Migraine: A Chronic Sympathetic Nervous System Disorder

Stephen J. Peroutka

Disclosures

Headache. 2004;44(1) 

In This Article

Biochemical

Plasma norepinephrine (NE) levels are one of the most useful biochemical markers of SNS activity since they represent an "online" measure of the activity.[3] Following neuronal release of NE into the synaptic cleft in response to a nerve impulse, approximately 10% of the released NE enters the plasma. Because of this neurotransmitter "spillover," plasma NE levels change rapidly (ie, within seconds) following any activation of the SNS. Any physiological or psychological stress activates the SNS. Thus, one of the classical methods for measuring sympathetic activity is by examining the increase in plasma NE levels that occurs in response to various biological stressors.

In Individuals With Pure Autonomic Failure and Multiple System Atrophy. Supine plasma NE levels in individuals with PAF are significantly decreased.[1] In multiple studies, they have been reported to be approximately 30% of levels in controls.[3,6] By contrast, supine plasma NE levels in individuals with MSA are generally within normal limits or slightly elevated.[3,4,6] These observations are consistent with the fact that PAF is a disorder of primarily peripheral postganglionic sympathetic neurons, whereas MSA is a disorder involving degeneration of preganglionic sympathetic (as well as other) neurons.

In Migraineurs During Headache-Free Periods. Multiple independent studies have analyzed supine plasma NE levels in migraineurs during headache-free periods. In a study of SNS function in patients with migraine during the headache-free period, supine plasma NE levels were significantly lower (51% to 53%) than in controls.[7] These lower levels have been confirmed by many other independent investigators.[8,9,10,11,12] The results of these studies are summarized in Table 1 .

Overall, these 5 published reports of supine plasma NE levels in migraineurs demonstrate lower plasma NE levels than in controls, ranging from 41% to 91% of the matched control values. This proportion of studies reporting lower supine serum plasma NE levels amongst the various studies (ie, 10 of 10 patient subgroups studied) is significantly greater than would be expected by chance alone (P< .002, sign test).

A weighted average of supine plasma NE levels from all of the subjects studied in the 5 published reports was calculated. One hundred thirteen migraineurs were analyzed (approximately half with aura and half without aura). On average, the supine plasma NE levels in migraineurs have been reported to be 61% of the values obtained in matched controls in this group of 5 studies. These data strongly suggest that migraineurs have significantly lower supine plasma NE levels than nonmigraineurs, although larger prospective studies are needed to more accurately determine the average supine plasma NE levels in migraineurs.

In controls, arising quickly from a supine position leads to a significant increase in plasma NE levels. This significant increase (ie, approximately 50% above the baseline value within the first few minutes) can be induced by standing or by using a tilt table.[3,4]

In Patients With Pure Autonomic Failure and Multiple System Atrophy. Plasma NE levels in patients with PAF rise minimally with postural changes, resulting in significant clinical symptoms since supine plasma NE levels are already significantly decreased.[3,4] Plasma NE levels in patients with MSA also rise minimally with postural changes, although these patients have relatively normal supine plasma NE levels.[3,4]

In Migraineurs During the Headache-Free Period. A third pattern in plasma NE level changes is observed in migraineurs following a postural change. Arising from a supine to standing or head-up tilt position induces a rapid increase in plasma NE levels in both migraineurs and controls. The proportional increase from the supine to standing position is essentially the same as in control groups (ie, approximately 50% above the baseline values). Since migraineurs in the headache-free period have lower supine plasma NE levels, however, their upright levels remain significantly lower compared to control groups after 3 to 30 minutes of standing or head-up tilt.[7,8,9]

Overall, the 3 published reports of plasma NE levels following an orthostatic change in headache-free migraineurs versus controls demonstrate lower upright plasma NE levels in 9 of the 9 patient subgroups studied. The levels in migraineurs ranged from 46% to 74% of the matched control values ( Table 1 ). This proportion of studies showing lower serum plasma NE levels following an orthostatic change is significantly greater than would be expected by chance alone (P< .004, sign test).

A weighted average of plasma NE levels after an orthostatic change from all of the subjects studied in the 3 publications was calculated. One hundred three migraineurs were studied (approximately half with aura and half without aura). On average, the plasma NE levels following an orthostatic change in migraineurs were 59% of the values obtained in matched controls in these studies. Thus, the observed increase in migraineurs parallels the increase seen in control groups, but remains significantly lower (ie, the plasma NE levels in migraineurs are approximately 60% of the controls' levels in both the supine and upright positions).

A schematic summary of the plasma NE levels reported in controls and patients with PAF, migraine, and MSA is provided in the Figure. Migraineurs are similar to patients with PAF in that both groups have lower supine plasma NE levels than controls, with the decrease being more significant in those with PAF. By contrast, supine plasma NE levels in patients with MSA are near normal. Patients with PAF and MSA are similar in that they fail to increase their plasma NE levels following an orthostatic postural change. By contrast, headache-free migraineurs do have a postural increase, but not to the levels achieved in controls. Thus, plasma NE levels provide an objective assessment of the specific type of SNS dysfunction in these 3 disorders and demonstrate both the similarities and differences between the 3 syndromes.

Figure 1.

Schematic summary of plasma norepinephrine levels. MSA indicates multiple system atrophy; PAF, pure autonomic function.

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