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Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease

Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease
Authors:
Lauren B Elman, MD
Leo McCluskey, MD, MBE
Colin Quinn, MD
Section Editor:
Jeremy M Shefner, MD, PhD
Deputy Editor:
Richard P Goddeau, Jr, DO, FAHA
Literature review current through: Dec 2022. | This topic last updated: Oct 21, 2022.

INTRODUCTION — Amyotrophic lateral sclerosis (ALS), first described by Charcot in the 19th century, is a relentlessly progressive, presently incurable neurodegenerative disorder that causes muscle weakness, disability, and eventually death. ALS is also known as Lou Gehrig's disease, after the famous New York Yankee baseball player who was affected with the disorder [1-3].

ALS has an annual incidence of one to three cases per 100,000 people that is believed to be the same worldwide. There appears to be no ethnic or racial predisposition to ALS. Prior to the age of 65 or 70, the incidence of ALS is higher in males than females, but thereafter the sex incidence is equal. ALS has an age distribution that peaks in the seventh to eighth decades. However, ALS can occur in people in their twenties. ALS is most commonly sporadic. Genetic or familial ALS represents only 10 percent of all ALS. (See "Familial amyotrophic lateral sclerosis".)

This topic will review the clinical features of ALS. The epidemiology, diagnosis, and differential diagnosis of ALS are discussed separately. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

CLINICOPATHOLOGIC FEATURES — The clinical hallmark of ALS is the combination of upper and lower motor neuron signs and symptoms.

The upper motor neuron findings of weakness with slowness, hyperreflexia, and spasticity result from degeneration of frontal lobe motor neurons located in the motor strip (Brodmann area 4) and their axons traversing the corona radiata, internal capsule, cerebral peduncles, pontine base, medullary pyramids, and the lateral corticospinal tracts of the spinal cord. At autopsy, the dorsolateral area of the spinal cord, the region containing the lateral corticospinal tract, is gliotic and hardened or sclerotic to palpation.

The lower motor neuron findings of weakness, atrophy or amyotrophy, and fasciculations are a direct consequence of degeneration of lower motor neurons in the brainstem and spinal cord producing muscle denervation.

The neuropathology of ALS is characterized by pathologic inclusions within both upper and lower motor neurons and glia. Such inclusions also occur in nonmotor frontal and temporal cortical neurons and in more widespread areas of the brain not typically associated with classic ALS. Inclusions stain positively for ubiquitin; a large subset also stains positively for TAR DNA-binding protein (TDP-43) and smaller subsets stain for fused in sarcoma (FUS) protein and optineurin. (See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis", section on 'Intracellular inclusions'.)

The term "amyotrophic lateral sclerosis" is derived from the combination of the clinical examination finding of muscle atrophy with the pathologic finding of hardening of the injury lateral corticospinal tracts [2-7]. While it was once presumed to be a pure motor disorder, it has become increasingly apparent that degeneration of other brain regions such as frontal and temporal cortical neurons may also occur as part of the clinicopathologic spectrum of ALS. (See 'ALS-plus syndrome' below and 'Cognitive symptoms' below and 'Autonomic symptoms' below and 'Parkinsonism and supranuclear gaze palsy' below and 'Sensory symptoms' below.)

SPECTRUM OF MOTOR NEURON DISEASE — ALS is one of multiple degenerative motor neuron diseases that are clinically defined, based on the involvement of upper and/or lower motor neurons [1,2,8]. ALS is the most common form of motor neuron disease and includes upper and lower motor neuron pathology.

Progressive muscular atrophy — Progressive muscular atrophy is a progressive lower motor neuron disorder. Some experts believe it represents a form of ALS [9,10].

When the disease remains confined to the lower motor neuron, survival may be prolonged compared with classic ALS. In the largest study, 91 patients initially diagnosed with progressive muscular atrophy had a longer median survival than 871 patients with ALS (48 versus 36 months) [9]. However, on Kaplan-Meier estimates, the survival curves of progressive muscular atrophy and ALS crossed at approximately 80 months. Thereafter, the estimated survival in progressive muscular atrophy was approximately the same as that of ALS. In an earlier series, 37 patients with progressive muscular atrophy had a median survival of 56 months [11].

