Neuropathology I: Headache disorders

Question 1

Primary headache:

Answer 1

associated features are the disorder itself

Question 2

Secondary headache:

Answer 2

caused by an exogenous disorder

-additional clinical features and pathology beyond the headache

Question 3

Epidemiology of primary headache:

Answer 3

second most common cause of primary headache, affects 15% of women and 6% of men over a one-year period.

Acceptable definition: benign recurring headache that is associated with particular additional neurologic signs and symptoms:
-typically accompanied by nausea, can also cause vomiting
-often associated with triggers

Question 4

Migraine:

Answer 4

the key pathway for pain in migraine => trigeminovascular input:

From the meningeal vessels => trigeminal ganglion => synapses on second-order neurons in the trigeminocervical complex (TCC) in the brainstem.

-TCC => thalamus => cortex

Important modulation of the trigeminovascular nociceptive (pain) input comes from midbrain nuclei:
-dorsal raphe nucleus, locus coeruleus, and nucleus raphe

Problems with modulation of pain sensation from these trigeminal afferents seems to be the cause:
-abnormal pain sensation related to vascular dilation & constriction? (vasomotion)

Question 5

Medications that act on migraine pathway:

Answer 5

5-HT 1 receptors: important in the trigeminal nucleus and the thalamus.

-These receptors bind to serotonin (neurotransmitter) that is released into the synapse

-Receptors blocked by drugs known as triptans (sumatriptan); usually acute early on as the migraine develops

Question 6

CGRI (calcitonin-gene-related-peptide):

Answer 6

is a peptide neurotransmitter active at the trigeminal ganglion and at the vasoactive efferents

-It’s a vasodilator and seems to increase pain sensation when it is released at these sites.

-Monoclonal antibodies that bind and eliminate CGRP (thus preventing it from binding to its receptors) are effective for headache prevention

Question 7

Other neurological finings for Migraine:

Answer 7

A number of theories were suggested, but best accepted is a neurovascular one:
-primary neural dysfunction: wave of spreading depression (slowly travelling wave of neural excitability) travels through the cortex and leads to activation of the trigeminal complex.

-leads to vascular-generated pain
-Spreading depression wave thought to be linked to other neurological findings (visual changes, other aura findings)
-Called “depression” because after the excitatory wave spreads, that area is often refractory to synaptic excitation or action potentials.
-may also be linked to modulation of nociceptor afferents by locus ceruleus and dorsal raphe nucleus

Question 8

Etiology of migraine:

Answer 8

strong genetic component, but no clear candidate genes for most causes.

-70% have a 1st degree relative with migraine

-Difficulty identifying the genes, though: perhaps VG calcium channels

Question 9

Early signs and symptoms of migraines:

Answer 9

Prodrome: symptoms that typically precede the migraine and the aura:
-can include: sensitivity to light, sound, odors
-Lethargy, fatigue or constant yawning
-food cravings, thirst, polyuria or anorexia
-constipation or diarrhea
-neck discomfort
-mood changes, brain fog

Question 10

Aura:

Answer 10

can occur before or during the migraine (55% have no aura)
-visual field deficits
-tunnel vision
-scotoma: an area of impaired vision w/ a flashing light border
-paresthesia’s
-heaviness of limbs
-confusion, speech/language difficulties

Question 11

Diagnostic criteria of Migraine:

Answer 11

Repeated attacks of headache lasting 4-72 hours in patients with a normal physical examination, no other reasonable cause for the headache, and:
At least two of the following:
-unilateral pain
-throbbing pain
-aggravation by movement
-moderate or severe intensity

Plus at least one of the following:
-photophobia & phonophobia
-nausea and/or vomiting

Question 12

Acephalgic migraine:

Answer 12

Migraine w/o headache:
-so just the aura and the prodrome
-1/3 of patients referred for vertigo or dizziness.

