Abstract
Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. ALS was first described in the medical literature in the mid-19th century, but despite its early recognition as a distinct disease process, the pathogenesis of ALS remains poorly understood. Even so, there are many aspects that are known about this disease. At its basic level, ALS is a progressive neurodegenerative disease, with classic clinical features, that typically follows a rapid course leading to significant disability and death. Although these features paint a seemingly simple picture, the complexities of ALS are numerous and ever present. In order to fully appreciate both the complexities of this disease, as well as the challenges involved in caring for patients with ALS, it is essential to understand its natural history.
Keywords
Neurodegenerative, progressive, sporadic, familial, epidemiology, pathogenesis
History
The term “amyotrophic lateral sclerosis” (ALS) was first proposed by Jean-Martin Charcot in 1874, deriving the name from his method of correlating clinical symptoms and signs with anatomical lesions found at autopsy. While working at the Salpetriere Hospital in France, Charcot and colleagues clinically followed patients with exclusively spastic weakness in addition to those with predominantly weakness and atrophy. Upon their death, Charcot then performed autopsies in order to identify anatomical changes that correlated with the patients’ clinical deficits. This led him to discover the “brownish-gray streak marks produced by sclerotic changes” in the lateral columns of the spinal cord correlating with clinical spasticity, as well as lesions that were “systematically limited to the anterior horns of the gray matter” in patients with muscle wasting, or “amyotrophy.”
The findings of Charcot built upon, and further validated, earlier works by Lockhart Clarke and Charles Bland Radcliffe. Although they failed to formally name the disease, Clarke and Radcliffe described the pathological changes of a patient affected with what appeared to be ALS in 1862. In their work, “An important case of paralysis and muscular atrophy, with disease of the nervous centres,” they describe autopsy findings of degeneration of the lateral columns in the spinal cord and atrophy of both the anterior roots of the spinal cord and the bulbar motor nerves. This work, performed over a century ago, was essential to the medical community’s understanding of both neuroanatomy and the pathological features of ALS. These early discoveries by Clarke, Charcot, and others have stood the test of time, and remain the clinical and pathological framework upon which current research efforts in ALS are built.
Over the next 100 years, different clinical presentations of diseases, primarily affecting the motor system, were further defined both clinically and pathologically. As these progressive motor disorders were further defined, William Richard Gowers was the first to suggest that these processes may represent syndromic variants of a single disease process. This idea was further refined by Walter Russell Brain in 1962 when he coined the term “motor neurone disease” (MND) as a category of disease including ALS, progressive bulbar palsy (PBP), progressive muscular atrophy (PMA), and progressive spastic paraparesis. The term “MND” remains in use today. The major subsets of MND include ALS, PMA, primary lateral sclerosis (PLS), and PBP. Despite the early pathologic and clinical descriptions of ALS, the salient features of ALS/MND remain unchanged from the original clinical descriptions.
Epidemiology
The majority of epidemiological data regarding ALS are derived from observational morbidity and/or mortality studies. These larger studies often fail to separate the different forms of MND, or distinguish sporadic cases of ALS from familial types. The potential analysis of numerous syndromes as a single disorder, ALS, may introduce errors into these studies, as well as prevent the identification of drastically different disease courses that may be present in the more rare types of MND. Other types of analyses, including case control or cohort studies, are also utilized for identifying possible risk factors for ALS. While these may be better suited to the analysis of specific subtypes of MND, they also carry a risk of introducing sampling bias or recall bias. Aside from the possible sources of error from these study types, they represent an important resource in our understanding of the natural history of ALS.
In their text , Mitsumoto and colleagues presented a review of multiple epidemiological studies of ALS that were reported from 1966 to 1994. This analysis combined data from Europe, Canada, the United States, Mexico, and the Middle East. The mean overall incidence of sporadic-onset ALS was 1.1 ± 0.5 cases per 100,000, while the prevalence was 3.6 ± 1.8 per 100,000 in the population. In that report, the peak age of onset was between 55 and 75 years old, with a male to female ratio ranging from 1.4 to 2.5:1. The average survival after onset of symptoms of ALS was calculated at 3 years with a median disease duration ranging from 23 to 52 months.
