Degenerative Disease of Basal Ganglia and Brainstem Overview Symptoms of lesions in these areas are assoc.

. w/ movement disorders: rigidity, abnormal posturing, and chorea General categorized as manifesting reduction of voluntary movement, or Abundance of involuntary movement The basal ganglia, esp. nigrostriatal pathway, important for positive & negative feedback of synaptic pathways modulating feedback from the thalamus to motor cortex Principal diseases involving the nigrostriatal system o Parkinson Disease (PD) o Multiple system atrophy, commonly assoc. w/ parkinsonism and other symptoms o Postencephalitic parkinsonism (late consequence of the 1918 flu pandemic) o Progressive supranuclear palsy o Corticobasal degeneration; May also show cognitive impairment Parkinsonism Diminished facial expression, Stooped posture, Slowness of voluntary movement, Festinating Gate (progressively shortened, accelerated steps), Rigidity, and a Pill-Rolling tremor Damage to the nigrostriatal dopaminergic system Also can be induced by drugs that effect this system, particularly dopamine antagonists and toxins Parkinson Disease AD and AR inheritance Patients w/ progressive L-Dopa-responsive signs of Parkinsonism (tremor, rigidity, bradykinesia) in the absence of toxin or o/ known etiology Morphology Macroscopic: Pallor of the substantia nigra & locus ceruleus Microscopic: Loss of pigmented, catecholaminergic neurons in these regions, assoc. w/ gliosis o Lewy Bodies are found in some remaining neurons Lewy body = single or multiple, cytoplasmic, eosinophilic, round-to-elongated inclusions, often w/ a dense core surrounded by a pale halo Ultrastructuraly, Lewy bodies are composed of fine filaments (made of -synuclein), densely packed in core but loose at the rim LBs may also be found In cholinergic cells of basal nucleus of Meynert, which is depleted of neurons (especially in patients w/ abnormal mental function Brainstem nuclei like locus ceruleus and dorsal motor nucleus of Vagus nerve Molecular Genetics 12+ genetic loci for PD, found via linkage studies; 5 are clearly associated w/ PD o Mutations in -synuclein Autosomal Dominant inherited form of PD

A normally pigmented substantia nigra is seen grossly in the midbrain on the right, but the midbrain on the left from the patient with Parkinson's disease shows a pale substantia nigra.

-synuclein is an abundant lipid-binding protein normally assoc. w/ synapses, also a major component of Lewy bodies Rare, point mutations and amplifications of 4q21 Changes in gene copy # Disease; this implies a gene dosage effect

A normally pigmented substantia nigra is seen on the left, but the patient with Parkinson's disease has decreased neurons and pigment as seen microscopically at the right.

Also suggests polymorphisms in -synuclein promoter; altering its expression may affect PD risk LRRK2 (Leucine-rich Repeat Kinase 2) gene mutations: more common cause of AD PD Found in some sporadic cases of disease Some are GOF mutations activity of LRRK2

Pathogenesis Parkin gene LOF mutation o E3 ubiquitin ligase w/ a wide range of substrates; causes juvenile AR PD o Lewy bodies mostly absent o Otherwise similar to -synuclein and sporadic PD DJ-1 gene mutation o Protein involved in regulating redox responses to stress; causes AR PD Kinase PINK1 gene mutation A rounded pink cytoplasmic Lewy o Regulates normal mitochondrial functions; causes AR PD body is seen microscopically with Mechanisms H and E stain at the left, while o Misfolded protein/stress response triggered by -synuclein immunoperoxidase staining with aggregation antibody to ubiquitin reveals the o Defective proteosomal function due to the loss of the E3 appearance at the right. ubiquitin ligase parkin o Altered mitochondrial function caused by loss of DJ-1 and PINK1 o Possible role of mitochondrial dysfunction Mitochondrial Complex I levels (component of oxidative phosphorylation cascade) Decreased in brains of patients w/ sporadic PD (LRRK2 gene mutation) Dopaminergic neurons of the substantia nigra project to the striatum; Degeneration in PD is assoc. w/ striatal dopamine content Severity of motor syndrome is proportional to dopamine deficiency (Tx w/ L-Dopa; immediate precursor to Dopamine) o Tx will not reverse morphologic changes or arrest disease progress o As the disease progresses, the drug becomes less effective (due to loss of Dopamine Rs) and symptoms become more difficult to manage Acute Parkinsonian Syndrome & Neuronal destruction in substantia nigra follows exposure to MPTP, a contaminant in illicit synthesis of psychoactive meperidine analogues (Demerol; used on street when heroin scarce) Pesticide is a risk factor for PD Caffeine and Nicotine may be protective Clinical Features Common to see impairment of cognitive function, along with the autonomic dysfunction of parkinsonism sometimes accompanied by dementia, either early in course or as a late additional morbidity L-Dopa is extremely effective, but over time it is less able to give relief of symptoms, and starts causing motor function problems on its own Neurosurgical interventions include lesioning elsewhere in the extrapyramidal system to compensate for nigrostriatal function loss; and placement of stimulating electrodes (deep brain stimulation) Huntingtons Disease - AD Progressive movement disorders and dementia w/ degeneration of striatal neurons Jerky, hyperkinetic, sometimes dystonic movements involving entire body (chorea) May later develop parkinsonism w/ bradykinesia and rigidity Relentlessly progressive; death in 15 years

Molecular Genetics HD gene on 4p16.3; encodes huntingtin gene o Polyglutamine trinucleotide repeat expansion disease o First exon of gene there are CAG repeats, encoding a Huntington's disease is shown polyglutamine region near the N terminus grossly in this coronal section of o Normal: 6-35 copies of the repeat; more disease the brain. It demonstrates o Inverse relationship b/w repeat number and onset more atrophy of the caudate with repeats = earlier onset resultant increase in size of o Repeat expansions occur during spermatogenesis Paternal lateral ventricles. transmission is assoc. w/ early onset in the next generation (anticipation) De novo mutations are uncommon; most apparently sporadic cases are related to non-paternity, death of a parent before expression of disease, or the father is unaffected w/ a mild repeat expansion that further enlarged during spermatogenesis Morphology Macroscopic o Brain is small; shows atrophy of caudate nucleus & (less at early stages) the putamen o Globus pallidus may be atrophied secondarily o Lateral and 3rd ventricles are dilated o Atrophy is also frequent in the frontal lobe, less often in parietal, occasionally the entire cortex Microscopic o Severe loss of striatal neurons o Most marked changes in caudate nucleus, esp. in tail and portions near the ventricle o Putamen is involved later in disease o Pathology develops medially to laterally in the caudate, and dorsally to ventrally in the putamen o Nucleus accumbens is the best preserved portion of the striatum o Both large & small neurons affected, but loss of small neurons occurs first o Medium-sized, spiny neurons that use GABA as a NT, along w/ encephalin, dynorphin, and substance P, are especially affected Microscopically, the caudate nucleus o 2 populations of neurons are relatively spared in Huntington's disease demonstrates Diaphorase + neurons contain nitric oxide loss of neurons along with gliosis. synthase (NOS) Large cholinesterase + neurons Both serve as local interneurons o Fibrillary gliosis is also present, and is more extensive than in usual reaction to neuronal loss o Direct relationship b/w the of degeneration in striatum and severity of clinical symptoms o Protein aggregates containing huntingtin are in neurons of striatum and cerebral cortex Pathogenesis Loss of medium spinal striatal neurons dysregulation of basal ganglia circuitry that modulates motor output (normally function to dampen motor activity) increased motor output manifested as choreoathetosis Cognitive changes due to neuronal loss from cerebral cortex Expansion of polyglutamine region toxic GOF effect on huntingtin o Expanded polyglutamine repeat protein aggregation & formation of intranuclear inclusions not injurious o Transcriptional dysregulation is implicated w/ mutant forms of huntingtin binding transcriptional regulators Sp1 and CBP (cAMP response-element binding protein) o Sequestration of critical TFs down-regulation of PGC-1, a TF itself, involved in mitochondrial biogenesis & protection against oxidative injury Clinical Features Age at onset most commonly 40s-50s but is related to length of CAG repeat in HD gene Motor symptoms precede cognitive impairment Movement disorder of HD is choreiform, w/ increased & involuntary jerky movements of all parts of body; writhing movements of extremities is typical Early symptoms of higher cortical dysfunction: forgetfulness, thought & affective disorders; progression to severe dementia

HD patients have increased risk of suicide, but intercurrent infection is MCC of (natural) death

Amyotrophic Lateral Sclerosis (ALS) aka Lou Gehrig's Disease Degenerative disease affecting motor neurons Loss of lower motor neurons in spinal cord and brainstem, and upper motor neurons that project in corticospinal tracts Denervation of muscles from loss of LMNs muscular atrophy, weakness, fasciculations 5-10% familial (fALS) mostly AD Molecular Genetics 25% of fALS caused by mutations in SOD1 on chromosome 21 o Mostly missense mutations o SOD1 encodes Copper-Zinc Superoxide Dismutase o ALS caused by adverse GOF phenotype w/ mutant SOD1 o Mutation is Alanine Valine substitution in residue 4 (most common in US) Assoc. w/ rapid course Rarely has UMN signs Other loci (nowhere near as prevalent as SOD1 mutations) o Dynactin involved in retrograde axonal transport o VAMP-associated protein B regulation of vesicle transport o Alsin containing guanine nucleotide exchange factor domains, assoc. w/ regulation of endosomal trafficking by interaction w/ Rab5b Pathogenesis A normal spinal cord is shown Mutated SOD1 protein is misfolded triggers injurious Unfolded Protein compared to the cord of a Response patient with ALS to highlight Mutated SOD1 in non-neuronal (glial & smooth muscle) cells may also the difference in size of the contribute to disease nerve roots. The atrophy is Alterations in axonal transport, neurofilaments abnormalities, toxicity apparent in the ALS cord. mediated increased levels of Glutamate (NT), and aggregation of other proteins (ex. TDP-43, sometimes found in ALS cytoplasmic inclusions), all suggested mechanisms for progressive loss of motor neurons Morphology Macroscopic: Anterior roots of the spinal cord are thin and precentral gyrus may be atrophic Microscopic: Reduced # of anterior-horn neurons throughout length of SC w/ assoc. reactive gliosis and loss of anterior root myelinated fibers o Similar findings in hypoglossal, ambiguous, and motor trigeminal CN nuclei Remaining neurons have Bunina Bodies = PAS+ cytoplasmic inclusions that are remnants of autophagic vacuoles Skeletal muscles innervated by degenerated LMNs neuro genic atrophy Loss of UMNs degeneration of corticospinal tracts volume loss & absence of myelinated fibers, particularly at lower segmental levels Clinical Features Early symptoms: asymmetric weakness of hands dropping objects and difficulty w/ fine motor tasks; and cramping and spasticity of arms and legs Progression muscle strength and bulk diminish involuntary contractions of individual motor units = fasciculations Disease eventually involves respirato ry muscles, causing recurrent pulmonary infections Severity of involvement of UMNs and LMNs varies; progressive muscular atrophy applies to relatively uncommon cases where LMN involvement predominates

In some, degeneration of lower brainstem cranial motor nuclei occurs early and progresses rapidly = Progressive Bulbar Palsy aka Bulbar ALS o Abnormalities of deglutition and phonation dominate; clinical course is unstoppable during a 1-2 year period; when bulbar involvement is less severe, about 50% of affected are alive 2 years after diagnosis Familial cases develop symptoms earlier than most sporadic cases, but clinical course is comparable

There is lateral column degeneration of There is loss of anterior horn cells the spinal cord microscopically in this apparent in this H and E stained section Demyelinating and Degenerative Diseases case of ALS, as seen with Luxol fast blue of spinal cord in this microscopic section Multiple Sclerosis (MS) stain. in a case of ALS. Autoimmune demyelinating disorder most common disease of young adults; Women 2x > Men; Common in Caucasians Distinct episodes of neuro defects separated in time, attributed to white matter lesions separated in space Relapsing and remitting episodes of varying duration w/ neuro defects, followed by gradual, partial recovery of function Experimental Autoimmune Encephalomyelitis (EAE) Inducing MS modeled in animals by immunizing them w/ Ags normally present in the CNS myelin to elicit an immune response 1-2 weeks Animals develop encephalomyelitis (perivascular infiltrates of lymphocytes and macrophages in CNS white matter, followed by demyelination) o EAE is shown by Epitope Spreading: tissue breakdown results in new release of protein antigens and expression of previously sequestered epitopes that activate more autoreactive T-cells Pathogenesis Abs against myelin sheath components Major Basic Protein (MBP) o CD4+ and CD8+ T cells w/ specificity for MBP are in blood and brains of patients w/ MS CD8+ cells cause oligodendrocyte death CD4+ cells cause inflammation Macrophages are involved as well Genetic linkage of MS susceptibility: HLA-DR2, HLA-DR1, and HLA-DQ1 extended haplotype of MHC Assoc. w/ SNPs in IL-2 and IL-7 R genes o Polymorphism in the non-coding region of CD25, the gene encoding IL-2 R chain Or disease could be from defective T-regulatory cell lineage Disease is initiated by CD4+ TH1 and TH17 cells reacting against self-myelin Ags o TH1 secretes IFN- macrophages o TH17 recruits leukocytes demyelination caused by the activated leukocytes and their products Humoral Immunity role: Immunoglobulin oligoclonal bands in CSF; B-cell depletion demyelinating lesions Viral infection likely causes the activation of myelin-reactive T-cells via Molecular Mimicry o Observations that support infectious agents as cause MS is a disease of temperate climates barely any cases at the equator Occasional MS epidemics have occurred 40% of new clinical events follow viral infections Raised titers of CSF Abs to measles virus found Self-tolerance may fail from inheriting Susceptibility Genes; identical twins have a higher rate of MS if one is found to be a carrier Morphology Lesions: Multiple, well-circumscribed, somewhat depressed, glassy, gray-tan, irregularly shaped plaques o Firmer than surrounding white matter in fresh state = sclerosis o Found throughout the white matter o Occur adjacent to lateral ventricles o Frequently also in optic nerves and chiasm, brainstem, ascending and descending fiber tracts, cerebellum, and spinal cord o Plaques = area of white matter where myelin & oligodendrocytes are absent Early stage: tissue edema, apoptotic oligodendrocytes, & infiltrating cells; lymphocytes & macs are seen around the venules in the area B cells produce Ig locally, & T cells and macs are part of the acute inflammatory process Active Plaques o Microscopically, active plaques show ongoing myelin breakdown w/ abundant macrophages containing lipid-rich, PAS+ debris Lymphocytes, monocytes are present as perivascular cuffs @ outer edge of lesion o Active lesions usually centered on small veins o Within the plaque: relative preservation of axons and depletion of oligodendrocytes o Grouped into 4 patterns:

