Differential Diagnosis in Neurology

10.15. Neuropathies Associated with Tumors

• General features:
  • Metastasis
  • Primary tumors of nerve
  • X-RT associated
  • Effects of chemotherapy
  • Rarely paraneoplastic
  • Dysproteinemic neuropathy:
    • M-proteins
    • Anti MAG antibody associated
  • Immune mediated

Pure Sensory Neuropathy

• General features:
  • Rare; dorsal root ganglionitis
  • Most frequently seen with small cell cancer of the lung (anti-Hu), GI tract, breast and ovarian cancer (anti-Yo antibody) malignancy by may precede the neuropathy three years
  • Sensory symptoms; may precede systemic signs and symptoms of the malignancy
  • Incidence is greater in females than males
• Clinical presentation:
  • Subacute; progression over weeks to months
  • Rarely an explosive onset
  • Initially may involve the face, legs and upper extremities
  • Pain may be severe; burning may be the initial symptom
  • Proprioceptive deficits are the predominant symptom; autonomic involvement occurs
  • A progressive process that rarely stabilizes; rarely improves with tumor removal
  • 50% of patients demonstrate associated dementia, cerebellar ataxia (Purkinje cell) or myelopathy
  • Minimal muscle weakness; depressed reflexes
  • Sensory ataxia; pseudoathetosis
• EMG:
  • Decreased sensory nerve conduction velocity
• Laboratory:
  • Antinuclear-1 antibodies (anti-Hu); anti Yo antibodies (ovarian cancer; often associated with cerebellar involvement)
  • CSF: elevated protein; <30 lymphocytes or neutrophils/mm³
• Pathology:
  • Mononuclear cell inflammation of the dorsal root ganglion

Sensorimotor Neuropathy

• General features:
  • More common than a pure sensory type of neuropathy
  • All solid tumors reported as the primary malignancy
• Clinical presentation:
  • Subacute or chronic presentation
  • Rarely acute presentation
  • Mixed motor and sensory neuropathy; occasional Vth nerve trigeminal involvement
  • Neuropathy may precede the onset of the diagnosis of malignancy
  • Lower limbs affected > upper limbs
  • Relapsing remitting neuropathy of demyelinating type associated (with testicular seminoma (anti Ta antibody))
• EMG:
  • Sensory action potentials are absent in sensory neuropathy
  • Motor NCVs are normal or minimally decreased
  • Sensorimotor neuropathy demonstrates increased terminal motor latencies
  • Mildly decreases or normal motor NCVs
  • Relapsing form demonstrate slowed motor NCVs
• Laboratory:
  • CSF protein is mildly increased
• Pathology:
  • DRG, peripheral sensory fibers and posterior column degeneration
  • Axonal degeneration with loss of myelinated fibers

Motor Neuropathy or Motor Neurons Disease Syndrome with Cancer

• General features:
  • Associated with lymphoma, breast cancer, thymoma, Hodgkin's and non-Hodgkin's' lymphoma
  • Breast cancer:
    • Predominately an upper motor neuron syndrome
    • Syndrome initially resembles primary lateral sclerosis
    • Symptoms of upper motor neuron disease occur within three months of the diagnosis of cancer or its recurrence
    • Negative serum antineuronal antibodies
    • Patient has been described with pure lower motor neuron syndrome with involvement of the brainstem and cervical cord; antibodies reacted with the axonal initial segment and nodes of Ranvier
  • Lymphoma:
    • Rare
    • Sometimes associated with IgM anti GM1 antibodies
    • Increased CSF protein
    • Clinical presentation:
      • Variable extremity weakness; upper motor neuron signs are frequent
      • Subacute course; may has a primary spinal muscle atrophy profile
      • Course may be independent of the activity of the lymphoma
      • May improve spontaneously
• Pathology:
  • Neuronal degeneration of anterior horn cells
  • Mild demyelinations of the posterior columns
• Differential diagnosis of cancers that may produce motor neuron disease:
  • Waldenström's macroglobulinemia
  • Follicular cell lymphoma
  • Hodgkin's' disease
  • Multiple myeloma
  • Chronic lymphocytic leukemia
  • POEMS associated with angiofollicular lymphoma

