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

INTRODUCTION — 

Amyotrophic lateral sclerosis (ALS) is a 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 Yankees baseball player who was affected with the disorder [1-3].

Motor neuron disease (MND) generally refers to ALS and related degenerative motor neuron conditions. However, ALS and MND are sometimes used interchangeably in the United States, and MND is the preferred term for ALS in the United Kingdom.

This topic will review the clinical features of ALS and related forms of MND. Other aspects of ALS are discussed separately.

●(See "Epidemiology and pathogenesis of amyotrophic lateral sclerosis".)

●(See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

●(See "Disease-modifying treatment of amyotrophic lateral sclerosis".)

●(See "Symptom-based management of amyotrophic lateral sclerosis".)

CLINICAL SYMPTOMS AND SIGNS — 

ALS is a neurodegenerative condition classically characterized by the presence of both upper and lower motor neuron signs and symptoms. These features may produce impairments affecting limb (table 1), bulbar (table 2), axial (table 3), and/or respiratory (table 4) function. Additional nonmotor symptoms also frequently occur; cognitive features are most common.

Substantial variability exists between individuals with ALS due to differences in body site and nervous system segment (cranial, cervical, thoracic, or lumbosacral) of onset, pattern and speed of spread, and the degree of upper and lower motor neuron (LMN) dysfunction.

Terminology

●Upper motor neuron features – The upper motor neuron (UMN) features refer to symptoms due to dysfunction of central motor pathways in the brain and/or spinal cord. Dysfunction at this level can lead to disinhibition of tonically active peripheral nerve function. UMN features may include slowness, incoordination, stiffness, hyperreflexia (movie 1), pathologic reflexes (movie 2), and spasticity.

●Lower motor neuron features – The LMN features refer to symptoms due to dysfunction of peripheral motor pathways from the brainstem or anterior horn of the spinal cord to the effector muscle. Dysfunction is due to muscle denervation. LMN features may include weakness, atrophy or amyotrophy (movie 3), muscle cramps, and fasciculations (movie 4 and movie 5).

Core motor features

Limb weakness — 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. The "split-hand syndrome" describes a pattern of weakness and atrophy common in ALS that predominantly involves the lateral (thenar) hand intrinsic muscles with relative sparing of the medial (hypothenar) muscles [4-6]. Thenar muscles are innervated by multiple peripheral nerves, so the presence of this weakness pattern can help exclude isolated mononeuropathies as a cause of hand weakness. Arm or hand UMN symptoms in ALS include stiffness or cramping with poor dexterity resulting in difficulty performing activities of daily living. Muscle stretch reflexes are typically hyperactive.

Foot and ankle weakness results in tripping, a slapping gait, and falling. Examination typically reveals weakness beyond a single lumbosacral nerve root or peripheral nerve distribution. Proximal leg weakness results in difficulty arising from chairs, climbing stairs, and getting off the floor. Balance may also be adversely affected. Leg UMN symptoms manifest as a spastic gait with poor balance and may include spontaneous leg flexor spasms and ankle clonus. In addition to hyperactive muscle stretch reflexes, pathologic reflexes may be present including an extensor Babinski or the crossed adductor response.

Axial weakness — Motor impairment in ALS involving trunk and core muscles may produce fatigue, postural instability, and contribute to the risk of falls (table 3). Axial UMN dysfunction may contribute to cramping, stiffness, and imbalance. LMN weakness affecting the trunk and spine may produce difficulty holding up the head or maintaining an erect posture and may lead to an exaggerated lumbar lordosis with an abdominal protuberance.

Bulbar dysfunction — Bulbar motor neuron dysfunction from impairment of cranial nerves and their associated central pathways can result in both weakness and functional impairment in speaking, swallowing, and controlling secretions (table 2).

●Dysarthria and dysphagia – Dysarthria and dysphagia are the most common bulbar motor neuron symptoms and may be due either to UMN or LMN dysfunction. Dysarthria is frequently the initial bulbar symptom in ALS, but some patients may present with both dysarthria and dysphagia.

Dysarthria may result from LMN weakness of the lips, tongue, or palate. The speech is usually slurred and may have a nasal quality. Hoarseness may be present due to associated vocal cord weakness. UMN or spastic dysarthria produces a characteristically strained vocal quality with slow speech. The presence of both UMN and LMN features of dysarthria is a common bulbar finding suggestive of ALS [7].

