Differential Diagnosis in Neurology

10.21. Differential Diagnosis of Neuropathy by Predominant Symptom, Hereditary or Feature

Sensory Neuropathy

• Autoimmune epitopes:
  • MAG
  • SGPG (small fiber)
  • Anti-HU (Small fiber)
  • Anti-sulfatide (small fiber)
  • Gdlb (Miller–Fisher variant)
  • GD3
  • Gal (B1-2) Gal Nac
  • GTDIA
  • GALOP
  • GQ1b
• Demyelinating sensory neuropathy:
  • MAG
  • SGPG
  • CM Fisher variant of GBS
  • CIDP (sensory variant)
• Inherited sensory neuropathy:
  • HSN I-V:
    • HSAN-I: AD (hereditary sensory autonomic neuropathy)
    • HSAN-II: AR: myelin > unmyelinated
    • HSAN-III: Riley–Day syndrome
    • HSAN-IV
    • HSANV
  • Bassen Kornsweig disease (beta hypolipoproteinemia)
  • Fabry's disease (α galactosidase)
  • SANDO (sensory ataxia/dysarthria/ophthalmoplegia)
  • Perault's syndrome (ovarian/VIIIth nerve)
  • Neuropathy with spinocerebellar degenerations:
    • SCA-5
    • Friedreich's ataxia (large fiber)

Toxic Metabolic Sensory Neuropathy

• Vitamin B6 excess (pyridoxine); burning neuropathy
• Methyl mercury
• Docetaxel/paxcetaxel (large and intermediate fibers)
• Vitamin E deficiency (a-toxophil transporter I deficit)
• Vitamin B12 deficiency (large fiber modalities; dorsal column)
• INH (decreased vitamin B6)
• Ciguatera poisoning (paradoxical channelopathy)
• Adriamycin (dorsal ganglionopathy)

Infectious Cause of Sensory Neuropathy

• HIV (distal painful sensory neuropathy)
• Tabes dorsalis (posterior column deficits, Hertig's spots on the trunk)
• Herpes zoster (dermatomal)
• Herpes simplex (regional)
• HTLV-I (primarily small fiber)

Sensory Neuropathy Associated with Systemic Disease

• Diabetes (burning feet syndrome)
• Uremia (small fiber)
• Paraneoplastic (sensory ataxia; small fiber)
• Sjögren's (posterior column deficit)
• Hypothyroidism (carpal tunnel; tarsal tunnel; Vth nerve; generalized peripheral neuropathy)
• Sensory perineuritis (primarily around the ankle)
• Ischemic neuropathy (painful; all modalities)
• Malabsorption syndromes (primarily B12; large fiber)

Ataxic Sensory Polyneuropathy (large fiber)

• Immune mediated:
  • Carcinomatous sensory neuropathy
  • Sensory ganglionitis neuropathy
  • Sjogren's
  • Miller Fisher variant
  • MAG
  • Sensory CIDP
  • Immunoglobulin associated paraproteinemia

Idiopathic Sensory Neuropathy

• Acute
• Chronic
• Monomelic sensory neuropathy

Demyelinating Sensory Neuropathy

• CM Fisher variant of GBS
• CIDP-sensory variant
• SGPG (epitope)
• MAG (epitope)

Predominantly Small-Fiber Sensory Neuropathy – Autoimmune Epitopes

• TTR-transthyretin met 30 (amyloidosis)
• Anti-HU
• Anti sulfatide

Inherited Small Fiber Sensory Neuropathy

• Fabry's disease
• Tangiers's disease
• Familial amyloid (FAP)
• Hereditary sensory neuropathies II; IV (HSAN I, III, IV, V)
• Hereditary thermosensitive neuropathy (AD)

Sensory Neuropathy Associated with Systemic Illness

• Amyloid (secondary)
• Diabetes
• Primary biliary cirrhosis
• Sjögren's syndrome
• Rheumatoid arthritis

