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NEUROPATHOLOGY
INFECTIONS OF THE NERVOUS SYSTEM
An infectious agent must use one of several routes of entry to reach the CNS & cause a
disease.
1. Hematogenous spread via the arterial blood supply is the most common mode of entry.
There can also be retrograde venous spread, through the anastomoses between veins of the
face and the venous sinuses of the skull.
2. Direct implantation of microorganisms is almost invariably post-traumatic, with
introduction of foreign material.
3. Local extension from an established infection in the skull or the bony spine can occur. The
infection may originate from
a. air sinus, most often the mastoid or frontal
b. infected tooth
c. surgical operation on the cranium or spine causing osteomyelitis
d. congenital malformation, such as meningomyelocele.
4. Peripheral nerves can also serve as the path of entry for rabies and herpes zoster.
Epidural and Subdural Infections
These spaces can be involved with bacterial or fungal infections, usually as a consequence of
direct local spread. Epidural abscess, commonly associated with osteomyelitis, arises from an
adjacent focus of infection, such as sinusitis or a surgical procedure. When the process occurs
in the spinal epidural space, it may cause spinal cord compression and constitute a
neurosurgical emergency. Infections of the skull or air sinuses may also spread to the subdural
space, producing subdural empyema. A large subdural empyema may produce a mass effect.
In addition, thrombophlebitis may develop in the bridging veins that cross the subdural space,
resulting in venous occlusion and infarction of the brain.
Meningitis
This is an inflammatory process of the leptomeninges and CSF within the subarachnoid space.
Meningoencephalitis develops with spread of the infection from the meninges into the
underlying brain. Infectious meningitis is broadly classified into
1. Acute pyogenic (usually bacterial),
2. Aseptic (usually viral), and
3. Chronic (usually tuberculous, spirochetal, or cryptococcal)
Acute Pyogenic Meningitis (Bacterial Meningitis)
While a wide range of bacteria can cause acute pyogenic meningitis, there is a relationship
between the age of a patient and the most likely organisms. In neonates, common organisms
are Escherichia coli and the group B streptococci; at the other extreme of life, Streptococcus
pneumoniae and Listeria monocytogenes are more common. Among adolescents and in young
adults, Neisseria meningitides is the most common pathogen. Regardless of the organism,
patients typically show systemic signs of infection superimposed on clinical evidence of
meningeal irritation and neurologic impairment-including headache, photophobia, irritability,
and neck stiffness. Lumbar puncture reveals an increased pressure, abundant neurophils,
elevated protein, and reduced glucose. Bacteria may be seen on a smear stained with Gram
stain or can be cultured.
Pathological features
In acute meningitis, an exudate is evident within the leptomeninges over the surface of the
brain.
The meningeal vessels are engorged and prominent.
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When the meningitis is fulminant, the inflammatory cells infiltrate the walls of the
leptomeningeal veins and may spread into the substance of the brain (focal cerebritis), or
the inflammation may extend to the ventricles.
On microscopic examination, neutrophils fill the entire subarachnoid space in severely
affected areas or may be found predominantly around the leptomeningeal blood vessels in
less severe cases.
Bacterial meningitis may be associated with abscesses in the brain. Phlebitis may also lead to
venous occlusion and hemorrhagic infarction of the underlying brain.
Aseptic Meningitis (Viral Meningitis)
The clinical course is less fulminant than in pyogenic meningitis & is usually self-limiting.
The CSF shows an increased number of lymphocytes, the protein elevation is only moderate,
and glucose content is normal. The most common offending agent is an enterovirus.
Chronic Meningitis
Tuberculous Meningitis
There is only a moderate increase in cellularity of the CSF made up of mononuclear cells, or a
mixture of neutrophils and mononuclear cells; the protein level is elevated, often strikingly so,
and the glucose content typically is moderately reduced or normal. Infection with
Mycobacterium tuberculosis may also result in a well-circumscribed brain mass
(tuberculoma), which may be associated with meningitis. Tuberculous meningitis is a cause
of arachnoid fibrosis, which may produce hydrocephalus. The subarachnoid space contains a
gelatinous or fibrinous exudate, most often at the base of the brain. There may be discrete
white granules scattered over the leptomeninges. Microscopically, there are well-formed
granulomas, often with caseous necrosis and giant cells. Similar findings are observed in
tuberculomas within the brain.