Dysphagia results from tongue weakness with disruption of the oral phase of swallowing, 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. Tongue fasciculations may be seen in more than 50 percent [8]. Pharyngeal weakness often manifests as coughing and choking on food, liquids, or secretions such as saliva or mucus. Aspiration may occur. UMN dysphagia results from slow and discoordinated contraction of the swallowing muscles, which may lead to coughing and choking.

●Laryngospasm – Laryngospasm 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. It may occur as a UMN bulbar feature of ALS. The patient typically describes a squeezing feeling in the throat accompanied by impaired inspiration and difficulty speaking; there may be audible stridor.

●Trismus – Trismus refers to restricted movement of the jaw muscles, typically from increased musculoskeletal tone. Increased masseter tone from UMN dysfunction can cause trismus in patients with ALS. Involuntary jaw clenching with biting of the sides of the tongue and cheeks may also be present.

●Facial muscle weakness – Weakness of the muscles of the upper face may produce incomplete eye closure. Lower facial weakness is more common and may result in a poor lip seal that may contribute to dysarthria or to drooling and sialorrhea, particularly in patients with associated swallowing difficulty. Masseter muscle weakness can cause difficulty chewing; when severe, it may produce an inability to close the mouth. By contrast, weakness of the pterygoids may produce difficulty opening the mouth and moving the jaw from side to side. Severe weakness of both muscle groups may lead to disarticulation of the temporomandibular joint.

Eye movements controlled by motor neurons residing in the nuclei of the oculomotor (cranial nerve [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 the inability to move any voluntary muscle. Such patients may be alert and awake but completely unable to speak or communicate with visual communication-assistive devices. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Dysarthria and communication'.)

Respiratory impairment — Weakness of the diaphragm in ALS produces progressive dyspnea leading to orthopnea and decreased vocal volume and culminating in dyspnea with talking and eventually also at rest (table 4). Sleep-disordered breathing is an early sign of neuromuscular respiratory insufficiency.

Diaphragmatic muscle weakness can lead to respiratory failure, the most common life-threatening manifestation of the disorder. (See 'Life-threatening features' below.)

Nonmotor features — Although ALS is characterized by progressive motor dysfunction, nonmotor features accompany motor dysfunction in up to 50 percent of patients at diagnosis [9].

Cognitive symptoms — There is a well-established link between ALS and behavioral and cognitive dysfunction that may precede or follow the onset of motor dysfunction [10-15]. Common behavioral changes include:

●Apathy

●Loss of empathy

●Changes in eating behaviors

●Disinhibition

●Perseveration or compulsive behaviors

The pattern of cognitive impairment includes problems with executive function, language, grammar, and verbal fluency with relative sparing of memory and visuospatial function.

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 [13,16,17]. In a cross-sectional study of 161 patients with ALS, the rate of ALS-specific cognitive impairment ranged from 18 percent among patients with mild or early features to 39 percent among those with advanced disease (eg, nutritional or respiratory failure) [16]. Behavioral impairment was present in 18 percent of patients with early disease and 65 percent of those with advanced disease. Bulbar dysfunction is an independent predictor of cognitive and behavioral symptoms [16,17].

Approximately 15 percent of patients with ALS meet criteria for frontotemporal dementia (FTD) [10]. Core features include a combination of disinhibition, apathy, loss of empathy, perseveration, hyperorality, and executive dysfunction. Bulbar motor symptoms are common in these patients. Retrospective data suggest that ALS with FTD may be associated with shorter survival than ALS with normal executive and behavioral function [18]. (See "Frontotemporal dementia: Clinical features and diagnosis", section on 'Behavioral variant FTD with motor neuron disease'.)

Pseudobulbar affect — The UMN syndrome of the pseudobulbar affect is described as emotional incontinence and manifests as inappropriate laughing, crying, or yawning [19,20]. The observed behavior is often mood-incongruent and may be spontaneous or triggered by a minor emotional stimulus. Patients also report difficulty with cessation of the laughing or crying once it has begun. Pseudobulbar affect may occur as an early manifestation of ALS or may develop during the disease course. Pharmacotherapy may be used to suppress unwanted behaviors. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Pseudobulbar affect'.)