Associated Infections and Sensory Neuropathy

• HIV
• Leprosy
• CMV

Sensory Neuropathy Associated with Drugs and Toxins

• Ciguatera toxin
• Metronidazole
• Misonidazole
• Kepone
• Vacor
• Erythromelalgia (vincristine)
• Ergotamine

Associated with Trauma

• Chronic regional pain syndrome (CRPSI/II/RSD)
• CRPS II (associated with nerve injury)
• Triple cold syndrome
• Anti-backfiring C nociceptor syndrome (ABC syndrome; transmodality sensitization)

Chronic Painful Neuropathies

• Diabetes
• Alcohol
• Pantothenic acid deficiency
• Pyridoxine B6 excess or deficiency
• CRPS I/II (RSD/causalgia)
• Amyloid (primary or secondary)
• Paraneoplastic (sensory neuropathy/ganglionitis)
• TTR-met 30 (amyloidosis)
• Anti-sulfatide epitopes
• Uremia
• Arsenic
• Fabry's disease
• Erythromelalgia
• ABC syndrome
• Triple cold syndrome
• Hypertriglyceridemia
• Niacin
• Thiamine

Motor Neuropathies

• Acute intermittent porphyria (AIP)
• Variegate porphyria
• Coproporphyrinuria
• Lead
• Vincristine
• Diphtheria
• Diabetes (amyotrophy); plexopathy
• Acute inflammatory demyelinating polyneuropathy (AIDP)
• Rabies
• Thallium
• Phenytoin
• HIV
• Insulinoma (recurrent hypoglycemia)
• Osteoclastic multiple myeloma
• GMI ganglioside antibody
• Multifocal motor neuropathy with conduction block (MMNCB)
• Dapsone
• Phenytoin
• MAG

Acute Ascending Motor Paralysis with Minimal Sensory Dysfunction

• AIDP:
  • Hepatitis B virus
  • EBV (Ebstein Barr Virus)
  • Mumps
  • HIV
  • Lymphoma (Hodgkin's or non-Hodgkin's)
  • Post vaccination (influenza, typhoid, hepatitis, rabies, small pox)
  • Surgery
  • Campylobacter jejuni
• Tick paralysis
• Lyme's disease
• Porphyria (AIP/variegate)
• Thallium
• Ethylene oxide
• Triorthocresyl phosphate
• Diphtheria

Neuropathies with Prominent Autonomic Features

• Diabetes (gastroparesis; sexual dysfunction)
• Amyloidosis:
  • Transthyretin-related FAP (familial amyloid polyneuropathy)
  • Apolipoprotein A-1-related FAP
  • Gelsolin-related FAP
• Paraneoplastic
• SICCA complex
• Acquired generalized anhidrosis
• Porphyria:
  • AIP
  • Variegate porphyria
  • Hereditary coporphyruria
• B12 deficiency
• Uremia
• AIDP (acute demyelinating inflammatory neuropathy)
• HSNI–IV (hereditary sensory neuropathy I–IV)
• Fabry's disease
• Pandysautonomia (paraneoplastic/acute infectious)
• EBV
• Shy–Drager syndrome
• Holmes–Aides syndrome
• Familial sensory autonomic neuropathy (Navaho Indian)
• Ross syndrome
• Harlequin syndrome
• Vacor intoxication
• Chronic relapsing autonomic neuropathy

Hypertrophic Neuropathies

• HSMN-I, (CMT 1A-D)
• CIDP
• Longstanding diabetes
• Hypothyroidism
• Mucopolysaccharidoses (Scheie's variant)
• Amyloidosis
• Multifocal hypertrophic neuropathy
• Leprosy
• HSMN-III (Dejerine–Sottas)
• HSMN-IV (Refsum's disease)
• Acromegaly (compression/entrapment)

