Overview of Headaches

Physicians treating patients for headache must decide whether the headache represents a primary or secondary headache syndrome. Primary headaches are most common and include disorders such as migraine, tension-type headache, and trigeminal autonomic cephalalgias. The patient with primary headaches may have severe and incapacitating pain, but there is no identifiable cause leading to activation of nociception. In contrast, secondary headaches are symptomatic of a cranial or extracranial pathology, such as a brain tumor, ruptured aneurysm, meningitis, or hematoma. Headache diagnosis depends on a thorough history and neurologic and medical examinations. The history should seek information on premonitory symptoms, timing of onset (gradual vs. sudden) and duration, pain quality, and severity, location of pain, provoking factors, any associated symptoms, clinical circumstances, and details of previous investigations and treatments. A past medical history, family history, trauma history, social history, current medications, drug allergies, and review of systems are also indispensable. If a new headache is unlike any headache the patient has had in the past, it requires very expeditious evaluation, which may include ancillary laboratory and neuroradiologic imaging.

Secondary headaches, and possibly primary headaches, are thought to occur when primary afferent nociceptive neurons arising from either the trigeminal ganglion or upper cervical spinal ganglia (C1-3) are depolarized. These neurons innervate both extracranial and intracranial pain-sensitive structures. The first and second trigeminal nerve divisions provide sensory innervation for the anterior head and upper face. The trigeminal nerve innervates pain-sensitive dural structures, including the dural sinuses and tentorium cerebelli as well as many arteries, including the middle meningeal, temporal, proximal portions of the anterior and posterior cerebrals, and the internal/external carotid. The cervical spinal nerves (C1-3) provide innervation to the dural structures of the posterior fossa, the basilar and vertebral arteries, and to muscular structures in the upper neck and posterior portion of the head.

The cause of prolonged head pain is usually apparent when a secondary headache develops related to a tumor or other intracranial lesion producing ongoing traction upon a dural or vascular structure. However, patients with a primary headache disorder do not have a clearly discernible source for ongoing activation of nociceptive neurons. Therefore pathophysiologic mechanisms leading to a persistent primary headache are less clear. It is likely that the neurons within the trigeminal-cervical pain system are more than passive conduits for depolarization; however, because they also seem to play a role in pain sensitization. Sensitization is a process where, after repeated activation, neurons become increasingly responsive to painful and nonpainful stimulation. Peripheral sensitization (in the primary afferent neurons) and central sensitization (within second-order neurons in the trigeminal nucleus caudalis and higher-order neurons within the central nervous system [CNS]) may play a role in prolonging headaches and may contribute to the transformation of episodic migraine to the chronic form of migraine.

The evidence of peripheral sensitization of the primary afferents comes from both animal and human studies. In animal models, stimulation of the trigeminal system leads to increased concentrations of the vasoactive peptides, including substance P (SP), neurokinin A (NKA), and calcitonin gene–related protein (CGRP) in sagittal sinus blood. Similarly in humans, internal jugular CGRP levels reportedly rise during migraine attacks. Release of these neuropeptides is a marker for neuronal activation in primary afferents. Primary afferent neurons exposed to activating stimuli show increased spontaneous firing and lowered activation thresholds.

There is also evidence that initial activation of the primary afferent neurons leads to sensitization of second and possibly higher-order neurons. Chemical irritation of the meninges in animal models (peripheral nociceptors) causes sensitization of both trigeminovascular fibers innervating dura and central trigeminal neurons receiving convergent input from dura mater and skin. After sensitizing activation of the meninges, central trigeminal neurons respond to low-intensity mechanical and thermal stimuli from skin that previously induced minimal or no response. This change in activation threshold for central neurons receiving input from skin (which was not directly irritated) strongly implicates sensitization of second-order neurons within the central nervous system.

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