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Abstract
Objective To define patterns of spread through the order of lower motor neuron involvement (first, second or third order), relationships between interval or sites of affected areas from onset to involvement of a second region, and prognosis, including 5 year survival, normal preservation of motor function at onset of respiratory symptoms and cumulative occurrence of each region and direction of spread.
Method 150 patients with sporadic amyotrophic lateral sclerosis (ALS) underwent follow-up at 3 month intervals until the appearance of respiratory symptoms. Symptom appearances were determined using the revised version of the ALS Functional Rating Scale.
Result Median survival with combined type onset (two regions simultaneously) was shorter (18 months) than with bulbar onset (26 months, p=0.01). The interval from onset to involvement of the second region correlated significantly with survival, independent of particular combinations. 5 year survival rate was 21% for lower limb onset, 18% for upper limb onset and 16% for bulbar onset. No patient with a rapid spread pattern (two regions within 3 months from onset) survived >5 years. Early manifestations of bulbar symptoms within 1 year were associated with worse survival (p<0.001) although no significant difference in survival was seen between groups with and without bulbar symptoms (p=0.51). In terms of cumulative occurrence, symptoms spread longitudinally to adjacent regions. Bulbar function remained preserved in 27%, lower limb function in 10% and upper limb function in 2.7%.
Conclusion The interval between onset and involvement of the second region is an important predictor of survival. The data support the contiguous anatomical propagation of lower motor neuron involvement in sporadic ALS.
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Introduction
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that affects spinal, brainstem and cortical motor neurons, giving rise to weakness of the upper and lower limbs, bulbar palsy and eventual respiratory failure.1 Median survival from initial onset until death without ventilation assistance or tracheostomy, which is commonly used to define survival as a primary endpoint, ranges from 2 to 4 years all over the world.2–4 Motor function phenotype in terms of the pattern of spread for ALS patients is clinically variable in individual patients. Variations in the pattern of spread and survival in ALS are not well understood.5 Unexpected respiratory failure can occur in patients with normally preserved lower motor neuron (LMN) function6–8 and a minority of ALS patients survive >5 years.9
Older age,10 El Escorial category,11 shorter interval between first symptoms and first examination (FS-FE)12 and low score on the revised version of the ALS Functional Rating Scale (ALSFRS-R)13 14 are consistently reported to be associated with worse survival. Cases with bulbar onset are traditionally regarded as showing a poor prognosis.15 16 Bulbar symptoms directly (aspiration pneumonia17 18) or indirectly (impaired quality of life, reduced will to live19 and malnutrition20) accompany respiratory symptoms. However, no evidence of a direct correlation in LMN loss between bulbar and respiratory areas has been found.
The rostral–caudal distributions of LMN in the pontomedullary, cervical and lumbosacral segments of the CNS are related to bulbar, upper limb and lower limb symptoms, respectively.21 Respiratory function may be widely related to thoracic and truncal segments, in addition to innervations from the phrenic nerve arising from the cervical (C3–C5) region.22 Assessment of these segmental region involvements is performed using not only the internationally recognised El Escorial criteria but also ALSFRS-R.
A misfolding pathology involving mutant superoxide dismutase-1 and causing ALS has recently been suggested to spread from the site of disease onset to neighbouring areas in a prion-like manner in animal models.23 Whether this phenomenon occurs naturally in sporadic ALS remains unknown. A similar concept has been recognised in the Braak theory of Parkinson's disease regarding upward propagation from the olfactory bulb and gut autonomic nerves.24
Analysing the propagation of pathology from observation of motor phenotypes is easier in ALS than in other neurodegenerative disorders. Our aims were to clarify onset type in association with 5 year survival, the relationships between interval or sites from first symptoms to second symptoms (FS-SS) and prognosis, presence or timing of bulbar symptoms and survival. We also examined the pattern of spread and direction of clinical LMN involvement over time from onset until the appearance of respiratory symptoms, and sites and frequency of normally preserved motor function at the appearance of respiratory symptoms.
Patients and methods
Eligibility criteria
The initial study population comprised 189 consecutive patients with sporadic ALS. We then excluded 39 patients with ALS because of a lack of information available after diagnosis (n=17), suicide (n=2), concomitant cancer (n=3), complications of dementia (n=7), family history of ALS (n=3) and undetermined time of symptom onset in patients with significant cervical spondylosis (n=4). Acute respiratory failure was identified as the first manifestation of ALS in three patients.
