Pathology of the Central Nervous System PDF

PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM DR. HANNY, JOSHUA OKON OUTLINE INTRODUCTION/RELEVANT ANATOMY DEVELOPMENTAL ANOMALIES CEREBRAL EDEMA, HYDROCEPHALUS, RAISED ICP & HERNIATION INFECTIONS CEREBROVASCULAR DISEASES TRAUMATIC BRAIN INJURY DEGENERATING DISEASES SPONGIFORM E...

PATHOLOGY OF THE CENTRAL NERVOUS SYSTEM DR. HANNY, JOSHUA OKON OUTLINE INTRODUCTION/RELEVANT ANATOMY DEVELOPMENTAL ANOMALIES CEREBRAL EDEMA, HYDROCEPHALUS, RAISED ICP & HERNIATION INFECTIONS CEREBROVASCULAR DISEASES TRAUMATIC BRAIN INJURY DEGENERATING DISEASES SPONGIFORM ENCEPHALOPATHY CNS TUMOUR RELEVANT ANATOMY The average weight of the brain is about 1400 gm in men and 1250 gm in women. Covered by membranous connective tissue layers called Meninges There are 3: Dura mater (dura): tough, thick external fibrous layer. Arachnoid mater (arachnoid): thin intermediate layer. Pia mater (pia): delicate internal vasculated layer. The surface is thrown into folds – gyri, grooves – sulci RELEVANT ANATOMY RELEVANT ANATOMY RELEVANT ANATOMY RELEVANT ANATOMY RELEVANT ANATOMY Is composed of 2 types of tissues Neuro-ectodermal tissue (Neurons and Neuroglia cells) Mesodermal tissue (microglia, dura matter, leptomeninges, blood vessels) Neuroglial – Astrocytes, Oligodendrocytes and Ependymal cells Lacks lymphatic drainage RELEVANT ANATOMY RELEVANT ANATOMY CEREBRAL EDEMA Excess fluid within the brain parenchyma May be localized or generalized Vasogenic edema Due to increase vascular permeability or Disruption of blood brain barrier Cytotoxic edema Perturbation of normal plasma membrane permeability Generalized edema often have elements of both vasogenic and cytotoxic edema Morphology – Flattened gyri and narrow sulci, compressed ventricles CEREBRAL EDEMA CAUSES: CNS INFECTIONS CHRONIC LUNG DISEASES METABOLIC DISORDERS Complications Raised intracranial pressure Herniation Ischemic injury HERNIATION Herniation is the displacement of brain tissue past rigid dural folds or through openings in the skull due to increased intracranial pressure. Subfalcine (cingulate) herniation The cingulate gyrus of one hemisphere herniates under the falx cerebri This may cause compression of the anterior cerebral artery and its branches, resulting in secondary infarcts. Transtentorial (uncal, mesial temporal) herniation The medial aspect of the temporal lobe herniates through the free margin of the tentorium. Can cause compression of the third cranial nerve, resulting in pupillary dilation and impaired ocular movements on the side of the lesion HERNIATION Tonsillar herniation Displacement of the cerebellar tonsils through the foramen magnum. Life-threatening because it causes brainstem compression and compromises vital centers in the medulla HYDROCEPHALUS Hydrocephalus is the accumulation of excessive CSF within the ventricular system. Caused by a disturbance of formation, flow or absorption. Result in raised ICP and ventricular dilatation Common in children but can occur in adult HYDROCEPHALUS Common causes: A. In children i) Arnold–Chiari malformations. Ii) Stenosis of the aqueduct of Sylvius. Iii) Dandy–Walker syndrome. B. In adult mainly tumours e.g. choroid plexus papilloma HYDROCEPHALUS COMMUNICATING HYDROCEPHALUS OVERPRODUCTION OF CSF (choroid plexus tumour) IMPAIRED RESORPTION OF CSF (Arachnoid fibrosis from meningitis) NON-COMMUNICATING(OBSTRUCTIVE) HYDROCEPHALUS Aqueductal stenosis Tumours (Ependymoma, choroid plexus papilloma, Medulloblastoma) Inflammation(meningitis) Gross TRAUMATIC BRAIN INJURY Trauma to the CNS constitutes an important cause of death and permanent disability in the modern world. Physical forces or impacts on the head may result in: Skull fractures Parenchymal injury