History and exam
Key diagnostic factors
common
presence of risk factors
Key risk factors include age over 50 years and medicine and recreational drug exposure.
numbness
Numbness or loss of sensation can occur in any part of the body and is a common symptom of MNM. The sensory impairment is typically in the distribution of affected single or multiple nerves. A confluent MNM over time may result in asymmetrically diffuse distal sensory loss in limbs.
weakness
Weakness may occur in an extremity affected by MNM.
pain
Pain is a frequent symptom in vasculitic MNM, often with both neuropathic pain within the area of sensory impairment and a deep pain in the affected extremity.
sicca symptoms
Sicca symptoms and findings (dry conjunctivae, dry oral membranes) are consistent with sarcoidosis, Sjogren syndrome, and other connective-tissue associated vasculitides.
parotid gland enlargement
Parotid gland enlargement occurs in sarcoidosis, Sjogren syndrome, and HIV infection.
rash, ulcerations, or pigment changes
Many of the disorders that cause MNM potentially involve the skin.
All of the systemic vasculitides including hepatitis C-associated cryoglobulinaemia and hepatitis B-, hepatitis C-, and HIV-associated polyarteritis nodosa may cause palpable purpura, nodules, ulcerations, or similar findings.
Lyme disease presents initially with erythema migrans 7-10 days following a tick bite.
Tuberculoid leprosy features hypopigmented and insensate patches of skin. [Figure caption and citation for the preceding image starts]: Borderline tuberculoid leprosy showing depigmented anesthetic skin patchesFrom the personal collection of Professor Ashok Verma; used with permission [Citation ends].
Sarcoidosis can present with skin manifestations including erythema nodosum and purpura.
Rheumatoid vasculitis is indicated by palpable purpura, livedo reticularis, subcutaneous nodules, or ulcers.[34]
Livedoid vasculopathy with MNM may present with livedo reticularis and focal dermal atrophy and depigmentation (atrophie blanche).[33]
Systemic lupus erythematosus presents with malar or discoid rash, photosensitivity, and oral or nasopharyngeal painless ulceration.
Skin involvement is not present with non-systemic vasculitic neuropathy.[34][47]
wheeze, cough, other pulmonary signs
Eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome) often initially presents with pulmonary symptoms (e.g., wheezing) and may be diagnosed as asthma.
Granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis) often presents initially with upper and lower respiratory tract involvement (e.g., rhinorrhoea, epistaxis, sinusitis, otitis media, collapse of the nasal bridge, tracheal stenosis, cough, haemoptysis, dyspnoea, pulmonary haemorrhage) and haematuria.[9]
Sarcoidosis often presents with cough, chest discomfort, dyspnoea, and dry rales.
fever, night sweats, weight loss, and malaise
Polyarteritis nodosa may present with non-specific complaints such as fever, night sweats, weight loss, malaise, abdominal pain, and myalgias.
Other diagnostic factors
common
predisposing conditions causing vasculitis, inflammation, or other nerve damage
MNM is more common in people with recent HIV or other infections, autoimmune conditions, sarcoidosis, vasculitis, or connective tissue disease.
Risk factors
strong
age over 50 years
MNM is most commonly caused by a vasculitic neuropathy. Vasculitic neuropathy is most common in older patients.[30] However, MNM can present at any age.
hepatitis C
Up to 65% of patients with hepatitis C (HCV)-related cryoglobulinaemic vasculitis develop clinically significant neuropathy.[7] Patients may have either a classic polyarteritis nodosa (PAN) vasculitis or a mixed cryoglobulinaemic (MC) vasculitis.
MNM may be more common in patients with HCV-PAN than in those with HCV-MC.[32]
Prevalence of anti-HCV antibodies in proven classic PAN vasculitis has been reported in 5% to 12% of cases.[32]
Classic PAN is less common in patients with chronic hepatitis C than in those with a recent hepatitis B infection, and is less frequent in patients with hepatitis C than in those with cryoglobulinaemic vasculitis.[1]
cryoglobulinaemia
Cryoglobulins are present in most patients with hepatitis C with vasculitic neuropathy, although cryoglobulins may be present in other patients with MNM (e.g., HIV-positive patients).[32] About 55% to 86% of patients with chronic hepatitis C virus infection have mixed cryoglobulinaemia (MC). Less than 15% of patients with MC are symptomatic, however, and the prevalence of MNM in these patients is not known.[32]
hepatitis B
About 10% to 55% of patients with classic polyarteritis nodosa (PAN) have circulating antibodies against hepatitis B surface antigen.
MNM is a common clinical feature of classic PAN.
Classic PAN usually develops during the early stages of hepatitis B infection.
connective tissue disease
livedo reticularis
Livedo reticularis is reported to be associated with vasculitic MNM.[33]
primary vasculitis
MNM may occur in the primary vasculitides (except Takayasu's arteritis and Kawasaki disease).
MNM occurs most frequently in classic polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis (formerly known as Churg-Strauss syndrome), microscopic polyarteritis, and granulomatosis with polyangiitis (formerly known as Wegener's granulomatosis).[1][34]
MNM may be associated with temporal arteritis, but alternative aetiologies should be considered.
medications
Sulfonamides, propylthiouracil, hydralazine, colony-stimulating factors, allopurinol, cefaclor, minocycline, D-penicillamine, phenytoin, isotretinoin, methotrexate, interferons, TNF-alpha inhibitors, quinolone antibiotics, immune checkpoint inhibitors, and leukotriene inhibitors have been reported to cause hypersensitivity vasculitis.[35][36][37] Hypersensitivity vasculitis is an important cause of MNM.[35][38][39]
HIV infection
MNM is uncommon in HIV, although exact prevalence data are not known.[40]
When it occurs, MNM appears early in the infection, unless associated with cytomegalovirus (CMV) infection. HIV-associated, CMV-positive MNM presents in advanced AIDS cases.
non-HIV, non-hepatitis infections
MNM has been reported to occur in Lyme disease, leprosy, and infections with cytomegalovirus, varicella zoster virus, human T-cell lymphotropic virus type 1, and many other infections. Leprosy is endemic in Brazil, South Sudan, Liberia, Burundi, and Comoros.[41]
severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection
MNM has been reported in patients infected with SARS-CoV-2 (COVID-19) infection.[42][43] SARS-CoV-2 infection is linked to isolated mononeuropathy of limb or cranial nerves, multiple mononeuropathies, and confluent MNM, resulting in focal or asymmetric sensorimotor deficit. The pathophysiological basis of SARS-CoV-2-associated MNM (direct infection, immune-mediated damage, or both) is not known.
recreational drug use
Recreational intravenous drug use is a risk factor for hepatitis C, hepatitis B, and HIV infections that are associated with MNM.
Use of cocaine, heroin, and amfetamines has also been reported as a direct cause of MNM, but this is an uncommon aetiology.[1]
weak
genetic predisposition
MNM is not generally familial, although genetic susceptibility plays a role in connective tissue disease and primary vasculitides. A clear familial history of multiple, asymmetrical mononeuropathies is an indicator that the patient may have hereditary neuropathy with liability to pressure palsies or other hereditary neuropathy, and not a typical vasculitis MNM.[44]
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