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Indications

• Acute ischemic stroke within 4.5 hours of symptom onset (COR 1, 2026 AHA/ASA)
• Dose: 0.25 mg/kg IV bolus over 5 seconds (max 25 mg)
• Do NOT use 0.4 mg/kg (potential for harm, no additional benefit)
• Tenecteplase or alteplase are both Class I recommendations; tenecteplase preferred for ease of single-bolus administration
• Extended window (4.5–9 h): May be reasonable (COR 2a) if salvageable penumbra on perfusion imaging (wake-up stroke within 9 h from midpoint of sleep, or 4.5–9 h from last known well)
• Extended window (4.5–24 h): Emerging evidence supports TNK for anterior LVO without EVT access (TRACE-III) and non-LVO with perfusion mismatch (OPTION) — see Extended IVT Window tab

Absolute Contraindications

Contraindications / Cautions (Evaluate Risk vs. Benefit)

Relative Contraindications

• Minor or rapidly improving symptoms (consider if disabling deficit present)
• Seizure at onset — may treat if deficit is thought to be from stroke, not post-ictal
• Major surgery or trauma within 14 days
• GI or urinary bleed within 21 days
• Recent arterial puncture at non-compressible site within 7 days
• Pregnancy — weigh risk vs. benefit; may be considered for moderate-severe stroke
• Small (<10 mm) unruptured intracranial aneurysm or extra-axial neoplasm — treatment is reasonable
• High burden of cerebral microbleeds (>10) — use with caution
• Intracranial arterial dissection — uncertain risk
• Mild nondisabling stroke (NIHSS 0–5) — IVT generally not recommended

MRI Protocol — Wake-Up / Unknown Onset

Agent: Alteplase 0.9 mg/kg or TNK 0.25 mg/kg (max 25 mg)

2026 AHA/ASA: COR 2a (within 9 h from midpoint of sleep for wake-up stroke)

CTP Protocol — Known or Unknown Onset, 4.5–24h

Step 1: Determine vessel status (CTA)

• LVO (ICA, M1, basilar) or Non-LVO?
• Is EVT available and planned?

Step 2: Apply imaging criteria based on clinical scenario

A. Known onset 4.5–9h — Any occlusion (EXTEND 2019)

• Core <70 mL · Mismatch ratio >1.2 · Mismatch volume >10 mL
• Agent: Alteplase 0.9 mg/kg or TNK 0.25 mg/kg
• 2026 AHA/ASA: COR 2a

B. LVO, 4.5–24h, NO EVT access (TRACE-III 2024)

• Core <70 mL · Mismatch ratio ≥1.8 · Mismatch volume ≥15 mL
• Agent: TNK 0.25 mg/kg (max 25 mg)
• KEY: Benefit ONLY when EVT is NOT available/planned
• TIMELESS (same criteria) showed NO benefit when rapid EVT was performed

C. Non-LVO, 4.5–24h (OPTION 2026)

• Core <50 mL · Mismatch ratio ≥1.2 · Mismatch volume ≥10 mL
• NIHSS 6–25 (or 4–5 with disabling deficit)
• Agent: TNK 0.25 mg/kg (max 25 mg)
• Result: mRS 0–1 at 90d: 43.6% vs 34.2% (NNT = 11)

D. LVO or Non-LVO, No EVT planned, 4.5–24h (HOPE 2025)

• Salvageable tissue on CTP or MR DWI-PWI
• Agent: Alteplase 0.9 mg/kg

CTP Definitions (all protocols)

Quick Decision Rules

Anterior Circulation — Standard Window (0–6h)

Strongly Recommended — Moderate-to-Small Stroke (ASPECTS 3–10)

• ICA or M1 occlusion · NIHSS ≥6 · Prestroke mRS 0–1
• ASPECTS 3–10 on NCCT (or DWI-MRI)
• No upper age limit (benefit shown even in age ≥80)
• NNT for functional independence: ~3–5 (ASPECTS ≥6) vs ~8 (ASPECTS 3–5)

Reasonable — Very Large Stroke (ASPECTS 0–2)

• ICA or M1 · NIHSS ≥6 · Age <80 · Prestroke mRS 0–1
• No significant mass effect on imaging
• Discuss with patient/family — functional independence rate ~10% (vs ~4% with medical management); mortality benefit present
• Best data from LASTE (MRI-selected, within 6.5h); ATLAS meta-analysis supports benefit

Reasonable — Patients with Mild Pre-Stroke Disability (mRS 2)

• ICA or M1 · NIHSS ≥6 · ASPECTS ≥6 · Within 6h
• EVT is reasonable to improve functional outcomes and reduce accumulated disability

Anterior Circulation — Extended Window (6–24h)

Strongly Recommended — Small Core (ASPECTS ≥6)

• ICA or M1 · NIHSS ≥6 · Prestroke mRS 0–1
• Must meet one of the following imaging criteria:

NNT for functional independence: 2.8 (DAWN), 3.6 (DEFUSE-3)

Strongly Recommended — Large Core (ASPECTS 3–5) — 6–24h

• ICA or M1 · NIHSS ≥6 · Age <80 · Prestroke mRS 0–1
• ASPECTS 3–5 · No significant mass effect
• Multiple imaging modalities acceptable (NCCT ASPECTS, CTP, MRI-DWI)
• NNT ~8; functional independence ~20% vs ~8% with medical management

Reasonable but Limited Data — Very Large Core (ASPECTS 0–2) — 6–24h

• ATLAS meta-analysis suggests benefit in late window
• Individualize based on age, goals of care, mass effect
• Discuss with patient/family — benefit is smaller, risks are higher

Posterior Circulation — 0–24h

Strongly Recommended — Basilar Artery Occlusion

• Basilar artery occlusion · NIHSS ≥10 · Prestroke mRS 0–1
• PC-ASPECTS ≥6
• Within 24 hours of symptom onset
• ATTENTION: benefit within 12h; BAOCHE: benefit 6–24h
• Benefit regardless of age, intracranial atherosclerosis, or atrial fibrillation

