Introduction and background

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which the upper and lower motor neurons slowly die, usually following a fast and fatal course. Worldwide incidence is close to 2 cases per 100,000 people per year [1,2], and the estimated lifetime risk is about 1 in 350 [3]. Because most patients survive only two to four years after symptoms begin [1,3], the time spent reaching a diagnosis uses up part of the limited period in which treatment and planning are still possible.

Amyotrophic lateral sclerosis is divided into forms by where weakness first appears. Bulbar-onset ALS (about 25% to 30% of cases) begins with slurred speech, trouble swallowing, or changes in the voice [1]. Limb-onset ALS (about 60% to 70%) begins with weakness in an arm or a leg [1]. A smaller group first develops breathing problems. Onset site also carries prognostic weight, and bulbar-onset patients have generally been reported to have shorter survival from symptom onset [3,4].

Diagnosing ALS is inherently slow. There is no confirmatory test; the diagnosis is made clinically using established criteria, El Escorial, Revised El Escorial, Awaji, and, more recently, Gold Coast, which require signs of both upper and lower motor neuron damage and, in most versions, evidence that the disease is spreading [1,3]. Because this often depends on watching the disease evolve and ruling out look-alike conditions, it frequently cannot be made at a single visit.

As a result, diagnostic delay is a well-recognized problem. Patients commonly see several specialists before the diagnosis is confirmed, and the average time from first symptom to diagnosis has been reported at roughly 9 to 18 months across different health systems [3]. This interval has more than one stage: the time a patient takes to seek help, and the often longer time the health system takes to refer the patient and reach the diagnosis. Where the delay builds up matters, because different stages call for different solutions.

Much of the delay comes from mistaking early ALS for commoner conditions. Bulbar-onset ALS is often mistaken for stroke, a functional neurological disorder, myasthenia gravis, or ear, nose, and throat (ENT) disease [3]. Limb-onset ALS is frequently blamed on cervical or lumbar spine disease, peripheral neuropathy, or orthopedic problems, so these patients are often routed through orthopedic, spine, and rehabilitation services before reaching a neurologist [1]. Because the two forms present so differently, and are mistaken for different things, there is good reason to expect they are not diagnosed at the same speed.

A delayed diagnosis carries real costs. Disease-modifying drugs are started late - riluzole first and most widely, with edaravone and, for superoxide dismutase 1 (SOD1)-related disease, tofersen also available [3,5] - multidisciplinary care is delayed, less time remains for advance care planning, and patients and families carry a heavy emotional burden during the uncertainty. In a disease measured in months, avoidable delay directly shrinks the window for treatment, support, and planning.

Several studies have reported diagnostic delay separately for bulbar-onset and limb-onset ALS, but this evidence has never been pooled, and the figures vary widely between settings [3], leaving clinicians without a single combined estimate of how much the two forms differ. This matters for two reasons. First, a single pooled estimate gives clinicians a concrete figure to set expectations and counsel patients, rather than the widely varying numbers from individual cohorts. Second, and more importantly, if one form is consistently diagnosed later, that identifies exactly where efforts to shorten the delay should be directed. We therefore carried out this systematic review and meta-analysis comparing the time from symptom onset to diagnosis in bulbar-onset versus limb-onset ALS. Because disease-modifying treatment begins only after diagnosis and survival in ALS is measured in months, quantifying this difference has direct clinical significance for efforts to reduce the delay to treatment. This review compiles and synthesizes the available evidence on diagnostic delay in bulbar-onset versus limb-onset ALS, pooling reported estimates into a single comparison and rates how reliable the overall estimate is.