Headaches Flashcards
Headaches are a common symptom experienced by 90% of individuals living in developed countries. Headaches are the presenting complaint for 2% of all primary care office visits and 3% of ED visits in the US.
Average age for all patients presenting with headache is 37 years with a female to male ratio of 3:1. The estimated annual medical cost for the diagnosis and treatment of headache in the US is $15 billion.
Headaches may be categorized by one or more classification systems. The two most useful include:
the International Headache Society Classification into primary and secondary headaches. The distinguishing feature between the primary and secondary classification is the absence or presence of an underlying structural or metabolic cause for the headache.
A more practical classification exploits the temporal mode of onset and progression for symptoms and signs. Headaches with acute onset and rapid progression versus those with more gradual onset and progression.
What are the main causes of primary HAs?
ØMigraine
Ø Cluster
Ø Tension (Episodic & Chronic)
Ø Miscellaneous
What are the main causes of secondary HAs?
ØBrain tumor
Ø Meningitis/Encephalitis
Ø Idiopathic intracranial hypertension (Pseudotumor cerebri)
Ø Subarachnoid hemorrhage
Ø Giant cell (temporal) arteritis
Ø Cerebral vein thrombosis
Ø Post-traumatic headache
Ø Others
This slide presents a PARTIAL LIST of headaches that typically have an acute onset
This slide presents a PARTIAL LIST of headaches that typically have a subacute onset. Note that the more common Primary Headaches fall into this category.
What is the pathophysiology of headache?
All headaches share a final common pathway producing head pain that results in inflammation or physical traction of pain sensitive structures within or around the cranial vault.
Recall that the brain parenchyma has no pain sensitive receptors and thus is insensitive to pain. However, recognize that mechanical or electrical stimulation of the thalamus or the descending nucleus of V in the brainstem will trigger a pain response.
Most of the pain sensitive structures, that is those with pain receptors, are located where?
in the dura/meninges and large/medium-sized arteries that lie at the base of the brain.
The venous sinuses and skull periosteum are other intracranial pain sensitive structures.
Many extracranial structures including the skin, nasal sinuses, teeth, eyes, cranial and cervical muscles all contain pain receptors.
Stimulation of cranial pain receptors is transmitted centrally largely through:
CN V, IX, and cervical roots C2-3. CNs VII and X contribute but less so.
What innervates most pain sensitive structures above and including the tentorium as well as extracranial structures above the eyes?
the ophthalmic branch of the trigeminal nerve
CN IX, X, not shown in this figure, and cervical roots C2-3 innervate pain sensitive structures where?
of the posterior fossa, the posterior scalp and neck.
The first synapse for these pain pathways are in the descending nucleus of V, usually called the trigeminal nucleus caudalis in the headache literature, and in the dorsal horn of the upper cervical spinal cord with which it is contiguous.
Recall that the substantia gelatinosa and tract of Lissauer merge with the descending nucleus of V and its descending tract of V to produce one continuous system. The nucleus sends nerve fibers across the midline to form the trigeminothalamic tract to synapse in the VPM nucleus of the thalamus as part of the Lateral Pain System.
Pain signals are then relayed on to the sensory cortex and other cortical sensory systems. The trigeminal nucleus caudalis also send collaterals to the autonomic nuclei in the brainstem and to the hypothalamus to inform the Medial Pain System.
Polysynaptic connections between the trigeminal nucleus caudalis and the superior salivatory nucleus are believed to be responsible for ipsilateral autonomic changes that can accompany certain headaches, including red eye, tearing and rhinorrhea.
The trigeminal nucleus caudalis can be considered THE structure for anatomic and physiologic convergence of pain sensations. Hence pain from the face may be referred to the neck and vice versa, especially when the ophthalmic branch of CN V or V1 is involved.
The ipsilateral greater occipital nerve, carrying C2 sensory input, is often tender in an attack of migraine or cluster headache. Anesthetizing the nerve locally can sometimes terminate the attack. It is less clear if it is the blockade of specific sensory input that improves headache or a more generic reduction of overall input to the trigeminal nucleus caudalis that improves the headache. Numbing up other large areas of the head can also have a similar beneficial effect.