Medium Vessel Occlusions (M2, M3, distal)

Reasonable — Proximal Dominant M2 Only

• Dominant M2 (supplying ≥50% of MCA territory) · NIHSS ≥6
• Benefit primarily in patients with mismatch profile and higher stroke severity

No Proven Benefit — Distal M2, M3, and Smaller Vessels

Key Exclusions / Cautions (across all categories)

Imaging Selection Summary

Quick Reference for Non-Neurologists

Warfarin (VKA) — Goal INR <1.4 ASAP

• Vitamin K 10 mg IV — always give with PCC. Prevents INR rebound at 12–24h.
• FFP 15–30 mL/kg — only if PCC unavailable. Slower, volume overload risk.
• Recheck INR at 30 min post-PCC, then q3–6h × 24h

DOACs — Factor Xa Inhibitors (Apixaban / Rivaroxaban / Edoxaban)

If taken within 24h OR time unknown OR elevated drug-specific anti-Xa level:

• 4-factor PCC 50 units/kg IV — now primary reversal agent
• Alternative: aPCC (FEIBA) 50 units/kg if 4-factor PCC unavailable
• Activated charcoal 50g PO if intubated + last dose within 2h

DOACs — Dabigatran (Direct Thrombin Inhibitor)

If taken within 24h OR time unknown OR elevated drug-specific level:

• Idarucizumab (Praxbind) 5g IV (2 × 2.5g) — complete reversal in minutes
• If unavailable: aPCC 50 units/kg or 4-factor PCC 50 units/kg
• Consider hemodialysis if idarucizumab unavailable (dabigatran is dialyzable)
• Activated charcoal 50g PO if intubated + last dose within 2h

UFH (Unfractionated Heparin)

If elevated aPTT or anti-Xa level:

• Protamine 1 mg per 100 units UFH given in last 2–3h
• Max single dose: 50 mg IV slow push over 10 min
• Account for UFH half-life (~1h) when calculating dose

Enoxaparin (LMWH)

Reverse only if on therapeutic dosing (not prophylactic):

• ≤8h since last dose: Protamine 1 mg per 1 mg enoxaparin (max 50 mg)
• 8–12h since last dose: Protamine 0.5 mg per 1 mg enoxaparin
• >12h: Protamine likely not needed (unless renal impairment)
• If protamine contraindicated: consider rFVIIa 90 mcg/kg IV (last resort)

Key Principles

1Phase 1 — 0–5 min · Stabilization

• ABCs, O₂, IV/IO access, POC glucose, thiamine 100 mg IV then D50W if hypoglycemic
• Position patient safely, suction available, do NOT force anything into mouth
• Start timer — seizure >5 min = status epilepticus
• Order: continuous EEG (as soon as available), BMP, CBC, Mg, Ca, AED levels, tox screen, VBG

2Phase 2 — 5–20 min · Benzodiazepines (First-Line)

Choose ONE:

• Midazolam 10 mg IM (≥40 kg) — preferred if no IV access (RAMPART trial: 73% vs 63% for IV lorazepam)
• Lorazepam 0.1 mg/kg IV (max 4 mg/dose) — may repeat ×1
• Diazepam 0.15–0.2 mg/kg IV (max 10 mg/dose) — may repeat ×1

3Phase 3 — 20–40 min · Second-Line ASMs

Start when seizure persists after adequate benzodiazepine dosing. ESETT trial showed no difference in efficacy among the three main agents (~50% response rate each). Choose based on patient factors:

Fosphenytoin 20 mg PE/kg IV at 150 mg PE/min

• Avoid in: known cardiac conduction disease, bradycardia
• Monitor: telemetry during infusion, BP
• Caution in children (higher intubation rate vs LEV/VPA in ESETT)

Valproate 40 mg/kg IV over 10 min (max 3000 mg)

• Avoid in: liver disease, mitochondrial disease, pregnancy, pancreatitis
• Fastest infusion time of the three

Levetiracetam 60 mg/kg IV over 10 min (max 4500 mg)

• Fewest drug interactions, safest hepatic/cardiac profile
• May be less effective if already on LEV at baseline

Lacosamide 200–400 mg IV over 3–5 min

• Non-inferior to fosphenytoin (TRENdS trial)
• Avoid in: known cardiac conduction disease (PR prolongation)

Phenobarbital 20 mg/kg IV at 50–75 mg/min

• Highly effective; some RCT data suggest superiority over VPA
• Risk: respiratory depression, hypotension (especially after benzodiazepines)
• Have airway equipment ready; may require intubation

4Phase 4 — >40 min · Refractory SE (ICU)

Requires: intubation, continuous EEG, ICU admission

Midazolam 0.2 mg/kg bolus → 0.05–2 mg/kg/h infusion

• Lowest risk of hemodynamic compromise
• Tachyphylaxis common with prolonged use

Propofol 1–2 mg/kg bolus → 2–10 mg/kg/h infusion

• Rapid onset; effective seizure suppression
• ⚠ Propofol infusion syndrome risk: limit to 48h when possible, monitor triglycerides, CK, lactate
• Avoid in: children, mitochondrial disease, concurrent ketogenic diet

Pentobarbital 5–15 mg/kg load → 0.5–10 mg/kg/h infusion

• Greatest seizure suppression but highest risk of hypotension
• Often requires vasopressors
• Reserve for failure of midazolam/propofol

5Phase 5 — >24h on Anesthetics · Super-Refractory SE (SRSE)

Definition: SE that continues or recurs ≥24h after anesthetic initiation, or recurs on wean

Ketamine 1–2.5 mg/kg bolus → 1–7 mg/kg/h infusion (up to 10 mg/kg/h)

• NMDA antagonist — different mechanism; may be synergistic with GABAergic agents
• Does NOT cause respiratory depression or significant hypotension
• Meta-analysis: seizure cessation in ~64% of adults; earlier initiation → better response
• Consider earlier in the algorithm rather than as last resort

Add non-sedating ASMs for rational polytherapy (target different mechanisms)

