The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis

doi:10.1016/j.jns.2010.03.028

Journal of the Neurological Sciences

Volume 294, Issues 1–2, 15 July 2010, Pages 81-85

https://doi.org/10.1016/j.jns.2010.03.028 Get rights and content

Abstract

Background

Despite the inevitability of disease progression in amyotrophic lateral sclerosis, there is a high degree of prognostic heterogeneity in all subtypes. Some bulbar-onset (BO) patients may develop rapid anarthria yet remain ambulant for a prolonged period, whereas others progress rapidly, with early generalisation of motor weakness to the limbs and respiratory muscles. Diagnostic delay is a common occurrence in ALS, and many BO patients report having attended other specialist clinics prior to diagnosis.

Methods

A retrospective descriptive study of BO ALS patients seen in a tertiary clinic over a six year period.

Results

Forty-nine BO ALS patients were studied. Median survival from symptom onset was 27 months (range 6–84). 63% of subjects were female and the mean age at symptom onset was 68 years. Half had been referred to another speciality prior to diagnosis, either otolaryngology or stroke clinics, but this did not influence diagnostic latency or survival. Emotionality was reported in 45% of patients. Neurophysiological assessment was performed in 80%, brain imaging recorded in 69%, and antibody testing for myasthenia gravis in 22%. The median time to symptomatic progression beyond the bulbar region was approximately 1 year, with equal proportions progressing to the upper or lower limbs. The median interval from onset to anarthria was 18 months, and to loss of ambulation 22 months. There was a close correlation between the two (r² = 0.6) and median survival from loss of ambulation was only 3 months. Gastrostomy was carried out in 78% of patients with a median time of 13 months from symptom onset, and 3 months from diagnosis. Median survival from gastrostomy was 10 months.

Conclusions

Survival in bulbar-onset ALS is highly variable. Half of the patients were referred to an inappropriate clinic prior to diagnosis. The time interval to the development of anarthria predicted the timing of subsequent loss of ambulation accurately from which survival may then be only a few months.

Introduction

Understanding the clinical heterogeneity inherent in amyotrophic lateral sclerosis (ALS) remains an important challenge that might have some bearing on the disappointing results from clinical therapeutic trials for this degenerative disorder of cerebral and spinal motor neurons. Despite a median survival of 2–3 years from symptom onset in most clinic-based series, there is a skewed distribution with a significant number surviving beyond 10 years, a small minority of which also have bulbar-onset (BO) of their symptoms [1]. BO patients constitute up to 25% of most ALS clinic populations, and generally this phenotype is associated with more rapid progression [2]. It has been observed that older female patients are over-represented in BO patients [3], [4], [5], which links to the independent observation that the female:male ratio in ALS increases with each decade [5], [6], [7].

The insidious onset of symptoms in ALS, the lack of a diagnostic test, erroneous referral to other specialists [8], and even unnecessary surgery in some cases [9], are all factors involved in the consistent delay from symptom onset to formal diagnosis in ALS (frequently beyond 12 months [2]). This interval might represent a missed opportunity for a more effective therapeutic intervention. True ‘mimics’ of ALS are rare, possibly even more so for BO patients, who are observed to reach ALS clinics sooner after symptom onset than limb-onset patients [10], though this may simply reflect more rapid progression of symptoms. We have informally observed that BO patients are frequently referred to otolaryngology and stroke clinics prior to diagnosis in our tertiary centre, sometimes undergoing unnecessary investigations as a result.

Finally, we also recognise a group of patients, often female, who despite the relatively rapid development of anarthria, remain ambulant for months thereafter, and may derive proportionately a greater benefit from interventions such as enteral feeding.

In this retrospective analysis we sought to characterise the diagnostic pathway and aspects of clinical heterogeneity affecting survival in bulbar-onset ALS patients.

Section snippets

Methods

Patients with ALS seen at a tertiary referral centre since August 2003 were prospectively recorded in a database as part of routine clinical care. Since 2009 attendees have provided written informed consent for the use of anonymised clinical data for research and publication, and approval for the retrospective use of deceased patients (or those lost to follow up) was granted through application to the Ireland Health and Social Care Research Ethics Committee 2 (09/NIR02/35).

The diagnosis of ALS

Results

A total of 49 patients with bulbar-onset were identified from 262 sporadic ALS cases recorded in the database. The results are summarised in Table 1.

