Neuropathology

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Neuropathology

• How to discuss the most complicated organ in the
  human body with the greatest diversity of
  function, symptoms, and pathology in a very short
  time?
• Strategies
• Ignore the PNS and muscle
• Simplify
• Be selective

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Importance of Neuropathology

• Basis for understanding disorders of the brain
• Basis for diagnoses of many brain diseases
• Needed for appropriate choice of therapy
• Needed for developing new therapies
• Aspects will never be replaced by other
  technologies

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Goals

• Develop an appreciation for neuropathology
• Learn how to communicate with a neuropathologist
• Improve your practice of medicine as it relates
  to diseases of the CNS
• Develop an appreciation of how to use
  neuropathology information
• Learn critical terminology

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Outline

• Gross Anatomy
• Microscopic Anatomy
• Selective Vulnerability and Response to Injury
• Classification of CNS Disorders
• Vascular Disorders
• Neurodegenerative Diseases
• Neoplastic Disorders
• Infectious/Inflammatory Disorders

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Brain Facts

• Adult brain weight 1.4 kg (MgtF)
• 2 TBW, 14 C.O., 18 O2 Consumption
• 100 Dependent on adequate O2 and glucose
• 50 genome codes for the brain

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Gross Structure of the Head and Brain

• Skull
• Layers and Spaces
• Gray Matter
• White Matter
• Sulci and Gyri
• Laminated Structures and Nuclei
• Ventricles
• Cranial and Spinal Nerves
• Spinal Cord

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Layers and Spaces
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Layers and Spaces - Hemorrhages
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Layers and Spaces - Infections
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Dorsal Surface of Brain
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External Surfaces
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Coronal Sections
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Transverse Sections
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Circle of Willis
Ant. Cerebral a.
Ant. Comm. a.
Mid. Cerebral a.
Int. Carotid. a.
Post Comm. a.
Post Cerebral a.
Basilar a.
Vertebral a.
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Cells of the Nervous System

• Neurons
• Astrocytes
• Oligodendroglia
• Microglia
• Ependymal cells and arachnoid cap cells
• Endothelial cells and fibroblasts
• White blood cells

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Neurons

• Specialized function to communicate, integrate,
  and store information
• Many unique features
• Great diversity of size (5-100 ?m diameter, 10 ?m
  to
• 2 m in axon length), shape, gene expression
• Postmitotic
• Found in nuclei and gray matter
• Require antegrade and retrograde transport

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Neurons
Retinal Bipolar
Mitral Bipolar
Mulipolar Neuron
Mulipolar Purkinje Cell
Interneuron
Pyramidal Neuron Motor Cortex
Unipolar Sensory Neuron
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Astrocytes

• Found everywhere in CNS
• Multiple metabolic functions
• Barrier functions between vasculature and
  neurons
• Known for processes

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Oligodendroglia

• Synthesize myelin or insulation of nerve fibers
• Found in white matter more than gray matter

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Others

• Ependymal Cells
• Arachnoid Cap Cells
• Non-unique cells similar to rest of body

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Glia
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Unique Aspects of the Brain

• Many specialized functions
• Location, location, location
• Selective vulnerability
• Neurons postmitotic

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Selective Vulnerability

• Pattern of abnormalities manifested in a
  particular disorder represent by
• Unique brain region (cerebral cortex)
• Parts of a region (motor cortex)
• Portion of region affected (gray or white
  matter)
• Type of cell involved (neuron or glia)
• Subtype of cell (motor neuron)

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Contributions to Selective Vulnerability

• Genes
• Development
• Function and Metabolism
• Neuronal Lifespan and Size
• Limited Regeneration and Repair
• Complexity
• Blood-Brain Barrier
• Environment

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Gross Responses to Injury

• Increased Intracranial Pressure
• Hydrocephalus
• Edema
• Herniation
• Necrosis
• Hemorrhage

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Edema and Herniation
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Microscopic Responses to Injury

• Neuronal dysfunction
• Neuronal cell death (necrosis vs apoptosis)
• Death of other cell types
• Gliosis
• Inflammation
• Intracellular inclusions and extracellular
  deposits

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Cell Death
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Gliosis
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Inflammation
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Cellular Inclusions
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Extracellular Deposits
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Major Groups of CNS Disorders

• Vascular
• Neurodegenerative
• Neoplastic
• Infectious/Inflammatory
• Toxic/Metabolic/Nutritional
• Traumatic
• Developmental

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Vascular Diseases

• Vascular Disease - Causes
• Atherosclerosis, Hypertension, Embolism
• Vasculitidies, Angiopathy
• Aneurysm, Dissection, Malformations
• Hematologic
• Vascular Disease - Consequences
• Infarct
• Hemorrhage

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Atherosclerosis
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Aneurysms
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Dissection
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AVM
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Thrombosis
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Embolic Disease
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Embolic Disease
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Venous Thrombosis
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Infarcts
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Infarcts
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Infarcts
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Hypertensive Hemorrhage
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Multiple Hemorrhages
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Duret Hemorrhage
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Subarachnoid Hemorrhage
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Vascular Case

• A 38 year old woman is brought to the ER by her
  boyfriend at 3 AM after a night out because of
  acute dysarthria.

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What do you do?

