Motor Neuron Disease

Motor neuron disease refers to a disease process affecting one or both of the two neurons in the motor circuit: (1) the upper motor neurons (UMNs), which originate in the primary motor cortex and project through the corticospinal tract; and (2) the lower motor neurons (LMNs), which originate in the anterior horn of the spinal cord and project peripherally to the skeletal muscle. A motor neuron process should be considered in patients with isolated weakness (no associated sensory symptoms), and particularly in those with LMN signs such as atrophy or fasciculations.

A.

The presence of hyperreflexia indicates involvement of the UMN pathways either in the brain or spinal cord. Hyperreflexia in the setting of weakness and atrophy is seen in most patients with amyotrophic lateral sclerosis (ALS). However, a structural spinal cord lesion can cause LMN signs at the level of the lesion due to anterior horn cell involvement and UMN signs below the lesion due to corticospinal tract involvement. For example, a C6 spinal cord lesion may cause ipsilateral biceps atrophy and hyperreflexia in the leg. The combination of cervical and lumbar spine disease can cause LMN signs at both levels and UMN signs below the cervical spine lesion. To identify the cause of UMN signs, neuroimaging should be performed at every level rostral to the highest level of clinical UMN findings. For example, if hyperreflexia is present only in the legs, magnetic resonance imaging (MRI) of the brain and cervical and thoracic spine should be performed, whereas only MRI of the brain and cervical spine would be indicated in a patient with arm and leg hyperreflexia.
B.

A diagnosis of clinically definite ALS requires (1) clinical UMN signs in at least three of the following four regions: bulbar, cervical, thoracic, and lumbar; (2) clinical or electrophysiologic LMN signs in three of these four regions; and (3) no alternative explanation. A diagnosis of clinically probable ALS has the same requirements, but only two regions need be clearly involved. Unexplained hyperreflexia and a single region of motor neuron injury are concerning but not diagnostic for ALS. Such patients should be followed closely with serial examinations to assess for progression.
C.

In a patient with diffuse weakness, hyperreflexia, unremarkable imaging, and diffuse active on chronic denervation on electromyography (EMG) with normal sensory responses, ALS is the likely diagnosis.
D.

Hereditary spastic paraparesis (HSP) typically presents with slowly progressive weakness and UMN findings in the lower extremities. Complicated HSP may involve systems beyond the corticospinal tracts including LMN and sensory pathways. Adrenomyeloneuropathy (AMN) is an X-linked disorder often manifesting in early adulthood with gait impairment. Adrenal insufficiency, sexual dysfunction, and neurogenic bladder may also be present. Serum very long chain fatty acid levels are elevated in AMN. Sequencing of the ABCD1 gene provides definite diagnosis.
E.

While rare, isolated demyelination of the motor neurons (multifocal motor neuropathy [MMN]) is a frequent consideration in the differential of motor neuron diseases, since it can be treated with intravenous immunoglobulin or plasma exchange. Clinically, MMN causes slowly progressive asymmetric weakness, most typically beginning in the upper extremities. The disorder is more common in men. Anti-GM1 bodies are seen in some but not all patients with MMN. Conduction block is the demyelinating feature most frequently described in MMN.
F.

In a patient with diffuse weakness, normal or reduced reflexes, normal sensory responses on NCS, and diffuse active and chronic denervation on needle EMG, motor neuron disease and polyradiculopathies from a subarachnoid process are both diagnostic possibilities. A lumbar puncture should be performed to evaluate for malignancy (cytology and flow cytometry), albuminocytologic dissociation (elevated protein) as may be seen in chronic inflammatory demyelinating polyneuropathy (CIDP), or a pleocytosis as may be seen in infectious (e.g., human immunodeficiency virus or inflammatory (e.g., sarcoidosis) polyradiculitis.
G.

Kennedy disease (spinal-bulbar muscular atrophy) is a slowly progressive X-linked disorder of the androgen receptor that causes progressive weakness, atrophy, and fasciculations, particularly of the proximal limbs and bulbar muscles. Patients often have a tremor and facial twitching. Sensory symptoms are often not a prominent complaint, but NCS typically reveals absent or severely reduced sensory responses. Genetic testing provides definitive diagnosis.
H.

If the lumbar puncture is normal, the most likely diagnosis is progressive muscular atrophy (PMA), which is an exclusively LMN form of ALS. Approximately a quarter of patients with PMA will eventually develop some UMN signs, typically within 2 years of disease onset.
I.

Late-onset Tay Sachs (LOTS) disease is a rare disorder that can be misdiagnosed as PMA, since it also presents with predominantly LMN signs. However, patients with LOTS often have an accompanying cerebellar ataxia and psychiatric symptoms (e.g., bipolar disorder and psychotic symptoms). LOTS is an autosomal recessive disorder caused by mutations in the HEXA gene, resulting in reduced hexosaminidase A activity. Brain MRI commonly demonstrates cerebellar atrophy.