What is Multifocal Motor Neuropathy (MMN)
Multifocal Motor Neuropathy (MMN) is a rare form of acquired motor neuropathy that manifests as progressive asymmetric weakness in the absence of sensory deficits.
After being described in 1986, the syndrome has a relatively recent nosological history, dating back to 1986. When it comes to the upper limbs, it is usually more noticeable than when it comes to the lower limbs.
Electrodiagnostics often show asymmetric motor neuropathy with distinct conduction blockades. The vast majority of patients have anti-ganglioside antibodies in their serum IgM. (anti-GM1).
Intravenous immunoglobulin therapy often works well for these patients (IVIg).
This activity describes the diagnosis and treatment of multifocal motor neuropathy with conduction blocks. It emphasizes the critical role played by the healthcare team in providing the best possible care for patients suffering from this illness.
The syndrome is not classified as a neuropathy because it has a high clinical burden and a poor prognosis, but it is classified as such. In some cases, the symptoms are so mild that there is no need for medical intervention.
Decline in Muscle Strength
A progressive decline in strength will occur in the majority of patients, particularly in the hands and arms, which can result in difficulty performing even simple daily tasks like writing, washing, or putting on one’s clothes. On the other hand, these patients may benefit from pharmaceutical interventions, as they frequently respond favorably to intravenous immunoglobulin (IVIG).
What Causes MMN?
Inflammatory bowel disease (IBD) is a type of motor neuropathy that is believed to be caused by the immune system. Serum IgM anti-GM1 antibodies and IVIG response in these patients support this hypothesis. The higher concentration of GM1 in motor neuron myelin compared to sensory neuron myelin may be responsible for the MMN’s characteristic motor involvement.
The conduction block observed in MMN was previously thought to be caused by severe focal demyelination, which was previously believed to be the case. Anti-GM1 antibodies appear to impair sodium and potassium channels near the node of Ranvier of myelinated motor axons, which are required for conduction block. As a result, the term “nodo-paranodopathy” is occasionally used to describe the condition. Activation of the complement system is almost certainly involved in the disease pathogenesis.
Prevalence and incidence
With a global prevalence of less than 1 in 100,000 people, multifocal motor neuropathy is a relatively uncommon condition to be diagnosed with. The prevalence of MMN has been reported to be 0.65 per 100,000 people in Austria and 0.29 per 100,000 people in Japan.
Men are 2.7 times more likely than women to be affected by this condition. Aside from adults in their third to fifth decades, the disease has been reported in children as young as six, the elderly, and adults in their third to fifth decades.
MNCB is thought to be caused by anti-GM1 antibodies, which have been linked to its pathophysiology. Peripheral motor nerves have a higher concentration of GM1 than do sensory nerves. Ranvier nodes, which are located near the motor nerves’ peripheral motor endings, contain a higher concentration of GM1.
Although its exact function is unknown, it is believed to be responsible for stabilizing and clustering the ion channels near the Ranvier nodes, which are critical for propagation action potentials. A decrease in potential action propagation is caused by the disruption of these ion channels, which can be observed electrophysiologically as a conduction block and a reduction in conduction velocity.
Anti-GM1 antibodies are common in MMNCB, but not always. The pathophysiology of motor neuron dysfunction without anti-GM1 antibodies is still debated. These patients may have anti-GM1 titers that are undetectable, or they may have multiple antibodies directed against different antigens in their system. Patients with MMNCB who have anti-GM1 antibodies and those who do not have anti-GM1 antibodies, on the other hand, have clinical characteristics that are identical.
History and Progression
When MMN manifests clinically, affected individuals experience progressive asymmetric muscle weakness that can range from subacute to chronic in nature. It is possible that the initial complaint will be unilateral wrist drop, hand weakness, or foot drop. Leg weakness is possible, despite the fact that the muscles of the upper limbs are primarily affected.
The cold has the potential to exacerbate the weakness. Despite the fact that sensory symptoms such as tingling and pain are not uncommon, they are usually mild.
Muscle cramps, twitching, fasciculation, and abnormal fatigue are all possible side effects in some patients. These patients rarely have cranial nerve, bulbar, or respiratory muscle involvement.
