motions. The amygdala and prefrontal cortex are brain regions that regulate emotional responses and connect with the paralysis pathways in the brainstem. Neurons in the amygdala and prefrontal cortex are active during cataplexy, and inactivating either of these regions markedly reduces cataplexy in mice with narcolepsy. As these triggering pathways become better understood, it may be possible to target them with new medications.
Understanding how narcolepsy develops
Over the past several years, researchers have made good progress in understanding the process that kills the orexin neurons.
Genetic factors clearly play a role. Most people with narcolepsy have inherited a gene that codes for the human leukocyte antigen (HLA) DQB1*06:02, which is important for immune function. This gene is found in 12–25% of the general population, and it increases the risk of developing narcolepsy 7- to 25-fold.3 Additional genes can increase or decrease the risk of developing narcolepsy, and, like HLA-DQB1*06:02, most of these affect the functions of the immune system. Normally, the immune system kills off bacteria and viruses. These discoveries suggest that narcolepsy is an autoimmune disease in which the immune system accidentally kills off the orexin-producing neurons.
Dr. Thomas Scammell discusses the role of a gene that appears to be important in the development of narcolepsy with cataplexy.
Researchers are now beginning to identify some of the triggers for this autoimmune attack on the orexin neurons. Just after the onset of narcolepsy, people tend to have increased levels of antibodies against streptococcus, the bacteria that causes strep throat and other infections.4 In addition, narcolepsy most commonly begins in the late spring and early summer, suggesting that an autoimmune attack on the orexin neurons may be triggered by strep or another winter infection.5
The most compelling evidence that an immune process can kill the orexin neurons comes from an event that triggered an increase in narcolepsy in Scandinavia and some other parts of Northern Europe. In the winter of 2010–2011, governments and the general public were very concerned about a severe form of influenza, known as H1N1, spreading around the globe. In many countries, most of the population received vaccination against this flu, and Finland and some other northern European countries chose to use a very potent brand of H1N1 vaccine known as Pandemrix. One to two months after receiving this brand of vaccine, dozens of children developed narcolepsy, and overall, the rate of new cases of narcolepsy in children increased 8- to 12-fold.6, 7 Importantly, all of these children who developed narcolepsy carried the gene HLA-DQB1*06:02. Only a few adults appeared to develop narcolepsy in connection with this vaccine.8 (Pandemrix, which is no longer in use anywhere, was never licensed for use in the United States.)
In the last few years, several research labs have found that adults and children with narcolepsy may have T cells, a type of immune system cell, that selectively target the orexin peptides.21-24 These T cells may directly kill the orexin neurons, or more likely, they trigger other immune cells to damage and kill the orexin neurons.
Thus, it appears that three factors are important for the development of narcolepsy:
Genes that influence the immune system, such as HLA-DQB1*06:02
A triggering factor that activates the immune system, such as infection with strep
A vulnerable age during which the immune response or some characteristics of the brain make an autoimmune attack on the orexin neurons more likely
By gaining a better understanding of this process, researchers hope to develop medications that can stop narcolepsy just as it begins and prevent further injury to the orexin neurons.
What are the practical implications of these discoveries? First, it is important to recognize that the hereditary aspects of narcolepsy are a relatively small concern. If a parent has narcolepsy, there is only about a 1% chance that her or his child will have the disorder. Up to 25% of the pop