More recent studies have largely confirmed these estimates for ALS incidence, prevalence, and age of onset. However, some mortality-based ALS studies suggest that there has been a rise in the incidence of ALS over the past several decades. This hypothesis of an increased incidence is challenged by other natural-history analyses. The seemingly aberrant increase in ALS incidence is most likely attributed to an overall improvement in diagnosis and a more accurate attribution of cause of death in the medical record, rather than a true spike in disease incidence.
An interesting and encouraging finding from recent epidemiological studies is the increase in survival of ALS patients over the last two decades. Both retrospective population analyses and cohort analyses suggest that certain patient populations diagnosed in the 1990s had a median survival almost 1 year longer than those diagnosed prior to that time. Despite the prolonged survival in those diagnosed in or after the 1990s as compared to earlier populations, the two patient populations showed no differences in their rates of functional decline. This pattern of improved survival without a significant change in functional abilities is similar to that seen in therapeutic trials in ALS patients. However, studies have shown this same increase in survival even after correcting for more recent additions to the clinical management of ALS patents, including the drug riluzole, noninvasive ventilation (NIV), and percutaneous endoscopic gastrostomy (PEG) tube placement. This suggests that the survival benefit may be derived from other undefined factors related to the institution of multidisciplinary care clinics, or perhaps to improvements in the management of non-ALS-related comorbidities. While increased survival in ALS patients has been noted by several groups, other ALS populations fail to display similar improvements, despite undergoing comparable disease management. Therefore, further evaluation is necessary to confirm the presence of this phenomenon, as well as to elucidate the actions that may be leading to an improved survival.
In an effort to better understand the underlying pathophysiology of ALS, many studies have attempted to identify risk factors for the development of ALS. To date, both age and gender have been consistently identified as risk factors for the development of ALS. The incidence of ALS begins to increase after the age of 40 years, with a peak incidence occurring in the sixth and seventh decades of life. Interestingly, the relationship of increasing age and incidence of ALS is reversed between ages 75 and 80 years. Therefore, advancing age alone is unlikely to be a lone risk factor, suggesting that during this age range, the motor neurons of susceptible individuals may cross a threshold of cumulative damage, which then leads to the appearance of clinical symptoms.
Traditionally, males have shown a higher incidence of sporadic ALS (SALS) than females. This notion has been challenged as some studies have suggested that the previously reported male:female ratio of ALS incidence of 2:1 is equalizing. Possible explanations for this change in the influence of gender on ALS incidence are multiple, but they are simply hypotheses at this time. Theories directed at explaining this finding range from relating this change to an improved physician awareness and diagnosis of MND, to alterations in socioeconomic factors that have increased female exposure to possible environmental risks. However, this change in the effect of gender on disease incidence is not consistent across all recent studies. Definitive evidence as to whether these reported changes in gender incidence of ALS truly represent a shift in the epidemiology of the disease will require continued analyses of MND.
There is a suggestion that race may impact one’s risk of developing ALS. Cronin et al. reviewed 61 epidemiological studies of ALS from Europe, Central and South America, North America and Canada, Asia, the Pacific, Africa, the Middle East, and Russia. They noted a lower incidence of ALS among African, Asian, and Hispanic ethnicities when compared to Caucasians, a finding that was corroborated when comparing Hispanic and African populations to Caucasians within the same country. The interpretation of these studies is complex, as the heterogeneity of ethnicities within a single racial group may be significant, which could skew the reported racial incidence. Regardless of these limitations, differences in incidence among racial groups suggest predisposing genetic factors play a role in the development of SALS. Prospective, population-based analyses of strictly defined racial groups are needed to further define any racial predilections in ALS.
There are multiple other possible risk factors for ALS reported in the literature, ranging from pesticide exposure to exposure to ultraviolet radiation. A relatively well-supported risk factor is smoking, which has been identified in multiple studies as an independent risk factor for ALS. Military service, irrespective of duration of service or time served during war, has also been associated with an increased risk of development of ALS.
