Etiology

MNM most frequently results from nerve ischemia secondary to either a primary or a secondary vasculitis. Vasculitides are classified as either primary or secondary to a variety of other conditions, including infections (e.g., hepatitis C, HIV) and malignancy. The most common vasculitic neuropathies are nonsystemic vasculitic neuropathy, polyarteritis nodosa-associated systemic vasculitic neuropathy, microscopic polyarteritis-associated vasculitic neuropathy, and rheumatoid vasculitic neuropathy.[6][7]​​​​​​[23]​​ Immune-mediated focal and multifocal motor neuropathy, a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) variant, can present as MNM without sensory involvement.[24]​ Focal interstitial infiltration and vasculopathy of nerve segments in sarcoidosis and amyloidosis can result in MNM.[7]​​[24]

Pathophysiology

Underlying events triggering primary vasculitis are unknown, although leukocyte and endothelial cell activation and altered function of adhesion molecules play a role.[8] Secondary vasculitides are triggered by the underlying disease or exposure. In necrotizing vasculitis, inflammatory cell infiltration and necrosis of the walls, and stenosis and occlusion of nutrient vessels with the consequent nerve ischemia and infarction, are the pathophysiologic basis of a focal and multifocal neuropathy. Necrotizing arteritis is the most common pattern of vascular involvement in MNM, usually involving the small, precapillary arteries of the vasa nervorum, leading to randomly distributed ischemia along the course of the nerve. Transmural inflammation, segmental fibrinoid necrosis, and endothelial proliferation occur in the arterial walls, resulting in narrowing and occlusion of vessels and ischemic injury to the nerve.[7][25][26]​​

Underlying events that lead to inflammation and vessel wall damage in specific disorders include:

  • Immune-complex formation, believed to be a prominent mechanism of vessel damage in polyarteritis nodosa and essential mixed cryoglobulinemia, and an important effector mechanism in hepatitis B-associated polyarteritis nodosa and hepatitis C-associated mixed cryoglobulinemia[8][27][28]

  • Hapten formation triggering an immune response, which is probably the underlying mechanism in most cases of drug-hypersensitivity vasculitis[29]

  • Pathogenic T-lymphocyte response and production of antineutrophil cytoplasmic antibodies (ANCA), resulting in damage to blood vessel walls in granulomatosis with polyangiitis (formerly known as Wegener granulomatosis) and eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome).[9]​ ANCA are also likely to be involved in vessel wall damage in microscopic polyarteritis.[8][9]

Classification

Disorders presenting with multifocal or asymmetric sensorimotor deficits[1]

Ischemic:

  • Peripheral nerve vasculitis (see vasculitides classification)

  • Diabetes mellitus.

Inflammatory/immune-mediated:

  • Sarcoidosis

  • Multifocal chronic inflammatory demyelinating polyradiculoneuropathy (also known as Lewis-Sumner syndrome; multifocal demyelinating neuropathy with persistent conduction block; multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]; multifocal inflammatory demyelinating neuropathy)

  • Multifocal motor neuropathy, with conduction block or without conduction block

  • Multifocal variants of Guillain-Barre syndrome

  • Idiopathic brachial or lumbosacral plexopathy

  • Neuropathy with eosinophilic conditions

  • Neuropathy with gastrointestinal conditions (Crohn disease, ulcerative colitis, celiac sprue)

  • Immune checkpoint inhibitor therapy in cancer

  • Graft-versus-host disease

  • Hashimoto thyroiditis.

Infectious:

  • Leprosy

  • Lyme disease

  • Viral (HIV, human T-cell lymphotropic virus type 1 [HTLV-1], varicella zoster virus [VZV], severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2], cytomegalovirus [CMV])

  • Other (bacterial, viral, fungal, and parasitic infections that occasionally involve peripheral nerves).

