GC225 Neuroimmunological Disorders Of The Central Nervous System
Neuroimmunological disorders of the central nervous system are conditions in which aberrant immune-mediated responses target neural tissues of the brain and spinal cord, leading to inflammation, demyelination, or neuronal injury, as seen in diseases such as multiple sclerosis, neuromyelitis optica, and autoimmune encephalitis.
Neuroimmunological Disorders of the Central Nervous System
The Big Idea: This lecture covers the three major CNS autoimmune demyelinating/inflammatory conditions — Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum Disorders (NMOSD), and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) — plus Autoimmune Encephalitis (particularly anti-NMDAR, LGI1, and GABABR encephalitis). The unifying theme is that the immune system attacks CNS structures, and distinguishing which target is attacked determines diagnosis, prognosis, and — critically — which treatments help and which can worsen disease. [1]
Why this matters for exams: These conditions are commonly tested because they cross neurology, immunology, ophthalmology, psychiatry, and radiology. Examiners love the differentials (MS vs NMOSD vs MOGAD), the MRI patterns, the specific antibodies, the management escalation ladders, and the trap that MS disease-modifying therapies should NOT be used in NMOSD.
Learning Objectives (inferred from slides):
- Understand epidemiology, pathophysiology, and clinical features of MS
- Classify MS subtypes (RRMS, PPMS, SPMS) and their natural history
- Know MRI and CSF findings in MS and how diagnosis is established
- Know acute attack management and the DMT escalation ladder for MS (especially HK-specific HA/Samaritan Fund tiers)
- Differentiate NMOSD from MS — antibody, imaging, clinical, treatment differences
- Understand MOGAD as a distinct entity
- Recognise autoimmune encephalitis syndromes — anti-NMDAR, LGI1, GABABR
- Understand the paraneoplastic associations and management of autoimmune encephalitis
Why Does the Immune System Attack the CNS?
Normally, the blood–brain barrier (BBB) prevents most immune cells from entering the CNS. In neuroimmunological disorders, autoreactive lymphocytes (both T cells and B cells) are activated in the periphery and cross the BBB. Once inside the CNS, they encounter self-antigens presented by microglia and other antigen-presenting cells, which amplifies the immune response locally. The specific target antigen determines the disease:
| Disease | Target Antigen | Antibody | Cell Type Driving Damage |
|---|---|---|---|
| MS | Myelin antigens (? exact target unclear) | Oligoclonal bands in CSF (non-specific) | CD8+ T cells, macrophages, microglia; B cells |
| NMOSD | Aquaporin-4 (water channel on astrocyte end-feet) | AQP4-IgG | Antibody + complement-mediated astrocyte destruction |
| MOGAD | Myelin oligodendrocyte glycoprotein (MOG on oligodendrocytes) | MOG-IgG | Antibody-mediated demyelination |
| Anti-NMDAR encephalitis | NMDA receptor (GluN1 subunit) | NMDAR antibody | Antibody → receptor internalization → loss of function |
| LGI1 encephalitis | LGI1 protein (synaptic) | LGI1-IgG4 | Antibody disrupts LGI1-ADAM22/23 complex |
| GABABR encephalitis | GABA-B receptor | GABABR antibody | Antibody → receptor dysfunction |
1. Multiple Sclerosis (MS)
"MS is an idiopathic inflammatory demyelinating disorder of the CNS and an important cause of non-traumatic disability in young adults (18–40 years)." [1]
- Prevalence: ranges from 5 per 100,000 (lowest, Western Pacific including Hong Kong) to 111–300 per 100,000 (highest, Europe & Americas) [1]
- ~2.8 million patients worldwide [1]
- F:M = 3:1 [1]
- Mean age at diagnosis ~32 years [1]
- Etiologies: genetic susceptibility + environmental factors (notably EBV infection) + lifestyle factors [1]
Why EBV?
Nearly 100% of MS patients are EBV seropositive. Recent large cohort studies (e.g., Bjornevik et al., Science 2022) show that EBV infection increases MS risk 32-fold. The leading hypothesis is molecular mimicry — EBV proteins resemble myelin antigens, so anti-EBV immune responses cross-react with CNS myelin.
