NF2: bilateral eighth-nerve schwannomas and multiple meningiomas, ependymoma of spinal cord
TS: subependymal giant-cell astrocytomas
VHL: Retinal and cerebellar hemangioblastoma
What are the major features of NF1?
Neurofibromas (plexiform and solitary), gliomas of the optic nerve, pigmented nodules of the iris (Lisch nodules), and cutaneous hyperpigmented macules (café au lait spots).
In individuals with NF1 there is a propensity for the neurofibromas, particularly plexiform neurofibromas, to undergo malignant degeneration
17q (encodes neurofibromin—a large protein with a GTPase-activating domain that inhibits RAS)
What are the criteria for diagnosis of NF1?
Six or more café-au-lait macules of more than 5 mm in greatest diameter in prepubertal individuals, and more than 15 mm in greatest diameter in postpubertal individuals
Two or more neurofibromas of any type or one plexiform neurofibroma
Freckling in the axillary or inguinal regions
Two or more iris hamartoma (Lisch nodules)
Distinctive bony lesion, such as sphenoid dysplasia, or thinning of the long bone cortex with or without pseudoarthrosis
A first-degree relative (parent, sibling, or offspring) with NF1 based on the above criteria
What are other manifestations of NF1?
Seizure and MR (slightly more common than general population, not severe)
................occurs in 100% of patients with NF1.
Cafe au Lait spot
What are the features of NF2?
bilateral eighth-nerve schwannomas and multiple meningiomas.
Gliomas, typically ependymomas of the spinal cord, also occur in these patients. Many individuals with NF2 also have non-neoplastic lesions, which include nodular ingrowth of Schwann cells into the spinal cord (schwannosis), meningioangiomatosis (a proliferation of meningeal cells and blood vessels that grows into the brain), and glial hamartia (microscopic nodular collections of glial cells at abnormal locations, often in the superficial and deep layers of cerebral cortex).
Which clinical manifestation is enough for diagnosis of NF2?
Bilateral vestibular schwannoma
What are the genetic abnormality underlying NF2?
The NF2 gene is located on chromosome 22q12, and the gene product, merlin, shows structural similarity to a series of cytoskeletal proteins.
NF2 gene is also commonly mutated in sporadic meningiomas and schwannomas. The protein is believed to regulate membrane receptor signaling, including contact growth inhibition
nonsense and frameshift mutations causing a more severe phenotype than missense mutations
What are the major features in TS?
1. Facial angiofibromas or forehead plaque
2. Nontraumatic ungual or periungual fibroma
3. Hypomelanotic macules (Ashleaf, three or more)
4. Shagreen patch (connective tissue nevus)
5. Multiple retinal nodular hamartomas
6. Glioneuronal hamartoma (cortical tuber)
7. Subependymal nodule
8. Subpendymal giant cell atrocytoma
9. Cardiac rhabdomyoma, single or multiple
11. Renal angiomyolipoma
What tumor is unique to TS?
Subpendymal giant cell atrocytoma
What are the four characteristic skin lesions of TS?
Hypopigmented macules, also known as ash-leaf spots, which are usually elliptic in shape (first to occur)
Angiofibromas which typically involve the malar regions of the face
Shagreen patches, seen most commonly over the lower trunk
A distinctive brown fibrous plaque on the forehead, which may be the first and most readily recognized feature of TSC to be appreciated on physical examination of affected neonates and infants
What are the CNS involvement in TS?
Hamartomas within the CNS take the form of cortical tubers and subependymal nodules; subependymal giant-cell astrocytomas are low grade neoplasms that appear to develop from the hamartomatous nodules in the same location.
What is the major complication of cortical tubers in TS?
What are the major neuropsychiatric problems in TS?
What is the genetic basis for TS?
One tuberous sclerosis locus (TSC1) is found on chromosome 9q34, and it encodes a protein known as hamartin;
the more commonly mutated tuberous sclerosis locus (TSC2) is at 16p13.3 and encodes tuberin.
These two proteins bind, forming a complex that inhibits the kinase mTOR, which is a key regulator of protein synthesis and other aspects of anabolic metabolism.
Of note, mTOR is well-known to control cell size, and the tumors associated with tuberous sclerosis are remarkable for having voluminous amounts of cytoplasm, particularly giant-cell astrocytomas in the CNS, and cardiac rhabdomyomas.
