Amyotrophic Lateral Sclerosis (ALS) Clinical Presentation

  • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD   more...
 
Updated: Aug 26, 2011
 

History

The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical. ALS may be suspected whenever an individual develops insidious loss of function or gradual, slowly progressive, painless weakness in 1 or more regions in the body, without changes in the ability to feel, and no other cause immediately evident.

In lower motor neuron involvement, fasciculations may present early on in the disease, particularly in the tongue. Patients with upper motor neuron involvement generally are hyperreflexic, though some reflexes may be diminished

In 75-80% of patients, symptoms begin with limb involvement, while 20-25% of patients present with bulbar symptoms. For those with limb involvement at presentation, the frequency of upper limb versus lower limb involvement is approximately equal.

Patients who have lower limb onset initially may complain of tripping, stumbling, or awkwardness when running. Foot drop is common. Patients may report a "slapping" gait.

Those with upper limb onset may notice wrist drop interfering with work performance. Alternatively, the patient may experience reduced finger dexterity, cramping, stiffness, and weakness or wasting of intrinsic hand muscles. This may lead to difficulty with actions such as buttoning clothes, picking up small objects, or turning a key.

With bulbar onset, patients note problems such as slurred speech, hoarseness, or decreased volume of speech. Aspiration or choking during a meal may occur.

ALS is more likely to be suspected based on clinical presentation alone when the disease is more widespread, (ie, when more parts of the body are involved, and when upper and lower motor neuron signs are present together in more regions of the body).

When the disease has progressed far in its course and involves many parts of the body, it may be possible to make the diagnosis based on the patient’s appearance and on the findings on the neurologic examination. However, when a patient presents with the first symptoms, making the diagnosis is not straightforward.[8]

Disease progression

As the disease progresses, muscle atrophy becomes more apparent, and spasticity may complicate gait and manual dexterity.

Immobility may predispose the patient to the development of painful joint contractures. Muscle cramps are common. In some patients, persistent stiffness or cramping of muscles may stress the related joints and the back. This can usually be ameliorated with medications and physical therapy exercises to relax the muscles and maintain joint range of motion.

In patients with bulbar involvement, a mixture of spastic and flaccid components may characterize speech, resulting in a dysarthria with severe disintegration and slowness of articulation. Hypernasality occurs from palatal weakness, and patients may develop a strained, strangled vocal quality. With time, speech may be lost, and patients may become dependent on other forms of communication such as writing, communication boards, or speech-generation devices.

Patients with bulbar involvement may develop swallowing difficulties (dysphagia). Swallowing liquids requires the greatest oropharyngeal muscle control; therefore, patients usually report more difficulty with liquids than with solids. Drooling affects some patients, and it results from a combination of excessive salivation, poor swallowing, and poor lip control; it can usually be ameliorated effectively with oral medications or a scopolamine patch.

Some individuals may have pseudobulbar symptoms associated with their disease. These patients have an involuntary exaggerated emotional response. The response may of one type (laughter or crying) and, less commonly, results in alterations in emotive expressions. Episodes of intense laughter may be followed immediately by tears. The patient's response often does not correspond to an apparent social stimulus or the current psychosocial situation, but it may be an exaggerated response to a minor trigger. The patient is aware of the lack of control. These symptoms can be ameliorated by medications.

Preserved functions

Certain motor neurons usually are spared, and, as a result, some functions are preserved. Most patients retain extraocular movements and bowel and bladder control. With progressive disease, patients may develop problems with urge incontinence and severe constipation because of weak abdominal musculature, but sphincter control generally is unaffected.

Since the disease primarily involves motor neurons, sensory function typically is preserved. Patients may complain of some numbness and paresthesias, but most do not have sensory symptoms. Sensory nerve conduction studies can be performed if indicated.

Abnormalities have been reported on sensory nerve conduction studies in a small number of ALS patients. Usually they reflect an unrelated coexistent condition..

Skin integrity usually is maintained, primarily from the combination of preserved sensory function along with continued control of bowel and bladder function. Some studies on these patients also have found morphologic changes in the skin that are complex and poorly understood but that may contribute to preservation of skin integrity.

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Physical Examination

The symptoms that some patients with ALS may experience and the signs that are found on their neurologic examination are summarized below. Not all patients experience all symptoms or have all signs.