Parkinsonism and supranuclear gaze palsy — Extrapyramidal symptoms and signs of parkinsonism may precede or follow motor symptoms in ALS. These extrapyramidal features may include tremor, bradykinesia, rigidity, hypomimia (masked facial expression), and postural instability [21,22]. 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 25 percent [23,24].

Autonomic symptoms — Autonomic symptoms may occur in ALS as the disease progresses, although they are typically mild [25].

●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.

●Early satiety and bloating consistent with delayed gastric emptying also occur as the disease progresses [26-28].

●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 [29,30]. Small studies have demonstrated abnormal sudomotor function, including one study that showed hyperhidrosis early in ALS, with a decline in later-stage disease [25,31,32].

Autonomic control of sphincter muscles is typically spared [33].

Sensory symptoms — Although ALS is characterized as a motor disorder, sensory symptoms may occur in 20 to 30 percent of patients with ALS [1,34]. Acral paresthesias are most common, particularly those with distal limb onset of symptoms. Some may also report dysesthesias (see 'Pain' below), but patients typically deny numbness or loss of sensation, and physical examination does not usually detect objective sensory loss. However, electrophysiologic studies may demonstrate a 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 [34-38]. Autopsy may demonstrate evidence of degeneration within sensory pathways in individuals with and without sensory loss.

While some patients with ALS will have sensory symptoms, they should be substantially less prominent than motor features.

Objective sensory loss may occur as part of an ALS-plus syndrome and may precede or follow motor symptoms. (See 'ALS-plus syndromes' below.)

Pain — Pain is common in patients with ALS. In a 2017 systematic review, the prevalence of pain in patients with ALS ranged from 15 to 85 percent [39]. The inconsistency of these findings may be due to the heterogeneous methods, varied inclusion criteria, and small sample size of the included studies.

Nociceptive pain in ALS can arise from a variety of causes including reduced mobility, muscle cramps, muscle spasticity, and comorbid conditions [39,40]. Reduced mobility predisposes to skin breakdown and musculoskeletal pain. Respiratory symptoms and interventions can lead to pain, discomfort and skin breakdown from noninvasive ventilation masks, and irritation from suctioning of secretions and weighing and pulling of ventilator hoses.

In addition, neuropathic pain (eg, dysesthesia, 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 [39,41,42]. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Pain'.)

CLINICAL COURSE

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 (UMN) or lower motor neuron (LMN) symptoms or signs.

Asymmetric progressive limb weakness is the most common presentation of ALS, accounting for 70 to 80 percent of cases [43]. Upper-extremity onset is most often heralded by hand weakness but may begin in the shoulder girdle muscles in some patients. Lower-extremity onset of ALS most often begins with weakness of foot dorsiflexion (foot drop), while proximal pelvic girdle onset is less common.

Bulbar-onset presentation occurs in 20 percent of patients [44]. The most common initial bulbar symptoms include dysarthria and dysphagia.

Other patterns of ALS onset are less common, including respiratory muscle weakness (1 to 3 percent) [45], generalized weakness in the limbs and bulbar muscles (1 to 9 percent), and rare presentations such as axial onset with head drop or truncal extension weakness and weight loss with muscle atrophy, fasciculations, and cramps [1].

Progression — ALS is a neurodegenerative disorder with a clinical course that is gradual and progressive over time without intervening remissions or exacerbations. Symptoms typically progress over weeks to a few months [46]. While the rate of progression between individuals is variable, progression in any individual patient is generally linear with a relatively constant slope.

●Clinical patterns of progression – Initial symptoms typically spread within the segment of onset and then to other regions in a relatively predictable pattern [1,43,47-49]. Focal symptoms typically spread contralaterally and then to adjacent body segments. 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 [1,47].

●Clinical staging systems – Multiple clinical staging systems have been developed to help provide 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 [50]. Stage 1 reflects initial symptoms present in one body region; stage 2 reflects progression to involvement of two body regions; stage 3 reflects progression to involvement of three body regions; and stage 4 reflects the need for gastrostomy or noninvasive ventilatory support.

