Upper Motor Neuron Disorders: History
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Subjects: Biology
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Timothy Fullam

Following the exclusion of potentially reversible causes, the differential for those patients presenting with a predominant upper motor neuron syndrome includes primary lateral sclerosis (PLS), hereditary spastic paraplegia (HSP), or upper motor neuron dominant ALS (UMNdALS). Differentiation of these disorders in the early phases of disease remains challenging. While no single clinical or diagnostic tests is specific, there are several developing biomarkers and neuroimaging technologies which may help distinguish PLS from HSP and UMNdALS. Recent consensus diagnostic criteria and use of evolving technologies will allow more precise delineation of PLS from other upper motor neuron disorders and aid in the targeting of potentially disease-modifying therapeutics. 

  • primary lateral sclerosis
  • amyotrophic lateral sclerosis
  • hereditary spastic paraplegia

1. Introduction

Jean-Martin Charcot (1825–1893) and Wilhelm Erb (1840–1921) are credited with first describing a distinct clinical syndrome of upper motor neuron (UMN) tract degeneration in isolation with symptoms including spasticity, hyperreflexia, and mild weakness [1][2]. Many of the earliest described cases included cases of hereditary spastic paraplegia, amyotrophic lateral sclerosis, and underrecognized structural, infectious, or inflammatory etiologies for upper motor neuron dysfunction which have since become routinely diagnosed with the advent of advanced neuroimaging as well as genetic testing [2][3][4].
The core clinical features of a distinct clinical entity, primary lateral sclerosis (PLS), were first described in 1945 and included insidious onset, slow progression without plateau or remission, and examination findings limited to the pyramidal tracts without evidence of involvement of additional parts of the central nervous system [5]. While controversy remains as to whether there is a pathologic ‘gold standard’ to distinguish PLS from amyotrophic lateral sclerosis (ALS), especially those variants with a predominant upper motor neuron phenotype, the more benign clinical prognosis, as well as differing findings on neuroimaging and biomarker studies, continues to make this entity a clinical category of interest for further research and therapy development [2][4][6]. Several diagnostic criteria have been proposed with relative agreement on the core criteria of the presence of upper motor neuron dysfunction on exam, presentation most commonly in the legs, bulbar region, or mixed limb/bulbar regions, slow progression with ≥4 years from symptom onset, with age at diagnosis ≥ age 20, and lack of marked fasciculations, atrophy, sensory findings, or a family history. PLS remains a diagnosis of exclusion—and requires testing to exclude alternative diagnosis (e.g., EMG, MRI, etc.). The main point of differentiation between criteria is the time lapse between symptom onset and monitoring for development of lower motor neuron development [6]. While initial criteria proposed by Pringle recommended ≥3 years, later criteria by Singer and Gordon recommended ≥4 years and the COSMOS study in PLS required ≥5 years [3][7][8][9]. In general, the possibility of a false positive diagnosis or transition into ALS decreases with time. More recent consensus criteria have proposed a diagnosis of ‘probable PLS’ after 2 years of a pure upper motor neuron phenotype with ‘definite PLS’ diagnosed after 4 years [4]. The goal of more permissive and accepted clinical criteria is to allow for more uniform investigations into the histopathology and biomarkers related to PLS in order to more accurately distinguish this condition from other conditions presenting with upper motor neuron dysfunction as well as allow for targeted testing of therapeutics [2][4].

2. Clinical Presentation of Select Upper Motor Neuron Disorders

2.1. Primary Lateral Sclerosis

Primary lateral sclerosis is often considered on a spectrum of motor neuron disorders including those that are lower motor neuron (LMN) dominant (progressive muscular atrophy) on one end, ALS in the middle with various degrees of upper/lower motor neuron dysfunction, and the pure upper motor neuron phenotype of PLS making the opposite end of the spectrum. The pure upper motor neuron phenotype represents 1–4% of all patients with motor neuron disease [3][10][11][12].