Pattern 1: Sharply demarcated, centered on BVs, w/ deposition of Ig & complement Pattern 2: Sharply demarcated, centered on BVs, w/o deposition of Ig & complement Pattern 3: Less well-demarcated, not centered on BVs, oligodendrocyte apoptosis in widespread Pattern 4: Less well-demarcated, not centered on BVs, oligodendrocyte apoptosis is central only Only 1 pair of patterns may be present in a patient: 1 & 2, or 3 & 4 o Active quiescent: Inflammatory cells slowly disappear Inactive Plaques o Little/no myelin found o Reduction in number of oligodendrocyte nuclei; instead, astrocytic proliferation and gliosis are seen o Axons in old gliotic plaques show severe depletion of myelin and are greatly diminished in number o Shadow Plaques border b/w normal and affected white matter is not sharply circumscribed Can see abnormally thinned-out myelin sheaths, especially at outer edges = Evidence of partial and incomplete re-myelination by surviving oligodendrocytes The remaining axons in most MS plaques remain unmyelinated

Clinical Features Unilateral visual impairment: Due to involvement of the optic nerve = optic neuritis; Frequent initial manifestation of MS (not everyone w/ optic neuritis gets MS) Brainstem involvement Cranial nerve signs, ataxia, nystagmus, and internuclear opthalmoplegia: Due to interruption of fibers of medial longitudinal fasciculus Spinal cord lesions Motor and sensory impairment of trunk and limbs, spasticity, and voluntary bladder control dysfunction CSF: Mildly Protein level; Moderate pleocytosis (= presence of a greater number of cells than normal in CSF); IgG levels are and oligoclonal IgG bands are observed on immunoelectrophoresis, indicative of a small number of activated B cell clones, possibly self-reactive, in the CNS MRI to assess disease progression; show some plaques may be clinically silent, even in otherwise symptomatic patients CSF [IgG] is best expressed w/ albumin (serum protein, not made in brain) which indicates the blood-CSF barrier integrity o Intracerebral synthesis of IgG rise in IgG/Albumin ratio o If the raised CSF [IgG] is due to a leaky BBB, then albumin will also be elevated, and the ratio will be constant o IgG synthesized in the brain appears as typical oligoclonal bands on isoelectric focusing o CSF findings from patients w/ definite MS Oligoclonal bands ( > 95% of MS patients) CSF IgG index (70-80% of MS patients) cell count (50% of MS patients) Raised IgG/Albumin ratio (50% of MS patients) Treatment Immunotherapy Abs against VLA-4 integrin blocks leukocyte migration into CNS beneficial, but also reactivation of JS virus infection Fingolimoid (FTY720) blocks sphingosine 1-phosphate-mediated pathway of T cell egress from lymphoid tissues B cell depletion is a useful treatment method (B cells aid in activation of pathogenic T cells) Corticosteroids have been used in acute attacks to suppress the inflammatory response, but does not stop progression Central Pontine Myelinolysis Pathogenesis Loss of myelin w/ relative preservation of axons and neuronal cell bodies, in a roughly symmetric pattern Involves basis pontis & portions of pontine tegmentum, sparing the periventricular and subpial regions Lesions may be found more rostrally Extremely rare for the process to extend below the pontomedullary junction Extra-pontine lesions occur in the supratentorial compartment Assoc. w/ rapid correction of hyponatremia o MCC of CPM o Due to quick rise in bodys Na+ levels, most often occurring when someone is treated for low levels of Na+ (hyponatremia), and the levels rise too quickly o Does not occur on its own it is a complication of treatments for o/ conditions, or from the conditions themselves

Clinical Presentation Rapidly evolving quadriplegia Radiologic imaging studies localize the lesion to the basis pontis Morphology Myelin loss w/o evidence of inflammation; neurons and axons are well-preserved Because of the monophasic nature, all the lesions appear to be at the same stage of myelin loss Guillain-Barr Syndrome Immune-mediated acute peripheral neuropathy Acute Idiopathic Polyneuritis Uncommon, subacute onset PNS is infiltrated w/ lymphocytes and macrophages, destroying myelin as a result Half of cases occur in relation to an infectious illness, often Campylobacter jejuni (diarrhea); 10% follow surgical procedure; the rest are idiopathic Pathogenesis Production of auto-Abs to peripheral nerve tissue gangliosides, triggered by infection CSF protein, including IgG, which is often oligoclonal Antibodies to known gangliosides like GM1b are found in 70% of patients Evidence for autoimmune nature of GBS o Assoc. w/ preceding infection o Cross-reactive epitopes b/w pathogen & autoantigen gangliosides o IgG & C1q are deposited in nerves, seen on biopsies o Anti-ganglioside and anti-myelin Abs are in serum o Correlation of Abs w/ clinical disease course o Oligoclonal IgG in CSF o Successful therapy w/ plasma exchange or IVIG Most patients improve w/in a few weeks of onset, recovery is usually complete and therapy is avoided In severely affected patients, recovery time shortened if IVIG given in large doses as soon as the diagnosis is made Plasma Exchange: beneficial in severely affected patients when used within 48 hours of start of symptoms Peripheral Neuropathies Multiple Myeloma Presents with a mixed sensory and motor peripheral neuropathy asymmetrically involving upper and lower extremities Amyloidosis: patches of amorphous pink material on Congo red stain amyloid becomes apple green when viewed though polarized light. Sural nerve - purely sensory - so okay to biopsy Chronic Arsenic Poisoning Results in mixed peripheral neuropathy Always should be considered in cases of unexplained neuropathy Diabetes Typically symmetrical and mixed sensory and motor The nerves show segmental demyelination, fiber loss, and sclerosis of small blood vessels This lesion may be ischemic, metabolic, or a combination of the two

Cancers Peripheral Nervous System Tumors Schwannomas Case Ex: Slowly growing nodule in the subcutaneous tissue of the flexor aspect of her right forearm. The nodule appeared to be attached to a nerve. It had a smooth outer surface and no distinctive features on cut surface. No other nodular lesions and no skin lesions Encapsulated tumor which has a biphasic growth pattern, benign neoplasm of Schwann cell origin.

Can occur in any age group, but are most common in young adults. Arise most frequently in the head and neck area, one classic site being the 8th cranial nerve (so - called acoustic neuroma). Flexor aspects of the extremities represent another common location Most are sporadic, but they can be associated with neurofibromatosis. Although attached to peripheral nerve, schwannomas do not include nerve fibers within the tumor Left - Antoni A pattern, =bland spindle cell proliferation, the nuclei and cytoplasm of adjacent cells often line up in characteristic arrays called Verocay bodies right =Antoni B.=is a more loosely structured, vacuolated tissue

Schwann Cell Origin Sarcoma Malignant peripheral nerve sheath tumor tumors are more cellular, more pleomorphic, and more mitotically active than schwannoma. Patients with neurofibromatosis are at high risk for this malignancy. Neurofibroma Benign neural tumor occurring in all age groups and in many sites, but most commonly as a skin nodule. In contrast to schwannoma, neurofibroma includes nerve fibers, which can be identified by silver stains. These tumors also are usually sporadic, but in 10% of patients they are related to the inherited condition neurofibromatosis, in which case they typically are numerous and disfiguring

Bug Keywords L. monocytogenes

N. meningitidis

Broad temp & High [salt] growth Survives proteolytic enzymes, low pH, bile salts 2-3 day growth on enrichment (sheep blood agar) @ 4 C Room Temp Tumbling (end - over - end) Cabbage Transplacental Warmer months CMI - Immunocompromised Stress - Response Genes Internalin A E-cadherin Coffee bean shape Grows best 35 - 37 C in humid atmosphere Oxidase + Polysaccharide capsule Pili colonization of nasopharynx (non ciliated columnar cells) Lipooligosaccharide (LOS) = Endotoxin Diffuse vascular damage Survive intracellular killing if no humoral immunity R host transferring to steal iron Humans only natural hosts Institutionalized people, barracks, dormatories Serogroups A, B, C, Y, W135 Dry, cold months of year Waterhouse - Frederickson

FAE M (microfold) cells of Peyers patches Listerolysin O Lyses 2 PLCs ActA actin movement Filopod Siderophores steal Iron from transferrin Granulomatosis infantiseptica Gram + Motile

PorB Porin Protein interferes w/ neutrophil degranulation, facilitates invasion, makes it resistant to complement Rmp proteins Stimulation of Abs that block serum bactericidal activity Ig A1 protease Fc and Fab fragments URI presentation Arthritis Urethritis Dies rapidly when exposed to cold or dry conditions Rifampin chemoprophylaxis OPA proteins opacity Ag variation: Repeats of 5-nt sequence Increased among ppl w/ MAC formation deficiency (C5 - C9)

S. pneumoniae

H. influenzae M. leprae

C. neoformans

Breast-fed immunity MCC community - acquired meningitis (hemolytic strep, which is S. pneumoniae) Pneumolysin Lancefield Ags Rapid Ag test for pharyngitis classical complement Exudate in meningitis is usually basal PGL - 1 found only in M. leprae Armadillos! Acid Fast Unable to be cultured Leprosy tuberculoid (paucibacillary aka Hansen disease; granulomatous) and lepromatous (multibacillary; severe) Grows in low temperature areas skin, appendages Fungus Encapsulated yeast Lung is portal of entry Glucose < 20 Cryptococcal Antigen India Ink Staining Cats and their poop Extra-intestinal life cycle Oocysts, Pseudocysts, Bradyzoites, Tachyzoites Oral transmission Multiple, abscessing lesions in gray & white matter Parasite Warm, stagnant freshwater Primary amebic meningoencephalitis (PAM) West/Gambien African Sleeping Sickness West & Central Africa East African Sleeping Sickness (more severe) Acute fever, rigors, myalgia Die w/o Tx Reduviid/Kissing bugs N., Central, S. America Chagoma

T. gondii

Furuncles, carbuncles, impetigo Exudate in meningitis densest over cerebral convexities near sagittal sinus High amt of capsule polysacc gelatinous exudate arachnoid fibrosis = Chronic adhesive Arachnoiditis Vaccine (HiB) no longer major cause Infects skin and peripheral nerves Hypopigmented and hairless macules tuberculoid Sensory loss at face, extremities anesthetized, loss of eyebrows, thick nose, thick cheeks, infertility, disfiguring, nodules, plaques, thickened dermis lepromatous Skin testing to confirm tuberculoid, microscopy not sensitive PAS, Mucicarmine, and silver stains Soap bubbles in parenchyma (cysts), especially in basal ganglia and lenticulostriate arteries Aggregates of organism in Virchow - Robinson spaces w/ little/no inflammation or gliosis MCC of multiple enhancing brain lesions (HIV/AIDS) Brain abscesses in CC & deep gray nuclei Cystic spaces in chronic lesions w/ lipid- and hemosiderin-laden macrophages

N. fowleri T. brucei gambiense T. rhodiense T. cruzii

Cribiform plate olfactory nerves anterior cerebral fossae hemorrhage Lymphadenopathy CNS involvement after years Lethargy, anorexia, mental disturbances Tsetse fly (Glossina pallipedes, Moriades) NO LAD Romanas sign (rash, edema around eyes) Chronic Megacardia & ECG changes Granulomas in brain

Bug Quickies look at Micro/Immuno Packet for the whole thing Bacterial Meningitis Dissemination through blood or direct (traumatic) CNS in SAS proliferate Hyperemic phase in meningeal vessels PMNs recruited Cross BV walls SAS = Acute stage; Edema in underlying cerebral cortex Morphology CSF cloudy, sometimes frankly purulent Meningeal vessels encouraged, stand out prominently Location of exudate varies o H. influenza: basal o Pneumococcal meningitis: densest over cerebral convexities near sagittal sinus o Cute meningitis: exudate evident within leptomeninges over the surface of the brain From greatest accumulation areas, tracts of pus can be followed along BVs on surface of brain Fulminant meningitis: inflammation may extend to ventricles ventriculitis Microscope: Neutrophils fill SAS in severely affected areas and are found predominantly around the leptomeningeal BVs in less severe cases Pneumococcal meningitis: large quantities of capsular polysaccharide gelatinous exudate encourages arachnoid fibrosis = Chronic Adhesive Arachnoiditis Presentation