- Heterogeneity in clinical features, severity, and response to disease-modifying therapies [1]
85% present with relapsing-remitting MS (RRMS); 15% present with primary progressive MS (PPMS). [1]
| Subtype | Description | Key Points |
|---|---|---|
| RRMS | Recurrent acute attacks of CNS inflammation with full or partial recovery between attacks | Most common presentation; early disease is inflammatory |
| PPMS | Progressive neurological disability from onset without discrete relapses | 15% of MS; poorer prognosis; fewer DMT options |
| SPMS | Initially RRMS → transitions to progressive decline ± superimposed relapses | Historical untreated cohorts transitioned much faster than many modern DMT-treated cohorts; avoid memorising a universal “50% by 10 years” figure |
Why does SPMS happen? Early MS is primarily inflammatory (relapses driven by immune cell infiltration). Over time, chronic smouldering inflammation with microglia/astrocyte activation, iron deposition in macrophages, progressive axonal/synaptic loss, and cortical atrophy lead to irreversible neurodegeneration independent of acute relapses. This is why early aggressive DMT to prevent relapses may delay or prevent SPMS. [1]
Acute attacks commonly affect: cerebral hemisphere (supratentorial), brainstem and cerebellum (infratentorial), spinal cord (myelitis), and optic nerve (optic neuritis). [1]
Specific symptoms by lesion site: [1]
| Lesion Site | Symptoms |
|---|---|
| Supratentorial (cerebral hemisphere) | Motor weakness (hemiparesis); sensory symptoms (numbness, paresthesia); rarely: aphasia, dyslexia, memory loss, hearing loss, acute confusion |
| Optic nerve | Unilateral blurring of vision or visual loss (optic neuritis) — painful, with pain on eye movement; RAPD present |
| Brainstem | Dizziness, vertigo, diplopia, incoordination, unsteady gait, facial sensory symptoms/weakness, slurred speech, dysphagia |
| Cerebellum | Dizziness, vertigo, incoordination, unsteady gait (cerebellar ataxia) |
| Spinal cord (myelitis) | Motor weakness (paraparesis/tetraparesis); sensory symptoms; sphincter disturbance (urinary retention) |
Permanent disabilities in advanced disease: [1]
- Paraparesis, tetraparesis, spasticity, cerebellar ataxia, fatigue, visual impairment or loss, dysphagia, diplopia, oscillopsia, urinary retention/incontinence, constipation/bowel incontinence, dysarthria, weak voice, sexual dysfunction, cognitive impairment (can cause dementia with cerebral atrophy in young people) [1]
- Anxiety and depression are common in patients with chronic disease and significant disabilities [1]
High Yield – MS Can Cause Dementia in Young People
Students often forget that MS can cause cognitive impairment and even dementia due to cerebral atrophy. This is a favourite exam distractor — a young patient with progressive cognitive decline and white matter lesions may have MS, not Alzheimer's.
Autoreactive lymphocytes (T and B cells) in peripheral blood migrate into CNS → trigger acute attacks. [1]
The stepwise pathophysiology: [1]
- Peripheral activation: Autoreactive T and B cells are activated in the periphery (possibly by molecular mimicry with EBV or other triggers)
- Migration into CNS: These cells cross the BBB. The adhesion molecule VLA-4 on lymphocyte surfaces binds to VCAM-1 on endothelial cells, facilitating transmigration. (This is the target of natalizumab.)
- Intrathecal immune activation: CD4+ T cells are further activated by antigen-presenting cells (microglia, B cells) in the CNS [1]
- B cell activation: CD4+ T cells activate B cells which produce antibodies (detected as oligoclonal bands in CSF) [1]
- Tissue injury: CD8+ T cells, activated macrophages, and microglia cause demyelination, axonal and synaptic injury/loss [1]
- Complement activation: Antibodies bind to autoantigens (? myelin antigens) and trigger complement activation [1]
- Chronic smouldering inflammation: Activated macrophages phagocytose myelin debris and contain iron; microglia and astrocyte activation leads to chronic smouldering inflammation [1] — this drives the progressive/degenerative phase (SPMS)
MRI brain/cord: T2W hyperintense lesions or T1W contrast-enhancing lesions in 4 major regions suggestive of MS: periventricular, cortical or juxtacortical, infratentorial, spinal cord. [1]
What the MS MRI panel shows: periventricular plaques, a gadolinium-enhancing active lesion, juxtacortical spots, infratentorial lesions, and an enhancing cervical cord lesion — dissemination in space (and enhancing + non-enhancing = time) made visible. [1]
| Investigation | Finding / Purpose |
|---|---|
| MRI brain & spinal cord | T2-hyperintense lesions in characteristic locations; T1 gadolinium-enhancing lesions indicate active/new lesions (dissemination in time); "Dawson fingers" = periventricular lesions extending perpendicular to ventricles |
| MRI optic nerve | Enhancement/swelling in optic neuritis |
| Lumbar puncture — CSF | Oligoclonal bands (OCBs) — present in ~95% of MS; indicates intrathecal IgG synthesis |
| Blood tests | To exclude mimics: ANA, anti-dsDNA, anti-ENA, C3/C4, ANCA, AQP4-IgG, MOG-IgG, Lyme serology, syphilis serology [1] |
| VEP (Visual Evoked Potentials) | Look for evidence of subclinical optic neuritis — prolonged P100 latency [1] |
| Brain biopsy | In tumefactive demyelination when MRI abnormality suggests neoplastic lesion — rarely needed [1] |
Dissemination in Space and Time (DIS/DIT)
The McDonald criteria for MS diagnosis require evidence of lesions disseminated in space (≥2 of the 4 typical CNS regions) and time (new lesions on follow-up MRI, or simultaneous enhancing and non-enhancing lesions, or CSF OCBs can substitute for DIT in the 2017 revision). This is why MRI with specific regional lesions + CSF OCBs can clinch the diagnosis even after a single clinical event.
