Encephalopathy

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encephalopathy classification pathophysiology management

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Encephalopathy: Comprehensive Clinical Review

Definition

Encephalopathy is a broad term for any diffuse brain dysfunction characterised by an altered level of consciousness, cognitive impairment, and/or behavioural change — caused by a systemic, metabolic, toxic, or structural insult rather than primary intrinsic brain disease. Unlike focal lesions, metabolic encephalopathies preferentially impair phylogenetically newer brain structures first, sparing brainstem reflexes until late. — Localization in Clinical Neurology, 8e

General Features of Metabolic Encephalopathy

Common clinical signs include:

Altered consciousness: ranging from inattention → confusion → stupor → coma
Asterixis ("flapping tremor"): brief, sudden loss of postural tone; present with mild-moderate encephalopathy, wanes in deep coma. Elicited by dorsiflexing the wrist with fingers extended.
Tremor: coarse, irregular, 8–10 cycles/second, maximal with outstretched hands
Multifocal myoclonus: sudden, non-rhythmic muscle twitching (seen in uremic, hyperosmolar-hyperglycaemic, and CO₂ narcosis encephalopathy)
Hyperventilation / respiratory alkalosis: a prominent feature of both hepatic and septic encephalopathy
EEG changes: diffuse slowing; correlates with clinical severity

Key diagnostic principle: asymmetric motor findings speak against a purely metabolic cause. Focal deficits should prompt search for a structural lesion. — Localization in Clinical Neurology, 8e

I. Hepatic Encephalopathy (HE)

Epidemiology

HE develops in 50–70% of patients with cirrhosis. Its onset portends poor prognosis: projected 1-year and 3-year survival rates of 42% and 23%, respectively, without liver transplantation (LT). — Sleisenger & Fordtran's GI and Liver Disease

Classification

Classification	Basis	Types
By underlying disease	ISHEN/EASL	Type A (acute liver failure), Type B (portosystemic bypass, no liver disease), Type C (cirrhosis + portal hypertension — most common)
By severity	West Haven / SONIC	Unimpaired → Covert (minimal/grade 1) → Overt (grade 2–4)
By time course	—	Episodic, recurrent (≥2 episodes/6 months), persistent

West Haven Grading (Type C)

Grade	Cognition	Neuromuscular	SONIC
0	Normal	Normal	Unimpaired
Minimal	Normal exam; subtle work/driving changes	Minor visuospatial/psychometric deficits	Covert HE
1	Shortened attention, mild confusion	Tremor, incoordination	Covert HE
2	Lethargy, disorientation to time	Asterixis, ataxia	Overt HE
3	Gross disorientation, somnolence	Asterixis, rigidity	Overt HE
4	Coma	Decerebrate posturing	Overt HE

Pathophysiology

Fig. 94.1 — Proposed pathophysiology of hepatic encephalopathy. Sleisenger & Fordtran's GI and Liver Disease

Multiple converging mechanisms:

Hyperammonemia — the central neurotoxin. Ammonia is produced primarily in the colon (bacterial protein metabolism) and by enterocytes from glutamine. Normally cleared by hepatocytes; in cirrhosis, portosystemic shunting and reduced hepatocyte mass allow systemic accumulation. Arterial hyperammonemia is found in up to 90% of HE patients. Ammonia crosses the blood-brain barrier (predominantly as uncharged NH₃ gas), where astrocytes convert it to glutamine via glutamine synthetase — causing astrocyte swelling and cytotoxic edema.
Astrocyte swelling — considered the key pathological event. Cell swelling is aggravated by inflammatory cytokines, hyponatraemia, and benzodiazepines (which explains why these frequently precipitate HE). In chronic disease, Alzheimer type-2 astrocytes accumulate.
GABA-benzodiazepine system enhancement — increased astrocyte (peripheral-type) benzodiazepine receptor sensitivity amplifies GABAergic inhibition via neurosteroid production (allopregnanolone, THDOC).
Neuroinflammation — inflammatory cytokines directly impair neuronal function and sensitise the brain to ammonia's effects. Intercurrent infection (e.g., SBP) substantially worsens HE.
Other neurotoxins — serotonin, nitric oxide, manganese (dopaminergic dysfunction), circulating opioids, reactive oxygen species.
Gut microbiome — colonic mucosal microbiota differ in cirrhotic patients with vs. without HE; gut-derived metabolites influence ammonia and neurotoxin production.

Common Precipitants

GI bleeding · electrolyte abnormalities (especially hypokalaemia) · infection (UTI, SBP, pneumonia) · dehydration · constipation · excessive dietary protein · sedative/opioid medications · portosystemic shunt placement

Clinical Features

Onset often insidious; early features include forgetfulness, reversal of sleep-wake cycle, changes in handwriting, difficulty driving
Progression: asterixis → agitation → disorihibited behaviour → seizures → coma
Characteristic: quiet, apathetic delirium (10–20% present with boisterous/manic onset)
Respiratory alkalosis with hyperventilation is nearly invariable in all grades — an absence argues against hepatic coma
Pupillary and caloric responses remain normal until preterminal stages (unlike structural brainstem lesions) — Plum & Posner

Diagnosis

Primarily clinical in the appropriate context. Rule out hypoglycaemia, hyponatraemia, medication toxicity, and intracranial structural lesions (especially subdural haematoma given coagulopathy risk). Serum ammonia is neither sensitive nor specific but supports the diagnosis. Psychometric tests (Number Connection Test) and EEG are used for minimal/covert HE.

Management

Strategy	Details
Identify & treat precipitants	First and most important step
Lactulose	15–45 mL PO (or NG) BID–QID; titrate to 2–3 soft stools/day. First-line therapy; reduces colonic ammonia production by acidifying colonic pH and promoting NH₃ → NH₄⁺ trapping
Rifaximin	400 mg PO q8h (or 550 mg BID for secondary prophylaxis); non-absorbable antibiotic reduces ammonia-producing gut flora; superior to lactulose alone in several trials
Branched-chain amino acids (BCAA)	IV infusion; benefit shown without increased mortality
Neomycin, metronidazole	Second-line antibiotics; used adjunctively
Protein restriction	Moderate; avoid excessive restriction as muscle is the main extra-hepatic ammonia detoxifier; malnutrition worsens HE
Liver transplantation	Definitive treatment; generally reverses HE

In acute liver failure (Type A), intracranial hypertension develops in up to 80% of grades 3–4; ICP monitoring and osmotherapy (mannitol, hypertonic saline) may be required. — Sleisenger & Fordtran's

II. Uremic Encephalopathy

Definition & Epidemiology

A syndrome of delirium in untreated or inadequately treated ESKD. Slight neuropsychiatric symptoms are present in ~30% of patients on dialysis. Advanced grades (confusion/coma) occur mainly in those not yet on renal replacement therapy. — Bradley & Daroff's Neurology