HA, Fever Stiff neck Kernigs and/or Brudzinskis sign Rash possible in meningococcemia Lethargy & altered mental status Systemic signs of infection superimposed on clinical evidence of meningeal irritation and neurological impairment: HA, Photophobia, Irritability, Clouding of consciousness Petechial, purpuric or ecchymotic rash may be present = meningococcemia Leptomeninges are acutely inflamed Thrombosis of blood vessels Exudation of PMNs Surface of the brain is covered with thick purulent exudate No direct invasion of cerebral tissue CNIII, CNIV, CNVI or CNVII involvement in 5 - 10% Seizures in 20 - 30% of patients Brain swelling and increased CSF are associated with seizures, CNVI and CNIII dysfunction, abnormal reflexes and/or reduced consciousness or coma

Diagnosis LP unless signs of ICP: focal neuro deficits, new onset seizure, papilledema, impaired consciousness, immunocompromised CSF o Cloudy or frankly purulent o Under increased pressure o Glucose: o Protein: o Cell count: Neutrophils (up to 90,000) o Pressure: > 180 o Lactic Acid: o C - Reactive Protein: (not increased in viral meningitis) o PCR: S. pneumoniae, N. meningititis, E. coli, L. monocytogenes, H. influenzae o Latex particle agglutination: N. meningitidis, S. pneumoniae, H. influenzae o Very low (< 20) Age/bacteri Strep E. L. S. N. Glucose is a Co Monocyt pneum Mening suggestive of fungal Newborns X - 70% X X or tuberculous Infants/Chil X 45% X 31% meningitis dren Children X 59% Adults X Immunosup X X p Drug users

Stap h

Organisms E. coli Neonates Gram rods H. influenzae Infants and Children Gram coccobacilli, facultative anaerobe (generally aerobic though) N. meningitidis Adolescents and YA Gram diplococci, oxidase +, intracellular S. pneumoniae Older adults and Children Gram + cocci in chains; - hemolytic anaerobe L. monocytogenes Gram + facultative anaerobe; motile via flagella Cryptococcus Neoformans Fungal Treatment 1st choice: PCN G or ampicillin intravenously Chloramphenicol or 3rd generation cephalosporin (cefotaxime or ceftraixone) is indicated for patients with PCN allergies Rifampin Prophylaxis for some bugs Vaccines for H. influenzae (Hib), pneumococcus, and Neisseria have incidence of meningitis Steroids (dexamethasone) @ onset mortality; it is bacterial lysis and inflammatory response CNS complications Immunosuppressed: Klebsiella or anaerobes purulent meningitis

Parameningeal Infections Brain Abscesses o Circumscribed, enlarging, focal infections o Originate in or extend from extracerebral locations Blood borne metastases from unknown source or lung/heart Parameningeal spread Recent/remote head trauma or neurosurgical procedure o Most common pathogens: Streptococci, Bacteroides, Prevotella o Clinical Features Signs of infection frequently minimal/absent Headache, disturbed LOC, fever, hemiparesis, nausea/vomiting Classic triad is fever, headache and focal neurological deficits, although by no means will all patients demonstrate all three. Seizures can also result The lesion typically has a fibrous capsule surrounding an accumulation of pus and necrotic tissue Pathology trivia: this is one of the few times that you will find a fibroblastic proliferation within the substance of the brain. The fibroblasts are derived from the connective tissue around blood vessels o Treatment: Drug and surgical therapy Neisseria meningitidis Gram Aerobic Diplococci; Coffee Bean Shape; Non - Motile; Catalase +; Oxidase + Adolescents and Young Adults and Children < 2 Colonizes oropharynx normally; spread via respiratory invades respiratory epithelial cells basolateral side blood Increased incidence in pts w/ inherited defects of MAC formation (C5 - C9) 13 serotypes Antigenic variation as escape strategy Barracks, college dorms Endemic in US; Epidemics sometimes in Sub - Saharan Africa Grows best 35 - 37C in humid atmosphere on enriched media (sheeps blood aka chocolate agar) Produces acid from glucose and maltose oxidatively, but not gas Polysaccharide capsule; Antigen Pili; Specific meningococcal R in non - ciliated columnar cells of nasopharynx, urethra, cervix colonization; Antigen Endotoxin = Lipooligosaccharide (LOS) Diffuse vascular damage via release of TNF; Antigen; Composed of lipid A and a core oligosaccharide but LACKS the O antigen polysaccharide found in LPS 12 OPA proteins (make them opaque); Increase binding and entry; Each OPA gene has several repeats of a 5 nt sequence mutated frequently change reading frame encodes new sequences; or STOP and that decides whether the OPA is expressed or not Survive intracellular killing if absence of humoral immunity Iron is essential; have R that host cell transferrin Humans only natural hosts P- 2-P aerosolization of resp secretions Highest in children < 5, institutionalized people, people w/ late complement deficiencies Serogroups B, C, Y Meningitis and meningococcemia Serogroups Y, W135 Pneumonia Serogroups A, W135 disease in underdeveloped countries

Outer membrane proteins have been classified on the basis of MW o All strains have either class 1, class 2 or class 3 proteins (responsible for serotype specificity) o Help form pores in meningococcal wall o As many as 20 serotypes (types 2 & 15 associated with epidemic disease) Dry, cold months of year Breast - fed infants have passive immunity for 6 months PorB porin protein on surface interferes w/ degranulation of neutrophils, bacterial invasion, makes resistant to complement - mediated serum killing Rmp proteins stimulates Abs that block serum bactericidal activity Produces Ig A1 protease cleaves hinge region Waterhouse - Friederich Syndrome (WFS) aka Fulminant meningococcemia = bilateral adrenal gland destruction & failure due to bleeding into it shock, DIC, low BP, purpura Fatal if untreated. Neurologic sequelae is low w/ hearing deficits and arthritis common Meningococcemia: septicemia w/ or w/o meningitis is life threatening. Thrombosis of small blood vessels and multi - organ involvement are characteristic May present as URI Also arthritis and urethritis Culture is definitive Dies rapidly when exposed to cold or dry conditions Chemoprophylaxis w/ Rifamin Vaccination as adjunct for Serogroups A, C, Y, W135

Listeria monocytogenes Gram + Non - branching Facultative Intracellular Anaerobic Rod; Motile; Catalase +; Weak - hemolysis Rods singly, pairs, or short chains Grows @ high temp and high [salt] Motile @ room temp (22 - 28C ) in semi - solid agar; less/not @ 37 w/ end - over - end tumbling via flagella Produces acid, but not gas, in a variety of carbohydrates Grows on Mueller - Hinton agar; ID enhanced if done on sheep blood agar Characteristic small zone of hemolysis Serotypes Ia, Ib, and Ivb are 90% of human isolates Survives proteolytic enzymes, low pH, and bile salts w/ Stress - Response Genes Internalin A E - cadherin adherence Infxn initiated in enterocytes or M cells (in FAE Follicle - associated epithelium) of Peyers patches Phagolysosome low pH Listerolysin O = Exotoxin lyses phagolysosome and 2 different PLCs cytosol ActA protein on cell surf @ one end assembly of actin movement to cell mem (distal ends fixed; assembly adjacent to end of bacterium) Filopod formed into cell o The elegance of Listeria's molecular mimicry is remarkable. By producing a single protein, ActA, containing an amino acid sequence that mimics a host - cell VASP - binding protein, listeria causes host - cell actin to assemble into filaments behind the bacterium, thus providing the propulsive force required for pathogenesis. Using the host cell's actin machinery, listeria can move throughout the cytoplasm and form the filopods that become ingested by adjacent cells, thus avoiding contact with the extracellular environment. In addition to renal tubular epithelial cells, listeria can grow and spread in fibroblasts, epithelial cells, vascular endothelial cells, hepatocytes, enterocytes, and macrophages Produces Siderophores to steal Iron from host transferrin CMI req. to kill infxn Replicates w/i macs From food soft cheese, turkey, raw veggies especially cabbage Transplacental spread Peak in warmer months Young, elderly, pregnant, CMI - immunocompromised @ risk Granulomatosis infantseptica acquired transplacentally disseminated abscesses and granulomas in multiple organs Late onset: @ or shortly after birth meningitis or meningoencephalitis w/ septicemia Adults: Flu - like Sx

Preg & CMI - Immunocomp present as primary bacteremia or disseminated disease w/ hypoTN and meningitis Incubate 2 - 3 days enriched @ 4 C Penicillin of Ampicillin w/ or w/o Gentamicin

Escherichia coli Gram rods Neonates Haemophilus influenzae Gram negative coccobacilli; Facultative Anaerobe (generally aerobic) Infants and children H. flu needs hematin (X) and NADH (V) to grow o These factors can be supplied by a streak of Staph on a blood plate Involves base of brain

Streptococcus pneumoniae Gram + cocci in chains; - hemolytic; Anaerobic Older adults or Children Most important - hemolytic streptococcus is common cause of community - acquired meningitis (and pneumonia) in adults Can diagnose w/ rapid Ag test for pharyngitis Has capsule Pneumolysin; released on disruption of capsule inserts into host cell membrane lyses them increasing tissue damages; Also classical pathway of compliment (reduces compliment available for opsonizing bacteria) Infections characterized by diffuse interstitial neutrophilic infiltrates w/ minimal destruction of host tissues Skin lesions furuncles, carbuncles, impetigo not likely to cause formation of discrete abscesses Exudate in meningitis densest over cerebral convexities near sagittal sinus High amount of capsule polysaccharide gelatinous exudate arachnoid fibrosis = Chronic adhesive Arachnoiditis

Mycobacterium leprae Obligate Intracellular Aerobe; Strongly Acid - Fast; Cant be cultured; Lipid - rich cell wall; Leprosy Cannot be classified as gram +/ - (some say weakly Gram + rods/bacilli) o Use Ziehl - Neelsen technique o Medium for primary culture should include nonselective & selective medium Increased CO2 tension enhances growth Found singly, in parallel bundles or in globular masses in scrapings from skin/mucous membranes Naturally infected armadillos in TX and Mexico play no role in human transmission Unique mycoside: PGL - 1 found only in M. leprae o PGL - 1 and LAM have been implicated in survival & replication Incubation of 2 - 7 years (up to 4 decades) o Onset is insidious: Lesions involve cooler tissue of the body (eyes, skin, superficial nerves pharynx, larynx, testicles nose) o Skin lesions may be pale, anesthetic macules 1 - 10cm in diameter, discrete erythematous infiltrated nodules 1 - 5cm in diameter, or a diffuse skin infiltration o Neurological disturbances are manifested by nerve infiltration and thickening o Anesthesia, neuritis, paresthesia, trophic ulcers, bone resorption and shortening of digits Disease from host response to infection Tuberculoid (paucibacillary) and Lepromatous (multibacillary) forms of leprosy India, Nepal, Brazil, US < 100 Lepromatous form highly infectious Anchored in the plasma membrane = phosphatidylinositol mannosides and lipoarbinomanna (LAM is related to Ag O) Terminal D - arabinose is esterified to high MW, hydrophobic mycolic acids w/ attached glycolipid surface molecules P - 2 - P direct contact or infectious aerosols Grows in low temperature areas (skin, appendages) transmitted from nasal discharge Infects peripheral sensory cell nerve sheaths (macs & Schwann cells) o Causes patchy anesthesia Tuberculoid leprosy aka paucibacillary Hansen disease strong immune response w/ many lymphocytes and

granulomas (limits spread of inflammatory damage); thickened nerves (papable); 1 - 2 anesthetized, hypopigmented and hairless lesions o Few organisms are found in tuberculoid lesions o Granulomatous with extensive epitheloid cells, giant cells and lymphocytic infiltration Lepromatous leprosy weak immune response; cannot contain spread of inflammatory damage, especially in cooler skin, nerves, testes; causes sensory loss at face, extremities are anesthetized; host vulnerable to loss of eyebrows, thick nose, thick cheeks, and infertility o CMI is deficient, growth is unimpeded Leprosy is chronic; affects skin & peripheral nerves; Tuberuloid form is milder, w/ hypopigmented skin macules; Lepromatous form assoc. w/ disfiguring skin lesions, nodules, plaques, thickened dermis, nasal mucosa involvement Microscopy for lepromatous form only (skin scrapings show acid fast bacilli) Skin test to confirm tuberculoid leprosy by testing CMI response = Lepromin; Lepromatous gives negative skin test

Cryptococcus Neoformans Fungal; Mucoid - encapsulated Yeast; Opportunistic; PAS + Worldwide More extensive and severe in immunocompromised Lung is portal of entry Most common form of fungal meningitis Fulminant in 2 weeks or indolent (months years) Amphotericin + Flucytosine, then Fluconazole CSF: Glucose < 20; High [protein] Cell count: mild lymphocytic pleiocytosis; may be normal in immunocompromised Cryptococcal Ag (more sensitive) and India Ink (shows encapsulated yeast) staining Also use PAS, Mucicarmine, and silver stains Chronic meningitis affecting basal leptomeninges opaque and thickened by reactive CT that may obstruct CSF flow from foramina of Luschka and Magendie Hydrocephalus Gelatinous material within the subarachnoid space Small cysts within parenchyma = soap bubbles; especially in basal ganglia and lenticulostriate arteries Parenchyma lesions consist of organisms within expanded perivascular (Virchow - Robin) spaces assoc. w/ minimal or absent inflammation or gliosis