Some individuals with progressive muscular atrophy never develop clinical upper motor neuron signs. Many, however, develop upper motor neuron signs later in their clinical course, at which point the disease is called lower motor neuron-onset ALS. In the series cited above, upper motor neuron signs developed in 20 of 91 patients (22 percent) initially diagnosed with progressive muscular atrophy [9]. Typically, upper motor neuron involvement occurred within two years of symptom onset.

At autopsy, patients with progressive muscular atrophy who never developed clinically apparent upper motor neuron signs frequently have upper motor neuron pathology, including corticospinal tract abnormalities and TDP-43 positive inclusions in motor cortex, in a pattern identical to that of ALS [6,12].

Primary lateral sclerosis — Primary lateral sclerosis is a progressive isolated upper motor neuron neurodegenerative disorder [13]. Cases of pure upper motor neuron disease make up a small percentage of ALS/motor neuron disease [14,15].

Compared with ALS, primarily lateral sclerosis is characterized by slower progression, lack of weight loss, and absence of lower motor neuron findings on examination or electromyography in the first four years after symptom onset [16-20]. Symptoms usually begin in the lower extremities, with loss of fluidity in gait and spasticity and hyperreflexia on examination. Corticobulbar symptoms (eg, dysarthria, pseudobulbar affect) typically develop later in the course. Many patients also have bladder instability and urinary retention. The early phase of disease has significant clinical overlap with hereditary spastic paraparesis. (See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Hereditary spastic paraplegia'.)

Some individuals with primary lateral sclerosis never develop clinical lower motor neuron signs. Other patients develop lower motor neuron signs later in their clinical course [14,19,20]. In a retrospective review of 29 patients with primary lateral sclerosis and pure upper motor neuron signs, electromyographic or clinical evidence of denervation and lower motor neuron disease developed in 13 patients by a mean follow-up of nine years [16]. However, in another review of 39 patients with primary lateral sclerosis, only two patients subsequently developed lower motor neuron findings by a median follow-up of nine years [19].

Patients who develop delayed lower motor neuron findings are typically referred to as having upper motor neuron-onset ALS. Reports of pathology in clinically defined primary lateral sclerosis are limited, but disease pathologically isolated to the upper motor neuron has been described [21-24].

Pure primary lateral sclerosis and upper motor neuron-dominant ALS appear to have a more benign prognosis than typical ALS [13,19,20,25]. Survival tends to be longer and disease progression slower in patients classified as primary lateral sclerosis compared with ALS controls [16]. Survival for patients with upper motor neuron-dominant ALS is intermediate between that of primary lateral sclerosis and classic ALS.

Progressive bulbar palsy — Progressive bulbar palsy is a progressive upper and lower motor neuron disorder of cranial muscles. This condition may occasionally stay isolated to the bulbar segment, but more commonly, upper and lower motor neuron signs and symptoms spread to involve other segments [26]. This is then referred to as bulbar-onset ALS. There have been no reports of specific pathology in progressive bulbar palsy [1-3,27].

Flail arm syndrome — The flail arm syndrome (also called brachial amyotrophic diplegia) is characterized by progressive lower motor neuron weakness and wasting that predominantly affects the proximal arm [28-30]. It usually begins proximally and spreads distally to the point where arm and hand function is severely impaired. It is often asymmetric. Patients presenting with the flail arm variant of ALS have a longer survival time and a slower rate of progression both to the spread of signs and symptoms in other body segments and to development of respiratory muscle weakness [31,32].

Flail leg syndrome — The flail leg syndrome (also called the pseudo-polyneuritic variant of ALS/motor neuron disease) is characterized by progressive lower motor neuron weakness and wasting with onset in the distal leg [31,33]. Patients presenting with the flail leg syndrome have a lower rate of comorbid dementia, a longer survival time, and a slower rate of progression to involvement of other body segments and of the development of respiratory muscle weakness [31,32].

ALS-plus syndrome — Classically defined, ALS is considered a degenerative disorder of the upper and lower motor neurons, and does not include symptoms or signs outside of the voluntary motor system. However, some patients have the clinical features of ALS along with features of other disorders such as frontotemporal dementia (FTD), autonomic insufficiency, parkinsonism, supranuclear gaze paresis, and/or sensory loss. Such patients are considered to have ALS-plus syndrome.