Distal muscle weakness in the motor nerve distribution is discovered during a physical examination. When the radial nerve is involved, the extensor muscles of the wrist and fingers are more severely affected than when the triceps is involved. Some muscles within a myotome may be spared the pain of sharing a nerve with other muscles.
While the abductor pollicis Brevis (APB) and abductor depressor minimi (ADM) share the same myotome (C8-T1), the median nerve affects only the abductor pollicis Brevis (APB). Muscle atrophy occurs late in the disease’s progression and is often mild compared to the associated muscle weakness. Depending on the injury, the deep tendon reflexes may be normal or asymmetrically reduced. Upper motor neuron signs are typically absent in this condition, allowing for a clear distinction between it and amyotrophic lateral sclerosis, which is more common in the latter (ALS). Myokymia can occur in muscles that have been affected by myokymia.
The electrophysiological findings are consistent with multifocal motor neuropathy with normal sensory nerve conduction. Longer motor nerve latencies and slower conduction velocities are two signs of demyelination that can be detected. It is possible for F-wave responses to be absent or to be prolonged.
A motor conduction block and temporal dispersion in the motor output signal define MMNCB. The conduction block is absent or cannot be evaluated using routine nerve conduction studies due to its proximity. Proximal conduction blocks may reduce the recruitment of MUAPs in weak muscles, which can be detected using electromyography.
In this case, the CMAP amplitude or area is reduced by more than 50% between the proximal and distal nerve stimulation sites. It often indicates a new condition. Rarely, non-compressible sites are affected by MMNCB. Conduction blocks across known sites of nerve entrapment (e.g., the median nerve at the wrist) cannot be used to diagnose MMNCB. Conduction block occurs in addition to MMNCB in acquired demyelinating conditions like CIDP and Guillain-Barre syndrome (GBS).
Routine blood and urine tests for MMN patients are unremarkable. The protein level in the cerebrospinal fluid (CSF) is frequently normal or slightly elevated, depending on the condition. This is a critical feature that distinguishes MMN from CIDP and should not be overlooked.
The National Institutes of Health say that about half of all MMN cases have GM1 ganglioside antibodies. Treatment does not appear to have any effect on anti-GM1 titers, on the other hand. Anti-GM1 antibodies, even though they are not specific for MMN and can be found in the AMAN variant of GBS, help confirm the diagnosis. Look for GM1/galactocerebroside (GM1/GalC) complexes to improve antibody detection sensitivity.
The American Society of Neuroradiology says nerve ultrasound and MRI can help diagnose patients when electrophysiological tests are inconclusive. Indeed, when conduction blocks are not detectable or when a progressive axonal loss occurs, diagnosing MMN can be challenging.
Approximately half of the patients with MMN and CIDP have T2 hyperintense signals in the brachial plexus, with or without contrast enhancement. While MN signals are asymmetrical and often unidirectional, CIDP signals are bidirectional and symmetrical.
High-resolution ultrasound imaging may reveal an increase in the median and ulnar nerves’ cross-sectional area in MMN compared to controls (HRUS). Due to the fact that nerve diameters are typically reduced in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis (ALS), this finding is beneficial when clinical differentiation between the two conditions is difficult.
These diagnostic criteria were revised in 2010 by the Task Force of the European Federation of Neurological Societies (EFNS) and the Peripheral Nerve Society (PNS) to assist in the diagnosis of multiple myeloma neuropathy (MMN).
Standard Mandatory Criteria
- slowly progressive, focal asymmetric limb weakness that has been present for at least one month and is defined as motor involvement in the motor nerve distribution of at least two nerves (usually more than six months). If symptoms and signs are present in only one nerve’s distribution, it is only possible to make a diagnosis based on the evidence.
- There are no objective sensory abnormalities in the lower limbs, with the exception of minor vibration sense abnormalities in the limbs.
Supportive Clinical Criteria
- Predominant involvement of the upper limbs
- Tendon reflexes in the affected limb are diminished or absent.
- Absence of involvement of the cranial nerves
- In the affected limb, cramps and fasciculations
- Immunomodulatory treatment response
- Signs of the upper motor neuron
- Significant bulbar involvement
- Sensory impairment is more pronounced in the lower limbs than minor vibration loss.
