Introduction to NeuropathologyPart I

Dr. Hisham Alkhalidi

Outline• General comments

• Neonatal and Pediatric Neuropathology

• Cerebral Vascular Disease

• Infections of CNS

• Alcohol, Trauma and Transtentorial Herniation

• Neurodegenerative Diseases

• Demyelinating Diseases

• Tumors of CNS and PNS

The Glia

• Macroglia: astrocytes, oligodendrocytes, ependyma

• Microglia: Bone marrow

ASTROCYTES

• Metabolic buffers or detoxifiers• Suppliers of nutrients• Electrical insulators• Contribute to barrier functions controlling the

flow of macromolecules between the blood, the CSF and the brain

• The principal cells responsible for repair and scar formation in the brain.

• Oligodendroglial cytoplasmic processes wrap around the axons of neurons to form myelin

• Ependymal cells line the ventricular system. They are closely related to the cuboidal cells comprising the choroid plexus

Microglia

• Microglia serve as a fixed macrophage system in the CNS. They respond to injury by:– proliferation– developing elongated nuclei (rod cells), as in

neurosyphilis– forming aggregates about small foci of tissue

necrosis (microglial nodules)– congregating around cell bodies of dying neurons

(neuronophagia)

Pathological alterations, examples

• Red neurons:– evident with hematoxylin and eosin (H & E)

preparations at about 12 to 24 hours after an irreversible hypoxic/ischemic insult

Pathological alterations

• subacute and chronic neuronal injury ("degeneration"):– situations leading to neuronal death occurring as a

result of a progressive disease process of some duration, as is seen in certain slowly evolving neurologic diseases (such as amyotrophic lateral sclerosis).

Pathological alterations

• Axonal reaction:– the reaction within the cell body that attends

regeneration of the axon (central chromatolysis)

Pathological alterations

• Neuronal inclusions:– Aging– Genetically determined disorders of metabolism– Viral infection can lead to abnormal intranuclear

inclusions– Some degenerative diseases

Neural tube defects

• Most common• Failure of a portion of the neural tube to close, or

reopening of a region of the tube after successful closure, may lead to one of several malformations.

• Anencephaly is a malformation of the anterior end of the neural tube, with absence of the brain and calvarium.

• An encephalocele is a diverticulum of malformed CNS tissue extending through a defect in the cranium. It most often occurs in the occipital region or in the posterior fossa.

• Antenatal diagnosis:– imaging – maternal blood samples, elevated α-fetoprotein.

• The overall recurrence rate for a neural tube defect in subsequent pregnancies has been estimated at 4% to 5%

• Folate deficiency during the initial weeks of gestation has been implicated as a risk factor, possibly interacting with maternal or embryonic genetic factors.

FOREBRAIN ANOMALIES

• Polymicrogyria is characterized by a loss of the normal external contour of the cerebral convolutions, which appear small, unusually numerous and irregularly formed

• The volume of brain may be abnormally large (megalencephaly) or small (microencephaly).

• Holoprosencephaly is a spectrum of malformations characterized by incomplete separation of the cerebral hemispheres across the midline

POSTERIOR FOSSA ANOMALIES

• The Arnold-Chiari malformation (Chiari type II malformation) consists of:– a small posterior fossa– a misshapen midline cerebellum with downward

extension of vermis through the foramen magnum– almost invariably, hydrocephalus and a lumbar

myelomeningocele.

Perinatal brain injury

• A variety of exogenous factors may injure the developing brain– Injuries that occur early in gestation may destroy

brain tissue without evoking the usual "reactive" changes in the parenchyma and may be difficult to distinguish from malformations

– Brain injury occurring in the perinatal period is an important cause of childhood neurologic disability.

• The broad clinical term cerebral palsy refers to a non progressive neurologic motor deficit characterized by spasticity, dystonia, ataxia/athetosis, and paresis attributable to insults occurring during the prenatal and perinatal periods. – Intraparenchymal hemorrhage – Periventricular leukomalacia– Ulegyria

Cerebral Vascular Disease

• HYPOXIA, ISCHEMIA, AND INFARCTION• INTRACRANIAL HEMORRHAGE• HYPERTENSIVE CEREBROVASCULAR DISEASE

• Global cerebral ischemia (ischemic/hypoxic encephalopathy): – occurs when there is a generalized reduction of

cerebral perfusion, such as in cardiac arrest, shock, and severe hypotension.

