Approach to exaggerated startle reflex: a case of hyperekplexia minor

Abstract

A broad set of conditions may present with an exaggerated startle reflex in clinics. This, combined with the overall rarity of these disorders, may pose diagnostic uncertainty in the mind of the treating physician. Herein, we report a case of a patient who presented to us with the complaint of exaggerated startle reflex and outline a simple approach towards characterisation of these disorders.

Background

The ‘startle’ (Greek: sudden shock or alarm) reflex (SR) is a physiological phenomenon that occurs in response to a sudden unexpected stimulus.¹ Evolutionarily, it can be considered a protective reflex which orients the body towards the perceived threat and prepares it to take an appropriate action (fight or flight).² The reflex is mediated by the caudal brainstem and consists of a generalised, symmetrical and synchronous activation of muscles causing flexion at the neck, trunk, elbow, hips and knees along with facial grimace and abduction of shoulders¹; the movements predominantly involving the upper body. The inciting stimuli are mostly auditory and tactile but can also be visual and vestibular. This normal phenomenon may become exaggerated in terms of magnitude and lack of habituation, and a lower threshold, referred to as ‘exaggerated startle reflex’.^{1 3} An exaggerated SR has broad differential and given overall rarity, poses a diagnostic challenge. We report a case of exaggerated SR and discuss all the diagnostic possibilities with etiological categories and clinical features helpful in characterisation.

Case presentation

A 39-year-old man without known comorbid conditions, presented in our neurology clinic with 13-year history of brief generalised body jerks triggered by sudden unexpected auditory or tactile stimuli, the latter especially over the shoulders or back of the upper trunk. He reported onset after a brief febrile illness. These episodes were not associated with loss of consciousness or falls. The jerks were strictly stimulus sensitive without any premonitory sensation and were not suppressible (see video 1). He did not notice any variability with caffeine intake or stress and had never taken alcohol.

Video 1.

Download video file ^{(2MB, mp4)}

DOI: 10.1136/bcr-2019-232370.video01

The patient had never had any seizures. There were no symptoms to suggest any systemic medical illness. His parents were unrelated and there was no family history of similar symptoms. He denied alcohol use or a significant medication history. The neurological examination otherwise did not reveal any abnormality. Specifically, no startle response was elicited on tactile stimulation of the hands.

Investigations

MRI of the brain was unremarkable. Electroencephalography (EEG) with recording of exaggerated SR did not show any epileptiform correlation.

Treatment

Tablet clonazepam 0.5 mg every night at bedtime (qHS) was prescribed along with reassurance regarding the benign nature of disease.

Outcome and follow-up

The history, examination findings and the workup were consistent with the diagnosis of ‘hyperekplexia minor’. The patient experienced 90% subjective improvement in symptoms on clonazepam 0.5 mg qHS on follow-up visit at 4 weeks. As he could not physically come for further follow-up, he was interviewed over the telephone after 6 months, reporting almost complete remission of symptoms.

Discussion

The SR is mediated by the caudal brainstem, specifically nucleus reticularis pontis caudalis which receives input from the cochlear nuclei (auditory stimulus) and in turn excites the bulbar and spinal motor neurons.^{2 4} Strauss was the first to describe the phenomenology of startle motor behaviour following pistol shots (16 frames/s).¹ Many studies with extensive electromyography (EMG) have added considerably to our understanding. The initial motor phase, also called ‘muscular tension reflex’ starts by activity in the orbicularis oculi mediated by the caudal brainstem followed by rostrocaudal spread of activity involving the sternocleidomastoid, mentalis, masseter, trunk and limb muscles in succession. The first phase demonstrates limited intra-individual and inter-individual variability.¹ This has been thought of as a reflex that allows the body to adopt a stable defensive stance.^{1 4} The initial response is followed by a period of quiescence for up to 300 ms before a second ‘behavioural’ response is observed. This second orienting response is more variable and depends on the startling stimulus and the context in which the SR occurs. Manifestation of the increased autonomic activity in the form of decreased galvanic skin resistance, increased heart rate and blood pressure is seen during this phase.¹

The differential for exaggerated startle is broad. Major differentiating features of some of the disorders with exaggerated SR are given in table 1.