Neuropathy Secondary to Dysproteinemia (50% associated with bone marrow malignancy)

• General features:
  • Prevalence:
    • 50% are associated with bone marrow malignancy
    • 5–10% of patients have polyneuropathy; major proportion of which are monoclonal gammopathies of unknown significances (MGUS)
    • MGUS:
      • 50% are IgM gammopathies:
        • Half have Ab against MAG
        • Anti-MAG neuropathy possibly 1–5/100,000 persons
      • remainder are IgG or IgA gammopathies
      • Monoclonal protein:
        • Composition:
          • M, G, or A heavy chain
          • Kappa or Lambda light chain
          • Rarely only a light or heavy chain
      • Polyclonal gammopathy:
        • Composition:
          • Contain both light and heavy chains
          • Often more than one heavy chain
      • M Protein:
        • Found by SPEP analysis (serum protein cellulose acetate electrophoresis):
          • Further analysis accomplished with immunoelectrophoresis (IEP) or immunofixation IFE
          • IFE and IEP are more sensitive than SPEP for small proteins:
            • Characterize the single heavy or light chain
            • IFE greater than IEP in sensitivity
      • Monoclonal light chain:
        • May be seen in urine when serum is negative (Bence Jones proteins)
        • Associated with plasma cell dyscrasia or light chain amyloidosis
      • Plasma cell dyscrasia
        • A proliferation of a single clone of plasma cells
        • Neoplastic or non-neoplastic
          • Associated with monoclonal serum or urine protein

Monoclonal Gammopathies of Undetermined Significance (MGUS)

• General features:
  • Largest proportion of polyneuropathies with plasma cell dyscrasia
  • IgM and non-IgM associated
  • IgM associated with or without anti-nerve activity

Immunoglobulin M Monoclonal Gammopathy Associated Neuropathy

• General features:
  • Ab directed against myelin associated glycoprotein
  • Located in the myelin sheath of PNS and CNS
• Clinical presentation:
  • Insidious onset over months to years
  • Sensory gait ataxia; vibration and position loss
  • Progressive ascending numbness
  • Not painful
  • Minimally autonomic involvement
  • Enlarged nerves (occasionally)
  • Minimal weakness
• EMG:
  • Absent or decreased SNAPs
  • Slowing of motor NCVs
  • Prolonged distal latencies; conduction block; dispersion of CMAPs
• CSF:
  • Increased protein greater than 100 mg/dl
• Pathology: (sural nerve biopsy)
  • M protein deposited on myelin sheath
  • Axonal and demyelinative features
  • EM:
    • Splitting and widening of the outer myelin lamellae
  • Antibodies against glycosphingolipid epitopes in myelin

Myelin-Associated Glycoprotein-non-Reactive Immunoglobulin M Neuropathy

• General features:
  • Diverse IgM react with different antigens
  • Less clearly related to neuropathy
• Clinical presentation:
  • Features of an axonal neuropathy
  • Other demyelinating clinical presentations:
    • Similar to anti MAG polyneuropathy
    • No myelin lamellae splitting
    • Negative immunofluorescent studies

Immunoglobulin G and A monoclonal Gammopathy Associated Polyneuropathy

• General features:
  • Chronic and mild axonal neuropathy patterns
  • Respond poorly to therapy if axonal; those patients with demyelinating features respond to immunosuppressive treatment
• Clinical presentation:
  • Less sensory loss than IgM neuropathy
  • Less demyelinative features by EMG
  • Differential points:
    • Rule out amyloidosis if there is pain
    • Prominent autonomic dysfunction
    • Rapid progression in an axonal pattern

