A Practical Guide to Identify Patients With Multifocal Motor Neuropathy, a Treatable Immune-Mediated Neuropathy

Multifocal motor neuropathy (MMN) is a rare immune-mediated motor neuropathy characterized by asymmetric weakness that preferentially affects distal upper limb muscles. The clinical features of MMN may be difficult to differentiate from motor neuron disease. Other conditions that may be mistaken for MMN include inclusion body myositis, chronic inflammatory demyelinating polyradiculoneuropathy, hereditary neuropathy with liability to pressure palsy, focal neuropathies, and radiculopathies. A key distinguishing electrophysiologic feature of MMN is the motor nerve conduction block located at noncompressible sites. MMN is a treatable neuropathy; therefore it is important that primary care physicians are aware of the features of the disease to identify potential patients and make referrals to a neuromuscular specialist in a timely manner. This review provides an overview of the disease, highlights key differential diagnoses, and describes available treatment options for patients with MMN.


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ultifocal motor neuropathy (MMN) is a rare, immune-mediated neuropathy with a prevalence of less than 1 in 100,000. 1,2As with many rare diseases, recognizing characteristic clinical features of the disease can be challenging, especially when other disorders with overlapping signs and symptoms are far more common.In a study of 46 patients who eventually turned out to have MMN at a neuromuscular center, only 6 had been referred for suspected MMN. 3 The MMN diagnostic delay is common, often taking more than a year before the diagnosis is confirmed. 3,4When the diagnosis is delayed, treatment is as well, which may lead to missed opportunities to prevent the accumulation of irreversible neurologic impairment and disability. 4,5MN-associated weakness is often attributed to other conditions before a diagnosis of MMN is established.Motor neuron disease, or amyotrophic lateral sclerosis (ALS), is one common MMN mimic.4 Unlike ALS, in which median survival is 3-5 years after symptom onset, MMN is a treatable, non-life-threatening disease with a normal life expectancy.4 Other conditions with different prognostic and treatment opportunities that may be mistaken for MMN include inclusion body myositis (IBM), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), focal or entrapment neuropathies, and radiculopathies.6,7 Furthermore, because of the frequency with which focal neuropathies and radiculopathies occur, they represent an important group of conditions to highlight.
The implications of misdiagnosis may be substantial, potentially exposing patients to inappropriate medications or surgeries, delaying the initiation of disability-modifying MMN treatment, and placing an emotional burden on patients that can detrimentally affect the quality of life.The intent of this review is to differentiate the key features of MMN from more common mimics to help clinicians who do not routinely encounter MMN in their practice identify patients who may benefit from an expeditious referral to a neuromuscular specialist.

MMN: Key Clinical and Laboratory Features
MMN affects men more commonly than women, with a ratio of about 3:1. 8 Disease onset for most patients is in the fourth or fifth decade of life. 1,2In 80% of patients, weakness first develops in the upper limbs and preferentially targets distal muscles. 3Approximately 20% of patients experience the onset of weakness in the lower limbs. 3Weakness is typically focal and asymmetric, following the distribution of individual named nerves. 6After onset, some patients experience slowly progressive worsening, whereas others can have stepwise or abrupt deteriorations as new motor nerves become affected. 6Although w20% of patients with MMN report mild distal lower limb sensory changes, sensory loss and neuropathic pain are otherwise not part of the MMN clinical spectrum. 2,6Cramps and fasciculations may occur in the affected limbs of up to 40% of patients. 2Cranial nerve involvement is distinctly unusual.On neurologic examination, deep tendon reflexes may be reduced in the affected limb (but intact in areas without weakness) and pathologic upper motor neuron signs should not be present. 6MN is thought to be caused by dysfunction at the node of Ranvier rather than in the myelin or axon. 2 Nodal dysfunction prevents propagation of electrical impulses down the course of a nerve, which in turn, leads to the classical MMN electrophysiological finding on nerve conduction studies (NCS) of conduction block (CB). 2 Electrophysiologic studies may also reveal conduction velocity slowing and prolonged minimum F-wave latency. 1 CB is not always appreciated in patients who otherwise have a strong clinical case for MMN.1,2 Failure to detect CB can occur when it is located in proximal nerve segments.1 In patients with longstanding disease, axon loss can lead to muscle atrophy on examination and loss of compound muscle action potential amplitude on NCS.7 In these patients with equivocal electrophysiologic changes, laboratory testing can help support the diagnosis of MMN.
