Clinical Features of Amyotrophic Lateral Sclerosis and Other Forms of Motor Neuron Disease UpToDate PDF

28/2/2020 Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease - UpToDate
Official reprint from UpToDate®

www.uptodate.com ©2020 UpToDate, Inc. and/or its affiliates. All Rights Reserved.
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: Jan 2020. | This topic last updated: Sep 09, 2019.
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 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
symptoms.
https://www.uptodate.com/contents/clinical-features-of-amyotrophic-lateral-sclerosis-and-other-forms-of-motor-neuron-disease/print?search=amyotro… 1/21
● 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.
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 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
disorder [13]. Compared with ALS, it 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 [14,15]. In large series and population-based studies of patients with ALS/motor
neuron disease, only a small percentage has pure upper motor neuron disease [16,17].
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 [16]. 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 [18-21].
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 [14]. 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 [22].
Pure primary lateral sclerosis and upper motor neuron-dominant ALS appear to have a more benign
prognosis than typical ALS [13,22]. Survival was longer and disease progression slower in patients
classified as primary lateral sclerosis compared with ALS controls [14]. Survival for patients with
upper motor neuron-dominant ALS was 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 [1-3,23].
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 [24-26]. 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 [27].
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 [27,28]. 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 [27].
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 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 [29].
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 [30-32]. 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) [33],
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
[34,35]. 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 [36].
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 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 [37-42]. 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 [40,43,44]. 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) [43].
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 [43,44].
Approximately 15 percent of patients with ALS meet criteria for frontotemporal dementia (FTD) [37].
Retrospective data suggest that ALS with FTD may be associated with shorter survival than ALS with
normal executive and behavioral function [45]. 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 [46-48]. 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 [49,50]. Abnormal sympathetic activity with hyperhidrosis in
early ALS and a reduction in sweat production as the disease progresses have been demonstrated in
one study [51].
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 [52]. Another individual with ALS and the locked-in state related to a rare
SOD1 mutation (Val118Leu) developed cardiac arrest following autonomic failure [53].
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
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 [54].
Sensory symptoms — Sensory symptoms may occur in 20 to 30 percent of patients with ALS, but
the sensory examination is usually normal [1,55]. 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 [55-59]. 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 [60,61]. 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 [60,62,63].
A systematic review published in 2017 found that prevalence of pain in patients with ALS ranged from
15 to 85 percent [60]. 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 [1,20,64,65]. 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 [1,20].
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 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 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)")
SUMMARY
● 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.)
https://www.uptodate.com/contents/clinical-features-of-amyotrophic-lateral-sclerosis-and-other-forms-of-motor-neuron-disease/print?search=amyotr… 10/21
● 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.)
● Autonomic symptoms, parkinsonism, supranuclear gaze paresis, and/or sensory loss may occur
as part of an ALS-plus syndrome. (See 'ALS-plus syndrome' above and 'Autonomic symptoms'
above and 'Parkinsonism and supranuclear gaze palsy' above and 'Sensory symptoms' above.)
● 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 life-
threatening aspects of the disease, neuromuscular respiratory failure and dysphagia. (See
'Clinical patterns of progression' above and 'Life-threatening features' above.)
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Mitsumoto H, Chad DA, Pioro EP. Amyotrophic lateral sclerosis. In: Contemporary Neurology Se
ries, 49, F.A. Davis Company, Philadelphia 1998.
2. Rowland LP. Diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1998; 160 Suppl 1:S6.
3. Rowland LP. What's in a name? Amyotrophic lateral sclerosis, motor neuron disease, and allelic
heterogeneity. Ann Neurol 1998; 43:691.
4. Hirano A. Neuropathology of ALS: an overview. Neurology 1996; 47:S63.
5. Adamek D, Tomik B, Pichór A, et al. The heterogeneity of neuropathological changes in