CLINICAL SYMPTOMS AND SIGNS — The loss of motor neurons results in the primary clinical symptoms and signs of ALS. These may produce impairment affecting limb (table 1), bulbar (table 2), axial (table 3), and respiratory (table 4) function.

Differences in site and segment (cranial, cervical, thoracic, or lumbosacral) of onset, pattern and speed of spread, and the degree of upper and/or lower motor neuron dysfunction produce a disorder that is remarkably variable between individuals.

Initial presentation — The initial clinical manifestation of ALS may occur in any body segment (bulbar, cervical, thoracic, or lumbosacral) and may manifest as upper motor neuron (see 'Upper motor neuron symptoms' below) or lower motor neuron (see 'Lower motor neuron symptoms' below) symptoms or signs. Asymmetric limb weakness is the most common presentation of ALS (80 percent). Upper-extremity onset is most often heralded by hand weakness but may begin in the shoulder girdle muscles. The "split-hand syndrome" describes a frequent pattern of weakness and atrophy in ALS that predominantly involves the median- and ulnar-innervated lateral (thenar) hand intrinsic muscles with relative sparing of the medial (hypothenar) muscles [34-36]. Lower-extremity onset of ALS most often begins with weakness of foot dorsiflexion (foot drop), while proximal pelvic girdle onset is less common.

Twenty percent of patients will have onset in the bulbar segment, which most often presents with either dysarthria or dysphagia.

Less common patterns of ALS onset include respiratory muscle weakness (1 to 3 percent) [37], generalized weakness in the limbs and bulbar muscles (1 to 9 percent), axial onset with head drop or truncal extension weakness, and weight loss with muscle atrophy, fasciculations, and cramps [1].

Upper motor neuron symptoms — Loss of upper motor neurons results in slowness of movement, incoordination, and stiffness with relatively little overt weakness. Arm or hand upper motor neuron symptoms include poor dexterity with resulting difficulty performing activities of daily living. Leg upper motor neuron symptoms manifest as a spastic gait with poor balance and may include spontaneous leg flexor spasms and ankle clonus (table 1).

Dysarthria and dysphagia are the most common bulbar upper motor neuron symptoms (table 2). Upper motor neuron or spastic dysarthria produces a characteristically strained vocal quality with slow speech. Upper motor neuron dysphagia results from slow and discoordinated contraction of the swallowing muscles, which may lead to coughing and choking.

Another frequent bulbar upper motor neuron symptom is the syndrome of the pseudobulbar affect [38,39]. This is manifested as inappropriate laughing, crying, or yawning. This may occur as an early manifestation of ALS or may develop during the disease course. The observed affect is often mood incongruent or may be triggered by stimuli that would not have elicited such a response prior to the development of pseudobulbar affect. Patients also report difficulty with cessation of the laughing or crying once it has begun. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Pseudobulbar affect'.)

Upper motor neuron bulbar dysfunction may also result in laryngospasm. This is a short-lived (usually <30 seconds) reflex closure of the larynx that most often occurs in response to aspiration of food particles or liquids, including saliva. The patient typically describes a squeezing feeling in the throat accompanied by impaired inspiration and difficulty speaking; there may be audible stridor.

Additional manifestations of upper motor neuron bulbar dysfunction may include increased masseter tone and difficulty opening the mouth. When severe, this is referred to as trismus. At times there may be involuntary jaw clenching with biting of the sides of the tongue and cheeks.

Axial upper motor neuron dysfunction may contribute to stiffness and imbalance (table 3).

Lower motor neuron symptoms — Loss of lower motor neurons results in weakness, usually accompanied by atrophy (movie 1) and fasciculations (movie 2 and movie 3). Muscle cramps are also common [40].

Hand weakness causes difficulty manipulating small objects (buttons, zippers, coins) and using writing instruments (table 1). Proximal arm weakness results in difficulty elevating the arm to the level of the mouth or above the head. This can produce difficulty with bathing, dressing, grooming, and eating. Foot and ankle weakness results in tripping, a slapping gait, and falling. Proximal leg weakness results in difficulty arising from chairs, climbing stairs, and getting off the floor. Balance may also be adversely affected.