Neurosyphilis
This is a tertiary stage of syphilis and occurs in only about 10% of individuals with untreated
infection. One of the major manifestations is meningeal. As with other chronic infections,
there can be parenchymal disease as well that eventuates in severe dementia. Tabes dorsalis is
another form of neurosyphilis, resulting from damage to the sensory nerves in the dorsal roots
producing impaired joint position sense and resultant ataxia (locomotor ataxia); loss of pain
sensation, leading to skin and joint damage (Charcot joints); other sensory disturbances.
Individuals with HIV infection are at increased risk for neurosyphilis, and the rate of
progression and severity of the disease seem to be accelerated.
TUMORS
The incidence of CNS tumors is generally low; about 50% to 75% are primary, and the rest
are metastatic. In children, they constitute 20% of all tumors with a predilection for the
posterior fossa (in adults they are most tumors are supratentorial).
Tumors of the nervous system differ from neoplasms elsewhere in the body
1. Low-grade lesions may diffusely infiltrate large areas of the brain, thus associated with
poor prognosis.
2. The anatomic site of the tumor can affect the prognosis
a. it may have lethal consequences irrespective of the histopathologic type; for example, a
benign meningioma, by compressing the medulla, can cause cardiorespiratory arrest.
b. through influencing the extent of respectability.
3. Even the most highly malignant gliomas rarely metastasize outside the CNS, however, the
subarachnoid space does provide a pathway for spread so that seeding along the brain and
spinal cord can occur.
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GLIOMAS
Gliomas are tumors of the brain parenchyma that histologically resemble different types of
glial cells. The major types of gliomas are astrocytomas, oligodendrogliomas, and
ependymomas.
1. Astrocytomas: the most common of these are fibrillary and pilocytic astrocytomas.
Fibrillary Astrocytoma account for 80% of adult primary brain tumors. They are most
frequent in the ages of 30 to 60 years. Their usual location is the cerebral hemispheres. They
show a spectrum of histologic differentiation that correlates well with clinical course and
outcome. Based on the degree of differentiation, they are classified into three groups:
a. Astrocytoma (infiltrating astrocytoma) (WHO grade II)
b. Anaplastic astrocytoma (WHO grade III)
c. Glioblastoma multiforme (WHO grade IV)
For well-differentiated astrocytomas, which are slow growing, the mean survival is more than
5 years. Eventually, however, a more rapid growth occurs due to the appearance of anaplastic
features. However, many patients present with glioblastoma from the outset. The prognosis of
glioblastoma is very poor (mean survival 8 to 10 months despite treatment).
Gross features
Low-grade (infiltrating) astrocytoma is a poorly defined, gray, & infiltrative mass lesion
that leads to expansion and distortion of the affected regions of the brain.
The cut surface of the tumor is either firm, or soft and gelatinous; cystic degeneration may
be seen.
In glioblastoma, variation in the gross appearance of the tumor from region to region is
characteristic. Some areas are firm and white, others are soft and yellow (the result of
tissue necrosis), and yet others show regions of cystic degeneration and hemorrhage.
Microscopic features
Low-grade (infiltrating) astrocytomas are characterized by a mild to moderate increase in
the number of glial cells, slight nuclear pleomorphism, and an intervening feltwork of fine,
GFAP-positive astrocytic cell processes that give the background a fibrillary appearance.
The tumor cells can be seen infiltrating surrounding normal tissue for some distance from
the main lesion.
Anaplastic astrocytomas are more densely cellular with greater nuclear pleomorphism;
increased mitoses are often observed.
Glioblastoma, have a histologic appearance similar to anaplastic astrocytoma with
additional features of necrosis surrounded by pseudo-palisaded nuclei &/or prominent
vascular endothelial cell proliferation.
Pilocytic Astrocytoma (WHO grade I) is a relatively benign tumor, often cystic, that
typically occur in children and young adults and are usually located in the cerebellum. In the
cystic variant, there is usually a mural nodule in the wall of the cyst. The tumor is composed
of areas with bipolar cells with long, thin "hair-like" processes that are GFAP positive.
Rosenthal fibers, eosinophilic granular bodies, and microcysts are often present. Necrosis and
mitoses are absent.
2. Oligodendrogliomas are most common in the 30 to 50 years of age. It is mostly located in
the white matter of cerebral hemispheres. The prognosis is generally better than that of
astrocytoma.
Oligodendrogliomas are infiltrative gelatinous, gray tumors. Microscopically, the tumor is
composed of sheets of regular cells with spherical vesicular nuclei surrounded by a clear
halo of cytoplasm. It typically contains a delicate network of anastomosing capillaries
(chicken wire– type vasculature). Calcifications are frequently present; these range from
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microscopic foci to massive depositions. The current WHO classification grades
oligodendrogliomas into 2 different categories as WHO grade 2 and anaplastic WHO grade 3.
