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Clinical Analysis: 13-year-old with Fever, Vomiting, Bulbar Palsy, Ophthalmoplegia, Ptosis after Swimming

Most Likely Diagnosis: Primary Amoebic Meningoencephalitis (PAM)

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Why PAM Fits This Presentation

"After an incubation period of 2–15 days, severe headache, high fever, nausea, vomiting, and meningismus develop. Photophobia and palsies of the third, fourth, and sixth cranial nerves are common. Rapid progression to seizures and coma may follow. The prognosis is uniformly poor: most patients die within a week." — Harrison's Principles of Internal Medicine 22E, 2025

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Differential Diagnosis

1. Botulism (important to consider — normal sensorium + cranial palsies)

• Bilateral cranial nerve palsies (ptosis, ophthalmoplegia, bulbar = dysarthria/dysphagia) + descending flaccid paralysis + fully conscious patient is the classic botulism triad
• Against it: Fever is NOT a feature of botulism; CSF is normal; no GI prodrome of toxin-type (unless wound/food)
• Normal CSF protein distinguishes botulism from GBS

2. Miller Fisher Syndrome (GBS variant)

• Triad: ophthalmoplegia + ataxia + areflexia
• Can have bulbar weakness; can require ventilation
• Against it: Fever is atypical; swimming pool context not relevant; usually follows a viral infection 1–3 weeks prior; CSF shows albuminocytologic dissociation (elevated protein, no cells)

3. Brainstem Encephalitis (Rhombencephalitis)

• Listeria monocytogenes, Enterovirus 71, HSV-2 can cause brainstem involvement with cranial nerve palsies + fever
• Consider: Enterovirus rhombencephalitis in children

4. Bacterial Meningitis with Cranial Nerve Involvement

• CN VI palsy is most common in bacterial meningitis (elevated ICP)
• Combined ophthalmoplegia + bulbar + fever: consider TB meningitis (basal meningitis)

5. Wernicke's Encephalopathy — ophthalmoplegia + ataxia, but no fever; unlikely in 13-year-old

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Why the Sensorium is Normal (Key Feature)

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Investigations

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Treatment (Medical Emergency)

Combination Regimen (All survivors included these agents):

Adjunctive:

• Therapeutic hypothermia — associated with better outcomes in survivors
• Aggressive ICP management
• Mechanical ventilation (already on)

"All seven survivors among reported worldwide cases (381) included miltefosine as well as the five drugs above. Early diagnosis, prompt combination therapy including miltefosine, and aggressive management of neurologic complications, including therapeutic hypothermia, are important factors in better outcomes." — Harrison's 22E

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Summary Algorithm

13yo + fever + vomiting + swimming pool + CN III/IV/VI palsies + bulbar palsy + ventilator + NORMAL SENSORIUM
         │
         ↓
PRIMARY AMOEBIC MENINGOENCEPHALITIS (Naegleria fowleri) — MOST LIKELY
         │
         ↓
URGENT: Fresh CSF wet mount for motile trophozoites
         + CDC PCR (call CDC immediately)
         │
         ↓
START EMPIRIC TREATMENT WITHOUT WAITING:
Miltefosine + Liposomal AmB + Fluconazole + Azithromycin + Rifampin + Dexamethasone
+ Therapeutic hypothermia

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Prognosis

• Early suspicion and diagnosis
• Prompt initiation of miltefosine-containing combination therapy
• Aggressive ICU/neurological management

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Sources: Harrison's Principles of Internal Medicine 22E (2025); Bradley & Daroff's Neurology in Clinical Practice; Medical Microbiology 9e; Tintinalli's Emergency Medicine; Red Book 2021

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Revised Diagnosis: No Meningismus Changes Everything

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#1 Diagnosis: Wound/Water-Associated Botulism

Why This Is Now the Leading Diagnosis

"The distinct syndrome of bilateral cranial palsies and descending flaccid paralysis in a fully conscious patient should render the diagnosis of botulism straightforward." — Harrison's Principles of Internal Medicine 22E

"No fever or other signs of infection occur [in classic botulism]. A slower moving form of the disease occurs when the toxin is produced endogenously in the intestinal tract or a wound." — Sherris & Ryan's Medical Microbiology 8e

The Fever — How Does It Fit?

