Nervous System

• Nervous Tissue

  • Contains >10 billion neurons.
  • Evolved from primitive neuro-effector cells that respond to various stimuli by contracting.
  • In higher animals, contractions became the specialised function of muscle cells, while transmission of nerve impulses became the specialised functions of neurons.
  • distributed throughout the body as an integrated communications network.
• Anatomically::

  • CNS consisting of brain and spinal cord
  • Peripheral NS composed of nerve fibres and small aggregates of nerve cells - nerve ganglia

  Structurally:

  • Nerve cells or neurons which usually show numerous long processes
  • Several types of glial cells or neuroglia, which support and protect neurons and participate in neural activity, neural nutrition and the defence process of the CNS
• Central Nervous System


  The processing centre linking information between the outside world and the body
• Neuron


  The principle functional unit, unique in their ability to receive, store and transmit information
• Neurons


  • Differ greatly in functional roles (e.g. sensory, motor, autonomic)
  • Distribution of their connections
  • Neurotransmitters they use for synaptic transmission
  • Metabolic requirements
  • Level of electrical activity at a given moment
• Most mature neurons are post-mitotic cells that are incapable of cell division
• Destruction of even a small number of neurons responsible for a specific function may leave the patient with a severe clinical neurological deficit
• CNS characteristics:

  1. Protective bony enclosure of the skull and spinal column that contains it.
  2. A specialised system of autoregulation of cerebral blood flow.
  3. Metabolic substrate requirements
  4. Absence of a conventional lymphatic system
  5. A special cerebrospinal fluid
  6. Limited immunologic surveillance
  7. Distinctive responses to injury and wound healing

   
• Neurons

  Vary in structure and size throughout the NS and within a given brain region.

  • An anterior horn neuron in spinal cord has a cell body (perikaryon) ~ 50um wide, a relatively large nucleus, a prominent nucleoli and abundant NissI substance.
  • Nucleus of a granule cell neuron of the cerebellar cortex is ~10um across and its perikaryon and nucleus is not readily visible by light microscopy
  • Axon length may vary greatly - hundreds of microns for interneurons vs a meter for an upper motor neuron

  IHC markers for neurons and their processes: neurofilament protein, synaptophysin
• Cells of The CNS

  • Neurons
  • Glial Cells
  • Astrocytes
  • Oligodendrocytes
  • Ependymal Cells
  • Microglial Cells
• Glial Cells

  • Derived from neuroectoderm (macroglia: astrocytes, oligodendrocytes, ependymal) or from bone marrow (microglia)
  • Structural and metabolic interactions with neurons and their dendritic and axonal processes
  • Primary role in functions/reactions to injury, incl. inflammation, repair, fluid balance and energy metabolism.
  • Size and shape of the nucleus helps in the light microscopic distinction of one glial cell type from another as their cytoplasmic processes are often not apparent on H&E preparations

   
• Astrocytes

  • Name derived from its star shaped appearance which is imparted by the multipolar, branching cytoplasmic processes that emanate from the cell body containing the characteristic cytoplasmic intermediate filament protein called glial fibrillary acidic protein (GFAP)
  • Principal cells responsible for repair and scar formation in the brain
  • Astrocytes are glial cells that are found throughout the CNS in both grey and white matter. Protoplasmic astrocytes occur mainly in the grey matter while fibrous astrocytes occur in white and grey matter
• Oligodendrocytes

  • Each oligodendrocyte myelinates numerous internodes on multiple axons.
  • Injury to oligodendrocytes is a feature of acquired demyelinating disorders (e.g. multiple sclerosis) and also seen in leukodystrophies
  • Oligodendrocytes have cytoplasmic processes that wrap around the axons of neurons in a manner similar to the schwann cell of the PNS
• Ependymal cells

  • Line the ventricular system
  • Disruption of ependymal cells is often associated with a local proliferation of subependymal astrocytes to produce small irregularities on the ventricular surface
  • Certain infectious agents, particularly cytomegalovirus, may produce extensive ependymal injury
• Microglial Cells

  Mesoderm derived cells whose primary function is to serve as a fixed macrophage system in the CNS

  Similar to peripheral monocytes/macrophages

  Respond to injury by:

