CNS GENERAL REACTIONS TO INJURY. Reid Hefner, M.D. Department of Pathology and Anatomical Sciences Tuesday, November 7, 2017

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1 CNS GENERAL REACTIONS TO INJURY Reid Hefner, M.D. Department of Pathology and Anatomical Sciences Tuesday, November 7, 2017

2 LEARNING OBJECTIVES Review normal gross CNS anatomy Be familiar with normal cells in CNS Know special stains used in neuropathology Understand basic CNS reactons to injury Know in what conditons a reacton occurs Know defnitons discussed in lecture

3 REFERENCES Robbins Basic Pathology. Kumar et al. Pathologic Basis of Disease. 9th Editon. Saunders, Philadelphia, Chapter 28. Robbins 9th editon, 2013, Chapter 22 Or Robbins 10th editon, 2017, Chapter 23

4 MACROSCOPIC EXAM The enlarged brain Difuse=edema Hydrocephalus-early* Mass lesion(s) May create increased intracranial pressure The small brain Atrophic processes Hydrocephalus-late* Destructve processes The focal lesion Infarcts

5 BRAIN EDEMA normal edema Compare the ventricles for size Compare the sulci for width

6 Brain edema-ct scan Ventricles are slit-like

7 BRAIN EDEMA Widened gyri Narrow sulci

8 BRAIN EDEMA-CAUSES Trauma Tumor Stroke Metabolic Infecton

9 BRAIN EDEMA-MECHANISMS Cytotoxic-intracellular Vasogenic-extracellular Membrane permeability is increased Leaky hose= vascular permeability Transependymal-extracellular Increased ventricular pressure

10 CYTOTOXIC EDEMA Cells appear vacuolated Intracellular fluid

11 VASOGENIC EDEMA The leaky pipe principle

12 VASOGENIC EDEMA Most common type Located mainly in white mater Cytotoxic in gray mater Causes Tumor Stroke Abscess Trauma

13 What is wrong?

14 HYDROCEPHALUS Acute or chronic High pressure Block in ventricular fow Block in meningeal circulaton Block in reabsorpton Normal pressure Hydrocephalus Ex vacuo About 500 ml CSF produced each day

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17 Ventral brain

18 Brain-lateral view

19 CSF drainage system

20 HYDROCEPHALUS CLINICAL PROBLEM OF DILATED VENTRICLES Hydrocephalus vs atrophy

21 TRANSEPENDYMAL EDEMA Rapid elevaton of ventricular pressure Fluid crosses ependymal barrier Concentrated around ventricles Brain is large

22 MASS LESIONS The brain is enlarged Cerebral Hemorrhage

23 BRAIN EDEMA/HYDROCEPHALUS/MASS LESIONCONSEQUENCES Raised intracranial pressure (RIP) Diminished cerebral blood fow ischemia Herniatons Shifs within the cranial cavity Compression of third nerve and cerebellar tonsils Blood vessel damage in pons Pressure rises exponentally once all the extra-axial spaces are flled

24 HERNIATIONS Complicatons of edema and/or mass

25 Uncal herniaton

26 Increased intracranial pressure Pressure on third cranial nerve Fixed dilated pupil Parasympathetic fibers compromised

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29 What s happening here?

30 IIP-DURET HEMORRHAGES Downward movement of pons Stretching of the pontne vessels Secondary brainstem hemorrhages result Coma, death ensue

31 RAISED IP-TONSILLAR HERNATION Herniation through foramen magnum Compression of medulla

32 RAISED IP-TONSILLAR HERNATION Herniation into foramen magnum Compression of medulla

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34 RIP and EDEMA-TREATMENT Shuntng of CSF from ventricles Acetazolamide Mannitol Reduce CSF producton (temporary) Osmotcally remove fuid from brain Cortcosteroids Works in vasogenic edema Reduces synthesis of prostaglandins Seems to reduce vascular dilaton and permeability

35 ATROPHIC BRAIN Alzheimer s Disease Widened sulci Normal sulci

36 ATROPHIC BRAIN Alzheimer s Disease Hydrocephalus ex vacuo Normal ventricles

37 DESTRUCTIVE LESIONS Old Infarct

38 FOCAL LESIONS Lacunar Infarcts

39 MICROSCOPIC EXAM Neurons Axons Neuropil and myelin Glia Ependyma Meninges

40 CELLULAR REACTIONS Injury or death Regeneraton Proliferaton or hyperplasia Atrophy or cell loss Inclusions Storage Neoplasia

41 SPECIAL STAINS IN NEUROPATHOLOGY Nissl (cresyl violet) Luxol fast blue (LFB) Astrocytc processes stained with metallic tungstc acid Cajal (Nobel Prize)-not used diagnostcally Myelin stains blue PTAH-not used anymore Ribosomes in neurons Gold impregnaton for astrocytes Silver stains (e.g. Bodian) Nerve processes Several types of inclusions, senile plaques