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Pathophysiology of the Neurological Pattern

C. botulinum toxin (metalloproteinase)
         ↓
Cleaves SNARE proteins at presynaptic membrane
         ↓
Blocks ACh release at NMJ
         ↓
Descending flaccid paralysis:

  CRANIAL NERVES FIRST (CN III/IV/VI → ptosis + ophthalmoplegia)
         ↓
  BULBAR (CN IX/X/XII → dysphagia, dysarthria, dysphonia)
         ↓
  RESPIRATORY MUSCLES (diaphragm + intercostals → ventilator)
         ↓
  LIMB WEAKNESS (late)

  *** Brain unaffected → Normal sensorium throughout ***
  *** No meningeal inflammation → No neck stiffness ***

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Differential Diagnosis (with No Meningismus)

1. Wound Botulism ← Most Likely

• Swimming pool abrasion → C. botulinum spore germination → in situ toxin → descending NMJ blockade
• Fever from wound infection
• Normal CSF

2. Miller Fisher Syndrome (GBS variant)

• Triad: ophthalmoplegia + ataxia + areflexia
• No fever typically; can have bulbar; CSF shows elevated protein (albuminocytologic dissociation)
• Anti-GQ1b antibodies positive
• Against it: Fever is atypical; can have some overlap but no meningismus fits; ataxia is the key feature (check for it)

3. Foodborne Botulism

• If the child consumed contaminated food around the time of swimming
• Vomiting fits the gastrointestinal prodrome (nausea, vomiting, cramping precede neurological symptoms by hours)
• No fever expected — but possible co-existing illness

4. Myasthenia Gravis (MG) Crisis

• Ptosis + ophthalmoplegia + bulbar + respiratory failure
• Against: Fever not a feature; no exposure history; fatigability worse with exertion; usually chronic history; Tensilon test positive

5. Bickerstaff Brainstem Encephalitis

• Ophthalmoplegia + ataxia + hyperreflexia + impaired consciousness
• Against: Sensorium should be impaired; no fever typically

6. Enterovirus 71 Rhombencephalitis

• Children, fever, brainstem involvement, respiratory failure
• But: usually has altered sensorium, myoclonus, autonomic instability; typically preceded by hand-foot-mouth disease

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Investigations

• Botulism → Normal CSF
• GBS/MFS → Elevated protein, no cells
• PAM → Neutrophilic pleocytosis, low glucose
• Bacterial meningitis → Neutrophilic pleocytosis + positive culture

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Treatment

Wound Botulism:

1. Heptavalent Botulinum Antitoxin (HBAT) — give immediately, before lab confirmation; binds circulating free toxin (cannot reverse bound toxin)
2. Wound debridement + Penicillin G or Metronidazole (to eliminate C. botulinum from wound)
3. Mechanical ventilation — may be required for weeks to months
4. Supportive ICU care — recovery depends on new NMJ sprouting (weeks to months)
5. Do NOT give aminoglycosides — worsen NMJ blockade
6. Contact CDC (Emergency Operations: 770-488-7100) for antitoxin release

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Summary

Descending cranial nerve palsies (ptosis → ophthalmoplegia → bulbar) + respiratory failure requiring ventilation + fully conscious patient + NO meningism

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Revised Analysis: Bulbar Palsy First, Then Ophthalmoplegia + Ptosis

The Sequence Is the Diagnosis

Bulbar (CN IX/X/XII) FIRST
        ↓
Ophthalmoplegia + Ptosis (CN III/IV/VI) NEXT
        ↓
Respiratory failure (ventilator)
        ↓
Normal sensorium | No meningismus | Fever | Post-swimming

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#1 Diagnosis: Miller Fisher Syndrome / GBS Overlap (Pharyngeal-Cervical-Brachial variant or MFS-GBS overlap)

Why

"GBS with severe bulbar and facial paralysis, sometimes associated with antecedent cytomegalovirus (CMV) infection and anti-GM2 antibodies" — as a regional GBS variant

• Pharyngeal-cervical-brachial (PCB) weakness — a localized GBS form presenting with oropharyngeal, neck, and shoulder weakness (bulbar first), which can extend to involve ocular muscles
• MFS-GBS overlap — begins with ophthalmoplegia/ataxia then develops limb/bulbar weakness
• Bickerstaff Brainstem Encephalitis (BBE) — ophthalmoplegia + ataxia + impaired consciousness (against this here as sensorium is normal)

