BMS100_PAT2-01v2_F2022_UPDATED .pdf

Neuropathology I Headache disorders General Neurological Pathology BMS 100 Week 12 Overview Headache disorders Headaches – Definitions and Overview Primary Headaches Migraine and Tension Headaches Cluster and other Autonomic Headaches Secondary Headaches Intracranial Pressure and Head Pain Causes...

Neuropathology I Headache disorders General Neurological Pathology BMS 100 Week 12 Overview Headache disorders Headaches – Definitions and Overview Primary Headaches Migraine and Tension Headaches Cluster and other Autonomic Headaches Secondary Headaches Intracranial Pressure and Head Pain Causes of Elevated Intracranial Pressure Headache • There are a massive number of clinical entities that can cause headaches  for some, the pathogenesis is understood – for many, though, it’s less clear what exactly is going on  Can be divided into primary headaches and secondary headaches • Primary: headache and its associated features are the disorder itself • Secondary: caused by an exogenous disorder  Additional clinical features and pathology beyond the headache Headache – common causes Harrison’s Principles of Internal Medicine – 18th ed. Primary headache - migraine • Epidemiology:  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 Migraine – pathophysiology of pain 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 magnus • Problems with modulation of pain sensation from these trigeminal afferents seems to be the cause  Abnormal pain sensation related to vascular dilation and constriction? (vasomotion) Migraine – pathophysiology of pain • Medications that act on this pathway:  5-HT1 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” (i.e. sumatriptan) – they are used acutely, early on as the  CGRP (calcitonin-gene-related peptide) is a peptide migraine develops 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 receptor) are effective for headache prevention Migraine – pathophysiology of “other” neurologic findings • 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 (i.e. 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 • Etiology – 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 Migraine: signs/ symptom s Harrison’s Principles of Internal Medicine – 18th ed. Migraine: early signs/symptoms • 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 • Aura – can occur before or during the migraine (55% have no aura)  visual field deficits  tunnel vision  scotoma – an area of impaired vision with a flashing light border  paresthesias  heaviness of limbs  confusion, speech/language difficulties Migraine – diagnostic criteria • Repeated attacks of headache lasting 4 - 72 h in patients with a normal physical examination, no other reasonable cause for the headache, and:  At least 2 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 POUND screen for migraines: • Pulsatile quality? • Headache for 4 – 72 hours? • Unilateral? • Nausea and Vomiting? • Severe intensity? If >= 4 then migraine is likely (+LR = 24) Types of migraine • Acephalgic migraine  Migraine without headache… • So just the aura and the prodrome • 1/3 of patients referred for vertigo or dizziness • Common migraine – migraine without aura • Classic migraine – a migraine with an aura  Headache typically follows aura after no more than 60 minutes • Complicated migraine – has severe or persistent (reversible) sensorimotor deficits  i.e. diplopia, severe vertigo, ataxia, altered level of consciousness  Hemiplegia, loss of vision Tension-type headache • Definition: 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) • So not a migraine if lacking:  nausea, vomiting, photophobia, phonophobia, osmophobia, throbbing, and aggravation with movement  however, one or a couple of these may be present to a minor degree and still be TH Tension headache • Pathophysiology:  Increased muscle tension? • no difference in muscle “tension” between those with migraine and those with 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 Tension headache • Symptoms:  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) Tension-type headache – diagnostic criteria • At least 10 previous headaches • Duration of 30 minutes 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 both Cluster headache and TACs • actually a group of headache syndromes, known as trigeminal autonomic cephalalgias (TACs)  cluster headache  paroxysmal hemicrania  SUNCT (short-lasting unilateral neuralgia-form headaches with conjunctival injection and tearing)  SUNA (like above but with autonomic symptoms) • These headaches are quite intense – most describe them as excruciating Cluster headache and TACs • Pathogenesis:  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 Cluster headache and TACs Cluster Headache Paroxysmal Hemicrania SUNCT Gender M>F F=M F=M Type Stabbing, boring Throbbing, boring, stabbing burning, stabbing Severity Severe Severe Moderate-severe Site Orbit, temple Orbit, temple Periorbital Frequency 0.5 – 8/day 1-40/day 3-200/day Duration of attack 15min – 3 hours 2 – 30 min up to 5 minutes yes yes Autonomic features yes autonomic features: conjunctival injection, lacrimation, nasal congestion/rhinorrhea Cluster headaches and TACs • Episodic – 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 and photophobia also ipsilateral (different from migraines) Cluster headaches – diagnostic criteria • Must have had at least 5 attacks • Must:  last 15 – 180 minutes  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 and facial sweating  Ipsilateral miosis and/or ptosis  Restlessness or agitation • Attacks happen from every other day – 8/day during a cluster Secondary Headaches • Headaches that have a more clearly-defined underlying cause  Many are associated with elevations in intracranial pressure or irritation of the meninges • Structures that sense pain in the CNS and 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 Criteria for Low-risk Headaches • • • • • Age younger than 30 Features typical of primary headache Previous history of similar headaches No abnormal neurologic findings No concerning change in the usual headache pattern • No “red flag” findings in the history or physical exam  To discuss later as we address more neuropathology • No serious medical conditions that could have a secondary serious headache as a complication  (i.e. history of brain tumour, HIV) Secondary headaches – why do these pathologies cause pain? • Meningitis and encephalitis • Subarachnoid hemorrhage • Intraparenchymal hemorrhage • Intracranial mass – i.e. a tumour General Neuropathology Edema and hydrocephalus Selected