (EMG) activity in the abnormal startleresponse elicited by taps to the head in patient with symptomatic hy-perekplexia. The unrectified EMG activity in three single trials is su-perimposed. Each trial was started at the point of tapping. EMG activitywas recorded first in sternocleidomastoid (SCM), and then later inorbicularis oculi (Orbic oculi), masseter, trunk, and limb muscles. Thelatencies to the intrinsic hand muscles of the hand and foot were dis-proportionately long. 1DI, first dorsal interosseus; Rect abdominis,rectus abdominis; Tib anterior, tibialis anterior; Abd hal brevis, abduc-tor hallucis brevis. Reprinted from Brown et al. with permission.1

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sponse.3 Even more importantly, the subject’s posture,presence of voluntary contraction, or even preparation tomove can have a profound effect on the pattern of thenormal and abnormal startle.8,9 Such mutability maycome about through the ability of postural and otherinfluences to independently affect each component of aseries of waves of bulbospinal activity, resulting in reflexresponses of differing latency and form. The changeablenature of the startle response is most clearly seen duringgait, during which startle amplitude is modulated by thestep cycle, in a way that would promote stability.10

Etiology of Hyperekplexia

Familial Hyperekplexia

Hyperekplexia can be inherited, almost always as anautosomal dominant trait, or sporadic. Familial forms aredue to missense mutations in the gene for the alpha1

subunit of the glycine receptor on the fifth chromosome.7

As well as an exaggerated startle, patients have a historyof stiffness as a baby and often have episodes of repeti-tive myoclonic jerks, particularly during or when goingoff to sleep and hyperreflexia. A hesitant, wide-basedgait, apnoeic attacks as a baby, epilepsy, and low intel-ligence may also occur.11,12 However, the most impor-tant aspect of the condition for the patient is the existenceof attacks of generalised stiffness in response to someunexpected stimuli.11 These episodes tend to follow thebrief body jerk, last a few seconds, and are by no meanselicited by every stimulus presentation. Consciousness ispreserved. Nevertheless, these spasms frequently culmi-nate in a fall with injury. Tonic spasms, unlike the moreconsistent and shorter latency startle reflex, tend to im-prove with anticonvulsants. Opinion is divided as towhether tonic spasms are an obligate feature of geneti-cally defined hyperekplexia. In particular, in the Dutchpedigree, only family members with tonic spasms werefound to carry the mutation.13 Although clinically strik-ing, the startle response is not the only abnormality dem-onstrated by patients with hyperekplexia. As alreadymentioned, these patients may also have stimulus-induced tonic spasms and spontaneous paroxysms ofjerking, often at night. The origin of either phenomenonis unknown. Cortical abnormalities such as epilepsy andgiant evoked potentials may occur but are unusual. Theremaining functional abnormalities relate to brainstemand spinal function. Slowing of horizontal saccadic eyemovements may be found in familial hyperekplexia andis further evidence of disturbed activity in the pontinereticular formation. The first period of spinal reciprocalinhibition is deficient in similar patients, consistent withits mediation by the glycinergic Ia inhibitory interneu-

ron,14 and spinal flexor reflexes may be exaggerated.3

The increased excitability may very well account for thestiffness described in hyperekplexia.

Sporadic HyperekplexiaSporadic cases of hyperekplexia do not seem to have

a genetic basis.15,16Indeed, many are symptomatic and aconsequence of brainstem pathology such as infarct,haemorrhage, or encephalitis.1 They, too, may exhibittonic spasms and episodes of sustained myoclonic jerks,which are, therefore, not unique to hereditary hyperek-plexia.1,15 However, stiffness in the neonatal period isnot a feature.

Treatment and PrognosisIt is the tonic spasms of hyperekplexia that present the

greatest problem in this condition, as falls with injury arefrequent. These spasms improve with clonazepam, whichis the drug of choice in hyperekplexia. The startle itselfmay show less striking improvement with medication.Fortunately, the tendency is for hereditary hyperekplexiato improve after the first two decades of life.

CONCLUSIONIn summary, hyperekplexia is characterised by an ab-

normal startle response that is relayed in the brainstemand likely involves a pathological exaggeration of thephysiological startle reflex. The physiological and patho-logical startle responses are mutable, being modulated bya number of factors, including posture and gait. The hy-perekplectic startle is but one of several abnormal fea-tures in hyperekplexia, reflecting the distributed natureof glycinergic receptors within the central nervous sys-tem.

REFERENCES

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