amyotrophic lateral sclerosis. A review of own autopsy material. Folia Neuropathol 2002;
40:119.
6. Ince PG, Evans J, Knopp M, et al. Corticospinal tract degeneration in the progressive muscular
atrophy variant of ALS. Neurology 2003; 60:1252.
7. Ince PG, Lowe J, Shaw PJ. Amyotrophic lateral sclerosis: current issues in classification,
pathogenesis and molecular pathology. Neuropathol Appl Neurobiol 1998; 24:104.
8. Rowland LP. Amyotrophic lateral sclerosis. Curr Opin Neurol 1994; 7:310.
9. Kim WK, Liu X, Sandner J, et al. Study of 962 patients indicates progressive muscular atrophy
is a form of ALS. Neurology 2009; 73:1686.
10. Rowland LP. Progressive muscular atrophy and other lower motor neuron syndromes of adults.
Muscle Nerve 2010; 41:161.
11. Visser J, van den Berg-Vos RM, Franssen H, et al. Disease course and prognostic factors of
progressive muscular atrophy. Arch Neurol 2007; 64:522.
12. Tsuchiya K, Sano M, Shiotsu H, et al. Sporadic amyotrophic lateral sclerosis of long duration
mimicking spinal progressive muscular atrophy exists: additional autopsy case with a clinical
course of 19 years. Neuropathology 2004; 24:228.
13. Singer MA, Statland JM, Wolfe GI, Barohn RJ. Primary lateral sclerosis. Muscle Nerve 2007;
35:291.
14. Gordon PH, Cheng B, Katz IB, et al. The natural history of primary lateral sclerosis. Neurology
2006; 66:647.
15. Gordon PH, Cheng B, Katz IB, et al. Clinical features that distinguish PLS, upper motor neuron-
dominant ALS, and typical ALS. Neurology 2009; 72:1948.
16. D'Amico E, Pasmantier M, Lee YW, et al. Clinical evolution of pure upper motor neuron
disease/dysfunction (PUMMD). Muscle Nerve 2013; 47:28.
17. Chiò A, Calvo A, Moglia C, et al. Phenotypic heterogeneity of amyotrophic lateral sclerosis: a
population based study. J Neurol Neurosurg Psychiatry 2011; 82:740.
18. Heene R, Kolander D, Knisatschek H. [Chronic progressive spinobulbar spasticity (primary

lateral sclerosis)]. Fortschr Neurol Psychiatr 1996; 64:192.
19. Rowland LP. Primary lateral sclerosis: disease, syndrome, both or neither? J Neurol Sci 1999;
170:1.
20. Amyotrophic lateral sclerosis and other motor neuron diseases. Adv Neurol 1991; 56:1.
21. Tan CF, Kakita A, Piao YS, et al. Primary lateral sclerosis: a rare upper-motor-predominant form
of amyotrophic lateral sclerosis often accompanied by frontotemporal lobar degeneration with
ubiquitinated neuronal inclusions? Report of an autopsy case and a review of the literature. Acta
Neuropathol 2003; 105:615.
22. Tartaglia MC, Rowe A, Findlater K, et al. Differentiation between primary lateral sclerosis and
amyotrophic lateral sclerosis: examination of symptoms and signs at disease onset and during
follow-up. Arch Neurol 2007; 64:232.
23. Donaghy M. Classification and clinical features of motor neurone diseases and motor
neuropathies in adults. J Neurol 1999; 246:331.
24. Hu MT, Ellis CM, Al-Chalabi A, et al. Flail arm syndrome: a distinctive variant of amyotrophic
lateral sclerosis. J Neurol Neurosurg Psychiatry 1998; 65:950.
25. Katz JS, Wolfe GI, Andersson PB, et al. Brachial amyotrophic diplegia: a slowly progressive
motor neuron disorder. Neurology 1999; 53:1071.
26. Couratier P, Truong C, Khalil M, et al. Clinical features of flail arm syndrome. Muscle Nerve
2000; 23:646.
27. Wijesekera LC, Mathers S, Talman P, et al. Natural history and clinical features of the flail arm
and flail leg ALS variants. Neurology 2009; 72:1087.
28. Alemà G, Brusa A, Pastorino P, Sacco G. [On 3 cases of the pseudopolyneuritic form of
amyotrophic lateral sclerosis. Anatomic and electromyographic study]. J Neurol Sci 1967; 4:241.
29. McCluskey LF, Elman LB, Martinez-Lage M, et al. Amyotrophic lateral sclerosis-plus syndrome
with TAR DNA-binding protein-43 pathology. Arch Neurol 2009; 66:121.
30. Wilbourn AJ. The "split hand syndrome". Muscle Nerve 2000; 23:138.
31. Kuwabara S, Sonoo M, Komori T, et al. Dissociated small hand muscle atrophy in amyotrophic
lateral sclerosis: frequency, extent, and specificity. Muscle Nerve 2008; 37:426.
32. Eisen A, Kuwabara S. The split hand syndrome in amyotrophic lateral sclerosis. J Neurol
Neurosurg Psychiatry 2012; 83:399.
33. Shoesmith CL, Findlater K, Rowe A, Strong MJ. Prognosis of amyotrophic lateral sclerosis with
respiratory onset. J Neurol Neurosurg Psychiatry 2007; 78:629.
34. Thakore NJ, Pioro EP. Laughter, crying and sadness in ALS. J Neurol Neurosurg Psychiatry
2017; 88:825.
35. Tortelli R, Copetti M, Arcuti S, et al. Pseudobulbar affect (PBA) in an incident ALS cohort: results
from the Apulia registry (SLAP). J Neurol 2016; 263:316.
36. Caress JB, Ciarlone SL, Sullivan EA, et al. Natural history of muscle cramps in amyotrophic
lateral sclerosis. Muscle Nerve 2016; 53:513.
37. Ringholz GM, Appel SH, Bradshaw M, et al. Prevalence and patterns of cognitive impairment in
sporadic ALS. Neurology 2005; 65:586.
38. Rippon GA, Scarmeas N, Gordon PH, et al. An observational study of cognitive impairment in
amyotrophic lateral sclerosis. Arch Neurol 2006; 63:345.
39. Murphy J, Henry R, Lomen-Hoerth C. Establishing subtypes of the continuum of frontal lobe
impairment in amyotrophic lateral sclerosis. Arch Neurol 2007; 64:330.
40. Phukan J, Pender NP, Hardiman O. Cognitive impairment in amyotrophic lateral sclerosis.
Lancet Neurol 2007; 6:994.
41. Beeldman E, Raaphorst J, Klein Twennaar M, et al. The cognitive profile of ALS: a systematic
review and meta-analysis update. J Neurol Neurosurg Psychiatry 2016; 87:611.
42. Woolley SC, Strong MJ. Frontotemporal Dysfunction and Dementia in Amyotrophic Lateral
Sclerosis. Neurol Clin 2015; 33:787.
43. Crockford C, Newton J, Lonergan K, et al. ALS-specific cognitive and behavior changes
associated with advancing disease stage in ALS. Neurology 2018; 91:e1370.
44. Chiò A, Moglia C, Canosa A, et al. Cognitive impairment across ALS clinical stages in a
population-based cohort. Neurology 2019; 93:e984.
45. Olney RK, Murphy J, Forshew D, et al. The effects of executive and behavioral dysfunction on
the course of ALS. Neurology 2005; 65:1774.
46. Toepfer M, Folwaczny C, Klauser A, et al. Gastrointestinal dysfunction in amyotrophic lateral

sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 1999; 1:15.
47. Toepfer M, Folwaczny C, Lochmüller H, et al. Noninvasive (13)C-octanoic acid breath test
shows delayed gastric emptying in patients with amyotrophic lateral sclerosis. Digestion 1999;
60:567.
48. Toepfer M, Schroeder M, Klauser A, et al. Delayed colonic transit times in amyotrophic lateral
sclerosis assessed with radio-opaque markers. Eur J Med Res 1997; 2:473.
49. Kihara M, Takahashi A, Sugenoya J, et al. Sudomotor dysfunction in amyotrophic lateral

sclerosis. Funct Neurol 1994; 9:193.
50. Santos-Bento M, de Carvalho M, Evangelista T, Sales Luís ML. Sympathetic sudomotor function
and amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;
2:105.
51. Beck M, Giess R, Magnus T, et al. Progressive sudomotor dysfunction in amyotrophic lateral
sclerosis. J Neurol Neurosurg Psychiatry 2002; 73:68.
52. Kawata A, Kato S, Hayashi H, Hirai S. Prominent sensory and autonomic disturbances in
familial amyotrophic lateral sclerosis with a Gly93Ser mutation in the SOD1 gene. J Neurol Sci
1997; 153:82.
53. Shimizu T, Kawata A, Kato S, et al. Autonomic failure in ALS with a novel SOD1 gene mutation.
Neurology 2000; 54:1534.
54. Geser F, Martinez-Lage M, Robinson J, et al. Clinical and pathological continuum of multisystem
TDP-43 proteinopathies. Arch Neurol 2009; 66:180.
55. Hammad M, Silva A, Glass J, et al. Clinical, electrophysiologic, and pathologic evidence for
sensory abnormalities in ALS. Neurology 2007; 69:2236.
56. Feller TG, Jones RE, Netsky MG. Amyotrophic lateral sclerosis and sensory changes. Va Med
Mon (1918) 1966; 93:328.
57. Isaacs JD, Dean AF, Shaw CE, et al. Amyotrophic lateral sclerosis with sensory neuropathy:
part of a multisystem disorder? J Neurol Neurosurg Psychiatry 2007; 78:750.
58. Pugdahl K, Fuglsang-Frederiksen A, de Carvalho M, et al. Generalised sensory system