  1. Proliferation
  2. Developing elongated nuclei (rod cells) as in neurosyphilis
  3. Forming aggregates about small foci of tissue necrosis
  4. Congregating around cell bodies of dying neurons

   
• Peripheral Nervous System

  • Principle structural component is the nerve fibre: an axon, Schwann cells and myelin sheath.
  • A nerve consists of numerous fibres that are grouped into fascicles by connective tissue sheaths. Myelinated and unmyelinated nerve fibres are intermingled within the fascicle.
  • PNS axons are myelinated in segments (internodes) separated by nodes of Ranvier. A single Schwann cell supplies the myelin sheath for each internode
• Thickness of myelin sheath is directly proportional to the diameter of the axon = larger axon --> longer = internodal distance.

  Myelin is similar in over lipid and protein composition in both PNS and CNS

  Unmyelinated axons (more numerous) range in size from 0.2um to 3um. The cytoplasm of one Schwann cell envelops and isolates from each other a variable number of unmyelinated fibres (5-20 axons)

  The Schwann cells associated with either myelinated or unmyelinated fibres have pale oval nuclei with an even chromatin pattern and an elongated bipolar cell body.
• 3 major connective tissue components of peripheral nerve:

  1. Epineurium - encloses the entire nerve
  2. Perineurium - multilayered concentric connective tissue sheath that encloses each fascicle
  3. Endoneurium - surrounds individual nerve fibres
• CNS Tumors

  • accounts for 20% of all childhood cancers.
  • unique characteristics that set apart from neoplastic processes elsewhere
  • Ability to surgically resect infiltration neoplasms without compromising neurological function is limited.
  • Anatomic site of neoplasm can have lethal consequences, irrespective of histological classification.
  • The pattern of spread of primary CNS neoplasms differ from that of other tumours. Even the most highly malignant gliomas rarely metastasize outside the CNS.

   
• 4 classes of brain tumors:

  1. Gliomas
  2. Neuronal Tumors
  3. Poorly Differentiated Neoplasms
  4. Meningiomas
• Gliomas

  Derived from glial cells incl:

  • Astrocytes = Astrocytomas
  • Oligodendrocytes = Oligodendrogliomas
  • Ependymomas
• Tumors derived from astrocytes:

  • fibrillary astrocytoma
  • Glioblastoma
  • Pilocytic Astrocytoma
  • Pleomorphic xanthosatrocytoma
• Oligodendroglioma:

  • 5-15% of gliomas and most common in fourth and fifth decades of life.
  • May have several years of neurologic complaints, often incl seizures.
  • Lesions are found in cerebral hemispheres, common in white matter.
  • Grading is often II/IV, except in anaplastic oligodendrogliomas who's grading is III/IV.
  • Better prognosis than Astrocytoma's.
• Ependymoma:

  Epithelial like appearance and line ventricles of brain.

  Most often arise next to ependymal lined ventricular system

  First two decades of life, typically occur near fourth ventricle and make up 5-10% of primary brain tumours in this age group.

  In adults, spinal cord is most common location

  Most have a grading of II/IV, but location often makes surgical removal very difficult.
• Fibrillary astrocytoma & Glioblastoma:

  • Account for about 80% of adult primary brain tumours. Usually found In cerebral hemispheres, may also occur in cerebellum, brainstem or spinal cord.
  • Most often occur in fourth to sixth decades of life.
  • Most common presenting sign and symptoms are seizures, headaches and focal neurologic deficits.
  • Fibrillary astrocytoma's show a spectrum of histologic differentiation that correlates well with clinical course.
  • Grading schemes are helpful in predicting prognosis and determining treatment options.
• Pilocytic Astrocytoma:

  • Distinguished by appearance and relatively benign behaviour.
  • Typically occur in children and young adults. Usually located in cerebellum - also floor and walls of the third ventricle, the optic nerves and occasionally the cerebral hemisphere
  • Grow very slowly and considered grade I/IV and in cerebellum may be treated by resection.
  • Histologic separation of these tumours is supported by genetic studies. Shown that pilocytic astrocytoma's rarely have p53 mutations or other changes found in fibrillary astrocytoma's

   
• Pleomorphic Xanthoastrocytoma:

  • Occurs most often relatively superficially in the temporal lobe of children and young adults - usually with a history of seizures.
  • On microscopic examination - tumour consists of neoplastic, occasionally bizarre astrocytes which are sometimes lipidised.
  • Usually a low grade tumour, II/IV with a survival rate of 80% after 5 years.

