Asymmetric Neuropathies

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ASYMMETRIC NEUROPATHIES

Many asymmetric sensory-motor neuropathies are treatable.
They are a major indication for biopsies of nerve and muscle.

Mononeuritis Multiplex

Systemic disease
- Diabetes Mellitus
- Waldenström's macroglobulinemia
- Burns: Severe
Infectious
- Cytomegalovirus (in HIV)
- Leprosy
- Lyme
- Hepatitis A (Acute)
- Hepatitis C
Multifocal Demyelinating
- CIDP (Lewis & Sumner form)
- Multifocal Motor Neuropathy
Inflammatory-Immune
Multiple Intrinsic Lesions
- Neoplasm (e.g. Lymphoma)

Vascular Occlusion
- Arterial
- Cholesterol emboli
- Hyperviscosity
- Sickle cell disease
Multiple Compressive Lesions
- Trauma
- Neoplasm (Multiple)
  - Carcinomatous Meningitis
  - Schwannoma
- Liability to Pressure Palsies
- Amyloidosis
- Diabetes: Multiple lesions at common entrapment sites
- Hemorrhage
  - Extraneural: Hemophilia
  - Intraneural: Idiopathic thrombocytopenic purpura (ITP)
Other
- Polymyalgia rheumatica: Asymptomatic
- Wartenberg's migrant sensory neuritis

Other asymmetric neuropathies

Plexopathy
- Brachial
- Lumbosacral
Toxic
- Gold
- Spanish Toxic Oil
- Jelly fish
Hereditary
- CMT, X-linked, Type 1
- PMP-22 mutations
  - Point mutation
  - HNPP
- MPZ mutation
  - Entrapment neuropathy: Multiple
  - Focally folded myelin
- SH3TC2 heterozygote
  - Carpal tunnel syndrome
- ARCMT2: SPG11
- Neuralgic amyotrophy: Recurrent
- CMT 2P: LRSAM1
- CMT 2Z: MORC2

Cytopathies

Also see: Asymmetric myopathies

Lymphoma ⁵

Lymphoma & Disease subtypes
Anaplastic large cell (ALCL)
Angiotropic (Intravascular)
Ataxia telangectasia
Castleman disease
CLL
CNS infiltration
DLBCL
Hemophagocytic lymphohistiocytosis
Hodgkin
Non-Hodgkin
Lymphoepithelial thymoma
Lymphomatoid granulomatosis
Monoclonal gammopathies (MGUS)
PNS (Nerve) infiltration
Metastatic (Neurolymphomatosis)
Local
Waldenström's macroglobulinemia
Also see
Diffuse infiltrative lymphocytosis syndrome (DILS)

Lymphoma-related NM syndromes
Cryoglobulinemia
Paraneoplastic syndromes
Motor
Sensory (Hu)
Cerebellar: Tr; mGluR1
Myelopathy, Necrotic
Immune, Other nerve
Amyloid
IgM Antibody syndromes
MAG; GM1; Sulfatide; GD1b
POEMS
Weak association
CIDP (Varied lymphoma types)
GBS (Hodgkin & CLL)
Muscle & NMJ
Myasthenia gravis
Inflammatory myopathy
Toxic: Chemotherapy

Lymphoma Features

Epidemiology: Most common in industrialized countries

Lymphoma Types

Non-Hodgkin type (NHL) (90%)
- Defined by lymphocyte characteristics
  - B-cells (85%): Associated polyneuropathies
    - Aggressive
      - Type: Diffuse large B-cell lymphoma (DLBCL)
      - Neuromuscular complication: Radiculopathy & nerve invasion
    - Indolent: Demyelinating & Multifocal neuropathies
  - T/Natural killer (NK) cell
- Indolent, low grade, types
  - Follicular
  - Chronic lymphocytic leukemia (CLL)/Small lymphocytic lymphoma (SLL)
  - Marginal zone
  - Waldenström's macroglobulinemia (WM)/Lymphoplasmocytic lymphoma (LPL)
- Mantle Cell
Hodgkin (10%)
- Epidemiology: Younger patients
- Clinical
  - Spread: Less likely to be extra-nodal than NHL
  - Associated polyneuropathies
    - Demyelinating
    - Drug-induced (Checkpoint inhibitors)
  - Prognosis: Better than NHL
- Histology
  - Reed–Sternberg cells: Germinal center B-lymphocyte derived; Neoplastic
  - Surrounded by: Many reactive cells belonging to innate & adaptive immune system