Question 13

Common migraine:

Answer 13

Migraine w/o aura

Question 14

Classic migraine:

Answer 14

A migraine w/ an aura:
-Headache typically follows aura after no more than 60 minutes

Question 15

Complicated migraine:

Answer 15

Has severe or persistent (reversible) sensorimotor deficits:
-diplopia, severe vertigo, ataxia, altered level of consciousness
-Hemiplegia, loss of vision

Question 16

Tension type headache:

Answer 16

Chronic head-pain syndrome characterized by bilateral tight, bandlike discomfort:
-pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for many days
-headache may be episodic or chronic (present >15 days per month)

Question 17

Not a migraine if lacking:

Answer 17

-Nausea, vomiting, photophobia, phonophobia, osmophobia, throbbing and aggravation w/ movement

-However, one or a couple of these may be present to a minor degree and still be TH

Question 18

Tension headache pathophysiology:

Answer 18

Increased muscle tension:
-no difference in muscle “tension” between those w/ migraine and those w/ tension headache

Likely due to increased sensitivity to myofascial pain:
-chronic forms may be due to dysregulation of pain sensation in the central nervous system

No clear pathophysiology yet: much work to be done

Question 19

Symptoms of tension headache:

Answer 19

tension-type headaches are more variable in duration, more constant in quality, and less severe:
-most headaches that significantly impair function are migraines
-Pressing or tightening (nonpulsatile quality)
-frontal-occipital location
-Bilateral- mild/moderate intensity
-Not aggravated by physical activity (though physical activity during a tension headache isn’t really fun, doesn’t significantly make the headache that much worse)

Question 20

Diagnostic criteria of tension headache:

Answer 20

At least 10 different headaches

Duration of 30 min to 7 days

2 of the following characteristics must be present:
-Pressing or tightening (non-pulsating) quality
-Mild-moderate in severity (inhibits but does not prevent activity)
-Bilateral
-Not aggravated by routine activity
-No nausea or vomiting
-Photophobia or phonophobia may be present, but not bothersome

Question 21

Cluster headache and TACs:

Answer 21

Actually a group of headache syndromes, known as trigeminal autonomiccephalalgias (TACs):
-cluster headache
-paroxysmal hemicrania
-SUNCT (short-lasting unilateral neuralgia-form headaches with conjunctival injection and tearing)
-SUNA (like above but w/ autonomic symptoms

These headaches are quite intense: most describe them as excruciating.

Question 22

Pathogenesis of headache and TACs:

Answer 22

No universally accepted theories:
-might be linked to hypothalamic/circadian circuits
-vasodilation thought to be a result, not a cause, of underlying CNS dysregulation
-vasodilation may be responsible for the autonomic nervous system findings, though:
-dilation of carotid artery may compress sympathetic fibres, resulting in a “shift” towards parasympathetic activation

Question 23

Episodic cluster headaches and TACs:

Answer 23

tend to occur frequently (daily) for a period (weeks/months) and then there is a significant headache-free period:
-if there is no remission period, known as chronic

Patients with cluster headache tend to move about during attacks, pacing, rocking, or rubbing their head for relief; some may even become aggressive during attacks:
-quite different from migraine

Autonomic symptoms are unilateral:
-phonophobia & photophobia also ipsilateral (different from migraines)

Question 24

Diagnostic criteria of cluster headaches:

Answer 24

Must have had at least 5 attacks
Must:
-last 15-180 min
-Be severe
-Unilateral pain that is orbital, supraorbital, or temporal

Must be accompanied by at least one of:
-Ipsilateral conjunctival injection/lacrimation
-Ipsilateral nasal congestion/rhinorrhea
-Ipsilateral eyelid edema
-Ipsilateral forehead & facial sweating
-Ipsilateral miosis and/or ptosis
-Restlessness or agitation

Attacks happen from every other day: 8 day during a cluster

Question 25

Secondary headaches:

Answer 25

Headaches that have a more clearly-defined underlying cause:
-many are associated w/ elevations in intracranial pressure or irritation of the meninges

Structures that sense pain in the CNS & can cause headache:
-Intracranial vessels, dura mater are innervated by CN V (meningeal arteries, dural sinuses, falx cerebri, pial arteries)

