Other Neuroimmunology Topics
Other Neuroimmunology Topics
What Do You Need to Know?
- ADEM: monophasic post-infectious demyelination in children; encephalopathy is REQUIRED for diagnosis; large fluffy bilateral lesions with thalamic involvement; MOG-IgG+ in 40–60% of pediatric cases; all lesions enhance simultaneously (same age)
- Transverse myelitis: short-segment + partial = MS; LETM + central = NMOSD; LETM + conus = MOGAD; always exclude compressive myelopathy first
- Optic neuritis: MS = retrobulbar, unilateral, mild disc edema; NMOSD = severe, bilateral, poor recovery; MOGAD = anterior, bilateral, severe disc edema, perineural enhancement, good recovery
- Stiff-person syndrome: anti-GAD65 antibodies; progressive axial stiffness + stimulus-triggered spasms; associated with type 1 DM and other autoimmune diseases; treat with benzodiazepines, baclofen, IVIg
- Hashimoto encephalopathy (SREAT): steroid-responsive encephalopathy with anti-thyroid antibodies; diagnosis of exclusion; dramatic response to steroids
- Immune checkpoint neurotoxicity: anti-PD-1/PD-L1/CTLA-4 therapy causes myasthenia gravis, encephalitis, GBS, myositis, hypophysitis; hold immunotherapy + high-dose steroids
ADEM (Acute Disseminated Encephalomyelitis)
Overview
- Post-infectious or post-vaccination monophasic demyelinating disorder
- Predominantly affects children (mean age 5–8 years); rare in adults
- Typically follows a viral prodrome 1–4 weeks prior (measles, mumps, varicella, influenza, EBV, URI)
- Pathophysiology: molecular mimicry → autoimmune attack on CNS myelin
- Monophasic by definition — if relapses occur, reconsider MOGAD or MS
Clinical Features
- Encephalopathy is REQUIRED (altered consciousness, behavioral change, confusion) — distinguishes ADEM from first MS episode
- Multifocal neurological deficits: optic neuritis, hemiparesis, ataxia, cranial nerve palsies, seizures
- Fever common at presentation
- May present with LETM (longitudinally extensive transverse myelitis)
Diagnosis
- MRI brain: large, fluffy, bilateral but asymmetric T2/FLAIR lesions; deep white matter, thalami, basal ganglia, brainstem; poorly demarcated
- Thalamic involvement is characteristic of ADEM (rare in MS)
- All lesions enhance simultaneously (same age) vs. MS lesions of different ages
- CSF: lymphocytic pleocytosis, elevated protein; OCBs may be present but are transient (unlike MS where persistent)
- MOG-IgG: positive in 40–60% of pediatric ADEM; MOG+ relapsing disease → reclassify as MOGAD
ADEM vs MS
| Feature | ADEM | MS |
|---|---|---|
| Age | Children (5–8 yr) | Young adults (20–40 yr) |
| Encephalopathy | Required | Absent |
| Course | Monophasic | Relapsing or progressive |
| MRI lesions | Large, fluffy, bilateral; thalami/BG | Periventricular Dawson fingers; well-demarcated |
| Enhancement | All lesions same age | Lesions of different ages (DIT) |
| OCBs | Transient | Persistent (>95%) |
| MOG-IgG | + in 40–60% | Typically negative |
Treatment
- First-line: IV methylprednisolone (20–30 mg/kg/day, max 1 g) × 3–5 days, followed by oral taper over 4–6 weeks
- Refractory: IVIg or PLEX
- Prognosis: generally good; 70–90% recover fully or near-fully
Acute Hemorrhagic Leukoencephalitis (Hurst Disease)
- Most severe form of ADEM — hyperacute, often fatal
- Follows prodromal infection; rapid progression to coma over days
- Pathology: perivascular demyelination with ring and ball hemorrhages, fibrinoid necrosis of venule walls
- MRI: hemorrhagic white matter lesions with mass effect
- Aggressive treatment with steroids, PLEX, decompressive surgery if needed
💎 Board Pearl
- ADEM requires encephalopathy; MS does not — the single most important distinguishing feature
- All ADEM lesions enhance simultaneously vs. MS has lesions of different ages
- If “ADEM” relapses → check MOG-IgG; MOG+ relapsing disease = MOGAD, not multiphasic ADEM
- Thalamic involvement is characteristic of ADEM and rare in MS
Transverse Myelitis
Definition & Classification
- Inflammatory myelopathy causing motor, sensory, and autonomic dysfunction at and below the lesion level
- Acute to subacute onset (nadir within 4 hours to 21 days)
