The central nervous system ii

The The Central Central Nervous Nervous SystemSystem

Pathology of the Central

Nervous System

Pathology of the Central

Nervous System

Cerebrovascular Diseases




• Cerebrovascular disease is the third leading cause of death (after heart disease and cancer) in the United States

• The term cerebrovascular disease denotes any abnormality of the brain caused by a pathologic process of blood vessels

• Cerebrovascular disease is the third leading cause of death (after heart disease and cancer) in the United States

• The term cerebrovascular disease denotes any abnormality of the brain caused by a pathologic process of blood vessels



• Cerebrovascular diseases include three major categories:

• Thrombosis

• Embolism

• Hemorrhage

• “Stroke” is the clinical designation that applies to all these conditions, particularly when symptoms begin acutely

• Cerebrovascular diseases include three major categories:

• Thrombosis

• Embolism

• Hemorrhage

• “Stroke” is the clinical designation that applies to all these conditions, particularly when symptoms begin acutely



• Cerebrovascular diseases may be considered as two processes:

• Hypoxia, ischemia, and infarction resulting from impairment of blood supply and oxygenation of the CNS tissue

• Hemorrhage resulting from rupture of CNS vessels

• Cerebrovascular diseases may be considered as two processes:

• Hypoxia, ischemia, and infarction resulting from impairment of blood supply and oxygenation of the CNS tissue

• Hemorrhage resulting from rupture of CNS vessels



• The most common cerebrovascular disorders are thrombosis secondary to atherosclerosis, embolism, hypertensive intraparenchymal hemorrhage, and ruptured aneurysm

• The most common cerebrovascular disorders are thrombosis secondary to atherosclerosis, embolism, hypertensive intraparenchymal hemorrhage, and ruptured aneurysm

Hypoxia, Ischemia, and

Infarction

Hypoxia, Ischemia, and

Infarction

Hypoxia, Ischemia, and Infarction


• The brain is a highly aerobic tissue, with oxygen rather than metabolic substrate serving as the limiting substance

• The brain may be deprived of oxygen by any of several mechanisms:

• Functional hypoxia in a setting of a low partial pressure of oxygen (pO2), impaired oxygen-carrying capacity of the blood, or inhibition of oxygen use by tissue

• Ischemia, either transient or permanent, after interruption of the normal circulatory flow

• Cessation of blood flow can result from a reduction in perfusion pressure, as in hypotension, or secondary to small- or large-vessel obstruction, or both

• The brain is a highly aerobic tissue, with oxygen rather than metabolic substrate serving as the limiting substance

• The brain may be deprived of oxygen by any of several mechanisms:

• Functional hypoxia in a setting of a low partial pressure of oxygen (pO2), impaired oxygen-carrying capacity of the blood, or inhibition of oxygen use by tissue

• Ischemia, either transient or permanent, after interruption of the normal circulatory flow

• Cessation of blood flow can result from a reduction in perfusion pressure, as in hypotension, or secondary to small- or large-vessel obstruction, or both



• Two principal types of acute ischemic injury are recognized:

• Global cerebral ischemia (ischemic/hypoxic encephalopathy) occurs when there is a generalized reduction of cerebral perfusion, such as in cardiac arrest, shock, and severe hypotension

• Focal cerebral ischemia follows reduction or cessation of blood flow to a localized area of the brain due to large-vessel disease (such as embolic or thrombotic arterial occlusion, often in a setting of atherosclerosis) or to small-vessel disease (such as vasculitis or occlusion secondary to arteriosclerotic lesions seen in hypertension

• Two principal types of acute ischemic injury are recognized:

• Global cerebral ischemia (ischemic/hypoxic encephalopathy) occurs when there is a generalized reduction of cerebral perfusion, such as in cardiac arrest, shock, and severe hypotension

• Focal cerebral ischemia follows reduction or cessation of blood flow to a localized area of the brain due to large-vessel disease (such as embolic or thrombotic arterial occlusion, often in a setting of atherosclerosis) or to small-vessel disease (such as vasculitis or occlusion secondary to arteriosclerotic lesions seen in hypertension



• Hypotension, Hypoperfusion, and Low-Flow States (Global Cerebral Ischemia)

• The clinical outcome of a severe hypotensive episode that produces global cerebral ischemia (diffuse hypoxic/ischemic encephalopathy) varies with the severity of the insult

• When patients with this pervasive form of injury are maintained on mechanical ventilation, the brain gradually undergoes an autolytic process, leading to soft disintegrated tissue that does not fix well in formalin and stains poorly with dyes -- so-called “respirator brain”


• The clinical outcome of a severe hypotensive episode that produces global cerebral ischemia (diffuse hypoxic/ischemic encephalopathy) varies with the severity of the insult

• When patients with this pervasive form of injury are maintained on mechanical ventilation, the brain gradually undergoes an autolytic process, leading to soft disintegrated tissue that does not fix well in formalin and stains poorly with dyes -- so-called “respirator brain”




• In the setting of global ischemia, the brain is swollen, the gyri are widened, and the sulci are narrowed

• Early changes, occurring 12 to 24 hours after the insult, include acute neuronal cell change (red neurons)

• Pyramidal cells of the Sommer sector (CA1) of the hippocampus, Purkinje cells of the cerebellum, and pyramidal neurons in the neocortex are the most susceptible to global ischemia of short duration


• In the setting of global ischemia, the brain is swollen, the gyri are widened, and the sulci are narrowed

• Early changes, occurring 12 to 24 hours after the insult, include acute neuronal cell change (red neurons)

• Pyramidal cells of the Sommer sector (CA1) of the hippocampus, Purkinje cells of the cerebellum, and pyramidal neurons in the neocortex are the most susceptible to global ischemia of short duration

MorphologyMorphology




• Subacute changes, occurring at 24 hours to 2 weeks, include necrosis of tissue, influx of macrophages, vascular proliferation, and reactive gliosis

• Repair, seen after approximately 2 weeks, is characterized by gliosis

• In the cerebral cortex, the neuronal loss and gliosis produce an uneven destruction of the neocortex, with preservation of some layers and involvement of others, a pattern termed pseudolaminar necrosis


• Subacute changes, occurring at 24 hours to 2 weeks, include necrosis of tissue, influx of macrophages, vascular proliferation, and reactive gliosis

• Repair, seen after approximately 2 weeks, is characterized by gliosis

• In the cerebral cortex, the neuronal loss and gliosis produce an uneven destruction of the neocortex, with preservation of some layers and involvement of others, a pattern termed pseudolaminar necrosis


Cerebral infarction. A, At low magnification, it is possible to see the demarcated areas of an acute infarction. In the

underlying white matter, the areas of infarction are well

shown by the myelin stain. B, Acute ischemic injury causes

diffuse eosinophilia of neurons, which are beginning to shrink. C, infiltration of a

cerebral infarct by neutrophils begins at the edges of the

lesion where vascular supply has remained intact. D, After

about 10 days, an area of infarction is characterized by the presence of macrophages

and surrounding reactive gliosis. E, Remote small

intracortical infarcts are seen as areas of tissue loss with a

small amount of residual gliosis.

