less is known about the cause of narcolepsy without cataplexy. Most likely, it is caused by less severe injury to the orexin neurons, resulting in fewer and less severe symptoms. (See Key discoveries below for more on some of the studies that have shed light on the role of orexins in narcolepsy.)
How orexin loss affects the brain
In addition to revealing the normal role of orexin neurons in the brain, research has provided many insights into how a loss of orexin signaling causes sleepiness and cataplexy.
Many researchers theorize that the sleepiness of narcolepsy is a consequence of “sleep state instability,” a condition in which the thresholds between wake and sleep are easily crossed, resulting in both fragmented wakefulness during the daytime and fragmented sleep at night.
During normal wakefulness, orexin neurons send signals that produce long-lasting increases in the activity of many other neurons essential for sustaining alertness and wakefulness. These neurons include those that produce key neurotransmitters such as norepinephrine, serotonin, and dopamine. In narcolepsy, the loss of orexins may result in reduced or inconsistent activity in these target neurons. As a consequence, people with narcolepsy can be fully alert at times, but have great difficulty sustaining this alertness for long periods of time.
Cataplexy and sleep paralysis are unusual states in which the brain circuits that produce paralysis during REM sleep become active during wakefulness. During REM sleep, most muscles are paralyzed by circuits in the lower brainstem and spinal cord. These paralysis circuits are normally blocked by norepinephrine and serotonin during wakefulness. With loss of orexins, levels of these two neurotransmitters may be lower, permitting paralysis to occur even during wakefulness. This observation provides the main rationale for treating cataplexy with antidepressants that increase brain levels of norepinephrine and serotonin.
Ongoing research is also beginning to reveal how cataplexy may be triggered by positive emotions. 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 o