Exam 1 Flashcards

Question

Autonomic receptors in the Eye clinical importance (adrenergic and cholinergic) * Iris dilator * Iris Sphincter * Ciliary processes * Ciliary muscles * Conjunctivae blood vessels

Answer 1

**·Loss of Sympathetic Innervation** to the Eye Results in: * **Miosis:** Loss of Iris Dilator Function * **Ptosis** (Mild Lid Droop): Loss of Mueller’s Muscle Function * **Anhydrosis** (Above Orbit, Forehead): Loss of Sweat Gland function

Answer 2

**Cocaine** MOA: (Typically replaced with Apraclonidine now) * Prevents reuptake of NE that has been released at the synaptic junction between the Sympathetic Post-Ganglionic Neuron and the Iris Dilator: * **Normal Eye:** Causes DILATION (Increased Iris Dilator Function) * Horner’s Eye: Causes NOTHING (No Nerve Activity: No NE in Synapse) Hydroxyamphetamine (Stimulate Release of NE) * Differentiates Pre or Post Ganglionic Horner’s Syndrome * MOA: Causes release of NE from the presynaptic axon terminals of the Post-ganglionic Neuron on to the Iris Dilator * Preganglionic: Pupil DILATES from Topical Hydroxyamphetamine

Answer 3

* Pre-ganglionic Lesions can be serious: * Pancoast’s Tumor: Tumor of Apex of Lung * Thoracic Aortic Aneurysm ◦ S/p Carotid Endarterectomy * Postganglionic: NO Pupil Dilation from Topical Hydroxyamphetamine * Post-ganglionic Lesions typically less serious, but NOT always: * Goiter * Cavernous Sinus Syndrome

Answer 4

* Protective bony enclosure * Autoregulation of cerebral blood flow * Metabolic substrate requirements * No conventional lymphatic system * Special cerebrospinal fluid circulation

Answer 5

* neurons * astrocytes * oligodendrocytes * ependymal cells * microglia * choroid plexus epithelial cells * Schwann cells

Answer 6

**Neurons** Neuronal reactions to Injury * •Acute Neuronal Injury (“Red Neuron”) * •Necrosis * •**liquefactive** * •Subacute and chronic injury (Degeneration) * •Axonal Injury * •Neuronal Inclusions * •Intracytoplasmic Deposits

Answer 7

RED NEURON

Answer 8

* •Neuronal death over long duration * •e.g., ALS * •Morphology * •Cell loss, often selective – hard to detect at first * •Reactive gliosis – first sign

Answer 9

Axonal Sprouting after axonal injury / transection * Axonal Sprouting of proximal axon * Distal axon undergoes degenerative changes

Answer 10

Neuronal Inclusions Intracytoplasmic deposits * •Alzheimer Disease * •Neurofibrillary Tangles * •Parkinson Disease * •Lewy Bodies * •Creutzfeldt-Jacob Disease * •Abnormal vacuolization

Answer 11

* •Macroglia * •Astrocytes (Barrier Function; GLIOSIS) * •Oligodendrocytes (Myelin) * •Ependymal Cells (Line Ventricles) * •Microglia (Fixed Macrophage)

Answer 12

Astrocytes * •Cellular Swelling * •Failure of cell’s pump system in hypoxia, hypoglycemia, toxins, Creutzfeldt-Jakob Disease * •Corpora Amylacea (polyglucosan body) * •Concentrically lamellated * •Indicates degenerative change * •↑ with age * •Alzheimer type II astrocyte – long-standing hyperammonemia

Answer 13

Oligodendrocytes

Answer 14

Ependymal cells

Answer 15

**Cerebral Edema;** Increased "brain volume" (in a closed space) * •Cytotoxic – ↑ intracellular fluid * •Seen in cell membrane injury, e.g. ischemia

Answer 16

CSF * Subarachnoid space * •SECRETED: Choroid Plexus * •FLOW: Lateral Ventricles to Foramen of Munro into 3rd Ventricle then through Cerebral Aqueduct (Aqueduct of Sylvius) in Midbrain then into 4th Ventricle then through Foramina of Luschka and Magendie into the Subarachnoid Space and then to Superior Sagittal Sinus. * •ABSORBED: Arachnoid Villi of Superior Sagittal Sinus

Answer 17

Hydrocephalus

Answer 18

1. Non-Communcating Hydrocephals * •CSF does NOT Pass into Subarachnoid Space * •Congenital Causes: * •Aqueductal Stenosis or Atresia * •Dandy-Walker Syndrome * Acquired Causes: * •Neoplasms and cysts * •Gliosis of aqueduct * •Obstruction of 4th ventricle opening * •Organized subarachnoid hemorrhage at base of brain

Answer 19

**Communicating Hydrocephalus** * Choroid Plexus Papilloma ( ↑ Secretion) * •Deficient Absorption of CSF * •Dural sinus thrombosis * •Organized subarachnoid hemorrhage * •Organized meningitis * •? Deficiency of arachnoid villi

Answer 20

**Normal Pressure Hydrocephalus** (Hydrocephalus ex vacuo) * **Dementia, gait disturbance, incontinence**

Answer 21

ICP (Increased intracranial pressure) * •Definition: CSF pressure \>200mmH2O (\>20mm Hg) in the Lateral Decubitus Position * •Common cause of neurological sx * •May cause death from **herniation** * Etiology of Increased ICP * •Usually mass effect * •Diffuse – cerebral edema * •Local – tumor, abscess, hemorrhage * •Obstructive (non-communicating) hydrocephalus

Answer 22

**SUPRATENTORIAL Herniation**: * Subfalcine

Answer 23

**•TRANSTENTORIAL** Herniation

Answer 24

**•TONSILLAR** Herniation

Answer 25

Increase ICP signs * •Headache * •Vomiting * •Papilledema **•Do NOT do Lumbar Puncture**

Answer 26

* •Remove Mass, if present/possible * •Shunt to decompress 3rd ventricle * •Treat Cerebral Edema * •Mannitol * •Corticosteroids * •Stabilize Blood-Brain Barrier * •Decrease Cerebral Edema * •Mechanical ventilation Hypoxia and hypercapnia increase blood circulation to brain, O2 and increased respiratory rate improve hypoxia and hypercapnia (useful in trauma) May not actually be effective

Answer 27

* bacterial meningitis * tuberculous/mycobacterial meningoencephalitis * viral meningoencephalitis * fungal meningitis * neurosyphilis

Answer 28

1. **Bloodstream (hematogenous) is #1** a. Primary entry site: * 1) Respiratory tract (N. meningitides, H. influenza, S. pneumoniae,C. neoformans, many viruses) * 2) Skin (neonatal meningitis) * 3) Intestine (enterovirus) 2. Direct implantation * a. Skull fractures * b. Iatrogenic – surgery, lumbar puncture, etc. * c. Congenital malformations – e.g. meningomyelocele * d. Through the intact CRIBIFORM plate (free living amebas) 3. Local extension – otitis media, mastoiditis or frontal sinusitis, infected tooth, cranial or spinal osteomyelitis 4. Peripheral nervous system into CNS – rabies, herpes zoster, etc.

Answer 29

1. Acute BACTERIAL meningitis can be **rapidly fatal** * a. In U.S.A. 2000 deaths/yr * b. Neonatal (passage through the **birth canal)** * 1) Escherichia coli * 2) Streptococcus agalactiae (a group B streptococcus) * c. Children up to 5 years of age * 1) Streptococcus pneumonia * 2) Neisseria meningitidis * 3) Haemophilus influenza type b was most common but H. influenza cases in this age group declined 99% from 1989 to 2000 since vaccine was introduced in 1990 * d. Adolescents: Neisseria meningitidis * e. Older, debilitated, immunosuppressed: Listeria monocytogenes and gram-negative bacilli * f. All ages: Streptococcus pneumoniae 2. Acute VIRAL meningitis * a. 90% occur in patients under 30 years of age * b. Rarely causes death * c. Mild, benign course * d. Enteroviruses: Echovirus, coxsackievirus, nonparalytic poliomyelitis – 80% of cases * e. 10% develop meningitis when they seroconvert in HIV

Answer 30

1. Gross: Leptomeninges are congested and covered by exudates (yellow-white) 2. Microscopic: * a. Hyperemia * b. Fibrin * c. Inflammatory cells * 1) Bacterial: neutrophils * 2) Viral: lymphocytes

Answer 31

1. Present with fever, headache, neck pain and vomiting 2. **PE: Neck stiffness; Kernig sign** (pain with straight leg raising) both due to nerves passing across the inflamed meninges 3. Bacterial meningitis is serious due to risk of death 4. Viral meningitis is usually mild and self-limited 5. Waterhouse-Friderichsen syndrome; meningitis-associated septicemia

Answer 32

**Waterhouse-Friderichsen syndrome**

Answer 33

Diagnosis 1. Examine CSF by **lumbar puncture** * a. Cell count * b. Chemistry (protein, glucose, chloride) * c. Culture and Gram stain 2. Findings * *a. Bacterial** * 1) Cell count – neutrophils * 2) Chemistry: protein is HIGH, glucose is VERY LOW * 3) Culture is positive in 90% **b. Viral** * 1) Cell Count – lymphocytes * 2) Chemistry: protein is slightly elevated, glucose is NORMAL * 3) Viral cultures are positive in 70%

Answer 34

1. Antibiotics for bacterial * a. Until cultures are back from the lumbar puncture choose antibiotics based on * 1) Chemical examination (protein, glucose) * 2) Type of cells present * 3) Gram stain * b. Start antibiotics FIRST, LP within 30 minutes 2. **Viral** meningitis is usually **supportive** therapy

Answer 35

1. Brain Abscess 2. Subdural empyema

Answer 36

Cavity; pus: Liquefied brain and PMN's Etiology * **a. Streptococci and staphylococci most common, anaerobes common** * b. Complications of other diseases * 1) Chronic suppurative infections of the middle ear and mastoid air spaces and paranasal sinuses (local extension) 2) Infective endocarditis – often develop small and multiple abscesses 3) Right-to-left shunts (e.g. congenital cyanotic heart disease) 4) Tooth extraction 5) Suppurative lung disease (RARE cause); leads to parietal lobe abscesses

Answer 37

a. Appears as mass lesion b. Liquefied center with pus surrounded by c. Fibrogliotic wall - thickness depends on duration d. Adjacent brain: frequent vasogenic edema e. Most common sites: Frontal lobe, parietal lobe, and cerebellum

Answer 38

**BRAIN ABCESS** 3. Clinical features & diagnosis * a. Space-occupying lesion (increased intracranial pressure: headache, vomiting and papilledema) * b. Focal neurologic signs – depends on location * c. Evidence of infection (fever, elevated erythrocyte sedimentation rate, weight loss in chronic cases) * d. If untreated may cause death by increased intracranial pressure or rupture into ventricles * e. Dx’d clinically, confirmed by CT or MRI scan * 1) **Lumbar puncture dangerous, risk of herniation** * a) CSF normal -or- * b) Mild increases in **protein, neutrophils and lymphocytes** * c) Cultures: may or may not grow 4. Rx – surgical evacuation (drain abcess), followed by antibiotics. Former high mortality rate has been reduced to 5-10%

Answer 39

**Subdural empyema** \*\*Thrombophlebitis (inflammation of veins which gets prothrombotic)

Answer 40

* TB (tuberculosis) * Neurosyphilis * Neuroborreliosis (Lyme Disease)

Answer 41

4. Clinical Features * a. Acute onset with fever, headache, and signs of brain dysfunction * b. Convulsions may occur * c. May have papilledema * d. May have meningeal inflammation causing neck stiffness and CSF like viral meningitis * e. Dx by clinical picture * f. Lumbar puncture may give etiology 5. Rx * a. Supportive * 1) High dose corticosteroids to treat cerebral edema * 2) Anti-virals * b. In severe encephalitis * 1) Mortality HIGH * 2) Frequently left with permanent neurologic deficits due to irreversible neuronal necrosis

Answer 42

**TB (Tuberculosis);** seeded from a pulmonary infection 2. Clinical * a. Sx – headache, malaise, mental confusion, vomiting * b. Dx – Lumbar puncture * 1) Cell count – BOTH neutrophils and lymphocytes * 2) Chemistry: protein is VERY high, Glucose is low or normal * 3) **Acidfast stain positive** (may see mycobacterium) * 4) **Mycobacterial culture is positive**; takes 2 weeks to grow * c. Rx – long term antibiotics 3. Complications * a. Arachnoid fibrosis in long-standing cases, resulting in hydrocephalus * b. Obliterative endarteritis → arterial occlusion → infarction