Primary Systemic Amyloidosis

• General features:
  • Approximately 25% of primary systemic amyloidosis have M proteins; 15% of these patients develop peripheral neuropathy
  • Occurs in the 6–8th decade in men > women:
    • Rare underlying illness except for Waldenström's; macroglobulinemia and multiple myeloma
    • Presents as a multisystem illness due to deposition of fragments of the variable portion of light chains in tissue (lambda)
• Clinical presentation:
  • Presents as a medical illness with a polyneuropathy in 60%
  • Generally a dying back pattern of painful sensory neuropathy; sparing of proprioception initially
  • Similar presentation occurs with TTR met 30 (prealbumin) and inherited small fiber neuropathy
    • Polyneuropathy does not occur secondary to chronic inflammatory conditions or familial CNS amyloidosis
  • Dissociated sensory loss small fiber modality > large fibers; numbness of distal extremities; pain is lancinating
  • Orthostatic hypotension
  • Nocturnal diarrhea; chronic wasting
  • Concomitant involvement of heart, kidney, gut wall
  • Carpal tunnel presentation in 20% of patients
  • Rarely autonomic dysregulation overshadows sensory loss
  • Rare predominant motor presentation with severe wasting
  • Infiltrative proximal myopathy
  • Autonomic presentations:
    • Light near dissociation (better response to accommodation than light)
    • Orthostatic hypotension (coat hanger headache)
    • Bowel, bladder, sexual dysfunction, xerostomia and decreased sweating
    • Progressive; rarely stabilizes
• EMG evaluation:
  • Distal axonopathy legs greater than arms; decreased motor NCVs (<60% of normal) rare; low CMAPs and absent SNAP
  • Distal denervation with reinnervation
  • Super imposed CTS
• Laboratory evaluation:
  • CSF slight elevation of protein 50–70 mg/dl; no cells
  • 80–90% of patients have monoclonal protein (heavy or light chain in serum or urine by IFE or IME.
• Pathology (sural nerve biopsy):
  • Amyloid demonstrated in majority of patients:
    • Congo red or cresyl violet strands
    • Deposits in the epineurium or endoneurium
    • Apple green birefringence of congo stained amyloid under polarized light
  • Axonal involvement (degree of involvement often does not correlate with amount of amyloid deposition)
  • Rectal biopsy for amyloid positive in 70%; sural nerve >90% positive for amyloid

Multiple Myeloma Neuropathy

• General features:
  • Incidence of 0.1/100,000 per year; most common with osteosclerotic myeloma
  • High serum and urinary monoclonal proteins IgM > IgG > IgA
  • Destruction of the bone marrow by malignant plasma cells
  • Bony plasma cytomas
• Clinical presentation:
  • Peripheral neuropathy in 30% of patients; more commonly nerve root infiltration or spinal cord involvement: may herald the onset of myeloma
  • Sensorimotor neuropathy is mild; slowly progressive (axonal); tends to parallel status of the patient
  • Primary sensory neuropathy; proprioceptive loss; minimal motor loss; subacute presentation with subsequent stabilization
  • Demyelinating primarily motor neuropathy; course independent of the disease; may be remitting (CIDP pattern)
  • Amyloid neuropathy from light chain deposition
• EMG:
  • Axonal variant with minimal decrease of NCVs
  • Relapsing form slower NCV
  • Primary sensory of conduction velocity
  • Neuropathy minimal EMG changes

