Diseases of Nervous system

By Dr Kuazi Dil Afroz, MBBS, PhD Department of Pathology

Nervous System
Central Nervous System Brain Spinal Cord

Peripheral Nervous System

Cerebrum of The Human Brain Parts

Thalamus Pineal gland

Hypothalamus Pituitary gland Pons

Cerebellum
Medulla oblongata

Brain stem

Spinal cord

Normal Cells The principal cells of the CNS are neurons, glia, and the cells that compose the meninges and blood vessels. Neuron Cell body: extensions call dendrites

Axon Unmyelinated or bare Myelinated or sheathed

Glia Glial cells are derived from neuroectoderm :macroglia: Astrocytes Oligodendrocytes Ependyma or from bone marrow (microglia).

Overview of Major Diseases The nervous system is affected by many diseases such as Developmental and genetic diseases Diseases caused by trauma Circulatory disorders Infectious diseases Autoimmune disorders Metabolic and nutritional diseases Neurodegenerative diseases of unknown etiology Brain tumors

Factors Important to Understanding Nervous System Pathology

1. The nervous system consists of highly specialized functional units called neurons. Damage to neurons is irreversible because neurons cannot regenerate. Injury to certain areas of the brain result in loss of function to that particular area. A loss of vision center in the occipital lobe causes blindness. Lesions of the respiratory centers in the medulla oblongata causes death. 2. The central nervous system (CNS) is protected from mechanical injury by the bones of the skull and vertebrae. If the vertebrae were detached from one another or dislocated, the spinal cord may be severed.

Factors Important to Understanding Nervous System Pathology

3. The CNS is separated from the remainder of the body by meninges and by a bloodbrain barrier. The brain is protected from harmful substances in that the blood or cerebral spinal fluid (CSF) acts as filters. Examples: Bilirubin does not enter the CNS compartment, even in the most severe forms of jaundice. Glucose concentration in the CSF is at a level that is one-half that of the blood concentration.

Factors Important to Understanding Nervous System Pathology

4. The brain and the spinal cord are surrounded by CSF. CSF separates the brain from the meninges and serves as a mechanical buffer (cushion) between the brain and bones of the skull

CSF serves as a venue to remove metabolites and waste products from the brain CSF remains constant under normal circumstances in regards to rate of production, flow and reabsorption.

Factors Important to Understanding Nervous System Pathology

5. Neurons do not divide, but supporting glial cells are capable of dividing. The brain contains billions of neurons, all of which were formed during prenatal, intrauterine life. Neurons are long-lived cells. Nevertheless, every hour of our lives, we lose thousands of neurons due to natural death. Since neurons cannot divide, neurons cannot become tumors. However, support structures such as the meninges or blood vessels are capable of proliferation and/or malignant transformation Glial cell tumors are called gliomas Meningiomas are tumors of meninges Hemangioblastomas are tumors of blood vessels

Factors Important to Understanding Nervous System Pathology

6. The CNS may be affected by diseases that involve other organs, but also by diseases that are unique to the CNS. Examples: Atherosclerosis of the coronary arteries and aorta is often accompanied by CerebroVascular Accidents (CVA). Uremia or hepatic encephalopathy eventually would cause a coma Prions, minute infectious particles, survive only in nerve cells (kuru, mad cow disease, Creutzfeldt-Jacob disease)

Factors Important to Understanding Nervous System Pathology

7. The symptoms of CNS diseases result from dysfunction or loss of function of neurons. Examples: Headaches are a result of brain tumors, and increased intracranial pressure from massive bleeding causes generalized paralysis, coma, and death if vital centers in the brain are compressed. Loss of neurons in Alzheimers disease causes loss of memory Abnormal function of neurons in Parkinsons disease causes rigidity of muscles. Abnormal excitation of neurons causes convulsions in epilepsy