Discussion

This retrospective descriptive study of a group of bulbar-onset ALS patients confirms the long-recognised lower median survival overall, whilst specifically noting that nearly 10% of patients survived beyond 4 years from symptom onset (the upper limit of median survival in a review of prognostic factors in ALS [2]). We confirmed a higher proportion of females and higher mean age of symptom onset, and demonstrated that the development of anarthria is strongly predictive of the time to eventual

Acknowledgements

We would like to thank all the staff of the Oxford MND Care Centre (www.oxfordmnd.net), which receives funding from the MNDA, for their ongoing work in the care of ALS patients. MRT is supported by the MRC/MNDA Lady Edith Wolfson Clinician Scientist Fellowship.

References (16)

M. Kraemer et al.
Diagnostic problems and delay of diagnosis in amyotrophic lateral sclerosis
Clin Neurol Neurosurg
(2010 Feb)
Y. Iwasaki et al.
The diagnostic interval in amyotrophic lateral sclerosis
Clin Neurol Neurosurg
(2002)
A. Chen et al.
Otolaryngologic presentations of amyotrophic lateral sclerosis
Otolaryngol Head Neck Surg
(2005 Mar)
M.R. Turner et al.
Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990–2002
J NeurolNeurosurgPsychiatry
(2003)
A. Chio et al.
Prognostic factors in ALS: a critical review
Amyotroph Lateral Scler
(Oct–Dec 2009)
T.M. Li et al.
Clinical features and associations of 560 cases of motor neuron disease
J Neurol Neurosurg Psychiatry
(1990)
P.B. Christensen et al.
Survival of patients with amyotrophic lateral sclerosis in 2 Danish counties
Neurology
(1990)
L.J. Haverkamp et al.
Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction
Brain
(1995)

There are more references available in the full text version of this article.

Cited by (79)