Vascular injury The magnitude and distribution of the lesion depends on: The shape of the object causing the trauma The force of impact and whether head is in motion at the time of injury. Penetrating or blunt injury, open or close injury TRAUMATIC BRAIN INJURY SKULL FRACTURES Displaced skull fracture The skull bone that is fractured can indicate the nature of fall Basal skull fractures are usually associated with CSF leakage from the nose and ears and cranial nerve injury May be complicated by meningitis TRAUMATIC BRAIN INJURY PARENCHYMA INJURY (concussion contusion and laceration ) CONCUSSION. A transient altered consciousness secondary to head trauma Due to change in momentum of the head following impact. Invariably, there is complete neurologic recovery after some hours to day Usually no significant morphologic changes CONTUSION AND LACERATION Most often caused by blunt head trauma and is due to transmission of kinetic energy to the brain parenchyma Analogous to Bruise and tearing of soft tissue Usually accompanied by subarachnoid hemorrhage TRAUMATIC BRAIN INJURY Traumatic Vascular Injury Vascular injury is a frequent component of CNS trauma. Disruption of the vessel wall and leads to hemorrhage in different anatomic sites Epidural hematoma Subdural hematoma Intraparenchymal hematoma Subarachnoid hemorrhage TRAUMATIC BRAIN INJURY Epidural hematoma is accumulation of blood between the dura and the skull. Most commonly from rupture of middle meningeal artery. The hematoma expands rapidly since accumulating blood is arterial in origin The patient develops progressive loss of consciousness if hematoma is not drained early. TRAUMATIC BRAIN INJURY TRAUMATIC BRAIN INJURY Subdural hematoma Accumulation of blood between the dura and subarachnoid. Slow (venous bleed), clotted blood Develops most often from rupture of veins which cross the surface convexities of the cerebral hemispheres. May be due to trauma (acute subdural hematoma) or brain atrophy (chronic subdural hematoma) TRAUMATIC BRAIN INJURY TRAUMATIC BRAIN INJURY Subarachnoid hemorrhage Bleeding into the subarachnoid space Commonly due to ruptured berry aneurysm Is an arterial bleed (cerebral arteries) TRAUMATIC BRAIN INJURY INTRAPARENCHYMAL HEMORRAGE Rupture of a small intraparenchymal vessel Often associated with sudden onset of neurologic symptoms (stroke) Traumatic and nontraumatic Spontaneous (nontraumatic) intraparenchymal hemorrhages occur most commonly in middle to late adult life. Ganglionic hemorrhages and lobar hemorrhages Common causes are Hypertension and cerebral amyloid angiopathy INTRAPARENCHYMAL HEMORRHAGES CEREBROVASCULAR DISEASES (CVD) DR. HANNY, JOSHUA OKON INTRODUCTION Injury to the brain caused by altered blood flow Reduce blood flow (Ischemia) Extravasation (hemorrhage) Stroke is the clinical designation applied to these conditions. Defined as neurologic signs and symptoms of vascular origin, have an acute onset, and persist beyond 24 hours. CVD is the third leading cause of death in the United States, and The most prevalent cause of morbidity and mortality from neurologic disease. ETIOPATHOGENESIS There are two major pathogenetic mechanisms ISCHEMIA/HYPOXIA Thrombosis Embolism Hypoxia Atherosclerosis Vasculitides Hypotension HEMORRHAGE Hypertension Aneurysm and developmental malformations Localized (focal) or generalized ETIOPATHOGENESIS ISCHEMIA/HYPOXIA (80%) HYPOXIA Hypoxic hypoxia (low oxygen tension – COPD, Respiratory failure) Anemic hypoxia (Reduction in oxygen carrying capacity – hemoglobinopathies Toxic hypoxia (cyanide, Carbon monoxide poisoning) ISCHEMIA Thrombosis Embolism Atherosclrosis Global hypoxic-ischemic encephalopathy or Cerebral infarction HEMORRHAGE (20%) Due to Rupture of cerebral vessels Hypertension Aneurysm ETIOPATHOGENESIS Focal ischemia Focal cerebral ischemia follows reduction or cessation of blood flow to a localized area of the brain. Ischemic neurons may die by apoptosis as well as necrosis Localized area of necrosis – Cerebral Infarction Can also cause inappropriate release of excitatory neurotransmitters – Excitotoxicity. Hemorrhagic and non-hemorrhagic infarcts Penumbra MORPHOLOGY Non-hemorrhagic infarct GROSS 48 hours. Pale, soft, and swollen, and the gray-white matter junction becomes indistinct. 