- Must exclude compressive myelopathy first (urgent MRI spine)
| Feature | Partial TM | Complete TM |
|---|---|---|
| Cross-section | Asymmetric, partial cord | Full cross-section |
| Typical cause | MS (most common); sarcoidosis | NMOSD, ADEM, SLE, infectious |
| Length | Short segment (<3 segments) | Often LETM (≥3 segments) |
Etiologic Pattern Recognition
| Etiology | Cord MRI Pattern | Key Distinguishing Features |
|---|---|---|
| MS | Short segment, partial, dorsal/lateral, eccentric | Cervical > thoracic; brain lesions in MS-typical regions |
| NMOSD (AQP4+) | LETM (≥3 segments), central cord, bright spotty lesion | Severe; cervicothoracic; AQP4-IgG+ |
| MOGAD | LETM, central gray matter (H-sign) | Conus/lower thoracic predilection; better recovery |
| Sarcoidosis | Dorsal subpial enhancement (“trident sign”) | Persistent enhancement over weeks; may have leptomeningeal enhancement |
| SLE | LETM; associated with antiphospholipid antibodies | Systemic features; ANA, dsDNA positive |
| Infectious | Variable; VZV, enterovirus, HTLV-1 | HTLV-1: chronic spastic paraparesis (HAM/TSP); enterovirus: anterior horn cells (flaccid) |
Workup
- MRI spine with gadolinium (entire spine) + MRI brain
- Serum: AQP4-IgG, MOG-IgG, ANA, dsDNA, ACE, SSA/SSB, HIV, HTLV-1, B12
- CSF: cell count, protein, OCBs, cytology, cultures
- VEP: subclinical optic neuritis supports MS or NMOSD
💎 Board Pearl
- Short + partial + dorsolateral = MS; LETM + central = NMOSD; LETM + conus = MOGAD
- Partial myelitis predicts higher MS risk than complete myelitis
- Sarcoidosis: dorsal subpial “trident sign” + persistent enhancement
- HTLV-1 myelopathy (HAM/TSP): chronic progressive spastic paraparesis, NOT acute TM; endemic Caribbean, Japan, Africa
Optic Neuritis
Overview
- Inflammatory demyelination of the optic nerve; can be isolated or first manifestation of MS, NMOSD, or MOGAD
- Acute to subacute unilateral (or bilateral) painful vision loss over hours to days
- Pain worsened by eye movement; RAPD (Marcus Gunn pupil) on exam
- 20–25% of MS patients present with optic neuritis as initial manifestation
Optic Neuritis by Etiology
| Feature | MS-Associated ON | NMOSD ON | MOGAD ON |
|---|---|---|---|
| Laterality | Unilateral | Often bilateral; severe | Often bilateral; severe disc edema |
| Location | Retrobulbar | Long segment; may extend to chiasm | Anterior (papillitis); perineural enhancement |
| Pain | Mild–moderate | Severe | Moderate–severe |
| Vision loss | Mild–moderate | Severe (often <20/200) | Severe initially |
| Recovery | Usually good; may have residual dyschromatopsia | Poor without treatment | Good (steroid-responsive) |
| Disc appearance | Normal or mild edema (retrobulbar) | Disc edema ± hemorrhage | Prominent disc edema |
| Antibody | None (OCBs in CSF) | AQP4-IgG | MOG-IgG |
| OCT | RNFL thinning; temporal pallor | Severe RNFL thinning; poor recovery | RNFL edema acutely; good recovery |
Optic Neuritis Treatment Trial (ONTT)
- IV methylprednisolone (1 g/day × 3 days → oral taper) hastens recovery but does NOT change final visual outcome at 6 months
- Oral prednisone alone (1 mg/kg) showed NO benefit AND increased recurrence rate — contraindicated
- ~50% of patients with isolated ON eventually develop MS (higher risk if brain MRI abnormal)
- Best predictor of MS after ON: presence of ≥1 demyelinating lesion on brain MRI at presentation
Differential Diagnosis of Optic Neuropathy
| Condition | Key Distinguishing Features |
|---|---|
| AION (arteritic — GCA) | Sudden painless vision loss; age >50; disc edema + pallor; ESR/CRP elevated; jaw claudication; emergency steroids |
| NAION | Sudden painless vision loss; disc edema with small cup (“disc at risk”); altitudinal visual field defect; vascular risk factors |
| Leber hereditary optic neuropathy | Young males; sequential bilateral painless vision loss; mtDNA mutations (11778, 3460, 14484); pseudo-disc edema |
| Compressive optic neuropathy | Progressive painless vision loss; optic nerve sheath meningioma, pituitary adenoma; MRI with enhancement |
| Sarcoidosis | Optic perineuritis; optic nerve sheath enhancement; granulomatous inflammation |