Findings associated with upper or lower motor neuron dysfunction include the following:

  • Weakness (However, classic ALS weakness is usually due to lower motor neuron dysfunction or loss)
  • Muscle cramps
  • Difficulties with speech and swallowing
  • Unsteadiness

Findings associated with upper motor neuron dysfunction include the following:

  • Stiffness (spasticity)
  • Tendon reflexes which are brisk or spread abnormally
  • Presence of abnormal reflexes (eg, hyperreflexic jaw jerk, Babinski sign)
  • Loss of dexterity in the presence of normal strength

Findings associated with lower motor neuron dysfunction include the following:

  • Twitching muscles (fasciculations)
  • Reduction of muscle bulk (atrophy)
  • Foot drop
  • Depressed reflexes
  • Breathing difficulties

The key finding in an involved limb is the combination of lower and upper motor neuron dysfunction such as a weak, atrophic, fasciculating muscle occurring in combination with increased tone and hyperreflexia.

While the symptoms of motor dysfunction are best recognized, affecting all patients with ALS, a fair proportion of patients also experience emotional and special cognitive difficulties that are part of the disease. Emotional manifestations include involuntary laughing or crying and depression.

These difficulties may adversely affect the patients’ ability to plan and relate appropriately to others. Their interactions with caregivers and their willingness to accept treatment recommendations are impaired, and their prognosis is worse than of unaffected patients.[8]

Bulbar symptoms manifest as dysarthria or dysphagia and are the next most common presentation (20%).

Rarely, patients with ALS may present with respiratory muscle weakness, generalized weakness, and difficulty with head control. They may develop disturbed nocturnal sleep and exhibit excessive daytime sleepiness.

When patients have axial truncal weakness they have difficulty maintaining an erect posture when standing; to assist in attaining a standing position, they may support their torso by “walking” their hands up their thighs. Some patients feel more secure when pushing a heavy object on wheels such as a grocery cart.

A link exists between ALS and frontotemporal executive dysfunction that may precede or follow the onset of ALS, but most patients with ALS do not have overt dementia, and cognitive impairment is usually subtle. Approximately 15% of patients with ALS meet criteria for frontotemporal dementia%. Patients with ALS associated with frontotemporal dementia have shorter survival than those with ALS alone.[87]

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Diagnostic Criteria

The World Federation of Neurology (WFN) has developed an algorithm that combines the clinical findings and, in some cases, electrophysiologic findings, to express in each patient the degree of involvement by ALS at the time of the examination (the revised El Escorial criteria).[88]

The WFN uses adjectives that in usual speech imply a degree of certainty. However, when these criteria are applied to patients with ALS, the adjectives need to be understood as reflective of the degree of clinical involvement, particularly if no alternative diagnosis has been found and the disease has progressed beyond a single limb.

The WFN criteria recognize 4 regions or levels of the body, as follows (see the image below)[8] :

  • Bulbar - Muscles of the face, mouth, and throat
  • Cervical - Muscles of the back of the head and the neck, shoulders, and upper back, and the upper extremities
  • Thoracic - Muscles of the chest and abdomen and the middle portion of the spinal muscles
  • Lumbosacral - Muscles of the lower back, groin, and lower extremitiesThe 4 regions or levels of the body. Bulbar (musclThe 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities).

The degree of certainty of diagnosis is increased by the number of body segments that demonstrate upper motor neuron (UMN) and lower motor neuron (LMN) signs. WFN categories are as follows:

  • Clinically Definite ALS: UMN and LMN signs in at least 3 body segments
  • Clinically Probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs
  • Clinically Probable, Laboratory Supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by EMG in at least 2 limbs
  • Clinically Possible ALS: UMN and LMN signs in 1 body segment or UMN signs alone in at least 2 segments or LMN signs are found in segments above UMN signs
  • Clinically Suspected ALS (carried forward from the original El Escorial criteria): Pure LMN syndrome with other causes of LMN disease adequately excluded

Patients with a family history of Mendelian ALS are considered to have definite ALS as soon as any evidence of motor neuron disease arises that cannot be accounted for by an alternative explanation, regardless of the extent of involvement.

A group of experts has proposed that the WFN criteria be further revised , primarily by giving equal weight to clinical and electrophysiologic evidence of denervation.[89] However, even when there is no uncertainty, this system still retains use of the term probable ALS, which denotes uncertainty. There are other differences between this system and the previous one, and for now the author believes forgoing the use of the revised WFN criteria is premature.[88]

Previously, only patients with definite, probable, and laboratory-supported probable ALS were considered eligible for inclusion in clinical trials of disease-modifying treatments. Since most patients with possible ALS (upper and lower motor neuron findings in one limb) progress to more extensive disease, they have been included in more recent clinical trials. Their progression has been affirmed explicitly.

The term suspected ALS has special meaning in the WFN classification system: it is applied to patients with a pure upper motor neuron presentation, particularly if they cannot yet be diagnosed with primary lateral sclerosis, and to patients with a pure lower motor neuron presentation (particularly early in their presentation) before enough time has elapsed to be sure that their condition will remain restricted to lower motor neurons, and thus might be more precisely described as progressive muscular atrophy (PMA).