Infiltration of Nerve (Neurolymphomatosis) ⁸

Features
- General
  - During or after metastatic lymphoma
  - Nerve infiltration beyond dural sleeve or thecal sac
  - Frequency: 0.2% to 0.5% of NHL
- Neoplasm associations
  - Types
    - Non-Hodgkin lymphocytic
      - Usually B-cell type
        
        DLBCL 75%
        
        Foillicular 9%
        
        Peripheral T-cell 4%
        
        Mantle cell 2%
      - Pathological change in nerve in 40%
    - Acute leukemia: de novo or Transformation of Chronic myelogenous leukemia (CML)
    - 1° CNS lymphoma
  - Spread from: Hematogenous or Leptomeninges
  - May develop or progress when lymphoma in hematologic remission
    - Sensorimotor
    - Infiltration may be mainly endoneurial
    - ? 2° Endoneurial lymphoma not reached by treatment
- Clinical
  - Cranial nerves
    - Nerves
      - Often single cranial nerve
      - Common: III; V; VI; VII; Mental nerve
      - Rare: Optic nerve & chiasm; Trigeminal; Glossopharyngeal; Acoustic
    - Syndromes: Anatomic
      - Orbital: Frontal headache; EOM paresis; Trigeminal 1 sensory loss; Proptosis
      - Parasellar: Frontal headache; EOM paresis; Trigeminal 1 sensory loss
      - Middle fossa: Facial pain; Trigeminal sensory loss± VII palsy
      - Jugular foramen: Hoarseness; Dysphagia; Lesions of cranial nerves 9 to 11
      - Occipital condyle: Localized pain; Tongue weakness (Ipsilateral)
      - Mental foramen: Numb chin
    - Pathology: Varied
      - Nerve infiltration
      - Leptomeningeal involvement
      - Hematogenous dissemination
      - Intraocular: Muscles; Ciliary nerves
    - CSF Diagnosis of meningeal infiltration
      - Cytology: Abnormal in 80% of patients with ≥ 3 exams
      - Lactic dehydrogenase
      - β₂-microglobulin
      - Meningeal biopsy may be useful if other tests are negative
  - Peripheral nervous system syndromes
    - General: May be symmetric or asymmetric
    - Mononeuropathies
      - Most common with Non-Hodgkins lymphoma
    - Polyneuropathies
    - Motor neuropathy
      - Subacute
      - Asymmetrical & Patchy
      - Painless
      - Legs > Arms
      - Course: Benign, Self-limited
    - Radiculopathies
      - May be due to herpes zoster (VZV) infections
        
        Usually in a truncal distribution: Radicular pain
        Frequency: 3–10% of lymphoma patients
      - Some patients with tumor invasion: Usually Non-Hodgkins lymphoma
      - Diagnosis: Biopsy; CSF examination
    - Plexopathies
      - Causes
        
        Nerve infiltration
        
        Autoimmune disorders
        
        Iatrogenic: Radiation
      - Brachial plexus: Pain ± Lower plexus involvement
      - MRI: May show thickened or enhancing nerves or roots
    - Cauda equina syndrome: Neoplastic infiltration
    - Pathology: Axonal loss ± segmental demyelination
- Rule out: Other asymmetric neuropathies
- Laboratory
  - CSF
    - Cells: Often Increased
    - Protein: High 61%
    - PCR: Ig heavy chain or T-cell receptor
    - Glucose: May be low
  - IL-2R
  - MRI: Abnormal with enhancement in 76%
  - FDG-PET: Abnormal in 84% to 90%
    - Enhancement
    - Nerves or Roots: Thickening
    - May be used to monitor treatment response
  - Ultrasound of Nerve: Swelling or Loss of fascicular architecture
  - Nerve biopsy
    - Lymphoma cells
      - Locations
        