- During the initial weeks, there is widespread symmetric weakness.
Treatment / Management
For MMNCB, IVIg is the primary pharmacological treatment option available. Notably, IVIG treats over 75% of patients.
However, the improvement in muscle strength is only temporary, with only 20% of patients experiencing a long-term symptom remission.
The vast majority of patients require IVIg infusions on a regular basis.
It is possible that, despite routine IVIg infusions, motor deficits will worsen over time due to secondary axonal damage in the brain. According to a Cochrane review, IVIG is superior to a placebo in treating MMPN.
IVIG Infusion Rates
Initially, IVIG is given at 0.4 g/kg/day for five days, totaling 2 g/kg.
Some clinicians administer IVIG at a rate of 1 g/kg per day for two days.
Depending on the patient’s condition, maintenance IVIg infusion rates range from 0.04 g/kg weekly to 2 g/kg every eight weeks.
Due to the fact that Ig is typically administered for an extended period of time, often years, the subcutaneous route was investigated. The results of these studies show that SCIG is safe, effective, and easy to administer at home. SCIG is administered in the same way that IVIG is administered.
Non-responders have few treatment options available to them. Various immunomodulatory agents have been used to treat cancer, with varying degrees of success.
Oral cyclophosphamide has been shown to maintain disease remission and decrease IGIg frequency effectively, but it has significant side effects.
In 2007, an RCT involving 28 patients found no significant difference between mycophenolate mofetil plus IVIG and IVIG alone in patients with MMN. The efficacy of immunomodulatory drugs in multiple myeloma necrosis (MMN) must be established through multiple comparative randomized controlled trials (RCT).
In patients with MMN, corticosteroids and plasmapheresis are ineffective treatments.
ALS, CIDP, and hereditary neuropathy with susceptibility to pressure palsies are important differential diagnoses for multifocal motor neuropathy (HNPP). Notably absent from the list are radiculopathy, entrapment neuropathies, mononeuritis multiplex, hereditary motor neuropathies, porphyria, and lead intoxication.
Hereditary Neuropathy with Liability to Pressure Palsies
Electrodiagnostic studies reveal an asymmetric motor weakness in the distribution of multiple motor nerves and a conduction block in HNPP. Consistently found at known sites of nerve entrapment, these conduction blocks are beneficial (e.g., the median nerve at the wrist and the ulnar nerve at the elbow).
Sensory symptoms are also common in HNPP patients. Because the condition is autosomal dominant, it is common for affected people to have a strong family history. HNPP is genetically detectable due to a deletion of the PMP-22 gene. The treatment is supportive, and most patients recover on their own.
Chronic Inflammatory Demyelinating Polyneuropathy
Deep tendon reflexes and conduction blocks on electrodiagnostic studies are diminished or absent in patients with CIDP, which is characterized by chronic muscle weakness. The legs muscles are typically more affected than the arms in CIDP, despite muscle weakness being frequently symmetrical.
CIDP Vs. MMN
In contrast to MMN, where sensory involvement is more common, motor involvement is rare, making differentiation from MMN difficult. In patients with CIDP, CSF analysis reveals elevated protein levels as well as significant cytoalbuminologic dissociation. Antibodies against GM1 are frequently absent from the bloodstream. Corticosteroids and plasmapheresis are also beneficial in the treatment of patients with CIDP.
MADSAM is a rare CIDP variant that affects single nerves and appears to be similar to MMN. A genetic mutation causes it. MADSAM, on the other hand, is distinguished from MMN by the presence of distinct sensory signs and symptoms and electrodiagnostic studies demonstrating sensory nerve involvement.
Amyotrophic Lateral Sclerosis
The progressive pure motor weakness associated with both ALS and MMN is the same, but MMNCB progresses more slowly than ALS on average. MMN and ALS also differ in the absence of upper motor neuron findings and the preservation of respiratory and cranial muscles.
Muscle weakness in multiple myeloma occurs in the motor nerve distribution and does not follow myotomes in most patients. Muscle atrophy is less noticeable in the early stages of the disease. According to electrodiagnostic studies, there is a pattern of demyelination accompanied by conduction blockades in the brain.
