Differential Diagnoses

Tier 1: Most Likely Diagnoses

1. Progressive Muscular Atrophy (PMA) / "Flail Leg" Variant of ALS

2. Multifocal Motor Neuropathy (MMN) with Conduction Block

• Asymmetric and distal (often starts in one arm/hand but can affect legs)
• Slowly progressive over years
• Associated with anti-GM1 ganglioside antibodies (~50% of cases)
• Mimics ALS/PMA but responds to IVIg

3. Hereditary Motor Neuropathy (HMN) / Distal SMA ("Spinal CMT")

• Distal wasting and weakness in hands and feet
• Foot drop and intrinsic muscle wasting
• No sensory involvement on clinical or electrophysiological examination (distinguishing it from classic CMT)
• Chronic, slowly progressive course

Tier 2: Important Diagnoses to Exclude

4. Kennedy Disease (X-Linked Spinobulbar Muscular Atrophy)

• Mean onset is 30 years, but range is 15-60 years
• It is a pure LMN disorder without UMN signs
• Mild distal sensory loss is frequently present in legs but may be clinically silent
• Clues: gynecomastia, testicular atrophy, elevated CK, perioral fasciculations
• "The diagnosis should be considered in any male patient with a pure lower motor neuron disorder, particularly when the disease course is relatively indolent." - Goldman-Cecil Medicine, p. 1963
• It has a benign course and important genetic implications for the family

5. Adult-Onset SMA Type IV (SMN-Related)

6. Hirayama Disease (Juvenile Muscular Atrophy of the Distal Upper Extremity)

Tier 3: Rarer but Specific Considerations

Key Differentiating Points in This Case

Essential Investigations

1. NCS/EMG - Most critical: conduction block on motor NCS (MMN), denervation pattern, motor amplitudes, CV helps distinguish axonal vs demyelinating; sensory nerve action potentials should be normal in pure motor conditions
2. Anti-GM1 antibodies - for MMN
3. Genetic testing - androgen receptor CAG repeat (Kennedy), SMN1 copy number, PMP22 duplication, HMN gene panel
4. Hexosaminidase A/B assay - if other features suggest it
5. CK level - elevated in Kennedy, myopathies
6. MRI cervical spine - to exclude Hirayama, compressive myelopathy
7. Family history review - autosomal dominant HMN often has traceable pedigree

Differential Diagnosis - Revised by NCS Findings

Interpreting the NCS Pattern

The Classic Causes of Mononeuritis Multiplex (Axonal)

Tier 1: Top Diagnoses for This Specific Pattern

1. Vasculitic Neuropathy (Systemic or Non-Systemic)

• Pattern: Asymmetric, multifocal, axonal - exactly what is seen here
• Sensorimotor or mixed patterns depending on nerve affected
• Can be systemic (polyarteritis nodosa, ANCA-associated vasculitis, rheumatoid arthritis, SLE, cryoglobulinemia) or nonsystemic (isolated peripheral nerve vasculitis - most common form)
• "Vasculitic neuropathy... electrodiagnostic studies demonstrate a sensorimotor axonal neuropathy, often in a mononeuritis multiplex pattern" - Goldman-Cecil Medicine
• Nonsystemic vasculitic neuropathy has a peak onset at 40-70 years, fits the age perfectly
• Often painful (burning, aching), though the painless presentation here is atypical and should prompt consideration of a non-vasculitic cause, but not exclude it
• Sural nerve biopsy showing epineural vessel inflammation is diagnostic

2. Diabetic Mononeuropathy Multiplex (Diabetic Amyotrophy / Diabetic Radiculoplexus Neuropathy)

• Typically affects nerves susceptible to compression (ulnar at elbow, peroneal at fibular head), giving a bilateral but asymmetric pattern
• The motor-predominant clinical picture with subclinical sensory NCS changes is well recognized in diabetic neuropathy
• Can occur even without classical diabetic polyneuropathy
• Diabetes is one of the commonest causes of mononeuritis multiplex worldwide

3. Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

• PMP22 gene deletion on chromosome 17p11.2 (autosomal dominant)
• "Multiple recurrent local neuropathies... focal neuropathies and plexopathies are generally not painful... focal nerve lesions are often provoked by slight or even brief compression" - Adams and Victor's, p. 1340
• "In addition to recurrent focal nerve palsies, most individuals with HNPP have an underlying chronic but slowly progressive demyelinating sensorimotor neuropathy"
• However, NCS typically shows demyelinating features at compression sites (focal slowing, prolonged distal latencies) with an underlying mild sensorimotor neuropathy - axonal findings are less typical unless chronic
• The bilaterality and pattern of ulnar + median + peroneal exactly matches HNPP
• Nerve biopsy: tomaculous (sausage-shaped) myelin thickening
• Family history may be positive (autosomal dominant, but variable penetrance)

4. Leprosy (Hansen's Disease)

• "The muscle functions most affected in leprosy are... finger abduction (ulnar nerve), thumb opposition (median nerve)... and ankle extension (common peroneal nerve)" - Harrison's Principles, p. 2457
• Causes asymmetric, predominantly motor involvement of superficial nerves
• The borderline/lepromatous forms can present without obvious skin lesions, especially in endemic regions or in migrants
• Clinically silent sensory NCS abnormalities alongside motor weakness fits the pure neural form
• Thickened peripheral nerves are palpable (ulnar at elbow, peroneal at fibular head)

Tier 2: Important Additional Diagnoses

5. Multifocal Motor Neuropathy (MMN)

• However, it remains on the list because:
  • It causes asymmetric distal motor weakness in ulnar/median/peroneal distributions
  • Anti-GM1 antibodies (~50%), responds to IVIg
  • The sensory NCS changes may represent a coincidental entrapment (median at wrist, ulnar at elbow)
• "Multifocal motor neuropathy shares many diagnostic features with [ALS], including distal asymmetrical upper extremity weakness and atrophy... Key differentiating features include the time course (slowly progressive)..." - Goldman-Cecil Medicine, p. 2525

6. Sarcoid Neuropathy

• Systemic features (bilateral hilar lymphadenopathy, uveitis, skin lesions) may be absent in pure neurological sarcoidosis
• Cranial nerve involvement, especially facial nerve, is more common but limb mononeuropathy multiplex occurs
• Listed explicitly among causes of mononeuropathy multiplex - Adams and Victor's, p. 2479

7. Cryoglobulinemic Neuropathy

• Type II and III mixed cryoglobulinemia (often hepatitis C-associated) classically causes mononeuritis multiplex via immune complex-mediated vasculitis of vasa nervorum
• Pattern: asymmetric, axonal, sensorimotor
• Screen with serum cryoglobulins, HCV antibody

8. Multifocal Acquired Demyelinating Sensory and Motor Neuropathy (MADSAM / Lewis-Sumner Syndrome)

• A variant of CIDP with asymmetric, multifocal involvement of individual nerves
• Unlike MMN, affects both motor and sensory fibers
• Fits the bilateral asymmetric pattern here with both sensory and motor NCS abnormalities
• However, the pathology should be demyelinating on NCS (conduction block, temporal dispersion, slowed velocities); this patient shows axonal changes, making MADSAM less likely unless secondary axonal degeneration has supervened

Tier 3: Less Common but Relevant

Revised Hierarchy - Most to Least Likely

1. Vasculitic neuropathy (non-systemic or systemic) - axonal mononeuritis multiplex is vasculitis until proven otherwise
2. Diabetic mononeuropathy multiplex - extremely common, exact nerve pattern fits
3. HNPP - bilateral, multifocal at compression sites, ulnar + peroneal + median classic triad
4. Leprosy - if epidemiologically relevant; nerve pattern is pathognomonic
5. Cryoglobulinemic/HCV-associated neuropathy
6. MMN (with coincidental entrapment) or MADSAM
7. Sarcoidosis
8. CMT2 (axonal hereditary; needs genetic testing)

Refined Investigation Plan