Encephalopathy: Comprehensive Clinical Review

Definition

General Clinical Features of Metabolic Encephalopathy

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

I. Hepatic Encephalopathy (HE)

Epidemiology

Classification

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

Pathophysiology

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

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.
2. 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.
3. GABA-benzodiazepine system — enhanced astrocyte peripheral benzodiazepine receptor sensitivity → ↑ neurosteroid production (allopregnanolone, THDOC) → amplified GABAergic inhibition.
4. Neuroinflammation — intercurrent infection drastically worsens HE by direct cytokine-mediated brain dysfunction.
5. Other: manganese (dopaminergic toxicity), nitric oxide, reactive oxygen species, gut microbiome dysbiosis.

Common Precipitants

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

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

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

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

At-Risk Groups

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

1. Mental status change — inattention → delirium → coma; often apathy/abulia
2. Oculomotor dysfunction — nystagmus, dysconjugate gaze, gaze palsies
3. 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

• 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)

VI. Radiation Encephalopathy

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

Paraneoplastic Syndromes: Comprehensive Clinical Review

Definition

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

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

Antibody Table and Tumour Associations

Classic Onconeural Antibodies (Intracellular Targets)

Cell-Surface / Synaptic Antibodies

Classic Syndromes

1. Paraneoplastic Encephalomyelitis (PEM)

• 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%

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

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

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

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

1. Classical syndrome + cancer within 5 years (antibody-independent)
2. Non-classical syndrome that objectively improves with cancer treatment
3. Non-classical syndrome + paraneoplastic antibodies + cancer within 5 years
4. 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

Non-Neurological Paraneoplastic Syndromes

Recent Development