• Starts with dysphagia, dysarthria (bulbar = CN IX/X/XII)
• Progresses upward to involve CN III/IV/VI (ophthalmoplegia, ptosis)
• Can progress to respiratory failure requiring ventilation
• Normal sensorium throughout
• Associated with anti-GT1a antibodies (not GQ1b, which is MFS)

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Differential Framework by Cranial Nerve Sequence

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Full Differential (Reordered by Fit)

1. Pharyngeal-Cervical-Brachial (PCB) variant of GBS ← Top Diagnosis

• Bulbar weakness first (dysphagia, dysarthria, nasal voice)
• Extends to CN III/IV/VI (ophthalmoplegia, ptosis)
• Respiratory failure in severe cases
• Normal sensorium, no meningismus
• CSF: albuminocytologic dissociation (elevated protein, no cells)
• Anti-GT1a IgG antibodies — highly specific for PCB
• Trigger: swimming pool → possible enteric infection (Campylobacter, CMV) 1–3 weeks prior

2. MFS-GBS Overlap Syndrome

• Classic MFS (ophthalmoplegia + ataxia + areflexia) with additional bulbar/limb weakness
• Can begin with bulbar if overlap is significant
• Anti-GQ1b IgG (present in >85% MFS cases)
• Fever uncommon but possible with antecedent infection

3. Bickerstaff Brainstem Encephalitis (BBE)

• Ophthalmoplegia + ataxia + impaired/fluctuating consciousness
• Anti-GQ1b positive (same spectrum as MFS)
• Against here: sensorium is described as normal
• MRI may show brainstem hyperintensities

4. Botulism (Wound)

• Now less likely given bulbar-first sequence (botulism is strictly cranial-first descending: CN III/IV/VI → bulbar)
• However, wound botulism with a scratch from pool floor remains possible if one argues the sequence was misidentified

5. Listeria Rhombencephalitis

• Fever + brainstem involvement (CN palsies + bulbar)
• Usually has altered sensorium or cerebellar signs
• CSF typically abnormal
• Against: normal sensorium, no meningismus

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Why Swimming Pool is Still Relevant

• Pool water → swallowing of pool water → enteric infection (Campylobacter jejuni, CMV, hepatitis E)
• Incubation 1–3 weeks → molecular mimicry → anti-ganglioside antibodies → cranial nerve demyelination
• The same-day onset suggests either a very rapid post-infectious response or the swimming event itself is coincidental while the antibody-mediated attack was already underway

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Investigations

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Treatment

1. IVIg (Intravenous immunoglobulin) — 2 g/kg over 5 days — first line
2. Plasmapheresis — equally effective alternative; 4–6 exchanges
3. Do NOT use steroids — not beneficial in GBS and may worsen
4. Mechanical ventilation — already established; monitor FVC, NIF
5. Supportive care: DVT prophylaxis, nutrition, dysautonomia monitoring, pain management

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Key Teaching Point

Bulbar-first then ophthalmoplegia = ascending cranial nerve pattern = PCB-GBS or MFS-GBS overlap

Ophthalmoplegia-first then bulbar = descending pattern = Botulism

The direction of cranial nerve involvement is the single most important localizing clue in this presentation.

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Palatal Tremor vs Palatal Myoclonus

Terminology First

• "Palatal myoclonus" — older term; used because the movements appeared myoclonic
• "Palatal tremor" — current preferred term; reclassified because of persistent rhythmicity (tremors are rhythmic; myoclonus is typically arrhythmic)

• True tremor = oscillatory movement from synchronous or alternating contractions of antagonist muscles
• True myoclonus = rhythmic contractions of agonist muscles only (uniphasic)

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The Two Subtypes: The Critical Clinical Distinction

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Pathoanatomy of Symptomatic Palatal Tremor

Contralateral Dentate Nucleus (cerebellum)
              ↓  (superior cerebellar peduncle / brachium conjunctivum)
Ipsilateral Red Nucleus (midbrain)
              ↓  (Central Tegmental Tract — CTT)
Ipsilateral Inferior Olivary Nucleus (medulla)
              ↓  (inferior cerebellar peduncle / climbing fibers)
Back to Dentate Nucleus