Most headaches have no serious underlying structural or metabolic cause (i.e. primary). However, the physician must consider that there may be a serious etiology when the patient tells you “Doctor, I have a bad headache.”
This slide lists some of the more prominent RED FLAGS that may signal an underlying secondary etiology for the headache.
What are migraines?
Chronic neurological disorder causing recurrent headaches with some or all of the following features:
§ Frequently unilateral, may be bilateral or switch sides
§ Pulsating
§ Moderate to severe intensity
§ Duration of 4 – 72 hours
§ Nausea with or without vomiting
§ Photophobia and/or phonophobia
§ May be preceded by a prodromal phase
§ May be preceded by an aura in ~ 20% migraineurs
§ “Triggers” or precipitating factors are frequent
§ Frequent family history
Migraine is more than just head pain. Migraine is a process that can start long before head pain begins. The process of headache is generally believed to come in phases: describe them.
pre-headache, that is prodrome and aura, headache, and post-headache.
The migraine process can begin at any phase, and not all phases present themselves in every migraine attack. The process of migraine can also stop at any phase. Sometimes, migraineurs experience an aura but the headache never develops. This is relatively common with visual aura in the older population. The variability inherent in the migraine process and symptoms makes multiple migraine treatment options very important.
How common is migraine prodrome?
The migraine prodrome is not experienced by all migraineurs, but in those who recognize these early symptoms, they are helpful in providing a warning of an impending headache and that allows the patient to take preemptive measures to abort the headache.
How might migraine prodrome present?
• It is a vague constellation of symptoms that may include:
§ mood swings (depression, anxiety, irritability)
§ odd food cravings
§ malaise or vague feeling of un-wellness
§ fatigue
§ muscle aches and stiffness
The migraine aura, like the prodrome, is not experienced by all migraineurs. In fact only 20% of migraineurs have clearly defined auras.
While you may be familiar with the visual migraine aura, auras may present in a variety of ways, all of which depend upon what part of the brain is being affected by a wave of “cortical spreading depression” causing these symptoms.
Auras may present, for example, as transient sensory symptoms, as transient limb weakness, or as transient aphasia.
Auras can mimic the symptoms of transient ischemic attacks (TIAs) and at the outset, they often provoke a workup and treatment as if they were TIAs.
More typically, a migraine aura affects the occipital (visual) cortex and causes a spreading zigzag line to migrate across the visual field that is then replaced by an scotoma, that is, a transient absence or hole in vision. The zigzag lines are called what?
“fortification spectra” named after medieval forts that had zigzagging walls around them. The figures below presents artistic renditions of visual auras. Note the small round white spots (scotomas) in the left hand figure.
Be aware however that scotomas more often than not, do not involve white or black spots, but an absence of vision. What is that like?
Think about the blind spot in your field of vision due to the optic nerve’s entry into the retina. You probably didn’t even know you had such a spot. By the way, if you want to detect your own blind spot, take a red match, white cotton tipped applicator or even a pencil with an eraser end, look straight ahead and move the match at arms length horizontally about 15 degrees lateral of the midline for the eye being tested. Explore this area with small movements of the match, and at some point, you will see it disappear and reappear. Once gone, move the match up and down and in other directions to map out the extent of your blind spot. It is a rather amazing phenomenon the first time you recognize your eye has a hole in its field of vision.
Many migraineurs recognize specific circumstances such as missing a meal, inadequate or too much sleep, red wines, certain nuts, chocolates, other foods, and smells, and so on, that can ‘trigger’ a migraine attack. This and the next two slides present some of these triggers in a graphic manner.
A frequent trigger that fits under the diet heading is monosodium glutamate. MSG is present as a taste enhancer in many foods, especially some Chinese dishes leading to the term “Chinese Headache”.
Emotional swings may trigger a migraine.
How common are migraines?