• Topiramate (AMPA/kainate), perampanel (AMPA), phenobarbital (GABA-A), lacosamide (Na+ channel)

Immunotherapy — if autoimmune etiology suspected

• IV methylprednisolone, IVIG, PLEX
• Consider early if young patient, no clear structural/metabolic cause, CSF pleocytosis

Other considerations

• Ketogenic diet (limited evidence, logistically complex)
• Hypothermia — NOT shown to confer benefit
• Allopregnanolone — RCT showed no efficacy in SRSE

Key Principles

Quick Dosing Table

1Step 1 — Recognize & Stabilize

Warning Signs of Herniation

Immediate Actions

• ABCs — intubate if GCS ≤8 or unable to protect airway
• Head of bed 30–45°, head midline, avoid neck flexion/compression
• Loosen cervical collar if present (may impede venous drainage)
• Avoid hypotension (MAP goal ≥80 mmHg), hypoxia (SpO₂ ≥94%), hyperthermia (target 36–37.5°C)
• Avoid hypo-osmolar fluids (no D5W, no half-normal saline) — use isotonic NS only
• Stat CT head — do NOT delay osmotherapy if clinical herniation is suspected

2Step 2 — Osmotherapy (First-Line Medical Treatment)

Use for symptomatic edema with neurological decline — NOT prophylactically.

Option A: Mannitol

• Acute herniation dose: 1 g/kg IV bolus over 15–20 min (through peripheral or central line)
• Maintenance dose: 0.25–0.5 g/kg IV q6–8h PRN for ongoing edema
• Monitoring:
  • Serum osmolality q6h — hold dose if >320 mOsm/L
  • Osmolar gap (measured − calculated osmolality) — hold if gap >10 (mannitol not cleared)
  • Strict I&O, daily weights — mannitol is an osmotic diuretic → risk of hypovolemia, hypotension, AKI
  • Replace urine output with isotonic fluids to maintain euvolemia
• Caution: Rebound edema possible with prolonged use; avoid in hypovolemic/hypotensive patients

Option B: Hypertonic Saline (HTS)

• Acute herniation dose: 23.4% NaCl 30 mL IV bolus over 10–15 min via CENTRAL LINE only
• Maintenance: 3% NaCl continuous infusion at 30–75 mL/h, titrate to target Na⁺ 145–155 mEq/L
• Bolus alternative: 3% NaCl 250 mL IV bolus over 15–30 min (can use peripheral IV)
• Monitoring:
  • Serum Na⁺ q4–6h — target 145–155 mEq/L, do not exceed 160 mEq/L
  • Monitor for volume overload (especially in CHF patients), hyperchloremic metabolic acidosis
• Advantage over mannitol: No diuretic effect → better in hypotensive patients; may be more effective in ICP crises

Choosing Between Mannitol and HTS

3Step 3 — Hyperventilation (Temporizing Measure Only)

• Mild hyperventilation: PaCO₂ 32–35 mmHg — Tier 2 intervention for elevated ICP
• Aggressive hyperventilation: PaCO₂ <30 mmHg — RESCUE ONLY for active herniation while preparing for surgery
  • Causes cerebral vasoconstriction → rapid ICP reduction
  • Risk of cerebral ischemia if sustained — use for shortest duration possible
• Normal ventilation target: PaCO₂ 35–40 mmHg (maintain when ICP is controlled)
• Severe hypocapnia (<30) and hypercapnia (>45) are both associated with increased mortality

4Step 4 — Additional Medical Measures

• Temperature control: Target normothermia 36–37.5°C; treat fever aggressively (acetaminophen, cooling devices); mild hypothermia (35–36°C) may be considered for refractory ICP but evidence is limited
• Sedation/analgesia: Propofol or midazolam + fentanyl to reduce metabolic demand and ICP; avoid agitation, coughing, straining
• Seizure prophylaxis: Consider continuous EEG — subclinical seizures worsen edema
• Glucose control: Avoid hyperglycemia (target 140–180 mg/dL) and hypoglycemia
• Venous drainage optimization: HOB 30–45°, head midline, avoid tight cervical collars, avoid IJ central lines on the side of pathology if possible

What Does NOT Work

5Step 5 — Surgical Decompression

Supratentorial (Malignant MCA Infarction)

When to consider:

• Large MCA territory infarction with clinical deterioration (decreasing consciousness)
• ~80% mortality with medical therapy alone in malignant edema
• Peak edema typically 48–72h post-stroke

Evidence (DESTINY/DECIMAL/HAMLET pooled + subsequent meta-analyses):

• Surgery reduces mortality: 70% survival vs 31% with medical therapy alone
• Functional outcome (mRS 0–3): 26% surgery vs 15% medical therapy
• Absolute mortality reduction ~50% when performed within 48h

Patient selection:

• Age <60: strongest evidence — recommended when deteriorating despite medical therapy
• Age >60: surgery reduces mortality but does NOT clearly improve functional outcomes (DESTINY-II) — individualize based on goals of care
• Discuss early with patient/family — ideally before deterioration occurs
• Prior tPA/TNK does NOT preclude surgery

Technique notes:

• Large craniectomy (≥12 cm diameter) with dural expansion
• Open dural closure preferred over tight closure (fewer complications, similar infection rates)

Posterior Fossa (Cerebellar Infarction)

Key differences from supratentorial:

• Outcomes are generally MUCH BETTER — 74% achieve mRS 0–1 in large series
• Suboccipital craniectomy is strongly recommended for neurological deterioration
• Ventriculostomy (EVD) is a reasonable first step for obstructive hydrocephalus, but NOT sufficient as definitive treatment alone — risk of upward herniation
• If EVD fails to improve neurological status → proceed to suboccipital decompression
• Cerebellar infarct volume ≥35 mL associated with need for surgical intervention
• Concomitant brainstem infarction worsens prognosis

6Step 6 — Monitoring & Escalation Framework

Neuro checks: q1h minimum during peak edema risk (24–72h)

ICP monitoring: Consider if available (target ICP <22 mmHg, CPP 60–70 mmHg)