💎 Board Pearl
- Oral prednisone alone for optic neuritis is contraindicated — ONTT showed increased recurrence
- Best MS predictor after ON: abnormal brain MRI at presentation
- NMOSD ON: severe, bilateral, long-segment involvement, poor recovery without treatment
- MOGAD ON: bilateral with prominent disc edema + perineural enhancement; excellent steroid response
- RAPD (Marcus Gunn pupil) is the most objective exam finding in optic neuritis
- Optic neuritis is painful; AION/NAION are painless — key distinction on boards
Stiff-Person Spectrum Disorders
Overview
- Rare autoimmune disorder characterized by progressive axial rigidity and stimulus-triggered spasms
- Median onset age 40–50; slight female predominance
- Strong association with anti-GAD65 antibodies (present in ~80%)
- Associated with type 1 diabetes mellitus and other autoimmune diseases (thyroiditis, pernicious anemia, vitiligo)
Clinical Features
- Axial stiffness: progressive rigidity of trunk and proximal limbs; exaggerated lumbar lordosis (hyperlordosis); board-like abdominal rigidity
- Painful spasms: triggered by unexpected stimuli (noise, touch, emotional stress); can be severe enough to cause fractures
- Task-specific phobia: fear of crossing streets, walking in open spaces (due to risk of falls from spasms) — often misdiagnosed as psychiatric
- Continuous motor unit activity on EMG even at rest; disappears with diazepam or sleep
- No UMN or LMN signs on exam; strength is normal; deep tendon reflexes preserved
Stiff-Person Spectrum
| Variant | Key Features | Antibody |
|---|---|---|
| Classic SPS | Axial + proximal limb stiffness; symmetric; anti-GAD65 | Anti-GAD65 (~80%) |
| Stiff-limb syndrome | Stiffness restricted to one limb (often leg); asymmetric | Anti-GAD65 or anti-amphiphysin |
| Progressive encephalomyelitis with rigidity and myoclonus (PERM) | Most severe form; brainstem involvement, myoclonus, autonomic dysfunction, encephalopathy; can be fatal | Anti-glycine receptor (GlyR); anti-DPPX |
| Paraneoplastic SPS | Associated with breast cancer, SCLC, thymoma; often anti-amphiphysin | Anti-amphiphysin (strongly paraneoplastic); anti-GAD65 (less paraneoplastic) |
Diagnosis
- Serum anti-GAD65 antibodies: typically very high titers (>10,000 IU/mL) — low titers are non-specific and seen in type 1 DM
- EMG: continuous motor unit activity in agonist and antagonist muscles simultaneously; normalizes with diazepam or general anesthesia
- If anti-GAD negative, check anti-amphiphysin (paraneoplastic) and anti-glycine receptor (PERM)
- Cancer screening: mandatory if anti-amphiphysin positive (breast cancer, SCLC); CT chest/abdomen/pelvis, mammography
Treatment
| Category | Agent | Notes |
|---|---|---|
| Symptomatic | Diazepam (high dose), baclofen | First-line for stiffness/spasms; GABAergic agents; often requires high doses |
| Immunotherapy | IVIg (most evidence); rituximab; PLEX | IVIg shown effective in RCTs (Dalakas 2001); rituximab for refractory cases |
| Long-term immunosuppression | Azathioprine, mycophenolate | Steroid-sparing agents for chronic maintenance |
| Tumor treatment | Surgery, chemo, radiation | Essential in paraneoplastic SPS (anti-amphiphysin) |
💎 Board Pearl
- Anti-GAD65 at very high titers (>10,000 IU/mL) = stiff-person syndrome; low titers are non-specific (type 1 DM)
- Anti-amphiphysin in SPS = paraneoplastic — screen for breast cancer and SCLC
- EMG shows continuous motor unit activity that resolves with diazepam — pathognomonic
- Commonly misdiagnosed as psychiatric — patients develop task-specific phobias from stimulus-triggered spasms
- IVIg is the best-studied immunotherapy for SPS (Dalakas RCT)
- SPS + anti-GAD65 + type 1 DM = classic autoimmune triad on boards
Hashimoto Encephalopathy (SREAT)
Overview
- Steroid-Responsive Encephalopathy Associated with Autoimmune Thyroiditis (SREAT) — preferred term over “Hashimoto encephalopathy”
- Subacute encephalopathy with elevated anti-thyroid antibodies (anti-TPO, anti-thyroglobulin)
- Diagnosis of exclusion — must rule out all other causes of encephalopathy
- Thyroid function is usually normal or mildly abnormal — the encephalopathy is NOT caused by thyroid dysfunction