Clinical Features

Early: lethargy, cognitive slowing, attention/memory deficits
Intermediate: confusion, hallucinations, psychosis, tremor, myoclonus, asterixis
Severe: seizures (generalised tonic-clonic or myoclonic), stupor, coma
Degree of azotaemia (BUN/creatinine) correlates poorly with severity — urea itself is not the neurotoxin — Plum & Posner

Pathophysiology

Guanidine compounds (guanidinusuccinic acid, methylguanidine) — elevated 100-fold in uremic brain tissue; activate NMDA receptors and modulate calcium channels → seizures
Cytokine-mediated neuroinflammation with increased BBB permeability
Secondary hyperparathyroidism: elevated PTH increases brain calcium content, disrupting neurotransmitter release
Anemia: erythropoietin therapy associated with improved cognitive performance
Gut-microbial metabolites (phenylalanine, benzoate, glutamate pathways) linked to cognitive impairment in dialysis patients — Brenner & Rector's The Kidney

Related Dialysis Syndromes

Syndrome	Mechanism	Features
Dialysis disequilibrium	Rapid urea clearance → intracellular osmotic gradient → cerebral edema	Headache, nausea, confusion, seizures (during or after HD)
Dialysis encephalopathy	Aluminium neurotoxicity (historical; aluminium-containing dialysate)	Dysarthria, aphasia, apraxia, myoclonus, seizures
PRES	Failed cerebral autoregulation + endothelial dysfunction; fluid overload	Headache, visual changes, altered consciousness, seizures; posterior white-matter edema on MRI
Thiamine deficiency encephalopathy	Water-soluble vitamin loss in dialysis; poor intake	Wernicke syndrome; 33% prevalence of thiamine deficiency in symptomatic dialysis patients (Hung et al., 2001)

Management

Institute renal replacement therapy (dialysis/transplantation) — definitive
Correct anaemia (erythropoietin)
Control hyperparathyroidism
Caution with AEDs: phenytoin protein binding altered by uraemia; prefer agents with less renal pharmacokinetic complexity
PRES: volume and BP management

III. Hypertensive Encephalopathy & PRES

Hypertensive Encephalopathy

Caused by failure of cerebral autoregulation with breakthrough hyperperfusion → vasospasm → ischemia → increased vascular permeability → vasogenic edema and punctate haemorrhages.

Clinical: severe headache, vomiting, altered mental status, seizures, coma; visual disturbance → blindness; papilloedema; hypertensive retinopathy. Focal deficits do not follow a single anatomic pattern (indicating diffuse dysfunction, not stroke).

Diagnosis: CT may be normal or show non-specific edema/haemorrhages. The combination of diffuse neurological dysfunction + markedly elevated BP ± papilloedema is sufficient to initiate treatment.

Management: promptly reduce BP by 30–40% (avoid overcorrection). IV agents (labetalol, nicardipine, sodium nitroprusside). Fully reversible with early treatment. In-hospital mortality <1%. — Rosen's Emergency Medicine

Posterior Reversible Encephalopathy Syndrome (PRES)

Similar but more posterior and region-specific than hypertensive encephalopathy
Characterised by: headache, altered consciousness, visual disturbances, seizures (up to 90%)
MRI: vasogenic oedema predominantly in posterior parietal-temporal-occipital white matter
Causes: hypertension (most common), eclampsia, vasculitis, thrombotic microangiopathy, calcineurin inhibitors, rituximab, sirolimus, ESKD
Reversible with treatment of underlying cause — Rosen's Emergency Medicine, Brenner & Rector's

IV. Wernicke Encephalopathy

Pathophysiology

Thiamine (B₁) deficiency impairs thiamine-dependent enzymes (pyruvate dehydrogenase, α-ketoglutarate dehydrogenase) in high-metabolic-demand brain regions: blood-brain barrier, anterior/centromedian thalamus, mammillary bodies, periaqueductal grey, floor of the fourth ventricle. Deficiency of α-ketoglutarate dehydrogenase in astrocytes leads to microglial activation and glutamatergic toxicity. Pathological changes: neuronal swelling, microscopic haemorrhages, gliosis.

At-Risk Groups

Chronic alcohol abuse (most common) · prolonged vomiting · bariatric surgery · AIDS/cancer cachexia · dialysis patients (30% thiamine deficiency in symptomatic patients) · severe malnutrition

Classic Triad (present in only ~1/3 of cases)

Mental status change — mild memory impairment → delirium → coma; often apathy/abulia
Oculomotor abnormalities — nystagmus, dysconjugate gaze, gaze palsies
Ataxia — predominantly gait and lower limb; less pronounced in non-alcoholic patients

⚠️ Only ~25% of cases are diagnosed antemortem. Always maintain a high index of suspicion.

Investigations

MRI (T2/FLAIR): symmetrical increased signal in periventricular thalamus, periaqueductal grey, floor of fourth ventricle, mammillary bodies
Thiamine level <50 μg/mL (may be normal in ~10% of cases)
Elevated serum lactate and pyruvate (disrupted carbohydrate metabolism)

⚠️ Do NOT give IV glucose before thiamine — can precipitate or worsen Wernicke's

Management

IV thiamine immediately — before any glucose administration
High-dose IV thiamine (200–500 mg TID) until clinical improvement
Followed by oral supplementation
Untreated → Korsakoff syndrome (irreversible anterograde amnesia + confabulation)

V. Septic / Systemic Inflammatory Encephalopathy

The CNS is affected by systemic inflammatory illness through several converging mechanisms:

BBB permeability changes with cytokine and LPS entry
Altered cerebral microcirculation and mitochondrial dysfunction
Neurotransmitter disturbances (glutamate, amino acid dysregulation)
Sickness syndrome: PGE₂ from inflammatory cells crosses BBB → hypothalamic effects (fever, anorexia, somnolence, lowered pain threshold)

Key feature: hyperventilation with respiratory alkalosis + impaired consciousness + no other metabolic cause should prompt a search for an occult infection (e.g., UTI, leg ulcer). Treatment of the infectious source alone often reverses the encephalopathy. — Plum & Posner's Diagnosis and Treatment of Stupor and Coma

VI. Toxic & Radiation Encephalopathy

Toxic Encephalopathy

Both bacterial invaders and the host inflammatory response can cause neuronal injury/death via reactive oxygen species, proteases, cytokines, and excitatory amino acids (apoptosis and necrosis). — Plum & Posner

Radiation Encephalopathy

Timing	Onset	Mechanism	Features
Acute	Days	Increased ICP, BBB breakdown	Headache, nausea, altered mental status; treat with high-dose corticosteroids
Early delayed	2 weeks–4 months	Demyelination	Headache, drowsiness, enhancement of prior deficits; self-limiting
Late (delayed)	Months–years (esp. >35 Gy)	Demyelinating lesions, vascular changes, necrosis	Cognitive/affective disturbances, frontal dysfunction, progressive dementia; bevacizumab may help

