Disorders of Upper and Lower Motor Neurons

Motor Cortex

In the cerebral cortex, UMNs are located in the primary motor cortex (Brodmann area 4) and the premotor areas (Brodmann area 6), which are subdivided into the supplementary motor area (sometimes called the secondary motor cortex ) and the premotor cortex, respectively. Betz cells (giant pyramidal neurons) are a distinct group of large motor neurons in layer 5 of the primary motor cortex and represent only a small portion of all primary motor neurons with axons in the corticospinal tracts. Individual motor neurons in the primary motor cortex initiate and control the contraction of small groups of skeletal muscles subserving individual movements. The entire motor area of the cerebral cortex controls the highest levels of voluntary muscle movement, including motor planning and programming of muscle movement.

Loss of Dexterity

Loss of dexterity is one of the most characteristic signs of UMN impairment. Voluntary skillful movements require the integrated activation of many interneuron circuits in the spinal cord; such integration is ultimately controlled by the corticospinal tract and thus by UMNs. Loss of dexterity may express itself as stiffness, slowness, and clumsiness in performing any skillful motor actions. Asking the patient to perform rapid repetitive motions such as foot or finger tapping assesses loss of dexterity at the bedside. It is useful to assess both sides of the body, as many motor neuron disorders are asymmetrical ( Box 97.2 ).

Loss of Muscle Strength (Weakness)

The degree of muscle weakness resulting from UMN dysfunction is generally mild. Extensor muscles of the upper extremities and flexor muscles of lower extremities may become weaker than their antagonist muscles because the UMN lesion disinhibits brainstem control of the vestibulospinal and reticulospinal tracts.

Spasticity

Spasticity is the hallmark of UMN disease, but its pathophysiology is complex and controversial. It seems to reflect altered firing of alpha motoneurons and interneurons within the spinal cord, together with increased activity of group II nerve fibers derived from muscle spindles. An excess level of excitatory input to gamma motoneurons exists via excess synaptic levels of excitatory neurotransmitters such as serotonin, norepinephrine, and glutamate. In addition, there is reduced inhibitory glycinergic and γ-aminobutyric acid (GABA)ergic neurotransmission. The result is a state of sustained increase in muscle tension when the muscle lengthens. Clinically, muscles exhibit a sudden resistive “catch” midway during passive movement of the limb. However, when a sustained passive stretch is continued, spastic muscles quickly release the tension and relax, an event often described as the “clasp-knife phenomenon.” In muscles that are severely spastic, passive movement becomes more difficult and even impossible. Sustained increases in muscle tone lead to a slowing in motor activities.

Pathological Hyperreflexia and Pathological Reflexes

Pathological hyperreflexia is another crucial manifestation of UMN disease. The Babinski sign (extensor plantar response) is perhaps the most important sign in the clinical neurological examination and is characterized by extension of the great toe (often, but not universally, accompanied by fanning of the other toes) in response to stroking the outer edge of the ipsilateral sole upward from the heel with a blunt object. This sign may only evolve at a later stage of disease and may be absent in the setting of marked atrophy of the toe extensor muscles.

Pseudobulbar (Spastic Bulbar) Palsy

Pseudobulbar palsy (or spastic bulbar palsy) develops when there is disease involvement of the corticobulbar tracts that exert supranuclear control over those motor nuclei that control speech, mastication, and deglutition. The prefix pseudo distinguishes this condition from true bulbar palsy that results from pure LMN involvement in brainstem motor nuclei. Articulation, mastication, and deglutition are impaired in both pseudobulbar and bulbar palsies, but the degree of impairment in pseudobulbar palsy is generally milder. Spontaneous or unmotivated crying and laughter uniquely characterize pseudobulbar palsy. This is also termed emotional lability , hyperemotionality , labile affect , or emotional incontinence and is often a source of great embarrassment to the patient.

Neuroimaging

The use of brain magnetic resonance imaging (MRI) in ALS is largely to exclude other conditions but sometimes shows abnormal signal intensity in the corticospinal and corticobulbar tracts as they descend from the motor strip via the internal capsules to the cerebral peduncles. In ALS, signal changes, best appreciated on proton density images of the internal capsules, probably represent Wallerian degeneration; similar changes also appear on conventional T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences. However, these changes do not appear to be sufficiently sensitive, and efforts continue to evaluate other potential MRI techniques such as diffusion tensor imaging (DTI) and high-field volumetric MRI, which may serve as markers of UMN disease ( ).