1.6 Diagnosis of MS
Clinical history: recurrent episodes of neurological symptoms or dysfunction with partial or complete (early) recovery, PLUS supportive investigation findings (typically compatible MRI findings & presence of CSF oligoclonal bands), PLUS exclusion of other diseases that mimic MS. [1]
Key principle: MS is a clinical diagnosis supported by investigations. There is no single diagnostic test. You must actively exclude mimics.
| Clinical attacks | Lesions with objective evidence | What is still required? |
|---|---|---|
| ≥2 | ≥2 | Nothing further, provided there is no better diagnosis |
| ≥2 | 1, plus clear historical evidence of a prior attack from a different site | Nothing further |
| ≥2 | 1 | Dissemination in space (DIS) |
| 1 | ≥2 | Dissemination in time (DIT) |
| 1 | 1 | DIS and DIT |
For a typical clinically isolated syndrome, DIS can be demonstrated by lesions in at least two characteristic CNS regions. DIT can be shown by a new lesion over time, simultaneous enhancing and non-enhancing lesions, or—under the 2017 criteria—CSF-specific oligoclonal bands. Apply these criteria only after excluding a better explanation; they are not a shortcut for atypical presentations.
Features that favour earlier high-efficacy discussion include a severe or poorly recovering first attack, motor/cerebellar/sphincter/cognitive involvement, multifocal onset, frequent early relapses, rapid EDSS accrual, high T2 burden, multiple enhancing lesions, infratentorial or spinal lesions, early T1 “black holes”/atrophy, smoking and older age at onset. These are risk markers, not a stand-alone diagnostic score.
DDx of MS: [1]
- NMOSD
- MOGAD
- Vasculitis (primary CNS angiitis / secondary: SLE, Sjögren's syndrome)
- Acute disseminated encephalomyelitis (ADEM) — post-viral
- Neuro-Behçet's disease
- Neurosyphilis
- Neuroborreliosis (Lyme disease)
- Leukodystrophies — genetic
- CADASIL — genetic
Exam Trap: CADASIL vs MS
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) can produce white matter lesions on MRI that look very similar to MS. Clues: family history of early strokes/dementia, involvement of anterior temporal lobe and external capsule (atypical for MS), and NOTCH3 mutation. This is a genetic condition, not inflammatory.
1.8 Treatment of MS
First-line: Pulse steroid — Intravenous Methylprednisolone (IVMP) 0.5–1 g daily for 3–5 days [1]
| Line | Treatment | When to Use |
|---|---|---|
| 1st line | IVMP 0.5–1 g daily × 3–5 days | Functionally significant acute relapse after excluding infection and pseudo-relapse; a mild sensory relapse may not require steroids |
| 2nd line (rescue) | Plasma exchange (PE) | If no significant neurological improvement ~2 weeks after IVMP; also first-line if IVMP contraindicated |
| 3rd line | IVIg | IVMP contraindicated AND PE unavailable/intolerant |
Why pulse steroids? High-dose methylprednisolone rapidly suppresses acute inflammation, reduces BBB permeability, and shortens the duration of acute relapses. It does NOT change the long-term course of disease (i.e., doesn't prevent future relapses or progression).
Why plasma exchange? PE physically removes circulating pathogenic antibodies and complement factors. It is effective as rescue therapy in severe attacks not responding to steroids; in a severe deficit, specialist teams may escalate earlier rather than waiting rigidly for two weeks.
DMTs are long-term treatments aimed at reducing relapse frequency, slowing disability progression, and reducing MRI lesion burden. They do NOT cure MS. The lecture organizes them by efficacy: [1]
| Efficacy Tier | Drug | Route | Mechanism | Key Side Effects |
|---|---|---|---|---|
| Modest | Beta-interferon | SC | Anti-inflammatory; shifts Th1 → Th2 | Deranged LFTs, injection site reaction |
| Modest | Teriflunomide | Oral | Inhibits pyrimidine synthesis → ↓ proliferation of activated T and B cells | Teratogenic, hepatotoxicity |
| Moderate | Dimethyl fumarate (DMF) | Oral | Anti-inflammatory via Nrf2-dependent and -independent pathways | GI discomfort (abdominal pain, diarrhea), infection |
| Moderate–High | Fingolimod | Oral | S1P modulator → traps lymphocytes in lymph nodes → circulating lymphopenia | Lymphopenia, herpes zoster, cardiac conduction defect, macular oedema, ↑risk basal cell carcinoma |
| Moderate–High | Siponimod | Oral | S1P modulator (approved for active SPMS) | Similar to fingolimod |
| High | Cladribine | Oral | Induces apoptosis of lymphocytes → immune reconstitution | Lymphopenia, infection |
| High | Anti-CD20 mAbs (ocrelizumab, rituximab, ofatumumab) | IV/SC | Deplete CD20+ B lymphocytes | Infusion reactions, infection, HBV reactivation |
| High | Natalizumab | IV | mAb against VLA-4 → prevents lymphocyte migration into CNS | Progressive Multifocal Leukoencephalopathy (PML) — potentially life-threatening |
| High | Alemtuzumab | IV | mAb against CD52 → depletion of lymphocytes and APCs → immune reconstitution | Secondary autoimmunity (thyroid disease, ITP), infections, HBV reactivation |
Critical Exam Point: PML Risk with Natalizumab
Natalizumab's most feared side effect is Progressive Multifocal Leukoencephalopathy (PML), caused by JC virus reactivation. Risk factors: JC virus seropositivity, prior immunosuppressant use, duration of natalizumab therapy > 2 years. PML can be fatal. This is a very commonly tested fact. [1]
HBV Reactivation Risk
Anti-CD20 (rituximab) and anti-CD52 (alemtuzumab) can reactivate HBV — this is important in Hong Kong where HBV carrier rates are significant. All patients should be screened for HBsAg and anti-HBc before starting these drugs. [2]
Hong Kong-specific tiering: [1]
This formulary/funding arrangement is a lecture snapshot, not a permanent prescribing rule. Eligibility and supported agents change; check the current HA/Samaritan Fund criteria in clinical practice.
