What are the causes of asymmetric sensory motor distal demyelinating neuropathy?

Asymmetric Sensory Motor Distal Demyelinating Neuropathy: Causes

Asymmetric sensory motor distal demyelinating neuropathy is most commonly caused by specific variants of chronic inflammatory demyelinating polyneuropathy (CIDP), particularly MADSAM (Multifocal Acquired Demyelinating Sensory And Motor) neuropathy, or by chemotherapy-induced peripheral neuropathy from agents like platinum compounds, vinca alkaloids, and taxanes that can present asymmetrically when affecting dorsal root ganglia. 1, 2, 3

Primary Inflammatory/Immune-Mediated Causes

MADSAM Neuropathy (Lewis-Sumner Syndrome)

• MADSAM is the prototypical cause of asymmetric sensory and motor demyelinating neuropathy, characterized by multifocal distribution affecting individual peripheral nerves with both motor weakness and sensory deficits 2, 3
• Presents with conduction block and demyelinating features on nerve conduction studies in an asymmetric pattern 2
• Distinguished from classic CIDP by its asymmetric multifocal pattern rather than symmetric proximal and distal involvement 2, 3

Distal Acquired Demyelinating Symmetric (DADS) Neuropathy

• While typically symmetric, DADS can occasionally present with asymmetric features, particularly when associated with anti-GM1 antibodies 4, 3
• Characterized by distal motor and sensory disturbances with markedly prolonged distal motor latencies 4, 5
• May be associated with IgM monoclonal gammopathy (with or without anti-MAG antibodies) 4, 3

Monoclonal Gammopathy-Associated Neuropathy

• IgM monoclonal gammopathies can cause demyelinating neuropathy with asymmetric features, particularly when associated with anti-MAG or anti-GM1 antibodies 1, 4
• Found in approximately 10% of patients with polyneuropathy of unknown etiology at referral centers 1
• Can be associated with Waldenström's macroglobulinemia, which commonly presents with slowly progressing demyelinating sensory peripheral neuropathy 1

Chemotherapy-Induced Causes

Platinum Compounds, Vinca Alkaloids, and Taxanes

• These agents can cause asymmetric sensory neuronopathy (ganglionopathy) by preferentially damaging dorsal root ganglion cell bodies, which lack blood-brain barrier protection 1
• The clinical picture may be asymmetrical and predominantly involves proprioception but can include motor system involvement 1
• Platinum compounds (oxaliplatin, cisplatin), vinca alkaloids (vincristine), taxanes (paclitaxel), and thalidomide are the primary culprits 1

Vasculitic and Autoimmune Causes

Vasculitic Neuropathy (Mononeuritis Multiplex)

• Presents with asymmetric sensory and motor deficits affecting multiple individual nerves, with pain as a prominent feature 6
• Can evolve into a more diffuse polyneuropathy pattern over time 6
• Associated with autoimmune rheumatologic conditions 1

Metabolic and Toxic Causes

Diabetes Mellitus and Pre-Diabetes

• While typically symmetric, diabetic neuropathy can occasionally present asymmetrically, particularly in the context of diabetic radiculoplexus neuropathy 1
• Impaired glucose tolerance documented in 25-36% of patients with idiopathic polyneuropathy 1

Vitamin B12 Deficiency

• Can cause demyelinating neuropathy, though typically symmetric; asymmetric presentations may occur 1
• Serum B12 with metabolites (methylmalonic acid and homocysteine) should be checked, as 44% of B12-deficient neuropathy patients have normal B12 levels but abnormal metabolites 1

Hereditary Causes

Charcot-Marie-Tooth Disease (CMT)

• CMT1A (PMP22 duplication) accounts for 70% of demyelinating CMT and can occasionally present with asymmetric features 1
• CMTX (Cx32/GJB1 mutations) accounts for 12% of CMT cases and may present with either demyelinating or axonal phenotype 1
• Should be ruled out in cases with severe motor involvement, particularly with characteristic deformities (hollow foot, stork legs) 1

Diagnostic Approach Algorithm

Step 1: Confirm demyelinating pattern

• Nerve conduction studies showing prolonged distal motor latencies, slowed conduction velocities, conduction block, or temporal dispersion 2, 3

Step 2: Document asymmetry

• Clinical examination showing multifocal nerve involvement or asymmetric distribution of weakness and sensory loss 6, 2

Step 3: Screen for treatable causes

• Blood glucose and hemoglobin A1c for diabetes/pre-diabetes 1
• Serum B12 with methylmalonic acid and homocysteine 1
• Serum protein immunofixation electrophoresis (more sensitive than SPEP) for monoclonal gammopathy 1
• Anti-MAG antibodies if IgM paraprotein present 1, 4
• Anti-GM1 antibodies if motor neuropathy predominates 1, 4

Step 4: Evaluate for inflammatory/immune causes

• CSF protein (typically elevated in CIDP variants) 5
• Consider nerve biopsy if vasculitis suspected, showing segmental demyelination, remyelination, and possible lymphocytic infiltration 5

Step 5: Medication/toxin history

• Detailed chemotherapy exposure history (platinum, vinca alkaloids, taxanes, thalidomide, bortezomib) 1
• Alcohol abuse, other neurotoxic agents 1

Step 6: Genetic testing if indicated

• Consider CMT1A duplication testing if family history present or phenotype suggests hereditary neuropathy 1
• Test for Cx32(GJB1) mutations if X-linked inheritance pattern or uninformative pedigree 1

Critical Clinical Pitfalls

• Do not assume all distal neuropathies are symmetric—asymmetric presentations require different diagnostic and therapeutic approaches than typical length-dependent polyneuropathy 6, 3
• Do not miss chemotherapy-induced ganglionopathy—this can present asymmetrically and may worsen after treatment cessation (coasting phenomenon) 1
• Do not rely on serum protein electrophoresis alone—immunofixation electrophoresis detects 30% more IgM monoclonal gammopathies under 5g/L 1
• Do not overlook treatable CIDP variants—MADSAM and some DADS cases respond to intravenous immunoglobulin, unlike typical DADS with anti-MAG antibodies 2, 4, 5
• Do not forget to check B12 metabolites—44% of B12-deficient neuropathy patients have normal serum B12 levels 1