Anti-monosialotetrahexosylganglioside (anti-GM1) immunoglobulin (Ig)M antibodies may be detected in at least 40% of patients with MMN. 9 Anti-GM1-positive patients more often have severe weakness, disability, and eventual axon loss than seronegative patients. 9It has been suggested that anti-GM1 antibodies induce complement-mediated injury at the nodes of Ranvier, which leads to CB and weakness. 2Thickened nerves on magnetic resonance imaging or ultrasound or objective responses to treatment with intravenous immunoglobulin (IVIG) also supports the diagnosis of MMN. 2,6N Burden of Disease Disability in MMN can be variable.Because of the preferential involvement of the distal upper limbs, most patients develop restrictions related to fine motor skills of the hand, causing limitations with household, professional, and leisure activities.10 Distal lower limb weakness can also limit walking ability.3 An important predictor of irreversible disability is the development and accumulation of axon loss, which can be exacerbated when the diagnosis and initiation of treatment are delayed.5,10 Although the physical burdens of the disease are apparent, there is also a psychological burden that may not be as noticeable.In 1 cohort of 17 patients with MMN, overall quality of life was reduced.11  affected, but psychological aspects were also affected, especially for patients with a longer disease duration.11 Economic burden because of the cost of treatment or lost employment may add to the psychological burden of the disease.Such factors vary greatly, depending on the health care system of the country or region where patients receive treatment, available support networks, and travel costs to sites of care.nerves for more than 1 month; and (2) no objective sensory abnormalities, except for minor vibration sense abnormalities in the lower limbs.6 Exclusion criteria for the diagnosis of MMN include the presence of upper motor neuron (UMN) signs, marked bulbar involvement, marked sensory loss, and symmetric weakness during the initial weeks of disease.6 Motor CB is the main electrophysiological criterion in the diagnosis of MMN. Alhough CB is most commonly found in mid-forearm nerves, it may also be present in more proximal areas that are difficult to assess with NCS. 6 For CB to support a diagnosis of MMN, its location must not be at common sites of compression (eg, median nerve at the wrist or ulnar nerve at the elbow).6 If weakness and CB at noncompressible sites are present in 2 or more nerve distributions, then a diagnosis of MMN can be strongly considered. 6For specific descriptions of definite and probable motor CB, please refer to the published guidelines.6

Differential Diagnoses
In Table 1, we provide an overview of the key clinical features for the differential diagnoses of MMN. Figure 1 presents a general approach that clinicians may take to identify patients with a motor neuropathy.