Symptoms of CNS Diseases Local Symptoms Headache caused by a brain tumor direct compression of nerve center increase intracranial pressure due to large mass or cerebral edema Systemic Symptoms Generalized paralysis and coma caused by massive intracerebral bleeding trauma ruptured aneurysm ultimately, death due to o compression of vital centers in brain stem (medulla) o apnea from coma o pulmonary edema secondary to inhibition of vital centers in the medulla

Symptoms of CNS Dysfunctions

headache

vomiting blurry vision loss of consciousness personality changes intellectual decline emotional liability loss of memory schizophrenia manic-depressive psychosis convulsions (seizures)

Diseases and Disorders of the Nervous System Developmental Disorders Genetic Diseases Tay-Sachs disease o accumulation of ganglioside and destruction of ganglion cells o serve mental retardation, blindness, death early in childhood Down Syndrome

o mental retardation with physical defects (mongoloid appearance) o congenital heart disease o vulnerable to infection due to immunologic defects o may or may not be a heritable disorder, however, test future pregnancies

Diseases and Disorders of the Nervous System

Developmental

malformations due to intrauterine infections

o toxoplasma (protozoon on cats) stillbirth, visual defects, hydrocephalus, severe mental retardation

o rubella virus (German measles) heart disease, eye and hearing defects, growth retardation
o cytomegalovirus (CMV) enlarged cells affect organs, cause mental retardation, infection is spread by saliva, sexually transmitted, or via blood donor) o herpesvirus herpes zoster (shingles), herpes simplex (warts/lesions on genitals, mucosa)

Developmental Malformations Meningocele : herniation of the meninges Myelomeningocele: herniation of the meninges and spinal cord

Spina bifida : absence of vertebral arches resulting in exposure of the meninges or spinal cord to the outer world

Intracranial Hemorrhages The brain cavity is enclosed by a solid bone, there is no room or space for swelling. Once a hematoma reaches the volume of 50-60mL, it is large enough to compress the brain and cause coma. Hemorrhage may be caused by head trauma, gunshot wound, stroke, or rupture of aneurysms. Epidural hematomas Hematoma located between the skull and dura, usually the result of trauma and rupture of the middle meningeal artery Subdural hematomas Hematoma located between the dura and arachnoid layer, commonly caused by traumatic rupture of bridging veins

Epidural hematoma

Epidural hematoma covering a portion of the dura. Multiple small contusions are seen in the temporal lobe.

Epidural hematoma (left) in which rupture of a meningeal artery, usually associated with a skull fracture, leads to accumulation of arterial blood between the dura and the skull. In a subdural hematoma (right), damage to bridging veins between the brain and the superior sagittal sinus leads to the accumulation of blood between the dura and the arachnoid.

A, Large organizing subdural hematoma attached to the dura. B, Coronal section of the brain showing compression of the hemisphere underlying the hematoma.

Subarachnoid hemorrhage due to aneurysm rupture Hematoma located between the arachnoid and pia layer, typical of ruptured berry aneurysm of the Circle of Willis at the base of the brain. They are treated surgically by placing permanent clips at the site of their origin

Common sites of saccular (berry) aneurysms in the circle of Willis.

Cerebrovascular Diseases (CVD) 3rd most common cause of death and the most common crippling disease in the U.S. Stroke a sudden loss of consciousness followed by paralysis caused by hemorrhage or atherosclerosis of cerebral arteries. Global Ischemia Widespread atherosclerotic narrowing of the entire cerebrovascular system develops multiple foci of ischemic necrosis, resulting in a slowly progressive mental deterioration called multifarct dementia.

Cerebral Infarct Most often caused by the thrombotic occlusion of an atherosclerotic artery that served a distinct anatomic part of the brain, or thromboemboli originating from the heart chambers following myocardial infarction or on the cardiac valves due to endocarditis The ischemic portion of the brain liquefies, undergoes necrosis, transforming into putty-like mush. Brain infarcts cannot heal and the neurologic deficits caused by them are permanent. Intracerebral Hemorrhage Arterial hemorrhage from rupture of small blood vessels due to hypertension, resulting in a well-circumscribed hematoma.

