1. Introduction to Neuropathology Part I
Dr. Hisham Alkhalidi

2. 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

3. The Glia Macroglia: astrocytes, oligodendrocytes, ependyma
Microglia: Bone marrow

4. 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.
Fibroblasts are present in certain situations

5. 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

6. 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)
macrophages go in inflammation

7. 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
The morphologic features consist of shrinkage of the cell body, pyknosis of the nucleus, disappearance of the nucleolus, and loss of Nissl substance, with intense eosinophilia of the cytoplasm. 

8. 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).

9. Pathological alterations
Axonal reaction:
 the reaction within the cell body that attends regeneration of the axon (central chromatolysis)
visible in the perikaryon include enlargement and rounding up of the cell body, peripheral displacement of the nucleus, enlargement of the nucleolus, and dispersion of Nissl substance from the center to the periphery of the cell (central chromatolysis)

10. Pathological alterations
Neuronal inclusions:
Aging
Genetically determined disorders of metabolism
Viral infection can lead to abnormal intranuclear inclusions
Some degenerative diseases

11. 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.
Talk about myelomeningeocele

12. 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.

13. 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

14. 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.

15. 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.

16. 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
Abnormal involuntary movements that are slow, repetitive, and sinuous.

17. Cerebral Vascular Disease
HYPOXIA, ISCHEMIA, AND INFARCTION
INTRACRANIAL HEMORRHAGE
HYPERTENSIVE CEREBROVASCULAR DISEASE

18. 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).
Under focal ceberbarl ishcemia we have thrombosis and embolism

19. 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

20. 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

21. The most susceptible cells to global ischemia:
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

23. Infections of CNS Routes: Hematogenous Direct implantation
Local extension
Peripheral nervous system
Direct is invariably traumatic
Local like sinuses
PNS like rabies and herpes zoster

24. ACUTE MENINGITIS Acute 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)

25. 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

26. 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

27. Aseptic meningits
In aseptic meningitis, there is a lymphocytic pleocytosis, the protein elevation is only moderate, and the sugar content is nearly always normal.
The presence of a greater than normal number of cells in the cerebrospinal fluid.

28. 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.

29. 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.

30. 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.

31. 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.

32. 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.

33. 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

35. 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

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

37. 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.

38. 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

39. Alzheimer Disease cortical atrophy
neuritic (senile) plaques, neurofibrillary tangles, and amyloid angiopathy.

40. 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.
Stooped means hunched

41. Parkinson’s disease

42. 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

43. 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.

44. 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.

45. 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