        Endoneurium: Subperineurial
        
        Epineurium: Perivascular
        
        Perineurium
      - Morphology
        
        Nuclei: Irregular; Nucleoli visible; Mitoses
        
        Cytoplasm: Minimal
    - Axon loss: Large & Small; May vary among fascicles
    - Demyelination: Some patients
Multifocal infiltrates primarily in nerve ¹
- Neoplasm: T-cell lymphoma
- Clinical
  - Distribution: Asymmetric; Mononeuritis or Multiple mononeuropathies
  - Cranial & Motor-sensory nerves
  - Course: Progressive or Relapsing-Remitting
  - Treatment: Temporary improvement may occur with corticosteroids
- Laboratory
  - CSF: Cells often increased
  - Nerve pathology
    - Axonal loss
    - Lymphoma: Angiocentric, in vessel walls
  - Muscle pathology: Angiocentric lymphoma
- Animal model: Marek's disease (T-cell lymphoma 2° oncogenic herpesvirus)

Infiltrates primarily in spinal cord & CNS ¹

Angiotropic large B-cell lymphoma
(Malignant angioendotheliomatosis; Intravascular B-cell lymphoma)
- General: Proliferation of neoplastic lymphoid cells within blood vessels
- Onset: Especially 7th & 8th decade
- Neurological features
  - Presenting feature in 54%
  - CNS lesions: Multifocal; "Stroke-like"
    - Encephalopathy: Sub-acute; Dementia; Coma
    - Cortical lesions: Multi-Focal; Hemiparesis
    - Myelopathy
      - Transverse or Diffuse
      - Clinical
        
        Paraparesis
        
        Sensory loss
        
        Urinary dysfunction
      - Pathology: Multifocal infarction
    - Deafness
  - Peripheral nerve involvement: Occasional
    - Mononeuritis: Sudden onset
    - Mononeuritis multiplex
    - Cranial nerves
      - Most common: VII & Hearing loss
      - Also EOM, Trigeminal
    - Radiculopathy: Pain; Sensory loss; Weakness
- Organ involvement
  - Eye: Visual loss; Papilledema; Retinal & Choroid vessels involved
  - Skin
    - Most common; Rash - Macular
    - Other: Papular, Nodular, Plaquelike, or Pigmented
  - Bone marrow: with More diffuse lymphoma
  - Muscle: Asymptomatic; Intravascular
  - Adrenal: Enlargement
  - Renal failure
  - Liver failure
  - Respiratory failure
  - General: Fever, Malaise
- Disease course
  - Untreated patients: High mortality rate; Up to 80% at 1 year
  - Treatment: May be curable with early chemotherapy (40%)
- Histopathology
  - Neoplasm features
    - Noncohesive masses of large, pleomorphic lymphoid cells
    - Location: Capillaries, venules & small arterioles
    - Neoplastic cell accumulations
      - May occlude vessels
      - Rarely extravasate into the neighboring tissues
  - Cell features
    - Nuclei
      - Contours: Irregular
      - Chromatin: Coarse
      - Nucleoli: Two or Multiple
    - Cytoplasm: Moderate amounts; Basophilic; Vacuolated
    - Antigens
      - Common: bcl-2 & CD-20 proteins
      - Other: CD10, bcl-6 & CD5 few
  - Lymphoma cell locations
    - Present in small vessels in:
      Skin; Brain; Kidney; Spleen; Liver; Bone marrow; Heart; Muscle
    - No mass
  - Diagnosis may be made on skin, muscle or nerve biopsy
- Laboratory
  - Hematologic
    - Anemia: Mild; Hemolytic
    - Peripheral blood: Pancytopenia with leukoerythroblastic picture
  - Erythrocyte sedimentation rate: High
  - Serum lactate dehydrogenase: Markedly elevated
  - Coagulopathy: Occasional patients; Thrombocytopenia pancytopenia
  - CSF: Normal
  - LDH: Very high
  - Tissue biopsy: CD20+ cells in vascular lumen and walls