Cerebral infarction. A, At low magnification, it is possible to see the demarcated areas of an acute infarction. In the

underlying white matter, the areas of infarction are well

shown by the myelin stain. B, Acute ischemic injury causes

diffuse eosinophilia of neurons, which are beginning to shrink. C, infiltration of a

cerebral infarct by neutrophils begins at the edges of the

lesion where vascular supply has remained intact. D, After

about 10 days, an area of infarction is characterized by the presence of macrophages

and surrounding reactive gliosis. E, Remote small

intracortical infarcts are seen as areas of tissue loss with a

small amount of residual gliosis.




• Border zone (“watershed”) infarcts are wedge-shaped areas of infarction that occur in the regions of the brain and spinal cord that lie at the most distal fields of arterial irrigation

• Border zone infarcts are usually seen after hypotensive episodes


• Border zone (“watershed”) infarcts are wedge-shaped areas of infarction that occur in the regions of the brain and spinal cord that lie at the most distal fields of arterial irrigation

• Border zone infarcts are usually seen after hypotensive episodes




• Infarction from Obstruction of Local Blood Supply (Focal Cerebral Ischemia)

• Cerebral arterial occlusion may lead to focal ischemia and ultimately, if it is sustained, to infarction of a specific region of CNS tissue within the territory of distribution of the compromised vessel

• The majority or thrombotic occlusions are due to atherosclerosis

• The most common sites of primary thrombosis causing cerebral infarction are the carotid bifurcation, the origin of the middle cerebral artery, and either end of the basilar artery


• Cerebral arterial occlusion may lead to focal ischemia and ultimately, if it is sustained, to infarction of a specific region of CNS tissue within the territory of distribution of the compromised vessel


• The most common sites of primary thrombosis causing cerebral infarction are the carotid bifurcation, the origin of the middle cerebral artery, and either end of the basilar artery





• Occlusive cerebrovascular disease is frequently associated with systemic diseases such as hypertension and diabetes



• Occlusive cerebrovascular disease is frequently associated with systemic diseases such as hypertension and diabetes




• Arteritis of small and large vessels was found most commonly in association with syphilis and tuberculosis; infectious vasculitis is now more commonly seen in the setting of immunosuppression and opportunistic infection (such as toxoplasmosis, aspergillosis, and CMV encephalitis)

• Polyarteritis nodosa and other collagen-vascular diseases may involve cerebral vessels and cause single or multiple infarcts throughout the brain


• Arteritis of small and large vessels was found most commonly in association with syphilis and tuberculosis; infectious vasculitis is now more commonly seen in the setting of immunosuppression and opportunistic infection (such as toxoplasmosis, aspergillosis, and CMV encephalitis)

• Polyarteritis nodosa and other collagen-vascular diseases may involve cerebral vessels and cause single or multiple infarcts throughout the brain




• Primary angiitis of the central nervous system is an inflammatory disorder that involves multiple small multinucleated giant cells, and destruction of the vessel wall

• Other conditions that may cause thrombosis and infarction (and intracranial hemorrhage) include hematologic disease with hypercoagulable states, dissecting aneurysm of extracranial arteries in the neck vessels supplying the brain, and drug abuse (amphetamines, heroin, cocaine)


• Primary angiitis of the central nervous system is an inflammatory disorder that involves multiple small multinucleated giant cells, and destruction of the vessel wall

• Other conditions that may cause thrombosis and infarction (and intracranial hemorrhage) include hematologic disease with hypercoagulable states, dissecting aneurysm of extracranial arteries in the neck vessels supplying the brain, and drug abuse (amphetamines, heroin, cocaine)




• Embolism to the brain occurs from a wise range of origins

• Cardiac mural thrombi are among the most common sources; myocardial infarct, valvular disease, and atrial fibrillation are important predisposing factors

• Next in importance are thromboemboli arising in arteries, most often originating over atheromatous plaques within the carotid arteries

• The territory of distribution of the middle cerebral artery -- the direct extension of the internal carotid artery -- is most frequently affected by embolic infarction; the incidence is about equal in the two hemispheres


• Embolism to the brain occurs from a wise range of origins

• Cardiac mural thrombi are among the most common sources; myocardial infarct, valvular disease, and atrial fibrillation are important predisposing factors

• Next in importance are thromboemboli arising in arteries, most often originating over atheromatous plaques within the carotid arteries

• The territory of distribution of the middle cerebral artery -- the direct extension of the internal carotid artery -- is most frequently affected by embolic infarction; the incidence is about equal in the two hemispheres




• Infarcts are subdivided into two broad groups based on their macroscopic and corresponding radiologic appearance

• Hemorrhagic (red) infarction is characterized by petechial hemorrhages, and is typically associated with embolic events

• Nonhemorrhagic (pale, bland, anemic) infarcts are usually associated with thrombosis

• The clinical management of patients with these two types of infarcts differes greatly: for obvious reasons, anticoagulation may be used in cases of thrombosis but is contraindicated in hemorrhagic infarcts


• Infarcts are subdivided into two broad groups based on their macroscopic and corresponding radiologic appearance

• Hemorrhagic (red) infarction is characterized by petechial hemorrhages, and is typically associated with embolic events

• Nonhemorrhagic (pale, bland, anemic) infarcts are usually associated with thrombosis

• The clinical management of patients with these two types of infarcts differes greatly: for obvious reasons, anticoagulation may be used in cases of thrombosis but is contraindicated in hemorrhagic infarcts

A, Sections of the brain showing a large,

discolored, focally hemorrhagic region in the left middle cerebral artery distribution (hemorrhagic,

or red, infarction)

A, Sections of the brain showing a large,

discolored, focally hemorrhagic region in the left middle cerebral artery distribution (hemorrhagic,

or red, infarction)

C, A bland infarct with punctate hemorrhages, consistent with ischemia-reperfusion injury, is present in the temporal lobe.