• Focal cerebral ischemia:– follows reduction or cessation of blood flow to a

localized area of the brain due to:• large-vessel disease (such as embolic or thrombotic

arterial occlusion, often in a setting of atherosclerosis)• small-vessel disease (such as vasculitis or occlusion

secondary to arteriosclerotic lesions seen in hypertension).

• Intracerebral infarcts:– Hemorrhagic (red) infarction:• multiple, sometimes confluent, petechial hemorrhages,

is typically associated with embolic events.• The hemorrhage is presumed to be secondary to

reperfusion of damaged vessels and tissue, either through collaterals or directly after dissolution of intravascular occlusive material.

– nonhemorrhagic (pale, bland, anemic) infarcts are usually associated with thrombosis

Intracranial hemorrhages

• Intraparynchemal: Hypertensive (putamen, thalamus, pontine tegmentum)

• Hypertenisve disease can also cause atreiroscelroris in adddition to lacunar infarcts (cystic infarcts from arterolar occlusion), and hypertensive encephalocpathy

• Subarachnoid, ruputred saccular anurysms• Vascular malformations

• Neurons are the most sensitive cells, although glial cells (oligodendrocytes and astrocytes) are also vulnerable.

• The most susceptible cells to global ischemia:– Pyramidal cells of the Sommer sector (CA1) of the

hippocampus– Purkinje cells of the cerebellum – Pyramidal neurons in the neocortex

Infections of CNS

• Routes:– Hematogenous– Direct implantation– Local extension– Peripheral nervous system

• ACUTE MENINGITISAcute Pyogenic (Bacterial) Meningitis– Acute Aseptic (Viral) Meningitis

• ACUTE FOCAL SUPPURATIVE INFECTIONS– Brain Abscess– Subdural Empyema– Extradural Abscess

• CHRONIC BACTERIAL MENINGOENCEPHALITIS– Tuberculosis– Neurosyphilis– Neuroborreliosis (Lyme Disease)

• VIRAL MENINGOENCEPHALITIS– Arthropod-Borne Viral Encephalitis– Herpes Simplex Virus Type 1 (HSV-1)– Herpes Simplex Virus Type 2 (HSV-2)– Varicella-Zoster Virus (Herpes Zoster)– Cytomegalovirus– Rabies– Human Immunodeficiency Virus– Progressive Multifocal Leukoencephalopathy– Subacute Sclerosing Panencephalitis

• FUNGAL MENINGOENCEPHALITIS

• OTHER INFECTIOUS DISEASES OF THE NERVOUS SYSTEM– Protozoal, e.g. Toxomplasmosis– Rickettsial– Metazoal

Acute Pyogenic (Bacterial) Meningitis

• Pathogens:– Neonates:Escherichia coli and the group B

streptococci– Old patients: Streptococcus pneumoniae and Listeria

monocytogenes– Among adolescents and in young adults: Neisseria

meningitidis

• purulent CSF, with as many as 90,000 neutrophils/mm3, a raised protein level, and a markedly reduced glucose

Aseptic meningits

• In aseptic meningitis, there is a lymphocytic pleocytosis, the protein elevation is only moderate, and the sugar content is nearly always normal.

• A true non infectious process that cause meningitis:– Some medications including NSAIDs and antibiotics; this

entity has been termed drug-induced aseptic meningitis– An aseptic meningitis-like picture may also develop

subsequent to rupture of an epidermoid cyst into the subarachnoid space

– The introduction of a chemical irritant ("chemical" meningitis)

• In these cases, the CSF is sterile, there is pleocytosis with neutrophils and a raised protein level, but the sugar content is usually normal.