2 to 19 days Gelatinous and friable MICRO Red Neurons, edema with neutrophilic infiltration MORPHOLOGY - Micro Presence of foamy macrophages and adjacent reactive gliosis with neovascularization MORPHOLOGY – Micro Red Neurons. Diffuse eosinophilia of neurons, which are beginning to shrink. MORPHOLOGY Lacunar infarct small cavitary infarcts or lacelike (necrotic) spaces Due to thrombosis of deep penetrating arteries Single or multiple Commonly involve the putamen, globus pallidus, thalamus, internal capsule, deep white matter, caudate nucleus, and pons Gross Micro Area of tissue loss surrounded by gliosis MORPHOLOGY Global hypoxic-ischemic encephalopathy Due to generalized reduction of cerebral perfusion Cardiac arrest, shock, and severe hypotension) or decreased oxygen carrying capacity of the blood Result in two types of infarcts – Watershed or border zone infarct and lamina necrosis Macro Watershed infarct – Border zone infarcts Wedge-shaped areas of coagulative necrosis located at the most distal reaches of the arterial blood supply Develop after severe hypotensive episodes Most commonly seen in patients resuscitated after cardiac arrest MORPHOLOGY laminar necrosis In global ischemia of the cerebral cortex, there is usually preservation of some layers and destruction of others. NEURODEGENERATI VE DISORDERS INTRODUCTION Neurodegenerative diseases are disorders characterized by progressive loss of particular groups of neurons. Common across most of these diseases is the accumulation of protein aggregates The protein aggregates typically are resistant to degradation and show aberrant localization within neurons. Histologically the protein aggregates appears as inclusions which serve as diagnostic hallmarks Neurodegenerative diseases vary with respect to the anatomic localization of involved areas and their specific cellular abnormalities – tangles, plaques, Lewy bodies INTRODUCTION The basis for aggregation varies from one disease to another. It may be due to: Mutation that alters the conformation of the affected protein Mutation affecting the pathways involved in the processing and clearance of normal protein A subtle imbalance between protein synthesis and clearance that allows gradual accumulation of proteins Huntington disease, Alzheimer disease, Parkinson disease and Prion Disease PRION DISEASES (SPONGIFORM ENCEPHALOPATHY) Prion diseases are rapidly progressive neurodegenerative disorders caused by aggregation and intercellular spread of a misfolded proteins called prion (PrP). The propensity of this pathogenic protein to spread from one cell to the other confers on them the characteristics of an infectious organism Prion diseases are characterized morphologically by spongiform changes and clinically by rapidly progressive dementia. They may be sporadic, familial, or transmitted. Examples of Prion diseases include Creutzfeldt-Jakob disease (CJD), PRION DISEASES (SPONGIFORM ENCEPHALOPATHY) PATHOGENESIS Normal PrP is an α-helix–containing isoform (PrPc), a 30-kD cytoplasmic protein of unknown function. Disease occurs when PrP undergoes a conformational change from its normal α-helix–containing isoform (PrPc) to an abnormal β- pleated sheet isoform, usually termed