ALS typically affects the entire myotome at once. This condition causes muscle atrophy and fasciculation. The presence of a split hand sign, which is characteristic of ALS, may be observed. It is possible to experience a pseudobulbar effect. The results of nerve conduction studies are consistent with the norm. An EMG of the needle may reveal evidence of denervation. It is critical to distinguish between MMN and ALS because the former responds well to treatment while the latter does not.
Survival rate or Prognosis
The Prognosis for multifocal motor neuropathy is generally favorable. IVIG therapy is effective in approximately 80 percent of patients. The remainder requires IVIG or SCIG therapy on a periodic basis. Muscle weakness progresses slowly in non-responders, and most patients can go about their daily lives without assistance.
In one study, over 94 percent of those who took part in it remained in their jobs. The Rasch-developed Overall Disability Scale for Multiple Myeloma was validated in 2015. (MMN). It is a 25-item questionnaire designed to track disease progression and treatment response.
Because the cranial and respiratory muscles are spared, multifocal motor neuropathy is rarely fatal. The vast majority of complications are related to the treatment process itself.
- These include thromboembolic events (myocardial infarction, stroke, or deep vein thrombosis), renal failure, allergic reactions, aseptic meningitis, and transfusion-associated acute lung injury.
- Cyclophosphamide can cause interstitial pneumonitis, hemorrhagic cystitis, and bone marrow suppression, among other side effects.
Right now, there are no known effective strategies for preventing this syndrome from manifesting itself. The need to educate patients about the disease’s diagnosis and natural history cannot be overstated. In the vast majority of cases, IVIg and SCIg treatments will be required for an extended period of time.
These treatments can be expensive and have unintended side effects. Despite routine treatment, the disease may progress, but it is almost always not fatal in its early stages.
Writing and other skilled hand movements may be restricted as a result of multifocal motor neuropathy, which primarily affects the hand muscles.
Improving Healthcare Team Results
The outpatient setting should provide patients with regular visits to a primary neurologist and physical and occupational therapists to address their neurological symptoms. As a result of the predominant involvement of distal muscles in the upper limbs in multifocal motor neuropathy, fine motor skills such as writing and drawing may be significantly impaired.
Therefore, it is recommended that patients receive regular physiotherapy and occupational therapy treatments to alleviate their symptoms.
QUESTIONS TO ANSWER
* What is multifocal motor neuropathy MMN )?
It is a rare form of acquired motor neuropathy that manifests as progressive asymmetric weakness in the absence of sensory deficits. After being described in 1986, the syndrome has a relatively recent nosological history, dating back to 1986. When it comes to the upper limbs, it is usually more noticeable than when it comes to the lower limbs. Electrodiagnostics often show asymmetric motor neuropathy with distinct conduction blockades.
* Is MMN an autoimmune disease?
Nobody knows for sure what causes MMN. Scientists have determined that it is an autoimmune disease, which means that your immune system mistakenly perceives your nerve cells as intruders and launches an attack against them. It is the goal of researchers to learn more about the disease and determine why it manifests itself.
* What are the symptoms of multifocal motor neuropathy?
If you have MMN, the first symptoms will most likely manifest in your hands and lower arms. Your muscles may feel sluggish and cramp or twitch in ways that you are unable to control. It may begin in a particular area of the arm or hand, such as the wrist or finger. Typically, one side of your body will exhibit more severe symptoms than the other. Your legs may eventually be affected by the disease.
* Can MMN affect breathing?
MMN does not cause premature death or significant difficulties breathing or swallowing, except for rare instances. It can, however, cause considerable dysfunction and disability, and the disorder appears to last indefinitely, with only a tiny percentage of cases returning to remission for an extended period.
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Dr. Stephanie Shieh, PharmD was born in Kentucky and raised in Southern Los Angeles. She attended the Western University of Health Sciences and has been a practicing pharmacist for 7 years. The most rewarding part of her job is seeing her patients happy – whether it’s helping them understand their medication, catching a drug interaction, or being able to communicate with their doctor to improve their therapy. She is currently precepting students from Marshall B. Ketchum University. In her free time, she enjoys spending quality time with her husband and 2 daughters. They love playing outside, doing arts and crafts, and having family dinner.