Protozoans Toxoplasmosis gondii - Opportunistic Merozoite sexual stage in cat GI Oocyst in cat poop Sporoblast Ingested Sporocyte Trophozoite asexual disease causing stage Sexual reproduction occurs only in felines Invade epithelium of ileum, undergo schizogony inside vacuole Merozoites released upon rupture and either continue asexual reproduction or initiate sexual reproduction (diff. into gametocytes) Fusion of M & F gametocytes leads to formation of immature oocyst which is shed in the feces Mature oocyst completes sporulation in environment (2 sporocysts 4 sporozoites) Enter macs in intermediate host, continued intracellular schizogony leads to cell rupture & continued release Host immunity destroys many; Create tissue cysts in brain, heart & skeletal muscle o Can contain 1000+ organisms o Can persist for life Oocyst: Thick wall, resistant to environment, immature form lacks internal structure, mature form contain sporocysts Trophozoite: Asexual proliferative form, responsible for cell invasion & clinical disease, also called merozoite & tachyzoite, crescent - shaped, can invade all nucleated cell types and in body fluids Tissue cyst: Contain bradyoites, resistant to digestive enzymes, infectious to animals Reservoir hosts = cats & o/ felines o Develops in intestinal cells o Has extra - intestinal cycle (passage to tissues via bloodstream) o Passed in cat poop Mature into infective oocytes in 3 - 4 days Transmission to human by oral rou (undercooked meat, soil w/ cap poop) Transplacental transmission Pseudocysts contain the T. gondii organisms (bradyzoites); may remain quiescent for years Cyst wall breaks w/ release of tachyzoites vigorous inflammatory response w/ subsequent tissue necrosis Patients w/ severe cellular deficiency may not have as vigorous a response Multiple necrotic, abscessing lesions in both gray and white matter

HIV/AIDS Toxoplasmosis is MCC of multiple enhancing brain lesions CT & MRI may show multiple ring - enhancing lesions (not pathognomonic) CNS Brain abscesses (most often in cerebral cortex near gray - white junction, and in the deep gray nuclei) Acute lesion: Central foci of necrosis, petechial hemorrhages surrounded by acute and chronic inflammation, macrophage infiltration, vascular proliferation Free tachyzoites and Encysted bradyzoites found at periphery of necrotic foci (H&E, Giemsa) BVs in lesion area show marked intimal proliferation or frank vasculitis w/ fibrinoid necrosis and thrombosis Chronic lesions contain small cystic spaces w/ scattered lipid - and hemosiderin - laden macrophages surrounded by gliotic brain Pathogenesis o Primary infection: Stimulation of mononuclear inflammatory reaction Parasite - specific IgA response o Immunodeficient hosts: Rapid organisms proliferation Widespread foci of tissue necrosis o Infection is rapidly controlled in normal hosts with the development of humoral and CMI CMI is principle: IL - 2, IFN - , CTLs Tissue cysts produce little or no tissue reaction Immunity is lifelong Clinical Findings o Congenital Toxoplasmosis Abortion, stillbirth If CNS: microcephaly, hydrocephaly, cerebral calcifications, convulsions, psychomotor retardation Usually accompanied by visceral involvement including fever, hepatitis, pneumonia & skin rash Most common delayed manifestation: bilateral chorioretinitis (reactivation of tissue cysts) o Normal Host Asymptomatic localized lymphadenopathy of the cervical nodes Can be accompanied by fever, rash, sore throat, hepatosplenomegaly and lymphocytosis Rarely: visceral involvement meningoencephalitis, pneumonitis, myocarditis or hepatitis o Immunocompromised Host Serious, often fatal disease Necrotizing pneumonitis, myocarditis, encephalitis More common is reactivation of tissue cysts during immunosuppression (AIDS) Encephalitis occurs in 50%, fatal in 90% Occurs in almost all mammals & birds; Human infections throughout world o 50% of Americans have circulating Ab by adulthood Ingestion of oocytes frequently from feces of infected cats (acutely infected cats shed for a few weeks) Ingestion of tissue cysts reported in pork (25%), mutton (10%) and beef/chicken (<1%) o Cysts are killed at well - done cooking temperature Congenital o 1/500 pregnant women acquires & 10 - 20% symptomatic o Fetus involved in 33 - 50% of acute maternal infections o Earlier fetal infections are more severe o 20% experience severe consequences Sabin Feldman: Measures IgGs ELISA: IgM, A, E ISAGA: IgE Differential agglutinations: IgGs Do this to determine how recent exposure

Naegleria fowleri & Acanthamoeba Large nucleus, contractile vacuoles & mitochondria, cysts with single nucleus Free living in soil, warm soil contaminated pools & ponds Contacts, damages eye, skin ulcer Lab: Use nasal discharge, CSF and corneal scrapings Acanthamoeba o Subacute or chronic illness that is usually fatal o Found in soil & fresh/brackish water o Have been found in the oropharynx of asymptomatic humans o Infections usually involve, older/immunocompromised individuals o Amoeba probably reaches the brain by hematogenous spread from unknown site o Produces a diffuse, necrotizing, granulomatous encephalitis w/ frequent midbrain involvement Cysts & trophozoites found in lesions

Cutaneous ulcers & hard nodules found in AIDS pts o Clinical course is more prolonged & occasionally ends in spontaneous recovery o Mononuclear CSF response o Chronic granulomatous disease - weeks to months, causes brain edema o Lab: See trophozoites & cyst w/in tissue N. fowleri o Parasite o Found in warm, freshwater environments (especially stagnant water) o Affects children/young adults almost always fatal o Primary Amoebic Meningoencephalitis (PAM) HA, sore throat, altered sense of taste and smell, stiff neck, Kernig sign (rapidly fatal) o Few days to weeks after swimming NF migrates through cribiform plate anterior cerebral fossae along olfactory nerves & BVs Severe inflammation and hemorrhage in anterior cerebral fossae Rapid onset of bifrontal headache, seizures, and abnormalities in taste/smell Downhill course to coma & death o Lab: See just trophozoites w/in tissue; non - nutrient agar with Gram ( - ) enteric bacilli like E. coli o CSF provides presumptive dx Bloody fluid Intense neutrophilic response Protein Glucose No bacteria

Trypanosoma brucei gambiense (W. Africa); Trypanosoma rhodesiense (E. Africa); Trypanosoma cruzii (South America) Flagellated protozoans Kinetoplastida Have 1,000 variant surface glycoprotein (VSG) genes that can turn on/off host immuno response Congregate in capillaries particularly choroid plexus & leptomeninges Spread Panencephalitis = Sleeping Sickness E. African form way more virulent than West African form Tsetse fly for African trypanosomas Gambiense & Rhodesiense o Parasitemia is low grade & recurrent o Cycles of parasitemia ensue IgM Ab made to organism and destroy Trypomastigotes disappear from the blood and reappear after having undergone VSG switch o Trypanosomes localize in the small vessels of the heart and CNS, causing vasculitis Endothelial proliferation and perivascular infiltration of plasma cells/lyphocytes o Trypomastigote motile flagellated extracellular form o Within Tsetse fly: Epimastigote multiplies in fly salivary gland Trypomastigote (has free flagellum and undulating membrane; = infectious stage; in salivary gland of Tsetse o Multiplies in blood in humans via binary fission o Infective Stage: Trypomastigote o Pathogenic As: Trypomastigote o Definitive Host: Tsetse Fly o Intermediate Host: Humans o Transmission: Bite; contaminated blood; Transfusion o Pathognomonic: Posterior cervical LNs are enlarged, non - tender, like ripe plums Winterbottom Sign: Lymphadenopathy with prominent supraclavicular & posterior cervical enlargement o Clinical CNS Behavioral and personality changes, psychological changes, sleep disturbances, tremor (Kerandels sign), LOC deteriorates Rhodesian: myocarditis & CNS involvement in 3-6 weeks; heart failure, convulsions, coma, death within 6-9 mos Gambian: Slower progression; bouts of fever for years, spontaneous activity diminishes, indistinct speech, tremors, seizures, etc., finally lapse into a coma o Cause of Death: Renal/cardiac complications; results in coma death usually after co - infection w/ malaria and agents causing pneumonia o Diagnosis: Visualize trypomastigote in blood, CSF, LNs; Serology: high IgM titers o Treatment: Suramin does not penetrate CNS

African Sleeping Sickness Hard, painful skin ulcer at the site of tsetse fly bite, heals in 2 weeks (chancre = 1 st sign), chagoma Fever, headache, lymph node swelling Fevers subside then relapses can occur, lasting for months CNS Symptoms: Daytime drowsiness, Behavioral changes; Difficulty walking; Slurred Speech; Coma; Death Gambiense W. & Central Africa West African/Gambien Sleeping Sickness Found in forest galleries that border streams Vector: Tsetse fly Reservoir: No animal reservoir Slow progression Fever, wasting, late neurologic symptoms Days - Weeks incubation Ulceration @ bite site Lymphadenopathy CNS involved after years Rhodesiense E. Africa East African Sleeping Sickness Tsetse fly (i.e., Glossina pallipedes, Morcidas) Short incubation; More severe SS w/ rapid cycling of fevers neurologic Sx death weeks to months Reservoir: Antelope, wild game, sheep, cattle More rapid fulminating; early CNS involvement Lethargy anorexia, mental disturbances Tsetse (Glossina pallipedes, Morcides) No lymphadenopathy

Cruzii o N., Central, S. America o Reservoir: Rats, cats, dogs, opossums, etc o Morphology: Kinetosome - large, rounded, C - shape @ terminal end Distinguished from brucei: C/U shape; Narrow undulating membrane; Large kinetoplast o Trypomastigote motile flagellated extracellular form o Amastigote Intracellular & non - motile, present in macrophages, LNs, and organs (brain, heart) o Epimastigote trypomastigote (in feces of eduviid bug enters through bite) loses flagella amastigote (in tissues) multiplies via binary fission in RES destroys host cell Remains as amastigote or matures to trypomastigote to re-infect bug o Infective Stage: Trypomastigote o Pathogenic As: Trypomastsigote o Definitive Host: Reduviid/Kissing bugs have Trypomastigote & Epimastigote o Intermediate Host: Humans o Transmission: Tunneling of the Trypomastigotes into the skin; Bug feeds then poops on you w/ trypanosomes in the doodoo; Contaminated blood; Transfusions o Disease: Chagas Disease Chagoma = hardened area @ bite site Acute Chagas disease: Fever, chills malaise, myalgia, fatigue Meningoencephalitis Acute myocarditis w/ tachycardia and EKG changes Intermediate: Low levels of parasite in blood; + Abs against T. cruzii; No signs and symptoms; Most people remain in this phase for life Chronic: Some progress to this stage Result of end - stage organ damage Many deny acute infection Heart disease: Chagas cardiomyopathy heart dilation, heart failure, arrhythmia Hepatosplenomegaly, myocarditis, enlarged esophagus and colon, Interstitial myocarditis Decreases lifespan Megadisease: large dilated, poorly functioning hollow organs Megacolon (constipation, abdominal pain) and Megaesophagus (dysphagia, vomiting) o Pathogenesis Multiplication of the parasite at the portal of entry leads to the accumulation of neutrophils, lymphocytes and fluid causing a focal chancre or chagoma

o o o o o

Subsequent dissemination produces a febrile illness that lasts 1-3 months Any nucleated host cell may be involved Mesenchymal cells (heart, skeletal muscle, smooth muscle, glial nerve cells) are most susceptible Cell entry is facilitated by host cell fibronectin and T. cruzi protein penetrin Parasite escapes the phagolysosome via pore - forming protein & transforms to amastigote form Multiplies in cytoplasm forming pseudocyst Rupture of pseudocyst leads to intense inflammatory reaction Development of Ab - dependent, CMI leads to eventual parasite destruction & termination of acute phase Parasitic antigens may bind to host tissue leading to sustained autoimmune inflammatory reaction Particularly damaging in the heart (muscle & ganglia loss, microvasculature damage, degenerative changes) & GI tract Diagnosis: Visualize trypomastigote in blood, CSF, LNs; Xenodiagnosis: 40 lab bugs are allowed to eat you, after 1 month theyre examined Romanas sign (rash, edema around eyes) MC in children < 5 Chronic Megacardia and ECG change CNS involvement Granulomas in brain w/ cyst formation & meningoencephalitis