Bradley & Daroff's Neurology in Clinical Practice

Approach to the Patient with Encephalopathy

History & exam → Exclude structural lesion (CT/MRI) → Check: glucose, electrolytes, renal/liver function, ammonia, TFTs, ABG, toxicology screen, sepsis workup
              ↓
        Common reversible causes:
        • Hypoglycaemia → IV glucose
        • Wernicke's → IV thiamine first
        • Hepatic → treat precipitant + lactulose ± rifaximin
        • Uremic → dialysis
        • Hypertensive → controlled BP reduction
        • Septic → source control + antibiotics
        • Toxic → remove offending agent

Sources: Sleisenger & Fordtran's Gastrointestinal and Liver Disease · Plum & Posner's Diagnosis and Treatment of Stupor and Coma · Bradley & Daroff's Neurology in Clinical Practice · Brenner & Rector's The Kidney · Rosen's Emergency Medicine · Goldman-Cecil Medicine · Localization in Clinical Neurology, 8eHere is a structured overview covering all major types of encephalopathy at a detailed clinical level.

Encephalopathy: Comprehensive Clinical Review

Definition

Encephalopathy is diffuse brain dysfunction caused by a systemic, metabolic, toxic, or inflammatory insult rather than primary intrinsic brain disease. It manifests as a spectrum from mild inattention → confusion → stupor → coma. Phylogenetically newer brain structures (cortex, complex polysynaptic pathways) are affected first; brainstem reflexes are preserved until near-terminal stages. — Localization in Clinical Neurology, 8e

General Clinical Features of Metabolic Encephalopathy

Sign	Details
Asterixis	Sudden, brief loss of postural tone ("flapping tremor"); elicited by dorsiflexing wrist with fingers extended; present in mild–moderate encephalopathy, disappears in deep coma
Tremor	Coarse, irregular, 8–10 Hz; maximal with outstretched hands
Multifocal myoclonus	Non-rhythmic muscle twitching; seen in uremic, hyperosmolar-hyperglycaemic, and CO₂ narcosis
Hyperventilation / respiratory alkalosis	Prominent in hepatic and septic encephalopathy
EEG slowing	Correlates with clinical severity

Asymmetric motor signs argue against a purely metabolic cause — consider concurrent structural lesion.

I. Hepatic Encephalopathy (HE)

Epidemiology

Develops in 50–70% of cirrhotic patients; onset signals poor prognosis (1-year survival 42%, 3-year survival 23% without liver transplantation).

Classification

By underlying disease:

Type A — acute liver failure (ALF)
Type B — portosystemic bypass without liver disease
Type C — cirrhosis + portal hypertension (most common)

By severity — West Haven Criteria & SONIC Classification:

Grade	Cognition	Neuromuscular	SONIC Category
0	Normal	Normal	Unimpaired
Minimal	Subtle work/driving changes	Minor visuospatial abnormalities	Covert HE
1	Shortened attention, mild confusion	Tremor, incoordination	Covert HE
2	Lethargy, disorientation to time	Asterixis, ataxia	Overt HE
3	Gross disorientation, somnolence	Asterixis, rigidity	Overt HE
4	Coma	Decerebrate posturing	Overt HE

Pathophysiology

Proposed pathophysiology of hepatic encephalopathy — Sleisenger & Fordtran's GI and Liver Disease, Fig. 94.1

Hyperammonemia — ammonia from colonic bacteria/enterocyte glutamine metabolism bypasses the liver via portosystemic shunting → crosses BBB as NH₃ gas → astrocytes convert it to glutamine → astrocyte swelling, cytotoxic edema. Arterial hyperammonemia present in ~90% of HE cases, but serum levels are neither sensitive nor specific.
Astrocyte swelling — the key pathological event; amplified by inflammatory cytokines, hyponatraemia, and benzodiazepines (explaining why these precipitate HE). Depletion of intracellular myoinositol (which normally counteracts swelling) increases vulnerability.
GABA-benzodiazepine system — enhanced astrocyte peripheral benzodiazepine receptor sensitivity → ↑ neurosteroid production (allopregnanolone, THDOC) → amplified GABAergic inhibition.
Neuroinflammation — intercurrent infection drastically worsens HE by direct cytokine-mediated brain dysfunction.
Other: manganese (dopaminergic toxicity), nitric oxide, reactive oxygen species, gut microbiome dysbiosis.

Common Precipitants

GI bleeding · hypokalemia · infection (SBP, UTI, pneumonia) · dehydration · constipation · excess dietary protein · sedatives/opioids · TIPS placement

Clinical Features

Early: forgetfulness, sleep-wake reversal, changes in handwriting, difficulty driving
Progression: asterixis → agitation → disinhibited behaviour → seizures → coma
Typical onset: quiet, apathetic delirium (10–20% present with agitated/manic delirium)
Respiratory alkalosis with hyperventilation is nearly invariable — its absence argues against hepatic coma
Pupillary and caloric responses remain normal until preterminal stages (distinguishes from structural brainstem lesions) — Plum & Posner

Management

Intervention	Details
Identify and treat precipitants	First and most critical step
Lactulose	15–45 mL PO/NG BID–QID; titrate to 2–3 soft stools/day; acidifies colon, traps NH₃ as NH₄⁺
Rifaximin	400 mg q8h or 550 mg BID; non-absorbable antibiotic; superior to lactulose alone in several RCTs; used for secondary prophylaxis
Branched-chain amino acids	IV infusion; proven benefit without increased mortality
Protein management	Moderate restriction; avoid excess — muscle is the main extra-hepatic ammonia detoxifier
Liver transplantation	Definitive; generally reverses HE

In ALF (Type A), intracranial hypertension develops in up to 80% of grades 3–4 encephalopathy. ICP monitoring, mannitol, and hypertonic saline may be needed.