Amyotrophic Lateral Sclerosis.ALS is a degenerative disorder of motor neurons that presents clinically as asymmetric weakness without sensory loss. 4,12In its classic form, ALS is characterized by UMN and lower motor neuron (LMN) signs and symptoms in the same limb or body segment, with multiple body segments (bulbar, cervical, thoracic, and lumbosacral) that are affected as the disease progresses.arm syndrome), or lumbosacral (flail leg syndrome) segments. 12n contrast to the multifocal pattern of weakness in MMN that follows named nerve distributions, weakness in ALS follows a distribution that can be mapped to spinal cord segments. 4,6Weakness in ALS typically progresses in a predictable pattern as contiguous spinal cord segments become affected. 4,5n MMN, weakness may progress in a stepwise manner with periods of stable disease and unpredictable spreading from nerve to nerve. 4,6n examination, most patients with ALS present with UMN signs (hyperreflexia), whereas in MMN, reflexes tend to be absent or reduced. 4,6LMN signs (atrophy and fasciculations) are present in both conditions but are more prominent and widespread in ALS. 4 Bulbar (dysarthria or dysphagia) and respiratory involvement are common in ALS but infrequent in MMN. 4 Although the presence of UMN signs strongly favors a diagnosis of ALS, not all forms of ALS have UMN involvement. 4The LMN ALS variants can be more difficult to differentiate from MMN. 4 For these patients, the pattern of weakness and electrophysiological features play a key diagnostic role: MMN weakness is along the named nerve distributions and usually has CB on electrophysiologic testing, whereas in ALS weakness is segmental and electrophysiologic testing shows denervating and reinnervating changes without CB. 4,6If CB is not found but suspicion of MMN remains, imaging with an MRI or ultrasound may be helpful. 2,6The presence of nerve enlargement or enhancement in nerve segments that are clinically affected would favor a MMN diagnosis, whereas their absence may more likely suggest ALS. 2 Spinal Muscular Atrophy.Spinal muscular atrophy (SMA) comprises a group of hereditary diseases caused by damaged motor neurons. 12Although disease onset occurs very early in life for most patients (ie, SMA types I, II, and III), those with SMA IV may present in early adulthood. 12Unlike MMN, weakness in SMA IV preferentially affects the lower limbs in a relatively symmetric proximal pattern. 12ulbar dysfunction may also occur. 12Both NCS and electromyography (EMG) in SMA show active denervation and chronic reinnervation changes, rather than multifocal CB. 13 In suspected cases of SMA, identification of an SMN1 sequence variation with genetic testing may be diagnostic. 12clusion Body Myositis.IBM is an acquired muscle disorder that, similar to MMN, presents as painless and asymmetric weakness predominantly affecting men in mid and late life. 14The pattern of weakness plays a key role in IBM diagnosis, as it characteristically affects the finger or wrist flexor muscles and knee extensor muscles early in the disease course. 14Dysphagia, which is unusual in MMN, may be involved in between 40% and 80% of patients with IBM. 14,15Creatine kinase is typically elevated ( 15 Â upper limit of normal) in IBM but is normal or only minimally elevated in MMN. 14 IBM is a chronic active myopathy; therefore, EMG can be an important tool to distinguish IBM from MMN. 14 Chronic Inflammatory Demyelinating Polyradiculoneuropathy. CIDP is an immunemediated neuropathy that causes both numbness and weakness. 1,5Multifocal CIDP, a variant of CIDP, is similar to MMN in that it also manifests as asymmetrical weakness and may follow the distribution of individual named nerves.The differentiating clinical and electrophysiological feature between these 2 neuropathies is the presence of sensory involvement. 5,16Although CB as a key electrophysiological feature can be present in both MMN and CIDP, there is usually a lack of other demyelinating changes in MMN.In CIDP, widespread demyelinating changes including distal latency prolongation and slowing of conduction velocity are required. 2,16Cold paresis, where patients experience worsening of weakness in cold conditions, is a common symptom of MMN and not frequently seen in patients with CIDP. 17Cerebrospinal fluid (CSF) protein analyses can be considered in patients with CIDP or MMN; patients with MMN tend to have normal CSF protein levels, while patients with CIDP often have elevated CSF protein levels. 