How do you differentiate between Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Amyotrophic Lateral Sclerosis (ALS), and Guillain-Barré Syndrome (GBS)?

Differentiating CIDP, ALS, and GBS

Key Distinguishing Feature: Pattern and Timing of Weakness Progression

The most critical distinguishing feature is the temporal pattern of disease progression: GBS progresses rapidly over days to 4 weeks with areflexia, CIDP progresses over at least 8 weeks (often months) with areflexia, while ALS progresses over months to years with hyperreflexia and upper motor neuron signs. 1

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Clinical Algorithm for Differentiation

Step 1: Assess Reflexes (Most Important Initial Distinction)

Areflexia or hyporeflexia:

• Points toward GBS or CIDP 1, 2
• Rules out ALS as the primary diagnosis

Hyperreflexia with pathologic reflexes (Babinski sign, clonus):

• Strongly suggests ALS 1
• These features cast doubt on GBS diagnosis 1

Step 2: Determine Progression Timeline

Rapid progression (days to <4 weeks to nadir):

• GBS is the diagnosis 1
• Typically reaches maximum disability within 2 weeks 1, 3
• Monophasic course with subsequent plateau or improvement 1

Progression >8 weeks from onset:

• Consider CIDP (either primary or acute-onset CIDP) 1, 4
• If patient deteriorates after 8 weeks from initial onset, diagnose as acute-onset CIDP 4, 5
• If deterioration occurs ≥3 times, strongly suggests CIDP rather than GBS with treatment-related fluctuations 4, 5

Slow, relentless progression over months to years:

• ALS is most likely
• Progressive weakness without sensory symptoms
• Combination of upper and lower motor neuron signs

Step 3: Evaluate Sensory Involvement

Prominent sensory symptoms/signs:

• Supports GBS or CIDP 1, 3
• Distal paresthesias common in both 3

Absent or minimal sensory involvement:

• Does not exclude GBS (pure motor variant exists) 1
• ALS characteristically lacks sensory symptoms
• Severe sensory signs with limited weakness at onset casts doubt on GBS 1

Step 4: Check for Upper Motor Neuron Signs

Presence of:

• Spasticity
• Hyperreflexia
• Extensor plantar responses (Babinski sign)
• Clonus

These features:

• Are pathognomonic for ALS (combined with lower motor neuron signs)
• Cast strong doubt on GBS diagnosis 1
• Rule out CIDP

Step 5: Assess Autonomic Dysfunction

Dysautonomia (blood pressure/heart rate instability, pupillary dysfunction):

• Common in GBS 1, 3
• Less common in acute-onset CIDP 6
• Rare in ALS (late finding if present)

Step 6: Evaluate Respiratory and Bulbar Involvement

Rapid respiratory failure:

• Occurs in ~20% of GBS patients 2, 7
• Less common in acute-onset CIDP (A-CIDP patients less likely to need mechanical ventilation) 6, 4
• Late finding in ALS

Facial weakness:

• Common in GBS (bilateral facial palsy characteristic) 1
• Less common in A-CIDP 6
• Can occur in ALS but with upper motor neuron features

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Diagnostic Testing to Confirm

Cerebrospinal Fluid Analysis

Albumino-cytological dissociation (elevated protein, normal cell count):

• Supports GBS or CIDP 1, 2, 3
• Normal protein does not rule out GBS, especially early 1, 3

Elevated cell count (>50 × 10⁶/l):

• Casts doubt on GBS diagnosis 1
• Consider alternative diagnoses (infection, malignancy)

Normal CSF:

• Does not exclude GBS
• Typical for ALS

Electrodiagnostic Studies

Demyelinating features (prolonged distal latencies, conduction block, slow conduction velocities):

• Confirms GBS (AIDP subtype) or CIDP 7
• May not appear until 10-14 days after symptom onset 7
• Follow-up studies at 3-8 weeks may help distinguish GBS from CIDP 1

Axonal features (reduced amplitudes, normal conduction velocities):

• Suggests GBS (AMAN/AMSAN subtypes) 1
• Can occur in CIDP

Chronic denervation with reinnervation:

• Supports CIDP over GBS
• Characteristic of ALS (with fibrillations and fasciculations)

Normal studies early:

• Do not exclude GBS 1, 7
• Repeat in 1-2 weeks if clinical suspicion high

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Critical Timing Distinctions for GBS vs CIDP

Treatment-Related Fluctuations (TRF) vs Acute-Onset CIDP

GBS with TRF:

• First fluctuation always occurs within 8 weeks (median 18 days) 4
• Maximum of 2 fluctuations (31% have second TRF, none have more) 4
• Patients more severely affected, often need ventilation 4
• Cranial nerve dysfunction common 4

Acute-Onset CIDP:

• Deterioration after 8 weeks from onset = CIDP 1, 4, 5
• Three or more deteriorations = CIDP 1, 4, 5
• Patients less severely affected, remain ambulatory 4
• Rarely need artificial ventilation 4
• Less cranial nerve dysfunction 4
• More CIDP-like electrophysiologic abnormalities 4

Clinical implication: If patient deteriorates after 9 weeks or has ≥3 deteriorations, diagnose CIDP and initiate maintenance immunotherapy 4, 5

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Common Pitfalls to Avoid

Pitfall 1: Assuming normal reflexes rule out GBS

• Pure motor variant and AMAN subtype can have normal or even exaggerated reflexes 1
• However, hyperreflexia with Babinski sign rules out GBS 1

Pitfall 2: Diagnosing GBS too quickly in slowly progressive cases

• Progression >4 weeks should raise suspicion for CIDP or alternative diagnosis 1
• Continued progression >4 weeks casts doubt on GBS 1

Pitfall 3: Missing acute-onset CIDP

• ~5% of apparent GBS cases are actually acute-onset CIDP 1
• Monitor for deteriorations beyond 8 weeks 4, 5

Pitfall 4: Overlooking sensory involvement in ALS

• ALS should not have sensory symptoms or signs
• If sensory findings present, reconsider diagnosis

Pitfall 5: Waiting for CSF or EMG before treating suspected GBS

• GBS is a clinical diagnosis 2
• Normal early studies do not exclude GBS 1, 7
• Treatment should not be delayed for confirmatory testing in rapidly progressive cases