eMedicine Specialties > Neurology > Neuromuscular Diseases

Primary Lateral Sclerosis

Author: Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center
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Updated: Jun 8, 2009

Introduction

Background

Primary lateral sclerosis (PLS) is a progressive, degenerative disease of upper motor neurons characterized by progressive spasticity (ie, stiffness). It affects the lower extremities, trunk, upper extremities, and bulbar muscles (usually in that order).^1,2 The major clinical challenge that the presentation of PLS poses is distinguishing it from the more common form of motor neuron disease, amyotrophic lateral sclerosis (ALS)^3,4 , from hereditary spastic paraparesis (HSP)⁵ , and from nondegenerative conditions that may present similarly early in their course.

PLS usually affects adults and is usually sporadic. A rare, hereditary variant affecting infants and children (JPLS) was mapped to the gene ALS2 (alsin) on chromosome 2q33.2. According to Panzeri et al, "the protein encoded by the ALS2 gene, alsin, contains a number of cell signaling and protein trafficking domains. The structure of alsin predicts that it functions as a guanine nucleotide exchange factor (GEF). GEFs regulate the activity of members of the Ras superfamily of GTPases."⁶ At least 10 deletion mutations and 1 missense mutation of the alsin gene have been shown to cause JPLS.⁶

Recently, a unique locus for an autosomal dominant form of adult-onset PLS in a large French-Canadian family was mapped to chromosome 4ptel-4p16.1. This locus had not been implicated in ALS or in hereditary spastic parapareses, spinal muscular atrophy, or spinal and bulbar muscular atrophy.⁷

Classification of motor neurons

The cell bodies (soma) of lower motor neurons reside in the spinal cord or the brain stem, and the axons (fibers) are connected directly to muscles at the neuromuscular junctions. These are considered first-order motor neurons because they are connected directly to the muscles.

The soma of upper motor neurons reside in the brain, where they control the activity of lower motor neurons. Second-order motor neurons can be distinguished from higher-order motor neurons. Second-order motor neurons are upper motor neurons whose cell bodies reside primarily in the precentral gyrus or the primary motor cortex of the frontal lobe. They send fibers that directly connect to lower motor neurons in the brain stem that innervate the muscles of the face, pharynx, and larynx or to lower motor neurons in the spinal cord that innervate the limb, trunk, and respiratory muscles.

Third- and higher-order motor neurons are located in the frontal lobes of the brain anterior to the precentral gyrus (ie, the prefrontal cortex). These neurons are involved in planning and organizing motor activity and direct the second-order motor neurons. The soma of these third- and higher-order motor neurons reside in the brain, and their axons form associative or commissural projections within the brain.

Classification and terminology of motor neuron diseases

Motor neuron diseases (MNDs) are progressive degenerative diseases in which death of the cell bodies of motor neurons is the primary process. These should be distinguished from diseases in which primarily the axons of motor neurons are affected. The traditional classification of MNDs is according to the affected cell types, as follows:

• Upper motor neurons alone - PLS
• Lower motor neurons alone - Progressive muscular atrophy (PMA) and spinal muscular atrophies (SMAs)
• Upper and lower motor neurons - ALS

ALS is the most common of the MNDs. In British-English–speaking areas, ALS is often called motor neurone disease (singular), but this chapter reserves the term MNDs (usually in plural form) as an umbrella term. Therefore, not every MND is ALS.

Clinical presentation

ALS may present initially with signs of only upper or lower motor neuron involvement. Thus, a process that initially is considered PMA or PLS has the potential to be reclassified as ALS if sufficient signs of both upper and lower motor neuron involvement develop over time. In some cases, such reclassification may occur only at autopsy (eg, pyramidal tract involvement is found in patients who did not have signs of upper motor neuron involvement during life and whose disease was therefore classified on clinical grounds as PMA).

Recent reports have described patients with one of the genes for familial ALS in whom only lower motor neuron involvement was seen during life and at autopsy. Most investigators would classify this disease pattern as ALS, on the basis of the gene's presence (even though its clinical expression was incomplete). This position is supported by the recently revised World Federation of Neurology diagnostic criteria for ALS.

Patients with PLS occasionally have mild, nonspecific, and nonprogressive findings of denervation on electrodiagnostic testing. The severity of the denervation and re-innervation does not resemble that seen in ALS and does not justify these patients' being classified as having ALS. These patients may be concerned that their PLS eventually could evolve into ALS. Although absolute guarantees cannot be given, some measure of reassurance may be derived from the overall slow progression in these patients.

Pathophysiology

Five reports that include autopsy findings in 6 patients with PLS differ in the pathological changes they describe. Two major factors may account for the different pathological findings. First, uncertainties exist regarding the diagnosis in some of the series. This is discussed below in regard to one of the patients in the series described by Pringle et al in 1992.² Second, since the diagnosis of PLS is based on clinical presentation and the exclusion of known look-alikes, the identification of more than a single pathologic process once the histology becomes available is not surprising.