B-cell Lymphoma
Intravascular
Spinal cord (Thoracic)
Enlarged
Increased T2 signal

Hodgkins Lymphoma

Epidemiology
- Onset: Bimodal
  - Most common: 16–34 years
  - 2nd peak: Older ages
- Frequency: 3 per 100,000 in US
- Association: Prior viral infections
  - EBV
  - HIV: Associated with virulent form
  - May be related to subtypes of Hodgkins lymphoma
Clinical
- Disease beyond lymphoreticular system: Uncommon
- Neurological complications
  - Uncommon
  - May be due to associated autoimmune syndromes: GBS
- Prognosis: 80% cure rate
- Staging of HL relatively predictive of prognosis
Pathology: Associated with Reed–Sternberg cells

Non-Hodgkins Lymphoma

Frequency of neurological involvement
- Subclinical: 35%
- Clinical: 6 to 17%
- More with: Higher disease grade (DLBCL); B-cell lymphoma
Disease mechanisms
- Immunosuppression
- Autoimmune
- Tumor infiltration of PNS or CNS
Associated syndromes
- Radiculopathy
- Plexopathy
- Mononeuropathy
- Polyneuropathy
- Mononeuritis multiplex
- Motor neuropathy
- Immune myopathy

Lymphomatoid granulomatosis

Disease features: General
- Lymphoproliferative disorder
- Angiocentric & Angiodestructive
- Due to EBV infection
Onset: Pulmonary; Brain
Neurological features
- Frequency: 30%
- Neuropathy: Rare; Associated with lymphoid infiltration
Pathology: Angiitis
Treatment: Corticosteroids; Cytotoxic agents

Chronic lymphocytic leukemia (CLL/SLL)

Epidemiology
- 4 to 5 new cases/100,000 people/year
- Median age at diagnosis: 72 years
Clinical
- Subtypes
  - Indolent: No mutations in tumor suppressor gene TP53 or immunoglobulin heavy-chain
  - Aggressive: TP53 gene abnormalities and/or Complex karyotypes
- Neuropathies
  - Viral: Varicella zoster virus (VZV); Hepatitis C (HCV)
  - Iatrogenic: Ibrutinib, lenalidomide
  - Immune-mediated
  - Peripheral nerve invasion by leukemic cells
  - Amyloidosis, Light chain

Diffuse, Large B-cell lymphoma (DLBCL)

Lymphoma type
- NHL: High-grade
- Subtypes: Germinal center B-cell-like; Activated B-cell-like; Unclassified
Epidemiology
- 7 to 8 cases/100,000/year in US
- Median onset age: 70 years; May occur in children
- 5 year survival: 58%
Neuropathies
- Compression by lymphomatous mass
- Neurolymphomatosis
- Viral: VZV; HCV; HIV
- Drug-related
- Intravascular lymphoma
- Radiculopathy, Acute painful

Lymphoma-related syndromes: Other

Paraneoplastic syndromes
GBS: Associated with Hodgkin's
Ataxia telangectasia
Monoclonal gammopathies (MGUS)
- POEMS: Castleman disease
- IgM Anti-glycolipid antibody syndromes
- Waldenström macroglobulinemia
Also see
- Myasthenia gravis: Lymphoepithelial thymoma
- Inflammatory myopathy: Hemophagocytic lymphohistiocytosis
- Diffuse infiltrative lymphocytosis syndrome (DILS): HIV infection, Not lymphoma

Cholesterol emboli

Predisposing events
- Vascular catheterization
- Anticoagulant therapy
- Aortic atherosclerosis (Ulcerative)
Polyneuropathy
- May be presenting feature
- Motor-Sensory
- Axonal
- Distribution: Symmetric, or Mononeuritis multiplex
Systemic features
- Myalgia
- Livido reticularis
- Renal & GI disorders
- Weight loss & cachexia
Lab
- Sedimentation rate: Increased
- Anemia
Pathology
- Diagnosis by muscle (92%) & nerve (epineurial vessel change) biopsy
- Cholesterol crystals (with clefts) in lumina of small arteries
Treatment: ?
Progression
- Months
- Mortality: 73%