5,16Also, CIDP and MMN differ in prognosis and treatment paradigms.While both conditions respond to IVIG, unlike patients with CIDP, those with MMN may paradoxically worsen when exposed to corticosteroids and plasma exchange. 5,16reditary Neuropathies.Hereditary neuropathy with liability to pressure palsy (HNPP) is an uncommon mimic of MMN but an important consideration in certain populations. 2,6Unlike with MMN, where onset before 40 years of age is unusual, with HNPP, symptoms often manifest in the second or third decades of life. 18Similar to patients with MMN, those with HNPP present with asymmetric weakness and can have CB on electrodiagnostic studies. 5,18Although these features overlap with MMN, CB in HNPP is often present at common sites of nerve compression. 18Clinical and electrophysiological evidence of sensory loss is also present in HNPP. 18Approximately 80%-90% of patients with HNPP have a deletion of the PMP22 gene. 18Other genetically determined mimics of MMN may include hereditary motor neuropathies.When HNPP is suspected in patients who develop progressive weakness predominantly affecting the lower limbs, with an onset before 20 years of age, genetic testing can be diagnostic. 12rayama Disease.Hirayama disease is a rare disease that clinically manifests in a similar manner to MMN.Patients with Hirayama disease are more commonly men and present with unilateral or asymmetric distal weakness in the upper extremities with no sensory loss. 19Characteristics that can discriminate Hirayama disease from MMN include the age of onset, as Hirayama often appears during puberty (12-20 years of age), and imaging that shows asymmetric cord flattening and lower cervical cord atrophy. 19cal Neuropathies.Focal nerve entrapment or compression may be mistaken for MMN, especially in the early stages of the disease.Median neuropathy at the wrist (ie, carpal tunnel syndrome), ulnar neuropathy at the elbow (ie, cubital tunnel syndrome), radial neuropathy at the spiral groove (ie, Saturday night palsy), and peroneal neuropathy across the fibular head are the most commonly encountered focal neuropathies. 20,21Sensory symptoms and pain are common in these conditions.The absence of sensory findings may raise the possibility of MMN. 3,6,20NCS are also critically important for diagnosis.The location of CB in focal neuropathies is always across the site of compression or entrapment, but adjacent nerve segments should be normal. 20,21If CB is present in a motor nerve at a noncompressible site (eg, in the forearm rather than across the wrist or across the elbow) and sensory nerve conduction is normal, then suspicion of MMN is heightened. 6Other features of MMN, including fasciculations, cramps, and reduced reflexes, are also typically not appreciated in focal neuropathies. 6,21diculopathies.Cervical and lumbosacral radiculopathies may present with asymmetric weakness and diminished or absent reflexes in the affected limb. 22,23However, patients with radiculopathies also experience radiating neck or back pain and sensory disturbances in the affected limb. 22,23The distribution of weakness and numbness follows nerve root distributions as opposed to the individual motor nerve pattern in MMN. 6,22,23Both NCS and EMG play an important diagnostic role for radiculopathy. 23While both conditions can have abnormal motor NCS and normal sensory NCS, in radiculopathy the denervation and reinnervation changes may be mapped to a nerve root rather than a specific nerve distribution, and CB is not present. 6,23MRI can be used to view the cervical and lumbosacral spines to assess the source of impingement. 22,23eatment and Management of MMN IVIG is first-line treatment for patients with MMN. 2 Efficacy is established on the basis of several randomized clinical trials that have reported improved muscle strength and amelioration of disability in treated patients. 6These results have informed MMN treatment guidelines, which advise induction therapy with IVIG 2 g/kg administered over 2-5 days and maintenance therapy with IVIG 1 g/kg every 2-4 weeks or 2 g/kg every 1-2 months. 6ubcutaneous immunoglobulin (SCIG) has also been investigated for the treatment of patients with MMN. 6 For those with MMN who are IVIG-responsive, SCIG is shown to be as safe, tolerable, and equally effective as IVIG. 24,25Unlike other immune-mediated neuropathies, corticosteroids and plasma exchange are usually not effective and may worsen weakness in patients with MMN. 6 Adherence to accepted standards of practice, such as those provided by the Immunoglobulin National Society for Ig therapy in the United States, is vital to optimizing clinical outcomes for patients receiving Ig therapy. 