In this survey, 150 patients with sporadic ALS underwent follow-up every 3 months until the appearance of respiratory symptoms and the primary end point, for whom precise information was available regarding death or the time at which the patient required tracheotomy or ventilation assistance, including non-invasive positive pressure ventilation. Survival data until the primary end point were complete for 134 patients (89.4%). Sixteen censored subjects provided information about the time at the appearance of respiratory symptoms but the exact time of the primary end point was unknown. Follow-ups were conducted until 2010 at Osaka Medical College Hospital, a tertiary referral centre in Takatsuki-city (approximate population 400 000; Osaka, Japan). Patients provided informed consent after the study procedures had been fully explained. All patients were treated with riluzole, with the exception of eight patients who developed nausea or liver damage.
Definition of onset type
Time and site of initial symptoms were determined by subjective complaints based on ALSFRS-R when a reduction from a full score of 12 points at any site was first identified. Combined (C)-type ALS was defined as involvement of two regions within 1 month of initial presentation. C2–3 was defined as an FS-SS interval of 2–3 months. The ‘rapid spread type’ of FS-SS (C+C2–3) was categorised as involvement of two regions within 3 months from onset.
Data collection
The pattern of spread from onset in individual ALS patient was expressed as first, second or third order LMN involvements until the appearance of respiratory symptoms. Five year survival rates with each type of onset, including C and C2–3 types, were calculated from Kaplan–Meier survival curves. The cumulative occurrence of clinical LMN involvement from each site of onset was also analysed over time to clarify directions of spread.
Assessments of normally preserved LMNs
Normally preserved motor function at each site was defined as a full score of 12 points at the site, according to the ALSFRS-R. Percentages of normal preservation of the three motor functions (bulbar, upper limb and lower limb) were calculated at the appearance of respiratory symptoms.
In brief, lower limb function was estimated by walking or climbing stairs, upper limb function by writing, self-feeding or dressing and bulbar function by speech, salivation or deglutition. The item of ‘turning over in bed’ is considered to mainly represent lower limb functions but is also associated with truncal and upper limb functions. We therefore did not judge this item for onset involving or preservation of lower limb function, although no patient manifested onset in the form of effects on this item. We recognised the appearance of respiratory symptoms based on dyspnoea at meals or while bathing, orthopnoea or sleep disturbance due to dyspnoea. The primary end point for survival was determined as a score of ≤1 out of 12 points in the respiratory domain on the ALSFRS-R, indicating the time at which death would have occurred without tracheostomy or ventilatory assistance, including full time non-invasive positive pressure ventilation.
Statistical analysis
Data were analysed using Stat Mate V.3.0 software (Japanese version; Tokyo, Japan). Differences in data between groups were analysed using the χ2 test or Student's t test (two tailed). Univariate survival models and cumulative occurrence were obtained using Kaplan–Meier curves, with statistical analysis of log rank testing performed using Prism software (Graph Pad, California, USA). Survival data were also analysed using the Cox proportional model for multivariate regression. All times were calculated in months from initial onset. The ethics committee at Osaka Medical College approved the study protocols.
Results
Clinical profile and survival for each onset type
Onset of symptoms was in the upper limbs in 33% (n=50), lower limbs in 35% (n=52) and bulbar in 21% (n=32). Overall median survival time was 32 months and mean duration from FS-FE was 14.3 months (median 12 months; range 3–60 months). Survival was significantly shorter with bulbar onset (26 months) than with upper limb onset (33 months, p=0.023) or lower limb onset (32 months, p=0.047). A female predominance with older disease onset was seen in patients with bulbar onset (table 1, figure 1).
Demographic and clinical characteristics at each site of onset
Patterns of spread through the orders (1st to 4th) of lower motor neuron involvements from onset (1st: first symptom(s)) until respiratory symptoms. Left side of the box shows symptom site (U, upper limb symptoms; L, lower limb symptoms; B, bulbar symptoms; R, respiratory symptoms) and the right side of the box shows numbers of patients. ‘B,U’ represents combined- type amyotrophic lateral sclerosis (ALS) in which bulbar and upper limb symptoms appeared within 1 month of initial presentation. ‘U,L’ represents combined-type ALS in which upper and lower limb symptoms appeared within 1 month of initial presentation.