Younger et al described 3 patients who had demyelination of the corticospinal tracts without gliosis or discernible loss of Betz cells in the precentral gyrus. The pathology in these patients appeared to affect the myelin sheath of the axon of the upper motor neuron or the axon itself rather than that of the upper motor neuron cell body. The clinical course in these patients was faster than that of the typical patient with PLS; one died within 13 months of onset, and another was bedridden within 2 years of onset.¹

In contrast, histologic findings in the 3 other patients were of involvement of the precentral gyrus and loss of Betz cells. Brain MRIs of 7 patients reported by Pringle et al showed cerebral atrophy that was most pronounced in the region of the precentral gyrus in 5 patients, was present only in the precentral region in 1 patient, and was most prominent in the frontoparietal region in another patient. These imaging findings are consistent with the findings at autopsy.

Single photon emission computed tomography (SPECT) studies in 2 patients showed reduced uptake in the motor cortex, as did positron emission tomography (PET) studies in 2 of 3 patients.² Magnetic resonance spectroscopy (MRS) showed abnormal N -acetylaspartate/creatine ratios in 12 of 18 patients with PLS.

Fractional anisotropy (FA) studies comparing patients with PLS to patients with ALS and to controls, showed that patients with ALS in London showed a lower FA in several brain regions than controls. Patients in Oxford with PLS (compared with ALS and controls) showed a lower FA in the body of the corpus callosum and in the white matter adjacent to the right primary motor cortex (PMC), while patients with ALS (compared with PLS) showed reduced FA in the white matter adjacent to the superior frontal gyrus. Significant correlations were found between disease progression rate and (1) FA in the white matter adjacent to the PMC in PLS, and (2) FA along the corticospinal tract and in the body of the corpus callosum in ALS.⁸

Clinical neurophysiologic studies confirm upper motor neuron dysfunction in PLS: motor evoked potentials (MEPs) are absent or delayed, and peripheral conduction is normal. Minimal denervation activity (ie, fibrillation potentials) may be found in distal muscles.

Most reports (combining imaging and autopsy series) indicate neuronal loss in the precentral gyrus. However, more than one pathologic process may be responsible for the clinical presentation. For example, diffuse Lewy body disease was the underlying pathology in 1 patient who presented with PLS by clinical criteria.

Despite the availability of supporting imaging and clinical neurophysiologic features, described best in patients with established disease, the initial diagnosis of PLS is usually made on clinical grounds.

Frequency

United States

Data on the incidence of PLS are uncertain. In contrast, data on ALS are well documented: ALS affects 2-3 individuals per 100,000 population each year. The 8 patients with PLS reported by Pringle et al in 1992 were identified over a period of 10 years among a population of 500 patients with ALS. Inferring a population base of approximately 4 million people from the ALS patient data (assuming these are mixed prevalence and incidence data) would result in a prevalence of 2 per million for PLS, assuming all cases were identified.

Further assuming an average disease duration of 20 years (close to the reported median of 19 y), this prevalence would translate into an annual PLS incidence rate of 1 per 10 million (0.01 case per 100,000 population per year), which is approximately 0.5% of that of ALS. The tentative nature of these estimates should be emphasized. They are consistent with a conservative estimate that not more than 500 people with PLS currently are living in the United States. Independent validation of this estimate would be difficult. Recent review of the Pringle et al cases suggests that half may not have had PLS; this would reduce the estimates above accordingly.

Repeating this calculation, using the more recent numbers 43 patients with PLS and 661 patients with ALS seen over a period of 17 years⁴ results in a presumptive population base of 13,220,000. Factoring an average PLS duration of 20 years, of the 43 PLS patients, approximately one half would be alive at any point in time, giving a prevalence of 1.6 per million, which translates into an incidence rate of 0.8 per 10 million per year and an estimated 400 people with PLS currently living in the United States. These estimates are lower than the previous estimates, in which the author did not take into account loss of PLS patients over the time they were accrued.

Adult-onset PLS is a sporadic disease. An autosomal-recessive, childhood-onset form has been described, as well as a rare autosomal dominant adult form in a French-Canadian family.

A genetically mediated look-alike, progressive familial paraparesis (hereditary spastic paraparesis), is a separate condition with a more limited clinical extent and a more benign course.

Mortality/Morbidity

PLS has not been considered to shorten life expectancy. However, inspection of recently reported survival data from 36 patients with PLS⁴  suggests that the median survival is approximately 20 years.

Sex

The female-to-male ratio in a report of 8 patients was 1:1² . However, only 1 of 9 patients reported by Younger et al in 1988 was female.¹ A more recent report⁴ supports a 1:1 female to male ratio among 43 patients with PLS.

