Multifocal motor neuropathy

INTRODUCTION — Multifocal motor neuropathy (MMN), also known as multifocal motor neuropathy with conduction block, is a rare neuropathy characterized by progressive, asymmetric weakness and atrophy without sensory abnormalities, a presentation similar to that of motor neuron disease. This review will discuss the clinical aspects of MMN. Other immune-mediated neuropathies are discussed separately. (See "Immune-mediated neuropathies".)

PATHOGENESIS — MMN is considered an immune-mediated disorder given the following observations [1-3]:

●Clinical improvement with intravenous immune globulin (IVIG) therapy

●The presence of anti-GM1 antibodies in many but not all patients

●A perivascular lymphocytic infiltration observed on nerve biopsy in some reports

However, it is unclear whether anti-GM1 antibodies are involved in the pathogenesis of MMN or are merely an epiphenomenon of the disease [3,4]. Elevated titers of anti-GM1 antibodies may be seen in 30 to 80 percent of patients [2,5-7]. There are several reports of patients developing MMN after treatment with anti-tumor necrosis factor-alpha (anti-TNF-alpha) antibodies (eg, infliximab, adalimumab, ixekizumab) [8,9].

Although MMN is associated with conduction block on electrodiagnostic studies, segmental nerve demyelination is not a consistent feature of MMN, and some degree of axonal loss is often present [3]. One hypothesis is that the conduction block may be caused by an antibody-mediated attack affecting sodium channels and other nerve components at the nodes of Ranvier [10,11].

EPIDEMIOLOGY — MMN is a rare condition. The estimated prevalence of MMN is 0.6 to 2 per 100,000 population [4,12]. Males are affected more frequently than females, with a ratio of 2.7:1 [12]. Disease onset usually occurs between ages 20 to 50 years, with a mean onset ranging from age 30 to 40 years [4]. Although rare, intravenous immune globulin (IVIG)-responsive MMN has been described in children as well [13].

CLINICAL FEATURES — The typical clinical presentation of MMN is one of subacute onset with asymmetric weakness [1]. Lower motor neuron signs often present in a bibrachial pattern, producing arm and hand weakness without associated sensory loss [5,14]. The weakness usually begins as a focal mononeuropathy affecting the distal arms; wrist drop and hand weakness are common initial symptoms [15]. However, MMN can also present in the legs.

The neuronal involvement in MMN is typically patchy, with some nerves unaffected and others severely involved. In one series of 88 patients, onset of muscle weakness involving the distal arm or distal leg was noted in 61 and 34 percent of patients, respectively [12]. In patients with arm onset, progression usually involves spread of the weakness to the contralateral arm followed by the legs [1]. Some patients develop fasciculations or cramps. Muscle atrophy occurs late in the course of the disease. Deep tendon reflexes are variably affected, being decreased in most cases but normal or brisk (but not pathologic) in others [12]. Cranial nerves, bulbar muscles, and respiratory muscles are most often spared in MMN.

Motor nerve conduction studies often show evidence of conduction block, representing focal demyelination. Sensory conduction through the same segment of nerve is normal. (See "Overview of nerve conduction studies", section on 'Conduction block'.)

DIAGNOSIS — The diagnosis of MMN is suspected on the basis of a compatible clinical presentation with progressive, usually asymmetric weakness without sensory abnormalities, upper motor neuron signs, or bulbar involvement. The diagnosis is supported by nerve conduction studies that demonstrate focal demyelination and conduction block (see "Overview of nerve conduction studies", section on 'Conduction block') in motor nerves and normal sensory nerves [1]. However, some patients have a similar clinical disorder but lack conduction block on nerve conduction studies, and this has been termed multifocal motor neuropathy without conduction block (MMNWOCB) [14,16-18]. Other findings that support the diagnosis include finding abnormal A waves on electrodiagnostic studies [19], axonal sprouting in motor nerve biopsies [20], and abnormal hyperintense T2 signal and fascicular enlargement in affected nerves on magnetic resonance imaging (MRI) neurography [21,22]. In these patients who lack conduction block, responsiveness to treatment with intravenous immune globulin (IVIG) is another supportive feature for the diagnosis of MMN [3,14,23].

