This document discusses the differential diagnosis for motor lower motor neuron (LMN) disorders, with a focus on distinguishing multifocal motor neuropathy (MMN) from other conditions. It outlines disorders that can involve the motor unit including motor neuron diseases, radiculopathies, plexopathies, motor nerves, the neuromuscular junction, and myopathies. The key distinguishing features of MMN are its pure motor and focal or multifocal presentation, relative minimal atrophy, conduction block on electrophysiology, and lack of features seen in other LMN disorders like pain, sensory involvement, or acute onset.

1. DIFFERENTIAL DIAGNOSIS OF MOTOR LMN
DISORDER
As in the rest of neurology, differential diagnoses
should start with anatomical localization. Since MMN is
a pure motor disorder, all disorders localizable to the
motor unit, viz. alpha motor neuron, nerve root, plexus,
nerve, neuromuscular junction and muscle, should be
considered.

2. MOTOR NEURON LOCALIZATION:
Patients with motor neuron disease are often sent to
electrodiagnostic laboratories to rule out MMN, especially
when there are no upper motor neuron findings. Earlier
descriptions of MMN described this as a “reversible lower
motor neuron syndrome” resembling lower motor neuron
variant of amyotrophic lateral sclerosis. However, the
relentlessly progressive weakness with atrophy, fasciculations,
and the non-nerve distribution are features not seen in MMN.
Nerve conduction and electromyography (EMG) findings (see
below) of prominent diffuse denervation (fibrillation and
positive sharp waves) and lack of demyelinating changes
differentiate motor neuron disease from MMN.

3. OTHER MOTOR NEURON DISEASES:
Distal spinal muscular atrophy, Monomelic amyotrophy
(focal motor neuron disease or Hirayama disease),
Brachial amytrophic diplegia, Cord tumors, Syrinx, and
Poliomyelitis (as well as other infections such as
Enteroviruses, West Nile, HIV) may also be considered
in the differential diagnosis. Once again, the
distribution of weakness, time course, and relative
minimal atrophy in the face of severe weakness
(suggesting conduction block) are features that
distinguish MMN from other lower motor neuron
disorders.

4. RADICULOPATHIES:
Cervical and Lumbosacral radiculopathies from various
causes including disk disease, stenosis, Lyme, and
tumor infiltration need to be considered although the
invariable radicular pain, the myotomal distribution,
and imaging studies should easily differentiate this
localization from MMN.

5. PLEXOPATHIES:
Brachial plexus involvement, for example, with Thoracic
outlet syndrome (from cervical rib, lymphoma, and
other causes), Inflammatory (brachial neuritis), or
Tumor (such as lymphoma) infiltration may
masquerade as a differential diagnosis for MMN.
Sensory symptoms are invariably noted, and clinical
history and electrophysiological findings often are able
to distinguish between plexopathy and MMN.

6. MOTOR NERVE:
Other causes of multiple mononeuropathies include inherited
neuropathies such as Hereditary neuropathies with tendency to
pressure palsies (HNPP), CMT-2D with GARS mutation, Toxic
neuropathy from lead, Tumors along the course of the nerve
(Neurofibromatosis, Perineuriomas, Amyloidomas, and Lymphomas)
and Entrapment neuropathies. Although Vasculitic Mononeuropathy
Multiplex may be considered, pain and acute/subacute onset are not
seen with MMN. In this context, Multifocal Acquired Demyelinating
Sensory and Motor neuropathy (MADSAM; also known as Lewis
Sumner syndrome) and Focal upper limb predominant Multifocal
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) should be
mentioned, although given the sensory symptoms, these are
considered more as variants of CIDP.[5] MMN is distinguishable by its
pure motor focal or multifocal presentation and presence of
conduction block.

7. NEUROMUSCULAR JUNCTION:
Although myasthenia gravis (MG) is distinguished by
ocular, bulbar, and proximal muscle involvement, distal
MG has been described in 5% of patients.[6] Patients
may have foot drop, focal triceps or grip weakness,
although often other distinguishing features of MG are
present and conduction block is absent.

8. MYOPATHY:
Like MG, most myopathies’ distribution is symmetrical
and proximal. However, some myopathies may be distal
and asymmetrical such as muscular dystrophies
including Miyoshi, caveolinopathy, desminopathy, Laing
distal myopathy, Welander distal myopathy, and
myotonic muscular dystrophy.[7] Inclusion body
myositis may also present mainly as grip weakness
without the quadriceps involvement. Once again, the
clinical phenotype and electrophysiology features
should help separate from the myopathies.