Whole-body fasciculation detection in amyotrophic lateral sclerosis using motor unit MRI (MUMRI)
2024, Clinical Neurophysiology
Compare fasciculation rates between amyotrophic lateral sclerosis (ALS) patients and healthy controls in body regions relevant for diagnosing ALS using motor unit MRI (MUMRI) at baseline and 6 months follow-up, and relate this to single-channel surface EMG (SEMG).
Tongue, biceps brachii, paraspinals and lower legs were assessed with MUMRI and biceps brachii and soleus with SEMG in 10 healthy controls and 10 patients (9 typical ALS, 1 primary lateral sclerosis [PLS]).
MUMRI-detected fasciculation rates in typical ALS patients were higher compared to healthy controls for biceps brachii (2.40 ± 1.90 cm^-3min⁻¹ vs. 0.04 ± 0.10 cm^-3min⁻¹, p = 0.004), paraspinals (1.14 ± 1.61 cm^-3min⁻¹ vs. 0.02 ± 0.02 cm^-3min⁻¹, p = 0.016) and lower legs (1.42 ± 1.27 cm^-3min⁻¹ vs. 0.13 ± 0.10 cm^-3min⁻¹, p = 0.004), but not tongue (1.41 ± 1.94 cm^-3min⁻¹ vs. 0.18 ± 0.18 cm^-3min⁻¹, p = 0.556). The PLS patient showed no fasciculation. At baseline, 6/9 ALS patients had increased fasciculation rates compared to healthy controls in at least 2 body regions. At follow-up every patient had increased fasciculation rates in at least 2 body regions. The MUMRI-detected fasciculation rate correlated with SEMG-detected fasciculation rates (τ = 0.475, p = 0.006).
MUMRI can non-invasively image fasciculation in multiple body regions and appears sensitive to disease progression in individual patients.
MUMRI has potential as diagnostic tool for ALS.
Mapping of critical events in disease progression through binary classification: Application to amyotrophic lateral sclerosis
2021, Journal of Biomedical Informatics
Citation Excerpt :
Though that patient may require a wheelchair due to additional severe arm weakness (and inability to thus use a walker or cane), neither King’s nor MiToS can detect the associated equipment need. In the literature, few studies have analyzed the timing of some critical ALS stages/events, e.g., complete functional impairment or needing wheelchair [13,14]; however, analyses for several other critical ALS events (see Table 1) are needed. To this end, Dalgıç et al. proposed the Tollgate-based ALS Staging System (TASS) for measuring ALS progression.
The progression of many degenerative diseases is tracked periodically using scales evaluating functionality in daily activities. Although estimating the timing of critical events (i.e., disease tollgates) during degenerative disease progression is desirable, the necessary data may not be readily available in scale records. Further, analysis of disease progression poses data challenges, such as censoring and misclassification errors, which need to be addressed to provide meaningful research findings and inform patients.
We developed a novel binary classification approach to map scale scores into disease tollgates to describe disease progression leveraging standard/modified Kaplan-Meier analyses. The approach is demonstrated by estimating progression pathways in amyotrophic lateral sclerosis (ALS). Tollgate-based ALS Staging System (TASS) specifies the critical events (i.e., tollgates) in ALS progression. We first developed a binary classification predicting whether each TASS tollgate was passed given the itemized ALSFRS-R scores using 514 ALS patients’ data from Mayo Clinic-Rochester. Then, we utilized the binary classification to translate/map the ALSFRS-R data of 3,264 patients from the PRO-ACT database into TASS. We derived the time trajectories of ALS progression through tollgates from the augmented PRO-ACT data using Kaplan-Meier analyses. The effects of misclassification errors, condition-dependent dropouts, and censored data in trajectory estimations were evaluated with Interval Censored Kaplan Meier Analysis and Multistate Model for Panel Data.
The approach using Mayo Clinic data accurately estimated tollgate-passed states of patients given their itemized ALSFRS-R scores (AUCs > 0.90). The tollgate time trajectories derived from the augmented PRO-ACT dataset provide valuable insights; we predicted that the majority of the ALS patients would have modified arm function (67%) and require assistive devices for walking (53%) by the second year after ALS onset. By the third year, most (74%) ALS patients would occasionally use a wheelchair, while 48% of the ALS patients would be wheelchair-dependent by the fourth year. Assistive speech devices and feeding tubes were needed in 49% and 30% of the patients by the third year after ALS onset, respectively. The onset body region alters some tollgate passage time estimations by 1–2 years.
The estimated tollgate-based time trajectories inform patients and clinicians about prospective assistive device needs and life changes. More research is needed to personalize these estimations according to prognostic factors. Further, the approach can be leveraged in the progression of other diseases.
Time to diagnosis and factors affecting diagnostic delay in amyotrophic lateral sclerosis
2020, Journal of the Neurological Sciences
Citation Excerpt :
Turner et al. reported 49% of ALS patients were referred to other specialists prior to a neurologist, with 54% of this group seen by otorhinolaryngologists. Nonetheless, these referrals did not result in significant diagnostic delay [16]. However, in a study by Househam and Swash, the 47.2% of ALS patients who were first referred to a neurologist experienced a delay of 10.2 months compared to 12.3 months for those referred to another specialty, such as otorhinolaryngology (12.3%), rheumatology (8.8%), orthopedic surgery (7%), physiotherapy (5.3%), and psychiatry (3.5%) [27].
Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative neuromuscular disease with limited treatment options. The diagnosis of ALS can be challenging for numerous reasons, resulting in delays that may compromise optimal management and enrollment into clinical trials. Several studies have examined the process and challenges regarding the clinical diagnosis of ALS. Twenty-one studies that were almost exclusively from the English literature published between 1990 and 2020 were identified via PubMed using relevant search terms and included patient populations from the United States, Canada, Japan, Egypt, and several countries in South America and Europe. Probable or definitive ALS patients were identified using El Escorial or revised El Escorial/Airlie House Criteria. Time to diagnosis or diagnostic delay was defined as mean or median time from patient-reported first symptom onset to formal diagnosis by a physician, as recorded in medical records. The typical time to diagnosis was 10–16 months from symptom onset. Several points of delay in the diagnosis course were identified, including specialist referrals and misdiagnoses, often resulting in unnecessary procedures and surgeries. Bulbar onset was noted to significantly reduce time to ALS diagnosis. Future interventions and potential research opportunities were reviewed.
Atypical Motor Neuron Disease variants: Still a diagnostic challenge in Neurology
2019, Revue Neurologique
Motor neuron disease (MND) represents a wide and heterogeneous expanding group of disorders involving the upper or lower motor neurons, mainly represented by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis, progressive muscular atrophy and progressive bulbar palsy. Primary motor neuronopathies are characterized by progressive degenerative loss of anterior horn cell motoneurons (lower motor neurons) or loss of giant pyramidal Betz cells (upper motor neurons). Despite its well-known natural history, pathophysiological and clinical characteristics for the most common MND, atypical clinical presentation and neurodegenerative mechanisms are commonly observed in rare clinical entities, so-called atypical variants of MND-ALS, including flail-leg syndrome, flail-arm syndrome, facial-onset sensory and motor neuronopathy (FOSMN), finger extension weakness and downbeat nystagmus (FEWDON-MND) and long-lasting and juvenile MND-ALS. Herein, we provide a review article presenting clinical, genetic, pathophysiological and neuroimaging findings of atypical variants of MND-ALS in clinical practice.
Multi-disciplinary clinical protocol for the diagnosis of bulbar amyotrophic lateral sclerosis
2019, Acta Otorrinolaringologica Espanola
The objective of this study was to examine the role of different specialists in the diagnosis of amyotrophic lateral sclerosis (ALS), to understand changes in verbal expression and phonation, respiratory dynamics and swallowing that occurred rapidly over a short period of time.
22 patients with bulbar ALS were submitted for voice assessment, ENT evaluation, Multi-Dimensional Voice Program (MDVP), spectrogram, electroglottography, fiberoptic endoscopic evaluation of swallowing.
In the early stage of the disease, the oral tract and velopharyngeal port were involved. Three months after the initial symptoms, most of the patients presented hoarseness, breathy voice, dysarthria, pitch modulation problems and difficulties in pronunciation of explosive, velar and lingual consonants. Values of MDVP were altered. Spectrogram showed an additional formant, due to nasal resonance. Electroglottography showed periodic oscillation of the vocal folds only during short vocal cycle. Swallowing was characterized by weakness and incoordination of oro-pharyngeal muscles with penetration or aspiration.
A specific multidisciplinary clinical protocol was designed to report vocal parameters and swallowing disorders that changed more quickly in bulbar ALS patients. Furthermore, the patients were stratified according to involvement of pharyngeal structures, and severity index.
El objetivo de este estudio fue examinar la función de los diferentes especialistas en el diagnóstico de la esclerosis lateral amiotrófica (ELA), para comprender qué cambios se produjeron en cuanto a expresión verbal, dinámica fonatoria y respiratoria, y deglución, en un breve periodo de tiempo.
Se sometió a 22 pacientes con ELA bulbar a evaluación de la voz, examen ORL, programa de voz multi-dimensional (MDVP), espectrograma, electroglotografía y evaluación de la deglución mediante endoscopía de fibra óptica.
En la etapa temprana de la enfermedad, el tracto oral y el cierre velofaríngeo se vieron comprometidos. Transcurridos 3 meses de los síntomas iniciales, la mayoría de los pacientes presentó ronquera, voz entrecortada, disartria, problemas de modulación de la afinación y dificultades de pronunciación de las consonantes oclusivas, velares y linguales. Los valores del MDVP se vieron alterados. El espectrograma reflejó un formante adicional, debido a la resonancia nasal. La electroglotografía mostró una oscilación periódica de las cuerdas vocales únicamente durante el ciclo vocal corto. La deglución se vio caracterizada por debilidad y descoordinación de los músculos orofaríngeos, con penetración o aspiración.
Se diseñó un protocolo clínico multidisciplinar específico para reportar los parámetros vocales y los trastornos deglutorios que experimentan un cambio más rápido en los pacientes con ELA bulbar. Además, se estratificaron los pacientes con arreglo al compromiso de las estructuras faríngeas y el índice de gravedad.
Diagnostic delay in amyotrophic lateral sclerosis
2023, European Journal of Neurology

View all citing articles on Scopus

¹: These authors contributed equally to the manuscript.

View full text

The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis

Abstract

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Acknowledgements

Clin Neurol Neurosurg

Clin Neurol Neurosurg

Otolaryngol Head Neck Surg

Prolonged survival in motor neuron disease: a descriptive study of the King's database 1990–2002

J NeurolNeurosurgPsychiatry

Prognostic factors in ALS: a critical review

Amyotroph Lateral Scler

Clinical features and associations of 560 cases of motor neuron disease

J Neurol Neurosurg Psychiatry

Survival of patients with amyotrophic lateral sclerosis in 2 Danish counties

Neurology

Natural history of amyotrophic lateral sclerosis in a database population. Validation of a scoring system and a model for survival prediction

Brain