Sixteen patients (10.6%) showed C-type onset, comprising nine patients with bulbar and upper limb, and seven patients with upper limb and lower limb onset. No cases with C-type ALS showed combined bulbar onset and onset of the lower limbs. C-type patients were diagnosed significantly earlier compared with those with limb onset (C vs lower limb, p<0.001; C vs upper limb, p<0.001). Importantly, median survival time was shortest for C-type (18 months, bulbar vs C, p=0.01) as no differences in age distributions were seen between C-type and limb or bulbar onset (upper limb vs C, p=0.765; lower limb vs C, p=0.521; bulbar vs C, p=0.663).
Survival according to timing of second region
As our data indicated significantly shorter survival in C-type ALS, we hypothesised that the FS-SS interval offers an important predictor of survival. Median survival times were almost identical between the C-type group and the group showing an FS-SS interval of 2–3 months (C2–3) from onset (19 months, n=16, p=0.896). The ‘rapid spread-type’ of FS-SS (C+C2–3) showed significantly lower median survival time than other types with ALS manifesting an FS-SS >3 months (36 months, p<0.001). Cox regression analysis revealed shorter survival in patients with smaller FS-SS interval (p=0.002; 95% CI 1.232 to 1.673), after adjusting for age and sex (figure 2).
Kaplan–Meier curves at different intervals between the first symptoms and the second symptom (FS-SS). Patients were divided into three groups: C: FS-SS ≤1 month (n=16); C2–3, FS-SS 2–3 months (n=16); and C>3, FS-SS >3 months (n=118). The ‘rapid spread-type’ of FS-SS (C+C2–3) showed significantly lower median survival time than other types with amyotrophic lateral sclerosis (ALS), manifesting an FS-SS >3 months (p<0.001). No cases with C and C2–3 type of ALS survived for more than 5 years. M, months.
Long term survival of more than 5 years with sporadic ALS
Long term survival was defined as a patient with ALS living tracheostomy-free for >5 years following symptomatic onset. Survival estimates were obtained from Kaplan–Meier curves, including censored observations. Overall 5 year survival rate was 17%. In comparison, the 5 year survival rate was 21% for lower limb onset, 18% for upper limb onset and 16% for bulbar onset. Importantly, no patient with rapid spread-type survived >5 years, as shown in figure 2 and table 1.
Survival according to FS-SS combinations
In patients with upper limb onset, no significant difference in median survival time was seen between the groups with spread to the lower limb and bulbar areas. No significant difference was found between patients with lower limb onset and bulbar onset followed by spread to a contiguous region or skipped region. These findings indicated that the second affected site did not influence survival—that is, survival was not linked to any particular combination of FS-SS, but rather to the interval of FS-SS. However, there was no patient with bulbar onset spreading to the lower limbs who survived for 5 years or longer (figure 3).
Kaplan–Meier survival curves for combinations of first and second symptoms (A) group with upper limb (U) onset who showed spread to the lower limb (L) (U-L, n=37; median survival time (MST) 32 months) or to the bulbar region (B) (U-B, n=21; MST 29 months; p=0.628). (B) Group with lower limb onset who showed spread to the upper limbs (L-U, n=44; MST 32 months) or to the bulbar region (L-B, n=8; MST 31 months; p=0.899). (C) Group with bulbar onset who showed spread to the upper limbs (B-U, n=29; MST 26 months) or lower limbs (B-L, n=12; MST 27 months; p=0.785).
Survival in patients with and without bulbar symptoms
No significant difference in survival was seen between groups with bulbar symptoms and spared bulbar symptoms for the entire course (p=0.51). However, survival was significantly shorter when bulbar symptoms developed within 12 months after the initial onset than when bulbar symptoms developed after this time (p<0.001). Early manifestation of bulbar symptoms within 1 year was also an important predictor of lower median survival time (figure 4).
