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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

---

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

---

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

---

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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Amoebic Meningoencephalitis

Overview

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1. PRIMARY AMOEBIC MENINGOENCEPHALITIS (PAM)

Caused by Naegleria fowleri

Organism

• Thermophilic free-living amoeba; thrives in warm freshwater (lakes, rivers, poorly maintained pools, neti pots, waterslides)
• Exists in three forms: trophozoite (amoeboid) → flagellate (transient, non-feeding) → cyst
• Only trophozoite is pathogenic

Epidemiology

• Worldwide; ~381 cases globally through 2022; 0–8 cases/year in USA
• 75% male; median age 14 years (range 1 month–85 years)
• 91% had recreational freshwater exposure
• Cases rising in northern US states (climate change)
• Prevalence ~2.6 cases per million exposures

Pathogenesis

Warm freshwater inhaled nasally
        ↓
Trophozoites enter olfactory neuroepithelium
        ↓
Migrate along olfactory nerve → cribriform plate
        ↓
Enter CNS, bypass blood-brain barrier
        ↓
Fulminant necrotizing hemorrhagic encephalitis
        ↓
Neutrophilic response — olfactory bulbs/frontal lobes first
        ↓
Diffuse cerebral edema, uncal herniation → death (median <10 days)

Clinical Features

CSF Findings

Critical: CSF must be examined immediately as a fresh wet preparation — trophozoites are motile and die if refrigerated. This is the bedside diagnostic.

Diagnosis

Treatment (Medical Emergency)

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2. GRANULOMATOUS AMOEBIC ENCEPHALITIS (GAE)

Caused by Acanthamoeba spp. and Balamuthia mandrillaris

Comparison: Acanthamoeba vs Balamuthia

Acanthamoeba Keratitis (Separate Syndrome)

• Contact lens wearers (major risk — especially with homemade saline, swimming in lenses)
• Annular paracentral corneal ring — characteristic sign
• Irregular polygonal double-walled cysts on corneal scraping (see image below)
• Treatment: polyhexamethylene biguanide (0.2%) + propamidine isethionate (0.1%) drops; severe cases need keratoplasty
• Cysts are drug-resistant — difficult to treat

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Side-by-Side Comparison: PAM vs GAE

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Pathological Images

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When to Suspect Each

Young healthy person + warm freshwater swimming + acute meningitis-like illness
→ PAM (Naegleria) — CSF wet mount STAT

Immunocompromised + subacute focal brain lesions + skin nodules/ulcers
→ GAE (Acanthamoeba) — brain biopsy

Immunocompetent or immunocompromised + skin lesion on face + subacute encephalopathy
+ soil/water exposure or organ transplant recipient
→ GAE (Balamuthia) — CDC PCR + biopsy

Contact lens wearer + painful red eye + annular corneal ring
→ Acanthamoeba keratitis — corneal scraping for cysts

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Key Points for Exams

1. PAM = olfactory route (Naegleria); GAE = haematogenous route (Acanthamoeba, Balamuthia)
2. PAM mimics bacterial meningitis; GAE mimics brain tumour or toxoplasmosis
3. Diagnosis of PAM: motile trophozoites on fresh CSF wet mount (never refrigerate)
4. Miltefosine is the most important drug for all three — included in all 7 PAM survivors
5. Serology is not useful for PAM (antibodies found in healthy adults)
6. Acanthamoeba keratitis: contact lens wearers; cysts resist treatment — high recurrence
7. Balamuthia is the only free-living amoeba that regularly causes GAE in immunocompetent individuals

Sources: Harrison's Principles of Internal Medicine 22E; Robbins & Kumar Basic Pathology; Kaplan & Sadock's Comprehensive Textbook of Psychiatry; Medical Microbiology 9e; Tintinalli's Emergency Medicine

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Hypertrophic Olivary Degeneration (HOD)

Definition

First described by Oppenheim in post-mortem studies; the enlarged ION was first correlated with clinical palatal myoclonus by Guillain and Mollaret.

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The Guillain-Mollaret Triangle (GMT) — The Anatomical Key

          MIDBRAIN
    Red Nucleus (ipsilateral)
          /         \
Central Tegmental    Brachium Conjunctivum
    Tract (CTT)      (Superior Cerebellar Peduncle)
         ↓                    ↑
    MEDULLA               CEREBELLUM
Inferior Olivary         Dentate Nucleus
  Nucleus (ION)          (contralateral)
    (ipsilateral)
         ↓ __________________|
    Inferior Cerebellar
    Peduncle (climbing fibers)

Three limbs of the triangle:

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Pathophysiology

Why Does the Olive Enlarge (Not Atrophy)?