Tiered Escalation (adapted from SIBICC/BTF for general cerebral edema)

Quick Dosing Table

The 20/30/40 Rule

Monitoring Protocol (q2–4h During Decline)

Also intubate if: severe bulbar dysfunction, PaCO₂ >48, PaO₂ <60, VC <15 mL/kg regardless of NIF, significant atelectasis on CXR, or clinical respiratory distress

MG vs GBS — Key Differences

GBS — Red Flags for Ventilation

• Bulbar weakness (strongest predictor)
• Neck flexion weakness
• Autonomic instability
• Rapid progression (<7 days onset to admission)
• Unable to walk at admission
• mEGRIS score ≥18 → ~81% will need mechanical ventilation

MG — Medications to Avoid

Key Rules

Quick Differentiation

Serotonin Syndrome — Hunter Criteria

Must have serotonergic drug exposure + ANY ONE of:

• Spontaneous clonus
• Inducible clonus + agitation OR diaphoresis
• Ocular clonus + agitation OR diaphoresis
• Tremor + hyperreflexia
• Hypertonia + temp >38°C + ocular or inducible clonus

Management

• Mild: Stop drug + benzodiazepines → most resolve in 24h
• Moderate: Add cyproheptadine 12 mg PO/NGT → then 2 mg q2h → maintenance 8 mg q6h (max 32 mg/day)
• Severe (temp >41.1°C): Intubation + neuromuscular paralysis + active cooling

NMS — Management

• STOP offending agent
• Mild: Lorazepam 1–2 mg IV q4–6h
• Moderate–Severe (temp ≥38–40°C, severe rigidity):
  • Dantrolene 1–2.5 mg/kg IV, repeat q6–8h (max 10 mg/kg/day)
  • Bromocriptine 2.5 mg PO/NGT q8h (up to 45 mg/day) OR Amantadine 100 mg q8h
• Refractory: Consider ECT
• IV fluids targeting UOP 200–300 mL/h (rhabdomyolysis)
• Labs: CK, BMP, LFTs, coags (DIC screen), myoglobin

Parkinsonism-Hyperpyrexia

• Treatment = rapidly restart dopaminergic therapy at prior dose or higher
• Add dantrolene if severe

High-Risk Serotonergic Drugs

Blood Pressure Targets by Condition

Cerebral Amyloid Angiopathy — Boston Criteria v2.0

Applies to age ≥50 with spontaneous ICH, transient focal neurologic episodes, or cognitive impairment. Requires absence of any deep hemorrhagic lesions and no other cause of hemorrhage.

Key Definitions

• Hemorrhagic lesions: strictly lobar ICH, cerebral microbleeds (CMB), or cortical superficial siderosis (cSS) foci
• White matter features: severe centrum semiovale perivascular spaces (CSO-PVS) OR white matter hyperintensity multispot pattern (WMH-MS)

Diagnostic Categories (on T2*-weighted MRI)

Key Notes

Ischemic Stroke Etiology — TOAST Classification

Assign after history, exam, brain/vascular imaging, echocardiography, and cardiac rhythm monitoring.

TOAST Categories

• Large-artery atherosclerosis — ≥50% stenosis/occlusion of relevant extra- or intracranial artery; cortical/cerebellar or subcortical infarct >1.5 cm. No cardioembolic source.
• Cardioembolism — high/medium-risk cardiac source (e.g., AF, mechanical valve, recent MI, LV thrombus); typically cortical or large/multi-territory infarcts.
• Small-vessel occlusion (lacune) — clinical lacunar syndrome + relevant infarct <1.5–2.0 cm in perforator territory; no cortical signs; no proximal stenosis or cardiac source.
• Other determined etiology — dissection, vasculitis, hypercoagulable state, Moyamoya, etc.
• Undetermined (cryptogenic) — ≥2 causes identified, negative workup despite complete evaluation, or incomplete evaluation.

Multiple Sclerosis — McDonald Criteria (2024)

Diagnosis requires dissemination in space (DIS) + dissemination in time (DIT), with exclusion of better explanations.

Dissemination in Space (DIS) — ≥1 T2 lesion in ≥2 of these CNS regions

• Periventricular
• Cortical/juxtacortical
• Infratentorial
• Spinal cord
• Optic nerve (NEW 5th region in 2024 criteria)

Dissemination in Time (DIT) — any ONE of

• Simultaneous gadolinium-enhancing AND non-enhancing lesions
• New T2 or enhancing lesion on follow-up MRI
• Second clinical attack
• CSF-specific oligoclonal bands substitute for DIT (present since 2017)

2024 Additions / New Pathways

2024 Revisions of the McDonald Criteria (Lancet Neurol 2025)

NMOSD — IPND 2015

AQP4-IgG Positive

≥1 of 6 core clinical characteristics + positive cell-based assay + exclusion of alternatives.

Core Characteristics

• Optic neuritis
• Acute myelitis
• Area postrema syndrome (intractable hiccups/nausea/vomiting)
• Acute brainstem syndrome
• Symptomatic narcolepsy/diencephalic syndrome with typical MRI
• Symptomatic cerebral syndrome with typical MRI

AQP4-IgG Negative or Unknown

Wingerchuk et al. 2015 (NMOSD)

MOGAD — International Panel 2023

• Core clinical event (ON, myelitis, ADEM, cerebral cortical encephalitis, brainstem/cerebellar) + positive serum MOG-IgG (cell-based assay) + exclusion of better diagnosis (esp. MS)
• Clear positive titer = criterion met
• Low/borderline titer requires ≥1 supporting clinical/MRI feature

Guillain-Barré Syndrome — Brighton Criteria

Core requirements: bilateral flaccid limb weakness + decreased/absent reflexes in weak limbs + monophasic course (nadir 12h–28d) + absence of alternative diagnosis.

*Level 2 requires CSF OR NCS available and consistent (or if not done); Level 3 relies on clinical features alone.

Miller Fisher variant (Level 3): bilateral ophthalmoplegia + areflexia + ataxia, WITHOUT limb weakness or CNS involvement.