PrPsc (for scrapie) PrPsc is resistance to digestion with proteases, such as proteinase K. Accumulation of PrPsc in neural tissue seems to be the cause of the pathologic changes in these diseases PrPsc then facilitates the conversion of other PrPc molecules to PrPsc molecules PRION DISEASES (SPONGIFORM ENCEPHALOPATHY) CREUTZFELDT-JAKOB DISEASE (CJD) The most common prion disease, CJD is a rare disorder that manifests clinically as a rapidly progressive dementia. The sporadic form of CJD has an annual incidence of approximately 1 per 1,000,000 people and accounts or about 90% of CJD cases Familial forms are caused by mutations in PRNP, the gene that encodes PrP. The disease has a peak incidence in the seventh decade. The pathognomonic finding is a spongiform transformation of the cerebral cortex and deep gray matter structures ALZHEIMER DISEASE (AD) AD is the most common cause of dementia in older adults Incidence increases with age. Present clinically as insidious impairment of higher cognitive functions. Deficits in memory, visuospatial orientation, judgment, personality, and language gradually emerge Over a course of 5 to 10 years, the affected individual becomes profoundly disabled, mute, and immobile Alzheimer Disease (AD) The fundamental abnormality in AD is the accumulation of two proteins (Aβ and tau) in specific brain regions. The two pathologic hallmarks of AD are amyloid plaques and neurofibrillary tangles. Plaques are deposits of aggregated Aβ peptides in the neuropil Tangles are aggregates of the microtubule binding protein tau Both plaques and tangles appear to contribute to the neural dysfunction in patient with AD Alzheimer Disease (AD) The major morphologic abnormalities of AD are: Neuritic (senile) plaques Neurofibrillary tangles. Neuritic plaques Focal, spherical collections of dilated, tortuous, axonal or dendritic processes (dystrophic neurites) often around a central amyloid core, which may be surrounded by a clear halo Neurofibrillary tangles Tau-containing bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus. Progressive and severe neuronal loss and reactive gliosis Cerebral Amyloid angiopathy (CAA) invariably present, consist of AB40 Parkinson Disease (PD) PD is a neurodegenerative disease characterized by hypokinetic movement disorder that is caused by loss of dopaminergic neurons from the substantia nigra and protein accumulation and aggregation It is the second-most common neurodegenerative disorder that affects 2–3% of the population ≥65 years of age. Parkinson Disease (PD) Pathogenesis PD is pathologically heterogenous Most common is related to abnormality of the lipid-binding, presynaptic protein – α-synuclein and the microtubules binding protein – tau In idiopathic PD synuclein accumulate in neuronal cell body as the Lewy bodies and in the neuronal processes as the Lewy neurites The disease process is multifocal and involve selected CNS neurons and PANS neurons Cause multiple system atrophy. Abn of tau progressive supranuclear palsy which is clinically ass with severe postural instability leading to early fall. Affect both neurons and glial. Parkinson Disease (PD) Autosomal dominant PD is due to mutation in SNCA, a gene that encodes α-synuclein protein normally localized to synapses. This protein is a major component of the Lewy body, which is the diagnostic hallmark of PD Autosomal recessive PD is caused by Mitochondrial dysfunction resulting from mutations in genes that encode the proteins DJ-1, PINK1, and parkin. DJ-1 has multiple cellular roles, including acting as a transcriptional regulator, but in settings of oxidative stress, it can relocate to the mitochondria and have cytoprotective effects. PINK1 is a kinase that localizes to the outer membrane