Table 1.

Major differentiating features of causes of exaggerated startle reflex

	Hyperekplexia	Paroxysmal kinesogenic dyskinesia	Episodic ataxia-1	Cataplexy	Brainstem reflex myoclonus	Reflex epilepsy
Classification/types	Major, minor	Primary and secondary	–	–	–	Generalised, focal
Inheritance	AD, AR and sporadic	AD and sporadic	AD and sporadic	Mostly sporadic	Acquired	AD/unclear
Effector mechanism	Glycine receptor abnormality*	PRRT 2 dysregulation in primary PKD	Potassium channelopathy	Loss of hypocretin-producing neurons	Brainstem anoxic event	Hyperexcitable focus in brain (?cause)
Stimulus sensitivity	Unexpected auditory and tactile stimulus (especially over mantle area)	Sudden movement	Sudden movement, physical and emotional stress, also by startle	Laughing and startle	Tactile stimulus (especially over limbs)	Specific triggers (sound, light and so on)
Age of onset	Birth (major), later life (minor)	Children and young adults	Children and young adults	Teenage and young adults	Any age	Children and young adults
Associated findings	Generalised stiffness in major form	Secondary form associated with MS, CNS trauma	Myokymia	Narcolepsy	Usually decreased conscious level	Abnormal EEG
Loss of consciousness	Negative	Negative	Negative	Negative	Usually positive	Negative/positive
Duration	Few seconds for the startle response	Typically less than 1 min	Usually seconds to minutes	Few seconds to less than a minute	Brief	Usually up to 60 s
Number of episodes	Many per day	Up to 100 per day	Up to 30 times per day	Many per day to only a few in life time)	Variable	Variable
Treatment choice	Clonazepam	AED (CBZ, phenytoin)	Acetazolamide	Sodium oxybate	Clonazepam, 5-HT (generally unsatisfactory)	AED

*Most common.

AD, autosomal dominant; AED, antiepileptic drug; AR, autosomal recessive; CBZ, carbamazepine; CNS, central nervous system; EEG, electroencephalography; 5-HT, 5-hydroxytryptophan; MS, multiple sclerosis; PKD, paroxysmal kinesogenic dyskinesia; PRRT 2, proline-rich transmembrane protein 2.

We now review common causes of startle syndromes, highlighting salient features useful in characterisation.

Hyperekplexia

Hyperekplexia, also known as hereditary startle disease, is characterised by exaggerated startle response to ordinary stimuli and hypertonia in the neonates. It is a rare neurogenetic disorder which is possibly treatable.⁵

Hyperekplexia (Greek: exaggerated startle) was first described in 1958³ and thought to have both psychiatric (exaggerated response to emotional stimuli) and epileptic (presumed astatic seizures) origin.¹ The definite site of origin of startle is not established yet. However, loss of cortical neurons on magnetic resonance spectroscopy points towards a cortical origin. Whereas, in symptomatic patients, the pathology is mostly confined to the brainstem.⁶

Two clinical forms have now been described—‘major’ and ‘minor’. Hyperekplexia major is more severe form with symptoms at birth characterised by triad of excessive startling, generalised stiffness and temporary increase in stiffness with startle^{1 3}; without loss of consciousness. The earlier presumed ‘drop attacks’ are actually falls resulting from inability to maintain balance due to rigidity.

A second relatively benign form of primary startle syndrome is labelled as hyperekplexia ‘minor’. Patients present solely with exaggerated startle and lack other defining features of ‘major’ form.¹ These patients lack other neurological signs. EEG is unremarkable in both forms of primary hyperekplexia, and a confident diagnosis can usually be made once startle epilepsy is ruled out.