Prominent mitotic activity and microvascular/endothelial proliferation are the 2 features that
define anaplastic tumors.
3. Ependymoma most often arises next to the ependyma-lined ventricular system, including
the central canal of the spinal cord. In the first two decades of life, they typically occur near
the fourth ventricle. In adults, the spinal cord is their most common location. Because
ependymomas usually grow within the ventricles, CSF dissemination is a common
occurrence. In the fourth ventricle, ependymomas are typically solid or papillary masses
projecting from the floor of the ventricle. These tumors are composed of cells with regular,
round to oval nuclei. Between the nuclei there is a fibrillary background. Tumor cells may
form round or elongated structures (rosettes) with long, delicate processes extending into a
lumen; more frequently present are perivascular pseudo-rosettes in which tumor cells are
arranged around vessels with an intervening zone consisting of thin ependymal processes.
NEURONAL TUMORS
Central neurocytoma is a low-grade neuronal neoplasm that is typically but not exclusively a
periventricular lesion i.e., found within and adjacent to the ventricular system (most
commonly the lateral or third ventricles). It is characterized by evenly spaced, round, uniform
nuclei and often islands of neuropil.
Gangliogliomas are tumors with a mixture of glial elements (looking like a low-grade
astrocytoma) and mature-appearing neurons. Most of these tumors are slow growing.
Medulloblastoma occurs predominantly in children and exclusively in the cerebellum. This
highly malignant tumor is radiosensitive but without treatment the prognosis is poor. In
children the tumor is located typically in the midline of the cerebellum. It is often well
circumscribed, gray, and friable. Medulloblastomas are extremely cellular, with sheets of
undifferentiated small cells with little cytoplasm and hyperchromatic nuclei; mitoses are
abundant. Some tumors show differentiation along neuronal lines in the form of Homer
Wright rosettes. The latter consist of tumor cell nuclei disposed in circular fashion about
tangled cytoplasmic processes.
OTHER PARENCHYMAL TUMORS
Primary Central Nervous System Lymphoma
are rare but are the most common CNS neoplasm in immunosuppressed individuals
(including transplant recipients and persons with AIDS); under these circumstances the CNS
lymphomas are nearly all driven by Epstein-Barr virus. Most of these tumors are diffuse large
B-cell lymphomas.
Germ-Cell Tumors occur along the midline, most commonly in the pineal and the suprasellar
regions. They are a tumor of the young, with 90% occurring during the first two decades.
Germ-cell tumors in the pineal region show a strong male predominance. The histologic
classification of brain germ-cell tumors is similar to that used in the testis, but the CNS
equivalent of testicular seminoma is called a germinoma. It should be noted, however, that
CNS involvement by a gonadal germ-cell tumor is not uncommon.
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MENINGIOMAS
These predominantly benign tumors of adults arise from the meningothelial cell of the
arachnoid & are usually attached to the dura. Meningiomas may be found along any of the
external surfaces of the brain as well as within the ventricular system, where they arise from
the stromal arachnoid cells of the choroid plexus. They cause symptoms through compression
of underlying brain. Multiple meningiomas, especially in association with eighth nerve
schwannomas or glial tumors, may be a part of neurofibromatosis type 2 (NF2). About half of
meningiomas not associated with NF2 still have mutations in the NF2 gene.
Gross features
They are well-defined dural-based masses that compress underlying brain but are easily
separated from it.
On sectioning most meningiomas are grayish-tan and soft. Collagenized examples,
however, have rubbery texture and whorled or trabeculated cut surface.
Calcification may impart a gritty sensation on cutting.
Extension into the overlying bone may be present.
Microscopic features
There are many histologic patterns of meningiomas, including
1. Syncytial, showing whorled clusters of tight groups of cells without visible cell membranes
2. Fibroblastic, with elongated cells and abundant collagen deposition between them
3. Transitional, which shares features of the syncytial and fibroblastic types
4. Psammomatous, with numerous psammoma bodies (NB: psammoma bodies may also
occur in the above variants but less heavily).
Atypical meningiomas show a higher rate of recurrence, more aggressive local growth. They
are recognized by several histologic features including a higher mitotic rate.
Anaplastic (malignant) meningiomas are highly aggressive tumors that resemble a high-
grade sarcoma.
Although most meningiomas are easily separable from underlying brain, some tumors
infiltrate the brain. The presence of brain invasion is associated with increased risk of
recurrence.
