Pringle et al. 1992 — Primary Lateral Sclerosis as a Distinct Disease Entity
Before Pringle and colleagues published their 1992 paper in Brain, PLS existed as a clinical observation but not as a rigorously defined diagnostic category. The paper changed that. By combining a case series of patients with prolonged pure upper motor neuron syndromes with pathological data and a formal review of prior literature, Pringle et al. made the argument that PLS was a real, distinct disease — not simply a slow or incomplete form of ALS.
Historical context
By the early 1990s, cases of progressive pure upper motor neuron disease had been described in the literature for over a century, but their relationship to ALS remained contentious. Some neurologists argued that "pure PLS" was simply ALS with delayed or absent lower motor neuron involvement — that given enough time, all cases would eventually convert. Others held that PLS was a genuinely separate entity with different pathology, different prognosis, and different clinical significance. This debate had practical stakes: a patient told they had PLS faced a profoundly different trajectory than a patient told they had ALS.
The difficulty was that no systematic, large-scale clinical and pathological analysis of PLS had been conducted. Pringle et al. set out to provide one.
What they did
The study combined two approaches. First, a clinical case series of patients with progressive upper motor neuron syndromes seen at the authors' center, followed over years, with careful documentation of onset pattern, rate of progression, presence or absence of lower motor neuron signs, and survival. Second, a systematic review of pathological reports from autopsy cases of patients diagnosed with PLS, examining what was actually found in the brain and spinal cord — specifically whether the corticospinal tracts were selectively affected and whether anterior horn cells (lower motor neurons) showed significant degeneration.
The authors also proposed a set of clinical criteria for diagnosing PLS: progressive UMN syndrome for at least 3 years (their threshold); absence of lower motor neuron signs by clinical examination and EMG; absence of alternative diagnoses; and normal sensory examination.
What they found
The pathological evidence supported PLS as a distinct entity. In cases that had followed a pure UMN course clinically, autopsy findings showed selective degeneration of the corticospinal tracts — particularly Betz cells (the large layer V neurons in the primary motor cortex that give rise to the corticospinal tract) — without the widespread anterior horn cell loss characteristic of ALS. This was the pathological signature of a disease confined to the upper motor neuron system.
Clinical data showed that patients with pure UMN syndromes had substantially longer survival than ALS, and that a subset of patients who initially appeared to have pure PLS eventually developed lower motor neuron signs (suggesting ALS). The clinical criteria proposed by the authors — particularly the multi-year observation period before diagnosing "definite" PLS — were designed to exclude these converters.
The 3-year threshold Pringle proposed was later revised. The 2020 consensus criteria reduced the "probable PLS" threshold to 2 years and the "definite PLS" threshold to 4 years, based on accumulated natural history data suggesting that most ALS conversion happens within the first 4 years of symptom onset.
Why it matters
Pringle 1992 is the paper that gave PLS its modern diagnostic identity. It is cited in virtually every major PLS paper published since, including the 2006 Gordon cohort, the 2020 consensus criteria paper, and the 2025 Scirocco review. Before this paper, clinicians lacked a systematic basis for telling patients their disease was distinct from ALS. After it, they had clinical criteria, pathological evidence, and a framework for thinking about the PLS-ALS boundary.
For patients and families, this paper is the foundation of the statement that PLS is its own disease. The diagnostic criteria it proposed — the requirement for prolonged pure UMN progression before a diagnosis is made — are directly reflected in the waiting period that people with suspected PLS must endure before receiving a definite diagnosis.
The paper also established the intellectual framework for the conversion question: that some patients who appear to have PLS will eventually convert to ALS, that this conversion is most common early in the disease course, and that the diagnostic threshold exists specifically to minimize misclassification. This framework has been refined but not replaced in the 30 years since publication.
Limitations and legacy
The case series was small and conducted at a single center. Pathological data, while compelling, came from a limited number of autopsy cases. The 3-year threshold Pringle proposed was based on clinical experience rather than systematic evidence about conversion timing. And the paper predates modern neuroimaging, genetic testing, and ultra-sensitive EMG techniques — all of which now contribute to the differential diagnosis.
These limitations do not diminish the paper's importance. It was the right study for its time, conducted rigorously given what was methodologically available. The subsequent 30 years of PLS research have refined its conclusions without overturning them.
How this connects
The clinical criteria Pringle proposed were updated by the 2020 consensus criteria after systematic evidence from natural history cohorts became available. The natural history benchmarks that replaced Pringle's thresholds were established by Gordon 2006 and refined by subsequent cohorts including the PNHS. For the current diagnostic process in practice, see Diagnosis. The conversion question Pringle raised — and the waiting period it implies — is discussed on the Prognosis page.
Citation
Pringle CE, Hudson AJ, Munoz DG, Kiernan JA, Brown WF, Ebers GC. Primary lateral sclerosis. Clinical features, neuropathology and diagnostic criteria. Brain. 1992;115(Pt 2):495–520. doi:10.1093/brain/115.2.495