What causes primary lateral sclerosis (PLS)?

Updated: Sep 06, 2019
  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, MHCM, CPE, FAAPL  more...
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Answer

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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