Systems Cerebellum Gross Anatomy 2 hemispheres joined via vermis Connected to BS by peduncles/stalks (superior, middle, inferior) No ventricular space within Forms roof of the 4th ventricle Location of flocculonodular lobe and vermis o See images for location (know) Consists of 3 - layered cortex & deep nuclei in white matter = main source of output Functional Divisions Function of the cerebellum = coordinate movement o Compares motor commands from motor cortical areas o with sensory information sent from proprioceptors and the vestibular organs o Sends a corrective command back to motor pathways (corticospinal, vestibulospinal reticulospinal & MLF) to make adjustments in the movement Vestibulocerebellum (VC) o Flocculonodular lobe o Vestibular info to control balance/posture muscles o Inputs: Vestibular N o Deep Nuclei: Vestibular N o Outputs: MLF, vestibulospinal tract o Function: Regulates eye movements; equilibrium Spinocerebellum (SC) o Vermis and medial portion of hemispheres o Regulates ongoing movement Vermis axial and proximal limb muscle control Medial part of hemispheres just lateral to the vermis (Intermediate) distal limb muscle control o Vermis Inputs: Vestibular N; Spinal Cord (neck/trunk) Deep Nuclei: Fastigial Outputs: Vestibulospinal Tract; Reticulospinal Tract; Cortex (medial pathways) Function: Regulates balance o Intermediate Inputs: Spinal Cord (limbs)

Deep Nuclei: Interposed Outputs: Red Nucleus; Rubrospinal Tract; Thalamus/LCS Function: Adjust on - going limb movement Cerebrocerebellum (CC) o Large lateral portion of hemispheres o Inputs: Primary/Premotor Cortex o Deep Nuclei: thalamus/LCS o Function: Motor planning Information Flow o Input Mossy & Climbing fibers Carry afferent info Run through middle and inferior peduncles Terminate in deep nuclei & cerebellar cortex o Processing Cerebellar Cortex Afferent information processed Integrated information output conveyed by Purkinje (cortical cell type) Terminate in deep nuclei of cerebellum o Output Deep nuclei axons Carry cerebellar output Via superior and inferior peduncles To targets outside the cerebellum Constant active cerebellar output channels o Purkinje cells send inhibitory synaptic signals if need be Also Note: o So, climbing and mossy fibers run to deep nuclei directly, or to deep nuclei via Purkinje cells in cerebellar cortex o Climbing fibers excite Purkinje cells directly o Mossy fibers excite Purkinje cells Via Parallel fibers (axons) of Granule cells Orthogonal (90) to Purkinje cell dendrites o Mossy fiber input inhibited by 3 interneurons Basket Stellate Golgi o Climbing fiber to Purkinje cell ratio o Complex spikes produced on P. cells by climbing fibers

Lesions to the Cerebellum Deficits are ipsilateral to the lesion Do not cause paralysis or paresis Result in uncoordinated movements Typical Symptoms Associated with Cerebellar Damage o Ataxia: lack of coordination in truncal or limb muscles o Dysmetria: past - pointing (overshoot) o Intention tremor: tremor on movement o Decomposition of movement (puppet - like) o Dysdiadocokinesia: cant complete complex movements o Pendular reflexes Anatomic Lesions o Vermal: ataxia trunk; wide - based gate, scanning speech o Intermediate zone: appendicular ataxia (limb), dysmetria, intention tremor

Flocculonodular: wide based gate, eye movement difficulties (smooth pursuits, vol. eye movements), nystagmus o Lateral hemispheres: lack of coordination of voluntary movements, decomposition of movement, dysdiadochokinesia Five general aspects of cerebellar lesions o Cerebellar lesions produce disordered movements of limbs ipsilateral to the lesion o Cerebellar signs and symptoms can result from contralateral lesions in the output tract/targets of the cerebellum (e.g., red N., sup. cer. ped) o Given the somatotopic organization of the spinocerebellum, medial lesions affect trunk muscles and lateral lesions affect limb extremities. o Lesions of the peduncles & deep nuclei disrupt movement to a greater extent than lesions of the cerebellar cortex o If the underlying disease process is halted, lesions of the cerebellum tend to be compensated with time. In fact, childhood cerebellar tumors rarely cause permanent motor disabilities o

Functional region Vestibulocereb ellum (Phylogenetical ly oldest)

Anat. Region Flocculonodul ar lobe

Principal Input Vestibular labyrinth

Dp N. Output Lateral vestibular

Destination Medial systems: axial motor neurons and control of eye muscles

Function Axial control and vestibular reflexes. Stability of eye movements.

Lesions Loss/reduction of postural stability. Ataxic gait (improves on lying down), wide - based posture, nystagmus.

Spinocerebellu m (medial part)

Vermis

Vestibular labyrinth, proximal body parts, facial, visual, and auditory inputs to posterior lobe only Spinal afferents (distal muscles of limbs)

Fastigial

Medial systems: vestibular nucleus, reticular formation, and motor cortex

Axial and proximal limb motor control; regulation of ongoing execution of movement Distal motor control; regulation of ongoing execution Motor learning, initiation, planning, and timing Cognitive tasks! Timing, rhythm

Ataxic gait (does not improve on lying down). Titubation truncal tremors during standing or sitting. Truncal ataxia Action tremors. Ataxia of limb movements Dysmetria.

Spinocerebellu m (lateral part)

Intermediate part of hemisphere

Interposed (Globose and Embeliform ) Dentate (Largest nucleus)

Lateral systems: red nucleus (magnocellular part) and motor cortex for distal limb muscles. Integration areas: red nucleus (parvocellular part) and premotor cortex (area 6)

Cerebrocerebell um (Phylogenetical ly most recent)

Lateral part of hemisphere (Largest)

Cortical afferents

Dysdiadocho kinesia inability to perform rapidly alternating movements. Decomposition of movement.

Ear Normal Hearing Physiology Conductive pathway (External auditory canal to cochlea) Air conduction of sound energy down the EAC Vibration of the tympanic membrane (area effect) Sequential vibration of the middle ear ossicles: malleus, incus, stapes (lever effect) Transmission of amplified vibrations from the stapes footplate in the middle ear to the oval window of the cochlea in the inner ear Pressure differential on Cochlear fluid creates movement along the basilar membrane within the Cochlea from base to apex Neural pathway (Nerve to brain) Basilar membrane vibration stimulates overlying hair cells in the Organ of Corti Stimulation of bipolar neurons in the spiral ganglion of the cochlear division of CN VIII Cochlear nucleus Superior Olivary Nucleus Lateral lemniscus Inferior colliculus Sylvian Fissure of Temporal Lobe Acute Otitis Media (AOM) acute inflammation of middle ear Epidemiology 60 to 70% of children have at least 1 episode of AOM before 3 years of age 18 months to 6 years most common age group peak incidence January to April one third of children have had 3 or more episodes by age 3 Etiology S. pneumoniae 35% of cases (incidence decreasing due to pneumococcus vaccine) H. influenzae 25% of cases M. catarrhalis 10% of cases S. aureus and S. pyogenes (all beta-lactamase producing) anaerobes (newborns)

 Gram-negative enterics (infants) viral Predisposing Factors eustachian tube dysfunction/obstruction: swelling of tubal mucosa: upper respiratory tract infection (URTI) allergies/allergic rhinitis chronic sinusitis obstruction/infiltration of eustachian tube ostium: tumour nasopharyngeal carcinoma (adults) adenoid hypertrophy (not due to obstruction but by maintaining a source of infection) barotrauma (sudden changes in air pressure) inadequate tensor palati function cleft palate (even after repair) abnormal eustachian tube: Down syndrome (horizontal position of eustachian tube), Crouzons, and Aperts syndrome disruption of action of: cilia of eustachian tube Kartageners syndrome mucus secreting cells capillary network that provides humoral factors, PMNs, phagocytic cells immunosuppression/deficiency due to chemotherapy, steroids, diabetes mellitus, hypogammaglobulinemia, cystic fibrosis Risk Factors bottle feeding, pacifier use second-hand smoke crowded living conditions (day care/group child care facilities) or sick contacts male family history Pathogenesis obstruction of eustachian tube g air absorbed in middle ear g negative pressure (an irritant to middle ear mucosa) g edema of mucosa with exudate/effusion g infection of exudate from nasopharyngeal secretions Clinical Features triad of otalgia, fever (especially in younger children), and conductive hearing loss rarely tinnitus, vertigo, and/or facial nerve paralysis otorrhea if tympanic membrane perforated pain over mastoid process infants/toddlers ear-tugging hearing loss, balance disturbances (mild) irritable, poor sleeping vomiting and diarrhea anorexia otoscopy of tympanic membrane (TM) hyperemia bulging, pus may be seen behind TM loss of landmarks: handle and long process of malleus not visible Treatment antibiotic treatment hastens resolution 10 day course 1st line: amoxicillin 80-90 mg/kg/day divided into two doses safe, effective, and inexpensive if penicillin allergic: macrolide (clarithromycin, azithromycin), trimethoprimsulphamethoxazole (Bactrim) 2nd line (for amoxicillin failures): double dose of amoxicillin (80 mg/kg/day), amoxicillin-clavulinic acid (Clavulin) cephalosporins: cefuroxime axetil (Ceftin), ceftriaxone IM(Rocephin), cefaclor (Ceclor), cefixime (Suprax) AOM deemed unresponsive if clinical signs/symptoms and otoscopic findings persist beyond 48 hours of antibiotic treatment symptomatic therapy: antipyretics/analgesics (e.g. acetaminophen) decongestants may relieve nasal congestion but does not treat AOM prevention: parent education about risk factors (see above) antibiotic prophylaxis amoxicillin or macrolide shown effective at half therapeutic dose pneumococcal and influenza vaccine

 surgery: choice of surgical therapy for recurrent AOM depends on whether local factors (eustachian tube dysfunction) are responsible (use ventilation tubes), or regional disease factors (tonsillitis, adenoid hypertrophy, sinusitis) are responsible Eye
CLINICAL SETTING Normal Normal DRUG Sympathomimetic drugs Parasympathomimetic drugs Cocaine 4 - 10% PUPILLARY RESPONSE Dilation (mydriasis) Constriction (miosis) No dilation

Horner's syndrome Preganglionic Hydroxyamphetamine Dilation Horner's Pharmacology 1% of the Eye and Related Structures Table 641 Autonomic Postganglionic Hydroxyamphetamine No dilation ADRENERGIC RECEPTORS CHOLINERGIC Horner's 1% RECEPTORS Adie's pupil Pilocarpine 0.05 - SUBTY Constriction TISSUE SUBTY RESPONSE RESPONSE 0.1%a PE PE Normal Opioids (oral or Pinpoint pupils Corneal epithelium Unknown Ma Unknown 2 intravenous) Corneal Unknown Undefin Unknown 2 endothelium ed Iris radial muscle Mydriasis 1 Iris sphincter M3 Miosis muscle Trabecular Unknown 2 meshwork Ciliary epithelium b Aqueous 2/2 production Ciliary muscle Relaxationc M3 Accommodat 2 ion Lacrimal gland Secretion M2 , M 3 Secretion 1 Retinal pigment H2O 1/2 epithelium transport/unknown

Class Notes on Eye Laser Eye Sx Stroma Infection prevention Bowmans membrane Opaque cornea Endothelium Retina has rods and cones; Fovea just cones Foveolus = Just ones; center of Fovea Choroid Side RPE Rods & Cones Limiting Outer Nuclear Outer plexiform Rod & Cone Polar Inner Nuclear Inner plexiform Ganglion Bipolar - Ganglion Nerve Fiber Inner Limiting membrane Inner Retina side Histo Know where RPE, Retina, Pupil and Cornea are On & Off Light hyperpolarizes the photoreceptor cell so it releases less Glu Less Glu means the Off - bipolar cells Na channels close and it hyperpolarizes. So, the Off - ganglion cell does not fire Less Glu means that the On - bipolar cell has open Na cGMP gated channels, so it depolarizes and then the On - ganglion cell fires.

