What is the differential diagnosis for an exaggerated startle reflex?

Differential Diagnosis of Exaggerated Startle Reflex

The differential diagnosis for an exaggerated startle reflex includes hyperekplexia (startle disease), stimulus-induced disorders (including epileptic and non-epileptic causes), neuropsychiatric syndromes, drug-induced parkinsonism, serotonin syndrome, neuroleptic malignant syndrome, and paroxysmal movement disorders. 1, 2

Primary Neurological Causes

Hyperekplexia (Startle Disease)

Hyperekplexia is the most important diagnosis to consider when evaluating an exaggerated startle reflex, particularly in neonates and infants. 1

• Key diagnostic features: Excessive startle response to unexpected auditory, visual, or tactile stimuli (particularly auditory), typically including eye blinking and flexor spasm of the trunk, present from birth or evident prenatally in the last trimester 1
• Distinguishing characteristic in neonates: Prolonged stiffening following the excessive startle, contrasting with the brief physiological startle response 1
• Pathognomonic clinical sign: Non-habituating head-retraction reflex to repeated nose tapping (forced flexion of head and legs toward trunk can be life-saving during prolonged stiffness) 3, 4
• Genetic basis: Mutations in the glycine receptor (commonly arginine residue 271), leading to impaired glycinergic inhibition and neuronal hyperexcitability 4
• Presentation timing: Can manifest as abnormal intrauterine movements, or from neonatal period to adulthood 3, 4
• Associated features: Generalized muscular rigidity, nocturnal myoclonus, sustained tonic spasms that may mimic seizures, potential apnea and bradycardia 4
• Critical distinction: Consciousness is preserved during episodes, distinguishing it from epileptic seizures 2
• First-line treatment: Clonazepam (GABA receptor agonist) is the treatment of choice 2, 4

Stimulus-Induced Disorders

This heterogeneous category includes both epileptic and non-epileptic conditions that can be difficult to distinguish clinically. 2

• Frontal lobe epilepsy: Presents with recurrent stereotypic chorea and dystonia, slight disturbance of consciousness, can occur during sleep (unlike hyperekplexia which only occurs when awake) 1
• Paroxysmal kinesigenic dyskinesia (PKD): Triggered by sudden movement, brief episodes (seconds to minutes), clear kinesigenic trigger, consciousness preserved 1
• Diagnostic approach: EEG and video registration are essential to distinguish epileptic from non-epileptic stimulus-induced disorders 2
• Treatment: Antiepileptic drugs including benzodiazepines are frequently effective 2

Drug-Induced Causes

Drug-Induced Parkinsonism (DIP)

DIP is the second most common cause of parkinsonian syndromes after idiopathic Parkinson's disease, accounting for 15-25% of cases in older adults, with 20-35% prevalence among antipsychotic users. 5

• Clinical presentation: Bradykinesia, tremors, and rigidity that develop within hours to weeks of antipsychotic initiation or dose increase 5
• Key distinction: Lacks the waxy flexibility and posturing characteristic of catatonia; responds to anticholinergic agents 6
• Management: Consider switching to quetiapine or clozapine; anticholinergics (trihexyphenidyl 1 mg daily, titrating to 5-15 mg total daily) for tremor and rigidity 5

Serotonin Syndrome

Serotonin syndrome presents with a clinical triad of mental status changes, autonomic hyperactivity, and neuromuscular abnormalities within minutes to hours (usually 6-24 hours) after starting or increasing serotonergic medications. 7

• Highly diagnostic features: Myoclonus, hyperreflexia, and clonus (particularly inducible clonus with agitation or diaphoresis) 7, 6
• Autonomic features: Hyperthermia (up to 41.1°C), tachycardia, hypertension, diaphoresis, mydriasis 7
• Hunter Criteria for diagnosis: Requires serotonergic agent exposure plus one of: spontaneous clonus, inducible clonus with agitation/diaphoresis, ocular clonus with agitation/diaphoresis, tremor and hyperreflexia, or hypertonia with temperature >38°C and ocular/inducible clonus 7
• Treatment: Immediate discontinuation of serotonergic agents; cyproheptadine 12 mg initially, then 2 mg every 2 hours until improvement 7

Neuroleptic Malignant Syndrome (NMS)

NMS develops after antipsychotic initiation or dose increase and presents with lead pipe rigidity, delirium, hyperthermia, autonomic instability, and elevated creatine kinase. 7, 6

• Distinguishing features: Lead pipe rigidity (not the hyperreflexia/clonus of serotonin syndrome), history of antipsychotic exposure 7, 6
• Critical distinction from hyperekplexia: NMS has altered consciousness and medication exposure history 6

Neuropsychiatric Syndromes

These disorders exist on the borderland of neurology and psychiatry with poorly understood etiology. 2

