Approach
Any patient with symptoms suggestive of ALS should be referred to a neurologist without delay, and investigations performed with high priority.[35][36][37] Diagnosis is based on the presence of upper motor neuron (UMN) and lower motor neuron (LMN) signs, disease progression, and absence of any other explanation for the presentation. Diagnosis of ALS is primarily based on clinical criteria. A thorough history and physical examination are central to the diagnostic process, followed by electrodiagnostic testing when required for additional evidence of occult LMN involvement.
History
ALS presents as a combination of UMN and LMN symptoms and signs, involving initially any segment of the neuroaxis (i.e., cranial, cervical, thoracic, or lumbosacral) and then progressively spreading typically to contiguous areas, without intervals of remission, exacerbation, or stabilisation. Patients will report insidious onset of focal weakness in the absence of pain or sensory symptoms, with symptoms worsening over time. Initial symptoms may include isolated dysarthria, hand weakness, foot drop, gait changes, or shortness of breath. On direct questioning, they may have noticed fasciculations, atrophy, muscle cramping, and sometimes weight loss.[37]
Clinical presentation and disease course can be quite variable between patients.
Asymmetrical limb involvement is the most common presentation (70% of cases). Typically, weakness then progresses from the first limb affected to involve the ipsilateral limb or the same limb on the contralateral side. It is uncommon for weakness to progress non-contiguously from one limb to the limb diagonally across from it.[17][21]
If the disease initially involves the bulbar muscles (occurring in around 25% of patients), the next affected segment will typically be neck muscles with head drop, or cervical with involvement of one arm; and then the contralateral arm or ipsilateral leg. Uncommonly, progression of weakness in patients with bulbar onset can initially skip the cervical segment and involve the lumbar segment.
Some patients may present with initial involvement of respiratory muscles (1% to 3%).[38]
The time interval between the onset of symptoms affecting one segment of neuroaxis and progression to the next is variable. For example, patients with severe bulbar symptoms (e.g., dysarthria, dysphagia) might have preserved limb function for months.
Up to 50% of patients will have concomitant cognitive or behavioural impairments, which can manifest as disinhibition, obsessive behaviours, impaired decision-making, and occasionally memory impairment.[5]
After elucidating symptom progression, it is important to obtain data regarding relevant family history of ALS, as well as other neurodegenerative conditions such as dementia and parkinsonism. Familial ALS represents about 10% of all ALS cases, the rest being sporadic.[22]
Dementia typically associated with familial ALS is frontotemporal dementia (FTD), which may have been labelled as Pick's disease. However, patients with FTD are sometimes misclassified as having Alzheimer's dementia, so a family history of Alzheimer's dementia may be relevant. Similarly, patients with motor neuron disease can sometimes be misclassified as having parkinsonism.
Physical examination
ALS presents with a combination of UMN and LMN symptoms and signs in a given segment of neuroaxis. These clinical features may involve the limb, axial, bulbar, and/or respiratory muscles.
UMN signs consist of:
Weakness in a pyramidal distribution
Spasticity
Hyper-reflexia and other pathological reflexes (usually found on examination): Babinski's sign, Hoffmann's or Trömner's reflexes, crossed adductors (elicited by tapping the finger placed on the medial condyle of the femur or malleolus internus triggering contraction of the adductors of the thigh), exaggerated jaw jerk (elicited by percussion of the finger placed on the chin, with the patient's jaw relaxed and slightly opened), and re-emergence of primitive reflexes such as the palmomental reflex or the snout reflex.
LMN signs include:
Weakness
Atrophy
Fasciculations.
The patient might present with limb and/or axial weakness, with associated hyper-reflexia in the affected segments of the neuroaxis. Alternatively, the patient's presentation might be with respiratory dysfunction (i.e., dyspnoea or orthopnoea) and bulbar signs such as dysphagia, dysarthria, sialorrhoea, and pseudobulbar affect (inability to control emotions, with uncontrolled crying and/or laughing). The dysarthria associated with ALS typically has mixed spastic and flaccid components. Symptoms of frontotemporal dementia may precede a diagnosis of ALS, or may occur during the disease course.
Testing to exclude alternate diagnoses that mimic ALS
Given that ALS is a clinical diagnosis, there are two reasons to perform laboratory and/or radiology evaluations. The first reason is to exclude alternate diagnoses that may resemble ALS, including neuropathies that affect only motor nerves or diseases that cause a combination of LMN and UMN signs due to anatomical compression of spinal cord and nerve roots.
Neuroimaging is performed primarily to rule out alternative causes for the signs and symptoms. Imaging the most affected portion of the neuroaxis is indicated in all cases.[35]
Nerve conduction studies are performed to evaluate the possibility of peripheral nerve disease mimicking ALS, such as multifocal motor neuropathy. The presence of severe slowing of motor conduction velocity or the finding of conduction block in motor nerves indicates the presence of an alternative aetiology and eliminates ALS as the diagnosis.[39]
If the nerve conduction studies suggest possible peripheral nerve disease, blood tests to assess vitamin B₁₂ level and the presence of specific antibodies (anti-GM1, acetylcholine receptor, muscle-specific tyrosine kinase, and voltage-gated calcium-channel antibodies) may be indicated.
In patients without clear bulbar signs, a combination of spinal cord and multiple spinal root compression may resemble ALS; magnetic resonance imaging is performed to rule out this possibility.
Very rarely, infectious diseases may resemble ALS; lumbar puncture is occasionally performed to rule out such diseases. Cerebrospinal fluid analysis, if considered, should include routine studies with cytology.
HIV testing may be considered if there is a history of exposure, and para-neoplastic antibody panels can be added if there is a history of malignancy.
Creatine kinase may be elevated to a maximum of 1000 units/L as a consequence of denervated muscles in ALS. Higher levels suggest an alternate diagnosis.
Testing to assess LMN involvement in asymptomatic limbs
The second role of laboratory evaluation in patients with suspected ALS is to detect the presence of LMN disease in limbs that are clinically unaffected.[21][40][41]
Electromyography (EMG) is performed for this purpose. Testing may be limited to the study of limbs in which clear symptoms or signs of LMN disease cannot be obtained. EMG of clinically unaffected limbs or muscles may demonstrate LMN disease and be diagnostic in patients whose clinical presentation is limited to one or two limbs.
Abnormalities sought include the presence of fibrillation or fasciculation potentials, as well as enlarged, prolonged, and polyphasic motor units that indicate chronic axon loss with subsequent compensatory re-innervation.
If initial results are equivocal, additional electrodiagnostic studies may include repetitive nerve stimulation and single-fibre EMG.
The sensory nerve conduction studies should be normal.
Genetic testing
Guidelines recommend that all patients with ALS are offered genetic testing with an ALS gene panel that includes the C9orf72, SOD1, FUS, and TARDBP genes. Additional genetic testing is recommended for genes strongly and definitively associated with ALS as determined by ClinGen, and any gene for which there is an approved gene-targeted therapy.[24]
Genetic counselling and education should be provided for all patients with ALS, and this should precede the offer of testing. Pre-test counselling should cover the range of possible testing outcomes, and prepare patients for possible personal, psychological, and economical impacts of testing on themselves and family members. Post-test counselling should also be provided, giving the patients the opportunity to discuss their result and understand the implications for them and their family.[24]
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