I. Mononeuritis Multiplex
Mononeuritis Multiplex (MNM), also referred to as multiple mononeuropathy, is characterized by peripheral neuropathy of both the motor and sensory nerves of at least two different nerve trunks. Initially, the nerves are damaged in a nonsensical pattern leading to the description of a painful, asymmetric, asynchronous distribution. As the disease progresses, the distribution becomes more symmetrical.
There are multiple causes of MNM, but it is most frequently associated with the primary vasculitides. Involvement of the peripheral nervous system in the vasculitides is driven by ischemia and eventually infarction in the vasa nervorum, the small blood vessels that supply peripheral nerves. It is for this reason that MNM, and peripheral nervous system involvement in general, is seen more commonly in small and medium vessel vasculitis, as opposed to large vessel vasculitis.
II. Diagnostic Approach.
A. Differential Diagnosis for the Causes of Mononeuritis Multiplex.
See Table I for the differential diagnosis for the causes of mononeuritis multiplex.
Polyarteritis Nodosa (PAN)
Granulomatosis with Polyangiitis (Wegener’s)
Giant Cell Arteritis
Systemic Lupus Erythematosus
|Diabetes||Idiopathic Thrombocytopenic Purpura|
Neoplastic Disorders: Lymphoma, Leukemia
Granulomatous Disease: Sarcoidosis, Amylodosis
Small Cell Carcinoma of the Lung
B. Differential Diagnosis of Mononeuritis Multiplex
The differential diagnosis of MNM includes both CNS causes as well as other peripheral neuropathies, see Table II.
|Acute to Subacute (days to weeks)||Chronic (months to years)(all sensory and motor)|
|Guillain-Barre (predominantly motor)Porphyria (motor)Medications and toxins(Isoniazid, dapsone, lead, solvents;sensory and motor depending on toxin)Alcoholic neuropathy (sensory and motor)B-complex deficiencies (sensory and motor)Heroin (sensory and motor)||Mononeuritis MultiplexDiabetic neuropathy (polyneuropathy)HyperthyroidismParaneoplastic neuropathyParaproteinemias (monoclonal gammopathies)Chronic Inflammatory Demyelinating Polyneuropathy Hereditary neuropathies|
C. Diagnostic Approach.
The diagnostic approach should include questions regarding: acute versus subacute versus chronic onset, asymmetrical versus symmetrical pattern, motor and/or sensory involvement, and proximal or distal involvement. Questions should also focus on excluding central nervous system causes of the patient’s symptoms.
1. Historical information.
Where is the pain? Quality? Pattern of onset? Duration? Is there associated weakness?
The patient will typically complain of a sudden onset of aching, burning, or throbbing pain (usually hours to days) followed by weakness or sensory loss. It usually occurs with sequential involvement of two or more nerve trunks leading to a generalized, asymmetric, distal to proximal pattern. Symptoms typically develop over weeks to months; although in the elderly progression can occur over months to years.
Commonly affected nerves in MNM, especially in vasculitis, include peroneal, tibial, ulnar, and median. The diagnosis should be questioned if the patient does not have pain or has only motor involvement.
Assess for etiology
A thorough history should be undertaken to assess for the cause of MNM. The initial focus should be on evaluation for a primary vasculitis, asking about symptoms such as weight loss, malaise, fever, and fatigue which are common in most systemic vasculitides. It is also important to assess for additional organ involvement, such as a corresponding history of asthma in Churg-Strauss Syndrome. Consider risk factors for HIV and Lyme disease, as well as Hansen’s disease in endemic areas. Cancer and treatment history (e.g., type of chemotherapy) is also important.
Rule out CNS dysfunction
Time course is important when trying to exclude CNS causes which generally present with acute onset and a focal pattern. Other clues to CNS dysfunction include previous or current involvement of cerebellar, urinary, or visual systems.
2. Physical Examination.
Physical exam can help differentiate between CNS and PNS causes.
The exam will show sensory and motor deficits in an asymmetrical pattern. On muscle exam, findings include fasciculations, flaccid tone, and atrophy. Reflexes may be normal or decreased.
Upper motor neuron signs (spasticity, hyperreflexia, upgoing plantar reflexes) are usually seen distal to the lesion. Sensory loss will involve several dermatomes with clear demarcation.
3. Laboratory, radiographic and other tests.
The diagnosis of MNM is based on laboratory testing, electrodiagnostic testing, and nerve biopsy.
Sensory and motor nerve conduction studies help differentiate primary axonal neuropathies from primary demyelinating neuropathies, and reveal the distribution of the neuropathy.
Studies for MNM will demonstrate low amplitude or absent response of the action potential and normal conduction. Needle EMG will show signs of axonal degeneration. It is important to note that the EMG in a patient with MNM may show transient conduction block (demyelination) if performed within a few days of ischemic nerve infarction.
Nerve biopsy is necessary to establish the diagnosis in cases of nonsystemic vasculitic neuropathy. It should be done in an affected nerve to increase yield as well as limit worsening existing nerve deficits and pain. In acute stages it will display inflammation and fibrinoid necrosis within the blood vessel wall. In later stages it may show intimal proliferation and hyperplasia. Many times in vasculitides, the diagnosis can be confirmed by a biopsy of another involved organ along with the support of clinical and electrophysiologic features.