ANS Regulation Nucleus Solitarius: coordinates activity of CN VII, IX, X and reflexes associated with the viscera (heart rate, respiration) Hypothalamus: origin of various descending pathways (medial forebrain bundle, dorsal longitudinal fasciculus, descending sympathetic pathway) which modulate parasympathetic (brainstem) and sympathetic (intermediolateral cell column) preganglionic neurons Cortex: cingulate, insular and somatosensory cortices Refractive Errors of the Eye and Corrective Lenses Presbyopia: In presbyopia, there is normal distance vision, but lens accommodation is reduced with age. With age, the lens loses its elasticity and becomes a relatively solid mass. During accommodation, the lens is unable to assume a more spherical shape and is unable to increase its refractive power for near vision (Figure 14.10). As a result, when an object is less than 30 ft. away from the presbyopic viewer, the image is focused somewhere behind the retina. In the presbyopic eye, when the object is moved closer to the eye, the lens is unable to accommodate and the image is focused beyond the retina. For the presbyopic eye a corrective lens that converges the light rays (i.e., a convex lens that reduces the angle of incidence of light on the cornea) will allow the presbyopic eye to view nearby objects. A convex lens (i.e., increased refractive power) is used to correct the presbyopic eye (Figure 14.10). These lenses refract the light rays so they strike the surface of the cornea at a smaller angle. However, because the corrective lens increases the refractive power, the presbyope with convex lenses will have problems with distance vision. Consequently, the corrective lenses are often half lenses (i.e., reading glasses) which allow the presbyope to view objects in the distance unimpeded by the convex lens. Hyperopia: In hyperopia (Figure 14.11), the refractive power of the eyes lens system is too weak or the eyeball too short. When viewing distant objects, the image is focused at a point beyond the retina. The hyperopic eye at rest cannot focus on the retina the image of an object more than 30 ft from the eye. The hyperopic lens system is too weak and the image is focused beyond the retina. The young hyperope can compensate by using lens accommodation, i.e., increase the refractive power of the eyes lens system (Figure 14.12). We call the hyperope "far-sighted" (hypermetropic) because the power of accommodation used for distance vision cannot be used for near vision. If the hyperopia is not severe; the hyperopic eye can use the lens accommodation process to increase the refractive power of the eye for distance vision. As the hyperope ages and becomes presbyopic, the power of accommodation is diminished. Consequently, the middle aged hyperope may have a limited range (near and far) of vision. To correct this effect of aging, the refractive power of the eye is increased with convex lenses (Figure 14.12). Myopia: In myopia (Figure 14.13), the refractive power of the eyes lens system is too strong or the eyeball too long. When viewing distant objects, the image is focused at a point in front of retina. The myopic eye at rest cannot focus on the retina the image of an object more than 30 ft. from the eye. The refractive power of the eye's lens system is too strong and the image is focused in front of the retina. The uncorrected myopic eye is "near-sighted" because it can focus unaided on near objects. That is, the young myope will see distant objects as blurred, poorly defined images but can see nearby small objects clearly (remember nearby

objects emit divergent light rays). For distance vision, the refractive power of the myopic eye lens system is corrected with concave lenses that diverge the light rays entering the eye (Figure 14.14). Note that as the power of accommodation diminishes with age, near vision is also affected in the presbyopic-myopic eye. The mature myope may require bifocals, the upper half of the lens diverging light rays for distance vision and the lower half with no or low converging power for near vision. A corrective lens that diverges light rays before they enter the eye (i.e., a concave lens) will allow the myopic eye to focus the image of a distant object on the retina. Astigmatism: An astigmatism results when the cornea surface does not resemble the surface of a sphere (e.g. is more oblong). In an eye with astigmatism, the image of distant and near objects cannot be focused on the retina (Figure 14.15). Astigmatism is corrected with a cylindrical lens having a curvature that corrects for the corneal astigmatism. The cylindrical lens directs light waves through the astigmatic cornea to focus a single, clear image on the retina. The astigmatic lens is asymmetrical and has multiple focal points, which produces multiple images of a point source.

The innermost layers are located nearest the vitreous chamber, whereas the outermost layers are located adjacent to the retinal pigment epithelium and choroid. The most important layers, progressing from the outer to inner layers, are: Retinal pigment epithelium, which provides critical metabolic and supportive functions to the photoreceptors; Receptor layer, which contains the light sensitive outer segments of the photoreceptors; Outer nuclear layer, which contains the photoreceptor cell bodies; Outer plexiform layer, where the photoreceptor, horizontal and bipolar cells synapse; Inner nuclear layer, which contains the horizontal, bipolar and amacrine cell bodies; Inner plexiform layer, where the bipolar, amacrine and retinal ganglion cells synapse; Retinal ganglion cell layer, which contains the retinal ganglion cell bodies; and o The optic disc is formed by the retinal ganglion cell axons that are exiting the retina. Optic nerve layer, which contains the ganglion cell axons traveling to the optic disc. The photoreceptors exhibit a fairly high basal release of glutamate. When light strikes the photoreceptor cell, it initiates a biochemical process in the cell that reduces the release of glutamate from its axon terminal. The glutamate, in turn, affects the activity of the bipolar and horizontal cells, which synapse with the photoreceptor. The bipolar cells, in turn, synapse with amacrine and retinal ganglion cells. It is the axons of the retinal ganglion cells that exit the eye as the optic nerve and terminate in the brain. Notice that the direct pathway for the transmission of visual information from the eye to the brain includes only the receptor cell, bipolar cell and ganglion cell. The horizontal cells modulate the synaptic activity of receptor cells and, thereby, indirectly affect the transmission of visual information by bipolar cells. Similarly the amacrine cells modulate the synaptic activity of the retinal bipolar and ganglion cells, thereby affecting the transmission of visual information by the ganglion cells. Bipolar Cells

Within the outer plexiform layer of the retina, approximately 125 million photoreceptor cells synapse with approximately 10 million bipolar cells. A smaller number of horizontal cells also synapse with the photoreceptor cells within the outer plexiform layer of the retina. The bipolar and horizontal cells respond to the glutamate released by the photoreceptor cells4. Bipolar cells o do not generate action potentials. o respond to the release of glutamate from photoreceptors with graded potentials (i.e., by hyperpolarizing or depolarizing). Bipolar cells differ based on their responses to photoreceptor stimulation. There are at least two types of bipolar cells based on their responses to glutamate. o The off bipolar cells are depolarized by glutamate. o The on bipolar cells are hyperpolarized by glutamate. The two bipolar cell types have different functional properties. o The off bipolar cells function to detect dark objects in a lighter background. o The on bipolar cells function to detect light objects in a darker background. The stimulus condition that produces a depolarizing response from a bipolar cell is used to name the bipolar cell type. An off bipolar cell depolarizes when the photoreceptors that synapse with it are in the dark (i.e., when the light is off, Figure 14.22). An on bipolar cell depolarizes when the photoreceptors that synapse with are in the light (i.e., when the light is on, Figure 14.22). Note that the depolarization of the on bipolar cell does not result from excitation of the presynaptic cell but rather from a reduction of the inhibitory action of glutamate produced by the light-induced decreased release of glutamate from the photoreceptor. Bipolar Cell Receptive Field: The receptive field of a bipolar cell is defined anatomically by the location and distribution of receptor cells with which it makes synaptic contact. Each cone-bipolar cell makes direct synaptic contact with a circumscribed patch of cone receptors, which may be as few as one foveal cone. Consequently, the receptive fields of bipolar cells synapsing with cones in the fovea are extremely small and are color sensitive. The cone-bipolars may be hyperpolarized or depolarized by glutamate and, consequently, may be on-type or off-type bipolar cells. Each rod-bipolar cell may make synaptic contact with a few to fifty or more of rod receptor cells. Consequently, the rod-bipolar cell receptive field is relatively large and color insensitive. All rod-bipolar cells are hyperpolarized by glutamate and, consequently, are on-type bipolar cells exclusively. The bipolar cell receptive field is also defined physiologically as the retinal area which when exposed to light produces a response (i.e., depolarization or hyperpolarization) in the bipolar cell. Bipolar cells have concentric receptive fields. Light directed on the photoreceptor(s) that synapse with a bipolar cell produces a response from the bipolar cell called the center response (Figure 14.23). In contrast, light directed on immediately surrounding receptors produce the opposite response (Figure 14.24). When both the center and surrounding receptor cells are illuminated with light, the on bipolar cell response to stimulation of the center receptors is reduced by stimulation of the surround receptors Consequently, the strongest on bipolar cell response is produced when the stimulus is a light spot encircled by a dark ring. For the off bipolar cell, a dark spot encircled by a light ring produces maximal depolarization. Horizontal Cells Within the outer plexiform layer, the photoreceptor cells make both presynaptic and postsynaptic contact with horizontal cells. The horizontal cells have large receptive fields involving presynaptic (axonal) contact with a small group of photoreceptors and postsynaptic (dendritic) contact with a larger group of surrounding photoreceptor cells. By controlling the responses of their center photoreceptors (based on the responses of the surrounding photoreceptors), the horizontal cells indirectly produce the bipolar cell receptive field surround effect. The surround effect produced by the horizontal cell is weaker than the center effect. The surround effect, produced by the horizontal cells, enhances brightness contrasts to produce sharper images, to make an object appear brighter or darker depending on the background and to maintain these contrasts under different illumination levels. Retinal Ganglion Cells

Within the inner plexiform layer, the axon terminals of bipolar cells (the 2 visual afferents) synapse on the dendritic processes of amacrine cells and ganglion cells. As in most neurons, depolarization results in neurotransmitter release by the bipolar cell at its axon terminals. Most bipolar cells release glutamate, which is excitatory to most ganglion cells (i.e., depolarizes ganglion cells). The amacrine cells may synapse with bipolar cells, other amacrine cells or ganglion cells. It is the axons of the retinal ganglion cells (the 3 visual afferents) that exit the eye to form the optic nerve and deliver visual information to the lateral geniculate nucleus of the thalamus and to other diencephalic and midbrain structures. Ganglion Cell Response Properties. The retinal ganglion cells are the final retinal elements in the direct pathway from the eye to the brain. Because they must carry visual information some distance from the eye, they posses voltagegated sodium channels in their axonal membranes and generate action potentials when they are depolarized by the glutamate released by the bipolar cells. The off bipolar cell (Figure 14.27, Right) will depolarize when it is dark on its center cones and will therefore release glutamate when it is dark on the center of its receptive field. This will result in the depolarization of the retinal ganglion cells with which the off bipolar synapses and in the production of action potentials (i.e., discharges) by these ganglion cells (Figure 14.27, Right). Consequently, the retinal ganglion cells that synapse with off bipolar cells will have offcenter/on-surround receptive fields and are called off ganglion cells. The on bipolar cell (Figure 14.28, Left) will depolarize when there is light on its center cones and will therefore release glutamate when it is light on the center of its receptive field. This will result in the depolarization of the retinal ganglion cells with which the on bipolar synapses and in the production of action potentials (i.e., discharges) by these ganglion cells (Figure 14.28, Left). Consequently, the retinal ganglion cells that synapse with on bipolar cells will have oncenter/off-surround receptive fields and are called on ganglion cells. In short, the receptive fields of the bipolar cells with which the retinal ganglion cell synapses determine the receptive field configuration of a retinal ganglion cell. The retinal ganglion cells provide information important for detecting the shape and movement of objects. In the primate eye, there are two major types of retinal ganglion cells, Type M and Type P cells, that process information about different stimulus properties. Figure 14.28 Left: The on ganglion cell synapses with an on bipolar cell and produces action potentials (i.e., is excited) when the on bipolar cell is depolarized (i.e., when the light is on). Right: In contrast, an off ganglion cell that synapses with an off bipolar cell reduces the rate at which it produces action potentials (i.e., is inhibited) when the off bipolar cell is hyperpolarized (when the light is on). Type P retinal ganglion cells are color-sensitive object detectors. The P ganglion cell(s) outnumber the M-ganglion cells, by approximately 100 to 1 in the primate retina makes synaptic contact with one to a few cone bipolars that are innervated by cone receptors in the macula fovea is color sensitive has a small concentric receptive field produces a sustained, slowly adapting response that lasts as long as a stimulus is centered on its receptive field. produces weak responses to stimuli that move across its receptive field. The slowly adapting response of the Type P retinal ganglion cell is best suited for signaling the presence, color and duration of a visual stimulus and is poor for signaling stimulus movement. Type M retinal ganglion cells are color-insensitive motion detectors. The M ganglion cell is much larger than P ganglion cells synapses with many bipolar cells is color insensitive has a large concentric receptive field is more sensitive to small center-surround brightness differences responds with a transient, rapidly adapting response to a maintained stimulus. responds maximally, with high discharge rates, to stimuli moving across its receptive field.

The rapidly adapting responses of Type M ganglion cells are best suited for signaling temporal variations in, and the movement of, a stimulus. The axons of the M and P retinal ganglion cells travel in the retina optic nerve fiber layer to the optic disc where they exit the eye. Most of the axons travel to and terminate in the lateral geniculate nucleus of the thalamus. Amacrine Cells Amacrine cells synapse with bipolar cells and ganglion cells and are similar to horizontal cells in providing lateral connections between similar types of neurons (e.g., they may connect bipolar cells to other bipolar cells)5. They differ from horizontal cells, however, in also providing vertical links between bipolar and ganglion cells. Amacrine cell types. There are 20 or more types of amacrine cells based on their morphology and neurochemistry. The roles of three types have been identified. One type is responsible for producing the movement sensitive (rapidly adapting) response of the Type M ganglion cells. enhances the center-surround effect in ganglion cell receptive fields. connects rod bipolar cells to cone bipolar cells, thus allowing ganglion cells to respond to the entire range of light levels, from scotopic to photopic Convergence of Inputs and Visual Acuity Low convergence of cones to cone bipolar cells and low convergence of cone bipolar cells to P-retinal ganglion cells produce high visual acuity in the central visual field. Recall that visual acuity and color vision are greatest in the central visual field. the image of the central visual field is projected onto the fovea. the cones are concentrated in the fovea, whereas the rods predominate in the peripheral retina. there is low convergence of foveal cones onto macular bipolar cells, as low as one cone receptor to one bipolar cell. In addition, the cones in the fovea are of smaller diameter than those in the periphery of the retina, which allows for a greater packing density of foveal cones. The high packing density of cones and the low convergence of cones onto bipolar cells in the macula support higher visual acuity in the central visual field. Consequently, the foveal cones, macular bipolar cells and the P-retinal ganglion cells are responsible for photopic, light-adapted vision in the central visual field. In contrast, the higher convergence of the rods onto peripherally located bipolar cells and of peripheral bipolar cells onto amacrine cells forms the basis for the poor visual acuity but high light sensitivity of scotopic vision. 14.5 Clinical Manifestations of Retinal Dysfunction The chemical and physical integrity of the retina is essential for normal visual function. Abnormalities in the blood supply and retinal pigment epithelium result in retinal dysfunctions. Vitamin A deficiency can cause permanent blindness. An adequate supply of photopigments is necessary to sustain photoreceptors. The supply of all-trans retinal as a photopigment breakdown product is insufficient to maintain adequate photopigment production. Vitamin A can be oxidized into all-trans retinal, and is, therefore, critical in the synthesis of photopigment. In the eye, it is the retinal pigment epithelium that stores vitamin A. The retinal pigment epithelium is also the site of the oxidization of vitamin A into all-trans retinal and conversion of all-trans retinal into 11cis-retinal. Vitamin A cannot be synthesized by the body and must be ingested. It is found in blood and stored in the liver and retinal pigment epithelium. Vitamin A deficiency, which can result from liver damage (e.g., from alcoholism or hepatitis), produces degeneration of photoreceptors with visual symptoms first presenting as night blindness (i.e., extremely poor vision under low illumination). Retinitis pigmentosa is an inherited disorder in which there is a gradual and progressive failure to maintain the receptor cells. One form involves the production of defective opsin that normally combines with 11-cis retinal to form rhodopsin. Consequently, the rods do not contain sufficient rhodopsin and do not function as the low illumination receptors. A symptom of this condition is night blindness and loss of peripheral vision. In this form of retinitis pigmentosa, the cones receptors function normally and central vision remains intact. Other forms of retinitis pigmentosa that affect the cones may progress to destroy central vision. Macular Degeneration. The leading cause of blindness in the elderly is age-related macular degeneration. The dry form of macular degeneration involves intraocular proliferation of cells in the macular area (i.e., in the fovea and the immediately surrounding retinal areas). In the wet form of macular degeneration, the capillaries of the choroid coat invade the macular area and destroy receptor cells and neurons. In both forms, the visual loss is in the central visual field and the patient will complain of blurred vision and difficulty reading. Laser surgery is the most common treatment for the wet form but has the disadvantage of destroying normal retinal cells. It also may not be effective in preventing cell proliferation following treatment. Retinal detachment. When the neural retina is torn away from the retinal pigment epithelium (e.g., by a blow to the

