Extrapyrammidial effect

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Extrapyramidal Effects (EPS)

Overview

Extrapyramidal side effects (EPS) are movement disorders that arise from drug-induced disruption of the nigrostriatal dopaminergic pathway. They occur primarily with antipsychotics (neuroleptics) that block dopamine D2 receptors in the basal ganglia. High-potency first-generation (typical) antipsychotics (e.g., haloperidol, fluphenazine) carry the highest risk. Second-generation (atypical) antipsychotics cause fewer EPS because they have lower D2 affinity and higher 5-HT2A antagonism.

Key Mechanism: Blockade of D2 receptors in the striatum (caudate-putamen) reduces dopaminergic tone, disrupting the normal balance between dopaminergic inhibition and cholinergic excitation in the basal ganglia. EPS risk correlates directly with D2 receptor affinity.

Classification of EPS

EPS are divided into acute (onset within days to weeks) and chronic/tardive (onset after months of treatment).

1. Acute Dystonia

Onset: First 48-96 hours (50% within 48 h; 90% within 5 days)

Features:

Involuntary, sustained muscle spasms of the head, neck, trunk, and limbs
Oculogyric crisis - eyes deviated upward
Torticollis / retrocollis - neck twisted or pulled back
Opisthotonos - arching of the back
Macroglossia / tongue protrusion - risk of choking
Laryngeal dystonia - rare but life-threatening (stridor, dyspnea, respiratory distress)
Trismus (jaw spasm), facial grimacing

Risk factors: Young males, high-potency antipsychotics at high doses, first doses

Treatment: IV/IM diphenhydramine (25-50 mg) or benztropine (1-2 mg IV). Oral maintenance for 2-3 days afterward. Responds rapidly.

2. Akathisia

Onset: Within hours to days (most within the first week)

Features:

Subjective inner restlessness and compulsion to move
Objective signs: foot shuffling, leg crossing/uncrossing, rocking foot-to-foot, pacing
Can be mistaken for psychotic agitation, leading to dose escalation that worsens it
One study found 41% of patients on dopamine antagonists had mild akathisia; 21% had moderate-severe akathisia
Linked to suicidal ideation and aggression

Treatment: Reduce antipsychotic dose; propranolol (30-90 mg/day) is effective; benzodiazepines; switch to a lower-risk agent

3. Drug-Induced Parkinsonism

Onset: 5-30 days; up to 60% of antipsychotic-treated patients; 90% of cases within 3 months

Features:

Bradykinesia, mask-like facies, shuffling gait, cogwheel rigidity, pill-rolling tremor
Bradyphrenia (slowed thinking), hypersalivation
Diminished arm swing and reduced facial expressiveness are early signs
Positive glabella tap
Can be mistaken for depression or negative symptoms of schizophrenia

Risk factors: Older age, higher doses, history of parkinsonism, female sex

Treatment: Anticholinergic antiparkinson drugs (benztropine, trihexyphenidyl); reduce dose; switch to SGA. Note: anticholinergics only partially effective and carry their own side effects (dry mouth, constipation, memory loss).

4. Tardive Dyskinesia (TD)

Onset: After months to years of treatment (chronic EPS)

Features:

Orofacial movements: lip smacking, sucking, puckering, tongue protrusion ("fly-catching"), facial grimacing
Choreiform hand movements ("piano-playing" fingers), choreoathetoid movements of limbs and trunk
Pelvic movements
Severity ranges from mild to severely disabling (affecting speech, eating, breathing)

Mechanism: Chronic D2 blockade leads to receptor upregulation (supersensitivity) in the striatum. This is why dopamine agonists worsen TD and dopamine blockers transiently suppress it.

Prevalence: Approximately 4-5% new cases per year with D2 antagonists; 10-20% of patients on long-term treatment; 15-20% in chronically institutionalized patients

Risk factors: Older women are most vulnerable; affective disorders; higher doses and longer duration; prior acute EPS

Treatment:

Reduce/discontinue the offending agent (movements may temporarily worsen - "withdrawal-emergent dyskinesia" before improving)
Switch to clozapine or quetiapine (lowest EPS risk)
Valbenazine and deutetrabenazine (VMAT2 inhibitors) - FDA approved in 2017 for TD
Anticholinergics can WORSEN TD

Prognosis: Not necessarily progressive - may stabilize and improve. Younger patients with recent onset have best remission rates.

5. Perioral Tremor ("Rabbit Syndrome")

Rhythmic perioral (lip and nose) movements resembling a rabbit's chewing; tongue is spared
Associated primarily with FGAs but reported with SGAs
Responds to anticholinergic drugs (unlike TD)

6. Neuroleptic Malignant Syndrome (NMS)

Although sometimes classified separately, NMS represents a severe, potentially fatal EPS-related idiosyncratic reaction.