This has practical implication, because patients with primary lateral sclerosis have a course that is measured in decades (approximately 20 years). Some patients with a predominantly upper motor neuron form of ALS may have a longer course than those with classical ALS.[72]

Most patients with PMA have a course indistinguishable from that of patients with classical ALS (except for the absence of upper motor neuron findings). However, some patients may have a longer course, particularly those with "flail arm" or "flail leg" syndromes.[39]

Since the distinction between a diagnosis of PMA and laboratory-supported possible ALS hinges on the identification of 1 upper motor neuron sign, at some point in the patient’s disease, this distinction may prove to be of greater significance to researchers than to clinicians and patients, for whom rate of progression is the factor that determines the patients’ course and outcome.

Kim et al concluded that PMA should be considered a form of ALS. Review of the medical records of 91 patients with PMA and 871 with ALS showed that in patients with PMA were more likely to be male, older, and to live longer than those with ALS, but risk of death increased with age at onset in both patient groups and upper motor neuron signs developed in 22% of patients with PMA within 61 months after diagnosis.

Demographic and other clinical variables did not differ at diagnosis between those who did or did not develop upper motor neuron signs. In PMA, as in ALS, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower forced vital capacity, and lower ALS Functional Rating Scale-Revised (ALSFRS-R) score.[90]

Patients with progressive bulbar palsy (PBP) may be classified while the disease is restricted to the bulbar region as “suspected ALS” if only upper orlower motor neuron abnormalities are evident, and as “possible ALS” if there is upper andlower motor neuron involvement. When neurophysiologic or clinical spread beyond the bulbar level is evident, the condition would be reclassified as probable, laboratory-supported probable, or definite ALS.

In day-to-day practice, clinicians will inevitably use the term suspected ALS whenever they suspect ALS, regardless of the extent of clinical involvement at the time, and may or may not use the WFN qualifiers when they conclude that the patient has ALS. This leads to more dichotomous terminology in practice: the patient is either suspected of having ALS or confirmed as having the disease (or something else).

Complications

Complications of ALS may include the following:

  • Progressive inability to perform activities of daily living (ADLs), including handling utensils for self-feeding
  • Deterioration of ambulation
  • Aspiration pneumonia
  • Respiratory insufficiency
  • Complications from being wheelchair-bound or bedridden, including decubitus ulcers and skin infections (while rare in patients with ALS, these complications can emerge if appropriate padding is not used)
  • Deep vein thromboses and pulmonary emboli (these are rare in patients with ALS, but have been encountered with greater frequency in the active treatment arm of some clinical trials)
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Contributor Information and Disclosures
Author

Carmel Armon, MD, MSc, MHS  Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi

Disclosure: Avanir Pharmaceuticals Consulting fee Consulting

Specialty Editor Board

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Neil A Busis, MD  Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Chief Editor

Nicholas Lorenzo, MD  Consulting Staff, Neurology Specialists and Consultants

Nicholas Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and American College of Physician Executives

Disclosure: Nothing to disclose.

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The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities).
Malignant biochemical transformation hypothesis. Risk factors operate up-stream to a putative malignant biochemical transformation, which causes the appearance of endogenous ALS-specific toxins. These putative toxins spread, behaving like a metastasizing biochemical malignancy, and cause the downstream biochemical, histologic and clinical consequences of ALS. (Adapted from Armon C. ALS: Clinical and Epidemiologic Clues to Pathogenesis. In: Neurobiology of ALS. Course Syllabus, 51st Annual Meeting. American Academy of Neurology, 1999.) The author has suggested that an acquired nucleic acid change (a somatic mutation) is the "malignant biochemical transformation" (Armon C. Acquired nucleic acid changes may trigger sporadic amyotrophic lateral sclerosis. Muscle Nerve. Sep 2005;32(3):373-7).
Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.
Table 1. Familial Forms of ALS
GeneLocusProteinInheritance
ALS 121q22.1SOD1AD
ALS 22q33ALSINAR
ALS 318q21UnknownAD
ALS 49q34SETXAD
ALS 515q15UnknownAR
ALS 616q21UnknownAD
ALS 720ptel-p12UnknownAD
ALS 820q13.3VABPAD
ALS-FTD9q21-22UnknownAD
ALS-FTD9q21.3UnknownAD
ALS14q11.2AngiogeninAD
FTD 3CHMP2BAD
ALS 1TDP43AD
ALS2p13DynactinAD
AD –autosomal dominant; AR—autosomal recessive
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