Mononeuropathy multiplex (sometimes referred to as mononeuritis multiplex) is defined as lesions affecting two or more nerves that cannot be explained by a single root or plexus injury. The involvement of multiple nerves is usually in an asymmetric, non–length-dependent pattern and develops subacutely. If this process continues with additional individual nerve involvement, it can progress to appear clinically and electrophysiologically identical to a more common polyneuropathy. An extensive evaluation for the etiology of mononeuropathy multiplex should be performed, as treatable autoimmune and inflammatory causes are frequently identified.
Nerve conduction studies and electromyography (NCS/EMG) should be performed in all patients with suspected mononeuropathy multiplex to confirm the pattern of nerve injury and to characterize the specific nerve pathology (e.g., demyelinating vs. axonal).
In a patient with multiple mononeuropathies at common sites of compression (e.g., ulnar neuropathy at the elbow) and a family history of polyneuropathy, hereditary neuropathy with liability to pressure palsies (HNPP) and familial amyloidosis should be considered. HNPP is caused by a deletion of the PMP22 gene and would be suggested by moderate diffuse slowing of the motor conduction velocities that do not meet criteria for demyelination. Familial amyloidosis, which is most commonly caused by a transthyretin mutation, would be suspected in patients with autonomic dysfunction or systemic disease (e.g., cardiac abnormalities).
Neurolymphomatosis is the direct invasion of nerve roots or peripheral nerves by lymphoma cells. Depending on the extent of involvement, this can present as an individual mononeuropathy, radiculopathy, or mononeuropathy multiplex. In bone marrow transplant patients, graft-versus-host disease occurs when the transplanted immune cells attack organs of the bone marrow recipient. The skin, gastrointestinal tract, and liver are the most commonly affected organs, but rarely peripheral nerves can also be injured in this disease. Diagnosis of these conditions requires nerve biopsy.
Leprosy is rare in the United States, but should be considered as a cause of axonal mononeuritis multiplex in endemic areas in Mexico, Central America, South America, and Africa. In tuberculoid leprosy, nerve injury usually occurs around skin lesions. In lepromatous leprosy, nerve injury can be much more diffuse.
Lead toxicity is a very rare cause of neuropathy in adults. It has an unusual pattern that is classically an isolated motor neuropathy with a predilection for extensor muscles of the arms and legs. Gasoline and certain adhesives contain n-hexane, a chemical that is toxic to peripheral nerves. Chronic sniffing, or huffing, of these substances classically causes a motor-predominant axonal multifocal neuropathy.
Primary vasculitides frequently cause neuropathy in addition to other end-organ injury, and neuropathy often occurs early in the course of systemic vasculitis. Subacute onset and rapid progression of symptoms, severe pain, and the presence of concurrent systemic complaints suggest vasculitis. Peripheral nervous system involvement most commonly occurs in small and medium-vessel primary vasculitides, which include polyarteritis nodosa (PAN), granulomatosis with polyangiitis (formerly Wegner’s granulomatosis), microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis (formerly Churg-Strauss syndrome). Treatment is typically high-dose steroids and cyclophosphamide. A secondary vasculitic neuropathy can be caused by cryoglobulinemia and numerous autoimmune diseases, most commonly lupus, rheumatoid arthritis, Sjögren syndrome, and Behçet disease. Treatment is targeted to the underlying autoimmune condition. Patients with peripheral nerve injury from either primary or secondary vasculitides will likely also need physical therapy, bracing, and neuropathic pain management for the nerve injury.
Nonsystemic vasculitic neuropathy is an isolated vasculitis of the peripheral nerves without other end-organ involvement. These patients must be carefully monitored because up to 10% of these patients will eventually develop systemic vasculitis. Nerve and muscle biopsy is necessary for diagnosis. Biopsy of both muscle and nerve is recommended to increase the diagnostic yield of the biopsy. Treatment is similar to systemic vasculitis with high-dose oral steroids and cyclophosphamide.
Amyloidosis should be suspected in patients with autonomic dysfunction or systemic disease such as cardiac abnormalities or renal failure. Serum protein electrophoresis with immunofixation may show elevated serum free light chains. Amyloid deposition may be seen on a fat pad or nerve and muscle biopsy.
Isolated demyelination of the motor neurons (multifocal motor neuropathy, MMN) may clinically mimic anterior horn cell disease. MMN causes slowly progressive asymmetric weakness, typically beginning in the upper extremities. Anti-GM1 bodies are seen in some but not all patients.
Acquired demyelinating neuropathies can rarely cause mononeuropathy multiplex. Guillain-Barré syndrome is classically symmetric, but a small subset of patients may have asymmetric features. When chronic inflammatory demyelinating polyneuropathy presents as mononeuropathy multiplex, this variant is known as multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM). The key to distinguishing these disorders from vasculitis is evidence of multifocal demyelinating features on the NCS.