2.2. Upper Motor Neuron Dominant ALS

Following publication of the Pringle Criteria for PLS in 1992, there was renewed interest in studies related to PLS. Unfortunately, while the criteria were widely used, there was a lack of specificity and many subsequent studies included patients in the umbrella term of PLS despite findings of LMN abnormalities clinically or by electromyography (EMG) [3][8][11][13]. New pathologic criteria for ALS, as well as case reports of late conversion from a PLS phenotype to ALS reinvigorated debate as to the utility of PLS as a distinct clinical entity as well as the appropriate time to wait until providing patients with a diagnosis of PLS [14][15][16][17][18][19]. These questions ultimately led to further case reviews of patients with an upper motor neuron dominant phenotype and proposition of the subcategory of UMN-dominant ALS. UMNdALS is defined as having symptoms lasting less than 4 years or disability secondary to UMN signs with known EMG denervation or LMN signs on exam that do not yet meet criteria for clinically definite, clinically probable, or probable-laboratory-supported ALS as defined by the revised El Escorial criteria [8][20][21].

2.3. Hereditary Spastic Paraparesis

Hereditary spastic paraplegia (HSP) is a syndrome characterized by bilateral lower extremity spasticity and weakness, which are a predominant manifestation for which genetic mutations are a causative factor. There are over 70 genetic subtypes identified which include all patterns of inheritance (autosomal dominant, autosomal recessive, X-linked, mitochondrial) [22][23]. Age of onset is variable given the various causative genetic and molecular mechanisms of disease; however, the more common autosomal dominant forms typically occur in adulthood between the second and third decades. Onset of symptoms prior to age 35 reliably distinguishes HSP from PLS. Unlike PLS, HSP is assumed to be genetic and diagnosis can span the lifespan from childhood onset to older age. Based on phenotype, HSP can be classified as ‘pure’ or ‘uncomplicated’ when the spastic paraplegia and subtle lower extremity dorsal column impairment is the primary manifestation or ‘complicated’ when additional neurologic or systemic abnormalities, such as dementia, seizures/epilepsy, ataxia, mental retardation, neuropathy, distal atrophy, or visual changes, co-exist. The most common form of autosomal dominant disease, SPG4 (spastin, 30–40% of autosomal dominant families) is typically associated with ‘uncomplicated’ forms of disease while others such as SPG11 (spatacsin, autosomal recessive, 50% of recessive families) are frequently associated with cognitive delays and characteristic neuroimaging findings (i.e., thin corpus callosum) [6][24][25]. A detailed review of all the various forms of HSP is beyond the scope of this article, however, [18] and [19] provide an in-depth overview.

3. Future Directions

Unfortunately, given its reliance on being clinically defined and its long trajectory, PLS has continued to be neglected in terms of clinical trial and therapy development. Recent consensus criteria with ‘probable’ and ‘definite’ PLS categories along with emerging neuroimaging, electrophysiologic, genetic, and molecular studies to distinguish PLS from UMNdALS and HSP will help clear the path for reliable clinical trial development, both for disease modifying as well as symptomatic therapy. Until such technology becomes more reliable, distinguishing PLS and ALS from UMNdALS remains important as this cohort of patients have been shown to have an intermediate progression in terms of disability and survival as compared to either PLS and ALS and may confound results of future clinical trials if they are included in PLS or ALS patient cohorts. As the costs of genetic testing continue to lower and more clinical trials are targeted towards specific gene mutations in both ALS and HSP, genetic testing will likely become a more routine part of the workup for pure upper motor neuron disorders. Despite being considered on the spectrum of ALS, PLS clearly has a longer survival and much slower rate of decline, as much as 30 times slower than that of ALS when measured by the ALS functional rating scale-revised (ALSFRS-R). More sensitive clinical trial tools, such as the development of a unique PLS functional rating scale and advanced MRI imaging techniques, may help encourage therapeutic development for PLS therapies and help shorten the time required to study these interventions [9][26][27].

This entry is adapted from the peer-reviewed paper 10.3390/brainsci11050611

References

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