Two of the more controversial possible risk factors in the literature are heightened levels of physical activity and a history of traumatic brain injury. There are several reports suggesting that accomplished athletes, both amateur and professional, have a higher incidence of ALS, though this relationship of physical activity to ALS has not been a consistent finding. Head injury in professional athletes has received a lot of attention of late as a potential risk factor for ALS or even as a cause of a disorder that mimics ALS, but this work remains highly controversial. Indeed, a recent clinical and pathological evaluation of ALS patients with and without a history of traumatic brain injury failed to identify any difference in disease progression or pathological findings between the two groups. Clearly, both athleticism and head injury will require further evidence in order to definitively link them with an increased risk of developing ALS.
The most clearly defined risk factor for the development of ALS is a family history of ALS and the harboring of a pathogenic mutation. Familial ALS (FALS) is thought to represent 5–10% of cases. Through the discovery of several different genes associated with FALS, multiple possible genetic identifiers of increased risk of developing ALS now exist. Significant discoveries have been made in genetic causes for ALS, though disease causing gene mutations remain unknown for about 30% of FALS. Both FALS and the commonly identified genetic mutations in ALS will be further discussed in a later section of this chapter.
Clinical Presentation
Patients with ALS may initially present to the clinic with patterns of upper motor neuron (UMN) signs, lower motor neuron (LMN) signs, or both. Amidst the variable manners of clinical presentation in ALS, a focal onset of symptoms is the most common. When categorizing the clinical phenotype of ALS, individual cases are characterized by the region of disease onset, as well as the presence or absence of UMN and LMN signs. The UMN and LMN signs refer to clinical features that are associated with lesions in motor neurons of the central and peripheral nervous systems, respectively ( Table 2.1 ). The region of disease onset is typically defined as bulbar, limb, or the more rare presentation of diaphragmatic onset disease. Through the identification and monitoring of these phenotype qualities, patients with traditional ALS are separated from those with other types of MND. The distinction of subsets of MND allows for improved prognostication and informed decision making during the care of these individuals.
| Upper motor neuron signs | Lower motor neuron signs |
|---|---|
| Hyperreflexia | Hyporeflexia/areflexia |
| Spasticity | Flaccidity |
| Impaired dexterity | Muscle atrophy |
| Pathologic reflexes (Babinski, Hoffman) | Fasciculations |
| Muscle weakness | Muscle weakness |
The most common clinical presentation of MND is ALS, that is the presence of both UMN and LMN symptoms and signs. Typically, patients present with a mixture of muscle atrophy, fasciculations, spasticity, and pathologically brisk reflexes. The most common initial symptom is painless weakness, which is the chief complaint for approximately 60% of patients. This is typically a focal weakness involving limb or bulbar musculature, with less than 10% of patients presenting with generalized weakness. The most common site of onset for focal weakness is in a limb (60–70%), with an equal distribution of initial involvement between arms and legs. Weakness or spasticity in bulbar musculature accounts for an additional 20–30% of presenting symptoms in typical ALS. Rarely, patients may present with isolated weakness of the muscles of respiration which has been reported to occur in 1–3% of the ALS population.
Despite weakness being the most common symptom at the time of presentation, patients with typical ALS may first present with other complaints. Although rare, some patients will pursue medical evaluation due to isolated fasciculations, weight loss, or muscle cramps. While all of these symptoms are commonly seen during the course of ALS, they are less likely to represent the initial symptoms in these patients. Certainly, these symptoms are common to a number of disorders, which may lead to a rather broad differential diagnosis, especially when there are no other signs to support a diagnosis of ALS.
Progression of symptoms, and thus disability, is the norm for people with ALS. The spread of disease may occur in a contiguous manner from an initially focal region of onset. For example, progression from the limb of onset to the contralateral limb, or progression rostrally or caudally along the neuraxis. However, there are many clinical examples of what appears to be multifocal onset and/or spread of disease, and even examples where neurological dysfunction will skip a contiguous neuroanatomical region, raising the question of whether there truly is “spread” from a focal region of onset. This question remains an ongoing focus of research.