Trauma of the Nervous System Brain Injury Brain concussion blunt trauma causing transient loss of consciousness Brain contusion (bruise) blunt trauma causing disruption of cerebral or meningeal blood vessels serious injuries associated with considerable mortality, permanent neurologic deficits Laceration of the brain open trauma such as gunshot wounds that disrupt the integrity of the brain, lacerating brain tissue. High mortality, survivors have major neurologic deficits and may developepilepsy (seizures)

Neck and Spinal Cord Injuries

Hyperextension or hyperflexion injuries due to head impact causing flaccid paralysis accompanied by loss of sensation below site of injury (paraplegia or quadriplegia). Urination and defecation reflexes are lost. Reflex functions may return with time.

Infections of the Central Nervous System Infections reach the brain via direct entry by trauma, hematogenously, via the nerves or spread from the inner ear or nasal sinuses. Pathology Encephalitis: a diffuse infection of the brain, usually viral. Myelitis a diffuse infection of the spinal cord, usually viral. Cerebral Abscess: a localized suppurative infection of the brain caused by pyogenic bacteria, pus in a capsule. Meningitis: inflammation of the meninges, viral or bacterial

Meningitis Meningitis refers to an inflammatory process of the leptomeninges and CSF within the subarachnoid space. Meningoencephalitis refers to inflammation of the meninges and brain parenchyma.

Meningitis is usually caused by an infection, but chemical meningitis may also occur in response to a non bacterial irritant into the subarachnoid space. Infiltration of the subarachnoid space by carcinoma is referred to as Meningeal carcinomatosis. Infiltration of the subarachnoid space by lymphoma is referred as Meningeal lymphomatosis.

Causes of meningitis A. Bacterial meningitis 1. Neonates : Common Escherichia coli, Proteus, Streptococcus agalactiae.

2. Pre-school child : (a) Common - Haemophilus influenzae, Neisseria meningitidis (meningococcus), Streptococcus pneumoniae. (b) Less common Mycobacterium tuberculosis. 3. Older child and adult : (a) Common - Neisseria meningitidis (meningococcus), Streptococcus pneumoniae, (b) Less common - Mycobacterium tuberculosis.

Causes of meningitis B. Viral infections Measles Rubella Adenovirus Herpesvirus (causes encephalitis) Cytomegalovirus Neurotropic viruses transmitted by ticks Rabies virus C. Fungi infections (encephalitis and meningitis) Candida albicans Aspergillus flavus Cryptococcus neoformans

Types of meningitis Classification : Infectious meningitis is broadly classified on the basis of the characteristics of inflammatory exudate on CSF examination and the clinical evolution of the illness.

1. Acute pyogenic meningitis : usually bacterial meningitis .

2. Aseptic : usually acute viral meningitis (acute lymphocytic meningitis ) 3. Chronic : usually tuberculosis ,spirochetal or cryptococcal.

Acute pyogenic meningitis Aetiology : Common microorganisms : Neisseria meningitidis, Escherichia coli, Haemophilus influenzae, Streptococcus pneumoniae, streptococcus agalactiae. Morphology : The normally clear CSF is cloudy and sometimes frankly purulent. Inflammatory exudates accumulate over the surfaces of the brain. The meningeal vessels are engorged and stand out prominently. On microscopic examination, neutrophils fill the entire subarachnoid space in severely affected areas and are found predominantly around the leptomeningeal blood vessels in less severe cases. In untreated meningitis, Gram stain reveals varying numbers of the causative organism.

Acute pyogenic meningitis Laboratory diagnosis: CSF is purulent. Neutrophils may be a few thousand to 90,000/cumm. Protein is increased and sugar is reduced. Gram stain may show bacteria.

Pyogenic meningitis. A thick layer of suppurative exudate covers the brain stem and cerebellum and thickens the leptomeninges.