• History
• Exam
• Laboratory Tests
• Intervention

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Acute Dysarthria
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Points to Learn

• Intervention for vascular disease not indicated
• Workup and intervention for demyelinating
  disease needed

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Neoplastic Diseases

• Similar to other neoplastic disease in presumed
  etiology of uncontrolled cell proliferation
• Differences in cell types and manifestations of
  disorder
• General symptoms of mass lesion (headache,
  nausea, vomiting, seizure) and focal symptoms
• Focal symptoms based on location

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Juvenile Pilocytic Astrocytoma (WHO I)
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Astrocytoma (WHO II)
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Glioblastoma (WHO IV)
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Meningioma
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Uncommon Neoplasms
Ependymoma
Gangliocytoma
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Neoplasm Case

• A patient was operated on for a glioblastoma two
  years ago, followed by radiation therapy.
• He has routine MRIs and a rapidly enlarging
  lesion is now identified in the region of his
  previous tumor.
• What do you do?

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Neoplasm Case

• Biopsy
• Frozen section recurrent tumor
• Permanent sections radiation-induced necrosis
  and recurrent tumor
• What do you do?

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Recent Biopsy
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Previous Biopsy
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Neoplasm Case

• Review of his previous tumor reveals the
  original tumor was a highly-cellular ependymoma
  (WHO Grade II)
• Current diagnosis is radiation-induced necrosis
  and radiation-induced astrocytoma

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Points to Learn

• Pathologists make mistakes
• If you depend on others to produce the diagnosis
  for your case, make sure it is consistent with
  your impression
• All lab tests have finite sensitivity,
  specificity, and a false-positive rate.
• Acknowledge this and be vigilant

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Neurodegenerative Disease

• Diverse
• Insidious Stereotypic Onset
• Gradual Progression
• Exceed a Threshold
• Age-associated

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Neurodegenerative Disease
Classifications

• Clinical
• Pathological
• Genetic
• Etiologic
• Multifactorial or Attributable Risks

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Progression of Neuronal Loss in Neurodegeneration
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Alzheimers Disease

• Alzheimer's disease (AD) is the most common
  dementing illness in the United States affecting
  1 of those aged 65 to 75 and up to 50 of those
  over the age of 85.
• AD is not a single entity, but is a syndrome with
  multiple risk factors.
• The symptoms of Alzheimer's disease are insidious
  and progressive and involve cortical
  (subcortical) dysfunction, typically beginning
  with memory loss, language disturbance, and
  impaired spatial abilities and eventually may
  involve many higher cortical/subcortical
  functions. Behavioral and emotional disturbances
  may also occur.

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Alzheimers Disease

• Changes diagnostic of AD overlap with findings
  seen in the aging brain.
• Neurofibrillary tangles and neuropil threads are
  intraneuronal accumulations of abnormal paired
  helical filaments.
• Neuritic plaques (senile plaques) are present in
  the neuropil and are composed of abnormal nerve
  processes, degenerating synaptic terminals,
  microglial cells, astrocytes, and amyloid. The
  abnormal amyloid is deposited in a form known as
  the ß/A4 protein or ß amyloid and is derived from
  a larger membrane protein known as the amyloid
  precursor protein (APP).
• Cerebrovascular amyloid, also known as
  congophilic angiopathy, are deposits of amyloid
  within cerebral arteries, arterioles, and
  capillaries.

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Alzheimers Disease
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Alzheimers Disease
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Parkinsons Disease

• Clinical Phenotype
• Pathologic Phenotype
• Clinical-Pathologic Correlation
• Biochemical and Imaging Phenotype
• Genetic Phenotype

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Parkinsons Disease

• Parkinson's disease is the most common movement
  disorder in the elderly affecting 1 of those age
  65 to 75 and 2.5 of those over age 85.
• Risk factors include age, genetic predisposition,
  lifestyle, and environmental exposures.
• The disease is insidious, progressive, and is
  manifested by motor symptoms including tremor,
  rigidity, akinesia, and postural instability
  (TRAP). Symptoms may begin unilaterally, but
  shortly thereafter become bilateral. Behavioral,
  affective, cognitive, and autonomic disturbances
  may also occur. Patients may also develop a
  dementia.

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Parkinsons Disease

• Neuronal Loss SNpc gt VTA, LC, aminergic
  nuclei, spinal cord and ganglia, other gray
  matter regions
• Pigment laden macrophages, gliosis
• Neuronal inclusions Lewy bodies and neurites

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Parkinsons Disease
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Parkinsons Disease
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Neurodegenerative Case

• A 64 y/o widowed retired legal secretary is
  brought to you by her daughter. The patients
  bank contacted her daughter because her account
  was overdrawn. The daughter noticed the home to
  be unkempt compared to the past.

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What do you do?

• History
• Exam
• Labs
• Diagnosis

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Laboratory Tests

• Tests for reversible causes of dementia TFTs,
  B12, VDRL, CBC, sed rate,
• EEG rarely

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CT
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Mixed Dementia

• Mixed AD and vascular disease common
• Definitions for dementias imperfect
• Diagnostic criteria will improve with time and
  as specific therapies improve
• Correct diagnosis is important despite lack of
  therapies because of familial implications

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Case Discussion

• Family physicians and internists right
• 50-60 of the time with dementia
• Neurologists right 75-85
• Dementia specialists right 90
• Pathologists right 50
• Neuropathologists right 80-90
• What is right?

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Demeyelinating Diseases

• Disorders with the primary manifestation of loss
  of myelin and preservation of axons in white
  matter tracts
• Several forms based on single vs multiple
  episodes, location(s), type of lesion, and
  precipitating cause
• Multifactorial with role for genetic background
  and environmental stimulus
• Some forms treatable

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MS Gross Appearance
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Microscopic Changes in MS