Answer 43

1. 10% of untreated cases progress to teriary or neurosyphilis 2. Three major forms * *a. Meningovascular neurosyphilis** * 1) Involves base of brain, cerebral cortex, spinal leptomeninges * 2) Obliterative endarteritis and perivascular inflammation with plasma cells and lymphocytes * 3) Cerebral gummas (masses of plasma cells) b**. Paretic neurosyphilis** * 1) Invasion of brain by Treponema pallidum * 2) Progressive loss of mental and physical functions * 3) Loss of neurons, increased microglia, gliosis and iron deposits in cerebral ctx **c. Tabes dorsalis** * 1) Damage to sensory nerves in dorsal roots by spirochetes * 2) Ataxia, loss of pain sensation and absence of deep tendon reflexes * 3) Loss of axons and myelin in dorsal columns 3**. Penicillin** will prevent the progression of developed neurosyphilis but will NOT reverse the damage

Answer 44

Meningovascular neurosyphilis

Answer 45

Paretic neurosyphilis

Answer 46

Tabes Dorsalis

Answer 47

**Neuroborreliosis (Lyme Disease)**

Answer 48

1. Arthropod-borne viral encephalitis 2. Herpes simplex encephalitis 3. Varicella Zoster 4. CMV (cytomegalvirus) 5. Poliomyelitis (poliovirus) 6. Rabies 7. HIV encephalopathy 8. PML (progressive multifocal leukoencephalopathy) 9. SSPE (Subacute sclerosing panencephalitis)

Answer 49

1. Parenchymal infection of brain with associated meningeal inflammation +/- spinal cord involvement 2. “Tropism” – some viruses infect certain cells and/or certain areas of brain 3. Pathology * a. Usually blood-borne * b. Affects brain * 1) Perivascular and parenchymal mononuclear infiltrates (lymphocytes, plasma cells, macrophages) * 2) Microglial nodules * 3) Neuronophagia * 4) May be specific inclusion bodies * 5) Severe cases, hemorrhage occurs * 6) Cerebral edema * c. Result: cerebral dysfunction and **increased intracranial pressure (HA, vomiting, papilledema)**

Answer 50

Arthropod-borne viral encephalitis

Answer 51

**Herpes Simplex encephalitis** a. Incidence (occurs in 2 groups) 1) Children and young adults, may be any age * a) Only 10% have h/o prior herpes * b) Usually HSV-1 * c) **HSV-1 is most common** cause of sporadic encephalitis in US 2) Neonates * a) Delivery in a woman with active herpes genitalis * b) Usually HSV-2 * c) Do caesarian section

Answer 52

**Varicela-Zoster** * Causes Shingles

Answer 53

**CMV (Cytomegalovirus)**

Answer 54

**Poliomyelitis (poliovirus)** * Acute paralysis * Asymmetircal * Flaccid muscle paralysis * Muscle wasting * Hyporeflexia (can sometimes affect the diaphragm) \*\*Post polio syndrome * 1) 25-35 yrs after initial illness * 2) Weakness, loss of muscle mass, pain

Answer 55

**Rabies** (aka Hydrophobia - fear of water. Seen first in dogs with rabies that couldn't drink water) * a. Rare in humans * b. From bite of infected mammal, rabies virus ascends along **peripheral nerves to CNS** * c. Incubation: 1-3 months (longer for virus to travel up nerve that bloodstream) * d. CNS infection causes severe neuronal degeneration and inflammation * **1) Midbrain** * **2) Medulla** * **3) Basal ganglia** * e. Dx: Diagnostic eosinophilic intracytoplasmic inclusion bodies **(Negri bodies )** * 1) In pyramidal neurons of hippocampus or Purkinje cells (no inflammation)

Answer 56

HIV Encephalopathy * HIV aseptic meningitis (no bacteria) * 1) 1-2 weeks after seroconversion 2) 10% of patients 3) Virus in CSF and antibodies in serum * HIV meningoencephalitis * **1) Morphology** * a) Virus gains access to CNS via infected macrophages b) Chronic inflammation c) Microglial nodules with **multinucleated giant cells** d) May see foci of necrosis and gliosis e) Virus found in CD4+ macrophages and microglia, not in neurons or oligodendrocytes * **2) Clinical** a) Mild to severe cognitive changes (HIV associated dementia) * b) Related to number of activated microglia in the brain

Answer 57

Progressive Multifocal Leukoencephalopathy **(PML)**

Answer 58

**Subacute Sclerosing Panencephalitis (SSPE)**

Answer 59

**Cerebral Cortex** Lobes are separated by the **major sulci** * 1. A sulcus termed the lateral fissure (of Sylvius) separates the frontal and temporal lobe * 2. The central sulcus separated the frontal and parietal lobe * a. On the medial aspect of the brain the cingulate sulcus separates the frontal and parietal lobes

Answer 60

* Most people (80-85%) are **right-handed** which implies that the **left hemisphere is dominant** and houses language production and comprehension. * 1. Many left handed people also have left hemisphere dominance (70-85%)

Answer 61

There are two main areas involved in the production and comprehension of language: a. **Broca’s Area** is located in the **frontal lobe** and sits adjacent to the primary motor cortex. * i. Damage to the Broca’s area by stroke or other structural defect causes impaired language production with intact language comprehension. b**. Wernicke’s area** is located in the **superior temporal gyrus** of the temporal lobe * i. Damage to the Wernicke’s area causes impaired language comprehension with intact language production in some sense. Because one does not comprehend the content of language, there language in-turn also makes no sense but has normal fluency and prosody (rhythm and emotional tone inflections of speech)

Answer 62

FRONTAL LOBE Premotor cortex * 1. This area is just anterior to the main motor strip. * 2. Damage results in apraxia (disruption of planning of patterning and execution of learned motor movements). * a. An example of ideomotor apraxia: A 76 y/o wood worker suffers a stroke. In follow-up he states he can no longer use his tools. In testing you hand him a hammer and he can readily tell you the function of the tool and its name but cannot perform the proper movements to use it. * 3. Damage in the region of the premotor cortex often affects the frontal eye field as well * a. Lesion to the frontal eye field results in impairment of horizontal gaze to the contralateral side. Patients have forced eye deviation toward the side of the lesion.

Answer 63

1. **Premotor cortex** * Damage results in **_apraxia_** (disruption of planning of patterning and execution of learned motor movements). * Damage also affect frontal field; patients have forced eye deviation TOWARD side of lesion 2. **Prefrontal Cortex** 1. Located in the anterior frontal lobe 2. Used in planning the intellectual and emotional aspects of behavior a. Some patients who suffer lesions to the prefrontal cortex have symptoms of apathy and abulia (dramatic lack of motivation). 3. **Motor Cortex** 1. This aspect of the frontal lobe is located anterior to the central sulcus 2. It controls motor functions and is designed in the form of the motor homunculus detailed below: a. Patients having lateral frontal lobe stroke tend to have greater facial weakness where as those with high frontal lobe infarcts have more arm and leg weakness.

Answer 64

**PARIETAL LOBE** **Primary somatosensory cortex** * 1. This aspect of the parietal lobe is located posterior to the central sulcus * 2. It controls the interpretation of somatosensory stimuli (light touch, pressure, two point discriminative touch, vibration, position sense, and temperature) and is oriented in the sensory homunculus below: * a. Lesion to this aspect of the parietal lobe results in contralateral impairment of all somatosensory input types **iii. Posterior parietal association cortex** * 1. This region is posterior to the somatosensory cortex. * 2. When lesioned it also presents with symptoms of apraxia (described above under “premotor cortex”) * 3. A lesion in this location may also result in the inability to recognize objects based on touch alone- **“astereognosia”.**

Answer 65

\*\*note that **hands and mouth** have an excessive area of dedicate cortical tissue to process the immense amount of neural information from the numerous nerve endings in these areas

Answer 66

Primary visual cortex * a. This area is on the very medial aspect of the occipital lobe adjacent to the interhemispheric fissure * b. It is designed in a way the each part of the retina is schematically arranged onto the cortical surface * i. When one small area is damaged by stroke, the corresponding retinal information is lost resulting in a scotoma (blind spot)

Answer 67

A. Right Optic nerve damgae; ipsilateral blindness in right eye B. Optic chaism; Bitemporal hemianopsia * Caused by pituitary tumor, MS, berry aneurysm C. Optic tract; homonymous hemianopsia D. Right meyer's loop; left upper quadrantonosia E. Occipital cortex? ; caused by PCA infarction (right) * Left homonymous hemianopsia with macula sparing. * If MCA (middle cerebral arteyr is lost, there will be no macula sparing)

Answer 68

•Patient is exhibiting classic symptoms for Anton’s Syndrome **_•Anton’s Syndrome_**- cortical blindness due to lesion of both occipital lobes (including primary visual cortex). •The patient exhibits profound **anosognosia** (lack of regard for deficit) which is common in this syndrome

Answer 69

**Visual Association Cortex;** lesions in this area cause; * **Achromatopsia-**complete loss of color appreciation in the contralateral visual field * **Prosopagnosia**-inability to recognize faces (they retain the ability to identify people based on voice) * **Visual Agnosia**- inability to recognize visual patterns, including objects, without having a visual field cut. 1. An example of visual agnosia is having a patient look at a pair of glasses and they describe seeing a bar and two circles but cannot identify the object as glasses.

Answer 70

**Temporal Lobe** _Primary Auditory Cortex_: 1. Located deep within the lateral sulcus, the auditory association cortex occupies the two transverse gyri of Heschl. 2. The primary auditory cortex functions to interpret sounds, including speech, and is a component of the Wernicke’s area in the dominant hemisphere. * a. Patients with a lesion to the area of the primary auditory cortex on the dominant hemisphere have a Wernicke’s Type Aphasia * i. Recall that Wernicke’s Aphasia is a receptive aphasia. Lesion resulting in this syndrome causes the inability to comprehend speech or written word. Speech production is intact but the content is nonsensical and often termed “word-salad”

Answer 71

**Thalamus** c. The most effective way to remember the functions of various elements of the thalamus is to divide into sections where nuclei share common function ( i.e. motor input, sensory input, etc..) and to use pneumonics

Answer 72

Thalamic Nuclei * **Motor Nuclei** * 1. Ventral Anterior **(VA)**- gets input from the basal ganglia * 2. Ventral Lateral **(VL)**-gets input from the basal ganglia AND cerebellum * **Sensory Nuclei** * 1. Ventral posteromedial **(VPM)**- input from the trigeminal nucleus (think M as Mouth) * 2. Ventral posterolateral **(VPL)** input from the medial lemniscus and spinothalamic tract (think L as Limbs) * 3. Medial Geniculate- input from the inferior colliculus, processes sounds (think Medial Geniculate= Music) * a. Auditory Pathway pneumonic “NCS LIMA” * i. Acoustic Nerve → Cochlea Nucleus → Superior Olive (Pons) → Lateral Lemniscus (Pons) → Inferior Colliculus (mid brain) → Medial Geniculate (thalamus) → Auditory Association Cortex * 4. Lateral Geniculate Nucleus- Input from the optic tract (think Lateral Geniculate= Light) * **Medial Nuclear Group** * i. Dorsal Medial Nucleus (main medial nuclei but not pictured above)- input from the limbic system- involved in memory and emotion * 1. Lesion here results in amnesia * **Pulvinar** * i. No true input from outside the thalamus- responsible for visual attention Hypothalamus * a. The hypothalamus is also a very complicated network of hard-to-remember nuclei that have multiple afferent and efferent connections throughout the nervous system. * b. It is involved in hunger, thermoregulation, water balance, reproduction, and even the sleep wake cycle. * c. It is also highly involved in the limbic and autonomic systems and has numerous projections to the pituitary gland 1. Paraventricular AND Supraoptic- These nuclei synthesize antidiuretic hormone and oxytocin. They function in the management of **water balance**. a. Lesion in this nuclear group results in central (central meaning from the brain, not the kidneys) diabetes insipidus i. Clinically appears as polyuria and excess water consumption. 2. **Satiety/Hunger** a. Ventromedial Nucleus- satiety center. Lesion in this area makes affected individuals obese b. Lateral Hypothalamic Area- hunger center. Lesion in this area makes affected individuals have no desire to eat (aphagia-refusal to eat or swallow) 3. Temperature Regulation a. Anterior Hypothalamic Area - senses increase in temperature and induces sweating to dissipate heat. Lesion here results in hyperthermia b. Posterior Hypothalamic Area-senses decrease in body temperature and induces shivering. Lesion here results in poikilothermy (body temperature will vary with environment) 4. Circadian Rhythm a. Suprachiasmatic nucleus obtains visual input from the retina via the optic tract. This area sets the circadian rhythm to the day/night surroundings. 5. Memory a. Mammillary bodies are part of the limbic system and critical to the formation of memory. Lesion here results in anterograde and retrograde memory impairment. i. Review of memory formation: Papez Circuit- memory formation (limbic system) 1. Think H. MACE for memory formation a. Hippocampus → Mammillary Bodies → Anterior Nucleus of the Thalamus → Cingulate Gyrus → Entorhinal Cortex

Answer 73

* Patient is exhibiting classic symptoms for **Wernicke’s encephalopathy (confusion, ataxia, and ophthalmoparesis).** * Wernicke’s encephalopathy is typically seen in alcoholism and severe malnourished states and is caused by a **deficiency vitamin B1 (thiamine**) * The deficiency results in **damage to the mamillary bodies and ultimately results in necrosis** (as seen on the MRI). If patients survive they often suffer from **Korsakoff’s syndrome** (anterograde and retrograde amnesia with confabulation.