Brighton Collaboration 2011 · Fokke et al. Brain 2014 · EAN/PNS 2023

Myasthenia Gravis — MGFA Clinical Classification

• Class I: ocular only (any ocular weakness; may include eye closure weakness)
• Class II: mild generalized
  • IIa — limb/axial predominant
  • IIb — oropharyngeal/respiratory predominant
• Class III: moderate generalized (IIIa / IIIb)
• Class IV: severe generalized (IVa / IVb)
• Class V: intubation required (with or without mechanical ventilation)

Jaretzki/MGFA 2000

CIDP — EAN/PNS 2021 (2nd Revision)

Diagnosis = clinical phenotype + electrodiagnostic demyelination (both motor AND sensory conduction now required), then upgrade with supportive criteria if needed. Only two certainty levels: CIDP and possible CIDP ("definite" and "probable" removed).

Clinical Phenotypes

• Typical CIDP — chronically progressive or relapsing, symmetric proximal AND distal weakness of ≥4 limbs, with sensory involvement, developing ≥8 weeks; reduced/absent reflexes in all limbs
• Variants (term "atypical" dropped):
  • Distal (DADS) — distal, sensory-predominant, LL>UL; exclude anti-MAG neuropathy
  • Multifocal/focal (Lewis-Sumner/MADSAM) — asymmetric, UL-predominant
  • Motor — motor only, no sensory signs
  • Sensory — sensory only, incl. CISP

Electrodiagnostic Criteria

Sensory: abnormalities (prolonged distal latency, low amplitude, slowed CV) in ≥2 nerves

Certainty

• CIDP — appropriate phenotype + motor (± sensory) criteria fully met
• Possible CIDP — criteria met in only 1 nerve / incompletely; upgrade to CIDP with ≥2 supportive criteria: CSF albuminocytologic dissociation, nerve US/MRI enlargement, objective (validated-score) treatment response, or biopsy demyelination

Van den Bergh et al. (EAN/PNS) 2021

ALS — Revised El Escorial & Awaji

Core requirement (all): LMN signs (clinical, electrodiagnostic, or pathologic), UMN signs (clinical), and progressive spread within/between regions — WITH absence of electrodiagnostic, pathologic, or imaging evidence of another disease. 4 regions assessed: bulbar, cervical, thoracic, lumbosacral.

Revised El Escorial Certainty Categories

• Clinically definite — UMN + LMN signs in ≥3 regions (or bulbar + 2 spinal)
• Clinically probable — UMN + LMN in ≥2 regions, with some UMN signs rostral to LMN signs
• Probable, laboratory-supported — UMN + LMN in 1 region (or UMN alone in 1 region) + LMN by EMG in ≥2 regions
• Clinically possible — UMN + LMN in 1 region, or UMN in ≥2 regions, or LMN rostral to UMN

Awaji Modification

EMG evidence of LMN dysfunction counts as equivalent to clinical LMN signs, and fasciculation potentials (when accompanied by chronic neurogenic change) count as a marker of acute denervation alongside fibrillations/positive sharp waves. Improves early sensitivity (esp. bulbar onset) without losing specificity; drops the "lab-supported probable" category.

Supportive workup: NCS to exclude conduction block/sensory involvement; normal serology (except mildly elevated CK); spinal MRI to exclude mimics.

Parkinson Disease (MDS 2015)

Step 1 — Establish Parkinsonism (essential)

Bradykinesia (with decrement/fatiguing) PLUS rest tremor and/or rigidity.

Step 2 — Attribute to PD by weighing three feature classes

Certainty Levels

• Clinically established PD: no absolute exclusions + no red flags + ≥2 supportive criteria (≥90% specificity)
• Clinically probable PD: no absolute exclusions; red flags balanced by supportive criteria (1 red flag ↔ ≥1 supportive; ≤2 red flags ↔ ≥2 supportive)

Progressive Supranuclear Palsy (MDS-PSP 2017)

Mandatory inclusion: sporadic, age ≥40 at onset, gradually progressive.

Core Clinical Features — 4 Domains (each graded 1 most specific → 3)

Supportive features (clues): levodopa resistance, hypokinetic/spastic dysarthria, dysphagia, photophobia; imaging clue = midbrain atrophy ("hummingbird"). Mandatory exclusion criteria reflect features of mimics (predominant early amnesia, prominent autonomic failure, appendicular ataxia, cortical/subcortical infarcts, etc.).

Certainty (from O+P+A+C combinations): vertical gaze palsy (O1) or slow vertical saccades (O2) + ≥1 other core feature = probable PSP; lower combinations = possible or "suggestive of" PSP (for early identification).

Clinical predominance types: Richardson syndrome (PSP-RS), PSP-parkinsonism (PSP-P), PSP-PGF (progressive gait freezing), PSP-CBS, PSP-SL, etc.

Multiple System Atrophy (MDS 2022)

Entry (essential): sporadic, progressive, negative family history, onset >30 years.

Core Clinical Features

• Autonomic dysfunction — neurogenic orthostatic hypotension (SBP drop ≥20/10 mmHg within 3 min standing) AND/OR urogenital failure (urge incontinence, erectile dysfunction, or voiding difficulty with postvoid residual >100 mL)
• Motor — poorly levodopa-responsive parkinsonism (MSA-P) OR cerebellar syndrome — ≥2 of gait ataxia, limb ataxia, cerebellar dysarthria, oculomotor dysfunction (MSA-C)

MRI markers: atrophy of putamen / MCP / pons / cerebellum; "hot cross bun" sign; putaminal rim; increased diffusivity.