• Characteristic EMG findings: Variable recruitment patterns and presence of a second "orienting" response, distinguishing them from organic causes 2
• Examples: Startle-induced tics, culture-specific disorders (Latah), functional startle syndromes 2
• Clinical challenge: Treatment options are limited but urgently required 2

Psychogenic Movement Disorders

Psychogenic disorders present with distractibility, variability of clinical presentations between episodes, and suggestibility. 1

• Red flags: Adult age of onset, altered responsiveness during attacks, additional psychogenic physical signs, medically unexplained somatic symptoms, atypical medication response 1
• Diagnostic tool: High-knee exercise test may help differentiate from organic causes 1

Vasodepressor (Vasovagal) Reactions

Vasovagal reactions can mimic anaphylaxis or other acute conditions but are distinguished by specific features. 1

• Characteristic presentation: Hypotension, pallor, weakness, nausea, vomiting, diaphoresis 1
• Key distinguishing feature: Bradycardia (not tachycardia), absence of urticaria/angioedema/flush/pruritus 1
• Note: Bradycardia can occur in anaphylaxis via the Bezold-Jarisch reflex (cardioinhibitory reflex from left ventricular sensory receptors transmitted by unmyelinated vagal C fibers) 1

Age-Specific Differential Diagnoses in Infants

Benign Conditions

• Benign myoclonus of early infancy (BMEI): Myoclonic jerks of head/upper limbs in clusters, consciousness preserved, normal ictal EEG, triggered by excitement 1
• Transient dystonia of infancy: Paroxysmal abnormal upper limb posture, onset 5-10 months, resolves between 3 months to 5 years, normal neuroimages 1
• Benign paroxysmal torticollis (BPT): Recurrent painless head postures alternating sides, onset before 3 months, episodes last minutes to days, associated with later migraines 1

Sandifer Syndrome

• Presentation: Paroxysms of head tilt after eating in young children, secondary to gastroesophageal reflux 1

Diagnostic Algorithm

Initial Assessment

1. Determine timing of onset: Neonatal/prenatal (hyperekplexia), hours-to-weeks after medication change (DIP, NMS, serotonin syndrome), childhood (paroxysmal movement disorders), or adult onset (psychogenic, acquired causes) 1, 5, 3

2. Characterize the startle response:

   • Stimulus type: Auditory (hyperekplexia), tactile, visual, or kinesigenic (PKD) 1, 2
   • Duration: Brief jerks (tics), prolonged stiffening (hyperekplexia), 10 minutes-1 hour (PNKD) 1
   • Consciousness: Preserved (hyperekplexia, PKD) vs. altered (epilepsy, NMS) 1, 2

3. Medication history: Recent initiation or dose increase of antipsychotics (DIP, NMS), serotonergic agents within 5 weeks (serotonin syndrome) 7, 5, 6

4. Physical examination specifics:

   • Test nose-tap reflex: Non-habituating head-retraction suggests hyperekplexia 3, 4
   • Assess muscle tone: Lead pipe rigidity (NMS), waxy flexibility (catatonia), hyperreflexia/clonus (serotonin syndrome) 7, 6
   • Vital signs: Hyperthermia with tachycardia (serotonin syndrome, NMS), bradycardia (vasovagal) 1, 7

Diagnostic Testing

• Video recording: Essential for characterizing episodes and distinguishing epileptic from non-epileptic causes 2
• EEG: Fast spikes during tonic spasms followed by slowing/flattening in hyperekplexia; helps distinguish epileptic stimulus-induced disorders 2, 4
• EMG: Almost permanent muscular activity with periods of electrical quietness in hyperekplexia; variable recruitment patterns in neuropsychiatric syndromes 2, 4
• Laboratory studies: Elevated creatine kinase (NMS, severe serotonin syndrome), genetic testing for glycine receptor mutations (hereditary hyperekplexia) 7, 4
• Neuroimaging: MRI brain to evaluate for structural causes, particularly in adult-onset cases or when secondary causes suspected 3

Critical Clinical Pitfalls

• Do not delay treatment in neonates with suspected hyperekplexia: Teach forced flexion maneuver (Vigevano maneuver) to families as emergency rescue measure for apneic episodes 3, 4
• Do not misattribute catatonic symptoms to medication side effects: Parkinsonism from antipsychotics can be mistaken for catatonia 6
• Do not add dopamine-blocking agents if tardive dyskinesia is present: This will worsen the condition 5
• Do not use anticholinergics in elderly patients without considering cognitive side effects: Use amantadine as alternative 5
• Do not assume absence of cutaneous symptoms rules out anaphylaxis: Severe episodes can occur without cutaneous manifestations 1