With unilateral palatal tremor → it is the contralateral olive that enlarges (because the CTT crosses: lesion on one side → contralateral olive disinhibited)

MRI in SPT: Hypertrophic Olivary Degeneration (HOD)

• T2/FLAIR: hyperintensity in inferior olive
• Enlargement of olive (not atrophy — hence "hypertrophy")
• Appears months after the causative lesion
• May eventually regress over years

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Quick Comparison Summary

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Associated Syndromes of SPT

1. Oculopalatal myoclonus
   • Lateral form: jerky nystagmoid eye movements + oblique/rotatory components + lateralized palatal myoclonus (unilateral lesion)
   • Midline form: vertical pendular eye movements + bilateral symmetric palatal myoclonus
2. Progressive Ataxia and Palatal Tremor (PAPT)
   • Low-frequency palatal tremor + progressive cerebellar degeneration + vertical nystagmus + internuclear ophthalmoplegia
   • Associated with Alexander disease, mitochondrial disorders, POLG mutations
   • Familial PAPT: brainstem/cervical cord atrophy, NO olivary pseudohypertrophy
3. Whipple disease — oculomasticatory myorhythmia (masseter contractions + pendular ocular convergence; analogous phenomenon)

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Treatment

"Selective injection of the palatal muscles with botulinum toxin, while technically demanding, affords modest relief; it is particularly helpful in eliminating the bothersome ear clicking." — Adams & Victor's Neurology 12e

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Memory Hook

Essential = Ear click, Extinguished in sleep, Extra-normal MRI, Etiologically unknown

Symptomatic = Sleep-persistent, Synchronized with nystagmus, Striking olivary hypertrophy, Secondary to Guillain-Mollaret triangle lesion

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Rhombencephalitis

Definition

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Clinical Syndrome

Characteristic Biphasic Course (especially Listeria)

1. Phase 1 (days 1–5): Fever, headache, nausea, vomiting — prodromal
2. Phase 2 (days 5–10): Asymmetric cranial nerve palsies, cerebellar signs, long-tract signs, respiratory failure

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Causes — Classified

Infectious

Bacterial

Viral

Fungal / Parasitic

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Autoimmune / Para-infectious

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Key Organism Comparison: Listeria vs Enterovirus 71

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Bickerstaff Brainstem Encephalitis — Special Status

• Preceded by systemic viral infection
• Ophthalmoplegia + ataxia + altered consciousness (consciousness = key differentiator from MFS)
• Anti-GQ1b IgG antibodies — same spectrum as Miller Fisher Syndrome
• MRI: T2 hyperintensity in brainstem, cerebellum, thalamus — or normal
• CSF: elevated protein, no cells (same as GBS/MFS)
• Treatment: IVIg or plasmapheresis (as for GBS)
• BBE + limb weakness = MFS-GBS overlap

"A brainstem disorder often confused with infection is Bickerstaff's brainstem encephalitis. Patients with this disorder have often had a preceding systemic viral infection, then acutely develop ataxia, ophthalmoplegia, long-tract signs, and alterations of consciousness including coma." — Plum & Posner's Diagnosis and Treatment of Stupor and Coma

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Investigations

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Treatment by Etiology

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Summary Framework

RHOMBENCEPHALITIS
       │
       ├─ INFECTIOUS
       │      ├─ Bacterial: Listeria ★ (classic), Melioidosis, TB, Brucella
       │      ├─ Viral: Enterovirus 71 ★ (children), HSV-2, Rabies, Tick-borne
       │      └─ Fungal: Cryptococcus, Aspergillus
       │
       ├─ AUTOIMMUNE / PARA-INFECTIOUS
       │      ├─ Bickerstaff Brainstem Encephalitis (anti-GQ1b) ★
       │      ├─ CLIPPERS (pontine perivascular)
       │      ├─ Paraneoplastic (anti-Hu, anti-Ri)
       │      └─ MS / neurosarcoidosis
       │
       └─ EMPIRIC APPROACH (while awaiting results)
              ├─ Cover Listeria: Ampicillin + Gentamicin
              ├─ Cover HSV: Acyclovir
              └─ Consider IVIg if anti-GQ1b pending (BBE)