II. Uremic Encephalopathy

Clinical Features

Early: lethargy, impaired attention/memory (~30% of dialysis patients have neuropsychiatric symptoms)
Intermediate: confusion, hallucinations, psychosis, tremor, myoclonus, asterixis
Severe: tonic-clonic or myoclonic seizures, stupor, coma
Degree of azotaemia correlates poorly with severity — urea itself is not the neurotoxin

Pathophysiology

Guanidine compounds (guanidinusuccinic acid, methylguanidine) — elevated 100-fold in uremic brain/CSF; activate NMDA receptors → seizures
Cytokine-mediated neuroinflammation + ↑ BBB permeability
Secondary hyperparathyroidism → elevated brain calcium → disrupted neurotransmitter release
Gut-microbial metabolites (phenylalanine, benzoate, glutamate pathways) linked to cognitive impairment
Anaemia — EPO therapy improves cognitive performance

Related Dialysis Syndromes

Syndrome	Mechanism	Features
Dialysis disequilibrium	Rapid solute clearance → osmotic gradient → cerebral edema	Headache, confusion, seizures during/after HD; treat by reducing dialysis duration/frequency
Dialysis encephalopathy	Aluminium neurotoxicity (historical)	Dysarthria, aphasia, myoclonus, cognitive decline
PRES	Failed autoregulation + endothelial dysfunction + fluid overload	Headache, visual changes, seizures; posterior white-matter edema on MRI
Wernicke's (dialysis)	Thiamine loss via dialysis; 33% prevalence in symptomatic dialysis encephalopathy	Classic triad (see below)

Management

Renal replacement therapy (dialysis/transplantation) — definitive
Correct anaemia and hyperparathyroidism
PRES: volume control and BP management
Caution with AEDs: uraemia + hypoalbuminaemia alter phenytoin protein binding; free levels should be measured directly

III. Hypertensive Encephalopathy & PRES

Hypertensive Encephalopathy

Mechanism: autoregulatory failure → breakthrough hyperperfusion → vasospasm → ischemia → ↑ vascular permeability → vasogenic oedema + punctate haemorrhages

Clinical: severe headache, vomiting, altered mental status, seizures/coma; visual disturbance → blindness; papilloedema; hypertensive retinopathy. Focal deficits do not follow a single anatomic distribution (diffuse dysfunction, not stroke).

Diagnosis: clinical (diffuse neurological dysfunction + markedly elevated BP ± papilloedema) + CT showing non-specific or absent changes. Do not delay treatment waiting for imaging.

Management: controlled BP reduction by 30–40% using IV agents (labetalol, nicardipine, nitroprusside). Fully reversible with early treatment; in-hospital mortality <1%. — Rosen's Emergency Medicine

PRES

Similar pathophysiology, but more posterior and region-specific
MRI hallmark: vasogenic oedema in posterior parietal-temporal-occipital white matter
Seizures in up to 90% of PRES cases
Causes beyond hypertension: eclampsia, vasculitis, TMA, calcineurin inhibitors (ciclosporin, tacrolimus), rituximab, ESKD, erythropoietin therapy
Reversible with treatment of underlying cause

IV. Wernicke Encephalopathy

Pathophysiology

Thiamine (B₁) deficiency impairs oxidative metabolism in high-demand regions: mammillary bodies, anterior/centromedian thalamus, periaqueductal grey, floor of the fourth ventricle. Deficiency of α-ketoglutarate dehydrogenase in astrocytes → microglial activation → glutamatergic toxicity → neuronal swelling, microscopic haemorrhages, gliosis.

At-Risk Groups

Chronic alcohol abuse · prolonged vomiting (any cause) · bariatric surgery · AIDS/cancer cachexia · dialysis patients · malnutrition

Classic Triad (present in only ~1/3 of cases)

Mental status change — inattention → delirium → coma; often apathy/abulia
Oculomotor dysfunction — nystagmus, dysconjugate gaze, gaze palsies
Ataxia — gait and lower limb predominance; non-alcoholic patients have more ocular involvement

⚠️ Only ~25% of cases are recognised before death. Clinically missed in most patients.

Investigations

MRI T2/FLAIR: symmetrical hyperintensity at periventricular thalamus, periaqueductal grey, floor of fourth ventricle, mammillary bodies
Thiamine level <50 μg/mL (normal in ~10%)
Elevated lactate and pyruvate

⚠️ Give IV thiamine BEFORE any glucose — IV glucose alone can precipitate acute Wernicke's

Management

IV thiamine (200–500 mg TID) immediately, before glucose
Followed by oral thiamine supplementation
Untreated → Korsakoff syndrome (irreversible anterograde amnesia + confabulation)

V. Septic/Systemic Inflammatory Encephalopathy

Mechanisms (converging):

Cytokine/LPS-mediated BBB disruption
Altered cerebral microcirculation and mitochondrial dysfunction
Endotoxin-driven oxidative stress and neurotransmitter disturbances
Sickness syndrome: PGE₂ crosses BBB → hypothalamic activation (fever, somnolence, anorexia, lowered pain threshold)

Key clinical clue: hyperventilation + respiratory alkalosis + impaired consciousness with no other metabolic cause → mount an urgent search for occult infection (UTI, wound infection). Treating the infection source often reverses the encephalopathy. — Plum & Posner

VI. Radiation Encephalopathy

Type	Timing	Mechanism	Features	Treatment
Acute	Days post-RT	BBB breakdown, ↑ ICP	Headache, nausea, altered mental status	High-dose corticosteroids
Early delayed	2 wks–4 months	Demyelination	Headache, drowsiness, previous deficits enhanced	Self-limiting; no specific treatment
Late (delayed)	Months–years (esp. >35 Gy total dose)	Vascular changes, necrosis, neuronal loss	Progressive dementia, frontal dysfunction, gait disorder	Bevacizumab; experimental: stem cell/anti-inflammatory

Bradley & Daroff's Neurology in Clinical Practice

Diagnostic Approach

All encephalopathy patients:
1. Exclude hypoglycaemia → IV thiamine then glucose if malnourished
2. Structural imaging (CT/MRI) if focal signs, trauma, or anticoagulation
3. Basic labs: glucose, Na, K, Ca, Mg, BUN/Cr, LFTs, ammonia, ABG, TFTs
4. Toxicology screen; medication review
5. Sepsis workup (CBC, cultures, CXR, UA)
6. EEG if subclinical seizures suspected

→ Treat the identified cause:
   Glucose → hypoglycaemia
   Thiamine → Wernicke's
   Lactulose ± rifaximin → hepatic
   Dialysis → uremic
   BP control → hypertensive/PRES
   Antibiotics + source control → septic
   Remove offending agent → toxic

Sources: Sleisenger & Fordtran's GI and Liver Disease · Plum & Posner's Diagnosis and Treatment of Stupor and Coma · Bradley & Daroff's Neurology in Clinical Practice · Brenner & Rector's The Kidney · Rosen's Emergency Medicine · Goldman-Cecil Medicine · Localization in Clinical Neurology, 8e

Para neoplastic syndrome

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paraneoplastic neurological syndrome autoantibodies

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Paraneoplastic Neurological Syndromes (PNS): Comprehensive Clinical Review

Definition

Paraneoplastic neurological syndromes (PNS) are remote effects of cancer on the nervous system that are not caused by:

Direct tumor invasion or metastasis
Infection, ischemia, or metabolic/nutritional derangement
Surgery, radiation, or chemotherapy

They are considered autoimmune disorders triggered by an immune response against antigens shared between tumor tissue and neurons (onconeural antigens). — Bradley & Daroff's Neurology in Clinical Practice

Key clinical feature: neurological symptoms commonly precede detection of the underlying cancer by 4–12 months, and the clinical course can be rapidly progressive, leaving patients severely disabled within weeks to months.