C, A bland infarct with punctate hemorrhages, consistent with ischemia-reperfusion injury, is present in the temporal lobe.




• Venous infarcts are often hemorrhagic, and may occur after thrombotic occlusion of the superior sagittal sinus or other sinuses or occlusion of the deep cerebral veins

• Carcinoma, localized infections, and other conditions leading to a hypercoagulable state place patients at risk for venous thrombosis


• Venous infarcts are often hemorrhagic, and may occur after thrombotic occlusion of the superior sagittal sinus or other sinuses or occlusion of the deep cerebral veins

• Carcinoma, localized infections, and other conditions leading to a hypercoagulable state place patients at risk for venous thrombosis





• Incomplete infarction occurs in focal cerebral ischemia when there is selective necrosis of neurons with relative preservation of glia and supporting tissues

• Spinal cord infarction may be seen in the setting of hypoperfusion or as a consequence of interruption of the feeding tributaries derived from the aorta


• Incomplete infarction occurs in focal cerebral ischemia when there is selective necrosis of neurons with relative preservation of glia and supporting tissues

• Spinal cord infarction may be seen in the setting of hypoperfusion or as a consequence of interruption of the feeding tributaries derived from the aorta





• Clinical Features

• A sensory deficit, blindness, aphasia, or some other deficit, evolves over time, and the outcome either is fatal or is characterized by some degree of slow improvement during a period of months



• A sensory deficit, blindness, aphasia, or some other deficit, evolves over time, and the outcome either is fatal or is characterized by some degree of slow improvement during a period of months

Intracranial HemorrhageIntracranial Hemorrhage


• Hemorrhages within the brain parenchyma and subarachnoid space are often a manifestation of underlying cerebrovascular disease, although trauma may also cause hemorrhage in these sites

• Hemorrhages within the brain parenchyma and subarachnoid space are often a manifestation of underlying cerebrovascular disease, although trauma may also cause hemorrhage in these sites


• Intracerebral (Intraparenchymal) Hemorrhage

• Spontaneous (nontraumatic) intraparenchymal hemorrhages occur most commonly in middle to late adult life, with a peak incidence of about age 60 years

• Hypertension is the most common underlying cause of primary brain parenchymal hemorrhage


• Spontaneous (nontraumatic) intraparenchymal hemorrhages occur most commonly in middle to late adult life, with a peak incidence of about age 60 years

• Hypertension is the most common underlying cause of primary brain parenchymal hemorrhage



• Hypertension causes a number of abnormalities in vessel walls, including accelerated atherosclerosis in larger arteries; hyaline arteriolosclerosis in smaller vessels; and, in severe cases, proliferative changes and frank necrosis of arterioles

• Chronic hypertension is associated with the development of minute aneurysms, termed Charcot-Bouchard microaneurysms, which may be the site of rupture


• Hypertension causes a number of abnormalities in vessel walls, including accelerated atherosclerosis in larger arteries; hyaline arteriolosclerosis in smaller vessels; and, in severe cases, proliferative changes and frank necrosis of arterioles

• Chronic hypertension is associated with the development of minute aneurysms, termed Charcot-Bouchard microaneurysms, which may be the site of rupture



• Charcot-Bouchard aneurysms occur in vessels that are less than 300 μm in diameter, most commonly within the basal ganglia


• Charcot-Bouchard aneurysms occur in vessels that are less than 300 μm in diameter, most commonly within the basal ganglia


• Subarachnoid Hemorrhage and Ruptured Saccular Aneurysms

• The most frequent cause of clinically significant subarachnoid hemorrhage is rupture of saccular (berry) aneurysm

• It may also be the result from extension of a traumatic hematoma, rupture of a hypertensive intracerebral hemorrhage into the ventricular system, vascular malformation, hematologic disturbances, and tumors


• The most frequent cause of clinically significant subarachnoid hemorrhage is rupture of saccular (berry) aneurysm

• It may also be the result from extension of a traumatic hematoma, rupture of a hypertensive intracerebral hemorrhage into the ventricular system, vascular malformation, hematologic disturbances, and tumors



• Saccular (berry) aneurysms (congenital aneurysm) is the most common type of intracrtanial aneurysm


• Saccular (berry) aneurysms (congenital aneurysm) is the most common type of intracrtanial aneurysm

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



• Pathogenesis of Saccular Aneurysms

• There is an increased risk of occurrence among patients with certain heritable disorders (such as autosomal-dominant polycystic kidney disease, vascular type Ehlers-Danlos syndrome [type IV], neurofibromatosis type 1, and Marfan syndrome)

• Cigarette smoking and hypertension are predisposing factors

• The aneurysms are not present at birth but develop over time owing to the underlying defect in the media of the vessel


• Pathogenesis of Saccular Aneurysms

• There is an increased risk of occurrence among patients with certain heritable disorders (such as autosomal-dominant polycystic kidney disease, vascular type Ehlers-Danlos syndrome [type IV], neurofibromatosis type 1, and Marfan syndrome)

• Cigarette smoking and hypertension are predisposing factors

• The aneurysms are not present at birth but develop over time owing to the underlying defect in the media of the vessel




• Rupture of an aneurysm with clinically significant subarachnoid hemorrhage is most frequent in the fifth decade and is slightly more frequent in females

• Excrutiating headache

• In the healing phase of subarachnoid hemorrage, meningeal fibrosis and scarring occur, sometimes leading to obstruction of CSF flow as well as interruption of the normal pathways of CSF resorption



• Rupture of an aneurysm with clinically significant subarachnoid hemorrhage is most frequent in the fifth decade and is slightly more frequent in females

• Excrutiating headache

• In the healing phase of subarachnoid hemorrage, meningeal fibrosis and scarring occur, sometimes leading to obstruction of CSF flow as well as interruption of the normal pathways of CSF resorption


• Vascular Malformations

• Vascular malformations of the brain are classified into four principal groups:

• Arteriovenous malformations

• Cavernous angiomas

• Capillary telangiectasias

• Venous angiomas


• Vascular malformations of the brain are classified into four principal groups:

• Arteriovenous malformations

• Cavernous angiomas

• Capillary telangiectasias

• Venous angiomas



• Arteriovenous malformations involve vessels in the subarachnoid space extending into brain parenchyma or may occur exclusively within the brain

• In macroscopic appearance, they resemble a tangled network of wormlike vascular channels and have a prominent, pulsatile arteriovenous shunt with high blood flow through the malformation


• Arteriovenous malformations involve vessels in the subarachnoid space extending into brain parenchyma or may occur exclusively within the brain

• In macroscopic appearance, they resemble a tangled network of wormlike vascular channels and have a prominent, pulsatile arteriovenous shunt with high blood flow through the malformation




• Cavernous hemangiomas

• Occur most often in the cerebellum, pons, and subcortical regions, in decreasing order of frequency, and have a low flow without arteriovenous shunting

• Cavernous telangiectasias are microscopic foci of dilated, thin-walled vascular channels separated by relatively normal brain parenchyma and occuring most frequently in the pons

• Venous angiomas (varices) consist of aggregates of ectatic venous channels


• Cavernous hemangiomas

• Occur most often in the cerebellum, pons, and subcortical regions, in decreasing order of frequency, and have a low flow without arteriovenous shunting

• Cavernous telangiectasias are microscopic foci of dilated, thin-walled vascular channels separated by relatively normal brain parenchyma and occuring most frequently in the pons

• Venous angiomas (varices) consist of aggregates of ectatic venous channels





• Arteriovenous malformations are the most common type of clinically significant vascular malformation

• Males are affected twice as frequently as females

• Patients present with a seizure disorder, an intracerebral hemorrhage, or a subarachnoid hemorrhage

• The most common site is the territory of the middle cerebral artery, particularly its posterior branches, but arteriovenous malformations may occur anywhere along the midbrain, cerebellum, or spinal cord



• Arteriovenous malformations are the most common type of clinically significant vascular malformation

• Males are affected twice as frequently as females

• Patients present with a seizure disorder, an intracerebral hemorrhage, or a subarachnoid hemorrhage

• The most common site is the territory of the middle cerebral artery, particularly its posterior branches, but arteriovenous malformations may occur anywhere along the midbrain, cerebellum, or spinal cord

Hypertensive Cerebrovascu

lar Disease

Hypertensive Cerebrovascu

lar Disease

Hypertensive Cerebrovascular Disease


• The most important effects of hypertension on the brain include massive hypertensive intracerebral hemorrhage, lacunar infarcts and slit hemorrhages, and hypertensive encephalopathy

• Atherosclerosis and diabetes are frequently associated diseases

• The most important effects of hypertension on the brain include massive hypertensive intracerebral hemorrhage, lacunar infarcts and slit hemorrhages, and hypertensive encephalopathy

• Atherosclerosis and diabetes are frequently associated diseases



• Lacunar Infarcts

• Hypertension affects the deep penetrating arteries and arterioles that supply the basal ganglia and hemispheric white matter as well as the brainstem

• An important clinical and pathologic outcome of CNS arterial lesions is the development of single or multiple, small, cavitary infarcts -- lacunes, or lacunar state (etat lacunaire)

• These are lakelike spaces, less than 15 mm wide, which occur in the lenticular nucleus, thalamus, internal capsule, deep white matter, caudaste nucleus, and pons

• Lacunar Infarcts

• Hypertension affects the deep penetrating arteries and arterioles that supply the basal ganglia and hemispheric white matter as well as the brainstem

• An important clinical and pathologic outcome of CNS arterial lesions is the development of single or multiple, small, cavitary infarcts -- lacunes, or lacunar state (etat lacunaire)

• These are lakelike spaces, less than 15 mm wide, which occur in the lenticular nucleus, thalamus, internal capsule, deep white matter, caudaste nucleus, and pons

Lacunar infarcts in the caudate and putamen.Lacunar infarcts in the caudate and putamen.



• Slit Hemorrhages

• Hypertension also gives rise to rupture of the small-caliber penetrating vessels and the development of small hemorrhages

• In time, these hemorrhages resorb, leaving behind a slitlike cavity (slit hemorrhage) surrounded by brownish discoloration

• Slit Hemorrhages

• Hypertension also gives rise to rupture of the small-caliber penetrating vessels and the development of small hemorrhages

• In time, these hemorrhages resorb, leaving behind a slitlike cavity (slit hemorrhage) surrounded by brownish discoloration



• Hypertensive Encephalopathy

• Acute hypertensive encephalopathy is a clinicopathologic syndrome arising in a hypertensive patient characterized by diffuse cerebral dysfunction, including headaches, confusion, vomiting, and convulsions, sometimes leading to coma

• Patients who, over the course of many months and years, suffer multiple, bilateral, gray matter (cortex, thalamus, basal ganglia) and white matter (centrum semiovale) infarcts may develop a distinctive clinical syndrome characterized by dementia, gait abnormalities, and pseudobulbar signs, often with superimposed focal neurologic deficits

• Such syndrome is discussed in the next slide


• Acute hypertensive encephalopathy is a clinicopathologic syndrome arising in a hypertensive patient characterized by diffuse cerebral dysfunction, including headaches, confusion, vomiting, and convulsions, sometimes leading to coma

• Patients who, over the course of many months and years, suffer multiple, bilateral, gray matter (cortex, thalamus, basal ganglia) and white matter (centrum semiovale) infarcts may develop a distinctive clinical syndrome characterized by dementia, gait abnormalities, and pseudobulbar signs, often with superimposed focal neurologic deficits

• Such syndrome is discussed in the next slide




• Termed vascular (multi-infarct) dementia, the syndrome is caused by multifocal vascular disease, consisting largely of:

• Cerebral atherosclerosis

• Vessel thrombosis or embolization from carotid vessels or from the heart

• Cerebral arteriolar sclerosis from chronic hypertension

• When the pattern of injury preferentially involves large areas of the subcortical white matter with myelin and axon loss, the disorder is called Binswanger disease; this distribution of white matter injury needs to be distinguished clinically and radiologically from other diseases that affect the hemispheral white matter


• Termed vascular (multi-infarct) dementia, the syndrome is caused by multifocal vascular disease, consisting largely of:

• Cerebral atherosclerosis

• Vessel thrombosis or embolization from carotid vessels or from the heart

• Cerebral arteriolar sclerosis from chronic hypertension

• When the pattern of injury preferentially involves large areas of the subcortical white matter with myelin and axon loss, the disorder is called Binswanger disease; this distribution of white matter injury needs to be distinguished clinically and radiologically from other diseases that affect the hemispheral white matter