The inheritance is predominantly autosomal dominant but recessive inheritance as well as sporadic cases has been described.⁵ The most common mutation (80%) is in alpha-1 subunit of inhibitory glycine receptor followed by mutations in GlyT2 gene (20%), encoding pre-synaptic glycine transporter 2.¹ In humans, glycine receptors (GlyRs) have four functional subunits namely Glya1–a3 and b subunits, which exist in heteromeric ab combinations and span through the postsynaptic membrane. GlyR is a pentameric ligand-gated chloride channel which is strychnine sensitive and is responsible for synaptic inhibition with high expression in spinal cord and brainstem.⁷ Isolated few sporadic cases have been reported with mutations in other postsynaptic glycinergic synapses including the genes encoding the receptor clustering protein gephyrin (GPHN) and collybistin, which are less frequently involved in primary hyperekplexia.⁸ Similar mutations are not seen in patients with hyperekplexia minor, and it appears to be genetically heterogenous category without a direct genetic relationship with hyperekplexia major form.¹

Treatment of choice for hyperekplexia is clonazepam which provides symptomatic improvement, especially in gene-positive cases, by dampening the exaggerated reflex and alleviating associated anxiety.⁹ Other treatments such as clobazam, sodium valproate, piracetam,⁷ carbamazepine, diazepam, phenytoin, 5-hydroxytrptophan (5-HT) and phenobarbital have been tried with variable benefit. No randomised clinical trials are available to advocate the superior efficacy of these drugs.¹⁰ Physical and cognitive therapy may also be considered especially in major form which reduces the fear of falling, and in turn, improves ability to walk.¹¹ Attacks of tonic neonatal cyanosis, seen in the major form, can be stopped by the Vigevano manoeuvre, consisting of forced flexion of the head and legs towards the trunk.¹¹

Given the clinical features of purely exaggerated startle without rigidity and stiffness but with unremarkable EEG and brain imaging, we made diagnosis of hyperekplexia minor in our patient. Genetic testing for this disorder is not done at our hospital, hence, it was not pursued. Poly EMG was also not performed due to lack of availability.

Stimulus induced disorders

These disorders are provoked by a startling stimulus and show excessive responses beyond simply an exaggerated SR.³ These disorders are divided into epileptic (reflex epilepsy and progressive myoclonus epilepsy) and non-epileptic (paroxysmal kinesogenic dyskinesias (PKDs), episodic ataxias (EAs), cataplexy and reflex myoclonus).

Paroxysmal dyskinesias

These represent a group of movement disorders characterised by hyperkinetic movement phenomena only during the attacks with normal movements in between. Of these, PKD is characterised by paroxysmal episodes of abnormal movement phenomena (chorea, dystonia, ballism or a combination) triggered by a sudden movement or stimuli, including startle. The attacks are short lived (usually <1 min) and may occur up to 100 times a day.³ The age of onset is usually childhood to adolescence (7–15 years) with predominantly affecting males (4:1 up to 8:1). The proline-rich transmembrane protein 2, located on chromosome 16, has been identified as a major causative gene for PKD. Consciousness is always preserved during an attack and EEG is unremarkable, though patients have an excellent response to antiepileptic drugs (AEDs) such as carbamazepine and phenytoin.^{1 3} Other second line drugs may include acetazolamide, topiramate, hydantoin, barbiturates and benzodiazepines.³ In paroxysmal non-kinesogenic dyskinesia, even though the episodic hyperkinetic movements are not provoked by sudden movement or startle but they may occur spontaneously during stressful situations, fatigue, alcohol or caffeine intake. The attack may last anywhere between a few minutes up to 4 hours. EEG, neurological examination and brain imaging are unremarkable in primary paroxysmal non-kinesogenic dyskinesia.¹² Mutations in myofibrillogenesis regulator 1 gene on chromosome 2 have been described in patients with the classic variety, with onset at a young age and attacks precipitated by alcohol and caffeine intake.¹² The treatment is less successful than in the kinesogenic type, but clonazepam and carbamazepine may be tried.¹²