| Line | Drug(s) |
|---|---|
| First-line | Beta-interferons, teriflunomide, dimethyl fumarate, ofatumumab (classically for severe/aggressive MS) |
| Second-line | Fingolimod |
| Third-line | Natalizumab, alemtuzumab |
| For active SPMS | Siponimod |
Why does tiering matter? In exams, you may be asked about the escalation approach. Start with first-line agents. If the patient has breakthrough disease (continued relapses or new MRI lesions despite treatment), escalate to second-line, then third-line. For aggressive MS at presentation (high relapse rate, significant disability early), some patients may be started on high-efficacy therapy (e.g., ofatumumab) as first-line.
2. Neuromyelitis Optica Spectrum Disorders (NMOSD)
NMOSD is an inflammatory demyelinating disease of the CNS, typically presenting with relapsing severe myelitis and optic neuritis. [1]
| Feature | Detail |
|---|---|
| Historical name | Devic disease (1894) — originally described as monophasic bilateral optic neuritis + myelitis |
| Clinical hallmark | Severe myelitis + optic neuritis (can cause blindness, paraplegia, tetraplegia, mortality from respiratory failure in high cervical myelitis) |
| Brain involvement | ~60% — classically brainstem encephalitis in area postrema → refractory hiccups and vomiting |
| Aspiration risk | Bulbar palsy in brainstem encephalitis |
| Prevalence | Higher in Asians (3× compared to non-Asians) |
| Age | Any age, median onset age 40 yr |
| Sex | F:M = 9:1 (for AQP4-IgG +ve patients) |
NMOSD vs MS: Key Differentiators
| Feature | MS | NMOSD |
|---|---|---|
| F:M ratio | 3:1 | 9:1 |
| Age at onset | ~32 yr | ~40 yr |
| Myelitis | Short segment (< 3 vertebral segments) | Longitudinally extensive (> 3 vertebral segments) |
| Optic neuritis | Usually unilateral, mild–moderate | Often bilateral, severe, with chiasmal involvement |
| CSF OCBs | Present in ~95% | Usually absent |
| Biomarker | None specific (OCBs supportive) | AQP4-IgG (75–80%) |
| Brain MRI | Periventricular "Dawson fingers" | Area postrema, periventricular around 3rd/4th ventricle |
| MS DMTs | Effective | HARMFUL — contraindicated |
| Asian prevalence | Low | Higher |
Typical MRI abnormalities in NMOSD: [1]
- Longitudinally extensive optic neuritis, bilateral or unilateral, with optic chiasma involvement
- Longitudinally extensive transverse myelitis (> 3 vertebral segments)
- Lesion in dorsal medulla (area postrema)
- Lesions in periventricular areas around 3rd ventricle, aqueduct, and 4th ventricle (diencephalon, midbrain, pons)
- Longitudinally extensive lesion in cerebral hemisphere affecting corticospinal tract involving internal capsule and cerebral peduncle
Why area postrema? The area postrema in the dorsal medulla is a circumventricular organ with a "leaky" BBB. Astrocytes here are densely packed with AQP4 water channels. This makes it preferentially vulnerable to AQP4-IgG attack, explaining why refractory hiccups and vomiting are a classic presenting feature of NMOSD.
The six core clinical characteristics are optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic diencephalic/narcolepsy syndrome with a characteristic lesion, and symptomatic cerebral syndrome with a characteristic lesion.
| Antibody status | Lecture criteria |
|---|---|
| AQP4-IgG positive | At least one core clinical characteristic + positive serum AQP4-IgG by the best available method (cell-based assay preferred) + no better diagnosis |
| AQP4-IgG negative or unknown | At least two core characteristics from one or more attacks, including at least one of: optic neuritis with a long/chiasmal lesion or otherwise non-specific brain MRI; LETM; or area postrema syndrome with a dorsal medullary lesion + negative/unavailable AQP4 testing + no better diagnosis |
Seronegative criteria are deliberately stricter. A long cord lesion or severe optic neuritis alone is not enough without the required syndrome/MRI combination and exclusion of mimics.
NMOSD is an autoimmune astrocytopathy. [1]
The mechanism step by step: [1]
- T cell and B cell interaction in germinal centers produces AQP4-autoreactive T and B cells, memory B cells, and plasma cells secreting AQP4-IgG
- AQP4-IgG (IgG autoantibodies against aquaporin-4 water channel) detected in ~75–80% of patients
- AQP4 is expressed abundantly on astrocyte end-foot processes — these surround blood vessels and are critical for BBB function and water homeostasis
- During acute attacks, AQP4-IgG gains access to CNS AQP4, binds to astrocytic AQP4 → AQP4 loss, astrocyte cytotoxicity via:
- Antibody-dependent cellular cytotoxicity (ADCC)
- Complement activation product (MAC)-mediated cell lysis
- Downstream: demyelination, neuronal injury/loss from glutamate excitotoxicity and necrotic inflammation
Key distinction from MS: In MS, the primary target is myelin/oligodendrocytes. In NMOSD, the primary target is the astrocyte (via AQP4). Demyelination in NMOSD is secondary to astrocyte destruction. This is why it's called an "astrocytopathy" rather than a "demyelinating disease," though demyelination does occur.