Dysarthria and dysphagia can also result from lower motor neuron damage (table 2). Dysarthria may result from weakness of the tongue, lips, or palate. The speech is usually slurred and may have a nasal quality. Hoarseness may be caused by associated vocal cord weakness. Dysphagia results from tongue weakness with disruption of the oral phase of swallowing or from pharyngeal constrictor weakness with disruption of the pharyngeal phase of swallowing or both. Tongue weakness may lead to pocketing of food between the cheeks and gums. Pharyngeal weakness often manifests as coughing and choking on food, liquids, or secretions such as saliva or mucus. Aspiration may result.

Lower motor neuron weakness of the upper face may produce incomplete eye closure (table 2). Lower facial weakness is more common and may result in poor lip seal that may contribute to drooling or sialorrhea, particularly in patients with associated swallowing difficulty. Lower motor neuron weakness of the masseter can cause difficulty chewing; when severe, it may produce an inability to close the mouth. Lower motor neuron weakness of the pterygoids may produce difficulty opening the mouth and moving the jaw from side to side. Severe masseter and pterygoid weakness may contribute to disarticulation of the temporomandibular joint.

Lower motor neuron weakness affecting the trunk and spine may produce difficulty holding up the head and difficulty maintaining an erect posture as well as abdominal protuberance (table 3).

Lower motor neuron weakness of the diaphragm produces progressive dyspnea with decreasing amounts of effort culminating in dyspnea at rest and with talking along with reduced vocal volume (table 4). Diaphragmatic weakness may also result in orthopnea and sleep disordered breathing.

Extraocular motor neurons residing in the nuclei of the oculomotor (CN III), trochlear (CN IV), and abducens (CN VI) nerves are spared until very late in the disease course. Patients who choose long-term mechanical ventilation have a longer clinical course that can include progressive difficulty with ocular motility. This may culminate in the locked-in state, a clinical condition characterized by inability to move any voluntary muscle. Such patients may be alert and awake but completely unable to communicate.

Cognitive symptoms — There is a well-established link between ALS and frontotemporal behavioral and executive dysfunction that may precede or follow the onset of upper and/or lower motor neuron dysfunction [41-46]. The pattern of cognitive impairment includes problems with executive function, language, and letter fluency with relative sparing of memory and visuospatial function. Common behavioral changes include apathy, loss of sympathy/empathy, changes in eating behaviors, disinhibition, and perseveration.

While most patients with ALS do not have overt dementia, some degree of cognitive and behavioral dysfunction is present in approximately one-third to one-half of patients and becomes increasingly common with advancing disease [44,47,48]. In a cross-sectional study of 161 patients with ALS, the rate of ALS-specific cognitive impairment as measured by the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) ranged from 18 percent among patients with King's clinical stage 1 and 2 disease to 39 percent among those with stage 4 disease (nutritional or respiratory failure) [47]. Behavioral impairment was present in 18 and 27 percent of patients with stage 1 and 2 disease, respectively, and 65 percent of those with stage 4 disease. Bulbar dysfunction is an independent predictor of cognitive and behavioral problems [47,48]. (See 'Clinical patterns of progression' below.)

Approximately 15 percent of patients with ALS meet criteria for frontotemporal dementia (FTD) [41]. Retrospective data suggest that ALS with FTD may be associated with shorter survival than ALS with normal executive and behavioral function [49]. ALS with FTD may be familial or sporadic. (See "Familial amyotrophic lateral sclerosis", section on 'C9ORF72 gene'.)

Autonomic symptoms — Autonomic symptoms may occur in ALS as the disease progresses, although they are typically mild [50]. Constipation occurs frequently and is likely multifactorial. Delayed colonic motility has been demonstrated. Dysphagia for thin liquids related to pharyngeal muscle weakness may lead to dehydration that can exacerbate constipation. Symptoms of early satiety and bloating consistent with delayed gastric emptying also occur as the disease progresses [51-53]. Urinary urgency without incontinence is common, while incontinence is uncommon.