Lab testing should include general tests like ESR or CRP, renal and liver function tests, as well as a chest x-ray and urinalysis to assess for organ dysfunction. Other tests include specific labs to rule out etiologies of interest: p-ANCA/c-ANCA, rheumatoid factor (RF), ANA, Hepatitis A, B, and C, serum complement levels, HIV, cryoglobulins, hemoglobin A1c, , serum protein electrophoresis (SPEP), Lyme serology, and viral serologies.
While MRI should be considered if the etiology is unclear between the CNS and PNS dysfunction, differentiation should be done by history and physical if possible.
III. Management while the Diagnostic Process is Proceeding.
A. Management of Mononeuritis Multiplex.
Management is based on the underlying etiology.
When necrotizing vasculitis is suspected, early and effective treatment is critical. PAN, granulomatous polyangiitis, and other vasculitic neuropathies can be aggressive and lead to organ failure. When associated with a vasculitis, the presence of MNM at diagnosis is often predictive of more frequent sequelae, even in the absence of other poor prognostic features at diagnosis, despite having similar mortality as those patients without MNM.
Standard therapy consists of combined prednisone (1 mg/kg/day) and either oral cyclophosphamide (1-2 mg/kg/day) or intravenous pulse cyclophosphamide. Alternatively, in patients with severe general manifestations, pulses of intravenous prednisolone may help.
Long term treatment
Corticosteroids are usually given for about 6-8 weeks and then tapered slowly over 6-12 months. Another immunosuppressant (azathioprine or methotrexate) can replace cyclophosphamide after 3-6 months.
See Table III for specific treatment requirements based on etiology of mononeuritis multiplex.
|Vasculitic Neuropathy||Combined prednisone and cyclophosphamide|
|Nonsystemic vasculitic neuropathy||Combined prednisone and cyclophosphamide|
|HCV with Cryoglobulinemia||Pegylated-interferon, ribavirin, plasma exchange|
|Hepatitis B with PAN||Interferon α, plasma exchange|
|CMV vasculitic neuropathy||Foscarnet or ganciclovir, prednisone|
|Paraneoplastic vasculitic neuropathy||Treat with appropriate therapy directed at the malignancy.If unsuccessful, consider empiric treatment withcorticosteroids and cyclophosphamide.|
B. Common Pitfalls and Side-Effects of Management of Mononeuritis Multiplex.
Diagnosing mononeuritis multiplex can be very difficult considering that many of the causes are multisystemic and the patient may present with several complaints. It is important that the physician does not limit the clinical evaluation to one system. These patients can also be difficult if they present early in the course with only one neurological complaint, which may lead to a false diagnosis.
IV. What’s the evidence?
Callaghan, BC, Price, RS, Chen, KS, Feldman, EL. “The Importance of Rare Subtypes in Diagnosis and Treatment of Peripheral Neuropathy: A Review”. JAMA Neurol. vol. 72. 2015. pp. 1510-1518. (Discusses a thorough and broad approach to peripheral neuropathy that does not fit nicely into a clear cut description, and includes a discussion of mononeuritis multiplex. This article is particularly helpful when considering mononeuritis multiplex for a diagnosis but the diagnosis remains uncertain.)
Hughes, Richard. “Peripheral Nerve Diseases: The Bare Essentials”. Pract Neurol. vol. 8. 2008. pp. 396-405. (Similar to above, but covers more diagnoses at a surface level.)
Rossi, CM, Di Comite, G. “The Clinical Spectrum of the Neurological Involvement in Vasculitides”. Journal of Neurological Sciences. vol. 285. 2009 Oct 15. pp. 13-21. (Discusses the effects of vasculitides on the nervous system. This article is particularly helpful when a diagnosis of mononeuritis multiplex has been made and the etiology is thought to be related to a vasculitis.)
Samson, M, Puéchal, X. “Mononeuritis Multiplex Predicts the Need for Immunosuppressive or Immunomodulatory Drugs for EGPA, PAN and MPA Patients Without Poor-prognosis Factors”. Autoimmunity Reviews. vol. 13. 2014 Sep. pp. 945-53. (This article discusses the implications of mononeuritis multiplex for the patient. Provides helpful information that can be translated to information for patients that will inform them of how the condition will affect their life.)
Gorson, KC. “Vasculitic Neuropathies: An Update”. The Neurologist. vol. 13. 2007. pp. 12-19.
Said, G, Lacroix, C. “Primary and secondary vasculitic neuropathy”. J Neurol.. vol. 252. 2005. pp. 633-641.
Kelkar, P, Parry, GJ. “Mononeuritis multiplex in diabetic mellitus: evidence for underlying immune pathogenesis”. J Neurol Neurosurg Psychiatry. vol. 74. 2003. pp. 803-806.
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- I. Mononeuritis Multiplex
- II. Diagnostic Approach.
- A. Differential Diagnosis for the Causes of Mononeuritis Multiplex.
- B. Differential Diagnosis of Mononeuritis Multiplex
- C. Diagnostic Approach.
- 1. Historical information.
- 2. Physical Examination.
- 3. Laboratory, radiographic and other tests.
- III. Management while the Diagnostic Process is Proceeding.
- A. Management of Mononeuritis Multiplex.
- B. Common Pitfalls and Side-Effects of Management of Mononeuritis Multiplex.