Migraine affects a huge proportion of the population with women being affected 2-3 times more frequently than men. Migraine carries a strong family history and its inheritance is thought to be polygenic. One rare form of migraine, Familial Hemiplegic Migraine, is caused by dominantly inherited genetic abnormalities at several different loci.
The anatomical substrate for all migraine and many other causes of headache is:
the Trigeminovascular System involving CN V1 innervation of pain receptors located in the dura, meninges, and medium/large cerebral arteries and veins that lie on the surface of the brain and above the tentorium.
This slide demonstrates the extracranial innervation of the trigeminal nerve and the C2, C3 nerve roots.
This slide is a refresher for the pain sensitive pathways responsible for transmission of head pain
This slide highlights CN VII and the parasympathetic innervation of the Superior salivatory nucleus. Vasodilation and other parasympathetic symptoms associated with migraine reflect central connections between pain pathways from CN V and the superior salivatory nucleus.
This slide presents several other brainstem nuclei important in the pathogenesis of migraine including the magnus raphe, locus ceruleus, and dorsal raphe nuclei. These latter nuclei are FYI and will not be discussed further. However, this slide more clearly depicts the important connection between the trigeminal nucleus caudalis (shown in orange with the yellow afferent pathway) and the superior salivatory nucleus (green with the green efferent pathway to blood vessels). The afferent/efferent system comprises the trigeminovascular system that is responsible for mediating the vascular changes associated with migraine.
Migraine pathogenesis is complex and incompletely understood. Current evidence supports a polygenic predisposition that hypersensitizes both the peripheral, that is the trigeminovascular system, and central pain pathways including the trigeminal nucleus caudalis, thalamus, hypothalamus, limbic system and so on.
In the setting of hypersensitized pain pathways, migraine attacks may be triggered by either a so-called “Central Generator” located in the brainstem or by external triggers shown on prior slides.
The trigger initiates an aura that stimulates neurogenic inflammation of the meningeal vasculature that then further excites already hypersensitive peripheral and central pain pathways. In most migraineurs, who do not experience an aura, the Central Generator or the external trigger directly activates neurogenic inflammation
This slide addresses the current thinking on the pathogenesis of aura that accompanies migraine in approximately 20% of migraineurs.
The clinical manifestation of the aura depends on which anatomical part of the brain experiences the aura.
The most common aura involves visual scintillations followed by scotomata. These arise in the visual cortex and are triggered either remotely from a central brain stem generator or locally by a variety of internal or external stimuli.
The artist’s rendition of this visual aura begins in the upper left figure (a) and proceeds temporally through figures (b, c, and d).
Note the migration and increase in size of the jagged, multicolored scintillations as the patient focuses on a clock. Note also the movement of the minute hand of the clock that provides a sense of the time course of spread of the aura over a period of 5 to 6 minutes. These bright, multicolored scintillations represent excitation of the calcarine cortex as the initial or advancing front of a ‘cortical spreading depression’ wave. This wave moves across the cortex at a speed of 2 – 5 mm per minute. While aura are often restricted to one hemifield, here both visual fields are affected.
The wave of depolarization is mediated by what?
A glial syncytium whose membrane is depolarized by calcium influx, and in its wake, the neurons embedded in this altered environment also become depolarized, and it is their malfunction that produces the symptoms of aura.
This is an FYI slide presenting a Functional MRI in a patient experiencing a typical, visual migraine aura.
Simply speaking F-MRI BOLD imaging provides a real-time, that is second to second, imaging of the local circulating hemoglobin oxygen saturation-desaturation state. BOLD images reflect local tissue cerebral blood flow and metabolism.
In the upper left (labelled A) is a representation of the visual aura reported by the patient. The aura began as a small, circular area of scintillation and spread with time outward in a crescent shape (the thin red arrow shows the direction of spread). The lower left figure (C) presents the left visual hemifield in three colours and the representation of the field in the right calcarine/parietal cortex. The central figure (B) presents the patients right hemisphere with coloured arrows pointing to the points of BOLD measurements which are shown graphically on the right. Measurements of BOLD intensity are taken simultaneously at all eight points along the calcarine cortex.