Infectious Causes of Peripheral Neuropathy

• HIV
• Syphilis
• Lyme's disease
• C/MV
• EBV
• Brucellosis (L5 root)
• Campylobacter jejuni (AMAN)
• GBS (specific virus/nonspecific virus)
• Mumps
• Tick paralysis
• Herpes simplex
• Herpes zoster
• Whipple's disease
• Mycoplasma
• Sepsis syndrome
• Infective endocarditis
• Leprosy

Intermittent Neuropathies

• CIDP
• Vasculitis
• MAG
• SGPG
• Gal (B1-3) Gal Nac
• Asialo GM1
• Anti sulfatide
• Gd 1 B
• GQ 1 B
• Acute relapsing axonal GBS
• Acute intermittent porphyria
• Variegate porphyria
• Coproporphyrinuria
• Refsum's disease
• Fabry's disease
• Tangiers's disease
• Hereditary heat sensitive neuropathy
• Hereditary sensitivity to pressure (HNPP)
• Chronic relapsing autonomic neuropathy
• Hereditary neuralgic amyotrophy
• Hereditary sensory motor neuropathy (steroid sensitive)

Neuropathies from Traumatic/Physical Agents

• Overuse syndromes (tunnel entrapments particularly of the upper extremity)
• Brachial plexus fixation with secondary peripheral nerve tunnel syndromes
• Compartment syndromes (arm/leg)
• Perioperative neuropathies (compression during malplacement/anesthesia)
• Lithotomy position
• Diaphragmatic neuropathy (trauma); surgery (thoracic outlet; neck)
• Peripheral nerve (direct trauma)
• X-RT (ischemia of the vasovasorum)
• Bone marrow transplant (perineural/intraneural hemorrhage)
• Heat
• Cold (frost bite)
• Snake bite (compartment syndrome)
• Entrapment syndromes
• Double/triple crush syndromes (C5–C6 with concomitant CTS)

Large Fiber Neuropathy (12–22 μ)

• Vitamin B12
• Vitamin B6
• Vitamin E (acquired/genetic variants)
• Tabes dorsalis
• Diabetes
• Paraneoplastic (DRG form)
• HSMN I, III, IV
• Bassen–Kornsweig disease

Autoimmune Neuropathy with Specific Epitopes

• GM 1 (IgG/IgM) acute axonal (Campylobacter jejuni)
• GDIB – Miller Fisher variant
• GQIb – Miller Fisher variant
• SGPG (sensorimotor; small fiber)
• MAG (demyelinating)
• Anti sulfatide (IgM) with/without M protein
• Anti-Hu
• Anti-MA
• Anti-TA
• GALOP
• GM 1 (IgM) motor neuron/demyelinating
• Anti-TTR-30 (small fiber/painful)
• Asialo-GM 1 (demyelinating; sulfur containing epitopes; small fiber)
• Anti-chondroitin sulfate
• 301–314 B tubulin antigen

Inherited Neuropathies

• HSMN-I (CMT 1 A; CMT 1 B; CMT 1 C; CMT X)
• HSMN-II (CMT 2 A-L)
• HSMN-III (CMT3); Déjérine Sottas
• HSMN-IV (CMT4); Refsum's
• HSMN-V
• HSMN-VI (optic neuropathy with spastic paraparesis)
• Hereditary neuropathy with pressure palsy (deletion of chromosome 17); HNPP
• CMTX (1,2,3)
• AR-CMT with deafness
• Hereditary sensory autonomic neuropathy I (AD)
• HSAN-II (AR)
• HSAN-III: Riley–Day syndrome
• HSAN-IV
• HSAN-V
• Hereditary neurologic amyotrophy (HNA)
• Hereditary motor neuropathy (AR)
• CMT (optic atrophy/VIII nerve; AD; AR; X-linked)
• Mutilating neuropathy 3q 13q–q22
• HSMN – hand variant

Hereditary Causes of Demyelinating Neuropathy

• HSMN-I, III
• HNPP – familial liability to pressure palsy (deletion chromosome 17)
• Refsum's disease (HSMN – IV)
• Metachromatic leukoencephalopathy A, B, C
• Globoid cell (Krabbe's disease)
• Cockayne's Syndrome