Scalp is sensitive as well

Brain parenchyma, veins, other layers of the meninges, ventricular system are insensitive

Many secondary headaches have a poor prognosis: these need to be evaluated more fully

Question 26

Criteria for Low-risk headaches:

Answer 26

-Age younger than 30
-Features typical of primary headache
-Previous history of similar headaches
-No abnormal neurological findings
-No concerning change in the usual headache pattern
-No “red flag” findings in the history or physical exam
-No serious medical conditions that could have a secondary serious headache as a complication (history of brain tumor, HIV)

Question 27

Selected disorder involving elevated intracranial pressure:

Answer 27

Normal pressure hydrocephalus

Idiopathic intracranial hypertension

Question 28

Vasogenic cerebral edema:

Answer 28

BBB disruption and increased vascular permeability.

-fluid shifts from the intravascular compartment to the intercellular spaces of the brain

-Little to no lymphatics, therefore difficult to remove this excess fluid

-Localized (adjacent to inflammation or neoplasms) or generalized
(generalized can be due to uncontrolled hypertension; local can be due to infection or cancer)

Question 29

Cytotoxic cerebral edema:

Answer 29

Increase in intracellular fluid secondary to neuronal, glial, or endothelial cell membrane injury:
-from generalized hypoxic/ischemic insult or w/ metabolic damage-any cause of cell death

Question 30

Interstitial cerebral edema:

Answer 30

-Usually occurs around the lateral ventricles
-Increased intraventricular pressure causes an abnormal flow of fluid from the intraventricular CSF across the ependymal lining to the periventricular white matter
-mostly due to hydrocephalus, increased intracranial pressure

Question 31

Consequences of cerebral edema:

Answer 31

-Gyri flatten
-Sulci narrow
-Ventricular cavities are compressed
(or they can expand if the cause of edema is interstitial due to hydrocephalus)
-As the brain expands, herniation may occur
-Signs & symptoms of increased intracranial pressure

Question 32

Hydrocephalus:

Answer 32

CSF is produced by the choroid plexus, circulates through the ventricular system:
-produced at a rate of 0.3 ml/min
-total volume 120ml
-accumulation of excessive CSF w/in the ventricular system
-Most cases occure as a consequence of impaired flow and resorption of CSF (rarely overproduction of CSF causes hydrocephalus (tumors of the choroid plexus)

Question 33

Appearance of patient w/ hydrocephalus:

Answer 33

Depends on age at presentation:

-before closure of cranial sutures results in enlargement of the head (increase in head circumference = macrocephaly)

-after closure of cranial sutures results in enlargement of the ventricles and increased intracranial pressure
(can result in atrophy/compression of the surrounding brain tissue)

Question 34

Communicating hydrocephalus:

Answer 34

-Enlargement of the entire ventricular system

-The fluid (and increased pressure) can “communicate” with each ventricle => the major foramina must not be blocked: more likely due to fluid mass

What tissue/structure is most likely to produce this fluid? Choroid plexus

Question 35

Non communicating hydrocephalus:

Answer 35

-Only a portion of the ventricular system is enlarged

-Example is a mass in the third ventricle, with back-up of fluid in the lateral ventricles but normal volumes in the fourth ventricles (blockage of the cerebral aqueduct)

Question 36

Symptoms of raised intracranial pressure/hydrocephalus:

Answer 36

-Slowing of mental capacity
-Headaches (especially if more severe in the morning)
-Vomiting (more likely in the morning)
-Blurred and/or double vision
blurred= optic nerve atrophy due to papilledema, double vision=6th cranial nerve palsy (usually)
-In kids: precocious puberty, stunted growth due to hypothalamic impairment
-Difficulty walking (spasticity)

Question 37

Causes of hydrocephalus:

Answer 37

Normal pressure hydrocephalus:
-Relatively common, but very rare in those under 60 (more than 20/100,000 prevalence in general elderly population)

Question 38

Pathogenesis of hydrocephalus:

Answer 38

-Ventricular volume is increased, but subarachnoid volume is not

-Cause is not well understood: impaired absorption at the arachnoid granulations

-although pressures on lumbar puncture are fairly normal, ventricular enlargement and intracranial pressure is increased