1. Deafferentation of the ION from its inhibitory inputs
2. ION neurons undergo vacuolar change and astrocytic hypertrophy (not neuronal loss initially)
3. Gap junctions between olivary neurons become upregulated → rhythmic synchronized discharges
4. These discharges propagate via climbing fibers → cerebellar cortex → palatal muscles → palatal tremor
5. Over months to years → eventual neuronal loss and olivary atrophy (late stage)

Timeline of MRI Changes

The latency of months between the causative lesion and onset of palatal tremor / MRI changes is a hallmark of HOD.

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Causes of HOD — Lesions Disrupting the GMT

Most Common

Less Common

• Cavernous malformation (haemosiderin deposition in GMT)
• Arteriovenous malformation
• Radiation injury
• Metabolic/toxic (e.g., Wernicke encephalopathy affecting midbrain)

---

Unilateral vs Bilateral HOD

Rule: With unilateral palatal tremor, the contralateral olive enlarges. — Adams & Victor's Neurology 12e

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Clinical Features

Cardinal Feature: Symptomatic Palatal Tremor

• Rhythmic, 1–3 Hz contractions of the levator veli palatini (CN X)
• Persists during sleep (unlike essential palatal tremor)
• No auditory click (unlike essential palatal tremor)
• Onset: typically months after the causative lesion

Other Oculomotor Features

• Pendular nystagmus (synchronised with palatal movements)
• Oculopalatal myoclonus:
  • Unilateral lesion: jerky, nystagmoid, oblique/rotatory eye movements
  • Bilateral lesion: vertical to-and-fro pendular nystagmus

Other Movements

• Rhythmic contractions of pharynx, facial muscles, diaphragm, vocal cords, neck/shoulders
• Dentatorubral tremor — limb tremor from dentate/rubral involvement
• Cerebellar ataxia (from the primary lesion)

Neurological Deficits from Primary Lesion

• Hemiparesis, dysarthria, dysphagia — depending on brainstem lesion location

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MRI Findings — The Diagnostic Signature

• Brainstem neoplasm
• Demyelinating plaque
• Inflammatory lesion

Classic MRI Appearance:

---

Differential Diagnosis of Inferior Olive T2 Signal

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HOD vs Essential Palatal Tremor — Quick Recap

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Treatment

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Summary

HOD = trans-synaptic degeneration of the inferior olive, occurring months after a lesion interrupts the Guillain-Mollaret triangle (red nucleus → central tegmental tract → inferior olive → dentate nucleus → back)

MRI: T2/FLAIR hyperintensity + enlargement of ION, no gadolinium enhancement, delayed onset 1–6 months after causative lesion

Clinically: Symptomatic palatal tremor + pendular nystagmus ± rhythmic myoclonus of face/pharynx/diaphragm

Key concept: The olive hypertrophies (not atrophies) because the process is astrocytic vacuolation and gap junction upregulation — not simple neuronal loss

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Taking History in Dementia — Lobe by Lobe

Principle

Always obtain history from both patient AND a reliable informant (caregiver/family) — the patient may lack insight (anosognosia), especially in frontal or parietal disease.

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Framework: What Each Lobe Does and What to Ask

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🔵 FRONTAL LOBE

Questions to Ask:

• "Has he/she become disorganised? Does he/she struggle to plan a meal, manage money, or pay bills?"
• "Can he/she do tasks in the right order — like making tea (fill kettle, boil, pour)?"
• "Does he/she start tasks but not finish them?"
• "Can he/she switch between tasks, or does he/she get stuck on one thing?"

• "Has his/her personality changed? Is he/she a different person from before?"
• "Has he/she become disinhibited — saying rude or inappropriate things, making sexual remarks, or behaving badly in public?"
• "Is he/she impulsive — spending money recklessly, grabbing food off others' plates?"
• "Has he/she lost social awareness — does he/she embarrass the family?"

• "Has he/she become very passive, lost initiative, stopped doing things he/she used to enjoy?"
• "Does he/she sit all day without doing anything unless prompted?"
• "Is there poverty of speech — speaking very little spontaneously?"

• "Does he/she repeat the same actions or phrases over and over?"
• "Does he/she have rigid routines — insisting on eating the same food or following the same route?"