Brain Abscess

• Acute bacterial endocarditis, which tends to produce multiple abscesses

• Cyanotic congenital heart disease, in which there is a right-to-left shunt and loss of pulmonary filtration of organisms

• Chronic pulmonary sepsis, as can be seen with bronchiectasis.

Subdural Empyema

• Bacterial or occasionally fungal infection of the skull bones or air sinuses can spread to the subdural space and produce a subdural empyema.

• The underlying arachnoid and subarachnoid spaces are usually unaffected, but a large subdural empyema may produce a mass effect.

CHRONIC BACTERIAL MENINGOENCEPHALITIS

• A classical example is Tuberculosis:– Moderate CSF pleocytosis made up of

mononuclear cells or a mixture of polymorphonuclear and mononuclear cells; the protein level is elevated, often strikingly so; and the glucose content typically is moderately reduced or normal.

Progressive Multifocal Leukoencephalopathy

• Progressive multifocal leukoencephalopathy (PML) is a viral encephalitis caused by the JC polyomavirus; because the virus preferentially infects oligodendrocytes, demyelination is its principal pathologic effect.

Transmissible Spongiform Encephalopathies (Prion Diseases)• they are predominantly characterized by

"spongiform change" caused by intracellular vacuoles in neurons and glia.

• Clinically, most of these patients develop progressive dementia.

• The most common clinical presentation is CJD. Creutzfeldt-Jakob disease

Toxins• A classical example is Alcohol:– Direct toxic effect– Secondary nutritional deficits– Wernicke-Korsakoff syndrome – Cerebellar dysfunction occurs in about 1% of chronic

alcoholics– The fetal alcohol syndrome– The histologic changes are atrophy and loss of granule

cells predominantly in the anterior vermis – In advanced cases, there is loss of Purkinje cells and

proliferation of the adjacent astrocytes (Bergmann gliosis) between the depleted granular cell layer and the molecular layer of the cerebellum

Trauma• Skull fractures• Parenchymal injuryies• Concussion• Direct parenchymal injury• Diffuse axonal injury• Traumatic vascular injuries• Subdural hematoma• Epidural hematoma• Spinal cord injuries

Neurodegenerative Diseases

• These are:– diseases of gray matter– progressive loss of neurons– associated secondary changes in white matter tracts

• The pattern of neuronal loss is selective, affecting one or more groups of neurons while leaving others intact

• The diseases arise without any clear inciting event in patients without previous neurologic deficits.

Alzheimer Disease

• Insidious impairment of higher intellectual function

• alterations in mood and behaviour• Later, progressive disorientation, memory loss,

and aphasia indicating severe cortical dysfunction

• Eventually, in 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile

Alzheimer Disease

• cortical atrophy • neuritic (senile) plaques, neurofibrillary

tangles, and amyloid angiopathy.

Parkinsonism

• This diagnosis is made in the absence of a toxic or other known underlying etiology

• Parkinsonism is a clinical syndrome:– diminished facial expression– stooped posture– slowness of voluntary movement– festinating gait (progressively shortened, accelerated

steps)– rigidity– “pill-rolling" tremor.

Parkinson’s disease

Genetic Metabolic Diseases

• Many of these disorders express themselves in children who are normal at birth but who begin to miss developmental milestones during infancy and childhood

• Neuronal storage diseases are mostly autosomal-recessive diseases caused by a deficiency of a specific enzyme involved in the catabolism of sphingolipids, mucopolysaccharides, or mucolipids

• They are often characterized by the accumulation of the substrate of the enzyme within the lysosomes of neurons, leading to neuronal death

• Cortical neuronal involvement leads to loss of cognitive function and may also cause seizures.

• Leukodystrophies show a selective involvement of myelin (either abnormal synthesis or turnover) and generally exhibit no neuronal storage defects

• Diffuse involvement of white matter leads to deterioration in motor skills, spasticity, hypotonia or ataxia.

• Although most are autosomal-recessive disorders, adrenoleukodystrophy, an X-linked disease, is a notable exception.

• Mitochondrial encephalomyopathies are a group of disorders of oxidative phosphorylation, usually resulting from mutations in the mitochondrial genome

• They typically involve gray matter as well as skeletal muscle