Some patients complain of excessive sweating, but whether a disorder of sweating occurs in association with ALS is controversial [54,55]. Small studies have demonstrated abnormal sudomotor function, including one study that showed hyperhidrosis early in ALS, with decline in later-stage disease [50,56,57].

Parkinsonism and supranuclear gaze palsy — Extrapyramidal symptoms and signs of parkinsonism may precede or follow the upper and lower motor neuron symptoms. These extrapyramidal features may include facial masking, tremor, bradykinesia, and postural instability [58,59]. In a single-center cohort of 550 patients with ALS, ocular motility abnormalities were found in the majority of patients, and extrapyramidal abnormalities were seen in approximately one quarter [60,61].

Sensory symptoms — Sensory symptoms may occur in 20 to 30 percent of patients with ALS [1,62]. It is not uncommon for patients with ALS, particularly those with distal limb onset of symptoms, to complain of tingling paresthesia (see 'Pain' below). When queried regarding sensory loss, these patients typically will deny loss of sensation, and physical examination does not detect objective sensory loss. At times, however, objective sensory loss may occur as part of an ALS-plus syndrome and may precede or follow motor symptoms. Electrophysiologic studies may demonstrate reduction of amplitudes on sensory nerve conduction and/or slowing of dorsal column conduction on somatosensory evoked potential testing, even in patients without sensory findings on examination [62-66]. Autopsy may demonstrate evidence of degeneration within sensory pathways in individuals with and without sensory loss.

Pain — Nociceptive pain in ALS can arise from a variety of causes that include reduced mobility, muscle cramps, muscle spasticity, and comorbid conditions [67,68]. Reduced mobility predisposes to skin breakdown and musculoskeletal pain. Respiratory symptoms and interventions can lead to pain, with discomfort and skin breakdown from noninvasive ventilation masks, and irritation from suctioning of secretions and weighing and pulling of ventilator hoses. In addition, pain with neuropathic features (eg, paresthesia, allodynia, hyperalgesia) may affect some patients with ALS. Although generally of mild to moderate intensity, pain in the later stages of ALS can be severe enough to necessitate treatment with analgesic and sedative medications [67,69,70].

A systematic review published in 2017 found that prevalence of pain in patients with ALS ranged from 15 to 85 percent [67]. The inconsistency of these findings was attributed to the heterogeneous methods and relatively small size of the underlying studies.

Clinical patterns of progression — ALS is a relentlessly progressive disorder with a clinical course that is generally linear, with a relatively constant slope. While the rate of progression between individuals is variable, the history generally reflects gradual and progressive worsening over time without intervening remissions or exacerbations.

Symptoms initially spread within the segment of onset and then to other regions in a relatively predictable pattern [1,23,71,72]. In patients with unilateral arm onset, the most common (approximately 60 to 70 percent of patients) pattern of spread is to the contralateral arm, then to the ipsilateral leg, then to the contralateral remaining leg, and then to the bulbar muscles. In patients with unilateral leg onset, the most common (approximately 60 to 70 percent of patients) pattern of spread is to the contralateral leg, then to the ipsilateral arm, then to the contralateral arm, and then to bulbar muscles. In patients with bulbar onset, the most common pattern of spread is to one arm and then to the contralateral arm [1,23].

Multiple clinical staging systems have been developed to help identify an objective measure of disease progression. They may also help guide treatment decisions and aid in prognostication. Commonly used staging systems include the following:

The King's College ALS staging system classifies disease progression based on the number of body regions involved as well as the need for swallowing or respiratory support [73].

The MiToS system defines the progressive loss of independence in key functional domains: walking/self-care, swallowing, communicating, and breathing.

Both systems primarily use information that can be gathered from the revised ALS Functional Rating Scale, the most commonly used measure in ALS clinical trials.

Life-threatening features — The progressive course of ALS may eventually produce one or both of the life-threatening aspects of the disease: neuromuscular respiratory failure and dysphagia. Respiratory muscle weakness may be the first manifestation of the disease but more commonly develops after months or years of progressive limb and/or bulbar muscle weakness.