Demyelinating Diseases




• Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to myelin, with relative preservation of axons

• Other disease processes can involve myelin:

• In progressive multifocal leukoencephalopathy, JC virus infection of oligodendrocytes results in loss of myelin

• There are inherited disorders that affect myelin synthesis and turnover: leukodystrophies

• Demyelinating diseases of the CNS are acquired conditions characterized by preferential damage to myelin, with relative preservation of axons

• Other disease processes can involve myelin:

• In progressive multifocal leukoencephalopathy, JC virus infection of oligodendrocytes results in loss of myelin

• There are inherited disorders that affect myelin synthesis and turnover: leukodystrophies

Multiple SclerosisMultiple Sclerosis

Multiple SclerosisMultiple Sclerosis• Multiple sclerosis (MS) is an autoimmune

demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space

• The disease becomes clinically apparent at any age

• Women are affected twice as often as are men

• In most patients, the clinical course of the illness evolves as relapsing and remitting episodes of neurologic deficit during variable intervals of time (weeks to months to years), followed by gradual, partial recovery of neurologic function

• Multiple sclerosis (MS) is an autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits, separated in time, attributable to white matter lesions that are separated in space

• The disease becomes clinically apparent at any age

• Women are affected twice as often as are men

• In most patients, the clinical course of the illness evolves as relapsing and remitting episodes of neurologic deficit during variable intervals of time (weeks to months to years), followed by gradual, partial recovery of neurologic function

Multiple SclerosisMultiple Sclerosis• Pathogenesis

• The lesions of MS are caused by cellular immune response that is inappropriately directed against the components of the myelin sheath

• The risk of developing MS is 15-fold higher when the disease is present in a first-degree relative and even an order of magnitude greater for monozygotic twins

• Pathogenesis

• The lesions of MS are caused by cellular immune response that is inappropriately directed against the components of the myelin sheath

• The risk of developing MS is 15-fold higher when the disease is present in a first-degree relative and even an order of magnitude greater for monozygotic twins

Multiple SclerosisMultiple Sclerosis• Pathogenesis

• The available evidence indicates that the disease is initiated by CD4+ TH1 T cells that react against self myelin antigens and secrete cytokines, such as IFN-γ, that activate macrophages

• Therapies are being developed that modulate or inhibit TH1 responses and block recruitment of T cells into the brain

• Pathogenesis

• The available evidence indicates that the disease is initiated by CD4+ TH1 T cells that react against self myelin antigens and secrete cytokines, such as IFN-γ, that activate macrophages

• Therapies are being developed that modulate or inhibit TH1 responses and block recruitment of T cells into the brain


• Evidence of the disease may be found on the surface of the brainstem (e.g., basis pontis) or along the spinal cord, where myelinated fiber tracts course superficially

• Here lesions appear as multiple, well-circumscribed, somewhat depressed, glassy, gray-tan, irregularly shapes plaques, both on external examination and on section

• Evidence of the disease may be found on the surface of the brainstem (e.g., basis pontis) or along the spinal cord, where myelinated fiber tracts course superficially

• Here lesions appear as multiple, well-circumscribed, somewhat depressed, glassy, gray-tan, irregularly shapes plaques, both on external examination and on section


Multiple sclerosis. Section of fresh brain showing brown plaque

around occipital horn of the lateral ventricle.

Multiple sclerosis. Section of fresh brain showing brown plaque

around occipital horn of the lateral ventricle.


• In the fresh state, these plaques have firmer consistency than the surrounding white matter (sclerosis)

• In the fresh state, these plaques have firmer consistency than the surrounding white matter (sclerosis)



• Plaques commonly occur beside the lateral ventricles and may be demonstrated to follow the course of paraventricular veins

• They are also frequent in the optic nerves and chiasm, brain stem ascending and descending fiber tracts, cerebellum, and spinal cord

• Plaques commonly occur beside the lateral ventricles and may be demonstrated to follow the course of paraventricular veins

• They are also frequent in the optic nerves and chiasm, brain stem ascending and descending fiber tracts, cerebellum, and spinal cord



• The lesions have sharply defined borders at the microscopic level

• The lesions have sharply defined borders at the microscopic level


Multiple sclerosis. A, Unstained

regions of demyelination (MS plaques) around

the fourth ventricle (Luxol fast blue PAS stain for myelin). B, Myelin-stained section shows the sharp edge of a demyelinated

plaque and perivascular

lymphocytic cuffs. C, The same lesion stained for axons

shows relative preservation.

Multiple sclerosis. A, Unstained

regions of demyelination (MS plaques) around

the fourth ventricle (Luxol fast blue PAS stain for myelin). B, Myelin-stained section shows the sharp edge of a demyelinated

plaque and perivascular

lymphocytic cuffs. C, The same lesion stained for axons

shows relative preservation.


• In an active plaque, there is evidence of ongoing myelin breakdown with abundant macrophages containing lipid-rich, PAS-positive debris

• In an active plaque, there is evidence of ongoing myelin breakdown with abundant macrophages containing lipid-rich, PAS-positive debris



• Within the center of an inactive plaque, little to no myelin is found, and there is a reduction in the number of oligodendrocyte nuclei; instead, astrocytic proliferation and gliosis are prominent

• Within the center of an inactive plaque, little to no myelin is found, and there is a reduction in the number of oligodendrocyte nuclei; instead, astrocytic proliferation and gliosis are prominent



• Subclinical forms of the disease exist, and some plaques may be clinically silent even in symptomatic patients

• Subclinical forms of the disease exist, and some plaques may be clinically silent even in symptomatic patients




• Unilateral visual impairment during the course of a few days, due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis) is a frequent initial manifestation of MS


• Unilateral visual impairment during the course of a few days, due to involvement of the optic nerve (optic neuritis, retrobulbar neuritis) is a frequent initial manifestation of MS

Multiple SclerosisMultiple Sclerosis• Clinical Features

• Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus

• Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties with the coluntary control of bladder function


• Involvement of the brainstem produces cranial nerve signs, ataxia, nystagmus, and internuclear ophthalmoplegia from interruption of the fibers of the medial longitudinal fasciculus

• Spinal cord lesions give rise to motor and sensory impairment of trunk and limbs, spasticity, and difficulties with the coluntary control of bladder function