Onset: Usually first 2 weeks; incidence 0.01-3% of antipsychotic-treated patients; mortality ~5%

Classic Tetrad:

Altered mental status (confusion, stupor)
"Lead-pipe" muscular rigidity
Hyperthermia (fever)
Autonomic instability (labile BP, tachycardia, diaphoresis)

Risk factors: Males 20-25 years old; high-potency FGAs; parenteral formulations; rapid dose escalation; dehydration; previous NMS episodes

Treatment: Immediate discontinuation of antipsychotic; supportive care; dantrolene; bromocriptine or amantadine; cooling measures

Drugs by EPS Risk (Highest to Lowest)

Risk Level	Drugs
Highest	Haloperidol, fluphenazine, trifluoperazine (high-potency FGAs)
Moderate	Chlorpromazine, thioridazine (low-potency FGAs), risperidone (dose-dependent)
Low	Olanzapine, ziprasidone, aripiprazole
Lowest	Clozapine, quetiapine

Why SGAs Cause Less EPS

Second-generation antipsychotics (SGAs) are generally at least as potent in blocking 5-HT2A receptors as D2 receptors. Serotonin antagonism in the striatum enhances dopamine release, partially offsetting D2 blockade. Clozapine and quetiapine have particularly low D2 affinity. Aripiprazole and brexpiprazole act as partial agonists at D2 receptors rather than pure antagonists.

Treatment Summary Table

EPS Type	First-Line Treatment
Acute Dystonia	Diphenhydramine 25-50 mg IV/IM OR Benztropine 1-2 mg IV
Akathisia	Propranolol 30-90 mg/day; dose reduction
Drug-induced Parkinsonism	Benztropine, trihexyphenidyl; dose reduction
Tardive Dyskinesia	Valbenazine / Deutetrabenazine; switch to clozapine
NMS	Stop drug; dantrolene; bromocriptine; supportive care

Sources: Kaplan & Sadock's Comprehensive Textbook of Psychiatry; Kaplan & Sadock's Synopsis of Psychiatry; Maudsley Prescribing Guidelines, 15th ed.; Katzung's Basic and Clinical Pharmacology, 16th ed.; Rosen's Emergency Medicine; Tintinalli's Emergency Medicine

Transverse myelitis and gbs features

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Transverse Myelitis (TM) and Guillain-Barré Syndrome (GBS)

TRANSVERSE MYELITIS

Definition

Transverse myelitis is an acute/subacute inflammatory disorder that involves a complete (or nearly complete) transverse section of the spinal cord, disrupting both ascending and descending tracts. It is presumed to be autoimmune in origin.

Etiology / Associations

Category	Examples
Post-infectious (30%)	Viral infections (EBV, CMV, enteroviruses, HSV)
Autoimmune	SLE, Sjögren syndrome, antiphospholipid syndrome, mixed CTD
Demyelinating	Multiple sclerosis, NMOSD (anti-AQP4 antibody positive)
Post-vaccination	Rare
Idiopathic	~30% - no cause identified

Anti-AQP4 antibodies (aquaporin-4) are found particularly in NMOSD-related cases
When TM spans 3 or more spinal cord segments, it is termed Longitudinally Extensive Transverse Myelitis (LETM) - a hallmark of NMOSD

Clinical Features (Classic Triad)

Motor deficits - weakness progressing to paraplegia; initially UMN signs (hypertonia, hyperreflexia, clonus, Babinski sign)
Sensory level - distinct transverse band of sensory impairment; bilateral but may be asymmetric
Sphincter dysfunction - urinary retention/incontinence, fecal incontinence; anal sphincter dysfunction

Additional features:

Back or neck pain (often the first symptom)
Low-grade fever (raises concern for infectious etiology)
Autonomic instability: hypo/hypertension, tachy/bradycardia
Thoracic cord affected in 60-70% of cases

Onset: Rapid - 66% reach maximal deficit within 24 hours; can progress over days to weeks

Investigations

Test	Finding
MRI spine (with gadolinium) - investigation of choice	T2 hyperintensity, cord enlargement, gadolinium enhancement
CSF	Normal in 40%; others show mild elevated protein ± lymphocytic pleocytosis
Serology	Anti-AQP4, ANA, antiphospholipid antibodies

MRI findings may lag clinical presentation early in the disease.

Differential Diagnosis

Multiple sclerosis
Spinal epidural abscess (SEA)
Spinal cord infarct (anterior spinal artery syndrome)
Epidural hematoma
Spinal cord tumor (primary or metastatic)
Vitamin B12 deficiency

Treatment

Methylprednisolone 1g IV (commonly used; especially in NMOSD-associated TM)
Plasma exchange (if steroid-refractory)
Immunosuppressants (in NMOSD)
Neurologic consultation; hospitalization required
Supportive: bladder catheterization, DVT prophylaxis, physiotherapy

Prognosis

Most patients begin recovery within 1-3 months; maximal improvement at 3-6 months
30% "good" recovery, 25% "fair", 30% "poor"
15% mortality at 5 years

GUILLAIN-BARRÉ SYNDROME (GBS)

Definition

GBS is an acute immune-mediated polyradiculoneuropathy (primarily affecting peripheral nerves and nerve roots). The most common form - Acute Inflammatory Demyelinating Polyneuropathy (AIDP) - involves multifocal inflammatory demyelination of spinal roots and peripheral nerves. It is the leading cause of acute flaccid paralysis in the developed world.