Osteosclerotic Myeloma with Peripheral Neuropathy

• General features:
  • Found in 3% of MM patients
  • 50% develop polyneuropathy
  • No systemic manifestations
  • Rare involvement of bone marrow, no anemia, hypercalcemia or renal failure
  • Low serum M protein
  • Long course
  • Japanese > Occidental > African patients
• Clinical presentation:
  • Primarily motor; distal to proximal
  • Slowly progressive course; symmetric with proximal spread
  • Sensory loss large fiber > small fiber
  • Pain and autonomic dysfunction is rare
  • Enlarged nerves
  • Younger patients; less illness
• EMG:
  • Mixed axonal and demyelinating features
  • Slowing of NCV in CIDP form
• Laboratory:
  • M protein in the serum in 75–80% of patients often need IFE and IFP to detect:
    • M protein is IgG or IgA; Lambda > Kappa light chain; not in the urine (amyloid and MM) M protein is in the urine)
    • CSF-high protein > 100 mg/dl
• Pathology (sural nerve biopsy):
  • Mixed demyelination and axonal degeneration
  • Decreased myelinated fibers
  • Mononuclear infiltrate of the epineurium surrounding blood vessels
  • Osteosclerotic lesions:
    • Axial skeleton and proximal long bones; spine distal long bones and skull
    • Sclerotic or mixed sclerotic and lytic
    • Small number have only one lesion ("soup, bubble" with a sclerotic rim)
    • Radionuclide bone scan positive prior to bone destruction

POEMS Syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M Protein, Skin Changes)

• General features:
  • Organomegaly (liver, spleen, lymph nodes) hyperplastic changes resemble angiofollicular lymph node hyperplasia (Castleman's syndrome)
  • Patients with Castleman's Syndrome
    • May have clinical features of Crow–Fukase Syndrome without bone lesions, but with serum M proteins or polyclonal gammopathies
  • Endocrinopathy (hypothyroidism, hyperglycemia, hypogonadism with low testosterone levels, gynecomastia); hyperestrogenemia
  • Hyperpigmentation, hypertrichosis
  • Digital cribbing; white nails
  • Bilateral papilledema
  • Polycythemia, leukocytosis, thrombocythemia
• Clinical presentation:
  • Similar to OSM (osteosclerotic multiple myeloma)
• Pathology:
  • Endoneural deposits of immunoglobulin; axonal loss with demyelinative features
  • Over production of vascular endothelial growth factor or vascular permeability factor; microangiopathy, neovascularization; accelerated vasopermeability (VEFG 165 isoform of Crow–Fukase Syndrome)

Neuropathies Associated with IgM Monoclonal Gammopathies

• Associated diseases:
  • Waldenström's macroglobulinemia
  • Chronic lymphocytic leukemia or lymphoma
  • IgM monoclonal gammopathy of unknown significance (MGUS)
• Associated IgM antibodies to MAG, GM1 sulfatides, GD1a or GD1b
• Abnormal bone marrow or lymph node biopsy may be concomitant

Waldenström's Macroglobulinemia

• General features:
  • Plasma cell dyscrasia of B lymphocytes that make IgM globulins
  • Large quantity of M type IgM globulins in the serum
  • Anemia and bleeding manifestations; petechiae below the knees
  • Lymphadenopathy, splenomegaly and hepatomegaly evolve
• Features of IgM globulins that cause neurologic symptoms:
  • Cryoglobulins:
    • Raynaud's; cold urticaria, vascular occlusion with gangrene after exposure to cold
    • Viscosity related manifestations:
      • Retinal changes with sausage shaped veins and hemorrhages
      • Cerebral sludge syndrome (poor perfusions due decreased laminar flow); rare hemorrhages in the brain
    • Protein–protein interactions:
      • Complex formation between IgM globulins and fibrinogen, prothrombin, factor V and VII; leads to epistaxis and mucosal bleeding
• Clinical presentation:
  • Primarily a demyelinating sensorimotor neuropathy
  • Neuropathy associated with anti-MAG antibodies (similar to IgM-MGUS)
  • CIDP presentation
  • Distal axonal neuropathy
  • Sensory neuropathy
  • Neuro lymphocytosis variant:
    • Meningeal and nerve infiltration by lymphoplasmacytic cells
    • Rapidly progressive proximally by weakness
    • CSF pleocytosis of lymphoplasmacytic cells
    • MRI: tissue infiltration of nerve roots and the leptomeninges
    • May respond to chemotherapy and X-RT
• EMG:
  • Marked slowing of NCVs
• Laboratory:
  • High sedimentation rate; hemoglobulin of 5–6 gram/100 ml
  • Associated Comb's positive autoimmune hemolytic anemia
  • Seropositive rheumatoid arthritis laboratory values
  • IgM-cardiolipin syndrome
  • 50% of patients have serological autoimmune features; 40% have autoimmune manifestations at the time of diagnosis
  • Whole blood viscosity measured at low shear rates is the best indicator of rheological symptoms
• Pathology (sural nerve biopsy):
  • Primarily demyelinating
  • A few patients have axonal degeneration or endoneurial amyloid deposition