eye), there is a loss of vision in the area of detachment. The loss of vision results because the neural retina is dependent on the retinal pigment epithelium for 11-cis retinal, nutrients and photoreceptor integrity. The retinal pigment epithelium supplies glucose and essential ions to the neural retina, helps support the photoreceptor cell outer segment, removes outer segment disks shed by the receptor cells, and converts retinol and stores vitamin A for photopigment resynthesis. Lasers may be used to weld the detachment to prevent it from increasing in size. However, the detached and welded areas are functionally blind. Diabetic retinopathy. The pathological process in diabetic retinopathy involves microaneurysms and punctate hemorrhages in the retina. The tiny swollen blood vessels and/or bleeding in the underlying choroid coat damage the receptor cells and retinal neurons and result in blindness in the regions affected. Lasers may be used to seal swollen and/or leaking blood vessels.

Table I Classification of Consensual Ocular Responses & Their Motor Control Structures Ocular Function Afferent Input* & Motor Control Structures Responses Eye Blink Protects cornea from contact with foreign Free Nerve Endings in cornea that are afferent endings of the Reflex objects Trigeminal Nerve, Ganglion, Root & Spinal Trigeminal Tract* Spinal Trigeminal Nucleus* Reticular Formation (bilaterally to) Facial Motor Nuclei & Facial Nerves Orbicularis Oculi Pupillary Light Decreases pupil size (constriction) reduces Retina, Optic Nerve, Chiasm & Tracts and Brachium of Superior Reflex the amount of light that enters the eye. Colliculus* Pretectal Areas of Midbrain (bilaterally to) Edinger-Westphal Nuclei & Oculomotor Nerves Ciliary Ganglia & Short Ciliary Nerves Iris Sphincters Pupillary Increases depth of focus of eye lens system Visual System* including Visual Association Cortex Accommodatio Supraoculomotor Nuclei (bilaterally to) n Increases refractive power of lens Edinger-Westphal Nuclei & Nerve III Ciliary Ganglia & Short Ciliary Nerves Lens Iris Sphincters & Ciliary Muscles Accommodatio n Convergence Eyes directed nasally during accommodation Visual System* including Visual Association Cortex Supraoculomotor Nuclei (bilaterally to) Oculomotor Nuclei Medial Rectus Muscles * Afferent structures proving sensory input.

Gaze Stabilization: Eye Movements that Counter-Act Head Movement There are two functional classes of eye movements (Table I): those that stabilize the eye when the head moves or appears to move (gaze stabilization) and those that keep the image of a visual target focused on the fovea (a.k.a., foveation) when the visual target changes or moves (gaze shifting). Two gaze stabilization systems operate during head movement: the vestibulo-ocular and the optokinetic systems. Vestibulo-ocular and optokinetic movements are conjugate movements in which both eyes move in the same direction. Table I Classification of Eye Movements Eye Movement Type Function Vestibulo-ocular Gaze Stabilization Initiated by vestibular mechanisms during brief/rapid head movement Optokinetic (vestigial in humans) Initiate by visual mechanisms during slow head movement Vergence Gaze Shifting Adjusts for different viewing distance Smooth Pursuit Follows moving visual target Saccade Directs eyes toward visual target The Vestibulo-ocular Reflexes Vestibulo-ocular reflexes produce eye movements that compensate for head movements detected by the vestibular system. You have learned in earlier chapters how the vestibular system detects head movements and initiates the vestibulo-ocular responses. Optokinetic Nystagmus Optokinetic nystagmus is elicited by slow head movements undetected by the vestibular system,

by moving objects that produce the illusion of head movement (e.g., alternating bands of light and dark lines rotated around the viewer's head) as corrections for small spontaneous eye movements Notice that optokinetic nystagmus is a visual-ocular response - driven by visual stimuli moving across the visual field. Vestibular nystagmus is a vestibulo-ocular response - driven by a vestibular stimulus (i.e., accelerating head movement). In humans, the smooth pursuit system predominates in producing eye movements that track moving visual targets.
Table II Classification of Eye Movement & Their Neural Control Structures Eye Function Afferent Input* & Motor Control Structures Movement VestibuloInitiated by vestibular mechanisms Vestibular Receptors & Vestibular 1 Afferent Neurons* ocular during head movement Horizontal Movements: Medial Vestibular Nucleus* Vim Lateral Rectus of One Eye VIi (mlf) III Medial Rectus of Opposite Eye Vertical Movements: Superior Vestibular Nucleus* IV & III Sup. or Inf. Oblique, Sup. or Inf. Rectus Vergence Adjusts for different viewing distances Visual System* including Visual Association Cortex Supraoculomotor Nuclei III Medial Rectus Muscles Smooth Follows (watches) a moving visual Visual System* including Visual Association Cortex Pursuit target Temporal Eye Field Dorsolateral Pontine Nucleus Cerebellum Lateral Pursuit: Medial Vestibular nucleus Vim Lateral Rectus of One Eye VIi (mlf) III Medial Rectus of Opposite Eye Vertical Pursuit: Superior Vestibular Nucleus VI & III Sup. or Inf. Oblique, Sup. or Inf. Rectus Saccade Directs eyes toward visual target Visual System* including Visual Association Cortex Frontal Eye Field Superior colliculus & Basal ganglia Lateral Gaze: Pontine Paramedian Reticular Formation VIm Lateral Rectus of One Eye VIi (mlf) III Medial Rectus of Opposite Eye Vertical Gaze: Midbrain Vertical Gaze Center IV & III Sup. or Inf. Oblique, Sup. or Inf. Rectus KEY: VII - Abducens Interneurosn; VIm - Abducens Motor Neurons; III - Occulomotor Motor Neurons; IV - Trochlear Motor Neurons

[1] Note that each oculomotor nerve controls the extraocular muscles of its ipsilateral eye, i.e., the right nerve controls the superior and inferior oblique and superior and inferior rectus of the right eye. Coloboma of Iris The absence of a section of iris (Fig. B7.27) may result from a birth defect, in which the choroid fissure (Fig. B7.24B) fails to close properly, from penetrating or non-penetrating injuries to the eyeball, or a surgical iridectomy. When the iris is injured in such a manner, the iridial fissure does not heal. Pupillary Light Reflex light shone directly into eye travels along optic nerve optic tracts both sides of midbrain impulses enter both sides of midbrain via pretectal area and Edinger-Westphal nuclei nerve impulses then travel down CN III bilaterally to reach the ciliary ganglia, and finally to the iris sphincter muscle, which results in direct and consensual light reflex Pupil Abnormalities Denervation Hypersensitivity when post-ganglionic fibres are damaged, the understimulated end-organ develops an excess of receptor and becomes hypersensitive postganglionic parasympathetic lesions (i.e. Adies pupil) pupil will constrict with 0.125% pilocarpine (cholinergic agonist), normal pupil will not postganglionic sympathetic lesions (this test is used to differentiate between pre- and postganglionic lesions in Horners syndrome) pupil will dilate with 0.125% adrenaline, normal pupil will not Local Disorders of Iris posterior synechiae (adhesions between iris and lens) due to iritis can present as an abnormally shaped pupil

 ischemic damage [e.g. post-acute angle-closure glaucoma (ACG)] ischemic damage usually at 3 and 9 oclock positions result in a vertically oval pupil that reacts poorly to light trauma (e.g. post intraocular surgery) Anisocoria unequal pupil size idiopathic/physiologic anisocoria 20% of population round, regular, <1 mm difference pupils reactive to light and accommodation responds normally to mydiatrics/miotics

Wilibrand: upper temporal field, anterior part 1, Central scotoma from optic neuropathy. 2, Unilateral blindness due to optic nerve transection. 3, Bitemporal hemianopia from optic chiasmal lesion, may or may not be macular splitting (left lower inset): A, Lesion anterior to chiasmmore prominent defect in bitemporal upper quadrants early on and eventually evolving to full bitemporal field defect; B, lesion posterior to chiasm; more prominent defect in bitemporal lower quadrants early on and eventually evolving to full bitemporal field defect. 4, Anterior chiasm or junctional syndrome: ipsilateral optic nerve defect and contralateral superior temporal field

defect due to posterior optic nerve lesion involving the ipsilateral optic nerve and contralateral crossing fibers of Wilbrands knee (contralateral lower nasal fibers representing upper temporal field) (also see Fig. 3-9); this is to be differentiated from junctional syndrome of Traquair, represented in lesion C. 5, Unilateral nasal field defect due to ipsilateral lateral optic nerve lesion. 6, Macular-splitting homonymous hemianopia from complete optic tract lesion. 7, Complete (gray and black) homonymous hemianopia and incomplete (black only or gray only) field defects due to lateral geniculate body lesions (complete and incomplete lesions, respectively). Gray represents quadruple sectoranopia due to vascular lesions in the distribution of anterior choroidal artery; black represents horizontal homonymous sector defect due to vascular lesions in the distribution of posterior lateral choroidal artery. 8, Right superior homonymous quadrantanopia (pie in the sky) deficits from left temporal lesion affecting underlying optic radiations (lower bundle, called Meyers loop as fibers pass lateral to temporal horn of lateral ventricle). 9, Right inferior homonymous quadrantic (pie on the floor) deficits from left parietal lesion affecting the underlying optic radiations (upper bundle). 10, Macular-splitting homonymous hemianopia from lesion affecting both superior and inferior optic radiations (usually large hemispheric insults). 11, Temporal crescent (half-moon) syndrome due to lesion at anterior tip of striate cortex. 12, Macular-sparing homonymous hemianopia due to lesion involving entire medial occipital lobe, sparing the anterior tip (representing contralateral temporal crescent). 13, Partial homonymous hemianopia (macular-sparing) affecting the most posterior portion of medial occipital lobe, sparing posterior poles (macular representation). 14, Macular-splitting homonymous field defect limited to macular distribution and no involvement of peripheral visual fields (could be due to lesion of unilateral posterior occipital pole). Right lower inset: 1-6, layers of lateral geniculate nucleus.