-can also be caused by tumors, infections, subarachnoid hemorrhage

Question 39

Normal pressure hydrocephalus;
Clinical features:

Answer 39

-gradual progressive gait apraxia (magnetic feet) urinary incontinence, dementia are the typical triad

Question 40

Bradyphrenia:

Answer 40

slowness of thought, speech is another common finding

Question 41

Treatment, prognosis of hydrocephalus:

Answer 41

many patients improve after a shunt is placed into the peritoneum

Question 42

Idiopathic intracranial hypertension:

Answer 42

Disorder of unknown etiology that predominantly affects obese women of childbearing age:

-chronically elevated intracranial pressure (ICP) leading to papilledema, which may lead to progressive optic atrophy and blindness

-other names: pseudotumor cerebri, benign intracranial hypertension (BIH)

Question 43

Epidemiology of idiopathic intracranial hypertension:

Answer 43

-Incidence is 1 in 100,000 (not common, but possibility of seeing it in practice)

8-20 X increased risk in obese women

Question 44

Idiopathic intracranial hypertension pathogenesis:

Answer 44

Not clearly identified, however it is thought that there are subtle problems with drainage from venous sinuses, especially the transverse sinus:

-although venous outflow is normal in most, there is an increased rate of arterial inflow in most as well

-therefore rate of arterial inflow is subtly greater than rate of venous outflow, resulting in increased intracranial pressure

Unsure of how obesity contributes to patholphysiology

Question 45

Idiopathic intracranial hypertension signs & symptoms:

Answer 45

-typical headache of ICP
-diplopia
-tinnitus
-visual field defects (usually transient early on)

Question 46

Idiopathic intracranial hypertension diagnosis:

Answer 46

lumbar puncture to determine opening pressure:
-imagining is non-specific

Question 47

Idiopathic intracranial hypertension treatment:

Answer 47

acute emergency treatment for elevated ICP:
-weight loss can result in resolution in up to 90% of patients with

Question 48

Subfalcine (cingulate) herniation:

Answer 48

unilateral or asymmetric expansion of a cerebral hemisphere that displaces the cingulate gyrus under the falx cerebri:

-can lead to compression of branches of the anterior cerebral artery

Question 49

Transtentorial (unicate, mesial temporal) herniation:

Answer 49

medial aspect of the temporal lobe is compressed against the free margin of the tentorium:

-can result in 3rd cranial nerve palsy

-compression of the contralateral cerebral peduncle (hemiparesis)

-hemorrhagic lesions in midbrain and pons (duret hemorrhage)

Question 50

Tonsillar herniation:

Answer 50

-displacement of the cerebellar tonsils through the foramen magnum

-Acute, it can be life-threatening because it causes brainstem compression and comprimises vital respiratory and cardiac centers in the medulla oblongata

-Chronic often has less severe repercussions
(some congenital malformations of the contents of the posterior fossa can show tonsillar herniation, but with minimal clinical features)

Question 51

Acute neuronal injury:

Answer 51

“red neurons”
-on H&E stains, neurons look “redder” than usual due to increased eosinophilia

-pyknosis (a type of nuclear condensation), eosphinophilic cell body, cell shrinkage, disappearance of the nucleolus, loss of nissl substance

-typically found 12-24 hours after hypoxic/ischemic insult

Question 52

Subacute/chronic neuronal injury:

Answer 52

Often described as neuronal degeneration:
-typical of slower, progressive diseases such as ALS or Alzheimer disease

Cell loss and reactive gliosis:
-proliferation, hypertrophy of astrocytes
(hyperproliferative, hyperplastic astrocytes = gemistocytic astrocytes)
-activation of microglial cells
(activated microglial cells also change their morphology-thier processes also get “fatter” and shorter.
-neuronal cell loss can be difficult to detect: although neurons from certain functional areas are lost, they’re not usually lost “all at once”
(easier to see the gliosis than the cell loss)

Often cell loss is due to apoptosis, hence the absence of an inflammatory reaction and subtle histologic findings