Drug-induced:

  • Sulfonamides

  • Propylthiouracil

  • Hydralazine

  • Colony-stimulating factors

  • Allopurinol

  • Cefaclor

  • Minocycline

  • D-penicillamine

  • Phenytoin

  • Isotretinoin

  • Methotrexate

  • Interferons

  • TNF-alpha inhibitors

  • Quinolone antibiotics

  • Leukotriene inhibitors.

Genetic:

  • Hereditary neuropathy with liability to pressure palsies

  • Hereditary neuralgic amyotrophy

  • Other (porphyria, Tangier disease, Krabbe disease)

  • Hemophilia.

Mechanical:

  • Multiple peripheral nerve injuries

  • Multifocal entrapments not related to a genetic disorder.

Neuropathies secondary to malignancy:

  • Direct infiltration

  • Multifocal mass lesions with external compression (neurofibromatosis type 2)

  • Lymphomatoid granulomatosis

  • Intravascular lymphoma

  • Neoplastic meningitis

  • Systemic amyloidosis.

Miscellaneous:

  • Sensory perineuritis/Wartenberg migrant sensory neuritis

  • Cholesterol emboli syndrome

  • Idiopathic thrombocytopenic purpura

  • Atrial myxoma.

Primary vasculitides[2]​​

Large-vessel vasculitis (LVV):

  • Giant cell (temporal) arteritis

  • Takayasu arteritis.

Medium-sized vessel vasculitis (MVV):

  • Polyarteritis nodosa (classic)

  • Kawasaki disease.

Small-vessel vasculitis (SVV):

  • Granulomatosis with polyangiitis (formerly known as Wegener granulomatosis)

  • Eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome)

  • Microscopic polyarteritis (microscopic polyangiitis)

  • IgA vasculitis (Henoch-Schonlein purpura)

  • Cryoglobulinemic vasculitis

  • Cutaneous leukocytoclastic vasculitis

  • Hypocomplementemic urticarial vasculitis

  • Antiglomerular basement membrane disease.

Variable-size vessel vasculitis (VVV):

  • Behcet syndrome

  • Cogan syndrome.

Single-organ vasculitis (SOV):

  • Cutaneous leukocytoclastic angiitis

  • Cutaneous arteritis

  • Primary central nervous system vasculitis

  • Isolated aortitis

  • Others.

Vasculitis associated with systemic disease:

  • Lupus vasculitis

  • Rheumatoid vasculitis

  • Sarcoid vasculitis

  • Others.

Vasculitis associated with probable etiology:

  • Hepatitis C virus-associated cryoglobulinemic vasculitis

  • Hepatitis B virus-associated vasculitis

  • Syphilis-associated aortitis

  • Drug-associated immune complex vasculitis

  • Drug-associated ANCA-associated vasculitis

  • Cancer-associated vasculitis

  • Others.

Secondary vasculitides associated with neuropathy[1]

Vasculitides resulting from direct infection:

  • Bacterial: group A beta-hemolytic streptococcus, infective endocarditis, or Lyme disease

  • Viral: HIV, CMV, HTLV-1, or VZV.

Vasculitides resulting from immunologic mechanisms:

  • Systemic necrotizing vasculitis: classic polyarteritis nodosa, antineutrophil cytoplasmic autoantibody-associated (microscopic polyarteritis, eosinophilic granulomatosis with polyangiitis, or granulomatosis with polyangiitis), hepatitis B-associated polyarteritis nodosa, or vasculitis with connective tissue disease (rheumatoid arthritis, Sjogren syndrome, systemic lupus erythematosus, mixed connective tissue disease, relapsing polychondritis, or Behcet syndrome)

  • Hypersensitivity vasculitis: Henoch-Schonlein purpura; drug-induced vasculitis; vasculitis associated with HIV, SARS-CoV-2, or HTLV-1*; cryoglobulinemic vasculitis (hepatitis C)*; vasculitis associated with malignancy*; or diabetic and nondiabetic (idiopathic) lumbosacral radiculoplexus neuropathy

  • Giant cell (temporal) arteritis

  • Localized vasculitis: nonsystemic vasculitic neuropathy.

*Can also produce systemic necrotizing vasculitis.

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