Certainty Levels

• Clinically established MSA: ALL core features (autonomic failure + poorly levodopa-responsive parkinsonism or cerebellar syndrome) + ≥2 supportive features + ≥1 MRI marker, no exclusions (maximizes specificity)
• Clinically probable MSA: ≥2 core features (autonomic + parkinsonism and/or cerebellar) in any combination — MRI not required
• Possible prodromal MSA: research category (autonomic failure or RBD + only mild motor signs)

Possible Autoimmune Encephalitis

Subacute (<3 mo) working memory deficit / altered mental status / psychiatric symptoms + ≥1 of:

• New focal CNS findings
• Unexplained seizures
• CSF pleocytosis
• MRI suggestive

— with reasonable exclusion of alternatives

Definite Limbic Encephalitis

Antibody-Specific Syndromes

Anti-NMDAR, anti-LGI1, anti-CASPR2, anti-GABA_BR, anti-AMPAR, anti-DPPX, and others each have their own defined criteria (see original consensus paper for full syndrome-specific definitions).

Migraine Without Aura — ≥5 attacks

• Duration 4–72 h (untreated/unsuccessfully treated)
• ≥2 of: unilateral · pulsating · moderate–severe · aggravated by/causing avoidance of routine activity
• ≥1 of: nausea/vomiting · photophobia AND phonophobia
• Not better explained by another ICHD-3 diagnosis

Migraine With Aura

≥2 attacks with ≥1 fully reversible aura (visual, sensory, speech/language, motor, brainstem, retinal); each aura symptom 5–60 min; followed by headache within 60 min.

Chronic Migraine

Headache ≥15 days/month for >3 months, ≥8 days/month with migraine features.

Tension-Type Headache — ≥10 episodes

• Duration 30 min–7 days
• ≥2 of: bilateral · pressing/tightening (non-pulsating) · mild–moderate · NOT aggravated by routine activity
• Both: no nausea/vomiting · no more than one of photophobia OR phonophobia

Cluster Headache — ≥5 attacks

• Severe unilateral orbital/supraorbital/temporal pain, 15–180 min untreated
• Frequency every other day up to 8/day
• ≥1 ipsilateral autonomic feature (conjunctival injection/lacrimation, nasal congestion/rhinorrhea, eyelid edema, forehead/facial sweating, miosis/ptosis) AND/OR restlessness/agitation

Other Trigeminal Autonomic Cephalalgias (TACs)

Distinguished by attack duration/frequency + prominent autonomic features:

• Paroxysmal hemicrania — 2–30 min, >5/day, absolute response to indomethacin
• SUNCT/SUNA — 1–600 sec, very frequent; conjunctival injection + tearing (SUNCT)
• Hemicrania continua — continuous unilateral, indomethacin-responsive

Prerequisites (must satisfy ALL before exam)

• Established catastrophic, irreversible brain injury of known cause
• Neuroimaging consistent with the diagnosis
• Exclude confounders: core temp ≥36°C, SBP ≥100 mmHg (MAP ≥75), no severe metabolic/electrolyte/endocrine derangement, no drug/toxin/neuromuscular blockade effect
• Adequate observation period to exclude recovery

Clinical Exam — Must Demonstrate ALL

• Coma — no arousal/awareness to maximal noxious stimulation
• Pupils fixed, midsize or dilated, nonreactive to light
• Absent corneal, oculocephalic, and oculovestibular (cold caloric) reflexes
• No facial movement to noxious stimulation
• Absent gag (bilateral posterior pharyngeal) and cough (deep tracheal suction) reflexes
• No brain-mediated motor response to noxious limb stimulation (spinal reflexes allowed)

Apnea Test (positive = consistent with BD/DNC)

• Preoxygenate, establish normocarbia/normal pH
• Disconnect ventilator with apneic oxygenation; observe ≥8–10 min for respiratory effort
• Positive if NO respiratory effort AND PaCO₂ ≥60 mmHg (or ≥20 mmHg above baseline) with pH <7.30

Ancillary Tests

Only if exam/apnea test cannot be completed or is confounded:

• Cerebral blood flow studies (angiography, nuclear medicine/technetium, TCD) OR EEG
• Ancillary tests are NOT a substitute for a determinable clinical exam

Approach: Confirm no mass/herniation risk before LP when indicated, record opening pressure, and send cell count + differential, protein, glucose (with paired serum glucose), plus targeted studies (Gram stain/culture, PCR, cytology, oligoclonal bands, xanthochromia). Interpret each parameter together, not in isolation.

Normal Adult Reference Values

Pattern Recognition by Clinical Scenario

Opening Pressure & CSF-Pressure Disorders

Measure with the patient in the lateral decubitus position, legs extended, after neuroimaging excludes a mass or venous thrombosis. If done prone (e.g., fluoroscopy-guided), add the needle length (~9 cm) to the manometer column height or the reading is falsely low.

Autoimmune / Neuroinflammatory CSF Panel

Send with paired serum: oligoclonal bands (CSF + serum, isoelectric focusing), IgG index, albumin CSF:serum ratio (Reiber diagram for BBB integrity), and neuronal/glial autoantibodies (pair CSF and serum).

Key Pearls

Approach: In critically ill/altered patients, use continuous EEG (gold standard) to detect nonconvulsive seizures and status epilepticus. Classify patterns using ACNS 2021 terminology (main term 1 = localization; main term 2 = pattern type: periodic discharges, rhythmic delta activity, or spike-wave), then decide whether the pattern is an electrographic seizure, on the ictal-interictal continuum (IIC), or benign.

ACNS-Based Rhythmic / Periodic Patterns

Electrographic Seizure — Definite (any one)

Electrographic Status Epilepticus

Ictal-Interictal Continuum (IIC)

Purely electrographic "boundary" patterns not meeting seizure criteria:

Interpretation Pearls

Approach: Perform NCS first (amplitude, latency, conduction velocity on motor and sensory nerves), then needle EMG (spontaneous activity + MUAP morphology/recruitment). Localize the lesion and classify the process as axonal vs. demyelinating, and estimate severity and chronicity. Always compare to age-adjusted normative values — amplitudes decline substantially with age.