Magnetic Resonance Spectroscopy Imaging

Proton density magnetic resonance spectroscopy ( ¹ H-MRS) is a noninvasive nuclear magnetic resonance technique that combines the advantages of MRI with in vivo biochemical information. A significant reduction of N -acetylaspartate, a neuronal marker, relative to creatine or choline (used as internal standards) exists in the sensorimotor cortices of patients with ALS who have UMN signs. Alterations in the measured levels of these metabolites using ¹ H-MRS are useful in the detection of UMN dysfunction early in the evolution of ALS and are useful for monitoring progression over time. MRS still requires further technological improvements before it comes into widespread use.

Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) is an electrophysiological technique that has detected cortical hyperexcitability/impaired inhibition as well as cortical motor neuron and long-tract degeneration in ALS. The stimulus is a brief, high-intensity electromagnetic pulse generated from a series of capacitors and discharged through wire coils applied at the scalp over the motor cortex and the evoked response measured at skeletal muscle. Several different techniques are under investigation, including single-pulse TMS, cortical silent period measurement, paired pulse TMS, and repetitive TMS ( ). Overall, this promising, noninvasive tool requires further evaluation as a marker of UMN dysfunction. Recent evidence suggests that it may be useful in combination with other tools such as DTI.

Diagnosis

The diagnosis of PLS is essentially one of exclusion ( Table 97.1 ). Rare reports of UMN-onset ALS exist where the interval between onset of UMN signs and subsequent LMN signs has been up to 27 years. As such, it is vital to reassess patients diagnosed with PLS, as late signs of LMN involvement may occur that would reclassify their disorder as UMN-onset ALS.

Appropriate testing must exclude all definable causes for generalized UMN involvement. These include structural abnormalities (Chiari malformation and intrinsic and extrinsic spinal cord lesions) and myelopathies such as multiple sclerosis (MS) spondylotic cervical myelopathy, human immunodeficiency virus (HIV) myelopathy, human T-lymphotropic virus type 1 (HTLV-1) myelopathy, Lyme disease, syphilis, or adrenomyeloneuropathy. Spondylotic cervical myelopathy and MS are probably the most common causes among these disorders. The family history must be negative to rule out hereditary spastic paraplegia (HSP)/familial spastic paraparesis, spinocerebellar ataxia (SCA), hexosaminidase-A (Hex-A) deficiency, familial ALS (FALS), or adrenomyeloneuropathy. It is now apparent that some forms of HSP, including spastin and paraplegin mutation-associated HSP, may lack a family history; it is worthwhile to carry out genetic testing for HSP in patients presenting with symptoms and signs that are restricted to the lower extremities ( ). Paraneoplastic syndromes (especially in association with breast cancer) and Sjögren syndrome may clinically resemble PLS. Thus, it is important to consider paraneoplastic diseases, particularly in an older woman presenting with a pure upper motor syndrome and other genetic mimics.

Treatment

No specific pharmacotherapy is available, and treatment therefore focuses on symptom control and supportive care. However, antispasticity drugs such as the GABA-B agonist baclofen and the central α ₂ -agonist tizanidine may be tried for symptomatic treatment. Severe spasticity sometimes requires the insertion of an intrathecal baclofen pump. Tricyclic antidepressants, selective serotonin reuptake inhibitors, or dextromethorphan/quinidine may control pseudobulbar affect lability ( ).