2.5 Treatment of NMOSD
Both AQP4-IgG +ve and AQP4-IgG –ve patients: [1]
- 1st line: IVMP 0.5–1 g daily × 3–5 days
- 2nd line (rescue): Plasma exchange — recommended to initiate early if no improvement ~2 weeks after IVMP
- 3rd line: IVIg — if IVMP contraindicated and PE unavailable/intolerant
Conventional immunosuppressants: azathioprine, mycophenolate mofetil (MMF), oral prednisolone [1]
Newer biologics: [1]
- Eculizumab — anti-C5 complement inhibitor (blocks terminal complement pathway / MAC formation)
- Inebilizumab — anti-CD19 mAb (depletes B cells more broadly than anti-CD20)
- Satralizumab — anti-IL-6 receptor mAb (blocks IL-6 signaling important for plasma cell survival and AQP4-IgG production)
- Rituximab — anti-CD20 mAb
CRITICAL: MS DMTs Must NOT Be Used in NMOSD
"Disease-modifying drugs for MS (beta-IFN, DMF, fingolimod, natalizumab, alemtuzumab) should NOT be used in NMOSD: ineffective/worsen disease." [1]
This is one of the most important facts in the entire lecture. Beta-interferon and fingolimod have been shown to exacerbate NMOSD. This is why distinguishing MS from NMOSD (using AQP4-IgG testing) is critical before starting DMTs.
3. MOGAD (Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease)
MOGAD presents with acute attacks of optic neuritis (unilateral or bilateral), myelitis (extensive, conus), or encephalitis (ADEM, ADEM-like, brainstem, cerebellum involvement, unilateral cortical encephalitis). [1]
| Feature | Detail |
|---|---|
| Biomarker | MOG-IgG detected in serum (rarely in CSF) |
| Course | ~50% monophasic, ~50% relapsing |
| Severity | In general, less severe attacks with better recovery compared to AQP4-IgG+ NMOSD |
| Long-term outcomes | Permanent severe visual impairment in 16%; severe neurological disability (EDSS ≥ 6) in 5% |
| Feature | MS | NMOSD | MOGAD |
|---|---|---|---|
| Antibody | None specific | AQP4-IgG | MOG-IgG |
| OCBs in CSF | +++ | – | – |
| Optic neuritis | Unilateral, retrobulbar | Bilateral, severe, chiasmal | Bilateral or unilateral, often anterior (disc swelling), perineural enhancement |
| Myelitis | Short segment | LETM (> 3 segments) | Extensive, often involves conus |
| Brain pattern | Periventricular, Dawson fingers | Area postrema, diencephalic | ADEM-like (large fluffy lesions), cortical involvement |
| Encephalitis | Rare | Area postrema → hiccups/vomiting | Cortical encephalitis (seizures), ADEM |
| Course | Relapsing → progressive | Relapsing (rarely monophasic) | ~50% monophasic |
| Age | Young adults (~32) | Any age (~40) | Children & young adults |
| Recovery | Partial, cumulative disability | Poor per attack | Generally good |
| MS DMTs | Effective | Contraindicated | Not recommended |
- Acute attacks: Pulse steroid (IVMP), often followed by a slower oral taper; plasmapheresis or IVIg for selected severe/refractory attacks. The slide gives a taper of ~6 months, but duration is individualised rather than universal.
- Long-term immunosuppression (for relapsing patients with > 1 attack): steroid, azathioprine, MMF, methotrexate, rituximab, tocilizumab
Why a slower steroid taper? MOGAD may relapse during rapid withdrawal. This supports a specialist-guided taper after IVMP, but the balance between relapse prevention and steroid toxicity must be individualised.
4. Autoimmune Encephalitis
Autoimmune encephalitis is not uncommon and increasingly recognized. It contributes up to 30% of all encephalitis. More common in females. Diverse autoantibodies target intracellular antigens or synaptic proteins. Can be paraneoplastic. Potentially treatable — early immunotherapy leads to favourable prognosis. [1]
Neuropsychiatric symptoms predominant: [1]
- Limbic encephalitis: behavioural change, psychiatric symptoms, memory and cognitive impairment
- Brainstem encephalitis: double vision, gait disturbance, dysphagia, dysarthria
- Seizures, refractory seizure & status epilepticus
- Dyskinesia, dystonia
- Autonomic dysfunction
Why is this important? Autoimmune encephalitis is frequently misdiagnosed as a primary psychiatric disorder (schizophrenia, acute psychosis) or as viral encephalitis. The key is to think of it in any young patient with rapidly progressive neuropsychiatric symptoms, especially if they have seizures, movement disorders, or autonomic instability.
| Antibody | Target Location | Mechanism | Key Features |
|---|---|---|---|
| Cell-surface/synaptic (e.g., NMDAR, LGI1, GABABR, CASPR2, AMPAR) | Extracellular domain of surface proteins | Antibody directly pathogenic (blocks/internalizes receptor) | Better response to immunotherapy, better prognosis |
| Intracellular (e.g., Hu, Yo, Ri, Ma2, CV2, amphiphysin, GAD65) | Intracellular neuronal proteins | T-cell mediated neuronal death; antibody is a marker, not directly pathogenic | Strongly paraneoplastic, poorer response to immunotherapy |
What the Antibody-Mechanism Diagram Adds
The figure separates a peripheral immune phase from the final synaptic effect:
- GABA-B receptor antibody: functionally blocks receptor/G-protein signalling.