The red squiggly line in each graph presents the actual BOLD values; the small up-down variations reflect the normal noise in the BOLD measurement. Note that the aura and spreading depression wave began at the tip of the calcarine cortex (lowest graph). The average BOLD value increases (fat green arrow) reflecting increased metabolism and neuronal excitation. This corresponds clinically to the scintillations experienced by the patient. Within a minute, the average BOLD value declines (fat orange arrow) indicating the depolarized period of the spreading depression that correlates with the patient’s experience of a hole (scotoma) in his visual field.
Note how this spreading depression wave is moving across the visual cortex as shown by the activation (fat green arrow) and depolarization (fat orange arrow) seen in the sixth graph up from the bottom.
This slide highlights two important neurotransmitter chemicals in pain generation, CGRP and Substance P.
The concept that sensory fibers could act in an efferent capacity involving these neurotransmitter substances was shown but not especially emphasized.
It turns out that these same two neurotransmitters, CGRP and substance P, are important in the pathogenesis of neurogenic inflammation and pain underlying migraine.
We will now point out that sensory systems, in this case the trigeminal ganglion neurons, function as both an afferent system receiving signals and as an efferent system sending action potentials to the sensory nerve terminals where a variety of neurotransmitter chemicals may be released.
The figure presents a human brain with the trigeminovascular relationship highlighted. Note activation of the trigeminal ganglion cells can cause the release of CGRP and Substance P onto dural and meningeal blood vessels. Both CGRP and Substance P have potent vasodilator properties among other functions. Both neurotransmitters are importantly involved, especially CGRP, in the pathogenesis of migraine headaches.
CGRP plays a key role in mediating neurogenic inflammation and pain in migraine.
The actual sequence of events implied in this slide, however, may or may not be the typical sequence of events in a migraine attack.
The figure of a brain on the left depicts a cortical spreading depression or CSD stimulating a ‘brain stem generator’ to activate the trigeminal ganglion that in turn sends an efferent signal to a nerve terminal on a meningeal artery.
The top right figure is a blow up of this terminal and shows CGRP as small green circles being released and activating calcitonin-like receptors or CLR to relax vascular smooth muscle (vasodilate) and to cause degranulation of mast cells. The mast cell contents mediate the local inflammatory reaction. This entire process may sensitize this synaptic terminal to become hypersensitive and thereby fire off an antidromic, afferent signal back through the trigeminal nerve to the brain stem.
Note that in the lower right figure, the synaptic juncture between the trigeminal nerve and the central brain stem neuron is also partially mediated via the neurotransmitter CGRP. Thus the initial hypersensitizing signal and a secondary pain signal are both brought about by CGRP. Additional evidence that CGRP is an important mediator of migraine headache is that 1) CGRP given intravenously will trigger migraine headaches, and 2) the group of triptan drugs that are used to treat migraine block the release of CGRP from trigeminal nerve terminals.
This is a FYI slide to present a simplified picture of the important phenomenon of peripheral and central sensitization in many pain syndromes and in migraine headache. The slide shows that the chronic or repetitive activation of peripheral pain receptors causes the release of glutamate and other transmitter peptides in the brain which sensitize these CNS neurons to fire an antidromic volley back down the trigeminal nerve that further sensitizes the peripheral receptors. This self-propagating back and forth process leads to the sensitization of both peripheral and central pain pathways.
This slide shows the 5HT1 receptors on dural arteries, and on peripheral and central trigeminal nerve terminals.
Note that the 5HT1B receptor is present on vascular terminals, the 5HT1D receptor on peripheral trigeminal nerves, and the combination of 5HT1B,D,F receptors on the central synapse of the trigeminal nerve.
The triptans are 5HT1 agonists and through this receptor activation they inhibit the release of CGRP. Note that the triptans may function at several sites in treating migraine headaches.
Note the multiple points in migraine pain where CGRP release may be involved.
Inset 1 depicts the nerve terminal release of CGRP at a dural artery. Inset 2 shows CGRP release near a mast cell, and inset 3 shows CGRP acting as a neurotransmitter at a central trigeminal nerve synapse.