Answer 74

**BASAL GANGLIA** The main components include the **chief input nuclei** of the basal ganglia known as the **caudate and putamen** (collectively termed the striatum) which receive information from the brainstem, cerebellum, thalamus and supplementary motor cortex. The remainder of the basal ganglia includes the **globus pallidus, substantia nigra and the subthalamic nucleus**. The main output is to the thalamus, specifically the ventrolateral and ventroanterior nuclei (VL/VA)

Answer 75

* The **basic function** of the basal ganglia is to promote and inhibit movements. This is achieved through the “dreaded” direct and indirect pathways which will be reviewed below: Interestingly these two systems work to antagonize each other as one stimulates the primary cortex to cause movement and the other inhibits it. * **i. Direct Pathway:** In the simplest terms I can put it, the direct pathway takes excitatory information from the cerebral cortex (mostly the premotor area) and passes it through the striatum (caudate and putamen) to the internal globus pallidus then to the ventrolateral (VL) nucleus of the thalamus and finally back to activate the primary motor cortex where movement is stimulated. Direct Pathway = Stimulation of movement. * ii. **Indirect Pathway:** Once again excitatory information is sent from the supplemental motor area to the striatum. From there it travels to the external globus pallidus that project to the subthalamic nucleus. The subthalamic nucleus then inhibits the VL of the thalamus which does not send signal to the primary motor cortex. So no movement occurs. Indirect Pathway=Inhibits movements.

Answer 76

Problems in these pathways can result in **movement disorders** 1. Lesions to specific areas of the basal ganglia result in varying movement disorders a. Caudate and/or putamen lesion cause chorea b. Subthalamic nucleus lesion induces hemiballismus c. Substantia nigra lesion or degeneration results in Parkinsonism.

Answer 77

This case is the classic presentation for **Huntington’s disease (HD)**. HD is a neurodegenerative condition resulting in a **hyperkinetic** (fast irregular movements) movement disorder. Genetically there is a problem with **trinucleotide expansion of CAG** in the Huntington gene on **chromosome 4.** This disease has **genetic anticipation** meaning that each subsequent generation will have more trinucleotide repeats and will therefore **express the disease earlier** and often with more severe symptoms.

Answer 78

1. C 2. D 3. B

Answer 79

Muscarinic Receptors

Answer 80

**•Cardiovascular** * oCardiac effects (direct) * oSA node (↓ HR), AV node (↓ conduction), atria \> ventricle (↓ contractility) * oVascular effects * oVasodilation (indirect effect mediated through ↑ in nitric oxide) **•Gastrointestinal** * oIncreased motility, relaxed sphincters, and increased secretion

Answer 81

* •Salivary and nasopharyngeal glands * oIncreased secretion * •Urinary * omicturition * •Respiratory tract * obronchoconstriction, and increased respiratory secretions * •Eye * ocontraction of the iris sphincter → miosis * ocontraction of the ciliary muscle of the eye to induce accommodation for near vision * •Sweat gland (sympathetic effect) * o↑ sweating

Answer 82

\*\*\*If you have muscarinic activity means can activate ganglia? All Muscarinic agonist have **muscarinic activity and are blocked by atropine**

Answer 83

Muscarinic Agonists * Mechanism of action: **Bind to and activate muscarinic receptors**

Answer 84

1. •Methacholine * oDiagnosis of airway hyperreactivity 2. •Bethanechol * oStimulate urinary and GI tracts * oReverse urinary retention * oReverse gastric atony 3. ·Pilocarpine * oGlaucoma * oAngle closure glaucoma * oOpen angle glaucoma * oMiosis induction * oSjögren's syndrome – Xerostomia (destroy tear and salivary glands) 4. ·Carbachol * oGlaucoma (similar to pilocarpine) * oMiosis induction

Answer 85

**·SLUD(E) + BBB** * S - salivation * L - Lacrimation * U - urination * D(E) – defecation (emesis) * B –bronchoconstriction * B – bradycardia * B – blurred vision (spasm of ciliary muscle) **Muscarine poisoning (mushrooms)** * Inocybe & Ciltocybe (mushrooms) * SLUD(E) + BBB

Answer 86

* •Asthma & COPD (↑ risk for bronchospasms) * •Bradycardia, hypotension (↓↓ bradycardia, hypotension) * •Compromised integrity of GI or bladder wall (↑ GI and bladder wall contractions) * •Coronary artery disease (↓ coronary blood flow) * •Hyperthyroidism (↑ risk for atrial fibrillation) * •Peptic ulcer (↑ acid secretion)

Answer 87

A.Mechanism of Action * ·Prevent the effects of ACh by blocking its binding to muscarinic receptors at parasympathetic (and sympathetic) neuroeffector target tissue/cells. B. Drugs * •Atropine, scopolamine, tiotropium, ipratropium, benztropine, trihexyphenidyl, homatropine, oxybutynin, tolterodine, darifenacin, solifenacin, festoterodine

Answer 88

* **•Cardiovascular** * •Transient ↓ HR @ low dose (↑ in vagal release of ACh) * •↑ HR @ higher doses (direct cardiac effects) * •Dilation of cutaneous blood vessels (causes atropine blush) * **•Gastrointestinal** * •↓ tone & motility * •↓ secretions * **•Urinary** * •Urinary retention * **•Respiratory** * •Bronchodilation & decreased secretions * **•Eye** * •Cycloplegia (paralysis of the ciliary muscle of the eye). Near vision is compromised. * •Mydriasis (inhibition of the iris sphincter muscle) * **•Skin** * •↓ sweating (hyperpyrexia may result) * **•CNS** * •Confusion, and CNS depression

Answer 89

1. Atropine 2. Homatropine 3. Trihexyphenidyl and Benztropine 4. Scopolamine 5. Oxybutynin, tolterodine, darifenacin, solifenacin, festoterodine

Answer 90

* ·Narrow-angle glaucoma (contraindication) * ·Open-angle glaucoma (use with caution) * ·Cardiac disease (tachycardia) * ·Cycloplegia * ·Blurred vision * ·Mydriasis (lead to glaucoma attack) * ·CNS effects (dizziness, confusion) * ·Xerostomia (stoppage of saliva) * ·Prostatic hypertrophy (provoke urinary retention)

Answer 91

**•Old mnemonic**; Red as a beet; Dry as a bone; Blind as a bat; Hot as a firestone; and mad as a hatter * •0.5 mg * •Slight cardiac slowing; dryness of mouth; inhibition of sweating * •1 mg * •Definite dryness of the mouth; thirst; accelerated heart rate; sometimes preceded by slowing; mild dilation of pupils * •2 mg * •Rapid heat rate; palpitations; marked dryness of the mouth; dilated pupils; some blurring of near vision * •5 mg * •Above symptoms are marked (rapid heart rate, blurry vision); difficulty speaking and swallowing; restlessness and fatigue; headache; dry, hot skin; difficulty in micturition; reduced intestinal peristalsis * •≥ 10 mg * •Above symptoms are more marked; pulse rapid and weak; iris practically obliterated; vision very blurred; skin flushed; hot; dry; scarlet; ataxia; restlessness; hallucinations; and delirium; coma.

Answer 92

* ·Diphenhydramine (H1 antagonist) * ·Tricyclic antidepressants * oProtriptyline * oAmitriptyline * ·Antipsychotic drugs * oChlorpromazine * oThioridazine

Answer 93

* ·Nicotinic receptors mediate neurotransmission at the NMJ * ·ACh is the neurotransmitter at the NMJ. * ·ACh triggers depolarization at the NMJ that in turn induces muscle contraction. Clinical use of NMJ blockers * Induce muscle relaxation and diminish reflexes * tracheal intubation and surgery MoA of NMJ blockers * Suppresses cholinergic transmission at the NMJ by blocking the effects of ACh at the nicotinic receptor * There are two types of neuromuscular blocking agents with two different mechanisms of action: non-depolarizing NMJ blockers, and a depolarizing NMJ blocker

Answer 94

Non-depolarizing NMJ blocking drugs * •Atracurium * •Mivacurium * •Pancuronium * •Rocuronium * •Tubocurarine * •Vecuronium Mechanism of action * competes with acetylcholine for binding to nicotinic receptors at the NMJ and this prevents depolarization and thus inhibiting muscle contraction * Therefore, reversed by increasing the acetylcholine concentration in the neuromuscular junction with acetylcholinesterase inhibitors (e.g., neostigmine).

Answer 95

**Adverse effects:** * •Tubocurarine – Induces histamine release, partial ganglionic block (fall in blood pressure, tachycardia) * •Pancuronium -- partial ganglionic block (less than tubocurarine), vagolytic activity (blocks muscarinic receptors leading to tachycardia) * •atracurium, mivacurium, rocuronium, vecuronium are more selective for NMJ (cause very little ganglionic block) * •Prolonged apnea (all non-depolarizing blockers) * •Cardiovascular collapse (tubocurarine)

Answer 96

**Onset/duration of action:** * Tubocurarine: 6 min/85-100 min * Pancuronium: 1-3 min/85-100 min * Rocuronium: \< 1 min/45-90 min (rapid acting) * Mivacurium: 1-3 min/15-21 min * Atracurium, vecuronium: 1-3 min/45-90 min **Mode of elimination:** * Tubocurarine, pancuronium, vecuronium: renal and hepatic elimination * Rocuronium: renal elimination * Atracurium: elimination by plasma esterases * Mivacurium: hydrolysis by plasma cholinesterases

Answer 97

* •CNS Effects * •No CNS effects (quaternary amines) * •Drug interactions: * •Anticholinesterases (reverses neuromuscular block) * •Halogenated hydrocarbon anesthetics (desflurane, sevoflurane, isoflurane, and halothane) will increase neuromuscular block. * •Ca2+ blockers will promote NMJ block effects by promoting muscle paralysis * •Aminoglycoside antibiotics will increase the neuromuscular block. *(by inhibiting release of Ach?)*

Answer 98

* Drug * Succinylcholine * Mechanism of Action * Produces neuromuscular block by **overstimulation of the nicotinic receptor**, end plate is no longer able to respond to further stimulation. * This happens because **succinylcholine is more resistant to acetylcholinesterase** than acetylcholine leading to overstimulation. \*\*Depolarizing block at NMJ junction lead to paralysis? **Phase I block**; Mebrane **depolarize**, result in initial discharge that produce transient fasiculations followed by flaccid paralysis **Phase II block**; membrane **repolarizes** but receptor is desensitized to the effect of acetylocholine

Answer 99

**•Phase I depolarization:** prolonged depolarization (overstimulation), end plate can no longer respond to further stimulation and this leads to muscle paralysis. •There is no antidote (just stop administering drug). Acetylcholinesterase inhibitor potentiates Block. **•Phase II depolarization**: Repolarized, BUT blocked by succinylcholine (functioning like a non-depolarizing nicotinic receptor antagonist).

Answer 100

* Prolonged apnea * Muscle fasciculation * **Malignant hyperthermia** (more likely if succinylcholine is combined with halogenated hydrocarbon anesthetic (i.e., halothane, isoflurane, sevoflurane). * oUncontrolled Ca2+ release from sarcoplasmic reticulum is the trigger. * oClinical features: severe hyperthermia, muscle rigidity, tachycardia. * oLife threating (circulatory collapse). * **_oDantrolene is the antidote_** (blocks Ca2+ release from sarcoplasmic reticulum). * oGenetic component (mutations in the **RYR1 gene increases risk**).

Answer 101

**Succinylcholine** * •Drug interactions * •Anticholinesterases enhance (prolong) succinylcholine-induced neuromuscular block. * •Halogenated hydrocarbon anesthetic (i.e., halothane, isoflurane, sevoflurane) are more likely to cause malignant hyperthermia when combined with succinylcholine.