Inherited Axonal Neuropathy

• HSMN-II (CMT-2A-2L)
• HSN-I–IV
• Axonal neuropathies with spinocerebellar degenerations
• Giant axonal neuropathy (GAN)
• Ataxia telangiectasia

Specific Inherited Neuropathies

• Refsum's disease
• Krabbe's disease
• Amyloid polyneuropathy of Andrade
• Abetalipoproteinemia (Bassen Kornsweig)
• Alpha lipoproteinemia (Tangiers's Disease)
• Metachromatic leukodystrophy
• Acute intermittent porphyria
• Variegate porphyria
• Coproporphyrinuria
• Adrenomyeloneuropathy
• Adrenoleukodystrophy
• SANDO
• Perrault (ovarian dysgenesis; VIII nerve)
• Tangiers's Disease (classic/late onset)
• Pelizaeus Merzbacher Disease
• Familial amyloid polyneuropathy (gelsolin apolipoprotein A-1)
• Vitamin E deficiency (a-tocopherol transporter defect)
• Multiple symmetric lipomatosis (Madelung's); mitochondrial DNA dysfunction
• Fabry's disease
• Palmoplantar keratoderma
• Polyneuropathy, dementia, dysautonomic
• AR hypomyelination neuropathy
• Familial sensorimotor neuropathy with callosal agenesis
• Hereditary neuropathy with excessive myelin folding
• Wolman's syndrome (variant of adrenomyeloneuropathy)
• Familial polyglucosan body neuropathy
• Carbohydrate deficiency syndrome
• Gerstmann Straüssler syndrome (codon 102)

Mitochondrial Neuropathies

• Leber's hereditary optic neuropathy
• NARP (neuropathy/ataxia/retinitis pigmentosa)
• Leigh's syndrome
• MNGIE (mitochondrial neurogastrointestinal encephalopathy)
• PEO (progressive external ophthalmoplegia)

Immune Mediated Neuropathy

• AIDP
• CIDP
• Neuropathy with specifically identified epitopes
• Vasculitis with specific syndromes
• Vasculitis without specific disease association
• Allergic peripheral neuropathies
• Monoclonal gammopathies of undetermined significance (MGUS); IgA, IgG, IgM
• Neuropathy following insect and bee sting
• Transplantation polyneuropathy (graft vs host)

Neuropathy with Specific Enzyme Defects

• Fabry's disease (alpha-galactosidase)
• Krabbe
• Shies's disease (heparitin sulfatase)
• Familial B12 deficiency (biopterin tetrahydrofolate dehydrogenase deficiency)
• Metachromatic leukodystrophy (A, B, C, sulfatase)
• Refsum's disease (phytanoyl hydrolase)
• Phenylketonuria (phenylalanine dehydrogenase)
• Cystinuria (cystathionine synthetase)
• Phenytoin (folate dehydrogenase)
• GM2 (Sandhoff's disease)
• Tryptophane pathway defects
• Polyglucan body disease
• Glycogen branching enzyme defect