Kaplan–Meier survival plots of amyotrophic lateral sclerosis (ALS) patients with and without bulbar symptoms. (A) ALS patient groups with (median survival time (MST) 31 months, n=110) and without (MST 33 months, n=40) bulbar (B) symptoms at any time in the entire course (p=0.51). (B) ALS patient group displaying bulbar symptoms ≤12 months after initial onset (MST 21 months, n=58) or >12 months after initial onset (MST 47 months, n=52). Patients with bulbar symptoms were divided into two groups according to the median survival time (12 months). Patients presenting with bulbar symptom ≤12 months after onset showed shorter survival than patients with bulbar symptoms >12 months after onset (p<0.001).
Patterns of spread for each onset type
Figure 1 shows the orders of spread in the entire course of the disease from initial onset until respiratory symptoms. When the course started with the lower limbs, including C-type, 83% of cases were followed by upper limb symptoms, 3% by respiratory symptoms and 14% by bulbar symptoms. When the course began with bulbar symptoms, 71% of cases were followed by upper limb symptoms, 29% by lower limb symptoms and 0% by respiratory symptoms. When the course began with upper limb symptoms, 64% of cases were caudally followed by lower limb symptoms, 5% by respiratory symptoms and 32% were rostrally followed by bulbar symptoms.
Cumulative occurrences of symptomatic involvement from each region of onset to other regions are shown in figure 5. From the analyses of duration until occurrence in 50% of patients on Kaplan–Meier plots, patients with bulbar onset developed upper limb symptoms (9 months) more rapidly than lower limb symptoms (14 months, p<0.001; figure 5A). Patients with lower limb onset developed upper limb symptoms (10 months) more rapidly than bulbar symptoms (27 months, p<0.001; figure 5B). Patients with upper limb onset developed faster spread to caudal (lower limb, 14 months) than rostral (lower limb, 17 months) regions but there was no significant difference between them (p=0.196; figure 5C). From the analyses of cumulative occurrences, the development of LMN involvement demonstrated anatomically contiguous spread to body regions.
Cumulative occurrence of amyotrophic lateral sclerosis symptomatic involvement over time from bulbar onset (A), lower limb onset (B) and upper limb onset (C). Lines are coloured according to lower motor neuron involvement. Rostral spread after onset of lower limb symptoms was faster with spread to upper limb symptoms than with skipping spread to bulbar symptoms and vice versa. Occurrence of rostral and caudal spread was similar from onset of upper limb symptoms.
Preserved LMN functions
Respiratory symptoms developed as the second region in five patients (3.3%) and as the third region in 49 patients (32.6%), with 59 total preservation sites, as shown in figure 1. Bulbar function was normally preserved in 40 patients (26.7%), lower limb in 15 patients (10%) and upper limb in four patients (2.7%) (table 1). The lowest frequency of preservation was thus seen for upper limb and the highest for bulbar. In 87.5% of patients with bulbar onset, respiratory symptoms occurred as the fourth (last) order manifestations. No patient with bulbar onset skipped directly to respiratory symptoms without upper limb involvement. In contrast, patients in whom ALS started in the limbs showed preservation of one or more motor functions in 46% of upper limb cases and in 42% of lower limb cases. Patients with upper limb or lower limb onset frequently showed preserved normal LMN functions at the appearance of respiratory symptoms compared with those with bulbar onset.
Discussion
ALS often starts in a single part of the body but occasionally develops in two regions simultaneously. Such cases, the so-called C type, showed lower median survival time (18 months), even compared with bulbar onset (26 months). Moreover, the ‘rapid spread-type’ of ALS, presenting in two regions within 3 months from onset, was associated with poor survival. ALS is thought to have already undergone gradual progression by the time initial symptoms manifest, involving a long preclinical period.25 Progression in the early phase of ALS appears to be associated with future progression. In our previous study,26 rate of progression according to ALSFRS-R at the time of diagnosis predicted survival.27 A shorter interval from FS-FE, representing a well known predictor of poorer survival,12 is related to the FS-SS interval, as faster involvement of a second region can prompt the patient to seek early consultation. The association of survival with the latency of FS-SS is simply a surrogate for disease progression, independent of particular combinations of affected regions.
Patients surviving >5 years following symptomatic onset of ALS accounted for 14–20% of the total ALS population.9 28 This frequency has not changed over time. Patients surviving >5 years are clinically similar in terms of age, sex and site of onset, excluding patients with flail arm or leg syndrome. The proportion of 5 year survivors with bulbar onset was similar to that with limb onset. Particularly important information from our survey was the finding that no patient with rapid spread-type (including C-type) ALS survived >5 years.