Acute Aseptic (Viral) Meningitis It occurs due to viral infection. Common viruses are coxsackie viruses, Echoviruses. Herpes simplex virus, Epstein-Barr virus. CSF findings in aseptic meningitis, there is a lymphocytic pleocytosis, the protein elevation is only moderate , and the sugar content is nearly always normal. Morphology : There are no distinctive macroscopic characteristics expect for brain swelling ,seen in some instances. On microscopic examination, there is either no abnormality or a mild to moderate infiltration of the leptomeninges with lymphocytes.

Acute Aseptic (Viral) Meningitis

Characteristic findings of viral meningitis include perivascular cuffs of lymphocytes (A) and microglial nodules (B).

Chronic Meningitis Aetiology : Mycobacterium tuberculosis , Treponema pallidum, Brucella, Fungi, e g. Candida albicans. Morphology : On macroscopic examination, the subarachnoid space contains a gelatinous or fibrinous exudate, most often at the base of the brain, obliterating the cisterns and encasing cranial nerves. There may be discrete, white granules scattered over the leoptomeninges. On microscopic examination, there are mixtures of lymphocyes, plasma cells, and macrophages. Florid cases show well-formed granulomas , often with caseous necrosis and giant cells. The arteries may show endarteritis obliterans. Another manifestation of disease is development of a single or multiple well circumscribed mass . A tuberculoma may be up to several centimeters. On microscopic examination, central core of caseous necrosis surrounded by a typical tuberculous granulmatous reaction.

Autoimmune Disease of the Central Nervous System Multiple Sclerosis Demyelinating disease presumed to be of autoimmune origin. Leading neurologic disease in young adults, affecting 250,000 Americans. Occurs predominately in Caucasians who live in temperate climate zones above the 40th parallel. Affects certain families. Resembles allergic encephalitis. Has an unpredictable course, marked motor disability. Patients become physically incapacitated over a period of 2030 years.

Neurodegenerative Diseases/Disorders Alzheimers Disease A form of dementia, a progressive loss of mental capacities of unknown etiology Affects older people, mostly over 70 years of age. 600,000 people affected in the U.S. with at least 60,000 new cases each year. loss of memory predominates until the patient becomes completely dysfunctional and cannot perform any mental operations. Speech problems develop, finally becoming bedridden and completely dependent on nursing care. Patients live long lives, and death is not related to the disease but to the decreased resistance to infection that normally occurs with advancing age. X-ray studies show atrophy of the cortex.

Neurodegenerative Diseases/Disorders Parkinsons Disease (PD) Neurodegenerative disorder characterized by movement disorders and pathologic changes of the involuntary motor system such as tremors, rigidity, bradykinesia (extreme slowness of movement) and postural instability. Huntingtons Disease An autosomal dominant neurodegenerative disease characterized by involuntary, gyrating movements and progressive dementia.

Amyotrophic Lateral Sclerosis (ALS) Motor neurone disease A neurodegenerative disease characterized by motor weakness and progressive wasting of muscles and the extremities leading to generalized muscle loss and death.

Neoplasms of the CNS Brain tumors have a very high mortality occur at any age 50% are primary tumors, 50% are metastases Primary tumours A. Gliomas ( Tumours of Neuroglia) Tumors arising from glial cells, prognosis depends upon location Astrocytic gliomas (Astrocytoma ) Astrocytomas solid or cystic cerebral tumors, less malignant Glioblastoma multiforme very common, highly malignant, fatal Oligodendroglioma rare tumors , well circumscribed, cystic and calcified ,may progress to glioblastoma multiforme Ependymoma found in children, papillae or rosettes in neural tubes or part of the spinal cord

Neoplasms of the CNS B. Tumours of neurons : Neuroblastoma Ganglioneuroma C. Neural cell precursor tumors: Medulloblastoma cerebellar childhood tumor that grows quickly, has a poor prognosis, metastases via CSF to spinal cord D. Tumours of Meninges: Meningioma mostly benign, these tumors arise from the meninges compression from tumor arising at the base of the brain may cause epileptic seizures or motor deficits excellent prognosis after surgical excision Mengingeal sarcoma