Entrapment Syndromes

• Upper Extremity
  • Long neck sloping shoulder syndrome
  • Roos' congential bands (12 bands)
  • Cervical rib syndrome
  • Thoracic outlet syndrome
  • Rib-band syndrome (C8–T1)
  • Costo-clavicular syndrome
  • Secondary entrapment syndrome (primary plexus lesions)
• Brachial plexus entrapment:
  • Upper trunk
  • Medial cord
  • Lower trunk
  • Lateral cord
  • Posterior cord
• Cubital tunnel (ulnar)
• Arcade of Frohse (posterior interosseous, radial sensory)
• Ligament of Struthers (median)
• Pronator canal (median)
• Guyon's canal (ulnar)
• Medial antibrachial cutaneous nerve
• Dorsal scapular nerve
• Suprascapular nerve (suprascapular notch)
• Musculocutaneous nerve
• Intercosticobrachial nerve (from medial cord)
• Radial nerve (radial grooves of the humerus)
• Anterior/posterior interosseous nerve
• Recurrent nerve of Kunz (T1–T4 sympathetics)
• Lumbosacral syndrome (L5)
• Ilioinguinal nerve
• Genitofemoral nerve
• Sciatic nerve (sciatic notch compression)
• Pyriformis syndrome
• Posterior popliteal fossa syndrome
• Peroneal (common; superficial; deep)
• Intercostal nerve
• Rectus abdominis syndrome
• Sural nerve
• Obturator nerve (canal compression)
• Femoral nerve (under inguinal ligament)
• Lateral femoral cutaneous nerve
• Anterior femoral cutaneous nerve
• Intermediate femoral cutaneous nerve
• Recurrent nerve of Gonyea (branch of tibial nerve)
• Recurrent nerve of Spurling (L5 dura); radiate to anterior thigh)
• Medial plantar nerve (tarsal tunnel)
• Calcaneal branch of plantar nerve (posterior tibial)
• Gluteal nerve
• Iliohypogastric nerve
• Saphenous nerve
• Posterior tibial
• Anterior tarsal tunnel syndrome
• Digital nerves
• Metatarsal tunnels (digital nerves)
• Lumbrical canal (digital nerves)

Mononeuropathy Multiplex

Axonal

• Vasculitis
• Vasculopathy
• Rheumatoid arthritis
• Connective tissue diseases
• Systemic necrotizing vasculitides
• Polyarteritis nodosa
• Allergic granulomatous angiitis (Churg–Strauss)
• Hypersensitivity angiitis
• Wegener's granulomatosis
• "Overlap syndromes"
• Nonsystemic vasculitis (isolated vasculitic neuropathy)
• Mixed cryoglobulinemia
• Diabetes
• Amphetamine abuse
• Sarcoidosis
• Leprosy
• Cytomegalovirus (AIDS)
• Neurofibromatosis

Mononeuropathy or Multiple Mononeuropathy

• Pressure palsy
• Entrapments
• Traumatic
• Electrical injury
• X-RT
• Immunization
• Herpes zoster
• Carcinomatous infiltration
• Lymphoma
• Diphtheritic wound infection with neuropathy (local toxin production)
• Diabetes
• Collagen vascular disease
• Monomelic sensory neuropathy

Bilateral Carpal/Tarsal Tunnel Syndromes

• Occupational
• Rheumatoid arthritis
• Double crush syndrome (CTS and brachial plexus traction injury)
• Scleroderma
• Hypothyroidism
• Mucopolysaccharidoses
• Acromegaly
• Ganglion cysts
• Diabetes mellitus

Neuropathies Involving the Diaphragm

• Thiamine deficiency
• Pyridoxine deficiency
• Trauma (cervical fractures)
• Following brachial plexus decompression (injured with medial scalenectomy surgery)
• Chiropractic manipulation
• Hypophosphatemia
• Critical illness neuropathy
• Hereditary sensory neuropathy II (CMT-2C)
• CMT-1 (4C)
• AIDP
• CIDP
• Acute intermittent porphyria
• Remote effect of cancer
• Viral (acute)
• Hereditary (brachial plexopathies)
• Neuralgia amyotrophica

Peripheral Nervous System Disorders with Anhidrosis

• Pure autonomic failure
• Diabetes
• Amyloidosis
• Fabry's disease
• Acute autonomic neuropathy (autoimmune/viral)
• Acute intermittent porphyria
• AIDP
• Hereditary sensory neuropathy (I–IV)
• Tangiers's disease
• Sjögren's disease
• Ross's syndrome
• Holmes–Adie syndrome