Of note, conduction block can be missed on routine nerve conduction studies, particularly if demyelination is proximal or patchy [1]. Therefore, an extensive survey of multiple nerves in upper and lower limbs should be performed using proximal stimulation (Erb's point) and late responses (F waves and H reflex) to assess proximal nerve segments. (See "Overview of nerve conduction studies", section on 'Late responses'.)

Cerebrospinal fluid is acellular, and protein is typically normal.

Diagnostic criteria — Diagnostic criteria for MMN have been proposed by the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) [24].

The two core criteria for MMN (both must be present) are [24]:

●Slowly progressive or stepwise progressive, focal, asymmetric limb weakness; that is, motor involvement in the motor nerve distribution of at least two nerves, for more than one month. If symptoms and signs are present only in the distribution of one nerve, only a possible diagnosis can be made.

●No objective sensory abnormalities except for minor vibration sense abnormalities in the lower limbs.

Supportive clinical criteria are as follows [24]:

●Predominant upper limb involvement

●Decreased or absent tendon reflexes in the affected limb

●Absence of cranial nerve involvement

●Cramps and fasciculations in the affected limb

●Response in terms of disability or muscle strength to immunomodulatory treatment

Exclusion criteria are the following [24]:

●Upper motor neuron signs

●Marked bulbar involvement

●Sensory impairment more marked than minor vibration loss in the lower limbs

●Diffuse symmetric weakness during the initial weeks

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of MMN primarily involves conditions that cause progressive limb weakness and atrophy without sensory loss and without upper motor neuron or bulbar manifestations [24].

The main consideration in the differential diagnosis is amyotrophic lateral sclerosis/motor neuron disease. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

In addition, the differential includes the lower motor neuron variants of amyotrophic lateral sclerosis:

●Progressive muscular atrophy (see "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Progressive muscular atrophy')

●Flail arm syndrome (see "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Flail arm syndrome')

●Flail leg syndrome (see "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Flail leg syndrome')

Other considerations in the differential diagnosis of MMN include the following [24]:

●Chronic inflammatory demyelinating polyneuropathy (see "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis")

●Multifocal acquired demyelinating sensory and motor neuropathy (see "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Asymmetric sensorimotor (multifocal)')

●Hereditary neuropathy with liability to pressure palsy (see "Charcot-Marie-Tooth disease: Genetics, clinical features, and diagnosis", section on 'Hereditary neuropathy with liability to pressure palsy')

TREATMENT — MMN is treatable with intravenous immune globulin (IVIG) [12,14,25-29]. We suggest IVIG 2 g/kg, given over two to five days, for initial treatment of patients with MMN who require treatment due to disease progression or disability [30]. Our preferred regimen is 0.4 g/kg daily for five consecutive days. This recommendation is consistent with current guidelines from the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the American Academy of Neurology [24,28].

The benefit of IVIG for MMN has been demonstrated in several small randomized controlled trials [25-28,31]. As an example, a double-blind, placebo-controlled crossover trial evaluated IVIG (0.5 g/kg per day for five consecutive days once a month for three months) versus placebo in 18 patients with MMN [25]. At four months, seven of nine patients who received IVIG responded, compared with two of nine patients treated with placebo. A 2022 systematic review of three placebo-controlled treatment trials in patients with MMN found that initial therapy with IVIG may improve muscle strength (78 versus 4 percent; risk ratio [RR] 11.0, 95% CI 2.9-42.3) and functional disability (39 versus 11 percent; RR 3.0, 95% CI 0.9-10.1) [32]. However, the certainty of the evidence was low, owing to the small number of patients and variability in outcome measures used. Although data are less compelling, subcutaneous immune globulin (SCIG) therapy may also be beneficial for MMN, as reported in a meta-analysis that included mainly small observational studies [33].