• Examination of the CSF in MS patients shows a mildly elevated protein level, and in one third of cases, there is moderate pleocytosis

• The proportion of gamma globulin is increased, and most MS patients show oligoclonal bands


• Examination of the CSF in MS patients shows a mildly elevated protein level, and in one third of cases, there is moderate pleocytosis

• The proportion of gamma globulin is increased, and most MS patients show oligoclonal bands

Multiple Sclerosis Variants




• Some individuals, especially Asians, develop a demyelinating disease similar to MS with presenting symptoms of bilateral optic neuritis and prominent spinal cord involvement

• This disease is referred to as neuromyelitis optica or Devic disease

• The lesions in Devic disease are considerably more destructive (than MS), and gray matter involvement of the spinal cord can be striking

• Some individuals, especially Asians, develop a demyelinating disease similar to MS with presenting symptoms of bilateral optic neuritis and prominent spinal cord involvement

• This disease is referred to as neuromyelitis optica or Devic disease

• The lesions in Devic disease are considerably more destructive (than MS), and gray matter involvement of the spinal cord can be striking



• Another variant, acute MS (Marburg form), tends to occur in young individuals and is characterized clinically by a fulminant course during a period of several months

• Another variant, acute MS (Marburg form), tends to occur in young individuals and is characterized clinically by a fulminant course during a period of several months

Acute Disseminated

Encephalomyelitis and Acute Necrotizing

Hemorrhagic Encephalomyelitis

Acute Disseminated

Encephalomyelitis and Acute Necrotizing

Hemorrhagic Encephalomyelitis

Acute Disseminated Encephalomyelitis and Acute Necrotizing Hemorrhagic

Encephalomyelitis


Encephalomyelitis

• Acute disseminated encephalomyelitis (ADEM, perivenous encephalomyelitis) is a monophasic demyelinating disease that follows either a viral infection or, rarely, a viral immunization

• Symptoms typically develop a week or two after the antecedent infection and include evidence of diffuse brain involvement with headache, lethargy, and coma rather than focal findings

• Acute disseminated encephalomyelitis (ADEM, perivenous encephalomyelitis) is a monophasic demyelinating disease that follows either a viral infection or, rarely, a viral immunization

• Symptoms typically develop a week or two after the antecedent infection and include evidence of diffuse brain involvement with headache, lethargy, and coma rather than focal findings


Encephalomyelitis


Encephalomyelitis

• Acute necrotizing hemorrhagic encephalomyelitis (ANHE, acute hemorrhagic leukoencephalitis of Weston Hurst) is a fulminant syndrome of CNS demyelination, typically affecting young adults and children

• The illness is almost invariably preceded by a recent episode of upper respiratory infection

• Sometimes it is due to Mycoplasma pneumoniae

• The disease is fatal in many patients, but some have survived with minimal residual symptoms

• Acute necrotizing hemorrhagic encephalomyelitis (ANHE, acute hemorrhagic leukoencephalitis of Weston Hurst) is a fulminant syndrome of CNS demyelination, typically affecting young adults and children

• The illness is almost invariably preceded by a recent episode of upper respiratory infection

• Sometimes it is due to Mycoplasma pneumoniae

• The disease is fatal in many patients, but some have survived with minimal residual symptoms

Other Diseases With Demyelinatio

n

Other Diseases With Demyelinatio

n

Other Diseases With Demyelination


• Central pontine myelinolysis is characterized by loss of myelin in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum but sparing the periventricular and subpial regions

• The condition is believed to be caused by rapid correction of hyponatremia

• Central pontine myelinolysis is characterized by loss of myelin in a roughly symmetric pattern involving the basis pontis and portions of the pontine tegmentum but sparing the periventricular and subpial regions

• The condition is believed to be caused by rapid correction of hyponatremia



• The clinical presentation of central pontine myelinolysis is that of a rapidly evolving quadriplegia

• Radiologic imaging studies localize the lesion to the basis pontis

• It occurs in a variety of clinical settings, including alcoholism, severe electrolyte or osmolar imbalance, and orthotopic liver transplantation

• The clinical presentation of central pontine myelinolysis is that of a rapidly evolving quadriplegia

• Radiologic imaging studies localize the lesion to the basis pontis

• It occurs in a variety of clinical settings, including alcoholism, severe electrolyte or osmolar imbalance, and orthotopic liver transplantation



• Marchiafava-Bignami disease is a rare disorder of myelin characterized by relatively symmetric damage to the myelin of central fibers of the corpus callosum and anterior commissure

• Marchiafava-Bignami disease is a rare disorder of myelin characterized by relatively symmetric damage to the myelin of central fibers of the corpus callosum and anterior commissure

Degenerative Diseases




• These are diseases of gray matter characterized principally by the progressive loss of neurons with associated secondary changes in white matter tracts

• The pattern of neuronal loss is selective, affecting one or more groups of neurons while leaving others intact

• The diseases arise without any clear inciting event in patients without previous neurologic deficits

• These are diseases of gray matter characterized principally by the progressive loss of neurons with associated secondary changes in white matter tracts

• The pattern of neuronal loss is selective, affecting one or more groups of neurons while leaving others intact

• The diseases arise without any clear inciting event in patients without previous neurologic deficits



• Some degenerative diseases have prominent involvement of the cerebral cortex, such as Alzheimer disease; others are more restricted to subcortical areas and may present with movement disorders such as tremors and dyskinesias

• Some degenerative diseases have prominent involvement of the cerebral cortex, such as Alzheimer disease; others are more restricted to subcortical areas and may present with movement disorders such as tremors and dyskinesias



• A common theme among the neurodegenerative disorders is the development of protein aggregates that are resistant to normal cellular mechanisms of degradation through the ubiquitin-proteasome system

• The basis of aggregation varies:

• For example, it may be directly related to an intrinsic feature of a mutated protein (e.g., expanded polyglutamine repeat in Huntington disease), a feature of a peptide derived from a larger precursor protein (e.g., Aβ in Alzheimer disease), or an unexplained alteration of a normal cellular protein (e.g., α-synuclein in sporadic Parkinson disease)

• The aggregated proteins are generally cytotoxic, but the mechanisms by which protein aggregation in linked to cell death may be different in these various diseases

• A common theme among the neurodegenerative disorders is the development of protein aggregates that are resistant to normal cellular mechanisms of degradation through the ubiquitin-proteasome system