- NMDAR antibody: cross-links and internalises receptors, reducing surface NMDAR density; this is potentially reversible when antibody exposure falls.
- LGI1 antibody: disrupts LGI1 binding between presynaptic ADAM23 and postsynaptic ADAM22, with downstream reduction in AMPA-receptor organisation.
By contrast, antibodies to intracellular antigens usually mark a cytotoxic T-cell response, so tumour control is central and neurological recovery is often less complete.
Before antibody-specific labels, the lecture uses a possible AE screen — all three:
- Subacute onset (usually weeks, < 3 months) with change in personality/consciousness and/or limbic features (working-memory deficit, psychiatric symptoms, seizures)
- At least one of: new focal CNS finding; EEG epileptic/slow-wave activity; CSF pleocytosis; MRI suggestive of encephalitis (e.g. medial temporal T2/FLAIR hyperintensity or multifocal inflammatory lesions)
- Reasonable exclusion of alternatives (CNS infection, metabolic/toxic encephalopathy, stroke, neoplasm, CJD, primary psychiatric disease, etc.)
The antibody-negative panel requires all four:
- rapid progression (< 3 months) of working-memory deficit, altered mental status or psychiatric symptoms;
- exclusion of a well-defined autoimmune-encephalitis syndrome such as typical limbic encephalitis, ADEM or Bickerstaff brainstem encephalitis;
- no well-characterised serum/CSF antibody and at least two of: suggestive MRI, inflammatory CSF/CSF-specific OCB or raised IgG index, or inflammatory brain biopsy excluding tumour;
- reasonable exclusion of alternative causes.
This prevents “seronegative autoimmune encephalitis” becoming a label for any unexplained psychiatric or neurological presentation.
4.5 Anti-NMDAR Encephalitis
First identified in 2007. 4 young women with teratoma presenting with syndrome of memory, psychiatric and cognitive symptoms were reported in 2005. [1]
NMDAR autoantibody is pathogenic. Autoantibodies bind to NMDA receptors → internalization of receptors → loss of function. Intrathecal synthesis of antibody occurs. [1]
Why does receptor internalization matter? NMDARs are critical for synaptic plasticity, learning, and memory. They modulate GABAergic (predominantly), dopaminergic, noradrenergic, and cholinergic systems. Loss of NMDAR function on GABAergic interneurons leads to disinhibition → explaining the psychosis, seizures, and dyskinesias. [1]
The experimental graph reinforces that this is receptor dysfunction rather than immediate neuronal destruction: during antibody infusion, human IgG staining rose while synaptic NMDAR density and novel-object memory fell; after antibody exposure stopped, receptor density and memory recovered toward baseline. This helps explain why recovery can be substantial but slow.
Classical progression: prodromal → behavioural/psychosis → movement disorder → seizure → coma [1]
- Can also present with isolated psychosis, movement disorders, or seizures [1]
Typical patient: Young woman (though can affect men and children too) who develops flu-like prodrome, then rapidly progresses through psychiatric symptoms (hallucinations, paranoia, agitation), movement disorders (orofacial dyskinesias, choreoathetosis), seizures, decreased consciousness, and autonomic instability (labile BP, hyperthermia, arrhythmias).
| Phase | Approximate visual timescale | Dominant features |
|---|---|---|
| Viral-like prodrome | ~1 week | Non-specific constitutional symptoms |
| Psychiatric/acute phase | 1–2 weeks | Delusions, hallucinations, mania/agitation, disorganised thought, speech reduction/catatonia, insomnia; seizures may occur |
| Neurological complications | Weeks to months | Movement disorder, dysautonomia, central hypoventilation, seizures and reduced consciousness/coma |
| Recovery | Months to years | Improvement often reverses the order of deterioration; executive dysfunction, impulsivity, disinhibition and sleep disturbance may persist longest |
The figure's inflammatory marker tapers before full cognitive recovery, so a normalising CSF/MRI does not mean rehabilitation is complete.
~40% associated with tumour (mostly teratoma), especially in females aged 12–45 years. [1]
(Initially thought to be mainly paraneoplastic, but recent data shows 60% have no tumour.)
NMDAR antibody testing: [1]
- CSF is more sensitive than serum
- In the cited series, a proportion were serum-negative but CSF-positive; this is not the same as being antibody-negative in both compartments
- Test both CSF and serum
CSF: lymphocytic pleocytosis, elevated protein (but can be normal)
MRI brain: abnormal in only 30–50% (often normal! — this is a trap in exams)
EEG: extreme delta brush — a characteristic pattern (rhythmic delta activity with superimposed beta activity)
Exam Trap: Normal MRI Does NOT Exclude Anti-NMDAR Encephalitis
MRI is normal in 50–70% of anti-NMDAR encephalitis cases. A normal MRI in a young patient with progressive neuropsychiatric symptoms should NOT stop you from considering autoimmune encephalitis. Always send NMDAR antibodies (especially in CSF).
