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Multifocal Motor Neuropathy

Not an actual patient.

Multifocal motor neuropathy (MMN) is an immune-mediated demyelinating motor neuropathy that causes slowly progressive asymmetric distal limb weakness, with no objective sensory loss.1,2,3

Signs and symptoms of MMN include weakness in the hands, lower arms, and the lower limbs. Patients may experience cramping, involuntary contractions or twitching, and wasting of affected muscles.1 MMN is commonly misdiagnosed, which can lead to inappropriate treatment and progression of muscle weakness and/or disability.3,4,5,6,7

Epidemiology

In the U.S., the prevalence of MMN is approximately 1 to 2 per 100,000, and the disease can mimic the early symptoms of amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig’s disease), although it only has a third of the prevalence of ALS.3,8,9,10

First symptoms appear before the age of 50 in almost 80% of patients, with the mean age of onset at 40 years (range 20 to 70 years).3 Men are 2.7 times more likely to be affected by MMN than women.6

Diagnosis

The diagnosis of MMN requires clinical weakness without objective sensory loss and without upper motor neuron signs:5,11

  • In the distribution of ≥2 named nerves due to conduction block (CB)
  • In ≥2 motor nerves outside of common entrapment sites

Normal results are required for sensory nerve conduction studies.5 Laboratory and electrodiagnostic tests may help confirm the diagnosis but may not be definitive:3

  • CB on nerve conduction study: CB is the hallmark electrophysiological finding, however, it may not be detected and is not always necessary for diagnosis3
  • Immunoglobulin M (IgM) antibodies to ganglioside-monosialic acid (GM1) 
    • Present in approximately 50% of patients with MMN3
    • Antibodies against other gangliosides are present in a low percentage of patients and therefore have little diagnostic utility3
  • Cerebrospinal fluid (CSF) protein elevation: Normal or mild elevation (<1 g/L) in approximately 30% of patients3
  • Magnetic resonance imaging (MRI): Abnormal signal on brachial plexus MRI in approximately 40 to 50% of patients, including increased signal intensities in the brachial plexus and ventral rami of the roots on T2-weighted images which correspond to symptom distribution3
  • Nerve biopsy: Primary axonal degeneration and/or myelin pathology (limited studies)3,4,12

Pathophysiology

The exact mechanism of the disease is unknown.3 It is hypothesized that the slowed or faulty nerve conduction in MMN is due to demyelination of the myelin sheath or injury to the nerve itself by:3,13

  • Binding of anti-IgM antibodies to GM1 gangliosides
  • Complement protein recruitment
  • Membrane attack complex recruitment
  • Axonal damage

CB is the characteristic finding in MMN and is believed to be the underlying electrophysiological cause of muscle weakness.4 However, axon loss rather than CB is the most important determinant of permanent weakness and disability.3

Navigating MMN

A differential diagnosis is necessary to differentiate MMN from diseases with similar symptoms, such as ALS and chronic inflammatory demyelinating polyneuropathy (CIDP).3,4,5 Even with an accurate diagnosis, treatment options for MMN are limited and are aimed at modulating the aberrant immune responses.4,11,14,15

The goals of treatment are to:

  • Reverse motor CB15

  • Limit damage to axons to prevent permanent nerve damage8,15

  • Limit damage to myelin sheath and mitigate impaired signal conduction in nerves3,11

  • Improve strength and reduce disability4,7,14

  1. Genetic and Rare Disease Information Center. NIH — Multifocal motor neuropathy. https://rarediseases.info.nih.gov/diseases/11011/multifocal-motor-neuropathy. Accessed February 1, 2023. 
  2. Zivkovic S and Lorenzo N. Multifocal Motor Neuropathy With Conduction Blocks. Medscape. https://emedicine.medscape.com/article/1174021-overview. Accessed February 1, 2023.
  3. Vlam L, van der Pol WL, Cats EA, et al. Nat Rev Neurol. 2012;8(1):48-58. 
  4. Meuth SG and Kleinschnitz C. Eur Neurol. 2010;63(4):193-204. 
  5. Olney RK, Lewis RA, Putnam TD, et al. Muscle Nerve. 2003;27(1):117-121.
  6. Cats E, van der Pol WL, Piepers S, et al. Neurology. 2010;75(9):818-825.
  7. Van den Berg-Vos RM, Franssen H, Visser J, et al. J Neurol. 2001;249(3):330-336.
  8. Katirji B and Koontz D. Disorders of Peripheral Nerves. In: Neurology in Clinical Practice. Elsevier; 2012:1915-2015. 
  9. Nobile-Orazio E, Cappellari A, Priori A. Muscle Nerve. 2005;31(6):663-680. 
  10. International Alliance of ALS/MND Associations. What is ALS/MND? Published 2022. https://www.als-mnd.org/what-is-alsmnd/. Accessed February 1, 2023.
  11. Lawson VH and Arnold WD. Neuropsychiatr Dis Treat. 2014;10:567-576.
  12. Köller H, Kieseier B, Jander S, et al. N Engl J Med. Published online 2005:14.
  13. NIH. NINDS — Peripheral Neuropathy Fact Sheet. https://www.ninds.nih.gov/peripheral-neuropathy-fact-sheet. Accessed February 1, 2023. 
  14. van Schaik I, van den Berg LH, de Haan R, et al. Cochrane Database Syst Rev. 2005;(2).
  15. Hahn AF, Beydoun SR, Lawson V, et al. J Peripher Nerv Syst. 2013;18(4):321-330.

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