of dysfunctional mitochondria Parkinson Disease (PD) Morphology A characteristic gross finding in PD is pallor of the substantia nigra and locus ceruleus. Lewy bodies are usually found in some of the remaining neurons These are single or multiple, eosinophilic, round to elongated cytoplasmic inclusions that often have a dense core surrounded by a pale halo Parkinson Disease (PD) Normal substantia nigra. Depigmented substantia nigra in idiopathic Parkinson disease. Parkinson Disease (PD) Lewy body in a substantia nigra neuron, staining bright pink CNS INFECTION INTRODUCTION Infectious agents may cause damage to the nervous system by: Direct injury to the neurons and glial (toxin) Inciting or eliciting an inflammatory response Immune mediated mechanisms Microbial agents can gain entry into the CNS via 4 main routes: Hematogenous Direct implantation Local extension Along Nerves Infection may involve the meninges (meningitis) and/or the brain parenchyma (meningo-encephalitis or encephalitis) COMMON ETIOLOGIC AGENTS A large number of pathogens can cause infections of the nervous system. COMMON ETIOLOGIC AGENTS COMMON ETIOLOGIC AGENTS MENINGITIS Meningitis is an inflammatory process of the leptomeninges and CSF within the subarachnoid space. Infectious, chemical or immune. Infectious meningitis is broadly classified into: Acute pyogenic meningitis (bacterial) Aseptic meningitis (acute or subacute viral) Chronic (usually tuberculous, spirochetal, or cryptococcal). Each type is accompanied by characteristic pathologic and CSF changes. ACUTE PYOGENIC (BACTERIAL)MENINGITS Distinctive microorganisms cause acute pyogenic meningitis in various age groups In Neonates and infants: Escherichia coli and the group B streptococci and Haemophilus influenzae. Immunization against H. influenzae has markedly reduced the incidence of this infection in the developed world, particularly among infants In Adolescent and young adult: Neisseria meningitidies In the elderly: Streptococcus pneumoniae and Listeria monocytogenes ACUTE PYOGENIC (BACTERIAL)MENINGITIS PATHOGENESIS Inflammation ACUTE PYOGENIC (BACTERIAL)MENINGITS MORPHOLOGY Grossly Purulent exudate within the leptomeninges over the surface of the brain Basal – H. influenzae Cerebral convexities – pneumococcal Prominent leptomeningeal vessels ACUTE PYOGENIC (BACTERIAL)MENINGITS MICRO Dense Infiltration by neutrophils Dilated and engorged blood vessels Edema ACUTE PYOGENIC (BACTERIAL)MENINGITS CLINICAL CORRELATES Meningeal irritation Neck stiffness Raised ICP Headache Systemic inflammatory response Fever Neurologic impairment Photophobia Clouding of consciousness, irritability ACUTE PYOGENIC (BACTERIAL)MENINGITS COMPLICATIONS Waterhouse-Frederichsen syndrome Meningitis-associated septicemia and hemorrhagic infarction of the adrenal glands. It occurs most often with meningococcal and pneumococcal meningitis ACUTE PYOGENIC (BACTERIAL)MENINGITS DIAGNOSIS CSF EXAMINATION Cloudy or frankly purulent CSF. Neutrophilic leukocytosis in CSF (between 10-10,000/μl). Raised CSF protein level (higher than 50 mg/dl). Decreased CSF sugar concentration (lower than 40 mg/dl). BACTERIOLOGIC EXAMINATION Gram’s stain CSF culture reveals causative organism. ACUTE FOCAL SUPPURATIVE INFECTIONS BRAIN ABSCESS Localized focus of liquefactive necrosis of brain tissue with accompanying inflammation usually caused by a bacterial infection CHRONIC MENINGITIS Bacteria or fungal Chronic bacterial meningitis may be caused by Mycobacterium tuberculosis, Treponema pallidum, and Borrelia species Common cause of fungal meningitis is Cryptococcus Neoformans Typically cause meningoencephalitis CHRONIC MENINGITIS Tuberculous meningitis Manifestation of miliary tuberculosis. Hematogenous spread from