Sources: Adams & Victor's Principles of Neurology 12e; Bradley & Daroff's Neurology in Clinical Practice; Harrison's Principles of Internal Medicine 22E; Plum & Posner's Diagnosis and Treatment of Stupor and Coma; Localization in Clinical Neurology 8e

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Generalised Dystonia in a 20-Year-Old (Onset at Age 15)

Clinical Context

• Age of onset: 15 years (adolescent-onset)
• Current age: 20 years
• Duration: 5 years, progressive
• Distribution: Generalised

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Classification Framework (Consensus 2013 — Two-Axis System)

Axis I: Clinical Characteristics

Axis II: Etiology

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Priority Diagnosis: Wilson Disease ← Must Exclude First

1. It is treatable — delay causes irreversible neurological damage
2. It presents exactly in this age group (5–35 years, peak 2nd decade)
3. Neurological Wilson's = basal ganglia → generalised dystonia is a cardinal feature

Wilson Disease Features

• Autosomal recessive (ATP7B gene, chromosome 13)
• Copper accumulates in basal ganglia (especially putamen), liver, cornea
• Neurological forms: dystonia (most common), tremor, dysarthria, dysphagia, parkinsonism, psychiatric symptoms
• Kayser-Fleischer rings — golden-brown corneal deposits (slit-lamp examination)
• Investigations: Serum ceruloplasmin ↓, 24-hr urinary copper ↑, serum copper ↓, slit-lamp KF rings, MRI ("face of giant panda" sign in midbrain)
• Treatment: D-penicillamine, trientine, zinc salts — dramatic improvement if early

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Differential Diagnosis: Generalised Dystonia, Adolescent Onset

1. Primary (Isolated) Genetic Dystonias

DYT1 is the most common inherited generalised dystonia. It begins in one limb (usually a leg/foot during walking), progresses over years to become generalised. Adolescent onset at 15 is within range.

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2. Heredodegenerative Diseases Causing Generalised Dystonia

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3. Dopa-Responsive Dystonia (DRD) — DYT5 / Segawa Syndrome

• GCH1 gene (autosomal dominant) or TH gene (AR)
• Onset in childhood/adolescence, lower limb dystonia initially
• Diurnal variation — symptoms worse in evening, better in morning after sleep (pathognomonic)
• May have parkinsonism features
• Levodopa trial: dramatic and sustained response at low doses
• A levodopa trial should be performed in every young-onset generalised dystonia patient before any other diagnosis is accepted

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4. Neurodegeneration with Brain Iron Accumulation (NBIA)

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5. Biotin-Responsive Basal Ganglia Disease (BBGD)

• SLC19A3 mutation; AR
• Episodic encephalopathy triggered by febrile illness → dystonia, dysarthria, dysphagia, ophthalmoplegia
• MRI: bilateral caudate + putaminal lesions
• Responds to biotin + thiamine — treatable

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Investigations — Stepwise Approach

Step 1: Mandatory Screening (Never Skip)

Step 2: If Step 1 Negative

Step 3: Genetic Testing

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Treatment

Step 1: Levodopa Trial — ALWAYS FIRST

• Start 50–100 mg levodopa/day, titrate
• DRD: dramatic sustained response at low doses — diagnostic and therapeutic
• Even DYT1 patients may have partial response

Step 2: Oral Medications

Step 3: Deep Brain Stimulation (DBS)

• Globus pallidus interna (GPi) stimulation — treatment of choice for medically refractory primary generalised dystonia
• Most effective in DYT1 (TOR1A mutation) — 50–90% improvement in BFMDRS
• Less effective in secondary dystonias
• Consider after adequate trial of medical therapy

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Most Important Teaching Points

1. A levodopa trial is mandatory in every young-onset generalised dystonia — DRD is treatable and mimics all other forms
2. Wilson disease must be excluded urgently — it is the most common treatable secondary cause in this age group
3. MRI with SWI/T2 — look for "eye of the tiger" (PKAN) and Wilson changes (putaminal T2 changes, "face of panda")
4. Adolescent-onset generalised → DYT1 (TOR1A) is most likely primary cause if secondary workup negative
5. GPi-DBS is the most effective intervention for medication-refractory primary generalised dystonia

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