Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease (1)

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Clinical features of amyotrophic lateral sclerosis and other
forms of motor neuron disease
Authors: Lauren B Elman, MD, Leo McCluskey, MD, MBE
Section Editor: Jeremy M Shefner, MD, PhD
Deputy Editor: April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2020. | This topic last updated: Apr 21, 2020.
INTRODUCTION
Amyotrophic lateral sclerosis (ALS), first described by Charcot in the 19 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 men than in women, but thereafter the gender 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
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symptoms.
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 amyotrophy with the pathologic finding of lateral sclerosis [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
The upper motor neuron findings of weakness with slowness, hyperreflexia, and spasticity
result from degeneration of frontal motor neurons located in the motor strip (Brodman 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.
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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]. Whether it lies on the continuum of ALS or represents a
separate disorder is the subject of uncertainty and ongoing debate. 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 [16-18]. 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.
Most, however, do develop lower motor neuron signs later in their clinical course [14]. This is
referred to as 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 [19-22].
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In a retrospective study of 39 patients who were initially diagnosed with primary lateral sclerosis,
pure upper motor neuron signs were present on initial evaluation in 29 [16]. Over a mean 8.7 years
of follow-up, pure upper motor neuron signs were retained in 16 patients who were classified as
clinically pure primary lateral sclerosis, while electromyographic or clinical evidence of denervation
and lower motor neuron disease developed in 13 patients who were classified as upper motor
neuron-dominant ALS. The lower motor neuron findings developed by four years in 10 (77 percent)
of the 13 patients with upper motor neuron-dominant ALS. In another retrospective series involving
661 patients with ALS and 43 with primary lateral sclerosis, spasticity at clinical presentation and
absence of limb muscle wasting for at least three years were significantly more common in
patients with primary lateral sclerosis than those with ALS [23].
Pure primary lateral sclerosis and upper motor neuron-dominant ALS appear to have a more
benign prognosis than typical ALS [13,23]. 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. This is then referred to as bulbar-onset ALS. There have been no reports
of specific pathology in progressive bulbar palsy [1-3,24].
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 [25-27]. 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 slower rate of progression both to the spread of signs and symptoms in
other body segments and to development of respiratory muscle weakness [28].
Flail leg syndrome — The flail leg syndrome (also called the pseudopolyneuritic variant of
ALS/motor neuron disease) is characterized by progressive lower motor neuron weakness and
wasting with onset in the distal leg [28,29]. Patients presenting with the flail leg syndrome have a
slower rate of progression to involvement of other body segments and of the development of
respiratory muscle weakness [28].
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 all of the clinical features of ALS along with features
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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. In a case report, a patient with clinically definite ALS accompanied by a supranuclear
gaze disorder and an extrapyramidal syndrome reminiscent of progressive supranuclear palsy
demonstrated diffuse TDP-43 pathology at autopsy [30].
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 [31-33]. 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) [34],
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
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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
[35,36]. 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 [37].
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 of the floor.
Balance may also be adversely affected.
Dysarthria and dysphagia can also result from lower motor neuron damage (table 2). Dysarthria
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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). In
the lower face the result may be a 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 [38-43]. 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
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increasingly common with advancing disease [41,44,45]. 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) [44]. 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 [44,45].
Approximately 15 percent of patients with ALS meet criteria for frontotemporal dementia (FTD)
[38]. Retrospective data suggest that ALS with FTD may be associated with shorter survival than
ALS with normal executive and behavioral function [46]. ALS with FTD may be a familial disorder.
(See "Familial amyotrophic lateral sclerosis", section on 'C9ORF72 gene'.)
Autonomic symptoms — Autonomic symptoms may occur in ALS as the disease progresses,
although this is not an initial manifestation of the disease. 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 [47-49]. 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 [50,51]. Abnormal sympathetic activity with hyperhidrosis in
early ALS and a reduction in sweat production as the disease progresses have been demonstrated
in one study [52].
