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ALS and Extraocular Muscles

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease in which oculomotor activity is generally spared due to differences between extraocular muscles and skeletal muscles. Although this is the case, some oculomotor abnormalities are seen in ALS patients. Overall, extraocular muscles seem to be preserved, but their function is not completely spared.

Differences between Extraocular and skeletal motor units[edit]

Despite sharing fixed sequences of recruitment, extraocular muscles (EOMs) and skeletal muscles exhibit different characteristics. The following are characteristic of EOMs that differ from skeletal motor units. [1]

  • 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

Differences in diseased extraocular muscles[edit]

Preserved aspects[edit]

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.[2] EOMs affected by ALS preserve the GL and OL organization.[2] EOMs posses the neurotrophic factors brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF), and these neuroprotective factors are also preserved in EOMs affected by ALS.[2] Laminin is a structural protein typically found in the neuromuscular juntion (NMJ). Lnα4 is a laminin isoform that is a hallmark of skeletal muscle NMJs.[3] Patients with ALS showed preserved Lnα4 expression in EOM NMJs, but this expression was non-existent in limb muscle NMJs from the same patients.[3] Preservation of laminin expression may play a role in preserving EOM integrity in ALS patients. Patients with sporadic ALS (sALS) have increased levels of intracelluar calcium, causing increased neurotransmitter release.[4] Passive transfer of sera from sALS patients increases spontaneous transmitter release in spinal but not EOM terminals;[4]therefore, it is assumed that EOMs are resistant to changes in physiologic conditions typically found in ALS.

Affected aspects[edit]

Despite preservation of many aspects of EOMs, some effects of disease were seen. EOMs affected by ALS had a larger variation in fiber size compared to age-matched healthy EOM controls.[2] EOMs exhibited both clustered and scattered atrophic and hypertrophic fibers that are characteristic of disease; however, these muscles showed significantly less damage compared to limb muscles from the same donors.[2] These EOMs also showed an increase in connective tissue and areas of fatty replacement in compensation of fiber loss and atrophy.[2] Ophthalmoplegia, a loss of neurons in and around the ocular motor nuclei, has been noted in ALS patients.[5] 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.[2] 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.[2] Because EOMs are highly innervated, upon denervation, neighboring axons can compensate for a lack of innervation by innervating these newly denervatted EOM; thus, preserving function.[2]

Oculomotor abnormalities[edit]

Clinical examination[edit]

Patients, for the most part, have normal clinical examinations, with a few exceptions.

Voluntary movement impairment[edit]

Patients with ALS may have difficulty in generating voluntary saccades, fast movements of the eye.[5] Sacccade velocity is significantly slower in patients with ALS.[5] Problems in generating smooth pursuit and convergence movements have also been noted in patients with ALS.<[5] Testing the vestibulo-ocular reflex (VOR) should help in identifying these deficits in ALS patients.[5]

Electro-oculography[edit]

Electrooculography (EOG) is a technique that measures the the resting potential of the retina. EOG findings in patients with ALS show progressive changes that correlate with disease progression, and provide a measurement for clinically evaluating the effects of disease progression on oculomotor activity.[6] Additionally, EOG may allow earlier, subclinical, detection of oculomotor abnormalities in patients with ALS.

Myogenic precursor cell hypothesis[edit]

The embryonic lineage of EOMs differs from that of somite-derived muscles. EOMs are unique because they continuously remodel through life and maintain a population of active satellite cells during aging.[7] EOMs have significantly more myogenic precursor cells (mpcs) per mg muscle than limb skeletal muscle.[7]

EOMCD34[edit]

EOMCD34 contain a population of increased mpcs that are positive for CD34.[7] EOMCD34 is found in EOM and limb muscles in equal percentages in newborns; however, EOMCD34 maintains its percentage only in aged EOM and is scarcely found in aged limb muscle.[7] This difference may account for why EOM are resistant to elevated levels of oxidative stress and toxins and can actively proliferate throughout life.

Role of lactate[edit]

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.[8]

Cinnamate[edit]

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 (EDL), a muscle in the leg.[8] In contrast, replacing glucose with exogenous lactate increases fatiguability of EDL muscles but not EOM.[8] Fatiguability in EOM was only found when a combination of exogenous lactacte plus cinnamate replaced glucose. [8]

References[edit]

  1. ^ Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science. McGraw-Hill; 2000
  2. ^ a b c d e f g h i Ahmadi M, Liu JX, Brännström T, Andersen PM, Stål P, Pedrosa-Domellöf F. Human extraocular muscles in ALS. Invest Ophthalmol Vis Sci. 2010;51(7):3494-501
  3. ^ a b Liu JX, Brännström T, Andersen PM, Pedrosa-Domellöf F. Different Impact of ALS on Laminin Isoforms in Human Extraocular Muscles Versus Limb Muscles. Invest Ophthalmol Vis Sci. 2011
  4. ^ a b Mosier DR, Siklós L, Appel SH. Resistance of extraocular motoneuron terminals to effects of amyotrophic lateral sclerosis sera. Neruology. 2000;54(1):252-5
  5. ^ a b c d e Cohen B, Caroscio J. Eye movements in amyotrophic lateral sclerosis. J Neural Transm Suppl. 1983;19:305-15
  6. ^ Palmowski A, Jost WH, Prudlo J, Osterhage J, Käsmann B, Schimrigk K, Ruprecht KW. Eye movement in amyotrophic lateral sclerosis: a longitudinal study. Ger J Ophthalmol. 1995;4(6):355-62
  7. ^ a b c d Kallestad KM, Hebert SL, McDonald AA, Daniel ML, Cu SR, McLoon LK. Sparing of extraocular muscle in aging and muscular dystrophies: A myogenic precursor cell hypothesis. Exp Cell Res. 2011
  8. ^ a b c d Andrade FH, McMullen CA. Lactate is a metabolic substrate that sustains extraocular muscle function. Pflugers Arch. 2006;452(1):102-8

External links[edit]


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