The progression of ALS is quite variable, though it is generally assumed that the rate of symptom progression follows a linear course from the time of onset. Indeed, the course of the disease may vary from less than a year to many decades. In an attempt to determine why the rate of progression varies so greatly, risk factors for progression and disease survival have been evaluated. Epidemiological studies have identified multiple risk factors that may have a positive or negative influence on ALS progression. Factors described as being associated with slower progression and better prognosis include: prolonged time from symptom onset to diagnosis, younger age at onset (< 35–40 years old), pure UMN or LMN signs, no dyspnea at onset, nonbulbar region of onset, normal weight at the time of diagnosis, nonfamilial ALS, and normal cognition at the time of diagnosis ( Table 2.2 ). This is not an exhaustive list and certain factors listed require further clarification, as is the case with nonfamilial ALS being associated with improved prognosis. While ALS associated with chromosome 9 open reading frame 72 (C9orf72) mutations has been linked with a reduced survival versus nonmutants, there are other forms of FALS that have a very slow clinical course. These factors may be associated with a better survival prognosis; however, the absence of one or more of these disease characteristics does not necessarily impart a poor prognosis.
| Prolonged time from onset to diagnosis | Nonbulbar region of onset |
| Younger age of onset | Normal weight/nutritional status at diagnosis |
| Pure UMN signs | Nonfamilial ALS b |
| Pure LMN signs | Normal cognition at diagnosis |
| No dyspnea at onset |
a The presence or absence of these features does not definitively predict prognosis.
b Some types of familial ALS are associated with prolonged survival (e.g. select SOD1 gene mutations).
Unlike the combination of both UMN and LMN signs that is seen in typical ALS, patients with PMA present with pure LMN symptoms and signs. PMA represents < 10% of patients with MND in various population analyses. It is often difficult to differentiate patients with PMA from those with typical ALS with very few UMN signs (LMN-predominant ALS). Overall, patients with PMA have an improved survival time from symptom onset than those with clinically typical ALS. Within the PMA patient population, predictors of a decreased survival time include generalized weakness at onset and a reduced forced vital capacity at the time of diagnosis.
Analogous to PMA, PLS presents as a pure UMN disorder. PLS is also a rare presentation, representing 2–4% of the patients in the MND population. As with PMA, the diagnosis of PLS is complicated by the challenge of distinguishing those with pure PLS from those patients with UMN-predominant ALS. Of course, needle electromyography may identify LMN disease not evident on clinical examination, and many patients will develop more typical ALS over time. However, the continued presence of pure UMN signs 4 years after symptom onset is considered acceptable for making the diagnosis of PLS. The distinction between UMN-predominant ALS and PLS may be important because survival is believed to be longer in pure UMN ALS. The question of prognosis in PLS versus UMN-predominant ALS is currently under study.
Another relatively uncommon clinical phenotype of MND is PBP. Clinically, PBP is characterized by the selective, progressive paralysis of the bulbar musculature involving the UMN, LMN, or both. The portion of ALS patients diagnosed with PBP varies across different population analyses from 0% to 2.2%, despite bulbar onset disease occurring in 20–30% of ALS patients. As with PMA and PLS, the diagnosis of PBP requires longitudinal clinical evaluation of patients looking for other systemic signs that constitute a diagnosis of ALS.
FALS constitutes about 10% of the ALS population. The clinical presentation of patients from ALS families is largely indistinguishable from those with SALS, though the presence of coincident dementia may suggest an underlying genetic mutation. Certainly, obtaining a thorough family history for any relatives with ALS, dementia, or other neurodegenerative diseases is the best initial screening method to identify those with possible FALS. Numerous genetic mutations have been identified as either directly causing ALS, or increasing the risk for disease ( Table 2.3 ). The majority of disease-causing mutations, however, are four different genes: C9orf72, superoxide dismutase 1 (SOD1), TAR DNA binding protein (TARDBP), and fused in sarcoma (FUS). The known gene mutations that are associated with ALS are ever changing as this area of research progresses. With only 50–70% of the mutations responsible for FALS identified (depending on the population studied), ample room exists for further solidifying the genetics and heritability of ALS.
Related posts:
Genetics of Amyotrophic Lateral Sclerosis
An Introduction to the Natural History, Genetic Mapping, and Clinical Spectrum of Spinal Muscular Atrophy
Introduction to Gene and Stem-Cell Therapy
Gene Therapy for Amyotrophic Lateral Sclerosis: Therapeutic Transgenes
Cellular Therapy for Spinal Muscular Atrophy: Pearls and Pitfalls
Clinical Trials to Date
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