Tract

Origin Sensory nerve cell bodies located in the dorsal root ganglion

Dorsal (Posterior) Column Medial Lemniscus*

Pathway Enter SC via DRG and ascend via ipsilateral posterior columns (either fasciculus cuneatus or fasciculus gracilis); synapse on posterior column nuclei (cuneate nucleus or gracile nucleus) in the caudal medulla; 2 neurons decussate as internal arcuate fibers, form medial lemniscus & travel contralaterally to VPL; VPL neurons project through posterior limb of the internal capsule to the 1 somatosensory cortex Enter SC via DRG and synapse immediately (mainly lamina I and V of dorsal horn); some collaterals ascend/descend in Lissauers tract before entering central gray; cross over within 2 - 3 spinal segments in the anterior commisure and ascend in contralateral anterolateral white matter; main tract (spinothalmic) continues to VPL of thalamus and finally to the 1 somatosensory cortex Medial: Originates in rostral medulla in medial (1) or inferior/lateral vestibular nuclei & travels bilaterally in the medial vestibular tracts to cervical & upper thoracic cord to terminate in medial intermediate zone on medial motor nuclei Lateral: Originates in pons in the lateral vestibular nucleus and travels ipsilaterally through the lateral medulla, to the inferior olivary complex and then enters the SC (primarily lumbar region) to terminate on and motor neurons & interneurons Dorsal: Enters via DRG & ascends in fasciculus gracilus & synapses in Clarks nucleus (C8 - L2ish); then travels in dorsal spinocerebellar tract to the inferior cerebellar peduncle and onto the cerebellum Cuneocerebellar: Enters via DRG & ascends in fasciculus cuneatus & synapses in cuneate nucleus in the caudal medulla; then travels to the inferior cerebellar peduncle and onto the cerebellum Ventral (& Rostral?): Enters SC and immediately decussates in the ventral commisure, travels in the ventral spinocerebellar tract through the SC & brainstem to the superior cerebellar peduncle where it decussates again and terminates in the cerebellum Pontine fibers: from cerebral cortex, cross over in the midbrain & descend more

Decussation Caudal medulla (as internal arcuate fibers)

Termination

Function Vibration, propioception, fine touch sensory modalities

Other Large - diameter, myelinated axons Sign of a lesion: loss of fine touch & propioception on ipsilateral side (if below caudal medulla) or contralateral side (if in caudal medulla or above) Small - diameter, unmyelinated axons Sign of a lesion: loss of pain, temp & crude touch on contralateral side (2 - 3 spinal cord segments of entry & above) or ipsilateral side (if near point of entry)

Primary somatosensory cortex

Anterolateral (Spinothalmi c)* Tract

Sensory nerve cell bodies located in the dorsal root ganglion

Anterior commisure within 2 - 3 spinal segments of entry

Primary somatosensory cortex

Pain, temperature and crude touch sensory modalities

Vestibulospin al (Medial & Lateral) Medial Motor System

Medial: medial & inferior vestibular nuclei Lateral: lateral vestibular nuclei

----------

Medial: cervical & upper thoracic cord Lateral: entire cord

Medial VST: positioning of head & neck Lateral VST: balance

Medial: Excitatory & inhibitory Lateral: Primarily inhibitory

Spinocerebell ar

Dorsal: leg propioceptors Cuneocerebellar: arm propioceptors Ventral: leg interneurons Rostral: arm interneurons

Dorsal & Cuneocerebellar dont decussate Ventral & Rostral: Decussate immediately at ventral commisure and again in the superior cerebellar peduncle Cerebellum

Propioception, information from interneurons

Dorsal & Cuneocerebellar are ipsilateral pathways Ventral & Rostral are double crossed pathways cross immediately, travel contralaterally and cross in the superior cerebellar peduncle to terminate ipsilaterally

Reticulospina l Medial Motor System

Pontine & medullary reticular formation

medially in white matter, terminating on and motor neurons Medullary fibers: from cerebral cortex, cross over in the midbrain & descend more laterally in the white matter, terminating on and motor neurons Axons enter the corona radiata and descend towards internal capsule (posterior limb); descend through the ventral pons; fascicles collect on ventral medullary surface to form medullary pyramids; transition from medulla to SC @ cervicomedullary junction where 85 - 90% cross over; enter lateral columns & synapse on anterior horn cells Same as lateral corticospinal tract; except in the cervicomedullary junction the remaining 10 - 15% of fibers that do not cross over; continue ipsilaterally to the anterior columns of SC white matter

Dorsal tegmental decussation in midbrain

Cervical cord

Believed to be involved in coordination of head & eye movement

Lateral Corticospinal Tract* Lateral Motor System Anterior Corticospinal Medial Motor System

Primary motor cortex, Frontal, Parietal areas, Motor neurons in cortical layer 5

Pyramidal decussation (cervico - medullary junction)

Entire cord Concentrated in cervical & lumbosacral enlargements Cervical and upper thoracic cord

Movement of contralateral limbs

Sign of a lesion: Motor loss

Primary motor cortex; Supplementary motor areas

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Control of bilateral axial and girdle muscles

* Main long tracts

El Cancer Someone elses chart CNS tumors Incidence Fibrillary Together account astrocytoma for ~80% of brain tumors

Age Most occur in 4th-6th decades

Clinical Seizures, headache, focal neuro defects

Sites of origin Usually in cerebral hemis., may be found in cerebellum, brainstem, or spinal cord

Glioblastoma

Pilocytic astrocytoma

Children and young adults a)intrinsic pontine glioma, b) tumor of CM region, c) tectal glioma 5-15% of gliomas First two decades

Relatively benign

Brainstem glioma

Varying aggression

Usu. cerebellum, but may be in 3rd ventricle, optic nerves and cerebral hemispheres a) pons, b)cervicomedullary junction, c) tectum Cerebral hemispheres, esp white matter

Morphology Poorly-defined, gray, infiltrative tumor; histological differentiation correlates w/ clinical course Gross appearance varies between regions; necrosis present Cystic, with a mural nodule; Rosenthal fibers, eos. Granular bodies, microcysts

Grade WHO IIIV/IV (glioblast. incl.) WHO IV/IV

Genetics P53 inactivation, PDGF-A overexpression 2: p53 mutations; 1: EGFR amplification P53 mutations rare

Prognosis >5 years

8-10 mos. from Dx Tx in cerebellum is resection a) short survival, b) less aggressive, c) most benign Better than astrocytomas: 5-10yrs w/ chemotx and rad. Poor despite slow growth, avg. survival is 4yrs with Tx Dismal, but radiosensitive; 5-yr rate with total Tx 5yrs Predominantly benign, most easily separable from the brain Relatively poor response to chemotherapy

WHO I/IV

Oligodendroglio ma

4th-5th decades

Ependymoma

5-10% of 1 brain tumors in kids, in adults occur in setting of NF2 20% of brain tumors in children

Bimodal (see sites) Most often children Adults

Medulloblastom a Meningioma

Hydrocephalus from ventricle obstruction, CSF dissemination common Dissemination in CSF common Slow-growing lesions with vague symptoms, usually solitary

Near 4th ventricle (first 2 decades); spinal cord (adults) Cerebellum, midline (children) Along external surfaces of the brain (attached to dura) or ventricular system Brain parenchyma

Wellcircumscribed, gelatinous, gray masses w/ cysts, focal hemorrhage and calcification Sharply demarcated solid or papillary masses Well circumscribed, gray and friable tumor Rounded mass with a well-defined dural base that compresses underlying brain; en plaque variant grows in sheets Lesions frequently multiple, grey/white matter involved; central necrosis common Sharply demarcated masses, usually surrounded by zone of edema

WHO II/IV

LOH @ 1p and 19q; also loss of 9p, 10q, and CDKN2A mutation NF2 alterations in spinal cord type only Partial loss of 17p; SHH/patched, Wnt signalling Loss of X22 (incl. NF2)

WHO II/IV, anaplastic epend: WHO III/IV

Most I/IV, atypical II/IV, anaplastic III/IV High grade lymphoma

Primary CNS lymphoma

Metastatic tumors

2% of extranodal lymphomas, 1% of intracranial tumors; most common in immunosupp. 25-50% of intracranial tumors

Wide range, most common after 60

Aggressive disease of B cell origin

EBV genome found in transformed B cells in immunosup patients

Most comon primary sites are lung, breast, skin, kidney, GI

Often at grey matter-white matter junction, meninges also common site

Choroid plexus papilloma Colloid cyst

Children

Hydrocephalus from ventricle obstruction Noncommunicating hydrocephalus

Anywhere along choroid plexus, esp lateral ventricles Roof of third ventricle

Young adults

Gangliocytoma/ Ganglioglioma

(GG)Often present as seizure disorder

(GC) Floor of 3rd ventricle, hypothalamus, or temporal lobe (GG)Temporal lobe

Germ cell tumor

0.2-1% in people of Euro descent, up to 10% in Japs

Pineal tumor Peripheral nerve tumors Schwannoma Hereditary pattern Sporadic cases associated with NF2 gene

90% occurring in first 2 decades PB children

Tx responses mirror histologically similar lesions Range clinical presentation

Midline, esp in pineal and suprasellar regions Arise from pineocytes Sites of involvement Most common location is cerebellopontine angle, attach to vestibular branch of CN VIII Dermis and subcutaneous fat

Neoplastic and nonneoplastic lesions Nuclear pleomorphism, zanthomatous change, vascular hyalinization

Tumors recapitulate normal choroid plexus structure Non-neoplastic cyst has thin, fibrous capsule and contains gelatinous, proteinaceous material (GC)Lesion comprised entirely of matureappearing neurons (GG) Matureappearing neurons admixed with a glial neoplasm Share many features with counterparts in the gonads Well-differentiated PC to high-grade PB Clinical features

Choroid plexus carcinoma found in LiFraumeni Noncomm. hydrocephalus may be rapidly fatal

I-II/IV; Anaplastic ganglioglioma III/IV

(GG) Surgical resection effective for seizures

Range

May disseminate widely, complicating Tx PB associated PB spreads with RB mut throughout CSF Malignant potential Malignant change extremely rare

Neurofibroma, cutaneous (skin) or solitary (peripheral nerve) Neurofibroma, plexiform

Sporadic or in association with NF1

Skin lesions are nodules, sometimes hyperpigmented

Encapsulated tumor with a biphasic growth pattern Antoni A pattern: bland spindle cell proliferation. Incl. Verocay bodies Antoni B pattern: loosely structured, vacuolated tissue Cosmetic concerns are major morbidity

Extremely low

May only occur in patients with NF1

Irregular expansion of involved nerves (each fascicle is infiltrated)

Anywhere along a nerve, but large nerve trunks are most common site

Loss of wild-type NF1

Multiple cell phenotypes present, Impossible to separate lesion from the nerve

Malignant peripheral nerve sheath tumor

Familial tumor syndromes

Arise de novo or Poorly-defined tumor masses Follow plexiform Some S-100, not Recur frequently, Highly malignant, locally from with frequent infiltration along all eventually invasive transformation of the axis of the parent nerve, metastasize a plexiform invasion of adjacent soft tissue. neurofibroma, Necrosis common strongly associated with NF1 Characterized by the development of hamartomas and neoplasms throughout the body, with particular involvement of the nervous system

NF1

NF2

Tuberous sclerosis

Autosomal dominant, frequency = 1:3000 Autosomal dominant, frequency = 1:40,000-50,000 Autosomal dominant

Neurofibroma (plexiform solitary), CNII glioma, Lisch nodules, caf au lait spots Range: bilateral CN VIII schwannoma most common, multiple meningiomas, gliomas; non-neoplastic lesions common Hamartomas and benign lesions

Multiple locations

Loss of heterozygosity of NF1 Nonsense more severe than missense mutations at NF2 TSC2, X 16p13.3 (tuberin); TSC1, X 9q34 (hamartin) Tumor suppressor gene at 3p25-26, encodes pVHL

Higher than in sporadic cases, especially plexiform type

Multiple locations

Von HippelLindau syndrome

Autosomal dominant, freq 1:30,000-40,000

Hemangioblastomas, 10% associated with polycythemia (tumor a source of EPO)

Hamartomas in CSF occur as cortical tubers and subependymal hamartomas Cerebellar hemispheres, retina, and brainstem/spinal cord

Obligate carriers with no symptoms exist Vascular component: regulation of HIF-1 by pVHL

Tx is symptomatic, including anticonvulsant for seizures Tx directed at symptomatic neoplasms, laser for retinal hemangioblastomas

Stroke Syndromes According to Vascular Territory ACA: contralateral paresis and sensory loss, loss of bladder control (hypertonic detrusor) MCA: proximal occlusion involves all of the below findings superior division: contralateral face and arm paresis and sensory loss, Brocas (expressive) aphasia (if in dominant hemisphere) inferior division: contralateral homonymous hemianopsia (esp. inferiorly), contralateral agraphesthesia and astereognosis, anosognosia, contralateral neglect, Wernickes (receptive) aphasia (if in dominant hemisphere) Internal carotid: premonitory TIA or transient monocular blindness (amaurosis fugax), asymptomatic or similar to MCA occlusion PCA: contralateral homonymous hemianopsia (especially superiorly), midbrain findings (vertical gaze palsy, CN III palsy, INO), occipital findings (anomia, alexia without agraphia, visual agnosia) if bilateral: cortical blindness or prosopagnosia Basilar artery proximal (usually thrombosis) occlusion: CN VI palsy, impaired horizontal EOM impairment, vertical nystagmus, reactive myosis, hemi- or quadriplegia, coma, locked-in syndrome distal (usually embolic) occlusion (aka Top of the Basilar Sydrome): decreased LOC, CN III palsy, decerebrate or decorticate posturing PICA (Lateral Medullary or Wallenburg Syndrome): ipsilateral ataxia, ipsilateral Horners, ipsilateral facial sensory loss, contralateral limb impairment of pain and temperature, nystagmus, vertigo, N/V, dysphagia, dysarthria, hiccup Lacunar Infarcts (basal ganglia, thalamus, posterior limb internal capsule) pure motor hemiparesis: contralateral arm, leg, and face pure sensory loss: hemisensory loss (usually thalamic) ataxic hemiparesis: ipsilateral ataxia and leg paresis dysarthria-clumsy hand syndrome: dysarthria, facial weakness, dysphagia, mild hand weakness and clumsiness

Neurogenic and Spinal Shock 1. neurogenic shock: hypotension that follows SCI (SBP usually 80 mmHg) caused by interruption of sympathetics (unopposed parasympathetics) below the level of injury loss of muscle tone due to skeletal muscle paralysis below level of injury venous pooling (relative hypovolemia) blood loss from associated wounds (true hypovolemia)

2. spinal shock: transient loss of all neurologic function below the level of the spinal cord injury, causing flaccid paralysis and areflexia for variable periods