METASTATIC TUMORS
Metastatic lesions, mostly carcinomas, account for 25% to 50% of intracranial tumors. The
five most common primary sites are
1. Lung
4. Kidney
2. Breast
5. GIT
3. Skin (melanoma)
The meninges are also a frequent site of involvement by metastatic disease. In the brain,
metastases form sharply demarcated masses, often at the gray matter-white matter junction,
usually surrounded by a zone of edema. The boundary between tumor and brain parenchyma
is well defined microscopically as well, with surrounding reactive gliosis.
In addition to the direct and localized effects produced by metastases, paraneoplastic
syndromes may involve the peripheral and central nervous systems, sometimes even
preceding the clinical recognition of the malignant neoplasm. These syndromes are most
commonly associated with small-cell carcinoma of the lung. There are several manifestations
of paraneoplastic syndromes; some characteristic patterns include: Subacute cerebellar
degeneration resulting in ataxia, Limbic encephalitis causing a subacute dementia; the
pathological changes are centered in the medial temporal lobe, and Subacute sensory
neuropathy leading to altered pain sensation.
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PRIMARY DISEASES OF MYELIN
Within the CNS, axons are tightly ensheathed by myelin, which serves as an electrical
insulator to allow rapid propagation of impulses. Myelin consists of multiple layers of the
specialized plasma membrane of oligodendrocytes. Oligodendrocytes extend processes
toward many different axons and wrap them. Myelinated axons are the dominant
component in the white matter; therefore, most diseases of myelin are primarily white
matter disorders. The myelin in peripheral nerves is similar to the myelin in the CNS but is
made by Schwann cells, not oligodendrocytes. Therefore, most diseases of CNS myelin do
not significantly involve the peripheral nerves, and vice versa.
In general, diseases involving myelin are separated into two broad groups
1. Demyelinating diseases of the CNS are acquired conditions characterized by preferential
damage to previously normal myelin. The most common diseases in this group are multiple
sclerosis (MS) and related disorders. Others are exemplified by viral infection of
oligodendrocytes as in progressive multifocal leukoencephalopathy, and injury caused by
drugs and toxic agents.
2. Dysmyelinating diseases (leukodystrophies); these are due to improperly formed myelin
or to abnormal turnover kinetics of myelin. They are due to mutations affecting the
proteins required for formation of normal myelin or that affect the synthesis or degradation
of myelin lipids.
Multiple Sclerosis (MS)
is an autoimmune demyelinating disorder characterized by
separated episodes of neurologic deficits attributable to separated white matter lesions. It is
the most common of the demyelinating disorders. The clinical onset occurs usually in
adolescence or young adults, & women are affected twice as often as men. MS shows
relapsing and remitting episodes of neurologic deficits. Like other autoimmune diseases,
MS is caused by a combination of environmental and genetic factors that result in a loss of
tolerance to self myelin antigens. A transmissible agent has been proposed. The risk of
developing MS is 15-fold higher when the disease is present in a first-degree relative; this
indicates a strong, but not causative, role for genes.
T cell-mediated delayed type hypersensitivity reaction to myelin proteins is thought to be
central to the pathogenesis, which is experimentally supported.
Gross features (Fig. 14-30)
MS is a white matter disease.
Affected areas show multiple, well-circumscribed, gray-pink, irregularly shaped plaques.
These plaques are commonly paravenentricular in location but they are also frequent in
the optic nerves and chiasm, brain stem, and spinal cord.
Microscopic features
The lesions have sharply defined borders.
In an active plaque there is myelin breakdown with abundant macrophages containing
myelin debris with perivascular lymphocytes and histiocytes infiltration. Axons are
relatively preserved.
When plaques become quiescent (inactive plaques), the inflammation mostly disappears,
leaving behind little to no myelin.
The course of MS is variable, but commonly there are multiple episodes of new symptoms
(relapses) followed by episodes of typically incomplete recovery (remissions). The
consequence of this pattern of relapsing-remitting disease is the gradual, often stepwise,
accumulation of increasing neurologic deficits. Unilateral visual impairment is a frequent
initial manifestation of MS and is due to optic neuritis. Involvement of the brain stem
produces cranial nerve signs and ataxia. Spinal cord lesions give rise to motor and sensory
impairment, spasticity, and urinary incontinence.
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The CSF in MS patients shows a mildly elevated protein level with an increased proportion
of γ-globulin; in one-third of cases there is moderate increase in lymphocytes.
Other Acquired Demyelinating Diseases
Immune-mediated demyelination can be found after a number of systemic infectious
illnesses, including relatively mild viral diseases. It is believed that the immune response to
pathogen-associated antigens cross-reacts with myelin antigens; this results in myelin
damage.
