Neuropathology I 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 of...

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