• The basis of aggregation varies:

• For example, it may be directly related to an intrinsic feature of a mutated protein (e.g., expanded polyglutamine repeat in Huntington disease), a feature of a peptide derived from a larger precursor protein (e.g., Aβ in Alzheimer disease), or an unexplained alteration of a normal cellular protein (e.g., α-synuclein in sporadic Parkinson disease)

• The aggregated proteins are generally cytotoxic, but the mechanisms by which protein aggregation in linked to cell death may be different in these various diseases


Affecting the Cerebral Cortex


Affecting the Cerebral Cortex

Degenerative Diseases Affecting the Cerebral

Cortex

Degenerative Diseases Affecting the Cerebral

Cortex

• The major cortical degenerative disease is Alzheimer disease, and its principal clinical manifestation is dementia, that is, progressive loss of cognitive function independent of the state of attention

• The major cortical degenerative disease is Alzheimer disease, and its principal clinical manifestation is dementia, that is, progressive loss of cognitive function independent of the state of attention

Alzheimer Disease

Alzheimer Disease

Alzheimer DiseaseAlzheimer Disease• Alzheimer disease (AD) is the most common

cause of dementia in the elderly

• The disease usually becomes clinically apparent as insidious impairment of higher intellectual function, with alterations in mood and behavior

• Later, progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction, and eventually, in 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile

• Alzheimer disease (AD) is the most common cause of dementia in the elderly

• The disease usually becomes clinically apparent as insidious impairment of higher intellectual function, with alterations in mood and behavior

• Later, progressive disorientation, memory loss, and aphasia indicate severe cortical dysfunction, and eventually, in 5 to 10 years, the patient becomes profoundly disabled, mute, and immobile

Alzheimer DiseaseAlzheimer Disease

• Macroscopic examination of the brain shows a variable degree of cortical atrophy with widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal lobes

• Microscopic: neuritic (senile) plaques, neurofibrillary tangles, and amyloid angiopathy

• Macroscopic examination of the brain shows a variable degree of cortical atrophy with widening of the cerebral sulci that is most pronounced in the frontal, temporal, and parietal lobes

• Microscopic: neuritic (senile) plaques, neurofibrillary tangles, and amyloid angiopathy


Alzheimer disease with cortical atrophy most evident on the right,

where meninges have been removed.

Alzheimer disease with cortical atrophy most evident on the right,

where meninges have been removed.


• Neuritic plaques are focal, spherical collections of dilated, tortuous, silver-staining neuritic processes(dystrophic neurities), often around a central amyloid core, which may be surrounded by clear halo

• Neuritic plaques are focal, spherical collections of dilated, tortuous, silver-staining neuritic processes(dystrophic neurities), often around a central amyloid core, which may be surrounded by clear halo


Alzheimer disease. A, Neuritic plaque with a rim of dystrophic neurites surrounding an amyloid core.

Alzheimer disease. A, Neuritic plaque with a rim of dystrophic neurites surrounding an amyloid core.

Alzheimer DiseaseAlzheimer Disease• Plaques can be found in the hippocampus and

amygdala as well as in the neocortex, although there is usually relative sparing of primary motor and sensory cortices

• The dominant component of plaque core is Aβ, a peptide derived through specific processing events from a larger molecule, amyoid precursor protein (APP)

• The two dominant species of Aβ, called Aβ40 and Aβ42, share an N-terminus and differ in length by two amino acids

• Plaques can be found in the hippocampus and amygdala as well as in the neocortex, although there is usually relative sparing of primary motor and sensory cortices

• The dominant component of plaque core is Aβ, a peptide derived through specific processing events from a larger molecule, amyoid precursor protein (APP)

• The two dominant species of Aβ, called Aβ40 and Aβ42, share an N-terminus and differ in length by two amino acids



• Neurofibrillary tangles are bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus

• In pyramidal neurons, they often have an elongated “flame” shape

• In rounder cells, the basket weave of fibers around the nucleus takes on a rounded contour (“globose” tangles)

• Neurofibrillary tangles are bundles of filaments in the cytoplasm of the neurons that displace or encircle the nucleus

• In pyramidal neurons, they often have an elongated “flame” shape

• In rounder cells, the basket weave of fibers around the nucleus takes on a rounded contour (“globose” tangles)


Alzheimer Disease. B, Congo red stain of the cerebral cortex showing amyloid deposition in the blood vessels and

the amyloid core of the neuritic plaque (arrow)

Alzheimer Disease. B, Congo red stain of the cerebral cortex showing amyloid deposition in the blood vessels and

the amyloid core of the neuritic plaque (arrow)

Alzheimer Disease. C, Neurofibrillary tangles

(arrowheads) are present within the neurons.

Alzheimer Disease. C, Neurofibrillary tangles

(arrowheads) are present within the neurons.


• Cerebral amyloid angiopathy (CAA) is an almost invariable accompaniment of Alzheimer disease

• However, it can also be found in brains of individuals without Alzheimer disease

• Vascular amyloid is predominantly Aβ40, as is also true when CAA occurs without AD

• Cerebral amyloid angiopathy (CAA) is an almost invariable accompaniment of Alzheimer disease

• However, it can also be found in brains of individuals without Alzheimer disease

• Vascular amyloid is predominantly Aβ40, as is also true when CAA occurs without AD


Alzheimer DiseaseAlzheimer Disease• Granulovacuolar degeneration is the

formation of small (~5 μm in diameter), clear intraneuronal cytoplasmic vacuoles, each of which contains an argyrophilic granule

• Hirano bodies, found especially in Alzheimer disease, are elongated, glassy, eosinophilic bodies consisting of paracrystalline arrays of beaded filaments, with actin as their major component

• They are found most commonly within hippocampal pyramidal cells

• Granulovacuolar degeneration is the formation of small (~5 μm in diameter), clear intraneuronal cytoplasmic vacuoles, each of which contains an argyrophilic granule

• Hirano bodies, found especially in Alzheimer disease, are elongated, glassy, eosinophilic bodies consisting of paracrystalline arrays of beaded filaments, with actin as their major component

• They are found most commonly within hippocampal pyramidal cells


Alzheimer DiseaseAlzheimer Disease• Pathogenesis and Molecular Genetics

• There remains disagreement regarding the best correlate of dementia in patients with Alzheimer disease