Answer 102

Drugs: * oHexamethonium * oTrimethaphan * omecamylamine

Answer 103

Ganglionic blocking drugs •Clinical uses: * oNot used much. Severe toxicity (see below). Better agents are available. * oIntraoperative hypertension (reducing arterial pressure to control bleeding during various types of surgery * oHypertensive crisis •Effects * •See table above showing the effects of ganglionic block •Toxicity: * •Visual disturbance * •Dry mouth * •Urinary hesitancy * •Constipation * •Syncope * •Marked hypotension * •Paralytic ileus

Answer 104

* Mechanism of action: Nicotine acts as an agonist at the nicotinic-cholinergic receptors in the autonomic ganglia, adrenal medulla, neuromuscular junctions, and brain * Pharmacological actions--Complex and often unpredictable changes after administration of nicotine; due to its actions on a variety of neuroeffector and chemosensitive sites and the fact that nicotine can stimulate and desensitize receptors

Answer 105

NICOTINE * •Ganglion cells--stimulation with low doses, yet depolarizing block at higher doses. * •Adrenal medulla--biphasic action on the adrenal medulla; low doses evoke the discharge of catecholamines; larger doses cause depolarization block of nicotinic receptor. * •NMJ--similar to those on ganglia; stimulation phase (rapid and low dose) that is followed by depolarization block and then paralysis. * •CNS: Nicotine effects in CNS are in part attributed to stimulated release of neurotransmitters including acetylcholine, beta-endorphin, dopamine, norepinephrine, serotonin, and others that mediate pleasure, arousal, mood, appetite, and other desirable psychological states. •Low dose--stimulatory effect in the CNS •High dose--tremors leading to convulsions at toxic doses Suppression of respiratory controls in medulla oblongata (respiratory failure), Vomiting (emetic chemoreceptor trigger zone) •primary sites of action in the CNS are prejunctional releasing other transmitters

Answer 106

**NICOTINE** **•Absorption:** * Inhalation (respiratory tract), Buccal membranes, skin (transdermal patch), severe poisoning has resulted from percutaneous absorption **•Toxicity** * A regular cigarette may contain 13 to 30 mg of nicotine * Although an oral lethal dose has not been established, an estimated 40 to 60 mg of nicotine may be lethal

Answer 107

A. Seen most often in immunocompromised patients B. Causative agents * 1. Cryptococcus neoformans – important in HIV/AIDS pts * 2. Candida albicans * 3. Mucor sp. * 4. Aspergillus fumigates In endemic areas: * 5. Histoplasma capsulatum * 6. Blastomyces dermatitidis * 7. Coccidiodes immitis C. Three patterns of infection * 1. Vasculitis – direct invasion of vessel walls by fungus * 2. Chronic meningitis * 3. Parenchymal invasion – see granulomas and abscesses

Answer 108

**Protozoa** 1. CNS toxoplasmosis 2. Amebas - rare causes **Prion disease** 1. Creutzfeldt-Jakob disease 2. Variant Creutzfeldt-Jacob disease (vCJD)

Answer 109

A. Protozoa (pp. 1279-80) 1. CNS toxoplasmosis * a. Toxoplasmosis gondii, intracellular protozoa * b. Common cause of neurologic disease in HIV/AIDS pts 1) Morphology * a) Brain abscesses * i. Especially in cerebral cortex * ii. Central foci of necrosis with petechiae * iii. Surrounded by acute and chronic inflammation, macrophages, vascular proliferation tachyzoites and bradyzoites 2) Clinical * a) Fever * b) Symptoms of acute cerebral dysfunction * c) CT-scan: Ring-enhancing mass lesion (often multiple) * d) Rx: anti-toxoplasma agents are effective c. Congenital Toxoplasmosis * 1) Occurs when a pregnant woman becomes infected * 2) Risk of transplacental transmission increases with gestational age at which the mother becomes infected * 3) Infection causes calcification and ventricular dilation * 4) Also infects fetal retina causing retinochoroiditis * a) \< 10% have visual impairment * 5) 5% have serious neurologic complications * a) Microcephaly * b) Hydrocephalus * c) Death

Answer 110

**Creutzfeldt-Jakob Disease** Clinical a. Progressive **mental deterioration** (dementia, behavior changes, deficits in higher cortical functions) b. Myoclonus (involuntary muscle twitching), ataxia c. Progression to death within one year of symptom onset Morphology * First you see GLIOSIS then neuronal loss * Spongiform changes * No inflammatory cell infiltration

Answer 111

2. Amebas – rare causes * a. Naegleria fowleri * 1) Rapidly fatal encephalitis * 2) Transmitted by swimming in freshwater lakes * b. Acanthamoeba – chronic granulomatous meningitis \*\*Through cribiform plate

Answer 112

**Human Prion diseases** a. Kuru b. Creutzfeldt-Jakob disease (CJD) c. Variant Creutzfeldt-Jakob disease (vCJD) d. Gerstmann-Straussler-Scheinker syndrome (GSS) e. Fatal familial insomnia

Answer 113

**Variant Creutzfeldt-Jacob Disease (vCJD)**

Answer 114

Cerebrovascular disease

Answer 115

* 1. Brain needs a constant supply of glucose and oxygen * 2. Mechanisms of decreased oxygen * a. “Functional” hypoxia * 1) Low inspired partial pressure of oxygen * 2) Impaired oxygen-carrying capacity * 3) Inhibition of oxygen use by tissue * b. Ischemia – transient or permanent * 1) Reduction in perfusion pressure, e.g. hypotension OR * 2) Secondary to small or large vessel obstruction * 3. Survival of ischemic brain tissue depends on * a. Availability of collateral circulation * b. Duration of ischemia * c. Magnitude and rapidity of the reduction of flow * **4. Penumbra** – region between necrosis and normal brain that is at-risk tissue

Answer 116

* *_Global cerebral ischemia_** (**hypotension, hypoperfusion, and low-flow states**) 1. General a. Outcome varies with the severity of the insult b. CNS cells show selective vulnerability * 1**) Neurons are most sensitive** and have the greatest variability * a) Areas more sensitive to ischemia or hypoglycemia * i) Large pyramidal neurons – may get pseudolaminar necrosis of cerebral cortex (see below) * ii) Hippocampus – Sommer sector is especially sensitive * iii) Purkinje cells of the cerebellum * 2) Glial cells also vulnerable c. Severe global cerebral ischemia causes isoelectric – **“flat” – electroencephalogram (EEG)**

Answer 117

**Global Cerebral Ischemia**

Answer 118

**Focal Cerebral Ischemia** 1. General * a. Area of brain affected determines if patient is asymptomatic, develops hemiplegia, a sensory deficit, blindness, aphasia or another deficit * b. Fatal or slow improvement * c. Modifying factors affect size, location, shape * 1) Collateral flow, e.g. circle of Willis – NONE for thalamus, basal ganglia, and deep white matter 2. Pathophysiology * a. Caused by a **thrombus or embolism** * b. **Thrombosis** * 1) Atherosclerosis at carotid bifurcation or origin of middle cerebral artery or either end of basilar artery – frequently associated with hypertension and diabetes * 2) Arteritis; a) Infectious vasculitis is now seen in immunosuppression and opportunistic infection, e.g. toxoplasmosis * **c. Embolism** * 1) Wide range of origins * a) Cardiac mural thrombi due to * i) Myocardial infarct * ii) Valvular disease * iii) Atrial fibrillation * b) Atheromatous plaque in carotid arteries * c) Paradoxical embolus * d) Cardiac surgery * e) Tumor, fat, or air * 2) Middle cerebral artery is most affected * 3) Embolism most often lodges at a branch point or stenotic area

Answer 119

Focal Cerebral ischemia - morphology Morphology **a. NON-hemorrhagic infarct** – most often associated with thrombosis * 1) Gross * a) First 6 hours: little to observe * b) 48 hrs: pale, soft and swollen; corticomedullary junction becomes indistinct due to cerebral edema * c) 2 to 10 days: boundary of infarct is more distinct (edema resolves) * d) 10 days to 3 weeks: liquefies, fluid-filled cavity * 2) Microscopic * a) 12 hours: red neurons * b) 48 hours: neutrophils & microglia appear * c) 2-3 weeks: microglia are the most prominent cells;gliosis begins * d) Several months: astrocyte enlargement recedes **b. Hemorrhagic infarction** – most often associated with embolism * 1) Hemorrhage is presumed to be due to reperfusion of damaged vessels and tissues through collaterals or after dissolution of occlusion * 2) Morphology – same as for ischemic infarct plus: blood extravasation and resorption. * 3) If patient is taking an anticoagulant, he/she may get more extensive intra-cerebral hematoma/s * 4) Venous infarcts are often hemorrhagic * a) Occlusion of superior sagittal sinus or other sinuses or deep cerebral veins * b) Carcinoma, localized infection or other causes of a _hypercoaguable state which predisposes to venous thrombosis_ **c. Spinal cord infarction** * 1) Cause: hypoperfusion or feeding tributaries are interrupted * 2) Rarely by occlusion of anterior spinal artery by thrombosis or embolism

Answer 120

Synthesis is controlled by: *  Amount and activity of synthetic enzymes *  Availability of substrates *  Presence of catalytic cofactors Sites of Synthesis *  Cell soma - neuropeptides *  Nerve terminal cytosol - acetylcholine, GABA, etc. *  Vesicle - norepinephrine Termination of Neurotransmitter Action *  Diffusion - neuropeptides *  Enzymatic degradation - acetylcholine *  Active re-uptake : primary mechanism * o high-affinity uptake mechanisms for neurotransmitters; can be into neurons or glia: norepinephrine *  Non-specific uptake: GABA

Answer 121

* **Biogenic amines**; Acetylcholine, Dopamine, Norepinephrine, Epinephrine, Histamine, Serotonin * **Amino acids**; GABA, Glutamate, Glycine, Aspartate * **Nucleotides/Nucleosides**; Adenosine, ATP * **Peptides**; Enkephalins

Answer 122

A. **Direct gating or ionotropic receptors:**  receptor is part of an ion channel * o depolarize cells: *  AMPA (Na+), kainite (Na+) and NMDA (Ca2+ and Na+) classes of glutamate receptors; nicotinic ACh receptors (Na+ and Ca2+) and 5-HT3 receptors (Na+) * o hyperpolarize cells: *  GABAA (Cl-) and glycine (Cl-) receptors **B. Indirect gating (G-protein coupled receptors; GPCRs) or metabotropic receptors**:  receptor activates a GTP-binding protein which can either: * o directly interact with an ion channel * o activate a second messenger system (cAMP, diacylglycerol, inositol polyphosphates) alpha- & beta-adrenergic receptors, 5-HT receptors (except 5-HT3), all known dopamine, muscarinic, ACh, histamine and neuropeptide receptors, GABAB receptors and glutamate.