disorders involving elevated intracranial pressure Normal Pressure Hydrocephalus Idiopathic Intracranial Hypertension Cerebral edema One of three major types: • vasogenic: blood-brain barrier 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 (e.g., adjacent to inflammation or neoplasms) or generalized • generalized can be due to uncontrolled hypertension • local can be due to infection, cancer Cerebral edema • cytotoxic:  increase in intracellular fluid secondary to neuronal, glial, or endothelial cell membrane injury • i.e. from generalized hypoxic/ischemic insult or with metabolic damage – any cause of cell death • interstitial edema:  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 Consequences of cerebral edema • 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 (see video) • signs and symptoms of increased intracranial pressure (to be discussed below) Hydrocephalus • CSF is produced by the choroid plexus, circulates through the ventricular system  produced at a rate of 0.3 ml/min  total volume 120 ml Hydrocephalus • accumulation of excessive CSF within the ventricular system • most cases occur as a consequence of impaired flow and resorption of CSF  rarely overproduction of CSF causes hydrocephalus (tumours of the choroid plexus) Hydrocephalus • Appearance of the patient 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 Hydrocephalus • Communicating hydrocephalus:  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 to be due to a fluid-producing mass  What tissue/structure is most likely to produce this fluid? • Non-communicating hydrocephalus:  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 ventricle • Blockage of the cerebral aqueduct Symptoms of raised intracranial pressure/hydrocephalus • Slowing of mental capacity • headaches (especially if more severe in the morning)  Headache is rare in NPH – see next slides • 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) Causes of hydrocephalus Normal pressure hydrocephalus • Relatively common, but very rare in those under 60 (more than 20/100,000 prevalence in general elderly population) • Pathogenesis  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 tumours, infections, subarachnoid hemorrhage Causes of hydrocephalus Normal pressure hydrocephalus • Clinical features:  gradual progressive gait apraxia (“magnetic feet”), urinary incontinence, dementia are the typical triad • bradyphrenia – slowness of thought, speech is another common finding • Treatment, prognosis  many patients improve after a shunt is placed into the peritoneum Idiopathic intracranial hypertension • 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) • Epidemiology:  incidence is 1 in 100,000 (not common, but possibility of seeing it in practice  8-20 X increased risk in obese women Idiopathic intracranial hypertension • Pathogenesis:  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 pathophysiology Idiopathic intracranial hypertension • Signs and symptoms:  typical headache of ICP  diplopia  tinnitus  visual field defects (usually transient early on) • Diagnosis – lumbar puncture to determine opening pressure  imaging is non-specific • Treatment: acute emergency treatment for elevated ICP  weight loss can result in resolution in up to 90% of patients General Neuropathology – asynchronous e-learning Brain herniation General Cellular Neuropathology Acute ischemia Chronic findings in ischemia Neurodegeneration and neuronal inclusions Gliosis Herniation due to increases in intracranial pressure • Subfalcine (cingulate) herniation = 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 • Transtentorial (uncinate, mesial temporal) herniation = 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) Herniation due to increases in intracranial pressure Herniation due to increases in intracranial pressure • Tonsillar herniation  displacement of the cerebellar tonsils through the foramen magnum  Acute, it can be life-threatening because it causes brainstem compression and compromises 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 Patterns of neuronal injury • Acute neuronal injury – “red neurons”  on H&E stains, neurons look “redder” than usual due to increased eosinophilia  pyknosis (a type of nuclear condensation), eosinophilic cell body, cell shrinkage, disappearance of the nucleolus, loss of Nissl substance  Typically found 12-24 hours after hypoxic/ischemic insult Patterns of neuronal injury • Subacute/chronic neuronal injury:  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 their 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 Astrocytic reaction to injury • Gliosis (reactive gliosis):  hypertrophy and hyperplasia of astrocytes  nuclei enlarge and nucleoli become more prominent  cytoplasm becomes more eosinophilic, processes more stout • Known as gemistocytic astrocytes Astrocytic reaction to injury • ability to mediate 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 Reactions of other cells to injury • 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” • secrete 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 Patterns of neuronal injury • 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 disease)  Lewy bodies in Parkinson disease • Inclusions are often specific to a narrow range of diseases and will be discussed in the context of those diseases Infarction from Obstruction of Local Blood Supply (Focal Cerebral Ischemia) • The general mechanisms of ischemic necrosis have been discussed earlier this semester  see next slide for key features • There are, however, several special responses to ischemia in the central nervous system:  Excitatory amino acid neurotransmitters, such as glutamate, are released during ischemia • may cause cell damage by overstimulation and persistent opening of NMDA receptor – glutamate ionotropic receptors  These receptors allow calcium influx  Calcium influx can increase nitric oxide production in neuronal cells Necrotic cellular damage – focus on intracellular calcium • certain glutamate receptors, NMDA receptors in particular, are permeable to calcium • why might a cell depolarize with ATP depletion? • how does increased intracellular calcium lead to increased nitric oxide production? General pathological sequences • Ischemia (stroke)  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 – a day): 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) Liquefactive necrosis: • 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 nervous system often manifests as liquefactive necrosis • “glial scar” – hypertrophic astrocytes at the margins • Re-establishment of BBB