Age

A recent series of 43 patients reported a mean age of onset of 54.62 ± 10.9 years, with a range of 33-74 years.⁴ This is similar to the age of onset range of 35-66 years with a median of 50.5 years reported previously from the same center² . Onset in a patient as young as 20 years was reported by Younger et al.¹

Clinical

History

• PLS usually presents with gradual-onset, progressive, lower-extremity stiffness and pain due to spasticity. Onset is often asymmetrical.
• Pringle et al in 1992 reported ages of onset that ranged from 35-66 years (median 50.5 y)² , while Younger et al in 1988 reported onset in a patient as young as 20 years in another series. The median duration of PLS is approximately 20 years.¹
• As PLS progresses, patients may develop balance problems with a tendency to fall. Axial muscle involvement may result in lower back and neck pain, which may aggravate back or neck pain from other causes (eg, degenerative disc disease, osteoporosis).
• As the upper extremities become involved, patients may have difficulties with activities of daily living (ADLs). Involvement of the organs of speech may result in spastic dysarthria (which initially may be mild).
• Swallowing and breathing may be compromised late in the disease.
• The slow rate of progression provides most patients and families with time to adapt to the changes and identify resources for support. Conversely, the overall duration and magnitude of the burden placed on the family and caregivers is commensurately greater than it would be in a more rapidly progressing disease.
• General considerations
  • The most common causes of myelopathy in this age group are cervical spondylosis and chronic progressive multiple sclerosis (MS). Both are more common than PLS.
  • Some conditions may present initially with pure upper motor neuron dysfunction, such as progressive multifocal leukoencephalopathy (rarely without the characteristic MRI findings) or spongiform encephalopathy, but have a rapid course that would preclude consideration of PLS.
  • If appropriate, also consider and exclude HIV-associated myelopathy.
  • Whether serial electromyography (EMG) has a role in diagnosis of PLS is uncertain; EMG would be used to look for evolution of lower motor neuron findings in the absence of clinical evidence to suggest a change into ALS.

Physical

• Signs of upper motor neuron dysfunction may include limb and trunk spasticity, pathological spread of deep tendon reflexes, clonus, pathological reflexes (such as Babinski sign), and spastic dysarthria.
• Signs of involvement of other systems should not be present. In particular, no cerebellar findings, involuntary movements, sensory findings, findings suggesting lower motor neuron dysfunction (such as fasciculations), visual findings, or bladder dysfunction should be observed.
• Diagnostic criteria
  • The diagnostic criteria for PLS proposed by Pringle et al in 1992 include insidious onset of spastic paresis in adults, which usually begins in the lower extremities.² Affected individuals typically have no family history of similar disorders.
  • Some suggest that spastic paresis should be symmetric, but asymmetric presentation is not unusual. The paresis progresses gradually in a manner consistent with corticobulbar and corticospinal tract dysfunction. Duration should be at least 3 years, and other diagnoses should be excluded by imaging and laboratory tests.
  • The suggestion by Pringle et al that the diagnosis may be made within 3 years of symptom onset contradicts the 5 years' duration that was required by the criteria proposed by Stark and Moersch in 1945.⁹ The criteria of Pringle et al also permit bulbar or upper extremity onset for PLS.²  
  • One patient in the series of Pringle et al, who was diagnosed as having PLS by their criteria but not according to the criteria of Stark and Moersch, had bulbar onset and progressed to essentially anarthria within 2 years.
    • This patient showed occasional fibrillation potentials in the pronator quadratus, thenar, and interosseus muscles 4 years after onset of disease.
    • The reported follow-up (<5 y) was the shortest in that series.
    • This patient's course resembles that of ALS (albeit with a slower than average rate of progression) more than PLS.
  • Thirteen of 29 patients with upper motor neuron symptom onset reported by Gordon et al, initially diagnosed as having PLS, evolved to having upper motor neuron–dominant ALS within 3.7 years of symptom onset. Gordon et al advised a period of 4 years of observation before a patient is considered to have PLS.³ However, in patients with bulbar onset, requiring a 5-year period of observation and greater diligence to exclude lower motor neuron involvement may be prudent before diagnosing PLS (rather than ALS).
• In summary, concern for future evolution into ALS cannot be allayed by a workup shortly after symptom onset.
  • Lower extremity onset and slow progression (at least 3-5 y) increases confidence in the diagnosis of PLS and decrease the likelihood of a later evolution into ALS. A 5-year period of observation, without emergence of clinical lower motor neuron signs, provides greater confidence in the diagnosis than a shorter period of observation.
  • From the standpoint of disease impact on patient survival and disability, rate of progression rather than diagnostic classification is the determining factor. Nevertheless, acceleration of the course may be expected if lower motor neuron signs develop in a patient who was thought to have PLS.

Causes

The cause of sporadic PLS is not known.

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