Dermatologic Causes of Anhidrosis

• Local injury:
  • Thermal
  • X-RT
  • Scarring
  • Inflammatory
• Anhidrotic ectodermal dysplasia
• Psoriasis
• Exfoliative dermatitis
• Lichen sclerosis atrophicus
• Ichthyosis
• Miliaries
• Incontinent; pigmenti
• Dermatomally distributed vitiligo

Neuropathy of Connective Tissue Disease

• SLE
• Rheumatoid arthritis
• Scleroderma
• Mixed connective tissue disease (MCTD)
• SICCA-complex
• Relapsing polychondritis

Neuropathy with Systemic Necrotizing Vasculitis (small and medium sized arteries)

• Polyarteritis nodosa (PAN)
• Allergic angiitis granulomatosis (Churg–Strauss syndrome)
• Wegener's granulomatosis
• Vasculitis of connective tissue disease
• Polyangiitis overlap syndrome

Neuropathy with Hypersensitivity Vasculitis (small vessels; capillaries, arterioles and venules)

• Henoch–Schönlein Purpura
• Vasculitis with infectious disease
• In association with drug reactions
• Connective tissue disease
• Neoplasm

Neuropathy with Localized Vasculitis

• Isolated peripheral nerve vasculitis; probably localized form of PAN

Neuropathy with Vasculitis and Malignancy (malignancy and hypersensitivity vasculitis)

• More common in myelo and lymphoproliferative diseases
• Rare in association with solid tumors
• Prominent in hairy cell leukemia
• Chediak-Higashi disease

Unusual Vasculitis of Peripheral Nerves in Association with:

• Cryoglobulinemia
• Sjögren's disease
• Relapsing polychondritis
• Reiter's disease
• Hypereosinophilia syndrome

Acute Neuropathy (evolving over hours to days)

• AIDP
• Diphtheria
• Paraneoplastic
• Chronic lymphocytic leukemia
• Uremia
• Porphyrias
• Lead poisoning
• Thallium ingestion
• Pandysautonomia (viral)
• Polio
• Adriamycin
• Vasculitides
• Viral hepatitis
• Sarcoid
• Macroglobulinemia
• Carcinoma
• Lymphoma
• AMAN

Subacute Neuropathy (evolving over weeks to months)

• Diabetes
• Uremia
• B1
• B12
• Toxins
• Sarcoid
• Paraneoplastic
• Vasculitides
• CIDP
• MAG
• SGPG
• Anti sulfatide
• GTID
• GT 3
• TTP-met-30
• GdIb
• GQIb
• Asialo-GM 1
• GTIA

Differential Diagnosis of CIDP

• Osteoclastic myeloma
• Plasma cell dyscrasia
• HIV
• SLE
• Malignant melanoma
• Monoclonal gammopathy
• Hepatitis
• Inflammatory bowel disease

Differential Diagnosis of Dorsal Root Ganglion (primary pathology)

• Herpes zoster
• Syphilis
• Paraneoplastic (sensory variant)
• GD 1b
• Sjögren's
• Anti sulfatide epitopes
• SICCA complex

Axonal Restless Leg Syndrome

• Diabetes
• Chronic obstructive lung disease
• Primary amyloid
• Anemia
• Cancer
• Iron deficiency

Neuropathy Primarily of the Upper Extremity

• GM 1
• Lead
• Amyloid
• Porphyrias
• Multiple myeloma
• Hypoglycemia (insulinoma)
• Hypothyroidism

Neuropathy Associated with Lymphoma/Leukemia/Blood Dyscrasia

• Polycythemia vera
• Chronic lymphocytic leukemia
• Direct lymphomatous involvement of the nerves
• Bone marrow transplant (intra perineural hemorrhage)
• Acute leukemia (bleeding into nerves)
• Following X-RT (sarcoma; ischemia of the nervi vasorum)
• Chediak-Higashi
• Hypereosinophilic syndromes (idiopathic; tryptophan impurity induced)
• Paraprotein associated
• Waldenström's macroglobulinemia