Probable versus Definite Anti-NMDAR Encephalitis
Probable disease in the appendix requires rapid onset (< 3 months) of at least four symptom groups—psychiatric/cognitive change, speech dysfunction, seizures, movement disorder/rigidity, reduced consciousness, and autonomic dysfunction or central hypoventilation—plus either abnormal EEG or inflammatory CSF, with alternative causes excluded. Three symptom groups plus a systemic teratoma also qualifies for the probable category.
Definite disease requires at least one of those symptom groups and IgG GluN1 antibodies, with CSF included in testing, after excluding relevant post-infectious mimics. Serum-only positivity needs confirmatory methods because false-positive or non-specific serum results occur.
Intense immunotherapy in acute phase: [1]
- 1st line: IVIg + pulse steroids OR plasmapheresis — only 50% will respond
- 2nd line: rituximab, cyclophosphamide
- 3rd line: tocilizumab
Surveillance for ovarian teratoma & tumour removal
The slide proposes long-term immunosuppression, especially without a tumour, because relapse occurs: azathioprine or MMF for 1–2 years. Treat this as a specialist/lecture regimen rather than a universal duration.
Why tumour removal? In paraneoplastic cases, the tumour provides the ongoing antigenic stimulus for antibody production. Removing the teratoma dramatically improves outcomes and reduces relapse risk.
Prolonged recovery taking months to years. Recovery follows reverse order of symptom presentation. At 24 months follow-up: 81% favourable outcome (mRS 0–2); 7% mortality. [1]
LGI1 encephalitis: [1]
- Middle age/elderly
- M:F = 2:1 (unusual — one of the few autoimmune encephalitides more common in men)
- Presents as limbic encephalitis: memory deficit, confusion, seizures
- Early seizures: facio-brachial dystonic or tonic seizures (FBDS) — brief, frequent, stereotyped face-arm events; highly characteristic but not literally pathognomonic
- SIADH common (60%) — hyponatremia
- REM sleep behaviour disorder
- DDx: CJD (both present with rapidly progressive dementia)
- IgG4 subclass
- Good response to steroids
- Tumour rare, thymoma in ~5%
Why SIADH? LGI1 is expressed in the hypothalamus. Autoimmune attack on hypothalamic neurons disrupts osmoregulation, leading to SIADH and hyponatremia. Hyponatremia can worsen seizures, creating a vicious cycle.
Why does FBDS matter? Facio-brachial dystonic seizures are often the earliest manifestation and may precede the full-blown limbic encephalitis. Recognising FBDS and starting immunotherapy early can prevent progression to severe encephalitis.
GABABR encephalitis: [1]
- Mostly limbic encephalitis with early and frequent seizures
- Rarely brainstem encephalitis, cerebellar ataxia, opsoclonus
- Small cell lung carcinoma (SCLC) or neuroendocrine tumours in 50% — strongly paraneoplastic
- Neurological symptoms show good response to immunotherapy
Why the strong SCLC association? SCLC is a neuroendocrine tumour that aberrantly expresses neuronal surface proteins including GABABR. The immune system's anti-tumour response cross-reacts with neuronal GABABR.
| Feature | MS | NMOSD | MOGAD |
|---|---|---|---|
| Target | Myelin (oligodendrocytes) | AQP4 (astrocytes) | MOG (oligodendrocytes) |
| Antibody | None diagnostic (OCBs) | AQP4-IgG (75–80%) | MOG-IgG |
| Typical patient | F, 20–40 yr, Caucasian | F (9:1), ~40 yr, Asian predilection | Children & young adults |
| Course | RRMS → SPMS | Relapsing (severe) | 50% monophasic |
| Myelitis | Short segment | LETM (> 3 segments) | Extensive + conus |
| Optic neuritis | Unilateral, mild–moderate | Bilateral, severe, chiasmal | Anterior, disc swelling |
| Brain | Dawson fingers, periventricular | Area postrema, peri-3rd/4th ventricle | ADEM-like, cortical |
| CSF OCBs | Present (~95%) | Absent | Absent |
| Acute Rx | IVMP → PE → IVIg | IVMP → PE → IVIg | IVMP + oral taper → PE/IVIg |
| Long-term Rx | DMTs (beta-IFN, fingolimod, natalizumab etc.) | AZA, MMF, rituximab, eculizumab, satralizumab, inebilizumab | AZA, MMF, rituximab, tocilizumab |
| MS DMTs in NMOSD/MOGAD? | N/A | CONTRAINDICATED | Not recommended |
| Antibody | Age/Sex | Key Clinical Features | Tumour Association | Treatment Response | Unique Points |
|---|---|---|---|---|---|
| Anti-NMDAR | Young F (12–45) | Psychosis → movement disorders → seizures → coma | ~40% teratoma | 50% respond to 1st line; 81% good outcome at 24 months | CSF more sensitive; MRI normal in 50–70%; EEG: delta brush |
| LGI1 | Middle-aged/elderly M | Limbic encephalitis, FBDS, SIADH | ~5% thymoma | Good response to steroids | IgG4; DDx CJD; hyponatremia |