- Pathogenesis unclear — anti-thyroid antibodies are likely a biomarker of autoimmunity, not directly pathogenic
Clinical Features
- Two clinical patterns:
- Relapsing-remitting (vasculitic type): stroke-like episodes, seizures, focal deficits
- Progressive (diffuse type): gradual cognitive decline, psychiatric symptoms, dementia-like presentation
- Common features: confusion, cognitive impairment, tremor, myoclonus, seizures, psychiatric symptoms, ataxia
- Typically affects middle-aged women (F:M ratio ~4:1)
- May mimic CJD (rapidly progressive cognitive decline + myoclonus)
Diagnosis
- Anti-TPO antibodies: elevated (present in ~100%); anti-thyroglobulin also often elevated
- Thyroid function: usually euthyroid or subclinical hypothyroidism; NOT severely hypothyroid
- CSF: elevated protein in ~75%; mild pleocytosis possible; OCBs may be present
- EEG: diffuse slowing (non-specific); may show epileptiform activity
- MRI brain: often normal; may show non-specific white matter changes or transient T2 lesions
- Diagnosis requires: (1) encephalopathy, (2) elevated anti-thyroid antibodies, (3) exclusion of other causes, (4) response to steroids
Treatment
- High-dose IV methylprednisolone followed by oral prednisone taper — dramatic response is the hallmark
- Failure to respond to steroids should prompt reconsideration of the diagnosis
- Relapse is common on steroid taper — may need long-term immunosuppression (azathioprine, mycophenolate)
- IVIg or PLEX for steroid-refractory cases
💎 Board Pearl
- SREAT is a diagnosis of exclusion — must rule out autoimmune encephalitis (send anti-neuronal antibodies), infection, metabolic, and paraneoplastic causes first
- Anti-TPO antibodies are the key lab finding — but they are common in the general population (~10%); diagnosis requires clinical correlation
- Dramatic steroid response is expected — lack of response should prompt alternative diagnosis
- Can mimic CJD (rapidly progressive dementia + myoclonus) — always check anti-TPO in RPD workup
- Thyroid function is NOT severely abnormal — the encephalopathy is immune-mediated, not metabolic
Immune Checkpoint Inhibitor Neurotoxicity
Overview
- Immune checkpoint inhibitors (ICIs): anti-PD-1 (nivolumab, pembrolizumab), anti-PD-L1 (atezolizumab, durvalumab), anti-CTLA-4 (ipilimumab)
- ICIs remove T-cell inhibitory signals → enhanced anti-tumor immunity but also immune-related adverse events (irAEs)
- Neurological irAEs in ~1–5% of patients; can be severe and life-threatening
- Combination therapy (anti-PD-1 + anti-CTLA-4) carries highest risk
- Onset typically weeks to months after starting therapy
Neurological irAEs
| Syndrome | Frequency | Key Features | Management |
|---|---|---|---|
| Myasthenia gravis | Most common severe neuro-irAE | New-onset MG; often AChR-Ab+; can be fulminant with myasthenic crisis; may overlap with myositis and myocarditis (triad) | Hold ICI; high-dose steroids; IVIg or PLEX; intubation if crisis; MG + myositis + myocarditis = high mortality |
| Encephalitis | ~0.1–0.5% | Limbic or diffuse encephalitis; confusion, seizures, behavioral changes; may have anti-neuronal antibodies (anti-CASPR2, anti-LGI1, anti-NMDAR) | Hold ICI; high-dose steroids; immunotherapy per antibody type |
| Guillain-Barré syndrome | ~0.1% | Classic ascending weakness; areflexia; albuminocytologic dissociation; may be AIDP or CIDP-like | Hold ICI; IVIg or PLEX (NOT steroids alone); ICU monitoring |
| Myositis | ~0.5–1% | Proximal weakness; markedly elevated CK; may overlap with MG and myocarditis | Hold ICI; high-dose steroids; check troponin for myocarditis |
| Aseptic meningitis | ~0.5% | Headache, neck stiffness, fever; CSF lymphocytic pleocytosis | Hold ICI; steroids; usually self-limited |
| Hypophysitis | ~1–5% (highest with anti-CTLA-4) | Fatigue, headache, visual changes; pituitary enlargement on MRI; hypopituitarism (cortisol, TSH, gonadotropins) | Hormone replacement (often permanent); steroids for acute inflammation |
| Peripheral neuropathy | ~1% | Sensorimotor neuropathy; cranial neuropathies; plexopathy | Hold ICI; steroids; IVIg if severe |