Neoplasms of the CNS E. Tumors of the Cranial and Spinal Nerves: Neuroma Benign tumors originating from the nerves Neurilemoma (schwannoma) Benign tumors originating from Schwann cells Neurofibroma Benign tumors originating from neurofibroblasts Neurofibrosarcoma Malignant tumors originating from benign tumors F. Other tumours : Lymphomas primary or secondary Crainopharyngioma Metastatic Tumours: 50% of all brain tumors are metastases, especially from lung cancer, breast cancer, and melanoma

Astrocytic gliomas (Astrocytoma )

Several different categories of tumours are derived from astrocytes are recognized including fibrillary astrocytoma, Glioblastoma, pilocytic astrocytoma, and pleomorphic xanthroastrocytoma. Fibrillary (Diffuse) Astrocytomas and Glioblastoma These account for about 80% of adult primary brain tumours. Usually found in the cerebral hemispheres They may also occur in the cerebellum, brain stem or spinal cord. Most often in the fourth through sixth decades. The most common presenting sings and symptoms are seizures, hedaches and focal neurologic deficits related to anatomic site of involvement.

Fibrillary (Diffuse) Astrocytomas and Glioblastoma Morphology : Among the diffuse fibrillary astrocytomas, tumours can be well differentiated (astrocytoma) or less differentiated (higher grade), ranging from anaplastic astrocytoma to glioblastoma. The macroscopic appearance of diffuse fibrillary astrocytoma is poorly defined , gray, infiltrative tumour that expands and distorts the invaded brain. Tumours range in size from a few centimeters to enormous lesions that replace an entire hemisphere. Cut surface of tumour is firm or soft and gelatinous, cystic degeneration may be seen. In glioblastoma, variation in gross appearance, some areas are firm, and white, others are soft and yellow, others show cystic degeneration and hemorrhage.

Fibrillary (Diffuse) Astrocytomas and Glioblastoma Microscopically , more or less well differentiated astrocytes in a fibrillary background. There is mild to moderate increase in number of gial cell nuclei, variable nuclear pleomorphism and intervening feltwork of fine astrocyte cell processes that give the background a fibrillary appearance. Anaplastic astrocytoma show regions that are more densely cellular and have greater nuclear pleomorphism, mitotically active cells are observed.

Fibrillary (Diffuse) Astrocytomas

Well-differentiated astrocytoma. A, The right frontal tumor has expanded gyri, which led to flattening (arrows). B, Expanded white matter of the left cerebral hemisphere and thickened corpus callosum and fornices.

Fibrillary (Diffuse) Astrocytomas and Glioblastoma Glioblastoma (glioblastoma multiforme) has a histologic appearance similar to anaplastic astrocytoma with necrosis and vascular or endothelial cell proliferation. Necrosis in glioblastoma , often in a serpentine pattern, occurs in areas of hypercellularity with highly malignant tumours cells crowded along the edges of necrotic regions, producing a histologic pattern called as pseudopalisading . Vascular proliferation is characterized by tufts of piled up vascular cells that bulge in to the vascular lumen. The minimal criterion of this feature is double layer of endotheilal cell.

Glioblastoma

Computed tomographic (CT) scan of a large tumor in the cerebral hemisphere showing signal enhancement with contrast material and pronounced peritumoral edema. B, Glioblastoma multiforme appearing as a necrotic, hemorrhagic, infiltrating mass.

Glioblastoma

Glioblastoma. Foci of necrosis with pseudopalisading of malignant nuclei.

Pilocytic astrocytoma Pilocytic astrocytomas are distinguished from the other types by their pathologic appearance and relatively benign behavior. They typically occur in children and young adults. Usually located in cerebellum May also appear in the floor and walls of third ventricle , the optic nerves and occasionally the cerebral hemispheres. Tumours grow very slowly, may be treated by resection. Morphology On macroscopic examination, cystic with a mural nodule in the wall of cyst. If solid, it may be well circumscribed or less frequently infiltrative. On microscopic examination, tumour composed of bipolar cells with long , thin hair like processes , Rosenthal fibers , eosinophilic granular bodies and microcysts are present. Increase in number of blood vessels. Necrosis and mitoses are uncommon

Pilocytic astrocytoma

Pilocytic astrocytoma in the cerebellum with a nodule of tumor in a cyst.