Pathophysiology: Two Immunological Subtypes

The fundamental distinction in PNS is based on the location of the target antigen — intracellular vs. cell surface:

Comparison of encephalitis associated with intracellular vs cell-surface antigens

Fig. 99-1 — Intracellular vs. cell-surface antigen mechanisms in paraneoplastic encephalitis. Harrison's Principles of Internal Medicine, 22e

Feature	Antibodies vs. Intracellular Antigens	Antibodies vs. Cell-Surface/Synaptic Antigens
Examples	Anti-Hu, Anti-Yo, Anti-Ri, Anti-Ma2, Anti-CV2/CRMP5	Anti-NMDAR, Anti-LGI1, Anti-Caspr2, Anti-AMPAR, Anti-GABAR
Effector mechanism	Primarily cytotoxic T-cell mediated; antibodies are surrogate markers, not pathogenic	Antibodies are directly pathogenic — cross-link/internalise or alter receptor function
Neuronal damage	Irreversible neuronal loss with inflammatory infiltrates; T cells directly contact neurons via perforin/granzyme	Reversible synaptic dysfunction; moderate inflammation, IgG deposits, microglial proliferation
Cancer association	Highly predictive of malignancy; antibody = cancer marker	Less predictive; many autoimmune variants without cancer
Treatment response	Poor; stabilisation is the goal	Good; respond well to immunotherapy

Antibody Classification and Tumour Associations

Antibodies Against Intracellular Antigens ("Classic Onconeural Antibodies")

Antibody	Neurological Syndrome	Primary Tumour
ANNA-1 (Anti-Hu)	Sensory neuronopathy, PEM, autonomic neuropathy, GI dysmotility	SCLC (>90%)
ANNA-2 (Anti-Ri)	Opsoclonus-myoclonus, jaw dystonia, ataxia	Breast, SCLC
PCA-1 (Anti-Yo)	Subacute cerebellar degeneration	Ovarian, breast
PCA-2	Limbic encephalitis, cerebellar ataxia, motor neuropathy	SCLC
Anti-Ma2 (Anti-Ta)	Limbic/hypothalamic/brainstem encephalitis	Testicular germ cell (men <45 y), lung
Anti-CV2 (CRMP5)	Cerebellar ataxia, dementia, chorea, uveitis, sensorimotor neuropathy	SCLC, thymoma
Anti-amphiphysin	Stiff-person syndrome, PEM, sensory neuronopathy	Breast, SCLC

Antibodies Against Cell-Surface / Synaptic Antigens

Antibody	Neurological Syndrome	Tumour Association
Anti-NMDAR	Anti-NMDA receptor encephalitis (see below)	Ovarian teratoma (young women); no tumour in children/males
Anti-LGI1	Limbic encephalitis, faciobrachial dystonic seizures, hyponatraemia	Thymoma (<5%); mainly autoimmune
Anti-Caspr2	Morvan syndrome, encephalitis, peripheral nerve hyperexcitability, neuropathic pain	Thymoma (~20%), higher in Morvan (~50%)
Anti-AMPAR	Limbic encephalitis, prominent psychiatric features	Breast, SCLC, thymoma
Anti-GABA-B receptor	Limbic encephalitis, seizures	SCLC, neuroendocrine tumours (~50%)
Anti-GABA-A receptor	Encephalitis with severe refractory seizures, status epilepticus	Thymoma
Anti-GlyR	PERM (progressive encephalomyelitis with rigidity and myoclonus)	Thymoma, lymphoma, breast (~20%)
Anti-VGCC	Lambert-Eaton myasthenic syndrome, cerebellar ataxia	SCLC
Anti-VGKC (complex)	Neuromyotonia (Isaacs), Morvan syndrome	Thymoma, SCLC

SCLC = small-cell lung cancer; PEM = paraneoplastic encephalomyelitis; PERM = progressive encephalomyelitis with rigidity and myoclonus

Associated Tumours

Tumour	Most Common PNS
Small-cell lung cancer (SCLC)	PEM, sensory neuronopathy, LEMS, cerebellar degeneration, autonomic neuropathy
Ovarian teratoma	Anti-NMDAR encephalitis
Breast cancer	Cerebellar degeneration (anti-Yo), opsoclonus-myoclonus (anti-Ri), stiff-person syndrome
Ovarian/gynaecological carcinoma	Cerebellar degeneration
Testicular germ cell tumour	Limbic/hypothalamic encephalitis (anti-Ma2)
Thymoma	LEMS, myasthenia gravis, neuromyotonia, limbic encephalitis
Hodgkin lymphoma	Cerebellar degeneration, mGluR5 encephalitis
Neuroblastoma (children)	Opsoclonus-myoclonus

Classic Paraneoplastic Syndromes

1. Paraneoplastic Encephalomyelitis (PEM)

Multifocal involvement of the neuraxis (brain, brainstem, cerebellum, spinal cord, dorsal root ganglia, autonomic NS). Features depend on the predominant site:

Limbic involvement: memory loss, confusion, seizures, psychiatric symptoms
Brainstem: oscillopsia, diplopia, dysarthria, gaze palsies, hearing loss
Cerebellar: gait ataxia
Autonomic: postural hypotension, gastroparesis, intestinal dysmotility, neurogenic bladder, erectile dysfunction, cardiac dysrhythmia
Lower motor neuron (myelitis): in ~20%

Most often associated with SCLC and anti-Hu antibodies. Cardiac dysrhythmia and respiratory failure are frequent causes of death. Generally poorly responsive to treatment. — Bradley & Daroff's

2. Limbic Encephalitis (LE)

Clinical: sub-acute memory loss (with relative preservation of other cognition) + confusion + complex partial seizures + psychiatric symptoms (depression, agitation, anxiety, hallucinations).

MRI: unilateral or bilateral mesial temporal lobe increased T2/FLAIR signal — one of the few PNSs where imaging can suggest the diagnosis.

Antibodies by clinical clue:

Anti-Hu → part of PEM, usually SCLC
Anti-Ma2 → young men, upper brainstem + vertical gaze palsy, testicular germ cell tumour; ~1/3 improve with tumour treatment + immunotherapy
Anti-LGI1 → >50 years, male, faciobrachial dystonic seizures, hyponatraemia; responds well to immunotherapy
Anti-AMPAR → prominent psychiatric features, breast/thymoma/SCLC
Anti-GABA-B → seizures dominant, SCLC; better outcome without cancer

3. Anti-NMDA Receptor Encephalitis

The most common autoimmune encephalitis overall. A 5-stage clinical progression:

Prodrome: fever, headache (viral-like)
Psychotic phase: agitation, hallucinations, delusions (often misdiagnosed as primary psychiatric)
Unresponsive phase: decreased consciousness, catatonia
Hyperkinetic phase: orofacial dyskinesias, autonomic instability, central hypoventilation
Recovery: months

Tumour: ovarian teratoma in ~50% of young women; search with pelvic US/MRI. Children and males often antibody-positive without tumour.