Progressive neuromuscular respiratory failure is the most common cause of death in ALS. In the United States, 5 to 10 percent of patients choose tracheostomy and permanent ventilation when respiratory compromise becomes severe.

Similarly, progressive dysphagia may be one of the initial manifestations of the disease or may develop after months or years of progressive limb and/or other bulbar weakness. Dysphagia poses a risk for aspiration of food, liquids, or secretions with resultant pneumonia and may also lead to malnutrition and dehydration. These conditions can be minimized in patients who choose gastrostomy tube insertion and with aggressive management of secretions. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Management of swallowing and nutrition' and "Swallowing disorders and aspiration in palliative care: Definition, pathophysiology, etiology, and consequences" and "Swallowing disorders and aspiration in palliative care: Assessment and strategies for management".)

The median survival from the time of symptom onset is three to five years. However, approximately 10 percent of ALS patients can live 10 years or more. Survival beyond 20 years is possible but rare and in part depends on treatment decisions made by patients and their families.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Motor neuron disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Amyotrophic lateral sclerosis (ALS) (The Basics)")

PATIENT PERSPECTIVE TOPIC — Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Amyotrophic lateral sclerosis (ALS)".)

SUMMARY

Characteristic clinical features – The clinical hallmark of amyotrophic lateral sclerosis (ALS) is the combination of upper motor neuron and lower motor neuron signs and symptoms. Upper motor neuron findings result from degeneration of frontal lobe motor neurons and the corticospinal tract. The lower motor neuron findings are a direct consequence of degeneration of lower motor neurons in the brainstem and spinal cord. (See 'Clinicopathologic features' above.)

Spectrum of clinical disorder – ALS is the most common form of motor neuron disease and includes upper and lower motor neuron pathology. The spectrum of motor neuron disease also includes other conditions that may be variants of ALS or may represent different patterns of evolution in ALS. These include (see 'Spectrum of motor neuron disease' above):

Progressive muscular atrophy

Primary lateral sclerosis

Progressive bulbar palsy

Flail arm and flail leg syndromes

ALS-plus syndromes

Clinical symptoms – The primary clinical symptoms and signs of ALS may produce impairment affecting limb (table 1), bulbar (table 2), axial (table 3), and respiratory (table 4) function. (See 'Clinical symptoms and signs' above.)

Upper motor neuron symptoms result in slowness of movement, incoordination, and stiffness typically with relatively little overt weakness. (See 'Upper motor neuron symptoms' above.)

Lower motor neuron symptoms cause weakness, usually accompanied by atrophy (movie 1) and fasciculations (movie 2 and movie 3). Muscle cramps are also common. (See 'Lower motor neuron symptoms' above.)

Cognitive impairment, typically related to frontotemporal executive dysfunction, may precede or follow the onset of upper motor neuron and/or lower motor neuron dysfunction in patients with ALS. Frontotemporal dementia (FTD) may be associated with ALS in 15 to 50 percent of cases. (See 'Cognitive symptoms' above.)

Autonomic symptoms may occur in ALS as the disease progresses. Constipation occurs frequently and is likely multifactorial. Dysphagia for thin liquids related to pharyngeal muscle weakness may lead to dehydration, which can exacerbate constipation. (See 'Autonomic symptoms' above.)

Extrapyramidal symptoms and signs of parkinsonism may precede or follow the upper and lower motor neuron symptoms. These extrapyramidal features may include facial masking, tremor, bradykinesia, and postural instability. (See 'Parkinsonism and supranuclear gaze palsy' above.)

Sensory impairment may occur in 20 to 30 percent of patients with ALS, but the sensory examination is usually normal. Nociceptive pain in ALS can arise from a variety of causes that include reduced mobility, muscle cramps, muscle spasticity, and comorbid conditions. (See 'Sensory symptoms' above and 'Pain' above.)

Clinical progression – ALS is a relentlessly progressive disorder with a clinical course that is generally linear. Symptoms typically spread within the segment of onset and then to other regions in a relatively predictable pattern. The progressive course of ALS eventually produces life-threatening neuromuscular respiratory failure and/or dysphagia. (See 'Clinical patterns of progression' above and 'Life-threatening features' above.)

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Topic 5136 Version 35.0

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