Cases of ALS associated with autonomic disturbances have been reported. As examples, an
individual from a Japanese ALS 1 (superoxide dismutase type 1 [SOD1] Gly93Ser) kindred had
prominent sensory impairment, urinary disturbance, and blood pressure fluctuation due to
sympathetic hyperactivity [53]. Another individual with ALS and the locked-in state related to a rare
SOD1 mutation (Val118Leu) developed cardiac arrest following autonomic failure [54].
Neuropathology demonstrated widespread neurodegeneration including autonomic nuclei in the
medulla and spinal cord.
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.
At times, a supranuclear gaze abnormality occurs that is similar to that seen in progressive
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supranuclear palsy. A case report of a man presenting with symptoms and signs of ALS along with
clinical features resembling progressive supranuclear palsy included autopsy evidence of
degeneration of upper and lower motor neurons, as well as widespread TDP-43 inclusion
pathology that included the basal ganglia [55].
Sensory symptoms — Sensory symptoms may occur in 20 to 30 percent of patients with ALS,
but the sensory examination is usually normal [1,56]. 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 [56-60]. 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 [61,62]. 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 [61,63,64].
A systematic review published in 2017 found that prevalence of pain in patients with ALS ranged
from 15 to 85 percent [61]. 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 nearly always 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 [1,21,65,66]. 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
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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 [1,21].
Life-threatening features — The progressive course of ALS eventually produces 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 'Dysphagia, weight loss, and nutrition'
and "Swallowing disorders and aspiration in palliative care: Definition, consequences,
pathophysiology, and etiology" and "Swallowing disorders and aspiration in palliative care:
Assessment and strategies for management".)
The median survival from the time of diagnosis 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 5 to 6 grade reading
level, and they answer the four or five key questions a patient might have about a given condition.
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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 10 to 12 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.)
SUMMARY
th th
Basics topics (see "Patient education: Amyotrophic lateral sclerosis (ALS) (The Basics)")
●
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 of
weakness, hyperreflexia, and spasticity result from degeneration of frontal motor neurons. 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.
(See 'Clinicopathologic features' above.)
●
ALS is one of multiple degenerative motor neuron diseases that are clinically defined, based
on the involvement of upper motor neurons and lower motor neurons. The spectrum of motor
neuron disease includes progressive muscular atrophy, primary lateral sclerosis, and
progressive bulbar palsy, all of which may be variants of ALS, or represent different patterns of
evolution to ALS. (See 'Spectrum of motor neuron disease' above.)
●
Asymmetric limb weakness is the most common presentation of ALS (80 percent). Bulbar
onset, usually manifested as dysarthria or dysphagia, is the next most common pattern (20
percent). However, differences in site and segment (cranial, cervical, thoracic, or lumbosacral)
of onset, pattern and speed of spread, and the degree of upper and lower motor neuron
dysfunction produce a disorder that is remarkably variable between individuals. (See 'Clinical
patterns of progression' above and 'Upper motor neuron symptoms' above and '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.)
●
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●
ALS is a relentlessly progressive disorder with a clinical course that is nearly always linear.