abnormalities in amyotrophic lateral sclerosis: a European multicentre study. J Neurol
Neurosurg Psychiatry 2007; 78:746.
59. Amoiridis G, Tsimoulis D, Ameridou I. Clinical, electrophysiologic, and pathologic evidence for
sensory abnormalities in ALS. Neurology 2008; 71:779.
60. Chiò A, Mora G, Lauria G. Pain in amyotrophic lateral sclerosis. Lancet Neurol 2017; 16:144.
61. Handy CR, Krudy C, Boulis N, Federici T. Pain in amyotrophic lateral sclerosis: a neglected
aspect of disease. Neurol Res Int 2011; 2011:403808.
62. Goy ER, Carter J, Ganzini L. Neurologic disease at the end of life: caregiver descriptions of
Parkinson disease and amyotrophic lateral sclerosis. J Palliat Med 2008; 11:548.
63. Veronese S, Valle A, Chiò A, et al. The last months of life of people with amyotrophic lateral
sclerosis in mechanical invasive ventilation: a qualitative study. Amyotroph Lateral Scler
Frontotemporal Degener 2014; 15:499.
64. Ravits J, Paul P, Jorg C. Focality of upper and lower motor neuron degeneration at the clinical
onset of ALS. Neurology 2007; 68:1571.
65. Ravits J, Laurie P, Fan Y, Moore DH. Implications of ALS focality: rostral-caudal distribution of
lower motor neuron loss postmortem. Neurology 2007; 68:1576.
Topic 5136 Version 23.0
GRAPHICS
Limb signs and symptoms associated with amyotrophic lateral sclerosis
Upper motor neuron signs Upper motor neuron symptoms

Spasticity Stiffness, slowness, and incoordination of movement
Slowed rapid alternating movements Hand and/or arm

Difficulty performing activities of daily living
Increased reflexes
Difficulty manipulating small objects or writing
"Preserved" reflexes in weak/atrophic muscles
Leg and/or foot
Distal spread of arm reflexes
Gait dysfunction
Hoffman sign
Slow, stiff gait; difficulty turning
Crossed adduction
Legs "heavy"
Upgoing toe
Poor balance and falling
Triple flexion
Spontaneous clonus
Gait disorder
Spontaneous flexor spasms
Spastic
Lower motor neuron signs Lower motor neuron symptoms
Weakness Weakness and atrophy
Intrinsic hand weakness Arm and/or hand
Foot drop Difficulty performing activities of daily living
Proximal arm and leg weakness Difficulty manipulating small objects or writing
Poor heel and/or toe walking Leg and/or foot
Poor rise from chair Difficulty arising from chairs or from floor
Poor squat Difficulty climbing stairs

Foot drop
Gait disorder
Tripping, falling
Steppage
Fasciculations
Waddling
Reduced reflexes Cramps
Muscle atrophy and fasciculations
Graphic 72454 Version 2.0
Bulbar signs and symptoms associated with amyotrophic lateral sclerosis

Increased jaw reflex Jaw stiffness with difficulty opening the mouth
Jaw spasticity Spontaneous clenching or biting

Trismus
Facial diparesis (may be asymmetric)
Spontaneous jaw clonus
Increased facial reflexes
Dysphagia
Palmomental sign
Tongue incoordination disrupts the oral phase
Poor palatal elevation
Pharyngeal muscle incoordination disrupts the pharyngeal phase
Slow tongue movement
Dysarthria
Lower motor neuron signs Labial, lingual, and/or pharyngeal components
Weak masseter and/or pterygoids Spastic with slow, strained speech
Laryngospasm
Difficulty maintaining jaw closure
Often triggered by secretions (eg, saliva) or food particles
Facial diparesis (may be asymmetric)
Rapid onset
Poor palatal elevation
"Squeezing" feeling, inability to speak, strained speech
Tongue weakness Short-lived, less than 30 seconds
Muscle atrophy and fasciculations Pseudobulbar affect

Inappropriate laughing, crying, and/or yawning
Affective response >> emotional trigger
Mood incongruent
Sialorrhea (drooling)
Difficulty managing pharyngeal secretions
Lower motor neuron symptoms