Motor NCS Normal Limits (representative adult, lower/upper limits)

Sensory NCS Normal Limits (representative adult)

Axonal vs. Demyelinating Pattern

Needle EMG Interpretation

Localization Pearls

Approach: Non-contrast CT (NCCT) is the first study in suspected stroke — it rapidly excludes hemorrhage and mimics. Add CTA to identify a large-vessel occlusion (LVO) and CT perfusion (CTP) to estimate core vs. penumbra when extended-window reperfusion is considered. Read in sequence: (1) blood? (2) early ischemic change / ASPECTS, (3) vessel (CTA), (4) tissue at risk (CTP).

Sequence of Interpretation — Quick Map

• NCCT — rule out hemorrhage; detect early ischemic changes and hyperdense vessel sign; score ASPECTS.
• CTA head/neck — confirm LVO, localize occlusion, assess collaterals (single- or multiphase).
• CTP — quantify ischemic core and penumbra when 6–24 h or unclear onset; drives late-window EVT/thrombolysis selection.

Non-Contrast CT — Ischemic Findings

ASPECTS regions (subtract 1 point each for hypodensity): caudate, lentiform, insula, internal capsule, and cortical M1–M6.

CTA & Collaterals

CT Perfusion — Core vs. Penumbra Thresholds

Hemorrhage on NCCT

Key Pearls

Carotid duplex (ICA stenosis), SRU 2003 consensus

Note: Normal and <50% have the same velocities; visible plaque separates them.

Note: IAC-optimized criteria (Vasc Med 2021) for ≥50%: PSV ≥180, or PSV 125–179 with ICA/CCA ratio ≥2.0. The ≥70% criteria are unchanged.

Sources: Grant EG et al., SRU Consensus, Radiology 2003; IAC duplex velocity optimization study, Vasc Med 2021 (PMC8493430).

MCA vasospasm (MFV + Lindegaard ratio MCA/extracranial ICA)

Sources: Lindegaard 1989; ACR–AIUM–SPR–SRU TCD Practice Parameter 2022; J Neurosci Res 2018 (doi 10.1002/jnr.24148).

Basilar vasospasm (Sviri)

Sources: Sviri GE et al., Neurosurgery 2006; Soustiel JF et al., Stroke 2002.

Vasospasm in other vessels, MFV (cm/s)

Note: >30% MFV difference between corresponding right and left arteries is generally significant.

Source: original sheet (standard textbook values); no single guideline citation.

Intracranial stenosis, MFV (cm/s)

SPR = stenotic / prestenotic MFV ratio; SPR ≥2 supports ≥50%.

Sources: Zhao L et al., Stroke 2011 (velocity criteria revisited); Felberg/Alexandrov, Stroke 1994.

TIBI flow grades

Source: Demchuk AM et al., Stroke 2001.

Pulsatility index

PI = (PSV − EDV) / MFV

Breath-holding index (vasomotor reactivity)

BHI = [(V end of breath-hold − V baseline) / V baseline × 100] / seconds of breath-hold

Source: Markus & Harrison 1992; ACR–AIUM–SPR–SRU TCD Practice Parameter 2022.

Bubble study shunt grading (Spencer logarithmic scale)

Grade ≥III (>30 MES) = significant shunt.

MES criteria (emboli detection): duration <300 ms, intensity ≥3 dB above background, unidirectional, characteristic chirp.

Sources: Spencer MP et al., J Neuroimaging 2004; ACR–AIUM–SPR–SRU TCD Practice Parameter 2022.

Sickle cell screening (STOP), TAMMV on non-imaging TCD, ages 2–16

Note: imaging TCD (TCDi) reads about 10–15% lower; thresholds apply to non-imaging TCD.

Sources: ASH 2020 SCD cerebrovascular guideline; NHLBI 2014; AHA/ASA 2024 primary prevention guideline.

Brain death / DNC (TCD ancillary test, adults only)

• Required pattern: systolic spikes or oscillating (reverberating) flow.
• Vessels: right and left anterior circulation (ICA / MCA / ACA) and posterior circulation (VA or BA).
• Systolic spikes: sharp unidirectional signals in early systole, <200 ms, peak systolic velocity <50 cm/s (some consensus statements allow up to 100), no flow for the rest of the cycle. Changed from original "<20 cm/s mean".
• Oscillating flow: forward and reverse components with nearly equal area (net flow ≈ 0).
• Repeat: two examinations are normally required.
• Absent signal is not diagnostic (no temporal window in about 10% of adults).
• Flow present: cannot declare; repeat later or use another ancillary test.
• Not validated in children.

Sources: AAN/AAP/CNS/SCCM 2023 guideline (Neurology); World Brain Death Project, JAMA 2020; Ducrocq 1998 task force; Brazilian 2012 / Latin American 2014 consensus.

Insonation

Source: Aaslid / Fujioka, Ultrasound Med Biol 1990; ACR–AIUM–SPR–SRU TCD Practice Parameter 2022.

Velocities in cm/s. Reference values reviewed Oct 2026; confirm against your laboratory’s own criteria.

Approach: Core acute-stroke MRI = DWI + FLAIR, with blood-sensitive (GRE/SWI) and vascular (MRA) sequences. DWI detects ischemia within minutes; the DWI-FLAIR mismatch serves as a "tissue clock" for unknown-onset stroke; GRE/SWI detect hemorrhage; hematoma signal evolves predictably with age.

Ischemic Stroke — Sequence Behavior

Intracerebral Hemorrhage — Evolution by Stage (T1/T2 on standard-field MRI)

Hemorrhage Pearls

Approach: Match agent to seizure type and patient factors, start low and titrate. Broad-spectrum ASMs (valproate, lamotrigine, levetiracetam, topiramate, zonisamide, lacosamide, clobazam) are safe across seizure types; narrow-spectrum ASMs (carbamazepine, oxcarbazepine, phenytoin, gabapentin) may worsen absence/myoclonic seizures.

