There is evidence that superoxide dismutase 1 (SOD1) protein misfolding propagates between molecules in a similar fashion to prions.
Another very common cause of ALS is a lesion to the motor system in areas such as the frontotemporal lobes. Lesions in these areas often show signs of early deficit, which can be used to predict the loss of motor function, and result in the spread of ALS. The mechanisms of ALS are present long before any signs or symptoms become apparent. It is estimated that before any muscular atrophy becomes apparent during ALS, roughly one-third of the motor neurons must be destroyed.
Many other potential causes, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated but without consistent findings.
Pathophysiology
The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. Prior to their destruction, motor neurons develop protein-rich inclusions in their cell bodies and axons. This may be partly due to defects in protein degradation. These inclusions often contain ubiquitin, and generally incorporate one of the ALS-associated proteins: SOD1, TAR DNA binding protein.
Extraocular and skeletal motor units
Despite sharing fixed sequences of recruitment, extraocular muscles (EOMs) and skeletal muscles exhibit different characteristics. The following are characteristics of EOMs that differ from skeletal motor units.
One neural fiber connects with only 1 or 2 muscle fibers
No ocular stretch reflexes, despite being rich in muscle spindles
No recurrent inhibition
No special fast-twitch or slow-twitch muscles
All eye motor neurons participate equally in all types of eye movements—not specialized for saccades or smooth pursuit
There are also noted differences between healthy and affected EOMs. EOMs from postmortem donors preserved their cytoarchitecture, as compared to limb muscles. Healthy EOMs consist of a central global layer (GL) facing the globe and a thin orbital layer (OL) facing the walls of the orbit. EOMs affected by ALS preserve the GL and OL organization. EOMs possess the neurotropic factors brain-derived neurotropic factor (BDNF) and glial cell line-derived neurotropic factor (GDNF), and these neuroprotective factors are also preserved in EOMs affected by ALS. Laminin is a structural protein typically found in the neuromuscular junction (NMJ). Lnα4 is a laminin isoform that is a hallmark of skeletal muscle NMJs. People with ALS showed preserved Lnα4 expression in EOM NMJs, but this expression was non-existent in limb muscle NMJs from the same people. Preservation of laminin expression may play a role in preserving EOM integrity in people with ALS. People with sporadic ALS (sALS) have increased levels of intracellular calcium, causing increased neurotransmitter release. Passive transfer of sera from people with sALS increases spontaneous transmitter release in spinal but not EOM terminals; therefore, it is assumed that EOMs are resistant to changes in physiologic conditions typically found in ALS.
However, some effects of the disorder were noted. EOMs affected by ALS had a larger variation in fiber size compared to those in age-matched healthy controls. EOMs exhibited both clustered and scattered atrophic and hypertrophic fibers that are characteristic of disorder; however, these muscles showed significantly less damage compared to limb muscles from the same donors. These EOMs also showed an increase in connective tissue and areas of fatty replacement in compensation of fiber loss and atrophy. Ophthalmoplegia, a loss of neurons in and around the ocular motor nuclei, has been noted in ALS patients. Additionally, there was altered myosin heavy chain content of the EOM fibers, with a loss of normal expression of MyHCslow tonic in the GL and the OL did not contain MyHCemb, which is normally expressed in this layer. This change may represent a change in innervation pattern that may include reinnervation by a different type of motor neuron or loss of multiple innervations. Changes in MyHCslow and MyHCemb are the only fiber changes seen in EOMs, leaving the EOM fiber composition relatively normal. Because EOMs are normally highly innervated, any denervation, is compensated for by neighboring axons which preserve function.
Lactate and cinnamate
Lactic acid is an end product of glycolysis and is known to cause muscle fatigue. Lactate dehydrogenase (LDH) is an enzyme that exerts its effects bidirectionally and is able to oxidize lactate into pyruvate so it can be used in the Krebs Cycle. In EOM, lactate sustains muscle contraction during increased activity levels. EOM that have high LDH activity are thought to be resistant to ALS.
Cinnamate is a blocker of lactate transport and exogenous lactate on fatigue resistance. Cinnamate is able to cause fatigue in EOM, while decreasing EOM endurance and residual force; however, cinnamate has no effect on extensor digitorum longus muscle, a muscle in the leg. In contrast, replacing glucose with exogenous lactate increases fatiguability of EDL muscles but not EOM. Fatiguability in EOM was only found when a combination of exogenous lactate plus cinnamate replaced glucose.
Diagnosis
No test can provide a definite diagnosis of ALS, although the presence of upper and lower motor neuron signs in a single limb is strongly suggestive. Instead, the diagnosis of ALS is primarily based on the symptoms and signs the physician observes in the patient and a series of tests to rule out other diseases. Physicians obtain the patient's full medical history and usually conduct a neurologic examination at regular intervals to assess whether symptoms such as muscle weakness, atrophy of muscles, hyperreflexia, and spasticity are getting progressively worse.
MRI (axial FLAIR) demonstrates increased T2 signal within the posterior part of the internal capsule, consistent with the clinical diagnosis of ALS.
Because symptoms of ALS can be similar to those of a wide variety of other, more treatable diseases or disorders, appropriate tests must be conducted to exclude the possibility of other conditions. One of these tests is electromyography (EMG), a special recording technique that detects electrical activity in muscles. Certain EMG findings can support the diagnosis of ALS. Another common test measures nerve conduction velocity (NCV). Specific abnormalities in the NCV results may suggest, for example, that the patient has a form of peripheral neuropathy (damage to peripheral nerves) or myopathy (muscle disease) rather than ALS. The physician may order magnetic resonance imaging (MRI), a noninvasive procedure that uses a magnetic field and radio waves to take detailed images of the brain and spinal cord. Although these MRI scans are often normal in patients with ALS, they can reveal evidence of other problems that may be causing the symptoms, such as a spinal cord tumor, multiple sclerosis, a herniated disk in the neck, syringomyelia, or cervical spondylosis.
Based on the patient's symptoms and findings from the examination and from these tests, the physician may order tests on blood and urine samples to eliminate the possibility of other diseases as well as routine laboratory tests. In some cases, for example, if a physician suspects that the patient may have a myopathy rather than ALS, a muscle biopsy may be performed.
Infectious diseases such as human immunodeficiency virus (HIV), human T-cell leukemia virus (HTLV), Lyme disease, syphilis and tick-borne encephalitis viruses can in some cases cause ALS-like symptoms. Neurological disorders such as multiple sclerosis, post-polio syndrome, multifocal motor neuropathy, CIDP, spinal muscular atrophy and spinal and bulbar muscular atrophy (SBMA) can also mimic certain facets of the disease and should be considered by physicians attempting to make a diagnosis.
ALS must be differentiated from the "ALS mimic syndromes" which are unrelated disorders that may have a similar presentation and clinical features to ALS or its variants. Because of the prognosis carried by this diagnosis and the variety of diseases or disorders that can resemble ALS in the early stages of the disease, patients should always obtain a specialist neurological opinion, so that alternative diagnoses are clinically ruled out.
Amyotrophic Lateral Sclerosis cont.