Doctor of Philosophy
Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) is an inflammatory autoimmune peripheral nerve disorder. CIDP is associated with demyelination, slow motor nerve-conduction velocity, and distal muscle weakness. CIDP is under-recognized due to its heterogeneous presentation and the limitations of clinical diagnostic criteria. Using a combination of electrophysiology and muscle imaging techniques the four studies outlined in this thesis systemically investigate the impacts of this demyelinating disease on motor nerves and their innervated muscles.
The first two studies examine the neuronal consequences of demyelination caused by CIDP and the following two studies investigate how skeletal muscle is affected by these neuronal complications. Specifically, the purpose of study 1 was to investigate whether patients with CIDP demonstrate motor unit loss, and to determine the neuromuscular transmission stability of motor units. Results showed patients with CIDP have reduced motor unit number estimates (MUNEs), in addition to motor unit instability and transmission blocking in the tibialis anterior (TA) muscle. The purpose of study 2 was to investigate modifications to motor unit discharge characteristics of affected motor units. The results indicate CIDP leads to axonal or neuromuscular block and abnormally high motor unit firing rates of early recruited motor units as a compensatory mechanism to mitigate the frank neuronal loss in the TA.
The purpose of studies 3 and 4 was to assess the consequences of peripheral axon loss and motor unit instability on muscle quality and quantity in patients with CIDP. It is critical to investigate whether these neuronal changes precipitate uniform alterations in musculature. Study 3 showed that patients with CIDP have less overall muscle mass and more non-contractile tissue infiltration in the TA of the anterior leg compartment. Study 4, demonstrated that muscles in the posterior leg compartment, that differ functionally from the TA and are innervated by a different portion of the sciatic nerve undergo similar morphological changes to the TA. In combination, these neuronal deficits and skeletal muscle structural abnormalities likely lead to muscle weakness and functional impairment seen in patients with CIDP. Together these studies form a foundational understanding of how CIDP impacts both nervous and muscle tissue at a systems level.
Summary for Lay Audience
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an ultra rare immune mediated neurological disorder in which there is inflammation of peripheral nerves and destruction of the fatty protective covering (myelin sheath) surrounding the nerves, which affects how fast the nerve signals are transmitted to their attached muscles. This causes weakness, paralysis and/or impairment in motor function, especially of the arms and legs. Sensory disturbance may also be present. The motor and sensory impairments usually affect both sides of the body (symmetrical), and the degree of severity and the course of disease may vary greatly among individuals. Tests that can be of diagnostic help include nerve conduction testing and electromyography that demonstrate slow nerve conduction velocities, lumbar puncture with evidence of elevated spinal fluid protein and magnetic resonance imaging (MRI) of the nerve roots looking for enlargement and signs of inflammation. Despite this there is a lack of awareness and knowledge surrounding a specific cause and disease mechanism in CIDP making diagnosing the disease very difficult.
To date no studies have systematically investigated the neuronal and musculoskeletal consequences of this nerve disease. Therefore, it is critical to study the function of the peripheral nerves in this inflammatory disorder as well as their connection to skeletal muscle. In this work I investigated two main phenomenon related to CIDP. The first two studies of this thesis quantify the loss of motor nerves as well the health of the remaining motor nerves in response to the demyelinating process. The two subsequent studies investigate the repercussions of motor unit loss on the amount and quality of the muscles attached to these unhealthy nerves. The findings from this work demonstrate that patients with CIDP not only have fewer motor units; the remaining motor units are very unhealthy. This reduction of motor units in combination with the poor connection these motor units have with their attached muscle leads to major losses in the amount and quality of muscle tissue. Overall, this work provides compelling evidence for the reasoning behind the functional strength decrements patients exhibit with CIDP.
Gilmore, Kevin J., "The effects of Chronic Inflammatory Demyelinating Polyneuropathy on the Neuromuscular System in Humans" (2020). Electronic Thesis and Dissertation Repository. 6921.
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