Hemophilia A & B

Mononeuropathies in 13%
Multiple mononeuropathies in 6%
Nerve lesions more common
- Severe disease: < 1% factor VIII
- Increased age
- Lower extremity > Upper extremity
Nerves
- Femoral 10%: Hemorrhage into psoas or iliacus muscles
- Ulnar 4%
- Median 4%
- Peroneal 2%
- Sensory: Saphenous (2%); Lateral femoral cutaneous (2%)
Differential diagnosis
- Joint disorders due to hemarthrosis
- HIV
- Chronic liver disease

Idiopathic Thrombocytopenic Purpura ⁶

Epidemiology: Single patient; 8th decade
Clinical
- Onset: Pain; Sensory loss
- Systemic
  - Bleeding: Hematuria; Gums
  - Skin: Rash; Bruising
- Polyneuropathy
  - Weakness
    - Initial: Legs; Proximal & Distal
    - Progression: To quadriplegia
  - Sensory loss: Legs > Arms
  - Tendon reflexes: Reduced
  - Pain
  - Course: Stepwise progression over 8 months
Laboratory
- Platelets: 2000 to 4000/μl
- Bone marrow: Thrombocytopenia
- Associated neoplasm: B-cell lymphoma
- Nerve
  - Intraneural hemorrhage
    - Patchy
    - Perineurial & Subperineuial
    - Erythrocytes in Schwann cell tubes
  - Axonal loss: Chronic & Ongoing

Wartenberg's Migrant Sensory Neuritis ²

Onset age: Mean 35 years; Range 4th & 5th decades
Pure sensory mononeuritis multiplex
- Course
  - Episodic; Recurrent
  - Some sensory loss improves, Other is permanent
- Sensory loss
  - Discrete areas: Involvement of individual cutaneous nerves
  - Sudden onset
  - Distribution: Legs; Arms; Trunk; Face
- Pain
  - In areas of sensory loss
  - Painful dysesthesias: Induced by limb stretch or movement
Laboratory
- Electrodiagnostic: Multifocal axon loss
- Pathology: Biopsy of affected nerve
  - Perineurial scarring
  - Chronic inflammation
  - Axonal loss & regeneration: Differential fascicular involvement
  - Endoneurial edema
  - Immunoglobulin deposition

Sickle Cell Disease ⁴

Mononeuritis multiplex ³

Associated with: Sickle cell pain crisis
Frequency: Rare
Onset: Acute
Clinical
- Weakness: Lumbosacral; Asymmetric
- Pain
- Sensory loss: Legs
Course: Slow improvement
Electrodiagnostic testing
- Axonal loss
- Conduction block: Associated with acute nerve lesion
Treatment: Management of pain crises

Cranial neuropathies: Mental nerve
Toxic neuropathy
Rhabdomyolysis
- May occcur with sickle cell trait
- Associated with: Exertional heat illness; High altitude; Sudden death
- Most commonly reported in: Athletes; Military recruits
Focal myopathy
- Muscles: Quadriceps; Glutei
- Intramuscular injection of narcotics
Muscle edema: On MRI
Asymptomatic: Electrodiagnostic changes in 20% ⁷
- SNAPs: Reduced amplitude
- Asymptomatic ulnar or nedian neuropathy

Return to Polyneuropathy Index

References
1. Clinical Neurology and Neurosurgery 2000;101:275-279; JNNP 2001;71: 696-703
2. Muscle Nerve 2001;24:438-443
3. J Clin Neuromusc Dis 2001;3:63-69
4. Ann Neurol 2002;51:543–552, Handb Clin Neurol 2014;120:1015-1025
5. Muscle Nerve 2005;31:301–313, J Neurol Sci 2015; Jun 3
6. J Peripheral Nervous System 2007;12:286–289
7. European Journal of Neurology 2009;16:814–818
8. J Peripher Nerv Syst 2018 Dec 16

4/2/2020