Most patients experience a fairly rapid improvement in weakness with IVIG. Muscles that show the greatest initial weakness have the largest response [34]. However, the improvement is generally not sustained beyond a few months [1]. In a trial of 44 patients with MMN treated with IVIG at baseline, worsening functional disability at 12 weeks was more common in patients receiving placebo than those receiving maintenance IVIG (40 versus 17 percent) [35]. Therefore, maintenance IVIG infusions are typically required every two to six weeks. For patients who require maintenance IVIG infusions, subsequent dosing can be tailored to the individual patient based upon clinical response. Some patients will continue to require full-dose IVIG, while others will respond to lower doses. Maintenance IVIG is usually administered over a shorter time period if the initial five-day course is well tolerated. As an example, full-dose maintenance IVIG (total 2 g/kg) might be administered at 1 g/kg daily for two days.

For patients with severe or progressive disease that is refractory to, or becomes resistant to, IVIG therapy, options and evidence are limited [36]. Several reports suggest that cyclophosphamide is partially effective for treating MMN [5,37,38], but its use may be associated with serious toxicity. Responsiveness to rituximab was reported in a few cases [39,40], but rituximab was not associated with improvement on any outcome measures in a series of six patients with MMN [41].

MMN is generally unresponsive to glucocorticoids or plasma exchange [1], and these therapies have been associated with clinical worsening in some cases [1,37,42].

PROGNOSIS — The prognosis of MMN is one of slow progression of disease and disability in untreated patients [1,43]. Spontaneous remission has not been reported [3]. In patients with very slow progression and minimal disability, immunomodulatory treatment may be deferred so as to avoid the risk of side effects. However, treatment should begin early in the disease if activities of living are impaired [3].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathy".)

SUMMARY AND RECOMMENDATIONS

●Definition – Multifocal motor neuropathy (MMN), also known as multifocal motor neuropathy with conduction block, is a rare neuropathy characterized by progressive, asymmetric weakness and atrophy without sensory abnormalities. It is considered an immune-mediated disorder that generally responds to treatment with intravenous immune globulin (IVIG). (See 'Introduction' above and 'Pathogenesis' above.)

●Clinical features – The typical clinical presentation of MMN is subacute onset of asymmetric weakness and lower motor neuron signs producing arm and hand weakness without associated sensory loss. The neuronal involvement in MMN is typically patchy, with some nerves unaffected and others severely involved. Motor nerve conduction studies usually show evidence of conduction block. Sensory conduction through the same segment of nerve is normal. Elevated titers of anti-GM1 antibodies are present in 30 to 80 percent of patients. (See 'Clinical features' above.)

●Diagnosis – The diagnosis of MMN is suspected by a compatible clinical presentation of progressive, usually asymmetric weakness without sensory abnormalities, upper motor neuron signs, or bulbar involvement. The diagnosis is supported by nerve conduction studies that demonstrate focal demyelination and conduction block. (See 'Diagnosis' above.)

The main consideration in the differential diagnosis of MMN is amyotrophic lateral sclerosis/motor neuron disease. (See 'Differential diagnosis' above.)

●Treatment – For patients with MMN who require treatment due to disease progression or disability, we suggest IVIG 2 g/kg, given over two to five days (eg, 0.4 g/kg daily for five consecutive days), as initial treatment (Grade 2B). Maintenance IVIG infusions are typically required every two to six weeks. (See 'Treatment' above.)

●Prognosis – The prognosis of MMN is one of slow progression of disease and disability in untreated patients. Most patients experience a fairly rapid initial improvement in weakness with IVIG, but the improvement is generally not sustained beyond a few months. Maintenance treatment is typically required to slow disease progression. (See 'Treatment' above and 'Prognosis' above.)