Primary Lateral Sclerosis

Updated: Dec 30, 2015
  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, MHA, CPE  more...
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Overview

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. (See Differentials.)

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] (See Etiology.)

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]

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

Go to Amyotrophic Lateral Sclerosis, Amyotrophic Lateral Sclerosis in Physical Medicine and Rehabilitation, and Emergent Treatment of Amyotrophic Lateral Sclerosis for complete information on these topics.

Classification of motor neurons

The cell bodies (soma) of lower motor neurons reside in the spinal cord or the brainstem, 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 somas 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 somas 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.

Patients with PLS occasionally have mild, nonspecific, and nonprogressive findings of denervation on electrodiagnostic testing. The severity of the denervation and reinnervation 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.

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 a combination of upper and lower motor neuron involvement develop over time. In some cases, such reclassification may occur only at autopsy (eg, if 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). (See History, Physical Examination, and Differentials.)

Reports have described patients with 1 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 World Federation of Neurology diagnostic criteria for ALS.

Complications

Dysfunction and disability accrue as PLS progresses. These are dealt with by the treating physician as they arise. (See Prognosis and Treatment.)

The slow rate of progression of PLS 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.

Risks in daily activities

PLS and its treatment may interfere with the ability to operate a motor vehicle (or other mechanical machinery) safely. The work environment should be reviewed for potential risks (eg, working on a roof or a narrow ledge). Patients with early PLS may not be limited in these respects, but they should be reassessed as the disease progresses.

Patients and physicians should follow the specific laws of their jurisdictions regarding notification of licensing authorities and automobile insurers.

Patients should be informed of these risks and counseled in accordance with the laws of their jurisdiction, taking their present and future condition into consideration. Such communications should be documented carefully.

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Etiology

The cause of sporadic primary lateral sclerosis (PLS) is unknown. The term pathophysiology refers at this time to histologic consequences of unknown etiologic factors, which result, in turn, in the clinical manifestation of PLS.

Five reports that include autopsy findings in 6 patients with PLS differ in the pathologic changes they describe. Two major factors may account for the different pathologic 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 current practice they probably would not be considered as having had PLS.

In contrast, histologic findings in 3 other patients were of involvement of the precentral gyrus and loss of Betz cells. Brain magnetic resonance imaging (MRI) scans 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) scan studies in 2 patients showed reduced uptake in the motor cortex, as did positron emission tomography (PET) scan 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]

An additional study also examined changes in FA in patients with PLS and ALS, compared to controls, and showed differences between ALS and PLS patients in the regional distribution of white matter alterations.

In patients with ALS, the greatest reduction in FA occurred in the distal portions of the intracranial corticospinal tract, consistent with a distal axonal degeneration. In contrast, in patients with PLS, the greatest loss of fractional anisotropy and mean diffusivity occurred in the subcortical white matter underlying the motor cortex, with reduced volume, suggesting tissue loss. Clinical measures of upper motor neuron dysfunction correlated with reductions in FA in the corticospinal tract in patients with ALS and increased mean diffusivity and volume loss of the corticospinal tract in patients with PLS.

Both patient groups had reduced FA, and increased mean diffusivity of the reconstructed corticospinal and callosal motor fibers compared with controls, without changes in the genu or splenium. These findings indicate that degeneration in motor neuron disorders is not selective for corticospinal neurons, but also affects callosal neurons within the motor cortex. [9]

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 1 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.

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Epidemiology

Incidence in the United States

Data on the incidence of primary lateral sclerosis (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. [2] 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 for 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. In addition, review of the cases in the Pringle study suggests that half may not have had PLS; this would reduce the above estimates accordingly.

Repeating this calculation, using the more recent numbers 43 patients with PLS and 661 patients with ALS seen over a period of 17 years, [4] 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.

Sex predilection

The female-to-male ratio in a report of 8 patients was 1:1. [2] However, only 1 of 9 patients reported by Younger et al in 1988 was female. [1] A more recent report [4] supports a 1:1 female to male ratio among 43 patients with PLS.

Age predilection

A 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 earlier from the same center. [2]

Onset in a patient as young as 20 years was reported by Younger et al. [1]

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Prognosis

Dysfunction and disability accrue slowly as primary lateral sclerosis (PLS) progresses.

Issues of progressive disability are shared by all patients with all forms of MNDs, regardless of type.

Mortality

PLS has not been considered to shorten life expectancy. However, inspection of reported survival data from 36 patients with PLS [4] now suggests that the median survival is approximately 20 years.

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Patient Education

The physician's role in patient education about primary lateral sclerosis (PLS) includes informing the patient about the following:

  • The distinction between PLS and other MND (particularly ALS) and the uncertainty of PLS evolving into ALS
  • The availability of fairly effective symptomatic treatment using a multidisciplinary approach
  • The possible (current or future) impairment or medication effects that would make driving, operating some types of machinery, and certain work environments (such as roofs or ledges) unsafe

Information resources for patients

These resources are listed for informational purposes. Listing these resources does not imply endorsement. Patients should obtain specific treatment recommendations from their physicians.

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