Cortical and subependymal tubers are associated with an intact copy of the wild-type allele, while in subependymal giant-cell astrocytomas there is biallelic loss
What is the mc mutation in TS?
Tuberin on 16p
What is the cause of abundant cytoplasm in tumors of TS?
What are the histological features of hamartoma in TS?
Cortical hamartomas of tuberous sclerosis are firm areas of the cortex in contrast to the softer adjacent cortex.
Haphazardly arranged neurons that lack the normal laminar organization of neocortex.
In addition, some large cells have appearances intermediate between glia and neurons (large vesicular nuclei with nucleoli, resembling neurons, and abundant eosinophilic cytoplasm like gemistocytic astrocytes) and often express intermediate filaments of both neuronal (neurofilament) and glial (GFAP) types.
Consistent with the preservation of the wild-type allele, these cells usually stain for both tuberin and hamartin.
Similar hamartomatous features are present in the subependymal nodules, where the large astrocyte-like cells cluster beneath the ventricular surface. These multiple droplike masses that bulge into the ventricular system gave rise to the term candle-guttering.
In subependymal areas a tumor unique to tuberous sclerosis, .......................... occurs, which is marked by having very large amounts of eosinophilic cytoplasm.
subependymal giant-cell astrocytoma,
What are the clinical features of VHL?
hemangioblastomas and cysts involving the pancreas, liver, and kidneys, and have a propensity to develop renal cell carcinoma and pheochromocytoma.
Hemangioblastomas are most common in the cerebellum and retina
Individuals with VHL are at increased risk for developing................................
RCC and pheochromocytoma
The reason for polycytemia in hemangioblastoma of VHL syndrome is................
Increased expression of HIF (due to reduced degradation) causing increased expression of EPO
What is the genetic basis of VHL?
is a component of a ubiquitin ligase complex that down-regulates hypoxia-induced factor 1 (HIF-1), a transcription factor involved in regulating expression of vascular endothelial growth factor, erythropoietin, and other growth factors.It is the dysregulation of erythropoietin that is responsible for the polycythemia observed in association with hemangioblastomas in about 10% of cases
...................mutations in VHL, but not other types of mutations, are highly likely to be associated with pheochromocytomas.
What is the histological feature of hemangioblastoma?
Highly vascular neoplasms that occur as a mural nodule associated with a large fluid-filled cyst.
Mixture of capillary-size or somewhat larger thin-walled vessels with intervening stromal cells that are neoplastic (has the second hit loss of VHL)
When both gray and white matter are involved by extensive ischemic damage, large destructive cystic lesions develop throughout the hemispheres; this condition is termed ............................
multicystic encephalopathy (mainly in mature)
What are the histology of PVL?
chalky yellow plaques consisting of discrete regions of white matter necrosis and calcification
What are the two major patterns of injury in HIE of mature infants?
Two main patterns of brain damage have been defined by MRI and neuropathological studies: moderate ischemia causes mainly cortical damage in the border zones between major arterial territories (a parasagittal band of cortex that arches from the frontal to the occipital pole); severe ischemia damages the deep nuclei and the brainstem
What is the difference in brain ischemic injury between adults and mature infants?
unlike adults, the basal ganglia, thalamus and brainstem of mature infants are affected more severely than the cerebral cortex and hippocampus
In perinatal ischemic lesions of the cerebral cortex, .......................... bear the brunt of injury and result in thinned-out, gliotic gyri (ulegyria)
the depths of sulci
What is ulegyria?
In perinatal ischemic lesions of the cerebral cortex, the depths of sulci bear the brunt of injury and result in thinned-out, gliotic gyri (ulegyria)
what is the cause of status marmoratus?
The basal ganglia and thalamus may also suffer ischemic injury, with patchy neuronal loss and reactive gliosis. Later, aberrant and irregular myelinization gives rise to a marble-like appearance of the deep nuclei
The mc place for kernicterus in the brain is...............
which manifestation is seen in status marmoratus?
Because the lesions are in the caudate, putamen, and thalamus, choreoathetosis and related movement disorders are common clinical sequelae.
What are porencephaly, schizencephaly, hydranencephaly?