   
• Brainstem Glioma:

  • A clinical sub-group of astrocytomas
  • Occur mostly in first two decades of life and make up about 20% of primary brain tumours in this age group.

   
• Neuronal Tumours

  • Ganglion cell tumours
  • Dysembryoplastic neuroepithelial tumour
  • Cerebral neuroblastoma

   
• Ganglion Cell Tumours:

  • Several types of CNS tumours contain mature apperaing neurons (ganglion cells). May constitute the entire population of the lesions and are called gangliocytomas
  • More commonly, there is an admixture with a glial neoplasm and the lesion is called a ganglioglioma
  • Lesions that contain mixtures of neuronal and glial elements often present as a seizure disorder. Surgical resection of the tumour is usually effective in controlling the seizures.
• Dysembryoplastic Neuroepithelial Tumor:

  • Also have glial and neuronal components and are distinctively low-grade tumours of childhood that often present as a seizure disorder.
  • Show slow groth and a relatively good prognosis after surgical intervention
  • Typically located in the superficial temporal lobe.

   
• Cerebral Neuroblastoma:

  • Tumours only have neuronal elements and are rare neoplasm that occur in children and show highly aggressive clinical behaviour.
  • Although in pattern and shape the cells resemble oligodendroglioma, ultrastructural and IHC studies reveal the neuronal lineage of the tumour cells.
• Poorly Differentiated Tumours

  Although of neurectodermal origin, express few if any of the phenotypic markers of mature cells of the CNS and are described as poorly differentiated or embryonal

  • Medulloblastoma
  • Atypocal teratoid/rhatoid tumours
• Medulloblastoma:

  • Most common poorly differentiated tumour of CNS which accounts for 20% of brain tumours in children.
  • Occur Exclusively in the cerebellum
  • Neuronal and glial markers may be expressed but the tumour is often largely undifferentiated
  • Highly malignant and prognosis for untreated is very poor. Extremely radiosensitive and a good prognosis can be achieved if entire tumour is able to be excised
  • Five year survival rate may be as high as 75%

   
• Atypical Teratoid/Rhabdoid Tumour

  • Recently recognised highly malignant tumour of young children
  • Histologic component of Rhabdoid cells, resembling those of a Rhabdomyosarcoma - defining characteristic
  • Highly aggressive tumours of the very young, nearly all tumours occur before age of 5 and most patients survive less than a year after diagnosis

   
• Meningiomas

  • Predominantly benign tumours of adults, usually attached to the dura, that arise from the meningiothelial cells of the arachnoid
  • May be found along any external surface of the brain as well as within the ventricular system and spinal cord
  • Most are grade I/IV, with a low risk of reoccurrence or aggressive growth
  • Usually slow growing lesions that present with vague symptoms
  • Uncommon in children and show a moderate, 3:2 female predominance, although becomes 10:1 amongst patients with spinal meningiomas.

   
• Metastatic Tumours

  Usually carcinomas

  Account for ~ 1/4 - 1/2 of all intracranial tumours

  5 most common primary sites are:

  • Lung
  • Breast
  • Skin
  • Kidney
  • Gastrointestinal tract
• PNS Tumours

  Arise from cells of peripheral nerve, incl. Schwann cells, perineural cells and fibroblasts. Many express Schwann cell characteristics incl. presence of S-100 protein as well as the potential for melanocytic differentiation

  • Schwannoma
  • Neurofibroma
  • Malignant Peripheral Nerve Sheath Tumour
• Schwannoma:

  • Benign
  • Arise from Schwann cell
  • Symptoms caused by local compression of involved nerve or compression of adjacent structures
  • Malignant change is extremely rare, although local recurrence can follow incomplete resection
•  

  Neurofibroma:

  2 histologically distinct lesion:

  • Cutaneous neurofibroma/Solitary neurofibroma
  • Most common form and occurs in skin or in peripheral nerve
  • Plexiform neurofibroma
  • May arise anywhere along a nerve, although the large nerve trunk is most common site.