Migraine: A Chronic Sympathetic Nervous System Disorder

Stephen J. Peroutka


Headache. 2004;44(1) 

In This Article

Pupillary Control

The study of pupil diameter is a simple, useful, and noninvasive approach to analysis of the autonomic nervous system (ANS). Pupil size is under the direct and tonic control of the ANS and can be easily monitored under a variety of conditions. The parasympathetic nervous system mediates pupillary contraction via the short ciliary nerves that arise in the ciliary ganglion, where they synapse with cholinergic nerve fibers in the third cranial nerve. The parasympathetic ability to contract the pupillary sphincter muscles in response to light can be mimicked by exogenous cholinergic agonists such as pilocarpine. Adie syndrome represents the most commonly observed result of parasympathetic deficits.

By contrast, darkness or stimulation of sympathetic fibers to the eyes (as a result of arousal) causes mydriasis via contraction of the dilator pupillae muscle and vasoconstriction of the conjunctival vessels. The sympathetic neurons to the eye arise in the superior cervical sympathetic ganglion (SCSG). Bernard was among the first to note that destruction of the SCSG results in ptosis, miosis, and anhidrosis (ie, Horner syndrome). The effect of an SCSG lesion on pupil diameter confirms that the dilator muscles of the pupil are normally held in a state of partial contraction by the tonically active sympathetic fibers arising in the SCSG. The sympathetic fibers to the pupil join the ophthalmic branch of the trigeminal nerve and enter the orbit via the superior orbital fissure. These fibers release NE onto the dilator pupillae, causing contraction of the muscle and resulting in pupillary dilatation.

Milder forms of sympathetic dysfunction than a Horner syndrome can be identified in the eye using various pharmacological agents. The modulation of pupil size via pharmacological agents is a simple, sensitive, and noninvasive measure of peripheral SNS function. For example, the pupil dilates after the topical application of drugs that directly (eg, norepinephrine or phenylephrine) or indirectly (eg, fenfluramine, tyramine, cocaine) stimulate postsynaptic α 1 receptors located on the iris dilator muscles.

Pupillary Function in Individuals With Pure Autonomic Failure and Multiple System Atrophy. In individuals with PAF, a bilateral Horner syndrome is usually present.[24,25] The pupils of patients with PAF have been shown to dilate in response to extremely low doses of phenylephrine (ie, 0.5%) indicating a high degree of adrenergic receptor supersensitivity.[26] By contrast, in patients with MSA, the pupils are often completely normal, with normal responses to light.[25]

Pupillary Function in Migraineurs During the Headache-Free Period. A baseline mild Horner syndrome, clearly indicating a sympathetic deficiency, has been reported to exist in 5% to 20% of migraineurs.[27,28] A milder subclinical form of sympathetic dysfunction in the pupil has been documented in the majority of migraineurs using pharmacological agents that modulate pupil size.

The pupils of migraineurs are more sensitive than those of controls in the response to pharmacological agents that directly stimulate α-adrenergic receptors. For example, the pupils of headache-free migraineurs dilate after the topical application of 1% phenylephrine, whereas this low concentration of phenylephrine has no effect, or only a minor effect, on pupil diameter in controls.[29,30] A similar increased pupillary sensitivity to phenylephrine was seen in some, but not all, migraineurs obtained from a community sample.[28] Pupil dilatation after 1.25% epinephrine eyedrops is also significantly greater in migraineurs during the headache-free period than in controls.[7] These data indicate that the pupils of migraineurs display a sympathetic hypofunction.

Fenfluramine is a drug that releases NE stores from sympathetic nerve terminals, and thereby indirectly stimulates α-adrenergic receptors. Its mydriatic effect is therefore dependent on the presence of intact stores of neuronal NE in the iris. In contrast to the direct-acting α-adrenergic phenylephrine, the pupils of migraineurs dilate minimally compared to the pupils of controls in response to an oral dose of fenfluramine.[29] A single oral dose of fenfluramine (40 mg) caused a lesser and shorter duration mydriatic effect in migraineurs. Pupillary diameter was significantly greater in the control group at 4, 6, and 8 hours after fenfluramine.[29] These data indicate that migraineurs have smaller neuronal NE stores.

Guanethidine is a drug that depletes sympathetic NE stores by globally disrupting sympathetic terminal neuronal function. Topical application of 5% guanethidine causes a more intense and longer-lasting miosis in migraineurs than in controls, once again suggesting a relative deficiency of sympathetic terminal NE levels in migraineurs.[29] Moreover, the early mydriatic effect of guanethidine in controls was not observed in migraineurs. These data suggest that the process of intraneuronal NE resynthesis is defective in migraineurs since the guanethidine-induced miosis disappears more slowly than in controls.[30]

Cocaine, which blocks the re-uptake of NE, enhances or uncovers an anisocoria in 90% of migraineurs (both headache-free periods and mild attacks were studied) versus only 17% of controls.[27]

Taken together, these studies are consistent with a deficiency of sympathetic terminal NE stores within the pupil and a secondary postsynaptic hypersensitivity of adrenergic receptors in migraineurs.[29]


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