•The MiToS system defines the progressive loss of independence in key functional domains: walking/self-care, swallowing, communicating, and breathing [51]. Stage 0 reflects the presence of symptoms without loss of independence, and subsequent stages 1 through 4 reflect the progressive number of domains of functional dependence.

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 [52].

●Clinical factors associated with the rate of progression – While the rate of symptom progression in any individual patient is variable, some clinical features have been associated with slower rates of progression and longer survival. Favorable clinical factors include younger age at diagnosis, and limb-onset ALS [53]. Some variant forms of motor neuron disease (MND) are also associated with a more benign course than typical ALS (see 'Other forms of motor neuron disease' below). By contrast, factors associated with more rapid rates of progression include early involvement of respiratory impairment, bulbar-onset ALS, or weight loss with diffuse muscle atrophy (cachexia-type) disease.

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. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Prognosis'.)

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.

Progressive neuromuscular respiratory failure is the most common cause of death in ALS. 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. In the United States, 5 to 10 percent of patients choose tracheostomy and permanent ventilation when respiratory compromise becomes severe. (See "Symptom-based management of amyotrophic lateral sclerosis", section on 'Respiratory function management'.)

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'.)

OTHER FORMS OF MOTOR NEURON DISEASE — 

Motor neuron disease (MND) may refer to a group of degenerative conditions that are clinically defined by dysfunction in upper motor neurons (UMN) and/or lower motor neurons (LMN) [1,2,54]. ALS is the most common form of MND and includes upper and LMN pathology. Other forms of MND may be distinguished by clinical features including the pattern of progressive motor neuron involvement.

However, whether distinct phenotypes represent alternative conditions or a single pathophysiologic and etiologic continuum of ALS is debated. The classification of some of these forms of MND as distinct from ALS has evolved since the introduction of the Gold Coast criteria [55]. With the Gold Coast criteria, some patients with isolated UMN and LMN symptoms previously classified as having a form of MND can qualify for the diagnosis of ALS. (See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Diagnostic criteria'.)

Primary lateral sclerosis — Primary lateral sclerosis is a form of MND characterized by isolated UMN dysfunction [56].

●Core features – Diagnostic criteria for primary lateral sclerosis, developed in 2020 and subsequently validated, are based on clinical features and include all of the following [57,58]:

•Progressive UMN symptoms for ≥2 years

•UMN signs in at least two body regions

•Absence of active LMN signs or sensory symptoms

•Exclusion of alternative causes of symptoms

Symptoms frequently begin in the lower extremities with slowly progressive gait impairment. Hyperactive muscle stretch reflexes and pathologic reflexes along with spasticity and stiffness are present on neurologic examination. Bulbar symptoms such as spastic dysarthria and pseudobulbar affect typically develop later in the course. Many patients also have bladder instability and urinary retention. The early phase of the 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'.)

●Distinguishing UMN-onset ALS – Patients with initial UMN features suggestive of primary lateral sclerosis are instead classified as having UMN-onset ALS if LMN features subsequently develop. Diagnostic confidence in the diagnosis of primary lateral sclerosis is supported by the absence of both LMN signs on examination and evidence of denervation on electromyography two to four years from symptom onset [57].

The mean age of onset of primary lateral sclerosis is approximately 50 years old, younger than patients with ALS [59]. Survival tends to be longer and disease progression slower in patients with primary lateral sclerosis compared with ALS controls [60-63]. Survival for patients with UMN-dominant ALS is intermediate between that of primary lateral sclerosis and classic ALS [56,62-64].

Primary lateral sclerosis is rare, estimated to account for less than 3 percent of MND cases [59]. Uncertainty in the prevalence of the condition is likely related both to its rarity and the clinical overlap with UMN-onset ALS. The pathogenesis of primary lateral sclerosis is uncertain. Reports of pathology in clinically defined primary lateral sclerosis are limited, but disease pathologically isolated to the UMN has been described [47,65-67]. Intracellular inclusions of the TAR DNA-binding protein (TDP-43) have been identified pathologically in primary lateral sclerosis cases [68,69].

Progressive muscular atrophy — Progressive muscular atrophy is a form of MND characterized by isolated LMN dysfunction [70,71].

●Core features – Symptoms commonly present as weakness of a distal limb that progresses over months to years and then spreads to involve other body regions. Bulbar LMN symptoms may develop in nearly half of patients with progressive muscular atrophy [72].