| Transverse myelitis | Rare | Acute myelopathy; MRI cord lesion | Hold ICI; IV methylprednisolone; PLEX if refractory |
Management Principles
- Grade 1 (mild): consider continuing ICI with close monitoring
- Grade 2 (moderate): hold ICI; oral prednisone 0.5–1 mg/kg
- Grade 3–4 (severe/life-threatening): permanently discontinue ICI; IV methylprednisolone 1–2 mg/kg; IVIg or PLEX for refractory; ICU for MG crisis/myocarditis
- Do NOT rechallenge ICI after grade 3–4 neurological irAEs (especially MG, encephalitis, GBS)
- Involve neurology early; some syndromes (MG + myocarditis) carry high mortality without rapid treatment
💎 Board Pearl
- ICI-induced MG + myositis + myocarditis = the “overlap triad” — high mortality; check CK + troponin in any ICI patient with weakness
- Hypophysitis is most common with anti-CTLA-4 (ipilimumab); hormone replacement often permanent
- ICI-GBS: treat with IVIg or PLEX, NOT steroids alone (same as idiopathic GBS)
- ICI can trigger de novo autoimmune encephalitis with standard anti-neuronal antibodies (LGI1, CASPR2, NMDAR)
- Neurological irAEs are uncommon (~1–5%) but can be life-threatening — high index of suspicion in any ICI patient with new neurological symptoms
Other Immune-Mediated Conditions
PML (Progressive Multifocal Leukoencephalopathy)
- JC virus reactivation in immunosuppressed patients (natalizumab, rituximab, HIV CD4 <200)
- MRI: asymmetric white matter lesions involving subcortical U-fibers; NO enhancement, NO mass effect
- Diagnosis: CSF JC virus PCR (sensitivity ~80%); brain biopsy if PCR negative
- Treatment: immune reconstitution (stop causative drug; PLEX for natalizumab; cART for HIV)
- PML-IRIS: new enhancement appears after immune reconstitution; paradoxical worsening; treat with steroids
SSPE (Subacute Sclerosing Panencephalitis)
- Fatal late complication of measles; onset 6–15 years after infection
- Progressive cognitive decline → periodic myoclonus → rigidity → vegetative state → death
- EEG: Radermecker complexes (periodic high-amplitude slow-wave bursts every 5–15 seconds)
- CSF: markedly elevated measles antibody titers; elevated IgG
- No effective treatment; prevention = measles vaccination (MMR)
IRIS (Immune Reconstitution Inflammatory Syndrome)
- Paradoxical worsening after immune recovery (HIV starting cART; natalizumab withdrawal)
- MRI shows new enhancement in previously non-enhancing lesions
- Treatment: steroids if severe; continue immune reconstitution
- Delay cART 4–6 weeks after starting antifungals in cryptococcal meningitis to prevent IRIS
Neuromyelitis Optica Spectrum Disorder (NMOSD) — Quick Reminder
- See dedicated NMOSD & MOGAD topic for full coverage
- Key distinction from MS: MS DMTs (interferon, fingolimod, natalizumab) can WORSEN NMOSD — always test AQP4-IgG and MOG-IgG before starting MS therapy in atypical cases
💎 Board Pearl
- PML: white matter lesions + NO enhancement + NO mass effect + immunosuppression = JC virus; enhancement = IRIS
- SSPE: child with progressive cognitive decline + myoclonus + Radermecker complexes on EEG = pathognomonic
- Delay cART 4–6 weeks in cryptococcal meningitis to prevent fatal IRIS
References
- Krupp LB, Tardieu M, Amato MP, et al. International Pediatric MS Study Group criteria for pediatric MS and immune-mediated CNS demyelinating disorders. Mult Scler. 2013;19(10):1261-1267.
- Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002;59(4):499-505.
- Beck RW, Cleary PA, Anderson MM Jr, et al. Optic Neuritis Treatment Trial (ONTT). N Engl J Med. 1992;326(9):581-588.
- Dalakas MC, Fujii M, Li M, et al. A randomized, double-blind, placebo-controlled trial of intravenous immune globulin in stiff-person syndrome. N Engl J Med. 2001;345(26):1870-1876.
- Graus F, Titulaer MJ, Balu R, et al. A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol. 2016;15(4):391-404.
- Cuzzubbo S, Javeri F, Tissier M, et al. Neurological adverse events associated with immune checkpoint inhibitors: review of the literature. Eur J Cancer. 2017;73:1-8.
- Chong JY, Rowland LP, Utiger RD. Hashimoto encephalopathy: syndrome or myth? Arch Neurol. 2003;60(2):164-171.