42 Cast of characters Nero the neuron Astrocyte Oligodendroglia Microglia Pac(man) the macrophage Expendable the ependymal cell

43 Cells of the brain

44 Nero the neuron I m pretty special because I m like an emperor All cells pay homage to me-astrocytes dote on me Pear-shaped histologically Too lazy to have offspring-no regeneration

45 Olive the oligodrocyte Myelin Loves myelin Makes and maintains

46 Aster the astrocyte Dotes on Nero Provides support to Nero Has offspring=proliferation during injury

47 Mike the microglia Fights his way between the endothelial cells and the glial cells Battles disease and the Democrats

48 Cast of characters Pac(man) the macrophage Pretty feisty Eats everything in sight

49 Expendable the ependymal cell This boring cell doesn t react much

50 NEURONS Cells do not regenerate or proliferate But axon may regenerate or sprout Necrosis Apoptosis Atrophy Chromatolysis Inclusions Storage

51 NORMAL NEURON Vesicular nucleus Prominent nucleolus Abundant ribosomes Axon Microfilaments/tubules Synapses

52 NORMAL NEURON Pear-shaped Nissl substance Nucleolus

53 Not all neurons are created equal Internal granular layer

54 NISSL SUBSTANCE Rough ER

55 NORMAL NEURON Silver stain (Bodian) shows neuronal processes Neuroflaments and neurotubules

56 ACUTE NEURONAL INJURY normal necrosis apoptosis

57 Mechanisms of Cell Death Frequently inter-related Reduced energy Mitochondrial damage May lead to apoptosis Membrane damage ATP, glucose, oxygen permeability Free radicals

58 INCLUSIONS Accumulatons of virus or proteins Causes Misfolding of normal protein Accumulaton of abnormal protein Autophagic actvity Ofen seen as hyaline or flamentous material within cell Usually eosinophilic in H&E stains Glassy and homogeneous

59 NEURONAL ATROPHY Atrophy in aging

60 INCLUSIONS viral Neurofibrillary tangle tangle

61 AUTOPHAGIC VACUOLES Granulovacuolar change in hippocampus in aging Also seen are neurofibrillary tangle and neuritic plaque

62 Granulovacuolar change

63 AUTOPHAGY Granulovacuolar change Debris in cell Then surrounded by membrane Fuses with lysosome to form autophagic vacuole Debris may be degraded/removed Can trigger cell death by complex

64 NEURONAL STORAGE-LIPID Membranous cytoplasmic bodies Tay-Sachs disease Ganglioside storage due to hexosaminidase A deficiency

65 NEURONAL LOSS Normal cerebellum Loss of granular layer cells and Purkinje cells

66 AXONS AND DENDRITES Wallerian degeneraton Spheroids (swollen axons) Segmental demyelinaton Axonal sproutng

67 NEURON AND PROCESSES Disease targets Neuron Axon Wallerian-afer neuron dies Spheroid Wallerian-afer axon is cut Spheroid Myelin Demyelinaton

68 WALLERIAN DEGENERATION Severe axonal injury or afer neuron dies Changes occur distal to injury Axonal atrophy & break-up of myelin Myelin stain

69 WALLERIAN DEGENERATION Axon shrinks (black arrow) Myelin debris with phagocytosis

70 ALS-Tract degeneraton LFB stain Rob. Fig

71 AXONAL SPHEROIDS Axon swollen Causes-sublethal injury Trauma Aging Near an infarct Toxins Vincristne Bodian silver stain

72 AXONAL SPHEROIDS Axonal transport slows/stops Distended axon Myelin may be intact, at least early Axons contain Filaments Other organelles accumulate Debris collects

73 Peripheral Nerve Injury Segmental demyelinaton=primary myelin disease Remyelinaton with onion bulbs Axonal injury May be secondary to myelin loss May be Wallerian with axonal atrophy Myelin ovoids May produce spheroids Ofen induces axonal sproutng This probably also occurs in CNS too

74 Teased nerve fbers Axons stained with osmium

75 PERIPHERAL NERVE-TEASED FIBERS 1 2 Myelin stained with osmium tetroxide (black) Normal (1), demyelinated (2) and remyelinated axons (3)