●Distinguishing LMN-onset ALS – Distinguishing progressive muscular atrophy from LMN-onset ALS can be difficult. Since the introduction of the Gold Coast criteria for diagnosis of ALS, isolated LMN symptoms may be sufficient to make the diagnosis of ALS [55]. Some individuals who present with isolated LMN signs subsequently develop UMN signs, at which point the disease is clinically classified as LMN-onset ALS. Other patients with isolated LMN symptoms and examination findings may be found to have UMN features on neuroimaging or electrodiagnostic studies [73]. In one series, UMN signs developed in 20 of 91 patients (22 percent) initially diagnosed with progressive muscular atrophy [70]. Typically, UMN involvement occurs within two years of symptom onset.

In addition to the absence of UMN features, patients with progressive muscular atrophy are less likely to develop cognitive symptoms than other patients with ALS [74]. Median survival appears to be longer in patients that present with progressive muscular atrophy than 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) [70]. In an earlier series, 37 patients with progressive muscular atrophy had a median survival of 56 months [75].

Limited data suggest the prevalence of progressive muscular atrophy ranges from 2.5 to 11 percent of MND cases [70,76]. At autopsy, patients with progressive muscular atrophy who never developed clinically apparent UMN signs frequently have UMN pathology, including corticospinal tract abnormalities and TDP-43-positive inclusions in the motor cortex, in a pattern identical to that of ALS [73,77].

Progressive bulbar palsy — Progressive bulbar palsy is a progressive UMN and LMN disorder of cranial muscles. Most patients present with dysarthria and dysphagia [78]. Pseudobulbar affect occurs in approximately half. Examination findings include increased jaw jerk reflex and tongue wasting. Symptoms remain isolated to the bulbar segment in progressive bulbar palsy.

Progressive bulbar palsy can be difficult to distinguish from bulbar-onset ALS. Some patients with isolated UMN and LMN bulbar symptoms may qualify for the diagnosis of ALS [55]. Other patients initially diagnosed with progressive bulbar palsy may subsequently develop UMN and LMN signs and symptoms involving other body regions and are then classified as having bulbar-onset ALS [78]. Symptoms restricted to the bulbar region for >6 months after onset increase the diagnostic confidence in progressive bulbar palsy over bulbar-onset ALS [79,80].

Progressive bulbar palsy accounts for up to 4 percent of patients with MND [81]. There have been no reports of specific pathology in progressive bulbar palsy [1-3,82].

Flail arm syndrome — The flail arm syndrome (also called brachial amyotrophic diplegia) is a form of MND characterized by progressive LMN weakness and wasting that predominantly affects the proximal arm [83-85]. It usually begins proximally and spreads distally to the point where arm and hand function is severely impaired. It is often asymmetric at onset, involving the other arm after months to years. Examination typically shows weakness with wasting of affected arm and hand muscles with absent muscle stretch reflexes in the arms. Although the syndrome is characterized by arm symptoms, hyperreflexia may be seen in the lower extremities [86].

Patients who present with initial clinical features restricted to the arm who subsequently develop lower limb, bulbar, or respiratory symptoms are classified as having upper limb-onset ALS. The diagnosis of flail arm syndrome is supported by the presence of motor neuron symptoms confined to the arms for two to three years following presentation [81].

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 the development of respiratory muscle weakness [86,87].

Flail leg syndrome — The flail leg syndrome (also called the pseudo-polyneuritic variant of ALS) is characterized by progressive LMN weakness and wasting with onset in the distal leg [86,88]. Symptoms typically begin with weakness and wasting of muscles of one or both legs, and examination also shows absent muscle stretch reflexes in the legs.

Flail leg syndrome is distinguished from lower limb-onset ALS by the absence of involvement of upper limb, bulbar, or respiratory symptoms, and examination findings. 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 than those with ALS.

Flail leg syndrome represents up to 6 percent of MND cases [81].

Hemiplegic ALS — Progressive hemiplegia (also called the Mills syndrome) is characterized by progressive UMN and LMN symptoms on one side of the body. Cases describing this rare syndrome report onset in the distal lower extremity followed by involvement of the upper extremity and bulbar regions [89-91].