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
Axial signs and symptoms associated with amyotrophic lateral sclerosis

Absent abdominal reflexes Stiffness and imbalance

Neck extension weakness Neck extensors
Truncal extension weakness; bent spine Difficulty holding up the head

When severe produces head drop
Abdominal protuberance
Truncal extensors
Increased lumbar lordosis
Difficulty maintaining an erect posture
Lumbar extensors
Increased lumbar lordosis
Abdominal wall muscles

Abdominal protuberance
Cramps
Respiratory signs and symptoms associated with amyotrophic lateral sclerosis

Tachypnea Dyspnea and/or orthopnea
Vocal and speech Low speech volume

Reduced vocal volume Weak cough
Shortened sentences
Sleep disordered breathing
Frequent breath pauses
Frequent nocturnal awakenings, possibly with note of dyspnea
Use of accessory respiratory muscles
Excessive daytime sleepiness and/or fatigue
Abdominal paradox Morning headache
Confusion
Hallucinations
Contributor Disclosures
Lauren B Elman, MD Nothing to disclose 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

Clinical Features of Amyotrophic Lateral Sclerosis and Other Forms of Motor Neuron Disease UpToDate PDF

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Clinical Features of Amyotrophic Lateral Sclerosis and Other Forms of Motor Neuron Disease UpToDate PDF

Загружено:

Авторское право:

Доступные форматы

28/2/2020 Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease - UpToDate

Official reprint from UpToDate®

Clinical features of amyotrophic lateral sclerosis and other

SPECTRUM OF MOTOR NEURON DISEASE

Progressive muscular atrophy — Progressive muscular atrophy is a progressive lower motor

CLINICAL SYMPTOMS AND SIGNS

progresses [46-48]. Urinary urgency without incontinence is common, while incontinence is

Parkinsonism and supranuclear gaze palsy — Extrapyramidal symptoms and signs of

aspiration in palliative care: Definition, consequences, pathophysiology, and etiology" and

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Cognitive impairment, typically related to frontotemporal executive dysfunction, may precede or

Use of UpToDate is subject to the Subscription and License Agreement.

4. Hirano A. Neuropathology of ALS: an overview. Neurology 1996; 47:S63.

5. Adamek D, Tomik B, Pichór A, et al. The heterogeneity of neuropathological changes in

18. Heene R, Kolander D, Knisatschek H. [Chronic progressive spinobulbar spasticity (primary

46. Toepfer M, Folwaczny C, Klauser A, et al. Gastrointestinal dysfunction in amyotrophic lateral

49. Kihara M, Takahashi A, Sugenoya J, et al. Sudomotor dysfunction in amyotrophic lateral

58. Pugdahl K, Fuglsang-Frederiksen A, de Carvalho M, et al. Generalised sensory system

Topic 5136 Version 23.0

Limb signs and symptoms associated with amyotrophic lateral sclerosis

Upper motor neuron signs Upper motor neuron symptoms

Slowed rapid alternating movements Hand and/or arm

Lower motor neuron signs Lower motor neuron symptoms

Weakness Weakness and atrophy

Intrinsic hand weakness Arm and/or hand

Foot drop Difficulty performing activities of daily living

Poor heel and/or toe walking Leg and/or foot

Poor squat Difficulty climbing stairs

Reduced reflexes Cramps

Muscle atrophy and fasciculations

Graphic 72454 Version 2.0

Bulbar signs and symptoms associated with amyotrophic lateral sclerosis

Upper motor neuron signs Upper motor neuron symptoms

Jaw spasticity Spontaneous clenching or biting

Weak masseter and/or pterygoids Spastic with slow, strained speech

Muscle atrophy and fasciculations Pseudobulbar affect

Difficulty managing pharyngeal secretions

Lower motor neuron symptoms

Difficulty opening and/or closing the jaw

Poor lip closure and seal

Graphic 75146 Version 2.0

Axial signs and symptoms associated with amyotrophic lateral sclerosis

Upper motor neuron signs Upper motor neuron symptoms

Lower motor neuron signs Lower motor neuron symptoms

Truncal extension weakness; bent spine Difficulty holding up the head

Abdominal wall muscles

Graphic 67913 Version 1.0

Respiratory signs and symptoms associated with amyotrophic lateral sclerosis

Lower motor neuron signs Lower motor neuron symptoms

Vocal and speech Low speech volume

Graphic 58537 Version 1.0

Conflict of interest policy

Вам также может понравиться