Place in Therapy — Quick Map

• Focal onset — first-line: lamotrigine, levetiracetam, carbamazepine (also oxcarbazepine, lacosamide)
• Generalized tonic-clonic — first-line: valproate; levetiracetam or lamotrigine for people of childbearing potential
• Absence — first-line: ethosuximide (valproate if GTC also present)
• Myoclonic — first-line: valproate, levetiracetam
• Adjunctive/refractory: perampanel, brivaracetam, cenobamate, gabapentin, clobazam; felbamate, vigabatrin, cannabidiol, rufinamide (restricted/syndrome-specific)

Focal / Broad-Spectrum Agents

Generalized / Adjunctive Agents

Approach: Select a DMT by disease activity and prognostic risk. Traditional escalation starts with platform agents; there is a growing trend toward early high-efficacy therapy in young patients with active disease, multiple lesions, and no fixed disability. Ocrelizumab is the only DMT with proven benefit in PPMS.

Place in Therapy — Efficacy Tiers

• Modest/moderate (platform): interferon-beta, glatiramer acetate, teriflunomide — traditional first-line for low/moderate activity
• Intermediate: dimethyl fumarate (and diroximel fumarate)
• High / very-high efficacy: natalizumab, anti-CD20 (ocrelizumab, ofatumumab, ublituximab), S1P modulators (fingolimod, siponimod, ozanimod), cladribine, alemtuzumab
• Induction (2nd/3rd line, aggressive disease): alemtuzumab, cladribine, mitoxantrone, autologous HSCT
• PPMS: ocrelizumab

Platform / Moderate-Efficacy

Intermediate

High / Very-High Efficacy — Oral

High / Very-High Efficacy — Infusion / Injection

Approach: Start dopaminergic therapy when motor symptoms impair function. Levodopa gives the greatest motor benefit; MAO-B inhibitors or dopamine agonists are levodopa-sparing options in younger/milder patients. Add COMT/MAO-B inhibitors, amantadine, or istradefylline for fluctuations and dyskinesia.

Place in Therapy — Quick Map

• First-line, older or significant motor disability: carbidopa/levodopa
• First-line, younger or mild symptoms: MAO-B inhibitor or dopamine agonist (levodopa-sparing)
• Wearing-off / motor fluctuations: add COMT inhibitor, MAO-B inhibitor, amantadine, or istradefylline; ER levodopa
• Dyskinesia: amantadine
• On-demand "off" rescue: SC/SL apomorphine, inhaled levodopa

Dopamine Replacement

Dopamine Agonists (non-ergot)

MAO-B Inhibitors

Adjuncts for Fluctuations / Dyskinesia

Approach: Symptomatic control with an acetylcholinesterase inhibitor first, add corticosteroids/immunosuppression if goals not met, escalate to complement/FcRn agents for refractory disease, and use IVIg/PLEX for crisis or rapid worsening.

Place in Therapy — Quick Map

• First-line symptomatic: pyridostigmine
• First-line immunosuppression: corticosteroids (prednisone)
• First-line steroid-sparing: azathioprine; also mycophenolate, tacrolimus, methotrexate
• Refractory/novel: complement inhibitors (eculizumab, ravulizumab, zilucoplan) and FcRn blockers (efgartigimod, rozanolixizumab, nipocalimab)
• Crisis / rapid worsening: IVIg or plasma exchange; withhold pyridostigmine in crisis

Symptomatic Therapy

Immunosuppression

Novel Targeted Therapies (refractory / anti-AChR or MuSK+)

Acute / Crisis

Migraine Medications

Approach: Treat acute attacks early with a triptan ± NSAID; use gepants or lasmiditan when triptans are contraindicated or ineffective. Add preventive therapy for frequent/disabling attacks, choosing among oral agents and migraine-specific CGRP therapies.

Place in Therapy — Quick Map

• Acute, first-line: triptans + NSAIDs (or combination); acetaminophen for mild attacks
• Acute, if triptans contraindicated/ineffective: gepants (ubrogepant, rimegepant, zavegepant) or ditan (lasmiditan) — no vasoconstriction
• Preventive, first-line oral: topiramate, beta-blockers (propranolol, metoprolol), amitriptyline, valproate, candesartan
• Preventive, migraine-specific: CGRP mAbs (erenumab, fremanezumab, galcanezumab, eptinezumab), oral CGRP antagonists (atogepant, rimegepant)
• Chronic migraine (≥15 days/mo): onabotulinumtoxinA; CGRP mAbs

Acute Treatment

Gepants/ditans recommended after ≥2 triptans have failed, are not tolerated, or are contraindicated.

Preventive — Oral

Preventive — CGRP-Targeted

Chronic Migraine

Robbins, JAMA 2021 · VanderPluym, JAMA 2021 · Eller, Neurology 2025

Neuropathic Pain Agents

Approach: Start with a first-line agent (gabapentinoid, SNRI, or TCA), start low and titrate slowly; combining two first-line agents of different classes may add benefit. Localized peripheral pain can be treated with topical agents. Opioids are generally not recommended for chronic neuropathic pain.

Place in Therapy — Quick Map

• First-line: gabapentinoids (gabapentin, pregabalin), SNRIs (duloxetine, venlafaxine), TCAs (amitriptyline, nortriptyline)
• Second-line (localized peripheral): lidocaine 5% patch, capsaicin 8% patch/cream
• Third-line: botulinum toxin type A (focal), tramadol/opioids (short-term, selected patients)
• Trigeminal neuralgia: carbamazepine/oxcarbazepine (first-line, distinct pathway)

First-Line

Second-Line — Localized Peripheral

Third-Line / Selected

Soliman, Lancet Neurol 2025

Approach: Use oral agents for generalized spasticity (limited by fatigue/sedation, which caps usable dose) and botulinum toxin for focal spasticity; escalate to intrathecal baclofen or selective dorsal rhizotomy for severe refractory disease.

Place in Therapy — Quick Map

• First-line oral (generalized): baclofen, tizanidine, dantrolene
• Focal spasticity: botulinum toxin type A (targeted, avoids systemic AEs)
• Adjunct/selected: clonidine, benzodiazepines (diazepam, clonazepam), gabapentin
• Severe, refractory to oral agents: intrathecal baclofen (ITB); selective dorsal rhizotomy (selected ambulatory patients)

Oral Agents

Focal / Chemodenervation

Interventional (Severe / Refractory)