These three points present targets for a new class of compounds, called Gepants, that act as CGRP antagonists and block CLR receptors. They are currently undergoing Phase 3 clinical trials.
This slide attempts to summarize some of the more important features that help distinguish one primary headache subtype from another.
So with migraine, the head pain is throbbing, often unilateral, with nausea, photophobia, phonophobia and a desire to find a quiet dark room to fall asleep. The headache lasts 4 hours to 3 days when untreated. Most migraineurs experience one or more headaches per month.
A tension headache often begins after awakening and worsens as the day wears on. There is a sense of pressure or tightness, sometimes described as a band around the head, that involves both sides of the head and lasts several minutes to several days. The headaches are mild to moderate in intensity and occur several times a month.
A cluster headache is side-locked with respect to signs and symptoms. The pain is excruciating and localized to the eye, sometimes inside, sometimes behind and sometimes around the eye. It can be associated with facial flushing, tearing, red eye, swelling of the eyelid, nasal congestion and runny nose. It usually lasts 15 minutes to 3 hours but can be shorter or longer. It recurs several times per month, sometimes 8 times in the same day, with a repetitive and predictable frequency. Episodes usually subside after a 3 month period or so, and then may not return for months or years.
The hallmark of idiopathic intracranial hypertension is raised CSF pressure. What does this cause?
The pressure distorts the pain sensitive intracranial structures to cause headache and stretches the abducens nerve over the petrous pyramid to produce incomplete paresis of the nerve to cause horizontal diplopia. Elevated CSF pressure most famously produces papilledema, as shown in this slide.
How does the swelling of the optic disc occur with IIH?
The dura is contiguous with the optic nerve sheath which encloses a CSF space that extends along the optic nerve all the way to the eye.
Hence elevated CSF pressures are transmitted to the optic nerve head to cause a damming up of axonal transport from the retinal ganglion cells, as well as focal edema, to produce what you see in the figure, papilledema.
The ordinarily sharp disc margin is indistinct and the blood vessels have been buried by the swollen axons.
Papilledema is a cardinal sign of pseudotumor, and note that the swelling will impair retinal ganglion function surrounding the optic disc, hence producing an enlargement of the blind spot. Importantly, peripheral vision becomes constricted.
Visual perimetry is best quantified with automated computerized equipment in the Ophthalmology department. It can be crudely tested at the bedside by asking the patient to detect wiggling fingers in the peripheral visual fields. You should realize that once visual acuity starts to fall, blindness can occur rapidly within days or even hours.
There are many medical conditions and drugs that have been associated with pseudotumor cerebri as shown in this slide.
Importantly, cerebral venous thrombosis in its chronic phase produces intracranial venous hypertension and this can be indistinguishable from pseudotumor.
When the jugular vein is sacrificed in extensive tumor surgery of the head and neck, pseudotumor symptoms occasionally appear if the sacrificed jugular vein drained the dominant transverse sinus, again producing intracranial venous hypertension.
One important new understanding of the pathophysiology involved in idiopathic intracranial hypertension is that it may well be a two-step process. Describe this.
This first part is idiopathic, or involves one of the disorders mentioned above. It triggers the initial rise in CSF pressure via mechanisms that remain mysterious.
Once the CSF pressure reaches a critical level, however, it exerts pressure on the thin walled lateral sinuses and secondarily compresses them. Venous outflow is now compromised and intracranial venous hypertension results. This causes the CSF pressure to go up through the roof.
What is so dangerous about GCA?
It can cause blindness, first in one eye and then in the other.
There are monocular obscurations that rapidly lead to blindness due to occlusion of the ophthalmic artery. Stroke can occur as well particularly with occlusion of the vertebral artery just before its entry into the cranial vault. Although the granulomatous changes affect arteries outside the cranial vault, thrombosis in this diseased arteries can propagate and/or embolize to involve distal intracranial arteries.
How is GCA tx?
Treatment can and should precede the biopsy. Treatment is with corticosteroids. Importantly, treatment will not affect the histopathology for several days so the biopsy does not have be immediately done.