Answer 123

**Neurotransmitters** * Catecolamines * Dopamine * Norepinephrine (NE) * Indoleamines; Serotonin (5-HT) * Cholinergic (Ach) * Amino acid Neurotransmitters (can be excitatory or inhibitory in nature) * Excitatory receptors; Ligand gated ion channels and metabotropic receptors * Inhibitory receptors; GABAa and GABAb * Histamine * Purines Neuropeptides (3-100 amino acids) * Substance P * Opiod peptides * Leptin * Orexin

Answer 124

**Catecolamines**: The catecholamines of most interest for CNS pharmacology are: *  Dopamine (DA) *  Norepinephrine (NE) **Synthesis:** A common synthetic pathway is seen for each of the transmitters:  DA synthesis occurs in the nerve terminal  NE in Synaptic vesicles **Only NE neurons contain Dopamine ß-hydroxylase** **Termination of Catecholamine action**:  Monoamine oxidase (MAO-A, MAO-B) * o Outer membrane of mitochondria in neurons/glia * o MAO inhibitors used therapeutically-most inhibit both forms  Catechol-O-methyltransferase (COMT) * o Soluble form prevalent in brain * o Membrane form has a higher affinity for catecholamines * o Found in both neurons and glia  Reuptake (80%): * o separate pumps exist for norepinephrine and dopamine

Answer 125

**Three dopaminergic tracts:** *  Mesocortical/Mesolimbic Pathway * o Behavior/Emotion *  Nigrostriatal Pathway * o Motor Function (75% of brain DA) *  Tuberoinfundibular Pathway * o Neuroendocrine function

Answer 126

Norepinephrine (NE) * Receptors * alpha 1, alpha 2, beta receptors * Metabolites of NE * VMA; vanillymandelic acid

Answer 127

Indoleamines; serotonin (5-HT)

Answer 128

Cholinergic (Ach)

Answer 129

Excitatory amino acid neurotransmitters:  Glutamate, Aspartate  Glutamate is the major excitatory neurotransmitter found throughout the brain Involved in:  Regulation of neuronal function, LTP Synthesis, deactivation and metabolism:  Glutamine converted to glutamate in mitochondria and packaged into vesicles  Deactivated predominantly by astrocytic uptake, where it is converted to glutamine  Glutamine can be shuttled back to neurons Receptors: Ligand gated ion channels  AMPA, Na+, K+  Kainate, Na+, K+  NMDA, Na+, K+, Ca2+ Metabotropic  mGluR I o Gi activation  mGluR II & III o Gq activation

Answer 130

**HISTAMINE** Receptors: H1  Gq activated  Cortex, hippocampus, nucleus accumbens, thalamus H2  Gs activated  Basal ganglia, hippocampus, amygdala, cortex H3  Gi/o activated  Basal ganglia, hippocampus, cortex

Answer 131

1. Neuropeptides (3-100 amino acids) 2. Substance P

Answer 132

1. **Enkephalins**: (derived from proenkephalin) 2. **Endorphins**: (derived from proopiomelanocortin) 3. **Dynorphins**: (derived from prodynorphin) Opioid receptors are very important targets for pain treatment and are also important in drugs of abuse

Answer 133

1. Leptin 2. Orexin

Answer 134

* Hypokinesia refers to decreased bodily movement and is typically associated with diseases of the basal ganglia. * The prototypical hypokinetic movement disorder is Parkinson’s Disease * There are a number of Parkinsonisms (diseases which have similar initial presentations to Parkinson ’s Disease but dramatically different clinical course and underlying pathology). These diseases include progressive supranuclear palsy (PSP), Multi-Systems Atrophy (MSA), and Corticobasalgangionic Degeneration (CBGD) which can be read about elsewhere but are outside the scope of this lecture.

Answer 135

* Parkinson’s Disease (PD) is a neurodegenerative disorder in which neurons within the substantia nigra die prematurely. * ▪ Studies suggest that over 50% of the cells must die prior to the onset of evident symptoms. * ▪ In most patients, we do not know why it occurs and it is in these patients that we see neurodegeneration in the substantia nigra, as well as in some of the other pigmented nuclei, such as the locus coreuleus * • It is this group of patients that we refer to as idiopathic or primary Parkinson’s Disease

Answer 136

Disease. • Structural lesions * o Obviously, structural pathology within the substantia nigra from stroke, tumor, cavitary infection etc. can cause Parkinson’s Disease. However, in practice, such causes are extremely rare. • Infections * o In the 1920's, an epidemic of encephalitis, called Von Economo's encephalitis (or encephalitis lethargica) spread across the country. Patients would sometimes wake up from infectious coma with acute parkinsonism. Currently, there are still some forms of encephalitis that can cause parkinsonism (e.g. Japanese B encephalitis); fortunately these are quite rare. • Toxins * o It has long been known that carbon monoxide, carbon disulfide, manganese, and L-BMAA toxicity (the false sago palm plant on Guam), can be associated with clinical parkinsonism. * o It wasn’t until some would-be users of designer drugs (stove-top drugs that resemble known drugs of abuse closely enough to simulate their psychotomimetic effects, but that differed structurally enough to them that they were considered misdemeanor crimes of possession rather than felonies) stumbled across MPTP, a mistaken byproduct of attempted meperidine (Demerol). MPTP was found to have unmistakable and immediate Parkinson’s Disease effect. o MPTP is selectively and highly toxic to neurons within the substania nigra. Humans who take it can develop severe, acute Parkinson’s Disease. This enabled researchers to create a toxic model of parkinsonism in animals. ▪ Now genetic models of Parkinson’s Disease in animals are of more practical value, but MPTP toxicity remains a useful research tool. Prescription Medications * o Since the symptoms of Parkinsonism result from loss of nigrostrital dopamine neurons, it can be mimicked by drugs that impair dopamine neurotransmission. * o Most commonly, this is seen with neuroleptics, such as haloperidol or chlorpromazine (Thorazine), but it can also be seen with drugs that deplete dopamine, such as reserpine. * o Metaclopramide. (Reglan) is a drug for diabetic gastroparesis that has many features of neuroleptics. This frequently asked about by the USMLE as the cause of secondary parkinson’s disease\*\*HINT-HINT. • Trauma * o Parkinsonism can follow acute or chronic trauma. Muhammad Ali is a good example of this. * o It is felt that trauma induces parkinsonism by damaging the cells of the substantia nigra directly, or by causing shearing injuries to nigrostriatal connections. * o Acute trauma can also cause parkinsonism that may be in part reversible, this seems to be the result of acute edema that dissipates over 3-4 days. Remember that other structural lesions of the brain in the basal ganglia can cause a parkinsonian syndrome, but that such lesions (tumors, strokes, hemorrhages, aneurysms, etc) are quite rare.

Answer 137

Features of Parkinson’s Disease can be best remembered using the pneumonic TRAP (Tremor, Rigidity, Akinesia, Postural Instability) • Tremor * The tremor of Parkinson’s Disease is a rest tremor with a frequency of 3-5 Hz and you get the impression that, on exam, you can count along with it. * o Classically, Parkinson’s Tremor improves when the arm moves, so, if it is a rest tremor, it should improve with action to some degree * o The tremor is usually worse on one side early in the disease process • Rigidity * o The rigidity seen in Parkinson’s Disease is typically noted in the arms, but can be noted in the legs, neck or trunk as well * o “Cogwheeling” (ratchet-like feeling) with extension and flexion at the elbow and wrist are common • Akinesia-More often bradykinesia * o Slowness of movements * o Some patients can “freeze” (also known as being akinetic) with more advanced Parkinson’s Disease * ▪ Freezing is typically seen at times when there medication (Carbidopa-Levodopa-see below) wears off. • Postural Instability * o Parkinson’s Disease results in multiple problem areas which disrupt balance. The above described rigidity and the slowness of movements play a large role in the cause of frequent falls. • Other Signs Typically Observed in Parkinson’s Disease * o Gait impairment: slowness and difficulty rising from a chair, turning in tight quarters, taking small steps, * o Softening of voice * o Micrographia (small handwriting) * o Slowness in fine motor skills (buttoning buttons, stirring while cooking, flipping pancakes, tying shoes, etc.) • Other Symptoms Observed in Parkinson’s Disease * o Constipation * o Dry skin (seborrhea) * o Dizziness upon standing (orthostasis) * o REM Sleep Behavior Disorder (act out dreams) * o Depression * o Hallucinations (late in disease)

Answer 138

Carbidopa/Levodopa (Sinemet™) * o Gold standard treatment * o Acts by crossing the blood brain barrier and converting to dopamine by ALAA-decarboxylase * o Eventually all PD patients require it MAO-B Inhibitors * o Selegiline, Rasagiline * o Act by selective inhibition of MAO-B enzyme involved in dopamine metabolism * o Is possible neuroprotective * o Drawbacks: * ▪ Tons of drug interactions * ▪ Very mild anti-Parkinson’s dug • Dopamine Agonists * o Pramipexole and ropinirole * o Directly stimulate D2/D1 receptors * o Less efficacious than levodopa but more than MAO-BI and amantadine * o Also has indication in restless leg syndrome * o Drawback: * ▪ Pathologic gambling and impulsivity in general * ▪ Can cause sudden sleep attacks • Amantadine * o Mechanism of action not known: NMDA blockade? * o Effective at reducing dyskinesia • COMT Inhibitors * o Entacapone, Tolcapone * Inhibit COMT =\> slows dopamine breakdown =\> prolongs the half life of levodopa * o Used in advanced PD when patients are experiencing motor fluctuations * o Tolcapone has longer half-life but use limited by bimonthly LFT monitoring to monitor for hepatoxicity * o Always have to be given with levodopa **Surgical treatment** Deep Brain Stimulator (DBS) o Which patients to consider for DBS * ▪ Advanced PD patients, who are not demented, having any of the following symptoms which cannot be adequately controlled with medications. * • Motor fluctuations; * Disabling dyskinesia or dystonia * • Medically refractory tremor * • Medication induced intolerable side effects * o Positive effects of DBS on Parkinson’s Disease Patients * ▪ Marked improvement in motor symptoms * ▪ Improvement in tremor by ~80% * ▪ Increases the ‘On’ time and ‘smoothes’ out motor fluctuations when using carbidopa/levodopa * ▪ Dyskinesias improve 60-80 % * ▪ Quality of life improvement ~ 50% * o Symptoms which fail to improve with DBS * ▪ Speech (may even worsen) * ▪ Cognition * ▪ Postural instability and gait (if unresponsive to levodopa) * ▪ Autonomic symptoms (constipation, orthostasis)

Answer 139

▪ Lewy Body Disease results from the **deposition of abnormal Tau proteins (Tau-opathy)** throughout the subcortical white matter. o Clinical Features * ▪ Motor * • Parkinsonian motor features preceding cognitive and psychiatric features (generally only a year before) * ▪ Psychiatric * • Fluctuations in cognitive function with varying levels of alertness and attention (eg, excessive daytime drowsiness despite adequate nighttime sleep or daytime sleep \>2 hours, staring into space for long periods, episodes of disorganized speech) * • Visual hallucinations * o Well-formed and are typically people or animals. Initially they are insightful that these are not actually present o Cognition ▪ Anterograde memory loss: May be less prominent (vs prominent early sign in Alzheimer disease) ▪ More prominent executive function deficits and visuospatial impairment

Answer 140

Pathophysiology ▪ CSF volume increase results in increased subarachnoid space volume. This disrupts normal blood flow as well as the positioning and function of some subcortical white matter structures: * • Sacral motor fibers that innervate the legs and the bladder, thus explaining the abnormal gait and incontinence. * • Brainstem structures (ie, pedunculopontine nucleus) could also be responsible for gait dysfunction, particularly the freezing of gait that has been well * • Periventricular limbic system resulting in the dementia component o Clinical Features ▪ Motor * • Abnormal gait: Earliest feature and most responsive to treatment; bradykinetic, broad-based, magnetic, and shuffling gait ▪ Cognitive * • Dementia: Prominent memory loss and bradyphrenia; forgetfulness, decreased attention, inertia ▪ Other * • Urinary incontinence: Urinary frequency, urgency, or frank incontinence

Answer 141

* CSF volume increase results in increased subarachnoid space volume. This disrupts normal blood flow as well as the positioning and function of some subcortical white matter structures: * Decreased CSF absorption

Answer 142

o Autosomal Recessive mutation of ATP7B- hepatic copper accumulation  leak from damaged hepatocytes  deposits in tissues (e.g. basal ganglia and cornea). * ▪ The excess copper causes injury by binding to sulfhydryl groups of cellular proteins. o Clinical findings include: * ▪ Hepatic (acute liver failure, chronic hepatitis, cirrhosis) * ▪ Neurological (parkinsonism, gait disturbance, dysarthria) psychiatric (depression, personality changes). * ▪ Ophthalmic (Keiser Fleisher Rings) o Work-up * ▪ Ceruloplasmin (decreased) * ▪ Elevated transaminases * ▪ Urinary copper excretion (increased) o Treatment: * ▪ Chelators (D-penicillamine, trientine) or Zinc (interferes with copper absorption). * • D-penicillamine is the first line agent and chelates copper by containing a free sulfhydryl group.

Answer 143

Huntington’s Disease (HD) is a neurodegenerative disorder in which neurons within the caudate nucleus and putamen undergo rather striking degeneration compared to other cerebral structures. o Clinical Features ▪ Motor * • HD is the prime example of the hyperkinetic movement disorder Chorea. * o Chorea is derived from the Greek word meaning dance and appears as writhing type movements. * • Initially, mild chorea may pass for fidgetiness. Severe chorea may appear as uncontrollable flailing of the extremities (ie, ballismus), which interferes with function. * • As the disease progresses the patient can appear somewhat parkinsonian, with rigidity, bradykinesia, and postural instability replace the irregular choreaform hyperkinesis. * • In advanced disease, patients develop an akinetic-rigid syndrome, with minimal or no chorea. ▪ Cognition * • The dementia syndrome associated with HD includes early onset behavioral changes, such as irritability, untidiness, and loss of interest. * • Slowing of cognition, impairment of intellectual function, and memory disturbances are seen later. ▪ Psychiatric * • Depression is more prevalent, with a small percentage of patients experiencing episodic bouts of mania characteristic of bipolar disorder. * • Patients with HD also can develop psychosis, obsessive-compulsive symptoms, sexual and sleep disorders, and changes in personality. * • Patients with HD and persons at risk for HD may have an increased rate of suicide.