The analyses of cumulative occurrences revealed that lower limb onset patients showed spread to the upper limbs or rarely skipped to bulbar symptoms. Symptoms subsequent to bulbar onset frequently involved the anatomically close upper limbs compared with the more distant lower limbs.29 Moreover, C-types of ‘bulbar and upper limb’ and ‘upper limb and lower limb’ involvements were seen, but no ‘bulbar and lower limb’ combination. This finding supports the notion that the ALS pathology gradually spreads to adjacent regions in a longitudinal manner.30 Spread seems to occur in a prion-like manner without infectious ability. Knowledge about the pattern of onset and the anatomical direction of spread may provide valuable prognostic insights.
Bulbar symptoms are thought to represent an accelerator for the development of respiratory symptoms.18 19 Although accessory respiratory muscles affected by pontomedullary lesions would contribute in part to respiratory dysfunction, no evidence has suggested a direct process connecting bulbar symptoms to motor neuron loss causing respiratory dysfunction. The following evidence in our survey may be against a direct connection. Firstly, most patients (88%) with bulbar onset present with respiratory symptoms as the last order manifestation. Secondly, none of our patients with bulbar onset showed direct spread to respiratory symptoms. No significant difference in survival was seen between groups with and without bulbar symptoms throughout the entire course. Anatomically, the pontomedullary regions linked to bulbar symptoms are not longitudinally adjacent to the thoracic and trunk regions mainly related to respiratory function.
Poorer prognosis in patients with bulbar onset may involve malnutrition promoting progression of overall muscle atrophy, inducing respiration related muscle weakness.31 32 Malnutrition has been reported to affect prognosis in ALS.33 The finding that early manifestation of bulbar symptoms within 1 year offers an important predictor of shorter survival appears important. This finding is also compatible with the data that the involvement of the bulbar region at the time of diagnosis was associated with a worse prognosis.34 Adequate nutritional and multidisciplinary management prolonged survival in patients with bulbar palsy.35 36
We reported the frequency of normal preservation of bulbar (27%), lower limb (10%) and upper limb functions (3%) at the time of respiratory symptom development in accordance with ALSFRS-R. One reason for the low rate (2.7%) of preservation for upper limb motor function appears to be that the cervical region linked to upper limb symptoms is anatomically located between the lumbosacral region linked to lower limb symptoms and the pontomedullary region linked to bulbar symptoms. Also, deterioration of respiratory function appears closely related to upper limb involvement, likely due to a link to diaphragmatic function in the cervical region.37 38 The involvement of upper limb functions appears to represent a necessary step to the development of respiratory failure.
Several limitations to this study must be considered. Firstly, this survey lacked evaluations of physiological functions, such as electromyography (EMG) and functional vital capacity (FVC) of the lungs. While EMG is routinely used to detect LMN involvement in the diagnostic process, very few of our patients underwent repeated EMG examination in routine management, so this investigation is not carried out as a potentially more objective measure of LMN involvement. One reliable early feature of respiratory involvement is a reduction in FVC.39 40 However, there was no consensus about the correlation between %FVC and appearance of respiratory symptoms. A simplistic model in our survey based on ALSFRS-R was applied to clinical manifestations in order to standardise all patients. Secondly, all rating scales, including the ALSFRS-R, do not clearly differentiate between upper motor neuron and LMN impairment. For instance, gait will be impaired by upper motor neuron involvement with or without lower limb LMN involvement. Speech and swallowing dysfunction represent a mixture of corticobulbar and bulbar involvements. At the time of diagnosis and during follow-up, we confirmed the presence of LMN signs based on physical findings, including muscle atrophy.
This is the first report on sporadic ALS to use ALSFRS-R for determining anatomical spread at initial appearance of LMN involvement. Understanding the pattern of contiguous spread in the majority of ALS will help with counselling of patients and family members and in making future plans both for the care of the patient and in clinical research settings.
References
Footnotes
See Editorial commentary, p 1181
Linked article 300691.
Funding This work was supported by the Osaka Medical Research Foundation for Incurable Diseases 2011.
Competing interests None.
Ethics approval The ethics committee at Osaka Medical College approved the study protocols.
Provenance and peer review Not commissioned; externally peer reviewed.