Primary Lateral Sclerosis—An Uncommon, Midlife Cortico-Spinal System Disease
Abstracts & Commentary
Sources: Le Forestier NL, et al. Does primary lateral sclerosis exist? A study of 20 patients and review of literature. Brain. 2001;124:1989-1999; Kuipers-Upmeijer J, et al. Primary lateral sclerosis: Clinical, neurophysiological, and magnetic resonance findings. J Neurol Neurosurg Psychiatry. 2001;71:615-620.
Le Forestier and colleagues annually treat and follow 450 patients in the Amyotrophic Lateral Sclerosis (ALS) Center of the Salpetriere Hospital, Paris. Among this large group of patients with cortico-spinal motor neuron disease, they identified and followed 20 sufferers of primary lateral sclerosis (PLS) for at least 3-5 years. The sufferers themselves already had an average of 8 years of illness before they came to the ALS Center. Mean follow-up amounted to an average of 43 months with a single duration of 14 years, but with no deaths. (Criteria for diagnosis were based on Pringle CE, et al. Brain. 1992;115:495-520). Given the probability that most of the remaining ± 430 patients at the Salpetriere had been accurately diagnosed and treated for classic ALS, one might suspect at least a 25% annual mortality in that group. It follows that PLS incidence should amount to much less than 1% of classic ALS.
Clinical Diagnosis
The applied minimal diagnosis of PLS includes the following qualities: 1) a progressive, uneven, uncommon, middle aged adult degenerative neurological disease damaging predominantly the corticospinal motor system. Presumably it reflects a genetic abnormality; 2) the disorder always lasts more than 3 years and the suffering patient usually proceeds to a relatively continuous degenerative death 15 years or more after onset; 3) the anatomic-functional abnormality of the disease consists predominantly of symmetrical, bilateral spastic damage to the lower spinal and bulbar pyramidal motor systems. The upper extremities usually become somewhat less spastic than the lower, and the hands often show moderate atrophy greater than the feet. By contrast, both feet and hands in PLS become much less withered than develop in ALS; and 4) a small fraction of bulbospinal and spinal motor neurons may degenerate over the years but they seldom create sufficient weakness to cause the specific cause of death. No clues so far exist to understand the specific cause and development of LSE by blood, CSF analysis, brain imaging, or any other laboratory tests. Diligent autopsies are extremely rare, but muscle biopsies are frequent.
Most PLS patients experienced muscle cramps (16/20) and muscle fasciculations (18/20) but, as mentioned, not primary muscle atrophy. Eight of Le Forestiers et al’s patients developed moderate secondary muscle atrophy in the hands but severe spasticity impeded 10 patients, 2 of whom suffered sufficient stiffness to be motor dysfunctional. Standard, general, cognitive tests never reached a dementia pattern, although 16 patients displayed moderately impaired frontal lobe neuropsychological functions. Seven patients developed oculomotor defects. Two displayed typical, progressive supranuclear opthalmoplegia, while 5 additional patients developed errors in antisaccadic efforts.
Seventeen of the 20 PLS patients developed pseudobulbar palsy between years of 1-7 of their illness. This was characterized by emotional lability, difficult swallowing, slow monotonous speaking, and urinary urgency (the last symptom is rare in ALS).Ten patients became unable to take deep breaths voluntarily, but tracheostomy was seldom necessary as in ALS. Muscle strength in the limbs remained near normal in 6 patients, but in almost all others became either moderately or, in 2 patients, severely weak.
A number of electrophysiological tests were used but were not explicitly important.
EMG Studies
All patients had both EMG studies as well as muscle biopsies. Six EMGs early in PLS patients reflected an absence of ALS. Successive EMG tests over time and varying motor unit potentials (MUP) were conducted and indicated a pattern of partial motor neuronal denervation followed by patches of reinnervation. The same findings were substantiated by muscle biopsies. Others have argued that these changes were mirrors of spasticity, but the major evidence appears to be one of spontaneous neuronal disintegration and repair. Spinal motor cell losses in PLS were much fewer than one finds in ALS.
At the time of this writing, 6 patients retained almost normal muscular strength despite their spasticity. Ten more were weakened but not more seriously than grade 4-5 in the UK Medical Research Council scale. Weakness and spasticity mainly affected proximal hip muscles and distal muscles, ones in the upper extremities. Strength varied in several patients with loss during the relatively early years but regained strength later on. All patients developed at least mild pseudobulbar palsy. Dysfunction of noncorticospinal systems also appeared in random qualities such as abnormal VEPs and SEPs. Brain MRI demonstrated no abnormalities in 6 patients, temporobasal atrophy in 3, and mild atrophy of the primary motor area of 1.
Commentary
As Neurology Alert went to press, the report of 10 PLS patients reported by Kuipers-Upmeijer and colleagues appeared. This verified the long survival and slow progression of PLS. It also indicates the inconsistent motor deficits described by Le Forestier et al and unknowingly supported almost all their observations. Kuipers-Upmeijer et al emphasize the indication that mild lower motor neuron defects appeared during maximal voluntary contractions and that 1 patient had a consistently reduced capacity in lower motor neuron efforts. As in Le Forestier et al’s report, MRI atrophy affected the precentral cerebral gyrus but diffferently, the parietal-occipital regions. Both investigators conclude that PLS belongs to the relatively large cortico-bulbar-spinal family, the individual genes of which remain unsolved. —Fred Plum
Dr. Plum, University Professor, Weill Medical College, and Attending Neurologist, New York Presbyterian Hospital, is Editor of Neurology Alert.
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