A scientific review on autoimmune neurological diseases reveals what occurs in our body when the immune system, by mistake, produces antibodies that target a protein essential for the normal functioning of nerves. The result is hyperexcitability, that is, uncontrolled electrical signals that trigger continuous, involuntary muscle activity.

Autoimmune neurological diseases, such as Multiple Sclerosis, are conditions in which the immune system erroneously attacks structures of the central or peripheral nervous system, including neurons, axons, myelin, or specific proteins. One such protein is called Contactin-associated protein-like 2 (CASPR2), which is crucial for normal nerve function because it helps organise the channels that regulate electrical signals. Under normal circumstances, these signals reach the muscles in an orderly manner, enabling normal body movements.

Conversely, when the immune system produces antibodies that attack this protein, inflammation occurs, neurons are damaged, and various neurological symptoms arise. It is as if someone sabotaged the traffic lights in a city: traffic (electrical signals) becomes chaotic. In nerves, this translates into hyperexcitability, that is, uncontrolled electrical signals that cause involuntary muscle movements, spasms, and disruptions in communication between nerves and muscles.

A team of researchers, including neurologist João Moura (ULS Santo António, ICBAS-U.Porto), supported by the Bial Foundation, published the review Neuromyotonia and CASPR2 Antibodies: Electrophysiological Clues to Disease Pathophysiology in the scientific journal Biomolecules. The article focuses on antibodies that target the CASPR2 protein and explores particularly its role in Neuromyotonia, also known as Isaacs’ syndrome, a rare neuromuscular disorder characterised by peripheral nerve hyperexcitability, which leads to continuous and involuntary muscle activity.

The review analyses existing studies to explain how these antibodies interfere with potassium channels in axons, essential structures for maintaining the electrical balance of nerves. These channels act like “valves” that control the inflow and outflow of electrical charges, ensuring that nerve signals are transmitted safely. When antibodies attack CASPR2, these valves become disorganised, and nerves enter a state of hyperexcitability, sending repeated and mistimed signals.

The article also describes the most typical clinical manifestations, such as neuromyotonia (persistent, involuntary muscle contractions that can cause stiffness and fatigue) and myokymia (visible rippling movements under the skin, as if the muscles were “twitching” in small waves). In addition, it discusses these rare diseases' diagnostic challenges, which are often mistaken for other neurological conditions. Not all patients present detectable antibodies in current tests (the so-called seronegative cases), making further research even more necessary.

“This work is important because it helps consolidate current knowledge and identify research gaps, paving the way for faster and more accurate diagnoses and, in the future, more effective treatments”, reflects João Moura.

The review is part of the PhD project that earned the researcher the Nuno Grande Doctoral Scholarship 2023, dedicated to the study of autoimmune encephalitis, that is, inflammatory brain diseases caused by antibodies against neuronal proteins, which can lead to cognitive changes, epileptic seizures, and psychiatric symptoms.