| GABABR | Variable | Limbic encephalitis, early seizures | ~50% SCLC | Good immunotherapy response | Screen for lung cancer |
Exam Intelligence
| Trap | Correct Understanding |
|---|---|
| Using beta-IFN or fingolimod in NMOSD | Contraindicated — worsens disease. Must test AQP4-IgG before starting MS DMTs. |
| Normal MRI excludes anti-NMDAR encephalitis | Wrong — MRI is normal in 50–70% of cases. |
| MS always presents with relapses | Wrong — 15% have PPMS (progressive from onset without relapses). |
| OCBs are specific for MS | Wrong — OCBs indicate intrathecal IgG synthesis and can be seen in other CNS infections/inflammations. But in the right clinical context, they strongly support MS. |
| NMOSD is a subtype of MS | Wrong — NMOSD is a distinct disease with different pathophysiology (astrocytopathy vs. demyelination), biomarker (AQP4-IgG), and treatment. |
| Young woman with psychosis → schizophrenia | Consider anti-NMDAR encephalitis if there are movement disorders, seizures, autonomic instability, or rapid progression. |
| LGI1 encephalitis vs CJD | Both cause rapidly progressive dementia. LGI1: FBDS, SIADH, good treatment response. CJD: myoclonus, periodic sharp waves on EEG, no treatment. |
| MOGAD is the same as NMOSD | Wrong — different antibody (MOG-IgG vs AQP4-IgG), different target (oligodendrocyte vs astrocyte), better prognosis, ~50% monophasic. |
| Serum testing alone is sufficient for NMDAR Ab | Wrong — CSF is more sensitive. The lecture cites a serum-negative/CSF-positive subset; test both and interpret serum-only results cautiously. |
If asked "What is the MOST LIKELY diagnosis?":
- Longitudinally extensive transverse myelitis (> 3 segments) → NMOSD or MOGAD (NOT MS)
- Short segment myelitis + periventricular lesions + OCBs → MS
- Young woman with severe bilateral optic neuritis + area postrema syndrome (hiccups/vomiting) → NMOSD
- Child with ADEM-like presentation + MOG-IgG → MOGAD
- Young woman with psychosis → movement disorders → seizures → Anti-NMDAR encephalitis
- Elderly man with seizures + hyponatremia + memory loss → LGI1 encephalitis
High Yield Summary
-
MS
- Idiopathic inflammatory demyelinating CNS disorder; young adults (F > M 3:1); 85% RRMS, 15% PPMS; ~50% RRMS → SPMS within 10 years. MRI shows lesions in 4 regions (periventricular, cortical/juxtacortical, infratentorial, spinal cord). CSF OCBs in ~95%. Acute Rx: IVMP → PE → IVIg. DMTs escalation: beta-IFN/teriflunomide/DMF → fingolimod → natalizumab/alemtuzumab. PML risk with natalizumab.
-
NMOSD
- Autoimmune astrocytopathy (AQP4-IgG, 75–80%); F:M = 9:1; severe optic neuritis + LETM (> 3 segments) + area postrema syndrome. Higher in Asians. MS DMTs contraindicated — worsen disease. Treat with AZA/MMF/rituximab/eculizumab/satralizumab.
-
MOGAD
- MOG-IgG; optic neuritis, myelitis (conus), ADEM-like encephalitis; ~50% monophasic; better recovery. Treat acute attacks with IVMP + prolonged oral taper; immunosuppression for relapsing patients.
-
Anti-NMDAR Encephalitis
- Young women; prodrome → psychosis → movement disorder → seizures → coma; ~40% with teratoma; MRI often normal; CSF more sensitive for Ab testing; EEG: delta brush. Rx: IVIg + IVMP → rituximab/CYC → tocilizumab. Remove teratoma. 81% good outcome at 24 months.
-
LGI1 Encephalitis
- Elderly men; FBDS, limbic encephalitis, SIADH (60%); IgG4; good steroid response; DDx CJD.
-
GABABR Encephalitis
- Limbic encephalitis + early seizures; 50% SCLC; good immunotherapy response.
Active Recall - Lecture Notes
[1] Lecture slides: GC 225. Neuroimmunological disorders of the central nervous system.pdf (all pages/slides cited throughout) [2] Senior notes: Block A - I am a hepatitis B carrier.pdf (p.68 — anti-CD20 and anti-CD52 reactivation of HBV) [5] Senior notes: Ryan Ho Neurology.pdf (Ch 6 — Autoimmune and Demyelinating Diseases) [6] Senior notes: Ryan Ho Opthalmology.pdf (p.91 — Optic neuropathies including demyelinating optic neuritis) [7] Senior notes: Ryan Ho Fundamentals.pdf (p.322 — Sensory loss patterns in spinal cord lesions, MS)
GC224 Hypertension And Pregnancy
Hypertension in pregnancy encompasses a spectrum of blood pressure disorders—including chronic hypertension, gestational hypertension, preeclampsia, and eclampsia—that can lead to significant maternal and fetal morbidity if not promptly identified and managed.
GC226 Lumbar Spine Pathology
A unified guide to lumbar spine pathology covering clinical assessment, investigations, degenerative disease, disc herniation, spinal stenosis, spondylolisthesis, inflammatory disease, emergencies, and management.