Episodic ataxias

These are characterised by short lived brief attacks of ataxia with normal cerebellar function in between attacks. There are various types (1–7) and attacks in EA. EA-1 may be triggered by sudden movements, physical and emotional stress, and also by startle.¹³ Patients may have up to 30 attacks per day. In between these episodes, patients have varying degrees of neuromyotonia. EA-1 is a potassium channelopathy caused by mutation in KCNA1 gene. The dysfunction of this channel leads to neuronal hyperexcitability. Acetazolamide, a carbonic anhydrase inhibitor, is the drug of choice.³ Overall, EA-2 is the the most common subtype with attacks provoked by exercise, physical and emotional stress. Between the attacks, these patients may be normal or may have nystagmus and mild baseline ataxia.¹³ The other subtypes are rare with later age of onset (EA-4 and EA-5) and sometimes variable features between the attacks, such as tinnitus, vertigo and diplopia (EA-3), migraine (EA-6). The features in EA-7 are similar to EA-2 but without the clinical findings seen between the attacks.¹³

Cataplexy

Cataplexy is a sleep-related disorder characterised by sudden transient (3–50 s) bilateral muscle weakness with preserved consciousness. Patients may have sudden falls resulting in injuries during these episodes. They are usually triggered by emotions, particularly laughing and startle. Onset is usually during teenage and young adulthood. It is usually associated with narcolepsy which can be diagnosed by multiple sleep latency test. Pathology involves a loss of hypocretin-producing neurons in the posterolateral hypothalamus. Cataplexy attacks respond well to sodium oxybate, a natural metabolite of gamma aminobutyric acid (GABA) that acts on GABA-B receptors.³

Reflex myoclonus

Myoclonus manifests as brief, quick involuntary jerks (positive myoclonus) or interruptions of tonic muscle activity (negative myoclonus). It can be classified based on anatomic origin into cortical, subcortical (reticular), spinal and peripheral varieties. Brainstem or reticular myoclonus closely resembles the SR and is marked by a generalised and synchronised axial muscle contraction. It commonly occurs in temporal association with an anoxic event being generated by the reticular formation of the brainstem. The signal is transmitted both caudally down the spinal cord to the upper and lower limbs and rostrally to upper brainstem, just as in case of SR although with even shorter onset latencies.³ EEG is unremarkable. Differentiation from the SR based on the clinical findings alone is difficult. Stimulus sensitivity, particularly over the limbs is seen in cases of reflex myoclonus whereas patients with hyperekplexia are stimulus sensitive over the mantle area.¹ Treatment options are unsatisfactory but clonazepam and 5-HT may provide some relief.³

Reflex epilepsy

Reflex epilepsy is induced by a specific afferent stimulus or activity of the patient.³ Startle epilepsy has resemblance with startle syndromes and seizures occur in response to a startling stimulus (usually auditory). Patients are typically young and have preexisting structural brain disease of variable etiologies. They have startle induced and spontaneous seizures which are brief (up to 30 s), symmetrical and include axial tonic posturing, which frequently results in traumatic falls. Autonomic signs, automatisms and laughter may accompany the ictal events. The ictal and interictal EEG usually reveal an abnormality.³ The treatment is difficult and several AEDs including carbamazepine, valproic acid, levetiracetam may be tried.³

Neuropsychiatric startle syndromes

Neuropsychiatric startle syndromes such as Latah, Jumping Frenchmen of Maine and Myriachit are a group of culture-specific disorders characterised by exaggerated startle followed by automatic obedience sometimes in violent and humiliating forms.⁷ Their rarity and existence limited to specific cultural contexts does not make them a top differential in routine clinical settings. The reader is referred to literature¹⁴ for further discussion on these conditions.

Even though exaggerated startle can be a manifestation of many disorders, through history-taking and targeted workup can rule out differentials within each category. An algorithmic approach towards a patient with exaggerated SR is shown in figure 1.

Figure 1.

Flow chart for evaluation of exaggerated startle reflex. Red arrow: present/abnormal, green arrow: absent/normal. EA-1, episodic ataxia—type 1; EEG, electroencephalography; PKD, paroxysmal kinesogenic dyskinesia; PRRT 2, proline-rich transmembrane protein 2.

Learning points.

• Hyperekplexia or exaggerated startle reflex can be a presenting symptom in a number of diseases.

• If approached in a systematic manner, an underlying diagnosis can be reached in a quick time without having to undertake extensive diagnostic workup.

• Patients with hyperekplexia minor can be reassured of its benign nature and clonazepam prescribed for symptomatic control.