Dysmyelinating diseases (Leukodystrophies) are inherited dysmyelinating diseases that
result from either abnormal myelin synthesis or turnover. Some of these disorders involve
lysosomal enzymes, while others involve peroxisomal enzymes; a few are associated with
mutations in myelin proteins. Most are autosomal recessive. Much of the pathology is
found in the white matter, which is diffusely abnormal in color (gray and translucent) and
volume (decreased).
DISEASES OF THE PERIPHERAL NERVOUS SYSTEM
Neoplasms of the Peripheral Nervous System
These tumors arise from cells of the peripheral nerve, including Schwann cells, perineurial
cells, and fibroblasts. In addition to arising along the peripheral course of nerve, these tumors
can arise within the confines of the dura. When they do this, they may cause changes in
adjacent brain or spinal cord.
Schwannomas a
re benign tumors arising from Schwann cells. Symptoms are referable to
local compression of the involved nerve, or to compression of adjacent structures (such as
brain stem or spinal cord). They are often encountered in the cerebellopontine angle, where
they are attached to the vestibular branch of the eighth nerve. These patients often present
with tinnitus and hearing loss, and the tumor is often referred to as an acoustic neuroma.
Elsewhere within the dura, sensory nerves are preferentially involved, including branches of
the trigeminal nerve and dorsal roots. When extradural, schwannomas are most commonly
found in association with large nerve trunks. Sporadic schwannomas are associated with
mutations in the NF2 gene on chromosome 22.
Gross features
These tumors are well-circumscribed encapsulated masses that are attached to the nerve.
They form firm, gray masses sometimes with cystic change.
Microscopically
There is a mixture of two growth patterns. In the Antoni A pattern of growth, elongated
cells are arranged in fascicles with their nuclei palisade along "nuclear-free zones" forming
Verocay bodies.
In the Antoni B pattern of growth, the tumor is less densely cellular with a loose meshwork
of cells along with microcysts and myxoid changes.
In both areas, the cytology of the individual cells is similar, with elongated cell cytoplasm
and regular oval nuclei.
Neurofibroma
Solitary neurofibromas are mostly cutaneous or involving a peripheral nerve. These arise
sporadically or in association with type 1 neurofibromatosis (NF1). The skin lesions are
evident as nodules, sometimes with overlying hyperpigmentation; they may grow to be large
and become pedunculated. The risk of malignant transformation from these tumors is
extremely small, and cosmetic concerns are their major morbidity.
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The second type is the plexiform neurofibroma, mostly arising in individuals with NF1. In
the latter situation it is not only difficult to surgically remove these plexiform tumors when
they involve major nerve trunks but also their potential for malignant transformation.
Malignant Peripheral Nerve Sheath Tumors (MPNST) are highly malignant sarcomas that
are locally invasive, frequently leading to multiple recurrences and eventual metastatic spread.
Despite their name, these tumors do not arise from malignant transformation of
schwannomas. Instead, they arise de novo or from transformation of a plexiform
neurofibroma. These tumors can also occur after radiation therapy.
FAMILIAL TUMOR SYNDROMES are inherited diseases characterized by the
development of hamartomas and neoplasms throughout the body with particular involvement
of the nervous system. Most of these syndromes are linked to loss of tumor suppressor genes.
The follwing are autosomal dominant disorders.
Type 1 Neurofibromatosis (NF1) is characterized by neurofibromas (plexiform and solitary),
gliomas of the optic nerve, and cutaneous hyperpigmented macules (café au lait spots).
Individuals with NF1 have a propensity for the neurofibromas to undergo malignant
transformation. This is especially true for plexiform neurofibromas.
Type 2 Neurofibromatosis (NF2) is characterized by the development of a range of tumors,
most commonly bilateral vestibular (acoustic) schwannomas and multiple meningiomas.
Ependymomas of the spinal cord also occur.
Tuberous Sclerosis is another autosomal dominant syndrome characterized by the
development of hamartomas and benign neoplasms involving the brain and other tissues.
Seizures, which can be difficult to control with antiepileptic drugs, are associated with the
cortical lesion. Extracerebral lesions include renal angiomyolipomas, retinal glial
hamartomas, and pulmonary lesions and cardiac rhabdomyomas.
Von Hippel-Lindau Disease is characterized by the develop hemangioblastomas mostly
within the cerebellar hemispheres, and retina. Patients may also have cysts involving the
pancreas, liver, and kidneys and have a high propensity to develop renal cell carcinoma of the
kidney.
Note: the text with green color is self study