Diagnosis

The basis for diagnosis of HSP is evidence of a family history in the setting of progressive gait disturbance, evidence of lower-extremity spasticity, and sparing of craniobulbar function. However, difficulties arise when there is no clear family history in recessive or X-linked disease and in cases of apparently sporadic HSP. Furthermore, considerable variation in disease expression exists between and within HSP families. In the absence of a family history or a demonstration of a known mutation, it is important to consider alternative causes for the clinical presentation, including structural disease (e.g., cerebral palsy, hydrocephalus, myelopathy), degenerative/infiltrative/inflammatory disease (e.g., MS, ALS, SCA, leukodystrophy), infections (syphilis, HIV, HTLV), levodopa-responsive dystonia, metabolic/toxic damage (vitamin B ₁₂ deficiency [subacute combined degeneration of the spinal cord (SCDC)], vitamin E deficiency, copper deficiency, lathyrism), and paraneoplastic disorders. MRI may reveal that cervical and thoracic spinal cord diameters are significantly smaller in both pure and complicated HSP than in controls ( ). Perhaps the most important differential diagnosis is that between apparently sporadic pure HSP and PLS, especially as the later may present with a slowly evolving spastic paraparesis for many years prior to the development of upper limb or bulbar features. The only reliable way to distinguish such disorders is through genetic testing; age at onset, urgency of micturition, and signs of dorsal column involvement (clinical or abnormal somatosensory evoked potentials [SSEPs]) are not accurate indicators of HSP versus PLS ( ).

Treatment

At present, treatment of spastic paraplegia is limited to symptomatic interventions, supportive care to reduce spasticity, and appliances and orthotics such as canes, walkers, and wheelchairs. Antispasticity drugs such as baclofen, tizanidine, diazepam, and dantrolene are often suboptimal, and patients with very disabling spasticity may require intrathecal baclofen administered through an implanted pump.

Lathyrism

Lathyrism is a chronic toxic nutritional neurological disease caused by long-term (or subacute) ingestion of flour made from the drought-resistant chickling pea ( Lathyrus sativus ). It is an important example of a disease in which a natural excitotoxin causes selective UMN impairment. The responsible neurotoxin is β- N -oxalylamino-l-alanine (BOAA), an α-amino-3-hydroxyl-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor agonist. Ingestion of this neurotoxin results in increased intracellular levels of reactive oxygen species and subsequent impairment of the mitochondrial oxidative phosphorylation chain. Degeneration is most prominent in those Betz cells of the motor cortex (and the longest corresponding pyramidal tracts) that subserve lower-extremity function. Lathyrism occurs in the indigenous populations of Bangladesh, China, Ethiopia, India, Romania, and Spain. It also occurred in regional concentration camps during World War II. The condition may occur in epidemic form when malnourished populations increase consumption of flour made from L. sativus chickling peas during times of food shortage due to droughts. An analysis of an epidemic of neurolathyrism in Ethiopia showed a higher incidence in boys aged 10–14 years. The increased risk was associated with cooking grass pea foods in traditional clay pots ( ). The onset of clinical toxicity is either acute or chronic, manifesting as muscle spasms, cramps, and leg weakness. In addition to spastic paraparesis, sensory (including leg formications) and bladder dysfunction may occur. Occasionally there is a coarse tremor of the upper extremities. Although irreversible, the disorder is not progressive (unless there is continuing intoxication), and lifespan is not affected.

Konzo

Konzo (“tied legs”) is another toxic nutritional disorder of cortical motor neurons caused by chronic dietary ingestion of a neurotoxin derived from flour made from cassava roots that have not been soaked for a sufficient time. The disorder is endemic in protein-deficient communities in Tanzania, Zaire, and Eastern Africa and in times of famine can occur in epidemic form. The neurotoxic effect of chronic cassava root ingestion likely is derived from the liberation of cyanohydrins (cyanoglucoside linamarin) from the flour, which may be further metabolized to thiocyanate. The latter in turn may excessively stimulate the AMPA glutamate receptor subtype, causing excitotoxic neuronal injury. As with lathyrism, there appears to be a selective effect on Betz cells of the cerebral cortex and the longest corresponding corticospinal tracts. Patients typically present with spastic paraparesis (although some may exhibit only lower-extremity hyperreflexia). Occasionally one may detect weakness of the upper extremities, but not to the same degree as that of the lower extremities.