MRI: often normal or mild FLAIR changes — in contrast to LGI1/GABA-B encephalitis.

Treatment: responds well to immunotherapy + tumour removal (if present). — Harrison's, 22e

4. Paraneoplastic Cerebellar Degeneration (PCD)

Clinical: subacute, progressive pancerebellar syndrome — truncal and limb ataxia, nystagmus, dysarthria, diplopia, dysphagia. Develops over weeks to months. Accounts for ~12% of paraneoplastic neurological syndromes in lung cancer.

Pathology: severe loss of Purkinje cells with T-lymphocytic infiltrates (see histology above, Fig. 81.1).

Antibodies: Anti-Yo (ovarian/breast) · Anti-Hu (SCLC) · Anti-Ri · Anti-VGCC (often with LEMS) · anti-mGluR1 (Hodgkin lymphoma)

Prognosis: often leaves severe disability; improvement uncommon unless cell-surface antibody involved. — Bradley & Daroff's, Harrison's

5. Paraneoplastic Sensory Neuronopathy (PSN)

Clinical: progressive sensory loss (all modalities), painful dysesthesias; initially asymmetric → symmetric; sensory ataxia, pseudoathetosis; sensorineural hearing loss possible. Two-thirds develop neurological symptoms before cancer diagnosis.

EMG/NCS: small-amplitude or absent SNAPs; normal motor studies → consistent with dorsal root ganglion involvement.

Antibody: Anti-Hu in ~80% (associated with SCLC).

Management: prompt tumour control (SCLC) → neurological stabilisation; partial improvement with corticosteroids; IVIG/rituximab — uncertain efficacy. — Bradley & Daroff's

6. Paraneoplastic Opsoclonus-Myoclonus (POM)

Clinical: chaotic, arrhythmic, large-amplitude conjugate eye movements in all directions (opsoclonus) + myoclonus of head, trunk, extremities.

Children: usually neuroblastoma; prominent staggering/falling. Responds to ACTH, corticosteroids, IVIg. Relapses are common.

Adults: breast cancer (anti-Ri/ANNA-2), SCLC, testicular. More severe course; may include ataxia, encephalopathy.

Treatment (adults): tumour treatment + early aggressive immunotherapy (plasma exchange, immunoadsorption, steroids). — Bradley & Daroff's

7. Lambert-Eaton Myasthenic Syndrome (LEMS)

Mechanism: Antibodies against voltage-gated calcium channels (VGCC) at the presynaptic neuromuscular junction → impaired ACh vesicle release.

Clinical: proximal muscle weakness (legs > arms) + fatigue; autonomic features (dry mouth, constipation, erectile dysfunction); incremental response on repetitive nerve stimulation (distinguishes from myasthenia gravis, where decrement predominates).

Lambert's sign: brief exercise transiently improves strength (facilitates Ca²⁺ accumulation).

Tumour: SCLC in ~60%. If SCLC not found initially, screen every 6 months for ≥3 years.

Treatment: 3,4-diaminopyridine (increases ACh release) · pyridostigmine · IVIg · plasma exchange · tumour treatment. — Bradley & Daroff's, Harrison's

8. Stiff-Person Syndrome (Paraneoplastic)

Clinical: progressive rigidity of axial and proximal muscles, superimposed painful spasms triggered by stimuli; lumbar hyperlordosis.

Antibody: Anti-amphiphysin (paraneoplastic, associated with breast cancer, SCLC) · Anti-GAD65 (autoimmune, non-paraneoplastic).

Treatment: diazepam, baclofen, IVIg, plasma exchange; treat underlying tumour.

9. POEMS Syndrome

Polyneuropathy + Organomegaly + Endocrinopathy + M-protein + Skin changes

Associated with sclerotic myeloma or Castleman disease. The neuropathy is a subacute/chronic demyelinating symmetrical sensorimotor neuropathy (mimics CIDP but with more axonal loss features and greater CMAP/SNAP amplitude reduction). Monoclonal VEGF elevation is a key marker.

Treatment: high-dose chemotherapy + autologous stem cell transplantation; or low-dose alkylator + steroids. — Bradley & Daroff's

10. Paraneoplastic Visual Syndromes

Cancer-associated retinopathy (CAR): photosensitivity, progressive vision/colour loss, central scotomas, night blindness; SCLC (anti-recoverin antibodies); ERG abnormal
Melanoma-associated retinopathy (MAR): acute night blindness, photopsias; metastatic melanoma
Paraneoplastic optic neuritis/uveitis: associated with PEM; CRMP5 antibodies

Treatment responses are limited; stabilisation with steroids, plasma exchange, IVIg, rituximab, or alemtuzumab.

Diagnostic Criteria for Definite PNS (Graus et al., 2004)

A patient has definite PNS if any one of the following is met:

A classical syndrome (limbic encephalitis, PCD, sensory neuronopathy, PEM, opsoclonus-myoclonus, LEMS, dermatomyositis) + cancer diagnosed within 5 years — regardless of antibody status
A non-classical syndrome that objectively improves/resolves with cancer treatment (and is not prone to spontaneous remission)
A non-classical syndrome + onconeural antibodies + cancer diagnosed within 5 years
A neurological syndrome (classical or not) with well-characterised onconeural antibodies (anti-Hu, anti-Yo, etc.)

— Bradley & Daroff's Neurology in Clinical Practice

Diagnostic Approach

Clinical suspicion: subacute neurological syndrome in adult
     ↓
1. MRI brain (and spine if indicated)
   - Limbic LE: bilateral mesial temporal FLAIR signal
   - PCD: normal early; later cerebellar atrophy
   - Anti-NMDAR: often normal or mild FLAIR

2. CSF
   - Mild-moderate pleocytosis (<200 cells, lymphocytes)
   - Elevated protein; oligoclonal bands variable
   - Rule out infection, leptomeningeal metastasis

3. Onconeural antibody panel (serum AND CSF)
   - Only 60–70% of CNS PNS have detectable antibodies
   - <20% of peripheral PNS are antibody-positive

4. Tumour search (mandatory even if antibody-negative)
   - CT chest/abdomen/pelvis
   - PET-CT (identifies tumours missed by CT)
   - Testicular/pelvic US (germ cell tumours)
   - Mammography / breast MRI
   - If negative: repeat in 3–6 months × 2 years

5. EEG (limbic encephalitis with seizures)
6. Neurophysiology (NCS/EMG for peripheral PNS; VGCC antibodies + LEMS)

Important: combined CT+PET often uncovers tumours not detected by other tests. For testicular/ovarian tumours, US and MRI/CT pelvis may be required as PET may miss them. — Harrison's 22e