Incidence: 1.8 per 100,000/year; males > females (1.5:1); incidence increases with age.

Subtypes and Variants

Common Subtypes:

Subtype	Pathology	Features
AIDP (most common in West)	Demyelinating	Classic GBS; slowed NCV
AMAN (most common in Asia)	Pure motor axonal	Normal SNAPs, reduced CMAPs; often post-Campylobacter
AMSAN	Motor + sensory axonal	Severe; poor recovery

Rare Variants:

Miller-Fisher Syndrome (MFS) - triad of ophthalmoplegia, ataxia, areflexia (anti-GQ1b antibodies); 6% of GBS in West, up to 18% in Taiwan
Pharyngeal-cervical-brachial variant
Facial diplegia with paresthesias
Acute pandysautonomia
Paraparetic variant

Etiology / Precipitants

Typically follows infection by 1-4 weeks:

Campylobacter jejuni (most common; associated with AMAN)
CMV, EBV, Mycoplasma pneumoniae
Influenza, HIV, Zika virus
Post-vaccination (rare)

Clinical Features

Required for Diagnosis:

Progressive weakness of both legs and arms (ascending, relatively symmetrical)
Areflexia or hyporeflexia (universal; may be absent early)

Supportive Clinical Features:

Progression over days to 4 weeks (plateau then recovery)
Ascending pattern: starts in lower limbs, moves up
Mild sensory symptoms - distal paresthesias; sensory loss limited (vibration most affected)
Pain in extremities/back/interscapular area in ~70% of patients (may precede weakness)
Bilateral facial palsy in ~50% of patients
Cranial nerve involvement in 45-75%
Autonomic dysfunction in 65% of hospitalized patients (labile BP, sinus tachycardia, bradycardia/asystole from vagal spells, urinary retention, ileus, anhidrosis)
Respiratory failure in 9-30% (risk rises with age) - can require mechanical ventilation

Key: NO fever at onset, NO meningismus, absent or mild sensory loss, prominent areflexia despite active motor weakness.

Investigations

Test	Finding
CSF	Albuminocytological dissociation - elevated protein (>45 mg/dL) with <10 cells/μL (normal cell count); develops after first week
Nerve conduction studies (NCS)	Slowed conduction velocities, prolonged distal latencies, conduction blocks (AIDP); reduced CMAP amplitudes (AMAN)
Anti-GQ1b antibodies	Positive in Miller-Fisher syndrome and pharyngeal-cervical-brachial variant
Anti-GM1, anti-GD1a	Positive in AMAN

Treatment

IVIG (2 g/kg over 5 days) - equally effective as plasma exchange
Plasma exchange (plasmapheresis) - 5 sessions over 2 weeks
NOT corticosteroids (steroids are NOT beneficial in GBS)
Respiratory monitoring: intubate if FVC <15-20 mL/kg or rapid decline
Cardiac monitoring for arrhythmias (vagal spells can cause sudden asystole)
DVT prophylaxis, analgesia, bladder care

Prognosis

Recovery begins 2-4 weeks after progression ceases
Mortality: reduced from 33% (pre-ICU era) to 1-5% with modern critical care
~80% walk independently at 6 months
Poor prognostic factors: older age, rapid progression, preceding C. jejuni infection, axonal subtype, need for ventilation

KEY COMPARISON: TM vs GBS

Feature	Transverse Myelitis	Guillain-Barré Syndrome
Site of lesion	Spinal cord (CNS)	Peripheral nerves/roots (PNS)
Motor pattern	Paraplegia (UMN early → LMN in acute phase)	Flaccid weakness, ascending
Reflexes	Initially hyperreflexia (UMN) → may be reduced acutely	Areflexia - hallmark
Sensory level	Clear transverse sensory level	Distal sensory loss (mild); no sensory level
Bladder/bowel	Early and prominent	Late or absent (autonomic)
CSF	Normal or mild pleocytosis + elevated protein	Albuminocytological dissociation (high protein, normal cells)
MRI spine	T2 cord signal change	Normal spinal cord
Autonomic	Possible	Prominent (65%)
Cranial nerves	Rare (cervical cord)	Common (45-75%), especially facial diplegia
Respiratory failure	Rare (cervical cord involvement)	Common (9-30%)
Treatment	IV steroids ± plasma exchange	IVIG or plasmapheresis (NOT steroids)
Antibodies	Anti-AQP4 (NMOSD)	Anti-GQ1b (MFS), Anti-GM1 (AMAN)

Sources: Bradley and Daroff's Neurology in Clinical Practice; Rosen's Emergency Medicine; Tintinalli's Emergency Medicine

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