76 Segmental Demyelinaton Segments of myelin lost Between internodes typically Causes Guillain-Barré syndrome Diabetes

77 REMYELINATION Schwann cells proliferate Encircle demyelinated axon NORMAL NERVE ONION BULBS

78 Onion bulb Spiraling Schwann cells Rob. Fig. 27-5

79 AXONAL INJURY WITH MYELIN OVOIDS Myelin breaks down (ovoids) after axonal injury More diffuse, not segmental

80 Axonal sproutng Axon injury

81 NEUROPIL AND MYELIN Neuropil is the background in the grey mater Neuritc plaques Spongiform change Myelin is abundant in the white mater Primary demyelinaton-multple sclerosis Secondary demyelinaton-infarcton

82 NEUROPIL Senile (neuritc) plaque (Bodian) CJ Disease (spongiform)

83 MYELIN MS plaque NORMAL LFB STAIN

84 ASTROCYTES Proliferate to form a glial scar Cytoplasmic swelling (gemistocytes) Elaboraton of processes Inclusions Increased cellularity (see only nuclei) Rosenthal fbers, Alzheimer II cells Neoplasia

85 NORMAL ASTROCYTE STARS IN SKY CAJAL GOLD STAIN

86 NORMAL GLIA Oligos look like lymphocytes Astrocytes have larger, vesicular (open) nuclei

87 ASTROCYTES Glial fbrillary Acidic protein (GFAP)

88 GLIOSIS CNS s answer to fbrosis Increased astrocytes seen as increased numbers of nuclei

89 GLIOSIS Gemistocytes ([Gr] gemistos) Astrocyte cytoplasm is swollen or hypertrophic Seen in early gliosis but can remain for months

90 Gemeste or Greek stuffed pepper

91 FIBRILLARY GLIOSIS Glial processes form a scar (PTAH)

92 ASTROCYTE INCLUSIONS Rosenthal fbers Seen in long term gliosis, especially in benign childhood astrocytomas Masses of intermediate filaments Contain αβ-crystalline and ubiquitin

93 Alzheimer type II astrocytes Nothing to do with Alzheimer s disease Type of reactive astrocyte seen in hepatic disease Nucleus enlarged and clear

94 ASTROCYTE type II INCLUSIONS Seen in liver disease with serum NH3 Nucleus enlarged, clear, contains glycogen Alzheimer I cell larger, multiple nuclei, visible cytoplasm Alz II cell

95 OLIGODENDROGLIA Make and maintain myelin Limited regeneraton/limited remyelinaton Vacuolizaton Inclusions Damage and loss demyelination Ischemia, MS, PML Neoplasia

96 OLIGODENDROCYTES Major dense line (dark)=inner membrane Intraperiod line=extracellular space

97 OLIGODENDROCYTES LFB stain showing myelinated areas

98 OLIGODENDROCYTES NORMAL BRAIN Satellite oligos Near neurons Rows of oligos in white matter

99 OLIGODENDROCYTES Cytoplasmic vacuoles in (cytotoxic) edema

100 OLIGODENDROCYTES Intranuclear viral inclusions in PML

101 OLIGODENDROCYTE Necrosis Eosinophilic cytoplasm with fuzzy nucleus

102 MICROGLIA Derived mainly from monocytes in blood Begin as rod cells giter cells Proliferate at site of injury Difuse in large lesions Focal lesions Neuronophagia Glial nodules

103 MICROGLIA The Unglia -Not really glia Monocytes enter brain from blood

104 MICROGLIA Rod cells frst Flaten out to travel between axons and other cell processes

105 Pacman the macrophage Pac Man eats everything in sight

106 PHAGOCYTIC MICROGLIA Gitter cells (macrophages) Cytoplasm resembles a lattice

107 MICROGLIA Neuronophagia Phagocytotosis of neurons in apoptosis Glial nodules Focal clusters of microglia et al

108 EPENDYMAL CELLS The pathologically boring cell that doesn t react much Ependyma keeps CSF within ventricles Limited regeneratve or reactve potental Cell loss Infecton/infammaton Hydrocephalus, infecton Ependymits granularis (actually astrocytc gliosis) From meningits CMV infecton Neoplasia

109 NORMAL EPENDYMA Ciliated epithelium

110 EPENDYMAL CELLS Ependymits granularis Proliferaton of subependymal astrocytes Seen afer hydrocephalus or infammaton of the ventricles

111 CMV infecton of ependyma CMV loves ependyma Intranuclear and cytoplasmic inclusions

112 MENINGES: DURA AND PIAARACHNOID Blood or infammatory cells may be seen in these spaces Fibrosis of the leptomeninges Tumors Meningiomas

113 MENINGES Focal hyperplasia of arachnoid Derived from neural crest Pia-arachnoid (leptomeninges)

114 MENINGEAL FIBROSIS Causes Aging Meningits Bleeding Consequences Slows CSF circulaton or reabsorpton May result in hydrocephalus

115 MENINGES Meningioma

116 THE END Augustus Waller Franz Nissl Raymond Cajal del Rio Hortega