Oligodendroglioma Most common in middle life . Constitute 5% to 15% of gliomas. Lesions found mostly in cerebral hemispheres, with a predilection for white matter. Morphology : On macroscopic examination, well circumscribed , gelatinous, gray masses, often with cysts ,focal hemorrhage and calcification. On microscopic examination, the tumours are composed of sheets of regular cells with spherical nuclei containing finely granular chromatin surrounded by a clear halo of cytoplasm. The tumour contains a delicate network of anastomosing capillaries . Calcification present in 90% of these tumours.

Ependymoma

Most often arise next to the ependyma lined ventricular system, including central canal of spinal cord. In the first two decades of life , they occur near the fourth ventricle. 5% to 10% of primary brain tumours in this age group. In adult , spinal cord is common location . Morphology In forth ventricle , tumours are typically solid or papillary masses, extending from the floor of ventricle. On microscopic examination, tumour composed of cells with regular ,round to oval nuclei with abundant granular chromatin. Between the nuclei, there is a dense fibrillary background. Tumour cell may form gland like round or elongated structures (rosettes, canal) with long delicate process extending into a lumen.

Perivascular pseudorsettes in which tumour cells are arranged around vessels with an intervening zones consisting of thin ependymal processes directed toward the wall of vessel. Myxopapillary ependymomas are distatinct but related lesions that occur in the filum terminale of spinal cord and contain papillary element in a myxoid background ,admixed with ependymoma like cells. Cuboidal cells with clear ctytoplasm are arranged around papillary cores containing connective tissue and blood vessels. The myxoid areas contain neutral and acidic mucopolysaccharides. Prognosis depends on completeness of surgical resection.

Ependymoma. A, Tumor growing into the fourth ventricle, distorting, compressing, and infiltrating surrounding structures.

B, Microscopic appearance of ependymoma.

Medulloblastoma Occurs predominantly in children and exclusively in cerebellum. Morphology In children, located in the midline of cerebellum, but lateral locations are often found in adult. Rapid growth may occlude the flow of CSF, leading to hydrocephalus. Well circumscribed, gray and friable and may be extending to the surface of cerebellar folia and involving the leptomeninges. On microscopic examination, the tumour is extremely cellular with sheets of anaplastic cells. Indivdiual tumour cells are small with little cytoplasm and hyperchromatic nuclei that are crescent shaped. Mitoses are abundant.

Medulloblastoma. A, CT scan showing a contrast-enhancing midline lesion in the posterior fossa. B, Sagittal section of brain showing medulloblastoma destroying the superior midline cerebellum. C, Microscopic appearance of medulloblastoma.

Meningioma Predominantly benign tumours of adults. Usually attached to dura ,that arise from the meningothelial cell of arachnoid. Morphology. Usually rounded masses with a well-defined dural base that compress underlying brain but are easily separated from it. Extension into the overlying bone my be present. The surface of mass is encapsulated with thin , fibrous tissue and may have a bosselated or polypoid appearance. Characteristic growth pattern is en plaque variant,in which tumour spreads in a sheet like fashion along the surface of dura. The lesions range from firm and fibrous to finely gritty, or they may be extremely calcified with Psammoma bodies. Gross evidence of necrosis or extensive hemorrhage is not present.

Histology Vatrious histologic patterns are observed. Syncytial Whorled clusters of cells that sit in tight groups without visible cell membranes. Fibroblastic Elongated cells and abundant collagen deposition between them . Transitional Which share features of the syncytial and fibroblastic types Psammomatous With mnumerous psammoma bodies appearently forming from Calcification of syncytial nests of meningothelial cells. Microcystic Loose spongy appearance.