History and exam
Key diagnostic factors
common
upper extremity weakness
Results in difficulties performing activities of daily living, such as brushing teeth, dressing, and brushing hair. Can be the result of upper motor neuron (UMN) or lower motor neuron (LMN) weakness.
stiffness, with poor coordination and balance
Weakness as an UMN symptom is usually moderate, with progressive disability resulting from associated stiffness, poor coordination, and balance problems.
spastic, unsteady gait
May indicate UMN weakness affecting lower limbs.
painful muscle spasms
LMN symptom.
difficulties arising from chairs and climbing stairs
Caused by LMN weakness affecting proximal lower limbs.
foot drop
Caused by LMN weakness affecting distal lower limbs; associated with tendency to trip and fall.
stiffness and decreased balance with impact on gait
Caused by UMN-type truncal weakness.
head drop
Caused by neck extensor weakness; result of LMN-type axial weakness.
progressive difficulties maintaining erect posture, with stooping
Caused by paraspinal weakness; result of LMN-type axial weakness.
muscle atrophy
LMN symptom.
increased lumbar lordosis and tendency for abdominal protuberance
Caused by abdominal and paraspinal weakness; result of LMN-type axial weakness.
hyperreflexia
UMN sign.
Hyperreflexia in an otherwise weak, atrophic limb is suggestive of motor neuron disease pathology. In a plegic, severely atrophic limb, the presence of even a trace of reflex is considered pathologic.
Pathologic reflexes, such as Babinski sign, positive Hoffmann or Trömner reflexes, crossed adductors, or exaggerated jaw jerk can be found. Re-emergence of primitive reflexes such as the snout and palmomental reflexes may also be observed.
An equivocal/mute Babinski sign is considered positive if the contralateral side is clearly negative.
dyspnea
Dyspnea and orthopnea result from progressive diaphragmatic weakness.
Orthopnea causes frequent awakenings through the night, with subsequent lost sleep.
coughing and choking on liquids (including secretions) and eventually on food
Dysphagia of UMN type results from lack of coordination of the tongue and pharyngeal constrictor muscles.
Dysphagia of LMN type results from actual weakness of the tongue and pharyngeal muscles.
In both types, the consequence is dysfunction of the oral and pharyngeal phases of swallowing, with increased risk for aspiration.
Although severe coughing triggered by aspiration of liquid or food is acutely distressing for patient and caregiver, it is very unusual for a patient with ALS to choke to death.
With symptom progression, nutrition deficit and weight loss occurs.
strained, slow speech
Dysarthria of UMN type (i.e., spastic dysarthria) results from incoordination of the tongue, lips, and pharyngeal muscles.
slurred, nasal, and, at times, dysphonic speech
Dysarthria of LMN type results from actual weakness of the tongue, lips, palate, pharyngeal muscles, and, sometimes, vocal cords.
Resulting speech is poorly articulated (slurred), hypophonic (nasal quality), and, at times, dysphonic (hoarse).
hypophonic speech
Poor respiratory support due to respiratory muscle weakness can cause a hypophonic speech pattern, whereby the voice is quiet and cannot be projected, and frequent breaks for breaths interrupt sentences.
Other diagnostic factors
common
propensity for falls
Can result from UMN or LMN weakness.
sialorrhea and drooling
Usually result from a combination of facial diplegia with poor lip seal and dysphagia.
inappropriate bursts of crying or laughing
Pseudobulbar affect, otherwise called emotional incontinence.
Inappropriate bursts of crying or laughing are triggered by stimuli that would not be expected to cause such reaction, and are difficult to stop.
uncommon
cognitive impairment
Various domains of cognitive functions might be affected in a patient with ALS, including psychomotor speed, language, executive function, and memory.[42]
Most prominent presentation is that of frontotemporal degeneration.
features of frontotemporal dementia
May precede a diagnosis of ALS or may occur during disease course. Has a gradual onset and progression.
May present with behavioral dysfunction (including emotional blunting, lack of insight, abnormal social conduct, irritability) and/or cognitive impairment (especially executive dysfunction, decreased word generation) with relative sparing of the memory.
Presence in ALS may correlate with more rapid disease progression.[43][44]
Risk factors
strong
genetic predisposition or family history
Familial ALS represents about 10% of all ALS cases, the rest being sporadic.[22] Most cases of hereditary ALS are indistinguishable from sporadic ALS.
Patterns of inheritance involve predominantly autosomal dominant genetics, although less common autosomal recessive forms also occur.
The most common cause of familial ALS (30% to 40% of cases) is hexanucleotide expansion in the C9orf72 gene. Normal numbers of the C9orf72 gene hexanucleotide repeat are less than 30, whereas patients with autosomal dominant ALS can have repeat lengths of 700 to 1600.[23] Patients with an expansion in C9orf72 can present with ALS, ALS with frontotemporal dementia (FTD), or FTD. Even within the same family, patients may have different phenotypic presentations.
Other genes include SOD1 (15% to 20% of familial ALS cases), TARDBP, and FUS.[21][24] More recently discovered genes associated with ALS include VCP, SQSTM1, TBK1, KIF5A, TIA1, CHCHD10, and OPTN.[22] Commercial panels can test for 30 associated ALS genes.
age >40 years
weak
military service
professional athletic activity
The risk of developing ALS may be higher in professional athletes, such as soccer and American football players, and seems to correlate with the number of years of exposure.[28] High amounts of lifetime physical activity can slightly increase the risk of developing ALS, particularly in people with a genetic predisposition.[29][30]
cigarette smoking
agricultural chemical exposure
A positive association between ALS and occupational exposure to pesticides, herbicides, insecticides, fungicides, and fertilizers has been described.[33]
lead exposure
Occupational exposure to lead (total lifetime exposure of 200 hours) was found to correlate with increased risk of ALS.[34]
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