Answer 144

* ▪ Huntington’s Disease (HD) is a neurodegenerative disorder in which neurons within the caudate nucleus and putamen undergo rather striking degeneration compared to other cerebral structures. * ▪ Estimates of the prevalence of HD in the United States range from 4.1-8.4 per 100,000 people * ▪ The genetic basis of HD is the expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N -terminus of the protein product called huntingtin. This is a problem localized to chromosome 4. * ▪ This is a disease of genetic anticipation- each subsequent generation develops more CAG repeats which results in earlier and more aggressive disease. • \*\*USMLE and others like for you to know its due to CAG trinucleotide repeat on chromosome 4\*\*

Answer 145

▪ Tetrabenazine (Xenaxine™) * • Profound dopamine depleting agent (actually prevents a monoamine transporter protein) which can decrease choreaform movements * • Very high association with inciting depression. Patients and family must be warned about symptoms of depression ▪ Selective serotonin reuptake inhibitors (SSRIs) * • Should be considered as first-line therapy for depression ▪ Antipsychotics * • Treats the psychiatric symptoms of hallucination and delusions which can occur in HD

Answer 146

Viruses that can cause **meningiti****s** include: Herpes simplex virus (DNA virus) Mumps virus (RNA virus) Lymphocytic choriomeningitis virus (RNA virus) Poliovirus, Coxsackievirus and Echovirus and Enteroviruses(newly identified) (RNA viruses, Enteroviruses) Encephalitis viruses (RNA viruses, eg. Toga and Flaviviruses) HIV (RNA-Retrovirus) Numerous viruses can also cause **encephalitis**. Herpes simplex virus and Varicella zoster virus (DNA viruses) Human Herpes virus 6 (DNA virus) Cytomegalovirus (DNA virus) **Polioviru****s (RNA virus)** **Enteroviruses****,Coxsackie and ECHO (RNA virus)** Mumps virus (RNA virus) Measles virus (rubeola- RNA virus) Nipah virus (RNA virus) Rabies virus (RNA virus) Encephalitis viruses (RNA viruses) JC virus (papovavirus- DNA virus ) Zika virus (RNA virus) Adenovirus (DNA virus)

Answer 147

**Picornaviridae** Genera: **Enterovirus, Rhinovirus**

Answer 148

Possible infections by poliovirus a. Inapparent infections- vast majority of cases in young individual (90%) b. Abortive poliomyelitis - fever, malaise, headache, vomiting, sore throat- About 5% c. **Nonparalytic CNS disease ("aseptic meningitis")** - stiffness and pain in neck and back;crossesfenestrated endothelial cells at the choroid plexus,1-2% d. **Paralytic --spinal, bulbar** (back of neck, pons & medulla) - flaccid paralysis - changes in voluntary muscle most likely to occur in teenagers and young adults, 0.1-2% **Paralysi****s** induced by poliovirus infection **Spectrum of levels of flaccid paralysis** * Asymmetric paralysis with no sensory loss * Localized flaccid paralysis * Multiple Sites (arms and legs affected) 3 outcomes of recovery from flaccid paralysis * Full recovery * Residual paralysis * Death (bulbar poliomyelitis)

Answer 149

A.Single stranded, non segmented RNA B.+ polarity genome (can act as messenger RNA) Genome = AUGGC; mRNA = AUGGC Genome can “transfect” cells; naked genomic RNA is introduced into a cell and infection is initiated C. RNA has poly A at 3' end and VPg at 5' end (VPg is not a cap structure) D. Capsid has 4 structural proteins; VP1, VP2, VP3, VP4. Icosahedral capsid - no envelope F. Capsid structure is stable to acid (enteroviruses) and the environment, rhinoviruses not acid stable (rhinoviruses are not enterovirus)

Answer 150

* Viral serotype (1,2,3) * Quantity of live virus causing initial infection * Tissue specificity of viral serotype * Portal of entry (fecal-oral route for enteroviruses) * Age, gender, and health of individual(immune status) * **AG****E Factor**-First exposure to poliovirus at a young age -------\> less paralysis; * first exposure during adolescence and adulthood --\> paralysis more likely; delayed exposure leads to more severe disease * early exposure to poliovirus in developing countries and low socioeconomic conditions; yield inapparent or abortive infections * Pregnancy

Answer 151

Vaccine induced immunity, two primary types of vaccines --killed (Salk= IPV)) vs. live (Sabin= oral) vaccines **Salk (Killed)** induces serum AB vs. **Sabi****n (live attenuated)**induces both secretary Ab and serum AB "**vaccin****e - associated" paralysis** may be linked to the Sabin live vaccine, absolute need to maintain immunization, once begun

Answer 152

* The World Health Assembly has a goal to eradicate poliovirus infection from world populations during the next decade and progress is being made. The Western Hemisphere has been free of W+ (natural infection) since 1994. The Western Pacific region was certified in * 2000 and the European Region (Europe and Russia) was certified wild type polio free in 2002. **Three remaining major reservoirs** of natural * polio included: 1) Pakistan, 2) Afghanistan, and 3) Nigeria. \*\*\* **Northern India (eradicated by 2014)** * **Polioviru****s stocks** (W+= Wildtype) are in many research laboratories around the world. To ascertain the location of lab. stocks of poliovirus, inventories are being conducted and a database is being established. Stocks not being used for research and merely being held in the freezer are destroyed. It is therefore anticipated that natural poliovirus infections will be eliminated worldwide and all efforts to contain laboratory virus must be made. * In addition, **Vaccine derived poliovirus** (avirulentà neurovirulent mutation) is being tracked and a genome sequence database is being developed to determine how mutations occur and affect neurovirulence. * For global eradication of polio to occur, WHO has instituted **National Immunization Days** where susceptible children in a whole country will be vaccinated by door to door canvassing. * A **network of sophisticated diagnostic laboratories** has been developed to monitor natural and vaccine associated prevalence of poliovirus. Even after natural poliovirus has been eradicated it could possibly be re-introduced into the population by: 1) accidental release from research and diagnostic laboratories and * 2) mutation of OPV (Sabin). * **Vaccin****e recommendations**:**Previously**the oral poliovirus vaccine was recommended as a series of three primary doses. The concern then and now is that vaccine (live attenuated) viruses would mutate to neurovirulence, excreted into the environment, and cause paralytic disease in susceptible individuals. Over the last several years the recommendations for poliovaccine administration have changed significantly in**USA.** * **I****n the US**the**inactivate****d** poliovirus vaccine (IPV) is now recommended. If a live poliovaccine is used, it is a concern that a pathogenic form (mutant, neurovirulent form) of live vaccine virus will be released into the environment via fecal contamination. In other parts of world where poliovirus has been endemic, 3 doses of oral poliovirus vaccine **(live)** is still recommended. * Per January-December 2017 recommendations, IPV should be **administere****d for all children via a 4 shot series**. Immunization should be administered at 2 months, 4 months, between 6 and 18 months and between 4 and 6 years.

Answer 153

Lab diagnosis (paralytic disease with CNS involvement) * a. Increased leukocytes in CSF 10-200/ mm3 * Lacks neutrophils * b. Elevated protein in CSF 40-50 mg/dl(10-45 normal) * c. Glucose normal 40-70mg/dL * d. serological testing of types 1, 2, 3 * e.Virus isolation:rectal or pharyngeal swabs;foundin throat and stools before clinical illness poliovirus not usually found in CSF in paralytic disease (unlike coxsackie and echovirus induced meningitis and encephalitis where virus can be isolated from CSF) Antibody and antigen test available to diagnose serotypes including immunofluorescence and ELISA RT PCR (Reverse Transcriptase= RT) is being used for routine testing of a number of different enteroviruses

Answer 154

Coxsackieviruses - diverse disseminated infections - summer, fall **Group A (23 types) -** 1)vesicular pharyngitis or herpangina; tonsils pharynx, anorexia,dysphagia (posterior enanthem); Remember for HSV gingivostomatitis, lesions are seen throughout the oral cavity 2) summer grippe, febrile illness; 3) aseptic meningitis -stiff neck, back; nausea, headache, abdominal pain, fever virus in CNS; petechiae or rash may accompany meningitis, recovery uneventful except if meningoencephalitis develops NOTE: Non-polio enterovirues are leading infectious cause of aseptic meningitis in US; \> 80% of cases;age is major determinant of severity, older patients= more severe disease 4) colds, one of the many cold viruses 5) Hand, Foot & Mouth (HFM) disease lesion and exanthems) -no crusting of exanthem, * **Enterovirus 71 HFM Disease plus high frequency of neurological complication; Currently HFM Disease cases are being reported in colleges in various locations throughout the United States** 6) CA24 (variant) and enterovirus 70 cause acute hemorrhagic conjunctivitis in tropics **Group B (6 types) –** 1) summer grippe; 2) epidemic myalgia, severe pain in chest, (pleurodynia or devils grippe) fever; 3) aseptic meningitis (virus in CNS); 4) neonatal disease, primary Myocardial or pericardial disease;cyanosis (reduced Hemoglobin in skin, blue skin) tachycardia\>100 beats/min; dyspnea, difficulty breathing; 5) colds; 6) diabetes, 7) macular -papular rash **Lab diagnosis** a. Isolation of virus from throat (1st), feces (2nd) or CSF in encephalitis b. If (Immunofluorescence) c. RT PCR d. Neutralization ab (found early in infection)

Answer 155

**ECHOviruses** - enteric cytopathogenic human orphan (over 30 types) **- summer aseptic meningitis -type 11(virus in CSF), RT PCR used for diagnosis of type 11 Echovirus meningitis** - summer epidemics of febrile illness with rash, esp. in young, eg. Boston Exanthem, maculopapular rash - outbreaks of non-bacterial diarrheal disease in infants, ECHO 11,14, 18 - not pathogenic for mice (unlike Coxsackie) - recovered from throat and stools

Answer 156

I. Slow viruses * The term "slow infection" was first used in 1954 by Sigurdsson to describe chronic diseases which developed insidiously, following a prolonged, predictable course. The disease usually ends in death. * "Slow" now applied to long incubation diseases and the slow agents that produce them. The terms denotes a virus-host relationship. Incubation time, months to years **A. Conventional (viral) agents - are classic viruses** * 1. Replicate in vitro, producing CPE * 2. Antigenic viral proteins * 3. Evoke an inflammatory reaction of CNS; examples (SSPE measles, visna retrovirus) **B. Unconventional agents** * 1. Do not produce CPE in vitro * 2. Virus particles cannot be demonstrated by EM, can detect rod shaped particles which may or may not correspond to infectious entity * 3. No inflammatory response in CNS * 4. Do not evoke Ab response during disease development * 5. Do not cause interferon to be produced * 6. Can be propagated in animals

Answer 157

* **PrP****c** is anchored to phosphatidylinositol glycan that is embedded in the cell surface membrane * **PrP^c** is encoded by Pmp gene and is expressed at high levels in all adults, expression regulated during development * May control ion flow across membranes in neurons * Normal PrP^c has a N-terminal polypeptide which is flexible and a C-terminal polypeptide which is ridged * N-terminal polypeptide has toxic properties for neurons but this is held in check by the presence of the C-terminal polypeptide * Mab directed to C-terminal polypeptide causes the N-terminal polypeptide to express its toxic properties towards neurons

Answer 158

II. Diseases caused by unconventional agents or Prion (Small Proteinaceous Infectious Particle) designated PrPsc A. Scrapie - disease of sheep marked by tremors, ataxia, etc., no demyelination, no pleocytosis, no febrile reaction, no meningeal signs * Sheep scrape off wool from skin * Disease causes **spongiform changes** in gray matter - destruction of neurons * Scrapie as well as other similar human and animal CNS degenerative diseases may be **genetic and/or infectious in origin** Is scrapie a virus? It has beensuggested (historically)that the scrapie agent is: * a. A self-replicating membrane polysaccharide, unlikely * b. A nucleic acid covered by a polysaccharide * c. plant viroid-like - small circular ssRNA - membrane associated, Group I introns (self splicing intron) * d. protein (PRION) - aberrant protein (PrPsc) closely related to normal cell protein(PrPc); * PrP**sc** associates to form Scrapie Associated Fibrils (SAF) - found in Brain, spleen- none in normal tissue, may form rods which resemble amyloid ultra-structures * PrP**c** corresponds to protease sensitive protein with a mw of 33 to 35 kd, * PrP**sc** has a core polypeptide, 27-30 kd, which is protease resistant

Answer 159

multiple sclerosis, subacute sclerosing panencephalitis, and visna

Answer 160

Kuru, Creutzfeldt Jakob disease, and Gerstmann-Straussler Scheinker (GSS) Syndrome, fatal familial insomnia (FFI).