ALS-plus syndromes — Classically defined, ALS is considered a degenerative disorder of the UMN and LMN. However, some patients have the clinical features of ALS along with features of other disorders including:

●Frontotemporal dementia (FTD) (see "Frontotemporal dementia: Clinical features and diagnosis", section on 'Behavioral variant FTD with motor neuron disease')

●Cerebellar degeneration (see "Overview of cerebellar ataxia in adults", section on 'Chronic progressive ataxias')

●Parkinsonism (see "Clinical manifestations of Parkinson disease")

●Supranuclear gaze paresis (see "Progressive supranuclear palsy (PSP): Clinical features and diagnosis")

Of these, ALS-FTD is the most common, occurring in up to 20 percent of patients with ALS.

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^th to 6^th 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 10^th to 12^th 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

●ALS symptoms and signs – ALS is a neurodegenerative condition that classically is characterized by the presence of both upper and lower motor neuron (LMN) signs and symptoms. These may produce impairments affecting limb, bulbar, axial, and/or respiratory function. Additional nonmotor features such as cognitive and autonomic symptoms can also occur. (See 'Clinical symptoms and signs' above.)

•Motor features – Motor features can be categorized into upper motor neuron (UMN) features such as slowness, incoordination, stiffness, hyperreflexia (movie 1), pathologic reflexes (movie 2), and spasticity, and LMN features such as weakness, atrophy or amyotrophy (movie 3), muscle cramps, and fasciculations (movie 4 and movie 5). These features vary by body segment involved (see 'Terminology' above and 'Core motor features' above):

-Limb – Hand weakness causes difficulty manipulating small objects (buttons, zippers, coins) and using writing instruments (table 1). Arm or hand UMN symptoms include stiffness with poor dexterity. (See 'Limb weakness' above.)

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. Leg UMN symptoms manifest as a spastic gait with poor balance.

-Axial – Motor impairment in trunk and core muscles may produce fatigue, postural instability, and contribute to fall risk. Axial UMN dysfunction may contribute to stiffness and imbalance (table 3). (See 'Axial weakness' above.)

-Bulbar – Bulbar dysfunction can result in both dysarthria, dysphagia, laryngospasm, trismus, facial muscle weakness, and pseudobulbar affect (table 2). (See 'Bulbar dysfunction' above.)

-Respiratory – Weakness of the diaphragm can produce progressive dyspnea along with reduced vocal volume (table 4). Diaphragmatic weakness may also result in orthopnea and sleep-disordered breathing. (See 'Respiratory impairment' above.)

•Nonmotor features – Nonmotor features accompany motor dysfunction in up to 50 percent of patients at diagnosis. These may include behavioral changes (eg, apathy, loss of empathy, changes in eating behaviors, disinhibition, perseveration or compulsive behaviors), cognitive impairment, parkinsonism, autonomic symptoms, and sensory features. (See 'Nonmotor features' above.)

•Initial symptoms – Limb weakness is the most common presentation of ALS, accounting for 80 percent of cases, often beginning with distal hand or foot symptoms. Bulbar-onset presentation, typically with progressive dysarthria, occurs in 20 percent of patients. Other patterns of ALS onset are uncommon. (See 'Initial presentation' above.)

•Disease progression – ALS progresses gradually without intervening remissions or exacerbations. Initial symptoms typically spread within the segment of onset and then to other regions. (See 'Progression' above.)

●Other forms of motor neuron disease – Motor neuron disease (MND) may refer to a group of degenerative conditions that are clinically defined by dysfunction in UMN and/or LMN. ALS is the most common form of MND and includes UMN and LMN pathology. Other forms of MND may be distinguished by clinical features including the pattern of progressive motor neuron involvement. These include:

•Primary lateral sclerosis (see 'Primary lateral sclerosis' above)

•Progressive muscle atrophy (see 'Progressive muscular atrophy' above)

•Progressive bulbar atrophy (see 'Progressive bulbar palsy' above)

•Flail arm and leg syndromes (see 'Flail arm syndrome' above and 'Flail leg syndrome' above)

•Hemiplegic ALS (see 'Hemiplegic ALS' above)

•ALS-plus syndrome (see 'ALS-plus syndromes' above)