Question 53

Gliosis (reactive gliosis):

Answer 53

-hypertrophy and hyperplasia of astrocytes

-nuclei enlarge and nucleoli become more prominent

-cytoplasm becomes more eosinophilic, processes more stout
(known as gemistocytic astrocytes)

Question 54

Astrocytes reaction to injury:

Answer 54

Ability to meditate synaptogenesis/neurogenesis controversial; axons have trouble navigating the “glial scar”

-are very important in buffering excitotoxins, acid

-important in maintaining the BBB

-ability to support neuron energy metabolism increased

Question 55

Reactions of other cells to injury:

Answer 55

Oligodendrocytes and ependymal cells exhibit minimal changes when tissue is damaged:
-any changes will be discussed in the relevant pathologies

Microglial cells almost always exhibit changes:
-known as microglial activation (resident macrophages of the CNS)

Cells lose their ramifications and become more “ameboid”
-secreted pro-inflammatory molecules and cytokines that recruit peripheral leukocytes and aid astroglial activation

-secrete free radicals that can add to neuronal injury

-phagocytose dead or dying cells

Question 56

Patterns of neuronal injury:

Answer 56

Intracellular inclusions are common with a range of neurological diseases:
-lipofuscin: accumulates with aging, “wear-and-tear” complex of lipids
-Viral inclusions:
cowdry= intranuclear inclusion associated with herpes infection
negri body= intracytoplasmic inclusion associated with rabies

-Neurofibrillary tangles (Alzheimer’s disease)

-Lewy bodies in Parkinsons disease

Inclusions are often specific to a narrow range of diseases and will be discussed in the context of those diseases

Question 57

Infarction from obstruction of local blood supply (focal cerebral ischemia):

Answer 57

Excitatory amino acid neurotransmitters, such as glutamate, are released during ischemia:
-may cause cell damage by overstimulating and persistent opening of NMDA receptor: glutamate ionotropic receptors:
-these receptors allow calcium influx
-Calcium influx can increase nitric oxide production in neuronal cells

Question 58

Necrotic cellular damage: focus on intracellular calcium:

Answer 58

Certain glutamate receptors, NMDA receptors in particular, are permeable to calcium.

Question 59

Why might a cell depolarize with ATP depletion?

Answer 59

its depletion disrupts the functioning of various cellular processes, including ion pumps. Ion pumps are responsible for maintaining the proper concentrations of ions across the cell membrane, which is crucial for maintaining the cell’s resting membrane potential.

Question 60

How does increased intracellular calcium lead to increased nitric oxide production?

Answer 60

the increase in [Ca2+]i leads to the activation of CaMKII, which in turn activates NOS and increases NO production. This pathway is involved in various physiological processes, including blood vessel dilation, immune function, and nerve signaling. However, it is also implicated in pathological conditions, such as atherosclerosis and inflammation.

Question 61

Ischemia (stroke):

Answer 61

Early insult (minutes-hours): loss of intracellular ATP => destabilization of membrane potentials, excitotoxicity, calcium influx and nitric oxide production => destruction of membranes and necrosis

Later insult ( hours-days): development of red neurons (dead, shrunken, eosinophilic, pyknotic cells)
-microglial activation, disruption of BBB at this time

Subacute phase of the insult (day-days): reactive astrocytes, reactive microglia, influx of leukocytes across BBB-known as liquefactive necrosis

Resolution: astrocytic “scar” develops, liquefied mass removed:
-sometimes leaving a cavity bounded by scar
-Sometimes necrotic area is composed completely of gliotic tissue and new vascular elements (no neurons)

Question 62

Liquefactive necrosis:

Answer 62

characterized by digestion of the dead cells => transformation of the tissue into a liquid viscous mass

Seen in focal bacterial or occasionally, fungal infections => accumulation of leukocytes => purulent inflammation (pus)

For unknown reasons, hypoxic death of cells within the central nervus system often manifests as liquefactive necrosis:
-“glial scar”: hypertrophic astrocytes at the margins
-Re-establishment of BBB