Answer 161

* 1. Can withstand heating to 80o C * 2. Not inactivated by formalin - brain tissue in formalin is still infectious after 7 years - threat to pathologists * 3. Resistant to U.V. irradiation * 4. Resistant to ionizing irradiation * 5. Transmissible in animals * 6. Inactivate by chlorox (sodium hypochlorite) * 7. No immunity - except for Ab to neurofilaments

Answer 162

* Both normal and scrapie infected cells haveDNA (gene) which codes for PrPc (cellular prion protein), Pmp gene * PrPc coding region is within one exonand not varied via splicing process, * PrPc mRNA is constitutively expressed in brains of adult animals, but regulated during development * Alterations of PrPc in scrapie cells to form PrPsc is a protracted, posttranslational event, both PrPc and PrPsc are glycosylated in the form asparagines linked oligosaccharides in the Golgi via sialic acid addition; * **PrPc is transported to plasma membrane** and anchored there via phosphatidylinositol glycan * **PrPsc accumulates in cells and is deposited in cytoplasmic vesicles (vacuolation of neurons) or it can be released from the cell surface** * Several possible explanations of how an aberrant prion protein (PrPsc ) can cause disease and also be transmissible (infectious disease aspect) * - The PrPc (normal prion) gene is mutated to produce a protein product which folds at the tertiary level in an abnormal configuration PrPsc. * This abnormal protein in some way causes CNS degeneration. A small number of PrPsc proteins can act like infectious agents by interacting with normal PrPc to form a dimer (or other complexes). * PrPsc causes normal PrPc to fold in the pathogenic configuration thus amplifying number of the aberrantly folded proteins and increasing the number of pathogenic units.

Answer 163

* **Mad cow disease** (bovine spongiform encephalopathy, BSE) in United Kingdom. Cattle feed in UK supplement with ground up meat from scrapie infected sheep. * **Cows** exhibit symptoms of scrapie * Primary question: Can humans acquire the infection from eating contaminated beef? * **Several cats** have exhibited symptoms possibly from infected cat food. What about zoo animals? *(grind cat food and give to zoo animals)*

Answer 164

1) Genetically Based Disease (familial transmission) and 2)Infectious transmission In the case of humans, **familial** origins of prion disease results from mutations in the normal PrP gene, which is located on short arm of human chromosome 20 and in a homologous position of chromosome 2 in mice * a)for **CJD** a 144 bp insert found at codon 53 plus other mutations in the PrP gene have been noted, for **GSS** point mutation at codon 102 has been found protein product of mutated gene may become transmissible from person to person; mutated protein product equivalent to PrPsc or a variant thereof * b) Transmissible Disease- Infectious entity is not a typical infectious disease process

Answer 165

A. **Kuru** - a spongiform encephalitis in man similar to scrapie in sheep * Kuru was found among Fore' people in N. Guinea. The disease is marked by tremors, little or no dementia, incoordination, ataxia, somnolence, sleepiness * Kuru has been passed to animals * Kuru was transmitted by infected body parts of deceased to woman and children who consumed the remains of the dearly departed B. Creutzfeld-Jakob Disease - presenile dementia - ataxia (loss of muscular coordination) myoclonic fasciculations, semiconsciousness, involuntary contraction of groups of muscle fibers * - agent unknown - characteristic of unconventional agent - formalin treated brains produce infections after years - * - pathology of disease is like Kuru * - SAF found in infectious tissue * - Transmitted by corneal transplants and contaminated brain electrodes * Possibly transmitted from sheep to human, mutton consumption in large quantities by members of certain populations points to this relationship, ie Lybian * Jews eat eye balls of sheep. C. Other spongiform encephalopathies caused by mutated prions * - Fatal Familial Insomnia *(eventually die cause you can't sleep)* * - Sporatic fatal insomnia * Alper's, Pick's, Alzheimer's disease, possibly caused by unconventional agents

Answer 166

**A. Subacute Sclerosing Panencephalitis (SSPE)** * **Progressive demyelination, degenerative, neurological disease-----\>fatal; enormous increase in hypertrophic astrocytes and proliferation of microglial cells** * Causative agent of SSPE seems to be measles virus - helical nucleocapsid found in brain biopsy- * **co-cultivation** of biopsied cells with permissive cells grown in tissue culture induces measles virus-like formation * 1 case SSPE/million measles infection (high specific ab in blood and CSF) **B. Progressive Multifocal Leukoencephalopathy (PML)- Papovavirus (Small DNA virus)** * PML associated with lymphoproliferative disorders - the disease is a progressive neurological disorder - disease is rare, virus is not, by 14 years 65% have Ab to JC virus -- however, infection of immunocompromised -- lead to paralysis, mental deterioration ----\> death 1 year (lesions in both the gray and white matter infection of oligodendrocytes, non-inflammatory, normal

Answer 167

CSF, hard to diagnose by serology, biopsy brain 1. **Two viruses** associated with disease; both are papovaviruses * a. **SV40** (primary infection possible upper respiratory infection or urinary infection) * b. **JC virus** c**. both oncogenic** to lab animals

Answer 168

Differential Group B strep * Early onset; frist 7 days of life * **Late onset**; after 7 days of life CNS infections * Meningitis * encephalities Other infections * resp infection * UTI

Answer 169

1. Meningitis 2. more differential based on age

Answer 170

Introduction * •Most common cause of **fever** associated with signs/symptoms of CNS disease * •Viral \> bacterial \> fungal \> parasites * •Age specific pathogens Symptoms; **younger patients have unspecific findings** * •Headache * •Nausea * •Vomiting * •Anorexia * •Restlessness * •Altered state of consciousness * •Irritability Signs; **younger patients have unspecific findings** * •Fever * •Photophobia * •Bulging fontanel * •Neck pain * •Nuchal rigidity * •Obtundation * •Stupor * •Coma * •Seizures * •Focal neurologic deficits

Answer 171

•Diffuse * –Meningitis: meninges primarily involved * –Encephalitis: parenchyma * –Meningoencephalitis: both •Focal * –Brain abscess

Answer 172

**Diagnosis** of **diffuse** CNS infections **depends on examination of CSF by \*\*\*\*\*\*\*LUMBAR PUNCTURE\*\*\*\*\*\*** * ****Meningitis * Encephalitis * Menngoencephalitis

Answer 173

•Neonate * **–Group B Strep** * –E. coli * –Listeria •2 mos.-12 year * **–Strep pneumo** * –Neisseria meningitidis *(military barracks and college students)* * –H. flu b *(used to be the most common type in this age group but _vaccine_ has now helped it)* •Immunosuppressed * –Pseudomonas *(cystic fibrosis)* * –Staph *(cystic fibrosis)* * –Salmonella *(sickle cell anemia)* * –Listeria *(also neonates and unpasteurized milk)*

Answer 174

* •Age * Younger children are immuno naive. Milder infections in older child can be more serious in younger children. * •Recent colonization * •Close contact (Neisseria, H. flu b) * •Black, Native American, Eskimo, male * •Splenic dysfunction * Sickle cell people usually have autosplenectomy (small or no spleen) * •Congenital/acquired CSF leak * Bar fight - punch and fracture cribiform plate

Answer 175

Pathophysiology * •Meningeal purulent exudate * •Ventriculitis * •Cerebral infarction * •Increased intracranial pressure * •Raised CSF protein-from ↑ permeability * •Hypoglycorrhachia-from ↓ glucose transport Pathogenesis * •Bacteremia-posssibly from nasopharyngeal colonization * •Enter CSF through choroid plexus * •Multiply in CSF-low complement/Ab * •Inflammatory response triggered-can result in brain injury

Answer 176

•Sudden * –Shock * –Purpura * –Disseminated Intravascular Coagulopathy * –Can progress to coma, death w/in 24 h •Insidious * –Fever for several days * –Associated with URI, GI * –Nonspecific signs-lethargy, irritability

Answer 177

Meningeal irritation * •Nuchal rigidity * •Back pain * •Kernig * •Brudzinski

Answer 178

Spinal tap results * •Elevated white count * –Usually \> 1000/mm3 (\< 250 in 20%) * –Neonates may have 10-30 normally * –Children \< 5 * •Mostly neutrophils * •Positive Gram stain in 70-90% untreated Spinal tap - contraindications * •Evidence of increased intracranial pressure * –3rd or 6th cranial nerve palsy *(sign of increased ICP)* * –Hypertension/bradycardia/respiratory (Cushing’s triad) * –**_BULGING FONTANEL IS NOT A CONTRAINDICATION_** * •Severe cardiorespiratory compromise * •Skin infection over LP site

Answer 179

* •Brain abscess * •Subdural empyema * •Noninfectious causes * –Malignancy * –Collagen vascular diseases * –Toxins * •Acute viral meningoencephalitis

Answer 180

**CULTURE** is gold standard to tell you what organism. but you don't really wait till results come out before starting treat. treat **based on age**. **_NEVER DELAY THERAPY WAITING ON THE LP_** **Other non-abx** * •Corticosteroids * –Limits production of inflammatory mediators * –Data supports use only in H. flu b meningitis * •Supportive * –IVF * –ICP * –Seizures

Answer 181

Complications of Meningitis * •Seizures * •Increased ICP * •Cranial nerve palsies * •Stroke * •Subdural effusions Prognosis * •Mortality \< 10% after neonatal period * •Pneumococcal meningitis has highest mortality * •10-20% have severe neurodevelopmental sequelae * •Prognosis worst for \< 6 mo/o, high concentration bacteria in CSF * •Sensorineural hearing loss most common sequela Prevention * •Vaccination * –H. flu b * –Strep pneumo * –Neisseria * •Antibiotic prophylaxis * –Neisseria-rifampin for close contacts (household, daycare, nursery school, healthcare exposed to oral secretions) * •Also ciprofloxacin, ceftriaxone * –H. flu b-rifampin (4h/day for 5/7 days) * •Also ceftriaxone, cefotaxime

Answer 182

Viral meningoencephalitis * •Enteroviruses most common * •Arboviruses * –Summer months * –Mosquitoes, ticks are vectors * –West Nile, St. Louis, California * •Herpes * –Focal involvement * –Death in 70% if not treated

Answer 183

Viral Meningoencephalitis For diagnosis; EEG, CT, MRI may be helpful

Answer 184

Diagnosis * •Spinal tap * –Up to several thousand cells/mm3 * –Mononuclears appear by about 8-24 h * –Nml to slightly elevated protein * –Glucose usually normal * –Culture, PCR * •Nasopharyngeal, rectal swabs for viral culture * •CSF serology is test of choice for West Nile Virus * •Acute and convalescent serology may be useful for arbovirus **_Any findings suggestive of temporal lobe involvement should arouse suspicion of HSV_** **Treatment** * Supportive * Acyclovir

Answer 185

* •Most have complete recovery * •Mild to severe sequelae, especially with HSV * •Motor incoordination, seizures, deafness, visual disturbances, behavioral distrubances * •Poor prognosis if severe clinical illness and substantial parenchymal involvement * •Always do followup eye/ear

Answer 186

CSF - cerebrospinal fluid

Answer 187

**Indications for spinal tap** * •Suspected CNS infection * •Suspected subarachnoid hemorrhage * •Therapeutic reduction of CSF pressure * •Sampling of CSF for other reasons * •Delivering medications * *E.g in ALL (acute lymphoblastic leukemia), you need to deliver chemo into the CNS? (intrathecal chemo)* **Contraindications for spinal tap** * •Local skin infection (absolute) * •Increased ICP (except pseudotumor) * •Suspected spinal cord mass/intracranial mass * •Uncontrolled bleeding diathesis * •Spinal column deformities (relative contraindication, may require fluoroscopic assistance) * •Hemodynamic instability * •Lack of patient cooperation **Complications** * •Headache most common * •Epidermoid tumor-rare, manifests years later * •Infection * •Spinal hematoma * •Herniation-unlikely unless focal findings, coma **Procedure** * Know your opening and closing pressure * Patient laying down or sitting up * Have patient bent so needle can go through * Level L3 (top of iliac crest trace to midline) **Traumatic tap** * •1 WBC for every 500-1500 RBCs * WBCCSF=RBCCSF X (WBCperipheral/RBCperipheral