• "Does he/she put objects in the mouth? Eat excessively or indiscriminately?"

• "Has his/her speech become halting, effortful, or telegraphic (short sentences)?"
• "Does he/she struggle to get words out even though he/she seems to know what to say?"

Suggests: Frontotemporal dementia (bvFTD), non-fluent/agrammatic PPA, PSP, CBD

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🟠 TEMPORAL LOBE

Questions to Ask:

• "Does he/she repeat the same questions or stories within minutes — not realising they've already said it?"
• "Does he/she forget recent events — what happened yesterday, what he/she had for breakfast?"
• "Does he/she remember remote events (childhood, old friends) better than recent ones?"
• "Does he/she forget appointments, miss medications, forget names of recent acquaintances?"
• "Does he/she get lost in familiar places — e.g., going to the local shop?"

• "Has he/she lost knowledge of objects — not recognising what a 'kettle' or 'umbrella' is?"
• "Has he/she lost word meanings — uses words incorrectly or says 'that thing' instead of the name?"
• "Does he/she fail to recognise faces of famous people (e.g., politicians)?"

• "Does he/she have difficulty understanding what is said to him/her?"
• "Does he/she give nonsensical answers to questions — as if talking about something different?"
• "Is his/her speech fluent but empty — lots of words but no meaning?"

• "Does he/she fail to recognise familiar faces — even close family members?"

• "Any change in appreciation of music or sounds?"

Suggests: Alzheimer's disease (medial temporal first), LATE, semantic variant PPA (anterior temporal), Wernicke's aphasia in PPA

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🟡 PARIETAL LOBE

Questions to Ask:

• "Does he/she get lost in familiar places — his/her own house, or the route to the local shop or temple?"
• "Does he/she have difficulty parking the car, judging distances, or navigating in a mall?"
• "Does he/she bump into furniture or objects on one side?"
• "Does he/she have difficulty recognising objects or faces even with normal vision?"

• "Has he/she lost the ability to use everyday tools correctly — using a toothbrush, a key, a fork, a lighter?"
• "Has he/she become clumsy with buttons, zips, or shoelaces?"
• "Does he/she have difficulty imitating gestures (e.g., waving goodbye)?"

• "Can he/she still manage money — count change, do simple arithmetic?"
• "Has his/her writing become abnormal?"
• "Can he/she still read — newspaper, messages?"

• "Does he/she confuse left and right?"
• "Can he/she identify individual fingers?"

• "Does he/she ignore one side of the body or environment — only eating food from one side of the plate? Only shaving/grooming one side of the face?"

• "Does he/she have difficulty dressing — putting clothes on the wrong way, inability to work out how garments go on?"

Suggests: Posterior cortical atrophy (PCA — Alzheimer's variant), corticobasal degeneration, DLB (posterior parietal)

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🟢 OCCIPITAL LOBE

Questions to Ask:

• "Does he/she see things that are not there — people, animals, patterns?"
• "How vivid are they? Are they frightening or not?"
• "Do they occur in low light conditions?"

• "Can he/she recognise objects just by looking at them (with normal vision)?"
• "Does he/she mistake objects for other things?"

• "Any difficulty recognising colours or perceiving moving objects?"

• "Is he/she unaware of being blind — denying the visual problem even when it is obvious?"

Suggests: DLB (vivid visual hallucinations), posterior cortical atrophy, CJD, occipital strokes

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⚫ LIMBIC / CINGULATE

Questions to Ask:

• "Has he/she become emotionally flat — no joy, no sadness?"
• "Is he/she socially withdrawn, no longer interested in family or friends?"
• "Is he/she irritable, anxious, or depressed — a new change from baseline?"

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⚪ SUBCORTICAL / WHITE MATTER

Questions to Ask:

• "Has he/she slowed down mentally — takes much longer to answer questions or complete tasks?"
• "Is there forgetfulness that improves with prompting (subcortical — unlike cortical where cueing doesn't help)?"
• "Has there been change in gait — shuffling, falls, urinary incontinence (NPH triad)?"

Suggests: Vascular dementia, Binswanger's, NPH, Huntington's, PSP

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Putting It Together: Pattern Recognition

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Additional Screening History (Always Ask)

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Memory Aid: "FLPOT" — 5 Lobes × Signature Symptoms

Sources: Harrison's Principles of Internal Medicine 22E (Table 33-4, Functional Anatomy of Dementias); Localization in Clinical Neurology 8e; Adams & Victor's Principles of Neurology 12e