tuberculosis elsewhere in the body Direct spread from tuberculosis of a vertebral body CHRONIC MENINGITIS – TB MORPHOLOGY Gross Gelatinous or fibrinous exudate in the sub-arachnoid space that characteristically involves the base of the brain and encasing cranial nerves Well -circumscribed intraparenchymal masses (tuberculomas) A tuberculoma may be as large as several centimeters in diameter, causing significant mass effect CHRONIC MENINGITIS – TB CHRONIC MENINGITIS – TB MICRO Mixed inflammatory infiltrate with lymphocytes, plasma cells, and macrophages. Florid cases show well-formed granulomas with caseous necrosis and giant cells CHRONIC MENINGITIS – TB CSF EXAMINATION Clear or slightly turbid CSF which may form fibrin web on standing. Mononuclear leukocytosis consisting mostly of lymphocytes and some macrophages (100-1000 cells/μl). Raised protein content. Lowered glucose concentration. Tubercle bacilli may be found on microscopy of centrifuged deposits by ZN staining in tuberculous meningitis. CHRONIC MENINGITIS Neurosyphilis Infection of the CNS by T. pallidum Neurosyphilis is a manifestation of the tertiary stage of syphilis Occurs in only about 10% of individuals with untreated infection The major patterns of CNS involvement are: Meningovascular neurosyphilis Paretic neurosyphilis, and Tabes dorsalis CHRONIC MENINGITIS Meningovascular neurosyphilis Chronic meningitis involving the base of the brain and more variably the cerebral convexities and spinal leptomeninges. Distinctive perivascular inflammatory reaction rich in plasma cells and lymphocytes. Cerebral gummas (plasma cell-rich mass lesions) in the meninges and extend into the parenchyma. CHRONIC MENINGITIS Paretic neurosyphilis Caused by invasion of the brain by T. pallidum Parenchymal damage of the cerebral cortex particularly common in the frontal lobe. Loss of neurons, proliferation of microglia, gliosis, and iron deposits The spirochetes can, at times, be demonstrated in tissue CHRONIC MENINGITIS Tabes dorsalis Damage to the sensory axons in the dorsal roots. Micro: loss of both axons and myelin in the dorsal roots, with corresponding pallor and atrophy in the dorsal columns of the spinal cord. Organisms are not demonstrable in the cord lesion ACUTE ASCEPTIC MENINGITIS Inflammation of the meninges cause mainly by viral agents (may be bacterial, rickettsia, or autoimmune in origin). Diagnosed in a patient with manifestations of meningitis but with absence of bacterial in culture Common in children and young adults The viral aseptic meningitides are usually self-limited and are treated symptomatically. ACUTE ASCEPTIC MENINGITIS Etiologic agents are enteroviruses, mumps, ECHO viruses, coxsackie virus, Epstein-Barr virus, herpes simplex virus-2, arthropode-borne viruses and HIV. Grossly Some cases show swelling of the brain while others show no distinctive change. Microscopically There is mild lymphocytic infiltrate in the leptomeninges ACUTE ASCEPTIC MENINGITIS The CSF examination clear or slightly turbid CSF. Lymphocytosis in CSF (10-100 cells/μl). CSF protein usually normal or mildly raised. CSF sugar concentration usually normal. CSF bacteriologically sterile.  Marked by the perivascular accumulation of lymphocytes  Microglial cells form small aggregates, called microglial nodules PARASITIC CNS INFESTATION PARASITIC CNS INFESTATION MALARIA TOXOPLASMOSIS AMEBIASIS TRYPANOSOMIASIS CYSTICERCOSIS Cerebral malaria Cerebral malaria is a complication of infection by Plasmodium falciparum Most likely the result of sticking of infected red cells to inflamed vascular endothelium GROSS Slatty grey in appearance MICRO Vessels are plugged with parasitized red cells Dürck granulomata Ring hemorrhages and small focal inflammatory reactions