Answer 188

1. **Lacunar Infarct (associated with HTN)** 2. Slit Hemorrhage 3. Hypertensive Encephalopathy

Answer 189

Hypertension a. Affects deep penetrating arteries and arterioles * 1) Basal ganglia * 2) Hemispheric white matter * 3) Brain stem b. _**Cause arteriolar sclerosis\*\*\***_ c. Result: Single or multiple small cavity infarcts (lacunes) * 1) Tissue loss * 2) Scattered fat-laden macrophages * 3) Surrounding gliosis * 4) Occur in lenticular nucleus, thalamus, internal capsule, deep white matter, caudate nucleus, pons 2. Clinical spectrum ranges from silent to severe neurologic impairment *_**\*\*\*Hypertensive CV disease likes to occur in BASAL GANGLIA**_*

Answer 190

**Slit hemorrhages** * Caused by hypertension * Small hemorrhages * Hemorrhages resorb causing a slit-like cavity surrounded by a brownish discoloration

Answer 191

**Hypertensive Encephalopathy** 1**. Acute** * a. Headache, confusion, vomiting, convulsions, sometimes coma * b. Rx: must be rapid in order to reduce intracranial pressure 2**. Over months to years** – resulting in multiple infarcts – results in: a. Dementia, gait abnormalities, pseudobulbar signs, and often with superimposed neurologic deficits [syndrome called vascular (multi-infarct) dementia] b. Multifocal vascular disease * 1) Cerebral atherosclerosis * 2) Vessel thrombosis or embolism * 3) Cerebral arteriolar sclerosis from chronic hypertension * 4) *When predominantly white matter, called Binswanger disease*

Answer 192

**Intracranial Hemorrhage** * Intracerebral (intraparenchymal) hemorrhage * Subarachnoid hemorrhage and ruptured berry aneurysms * Vascular Malformations

Answer 193

**1. Spontaneous (non-traumatic) rupture of a small intraparenchymal vessel** * a. Occurs most frequently in mid to late adult life, peak age 60 years * b. Hypertension: causes more than 50%, htn results in * 1) Accelerated atherosclerosis (large vessel) * 2) Hyaline arteriolosclerosis (smaller vessel) * 3) In severe hypertension * a) Proliferative changes * b) Necrosis of arterioles * 4) Vessels are weaker, aneurysms form **(Charcot-Bouchard microaneurysms)** – most commonly in basal ganglia * 2. Morphology * a. Location when due to hypertension: * 1) Putamen (50-60%), thalamus, pons, cerebellar hemispheres (rarely) * a) Ganglionic hemorrhages * 2) Extravasation of blood causing compression of adjacent parenchyma * 3) If old there is a cavity * Clinical a. Location of bleed determines clinical manifestations: devastating, silent or evolving like an infarct b. Clinical improvement seen with resolution of hematoma

Answer 194

LOBAR HEMORRHAGES

Answer 195

1. Causes: * **a. Rupture of a saccular (berry) aneurysm – most frequent cause** * b. Extension of a traumatic hematoma * c. Rupture of a hypertensive intracerebral hemorrhage into the ventricular system * d. Vascular malformation * e. Hematologic disturbances * f. Tumors 2. Berry aneurysm (saccular aneurysm, congenital aneurysm) a. Most common intracranial aneurysm [b. Other aneurysms: these do NOT usually give rise to subarachnoid hemorrhage * 1) Atherosclerotic (fusiform, usually of basilar artery) * 2) Mycotic * 3) Traumatic * 4) Dissecting] c. 90% of Berry aneurysms occur in the ANTERIOR circulation at major branch points, multiple aneurysms exist in 20-30% or cases

Answer 196

a. Etiology: unknown, majority are sporadic * 1) Increases risk: Autosomal dominant polycystic kidney disease, Ehlers-Danlos syndrome type IV, neurofibromatosis type I, Marfan syndrome, fibromuscular dysplasia of extracranial arteries, coarctation of the aorta b. Predisposing factors: cigarette smoking, hypertension c. NOT identifiable at birth

Answer 197

Morphology a. Thin-walled outpouching * 1) Muscular vessel wall and internal elastic lamina are not in the wall of the aneurysm * 2) Wall of aneurysm has thickened, hyalinized intima; covered by adventitia that is continuous with parent artery b. May see: atheromatous plaque, calcification or thrombotic occlusion * *c. Usually ruptures at APEX of sac** Clinical * a. Rupture is the most frequent complication (74% of patients have evidence of rupture) * b. Fifth decade, slightly more females * c. Sudden, excruciating headache * d. Rapid loss of consciousness * e. First rupture: 25-50% die * f. Rebleeding common in survivors * g. Acutely: vasospasm occurs * 1) Can occur in other vessels not originally injured * 2) Can cause addition ischemic injury * h. Late sequelae * 1) Meningeal fibrosis and scarring * 2) Obstruction to CSF flow and reabsorption

Answer 198

* AV malformations * Cavernous hemangioma * Capillary telangiectasia * Venous angioma (varies)

Answer 199

1. Arteriovenous malformations * a. General * 1) Males 2X \> females * 2) Most often detected between 10 and 30 years of age as a * a) Seizure disorder * b) Intracerebral hemorrhage * c) Subarachnoid hemorrhage * 3) Most common site: middle cerebral artery, esp. posterior branches * 4) If large and occurring in a newborn can cause CHF due to shunt effect esp. if occurring in vein of Galen (internal cerebral vein) * b. Morphology * 1) Occurs in * a) Subarachnoid going into brain OR * b) Within the brain * 2) Gross: tangled web, pulsatile * *2. Cavernous hemangioma** a. Greatly distended, loosely organized vascular channels * 1) Thin collagenized walls * 2) Devoid of intervening nervous tissue (differentiates this malformation from a capillary telangiectasia) b. Most common locations: cerebellum, pons, and subcortical regions * *3. Capillary telangiectasia** a. Dilated, thin-walled vessels separated by relatively normal brain parenchyma b. Most commonly in pons **4. Venous angiomas (varices)** – aggregates of ectatic venous channels

Answer 200

A. Displaced fracture – bone is displaced into cranial cavity \> thickness of bone B. Occipital impact from fall while awake C. Frontal impact from fall while unconscious D. Basal skull fracture from impact to occiput or sides of head * 1. Fracture of at least one of five bones making up the base of the skull * a. Cribiform plate of ethmoid bone * b. Orbital plate of frontal bone * c. Temporal bone – petrous and squamous portions * d. Sphenoid bone * e. Occipital bone * 2. Symptoms: lower cranial nerve compromise * 3. Signs: **Orbital hematoma _(raccoon eyes)_ or mastoid hematoma _(Battle’s sign)_** * 4. Meningeal tear resulting in CSF leak through the nose (CSF rhinorrhea) or ears (CSF otorrhea) * a. CSF has low protein and the presence of glucose * b. Mucus has high protein and NO glucose * c. Pathway for infection * 5. High risk for epidural hematoma from injury to middle meningeal artery

Answer 201

1. Concussion 2. Direct parenchymal injury 3. Diffuse axonal injury

Answer 202

Concussion (closed injury) 1. Altered consciousness following head injury 2. Due to sudden change in momentum of head 3. No acute gross nor histologic abnormalities 4. Associated with * a. Temporary respiratory arrest * b. Loss of reflexes * c. Amnesia * 1) Retrograde – loss of memory of events shortly before trauma AND/OR * 2) Post-traumatic – loss of memory of events immediately after * d. Confusion * e. Headache – most common complaint * f. Other minor neurologic symptoms – impaired concentration, visual * disturbance, loss of balance, nausea, vomiting 5. Postconcussive syndrome (recurrent headaches, impaired concentration, minor neurologic symptoms) – usually resolves within 7 days but may persist for several weeks to months

Answer 203

**1. Cerebral contusion** a. Rupture of small vessels near the surface of the brain b. Acceleration-deceleration injuries * 1) Coup – lesion corresponding to site of impact * 2) Contrecoup – lesion opposite site of impact (occurs if head is mobile at time of injury) c. Morphology * 1) Early – pericapillary edema and hemorrhage * 2) Hours – bleeding throughout involved tissue, white matter and subarachnoid space * 3) 24 hours – evidence of neuronal injury (pyknosis of nucleus, eosinophilia of cytoplasm, disintegration of cell) * 4) Inflammatory response to injured tissue * 5) Old traumatic lesions – depressed, retracted, color changes to yellow-brown as heme is broken down (plaque jaune). May become site of epileptic focus **2. Cerebral laceration** a. Most severe type of injury b. Tearing of cerebral tissue causing acute hemorrhage into * 1) Subarachnoid OR * 2) Subdural space c. Profound neurologic dysfunction d. HIGH mortality * *3. Penetrating (open) injuries** a. Due to gun shots and severe blunt trauma b. Cause severe brain damage with a high incidence of infection c. Symptoms and sequelae depend on * 1) Extent * 2) Area of damage

Answer 204

* 1. Involves deep white matter regions * 2. Microscopic: Axonal swelling appearing hours after injury and focal hemorrhage. Later: increased microglia and degeneration of involved fiber tracts * 3. Cause: angular acceleration even without impact (up to 50% of pts who develop coma after trauma without cerebral contusions)

Answer 205

* Epidural Hematoma * **Accumulation of blood between the skull and dura** * **Most often middle meningeal artery** * **Lucid period** * Subdural Hematoma

Answer 206

**Epidural Hematoma** * 1. Accumulation of **blood between the skull and dura** *(virtual space)* * 2. Most common complication of NON-penetrating head injuries * a. 90% due to tear of a dural artery, most often **middle meningeal artery** (often associated with fracture of the temporal region of the skull) * b. 10% are venous in origin * 3. When arterial, expands rapidly – symptoms within hours * 4. When due to a venous bleed, symptoms develop more slowly * 5. Symptoms * a. Variable period of concussion (loss of consciousness) then * b. Conscious for up to several hours (lucid period) then * c. Headache, vomiting, altered consciousness, and papilledema * (ALL signs of increased intracranial pressure) then * d. Tentorial herniation rapidly follows * 1) Oculomotor nerve palsy (pupillary inequality first then failure to react to light * 2) Compression of brain stem (change of heart rate, blood pressure * and respiration) * 3) Untreated: coma and death * 6. Diagnose early since surgical evacuation early is successful

Answer 207

**1. Dura mater –** * a. Two layers * 1) External collagenous layer * 2) Inner border cell layer with scant fibroblasts, and abundant extracellular space devoid of collagen * b. Bleeding separates layers * c. Accumulation of blood between the layers of the dura (NOT in the subdural space despite the name) **2. Pathogenesis** * a. Trauma required is minimal – may have no history of trauma * b. Rupture of veins from cerebral cortex to the superior sagittal sinus (bridging veins) * 1) 10% are bilateral * 2) Bleeding is usually slow and self-limited * c. Common especially in elderly due to atrophy of the brain and stretching of the bridging veins **3. Morphology** * a. Organization of the hematoma * 1) Lysis of clot (1 week) * 2) Growth of fibroblasts into hematoma (2 weeks) * 3) Early development of hyalinized connective tissue (1-3 months) * b. Hematoma is firmly attached to dura * c. Multiple episodes of rebleeding may occur (chronic subdural hematoma) from thin-walled vessels in granulation tissue **4. Clinical** * a. Symptoms most often appear within first 48 hours * b. Intracranial pressure increases slowly causing symptoms: * 1) Headache, vomiting, papilledema * 2) Fluctuating consciousness * c. Also may develop * 1) Epileptic focus * 2) Neurologic symptoms (spastic paralysis is most common) * d. If prolonged, may cause atrophy and dementia * e. Treatment: surgical evacuation is curative – return of brain function is variable

Answer 208

A. Chronic traumatic encephalopathy (CTE) – * 1. Develops after repeated head trauma such as concussions despite the belief that there are not structural sequelae of concussions * 2. Dementia * 3. Brain is atrophic with enlarged ventricles * 4. Neurofibrillary tangles in superficial frontal and temporal lobe cortex B. Posttraumatic hydrocephalus – obstruction in subarachnoid space C. Posttraumatic epilepsy D. Increased risk of infection E. Psychiatric disorders

Answer 209

**Spinal Cord injuries** A. Caused by: * 1. Forced movements (whiplash) * 2. Vertebral fractures * 3. Subluxations B. Basic injuries * 1. Concussion, contusion, and laceration * 2. Often more severe due to concentration of neural pathways * 3. If high, then quadriplegia - death may occur if respiratory muscles are paralyzed * 4. Thoracic cord injury may lead to paraplegia and dysfunction of the bladder and rectum

Exam 1 Flashcards

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