26trategies to mitigate IVIG-associated adverse events include completion of a risk assessment by a certified Ig pharmacist, assessment of comorbidities, proper hydration, and appropriate infusion rate titration. 26For SCIG, ensuring appropriate needle size, number of infusion sites, and administration technique is critical to optimizing patients' experience. 26ther than Ig, there are no proven effective therapies for MMN. 2 Although some case reports or case series have reported benefits with immunosuppressant therapies such as cyclophosphamide and mycophenolate, the risks for each treatment must be weighed against the uncertain benefits. 27For example, an uncontrolled study of 6 patients with MMN treated with oral cyclophosphamide reported improvements in Rankin disability scores, upper and lower limb impairment scores, and muscle strength. 28However, because of the toxicity associated with cyclophosphamide and the lack of evidence surrounding its efficacy in a controlled setting, guidelines do not recommend it as a desirable treatment option for patients with MMN. 6 Summary and Implications for Primary Care MMN is characterized by asymmetric weakness without pain or sensory loss. 6The pattern of weakness follows the distribution of individual named nerves and most commonly affects the distal upper limbs. 2,3,6Mimics of MMN may include ALS, CIDP, HNPP, IBM, focal neuropathies, and radiculopathies. 6,7The pattern of weakness, absence of sensory findings or pain, and CB on electrophysiological testing at noncompressible sites are key features that raise suspicion of MMN. 6 When a diagnosis of MMN is considered, we encourage referrals to neuromuscular centers with expertise in the diagnosis and treatment of rare inflammatory neuropathies (https://www.gbs-cidp.org/support/centers-of-excellence/).
Physical domains were the most bility to pressure palsy, inclusion body myositis, focal neuropathies, and radiculopathies, which may be suspected before the identification of MMN.dThe pattern of weakness, absence of sensory findings or pain, and conduction block at noncompressible sites are key features that can raise suspicion of MMN.dWhen MMN is considered, referrals to a neuromuscular center with expertise in the diagnosis and treatment of rare inflammatory neuropathies are encouraged (https://www.gbs-cidp.org/support/centers-of-excellence/).

TABLE 1 .
5,12,14,[17][18][19][20][21][22]l Diagnoses of MMN5,12,14,[17][18][19][20][21][22] 52Pain, paresthesia, and sensory loss in the hand d Weakness of thumb abduction and opposition may develop after sensory loss Ulnar neuropathy at the elbow (ie, cubital tunnel) d Pain, paresthesia, and sensory loss in digit 4 and digit 5 of the hand d Weakness of the intrinsic hand muscles and grip weakness may develop after sensory loss Radial neuropathy at the spiral groove (ie, Saturday night palsy) d Abnormal sensory changes in the dorsum of the hand and along the posterior aspect of the arm d Weakness in finger extensors and wrist extensors Peroneal neuropathy at the fibular head d Often presents as foot drop that can range from a minor dragging of the toes to a steppage gait d Pain, numbness, paresthesia, and sensory loss may be present in the outer portion of the calf and top of the foot Radiculopathies Cervical radiculopathies d Commonly present as unilateral neck pain with radiation into the arm of the same side d Muscle weakness and sensory loss can manifest across varying locations down the arm Lumbosacral radiculopathies d Commonly present as unilateral low back pain with radiation into the leg of the same side d Muscle weakness and sensory loss can manifest across varying locations down the leg Abbreviations: ALS, amyotrophic lateral sclerosis; CB, conduction block; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; HNPP, hereditary neuropathy with liability to pressure palsy; IBM, inclusion body myositis; LL, lower limb; LMN, lower motor neuron; MMN, multifocal motor neuropathy; UL, upper limb.Adapted from Garg et al12and Lawson et al.5 General approach for the identification of patients with motor neuropathy.ALS, amyotrophic lateral sclerosis; CB, conduction block; CK, creatine kinase; EMG, electromyography; IBM, inclusion body myositis; NCS, nerve conduction studies; MMN, multifocal motor neuropathy; UMN, upper motor neuron.