Principles of Treatment

Intervention	Rationale / Application
Tumour treatment	Most critical — eliminating tumour removes antigen source; improves outcome especially for LEMS, anti-Ma2 LE, opsoclonus-myoclonus
First-line immunotherapy	IV methylprednisolone · IVIg · Plasma exchange
Second-line immunotherapy	Rituximab · Cyclophosphamide · Mycophenolate mofetil · Azathioprine
Symptomatic	AEDs for seizures; 3,4-diaminopyridine + pyridostigmine for LEMS; diazepam/baclofen for stiff-person

Response by Antibody Type

Antibody Type	Treatment Response
Cell-surface antigens (NMDAR, LGI1, Caspr2, AMPAR, GABA-R)	Good — often substantial improvement; immunotherapy ± tumour removal
Intracellular antigens (Hu, Yo, Ri, Ma2)	Poor — neuronal loss is irreversible; goal is stabilisation

⚠️ Concern that immunosuppression could promote tumour growth has not been reported clinically. — Fishman's Pulmonary Diseases and Disorders

Non-Neurological Paraneoplastic Syndromes (Brief Overview)

Paraneoplastic effects extend beyond the nervous system:

System	Syndrome	Mechanism
Endocrine	SIADH (SCLC), Cushing's (ectopic ACTH), hypercalcaemia (PTHrP), carcinoid syndrome	Ectopic hormone production
Haematological	DVT/PE (Trousseau), DIC, AIHA, thrombocytopenia	Procoagulant tumour products
Musculoskeletal	Dermatomyositis/polymyositis, hypertrophic osteoarthropathy	Immune-mediated muscle inflammation
Dermatological	Acanthosis nigricans, paraneoplastic pemphigus, Sweet syndrome, Leser-Trélat sign	Cytokine/antibody-mediated
Renal	Membranous nephropathy (solid tumours), minimal change disease (Hodgkin's)	Immune complex deposition

Recent Update (Lancet Neurology, 2024)

Immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4) used in oncology can unmask or de novo trigger paraneoplastic neurological syndromes by augmenting immune responses against shared tumour-neuronal antigens. This represents a growing clinical challenge in modern oncology — distinguishing immune-related neurological adverse events from true PNS. [PMID: 38101905]

Sources: Harrison's Principles of Internal Medicine, 22e · Bradley & Daroff's Neurology in Clinical Practice · Robbins & Cotran Pathologic Basis of Disease · Fishman's Pulmonary Diseases · Plum & Posner's Stupor and Coma · Lancet Neurology 2024 (PMID: 38101905)Here is the comprehensive review:

Paraneoplastic Syndromes: Comprehensive Clinical Review

Definition

Paraneoplastic syndromes (PNS) are remote effects of cancer on the nervous system (or other organs) that are not caused by direct tumour invasion, metastasis, infection, ischemia, metabolic derangement, or treatment. They are autoimmune disorders where the tumour expresses antigens normally confined to neurons — triggering an immune response that cross-attacks the nervous system (onconeural antigens). — Bradley & Daroff's Neurology

Critical clinical point: neurological symptoms often precede tumour detection by 4–12 months and progress rapidly over weeks to months. Recognising the syndrome early is the key to identifying a potentially treatable cancer.

Pathophysiology: The Two-Subtype Paradigm

The most clinically important distinction is based on where the target antigen is located:

Intracellular vs cell-surface antigen mechanisms

Fig. 99-1 — Harrison's Principles of Internal Medicine, 22e

Feature	Intracellular Antigens	Cell-Surface/Synaptic Antigens
Examples	Anti-Hu, Anti-Yo, Anti-Ri, Anti-Ma2, Anti-CV2	Anti-NMDAR, Anti-LGI1, Anti-Caspr2, Anti-AMPAR
Effector mechanism	Cytotoxic T cells → irreversible neuronal loss	Antibodies directly alter receptor function → reversible synaptic dysfunction
Cancer prediction	Highly predictive (almost always malignancy)	Less predictive; many autoimmune variants without cancer
Treatment response	Poor — stabilisation is the goal	Good — often substantial recovery

Antibody Table and Tumour Associations

Classic Onconeural Antibodies (Intracellular Targets)

Antibody	Syndrome	Primary Tumour
Anti-Hu (ANNA-1)	Sensory neuronopathy, PEM, autonomic neuropathy, GI dysmotility	SCLC
Anti-Yo (PCA-1)	Subacute cerebellar degeneration	Ovarian, breast
Anti-Ri (ANNA-2)	Opsoclonus-myoclonus, jaw dystonia, ataxia	Breast, SCLC
Anti-Ma2 (Ta)	Limbic/hypothalamic/brainstem encephalitis	Testicular germ cell (men <45 y); lung
Anti-CV2/CRMP5	Cerebellar ataxia, dementia, chorea, uveitis, sensorimotor neuropathy	SCLC, thymoma
Anti-amphiphysin	Stiff-person syndrome, PEM	Breast, SCLC

Cell-Surface / Synaptic Antibodies

Antibody	Syndrome	Tumour Association
Anti-NMDAR	Anti-NMDAR encephalitis (see below)	Ovarian teratoma (~50% in young women)
Anti-LGI1	Limbic encephalitis, faciobrachial dystonic seizures, hyponatraemia	Thymoma <5%; mostly autoimmune
Anti-Caspr2	Morvan syndrome, encephalitis, peripheral nerve hyperexcitability	Thymoma ~20% (Morvan ~50%)
Anti-AMPAR	Limbic encephalitis, psychiatric features	Breast, SCLC, thymoma
Anti-GABA-B	Limbic encephalitis, refractory seizures	SCLC/neuroendocrine (~50%)
Anti-GABA-A	Severe refractory status epilepticus	Thymoma
Anti-GlyR	PERM (rigidity + myoclonus)	Thymoma, lymphoma, breast (~20%)
Anti-VGCC	LEMS, cerebellar ataxia	SCLC

Classic Syndromes

1. Paraneoplastic Encephalomyelitis (PEM)

Multifocal neuraxis involvement. Features vary by predominant site:

Limbic: memory loss, confusion, seizures, psychiatric features
Brainstem: oscillopsia, diplopia, dysarthria, gaze palsies
Cerebellar: gait ataxia; Purkinje cell loss with T-cell infiltrates
Autonomic: postural hypotension, gastroparesis, neurogenic bladder; cardiac arrhythmia/respiratory failure = common causes of death
Spinal cord (myelitis): lower motor neuron features ~20%

Antibody: Anti-Hu with SCLC (most common). Poorly responsive to treatment.