Osteolytic Myeloma Associated with Systemic Amyloidosis

• General features:
  • Rare
  • Associated Bence Jones protein; monoclonal gammopathy
• Clinical presentation:
  • Distal axonal sensorimotor neuropathy
  • Autonomic neuropathy
  • Bilateral CTS; tarsal tunnel syndrome
  • Superimposed radicular syndrome; may resemble mononeuritis multiplex
  • Treatment of the myeloma does not improve the neuropathy

Differential Diagnosis of Malignancies Associated with M Proteins and Polyneuropathy

• General features:
  • Cryoglobulinemia (primary)
  • Lymphoma (anti-MAG)
  • Solid cancers
  • Leukemia
  • Waldenström's macroglobulinemia
• Clinical presentation:
  • Motor neuropathy
  • Sensory neuropathy
  • Sensorimotor:
    • Dependent upon the specificity of the IgM antibody

Differential Diagnosis of Plasma Cell Dyscrasia

• Monoclonal gammopathy of unknown significance (MGUS)
• Osteosclerotic myeloma
• Multiple myeloma
• Waldenström's macroglobulinemia
• Primary systemic amyloidosis
• Gamma light chain disease

Late Sensorimotor Neuropathy in Advanced Cancer

• General features:
  • Occurs in 10–50% of patients with cancer
• Clinical presentation:
  • Distal sensorimotor neuropathy
• EMG:
  • Slow motor and sensory NCVs
• Pathology:
  • Primarily axonal degeneration

Mononeuropathy or Mononeuritis Multiplex

• General features:
  • Incidences is rare
  • Misdiagnosed in the presence of overlapping radicular involvement
• Clinical presentation:
  • Focal or multifocal weakness in the distribution of the affected nerves
  • Painful
  • Sensory loss prominent
• EMG:
  • Denervation of the involved nerves
  • Decreased motor and sensory NCVs
• Pathology:
  • Nerves are infiltrated by tumor
  • Vasculitis of vas vasorum
  • Cryoglobulinemia with immune deposition in the vasovasorum

Lymphoma

• General features:
  • Neuropathy incidence is approximately 8%
  • Subclinical involvement detected by EMG maybe 30%
• Clinical presentation:
  • Sensory neuropathy; similar to that seen with cancer; paresthesias, dysesthesias; pain, sensory ataxia
  • Sensorimotor neuropathy
  • GBS presentation
  • Relapsing remitting (CIDP presentation)
• EMG:
  • Axonal features
• Pathology:
  • Malignant infiltration of nerve roots and peripheral nerves; lymphoma > carcinoma

Peripheral Neuropathy of Leukemia

• General feature:
  • Incidence: rare
  • Paraneoplastic neuropathy more common in chronic lymphocytic leukemia than red cell leukemia (di Guglielmo's) or in acute leukemia
• Clinical presentation:
  • Paraneoplastic neuropathy:
    • Acute GBS presentation
    • Sensorimotor neuropathy
    • Rarely sensorimotor neuropathy with myeloid leukemia

Polycythemia Vera

• General features:
  • Possibly 25% of patients have sensory or motor symptoms
  • Definable peripheral neuropathy is rare
  • Associated signs and symptoms; stroke, vertigo, headache, tinnitus
• Clinical presentation:
  • Paresthesias and burning pain in the distal extremities
  • Decreased sensibility in all modalities
  • Full strength; depressed reflexes
  • Itch with heat (C-fiber activation)
• EMG:
  • Significant decrease of sensory NCV
  • Minimal decrease of motor NCV
• Pathology:
  • Mild chronic axonal degeneration