All ischemic lesions and disruptions
Porencephaly -->fluid-filled cavity in the fetal or neonatal brain
Schizencephaly---> “congenital clefts in the cerebral mantle”, extending from the pial surface to the ventricles/ associated with polymicrogyria
hydranencephaly--> the cerebral hemispheres are replaced by a thin-walled, fluid-filled cyst (BS normal because ischemia is in the carotid artery)
Lesion of the ...... lobe in TBI may be clinically silent
Which location is most likely to be injured in fall when the person is awake?
Which location is most likely to be injured in fall when the person loss consciousness?
What are the symptoms of skull base fracture?
lower cranial nerves or the cervicomedullary region, and the presence of orbital or mastoid hematomas distant from the point of impact, raise the suspicion of a basal skull fracture, which typically follows impact to the occiput or sides of the head.
CSF discharge from the nose or ear and infection (meningitis)
fractures that cross sutures are termed ...............
True or false: With multiple points of impact or repeated blows to the head, the fracture lines of subsequent injuries do not extend across fracture lines of prior injury.
What is concussion?
Clinical syndrome of altered consciousness secondary to head injury typically brought about by a change in the momentum of the head (when a moving head is suddenly arrested by impact on a rigid surface).
Instantaneous onset of transient neurologic dysfunction, including loss of consciousness, temporary respiratory arrest, and loss of reflexes.
Although neurologic recovery is complete, amnesia for the event persists.
Dysregulation of the reticular activating system in the brainstem.
What are the two results of direct parenchymal injury to the brain?
Contusion and laceration
Which location is most susceptible to direct parenchymal injury?
crests of gyri
Where are the mc locations for brain contusion?
The most common locations for contusions correspond to the most frequent sites of direct impact and to regions of the brain that overlie a rough and irregular inner skull surface, such as the frontal lobes along the orbital ridges and the temporal lobes
Contusions are less frequent over the occipital lobes, brainstem, and cerebellum unless these sites .............................
are adjacent to a skull fracture (fracture contusions).
What are coup and countercoup injuries?
A person who suffers a blow to the head may develop a contusion at the point of contact (a coup injury) or a contusion on the brain surface diametrically opposite to it (a contrecoup injury).
If the head is immobile at the time of trauma, only a coup injury is found. If the head is mobile, both coup and contrecoup lesions may be found.
Whereas the coup lesion is caused by the contact between brain and skull at the site of impact, the contrecoup contusion is thought to develop when the brain strikes the opposite inner surface of the skull after sudden deceleration.
Sudden impacts that result in violent posterior or lateral hyperextension of the neck (as occurs when a pedestrian is struck from the rear by a vehicle) may ...................
avulse the pons from the medulla or the medulla from the cervical cord, causing instantaneous death.
What are the histology of contusions?
wedge shaped, with the broad base lying along the surface
In the earliest stages, there is edema and hemorrhage, which is often pericapillary.
During the next few hours, the extravasation of blood extends throughout the involved tissue, across the width of the cerebral cortex, and into the white matter and subarachnoid space.
Morphologic evidence of neuronal injury (pyknosis of the nucleus, eosinophilia of the cytoplasm, and disintegration of the cell) takes about 24 hours to appear, although functional deficits may occur earlier.
Neutrophil first, MQ next
What is the pathological presentation of Old traumatic lesions on the surface of the brain?
They are depressed, retracted, yellowish brown patches involving the crests of gyri most commonly located at the sites of contrecoup lesions (inferior frontal cortex, temporal and occipital poles). The term plaque jaune is applied to these lesions.
They can become epileptic foci.
Old contusion sites are important because .........................
They can become epileptic foci
More extensive hemorrhagic regions of brain trauma give rise to larger ............., which can resemble remote infarcts. In sites of old contusions, ...................... predominate
Cavitated lesion/ gliosis and residual hemosiderin-laden macrophages
The most common place for TBI is..................
Where is the location for DAI?
deep white matter regions (the corpus callosum, paraventricular, and hippocampal areas in the supratentorial compartment), cerebral peduncles, brachium conjunctivum, superior colliculi, and deep reticular formation in the brainstem
What is the major force that can cause DAI?
Angular acceleration alone, in the absence of impact,
What is the hallmark clinical feature of DAI?
Deep coma in the absence of elevated ICP
What is the pathogenesis of DAI?
The mechanical forces associated with trauma are believed to damage the integrity of the axon at the node of Ranvier, with subsequent alterations in axoplasmic flow.
What are the morphological feature of DAI?