Symptoms initially spread within the segment of onset and then to other regions in a relatively
predictable pattern. The progressive course of ALS eventually produces one or both of the
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Topic 5136 Version 24.0
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GRAPHICS
Limb signs and symptoms associated with amyotrophic lateral sclerosis
Upper motor neuron signs
Spasticity
Slowed rapid alternating movements
Increased reflexes
"Preserved" reflexes in weak/atrophic muscles
Distal spread of arm reflexes
Hoffman sign
Crossed adduction
Upgoing toe
Triple flexion
Gait disorder
Spastic
Lower motor neuron signs
Weakness
Intrinsic hand weakness
Foot drop
Proximal arm and leg weakness
Poor heel and/or toe walking
Poor rise from chair
Poor squat
Gait disorder
Steppage
Waddling
Reduced reflexes
Muscle atrophy and fasciculations
Upper motor neuron symptoms
Stiffness, slowness, and incoordination of movement
Hand and/or arm
Difficulty performing activities of daily living
Difficulty manipulating small objects or writing
Leg and/or foot
Gait dysfunction
Slow, stiff gait; difficulty turning
Legs "heavy"
Poor balance and falling
Spontaneous clonus
Spontaneous flexor spasms
Lower motor neuron symptoms
Weakness and atrophy
Arm and/or hand
Difficulty performing activities of daily living
Difficulty manipulating small objects or writing
Leg and/or foot
Difficulty arising from chairs or from floor
Difficulty climbing stairs
Foot drop
Tripping, falling
Fasciculations
Cramps
Graphic 72454 Version 2.0
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Bulbar signs and symptoms associated with amyotrophic lateral sclerosis
Increased jaw reflex
Jaw spasticity
Facial diparesis (may be asymmetric)
Increased facial reflexes
Palmomental sign
Poor palatal elevation
Slow tongue movement
Weak masseter and/or pterygoids
Difficulty maintaining jaw closure
Facial diparesis (may be asymmetric)
Poor palatal elevation
Tongue weakness
Muscle atrophy and fasciculations
Jaw stiffness with difficulty opening the mouth
Spontaneous clenching or biting
Trismus
Spontaneous jaw clonus
Dysphagia
Tongue incoordination disrupts the oral phase
Pharyngeal muscle incoordination disrupts the pharyngeal phase
Dysarthria
Labial, lingual, and/or pharyngeal components
Spastic with slow, strained speech
Laryngospasm
Often triggered by secretions (eg, saliva) or food particles
Rapid onset
"Squeezing" feeling, inability to speak, strained speech
Short-lived, less than 30 seconds
Pseudobulbar affect
Inappropriate laughing, crying, and/or yawning
Affective response >> emotional trigger
Mood incongruent
Sialorrhea (drooling)
Difficulty managing pharyngeal secretions
Incomplete eye closure
Difficulty opening and/or closing the jaw
Difficulty chewing
Disarticulation of the temporomandibular joint when severe
Poor lip closure and seal
May contribute to sialorrhea when severe
Dysphagia
Tongue weakness disrupts the oral phase
Pharyngeal muscle weakness disrupts the pharyngeal phase
Coughing and choking induced by drinking, eating, or saliva secretion
Often thin liquids followed by solids and thick liquids
Dysarthria
Labial, lingual, and/or pharyngeal components
Slurred, nasal, and/or hoarse speech
Hoarseness
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Axial signs and symptoms associated with amyotrophic lateral sclerosis
Absent abdominal reflexes
Neck extension weakness
Truncal extension weakness; bent spine
Abdominal protuberance
Increased lumbar lordosis
Stiffness and imbalance
Neck extensors
Difficulty holding up the head
When severe produces head drop
Truncal extensors
Difficulty maintaining an erect posture
Lumbar extensors
Increased lumbar lordosis
Abdominal wall muscles
Abdominal protuberance
Cramps
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Respiratory signs and symptoms associated with amyotrophic lateral sclerosis
Tachypnea
Vocal and speech
Reduced vocal volume
Shortened sentences
Frequent breath pauses
Use of accessory respiratory muscles
Abdominal paradox
Dyspnea and/or orthopnea
Low speech volume
Weak cough
Sleep disordered breathing
Frequent nocturnal awakenings, possibly with note of dyspnea
Excessive daytime sleepiness and/or fatigue
Morning headache
Confusion
Hallucinations
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Contributor Disclosures
Lauren B Elman, MD Grant/Research/Clinical Trial Support: Amylyx [ALS]; Acceleron [FSHD, CMT].
Consultant/Advisory Boards: Biogen [ALS, SMA]; Roche/Genentech [SMA]. Leo McCluskey, MD,
MBE Nothing to disclose Jeremy M Shefner, MD, PhD Grant/Research/Clinical Trial Support: Biogen Idec;
Cytokinetics; Amylyx; Orphazyme; Brainstorm; MT Pharma America; Medicinova [ALS]. Consultant/Advisory
Boards: Cytokinetics; Mitsubishi Tanabe Pharma America; AveXis; Pinteon; Neurosense [ALS]. April F
Eichler, MD, MPH Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must conform
to UpToDate standards of evidence.
Conflict of interest policy
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