2. Limbic Encephalitis (LE)

Clinical: subacute short-term memory loss + complex partial seizures + psychiatric symptoms (confusion, agitation, hallucinations)
MRI: unilateral or bilateral mesial temporal lobe T2/FLAIR signal increase — one of the few PNS with characteristic imaging
Antibody clues:
- Anti-LGI1 → faciobrachial dystonic seizures + hyponatraemia + male >50 years → responds well to immunotherapy
- Anti-Ma2 → young male + vertical gaze palsy + testicular tumour → ~1/3 improve with treatment
- Anti-Hu → part of PEM, SCLC → poor prognosis

3. Anti-NMDA Receptor Encephalitis

The most common autoimmune encephalitis. Five-stage progression:

Prodrome (flu-like)
Psychiatric phase — hallucinations, delusions, agitation (frequently misdiagnosed as first-episode psychosis)
Unresponsive/catatonic phase
Hyperkinetic phase — orofacial dyskinesias, autonomic instability, central hypoventilation
Recovery (months)

MRI: often normal. Tumour: ovarian teratoma in ~50% of young women; screen with pelvic US/MRI/CT. Children and males often have no tumour. Responds well to immunotherapy + tumour removal.

4. Paraneoplastic Cerebellar Degeneration (PCD)

Subacute pancerebellar syndrome: truncal + limb ataxia, nystagmus, dysarthria, diplopia
Accounts for ~12% of paraneoplastic syndromes in lung cancer
Pathology: massive Purkinje cell loss with CD3 T-cell infiltrates
Antibodies: Anti-Yo (ovary/breast), Anti-Hu (SCLC), Anti-VGCC (often with LEMS), Anti-Ri
Prognosis: severe, largely irreversible unless cell-surface antibody involved

5. Paraneoplastic Sensory Neuronopathy (PSN)

Progressive sensory loss all modalities + painful dysesthesias; initially asymmetric
Sensory ataxia, pseudoathetotic movements; hearing loss possible
2/3 develop symptoms before cancer diagnosis
NCS: absent/small SNAPs; normal motor studies (dorsal root ganglion pathology)
Antibody: Anti-Hu (~80%; SCLC)
Management: tumour control → stabilisation; corticosteroids may partially help

6. Paraneoplastic Opsoclonus-Myoclonus (POM)

Chaotic, arrhythmic conjugate saccades in all directions + multifocal myoclonus
Children: neuroblastoma; prominent gait disturbance; treat with ACTH, IVIg
Adults: breast (anti-Ri), SCLC, testicular; worse course

7. Lambert-Eaton Myasthenic Syndrome (LEMS)

Mechanism: Anti-VGCC antibodies → impaired presynaptic ACh vesicle release
Clinical: proximal leg > arm weakness, fatigue, dry mouth; brief exercise temporarily improves strength (Lambert's sign)
EMG: incremental response on repetitive stimulation (vs. decrement in MG)
Tumour: SCLC ~60%; if negative, screen 6-monthly for ≥3 years
Treatment: 3,4-diaminopyridine, pyridostigmine, IVIg, plasma exchange + tumour treatment

8. Stiff-Person Syndrome (Paraneoplastic)

Progressive axial rigidity + painful spasms on stimulation + lumbar hyperlordosis
Paraneoplastic: Anti-amphiphysin → breast/SCLC
Autoimmune variant: Anti-GAD65 (not paraneoplastic)
Treatment: diazepam, baclofen, IVIg, plasma exchange

9. POEMS Syndrome

Polyneuropathy · Organomegaly · Endocrinopathy · M-protein · Skin changes

Associated with sclerotic myeloma or Castleman disease. Neuropathy mimics CIDP but with more axonal loss; elevated serum VEGF is key. Treatment: high-dose alkylator chemotherapy + autologous stem cell transplantation.

Diagnostic Criteria (Graus et al., 2004) — Any ONE of:

Classical syndrome + cancer within 5 years (antibody-independent)
Non-classical syndrome that objectively improves with cancer treatment
Non-classical syndrome + paraneoplastic antibodies + cancer within 5 years
Neurological syndrome (any) + well-characterised onconeural antibody

Diagnostic Workup

1. MRI brain ± spine
   → LE: bilateral medial temporal FLAIR ↑
   → PCD: normal early → late cerebellar atrophy
   → Anti-NMDAR: often normal

2. CSF: lymphocytic pleocytosis, ↑protein, oligoclonal bands
   → Rule out CNS infection, leptomeningeal disease

3. Onconeural antibody panel — BOTH serum AND CSF
   → Only 60–70% of CNS PNS are antibody-positive
   → Positive antibody = mandatory tumour search

4. Tumour search
   → CT chest/abdomen/pelvis
   → PET-CT (best sensitivity for occult tumours)
   → Pelvic US/MRI (ovarian teratoma)
   → Testicular US (anti-Ma2 in young men)
   → Mammography/breast MRI
   → Repeat every 3–6 months × 2 years if initially negative

5. EEG — for subclinical seizures in LE / anti-NMDAR
6. EMG/NCS — LEMS (incremental response); PSN (absent SNAPs)

Treatment

Step	Intervention
1. Treat the tumour	Most critical; eliminates antigenic trigger; most beneficial for LEMS, anti-Ma2, opsoclonus-myoclonus, cell-surface antibody encephalitides
2. First-line immunotherapy	IV methylprednisolone · IVIg · Plasma exchange
3. Second-line immunotherapy	Rituximab · Cyclophosphamide · Mycophenolate · Azathioprine
4. Symptomatic	AEDs (seizures) · 3,4-DAP + pyridostigmine (LEMS) · Diazepam/baclofen (stiff-person)

Response rule: cell-surface antibody syndromes respond well and are often reversible; intracellular antibody syndromes respond poorly and neuronal loss is irreversible — stabilisation is the realistic goal.

Non-Neurological Paraneoplastic Syndromes

System	Syndrome	Example Tumour
Endocrine	SIADH, ectopic ACTH (Cushing's), hypercalcaemia (PTHrP), carcinoid	SCLC, lung, renal
Haematological	Trousseau syndrome (DVT/PE), DIC, AIHA	Adenocarcinomas, pancreas
Musculoskeletal	Dermatomyositis/polymyositis, hypertrophic osteoarthropathy	Various solid tumours
Dermatological	Acanthosis nigricans, paraneoplastic pemphigus, Leser-Trélat sign	GI, lymphoma
Renal	Membranous nephropathy, minimal change disease	Solid tumours; Hodgkin

Recent Development

Immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4) can unmask or de novo trigger paraneoplastic neurological syndromes by amplifying immune responses against shared tumour-neuronal antigens — an increasingly recognised complication in modern oncology. Distinguishing immune-related neurological adverse events from true PNS is an active clinical challenge. — [Farina et al., Lancet Neurol 2024, PMID: 38101905]

Sources: Harrison's Principles of Internal Medicine, 22e · Bradley & Daroff's Neurology in Clinical Practice · Robbins & Cotran Pathologic Basis of Disease · Fishman's Pulmonary Diseases & Disorders · Plum & Posner's Diagnosis and Treatment of Stupor and Coma

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