Diffuse axonal injury is characterized by the widespread but often asymmetric axonal swellings that appear within hours of the injury and may persist for much longer. These are best demonstrated with silver impregnation techniques or with immunoperoxidase stains for axonally transported proteins, including amyloid precursor protein and α-synuclein.
Later, there are increased numbers of microglia in related areas of the cerebral cortex and, subsequently, degeneration of the involved fiber tracts.
Which vascular brain injuries occur mainly in the setting of surface damage to the brain (contusion and laceration)?
What are the features of EDH?
Normally the dura is fused with the periosteum on the internal surface of the skull.
Dural arteries, most importantly the middle meningeal artery, are vulnerable to injury, particularly with temporal skull fractures in which the fracture lines cross the course of the vessel.
In children, in whom the skull is deformable, a temporary displacement of the skull bones leading to laceration of a vessel can occur in the absence of a skull fracture.
Once a vessel has been torn, the extravasation of blood under arterial pressure can cause the dura to separate from the inner surface of the skull
The expanding hematoma has a smooth inner contour that compresses the brain surface.
Have lucid interval
Does not cross the sutures
What are the features of SDH?
Bridging veins travel from the convexities of the cerebral hemispheres through the subarachnoid space and the subdural space to empty into the superior sagittal sinus.
Brain, floating freely bathed in CSF, can move within the skull, but the venous sinuses are fixed. The displacement of the brain that occurs in trauma can tear the veins at the point where they penetrate the dura.
In elderly individuals with brain atrophy, the bridging veins are stretched out and the brain has additional space for movement, hence the increased rate of subdural hematomas in these patients, even after relatively minor head trauma.
Infants are also particularly susceptible to subdural hematomas because their bridging veins are thin-walled.
Infants are also particularly susceptible to subdural hematomas because ......................................
their bridging veins are thin-walled.
Children are susceptible to EDH even...............................
in the absence of fracture
What are the histological features of acute SDH?
collection of freshly clotted blood along the brain surface, without extension into the depths of sulci.
The underlying brain is flattened and the subarachnoid space is often clear.
Typically, venous bleeding is self-limited; breakdown and organization of the hematoma take place over time
What are the stages in organization of SDH?
Lysis of the clot (about 1 week)
Growth of fibroblasts from the dural surface into the hematoma (2 weeks)
Early development of hyalinized connective tissue (1 to 3 months)
The organized hematoma is firmly attached by fibrous tissue only to the inner surface of the dura and is not adherent to the underlying smooth arachnoid, which does not contribute to its formation.
The lesion can eventually retract as the granulation tissue matures, until there is only a thin layer of reactive connective tissue (“subdural membranes”).
Which layer contribute to SDH organization?
What is chronic SDH?
common finding in subdural hematomas, however, is the occurrence of multiple episodes of repeat bleeding (chronic subdural hematomas), presumably from the thin-walled vessels of the granulation tissue. The risk of repeat bleeding is greatest in the first few months after the initial hemorrhage.
What are the clinical features of SDH?
Nonlocalized sign in most cases
Manifest within 48 hours of injury.
Most common over the lateral aspects of the cerebral hemispheres and are bilateral in about 10% of cases
What are the post TBI sequels?
Post-traumatic hydrocephalus is largely due to obstruction of CSF resorption from hemorrhage into the subarachnoid spaces.
Post-traumatic dementia and the punch-drunk syndrome (dementia pugilistica) follow repeated head trauma during a protracted period; the neuropathologic findings include hydrocephalus, thinning of the corpus callosum, diffuse axonal injury, neurofibrillary tangles (mainly in the medial temporal areas), and diffuse amyloid β (Aβ)-positive plaques.
Other important sequelae of brain trauma include post-traumatic epilepsy, tumors (meningioma), infectious diseases, and psychiatric disorders
Which tumor can occur as a sequel of TBI?
What are the pathologic features of post-traumatic dementia?
hydrocephalus, thinning of the corpus callosum, diffuse axonal injury, neurofibrillary tangles (mainly in the medial temporal areas), and diffuse amyloid β (Aβ)-positive plaques
What is the major reason of neurological symptoms in TCI?
White matter Long tract damage
How does location affect symptoms in TCI?
thoracic vertebrae or below can lead to paraplegia; cervical lesions result in quadriplegia; those above C4 can, in addition, lead to respiratory compromise from paralysis of the diaphragm