Interneurons

The interneurons constitute most of the anterior horn cells of the spinal cord and determine the final output of the LMNs. The interneuron system receives supranuclear excitatory and inhibitory motor control from the brainstem descending tracts, corticospinal tracts, and limbic system; this system also receives afferent information, directly and indirectly, from the afferent peripheral nerves. The interneuron system forms intricate neuronal circuits involving automatic and stereotyped spinal reflexes to coordinate and integrate the activation of synergist muscles while inhibiting antagonist muscles, contralateral muscles, and sometimes even a distant motor pool. The same interneuron network that mediates such automatic and stereotyped reflex behavior also acts as the basic functional unit involved in highly skillful voluntary movements. Ultimately, all of the interneuronal paths converge on the LMNs that innervate skeletal muscles, which Sherrington called the final common path .

Lower Motor Neurons

LMNs are located in the brainstem and spinal cord and send out motor axons that directly innervate skeletal muscle fibers. Spinal cord LMNs, also known as anterior horn cells , cluster in nuclei forming longitudinal columns; those innervating the distal muscles of the extremities are located in the dorsal anterior horn, whereas those innervating proximal muscles of the extremities are in the ventral anterior horn. Those LMNs that innervate the axial and truncal muscles are the most medially located. The normal cervical and lumbar enlargements of the spinal cord are the result of markedly enlarged lateral anterior horns containing the LMNs for the upper and lower limb muscles.

Large spinal cord LMNs called alpha motoneurons are the principal motor neurons innervating muscle fibers. Medium-sized motor neurons ( beta motoneurons ) innervate both extrafusal and intrafusal (muscle spindle) fibers, and intermediate and small motor neurons ( gamma motoneurons or fusimotor neurons ) innervate only spindle muscle fibers. The rest of the small anterior horn cells are interneurons.

Alpha motoneurons are among the largest neurons of the nervous system. Each has a single axon that branches to its target muscles and a number of large dendrites that provide an extensive receptive field. The motor unit is the smallest unit of the motor system and consists of one alpha motoneuron, its axon, and all of its target muscle fibers.

Loss of Muscle Strength (Weakness)

The loss of an LMN results in denervation of its motor unit, whereas an impaired LMN may lead to abnormal or impaired activation of its motor unit. In either case, the number of fully functional motor units decreases, which reduces overall muscle twitch tension.

In a disease causing chronic motor unit depletion, neighboring axons belonging to healthy motor neurons may reinnervate denervated muscle fibers belonging to a diseased motor unit by collateral sprouting. In this way, existing motor units continually modify in the face of persistent losses of motor axons to maintain muscle strength. For example, in patients who have recovered from acute poliomyelitis, depletion of more than 50% of LMNs occurs before residual muscle weakness is clinically detectable. Healthy individuals have sufficient motor units available to offset an unexpected loss of motor neurons ( Box 97.3 ).

Fasciculations

Fasciculations are spontaneous contractions of muscle fibers belonging to a single (or part of a) motor unit ( Video 97.2 ). Clinically, fasciculations appear on the muscle surface as fine, rapid, flickering, and sometimes vermicular contractions that occur irregularly in time and location. The impulse for the fasciculation appears to arise from hyperexcitable motor axons anywhere in their course. Fasciculations can occur both in healthy individuals and in patients with LMN involvement, so fasciculations themselves do not indicate LMN disease.

Video 97.2 Fasciculations.

In general, larger muscles have larger motor units and therefore larger fasciculations. In tongue muscles, fasciculations produce small vermicular movements on the tongue surface. Fasciculations usually do not cause any joint displacement but when they occur in muscles moving the fingers, joint movements can occur (mini-polymyoclonus) (see Video 97.2 ). Large fasciculations may occur in muscles undergoing extensive chronic reinnervation, such as chronic spinal muscular atrophy (SMA), Kennedy disease, and the postpoliomyelitis syndrome.

Muscle Cramps

Muscle cramps are common in the general population and are a common symptom of LMN involvement and many chronic neuromuscular diseases. The pathogenesis of cramps in all these diseases, as in normal individuals, is poorly understood. Cramps and fasciculations are likely to share a common pathogenic mechanism such as hyperexcitability of the motor neurons. Muscle cramps are an abrupt, involuntary, and painful shortening of the muscle, accompanied by visible or palpable knotting, often with abnormal posture of the affected joint. Relief of cramps is by stretching or massaging.