• The number of neurofibrillary tangles correlates better with the degree of dementia than does the number of neuritic plaques

• The best correlation of severity of dementia appears to be with loss of synapses

• Pathogenesis and Molecular Genetics

• There remains disagreement regarding the best correlate of dementia in patients with Alzheimer disease

• The number of neurofibrillary tangles correlates better with the degree of dementia than does the number of neuritic plaques

• The best correlation of severity of dementia appears to be with loss of synapses

Alzheimer DiseaseAlzheimer Disease• Pathogenesis and Molecular Genetics

• Several gene loci have been identified for familial Alzheimer disease:

• The first of these was the gene for APP on chromosome 21

• Two other genetic loci linked to early-onset of familial Alzheimer disease have been identified on chromosome 14 and 1


• Several gene loci have been identified for familial Alzheimer disease:

• The first of these was the gene for APP on chromosome 21

• Two other genetic loci linked to early-onset of familial Alzheimer disease have been identified on chromosome 14 and 1



• Distinct from these loci in which mutations cause Alzheimer disease, one allele (ε4) of the apolipoprotein E (ApoE) gene on chromosome 19 increases the risk of Alzheimer disease and lowers the age at onset of the disease


• Distinct from these loci in which mutations cause Alzheimer disease, one allele (ε4) of the apolipoprotein E (ApoE) gene on chromosome 19 increases the risk of Alzheimer disease and lowers the age at onset of the disease

Alzheimer DiseaseAlzheimer Disease• Clinical Features

• The progression of Alzheimer disease is slow but relentless, with a symptomatic course often running more than 10 years

• Initial symptoms are: forgetfulness and other memory disturbances

• With progression of the disease, other symptoms emerge, including language deficits, loss of mathematical skills, and loss of learned motor skills

• In the final stages of Alzheimer disease, patients may become incontinent, mute, and unable to walk

• Intercurrent disease, often pneumonia, is usually the terminal event in these individuals


• The progression of Alzheimer disease is slow but relentless, with a symptomatic course often running more than 10 years

• Initial symptoms are: forgetfulness and other memory disturbances

• With progression of the disease, other symptoms emerge, including language deficits, loss of mathematical skills, and loss of learned motor skills

• In the final stages of Alzheimer disease, patients may become incontinent, mute, and unable to walk

• Intercurrent disease, often pneumonia, is usually the terminal event in these individuals

Frontotemporal Dementias




• These are a group of disorders that were first gathered under a single broad term because they shared clinical features (progressive deterioration of language and changes in personality) that corresponded to degeneration and atrophy of temporal and frontal lobes

• These are a group of disorders that were first gathered under a single broad term because they shared clinical features (progressive deterioration of language and changes in personality) that corresponded to degeneration and atrophy of temporal and frontal lobes



• Frontotemporal Dementia with Parkinsonism Linked to Chromosome 17 (FTD(P)-17)

• This is a genetically determined disorder in which the clinical syndrome of a frontotemporal dementia is often accompanied by parkinsonian symptoms

• In these families, the disease has been mapped to chromosome 17

• In particular, it has been linked to a variety of mutations in the tau gene


• This is a genetically determined disorder in which the clinical syndrome of a frontotemporal dementia is often accompanied by parkinsonian symptoms

• In these families, the disease has been mapped to chromosome 17

• In particular, it has been linked to a variety of mutations in the tau gene




• There is evidence of atrophy of frontal and temporal lobes in various combinations and various degrees

• The atrophic regions of cortex are marked by fneuronal loss and gliosis as well as the presence of tau-containing neurofibrillary tangles


• There is evidence of atrophy of frontal and temporal lobes in various combinations and various degrees

• The atrophic regions of cortex are marked by fneuronal loss and gliosis as well as the presence of tau-containing neurofibrillary tangles




• Pick Disease

• Pick disease (lobar atrophy) is a rare, distinct, progressive dementia characterized clinically by early onset of behavioral changes together with alterations in personality (frontal lobe signs) and language disturbances (temporal lobe signs)

• Pick Disease

• Pick disease (lobar atrophy) is a rare, distinct, progressive dementia characterized clinically by early onset of behavioral changes together with alterations in personality (frontal lobe signs) and language disturbances (temporal lobe signs)



• Pick Disease

• The brain invariably shows a pronounced, frequently asymmetric, atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two thirds of the superior temporal gyrus and only rare involvement of either the parietal or occipital lobe

• The atrophy can be severe, reducing the gyri to a thin wafer (“knife-edge”) appearance

• This pattern of lobar atrophy is often prominent enough to distinguish Pick disease from Alzheimer disease on macroscopic examination

• Pick Disease

• The brain invariably shows a pronounced, frequently asymmetric, atrophy of the frontal and temporal lobes with conspicuous sparing of the posterior two thirds of the superior temporal gyrus and only rare involvement of either the parietal or occipital lobe

• The atrophy can be severe, reducing the gyri to a thin wafer (“knife-edge”) appearance

• This pattern of lobar atrophy is often prominent enough to distinguish Pick disease from Alzheimer disease on macroscopic examination




• Pick Disease

• On microscopic examination, neuronal loss is most severe in the outer three layers of the cortex

• Some of the surviving neurons show a characteristic swelling (Pick cells) or contain Pick bodies, which are cytoplasmic, round to oval, filamentous inclusions that are only weakly basophilic but stain strongly with silver methods

• Pick bodies do not survive the death of their host neuron and do not remain as markers of the disease

• Pick Disease

• On microscopic examination, neuronal loss is most severe in the outer three layers of the cortex

• Some of the surviving neurons show a characteristic swelling (Pick cells) or contain Pick bodies, which are cytoplasmic, round to oval, filamentous inclusions that are only weakly basophilic but stain strongly with silver methods

• Pick bodies do not survive the death of their host neuron and do not remain as markers of the disease




• Progressive Supranuclear Palsy (PSP)

• This is an illness characterized by:

• Truncal rigidity with dysequilibrium and nuchal dystonia

• Pseudobulbar palsy and abnormal speech

• Ocular disturbances, including vertical gaze palsy progressing to difficulty with all eye movements

• Mild progressive dementia in most patients


• This is an illness characterized by:

• Truncal rigidity with dysequilibrium and nuchal dystonia

• Pseudobulbar palsy and abnormal speech

• Ocular disturbances, including vertical gaze palsy progressing to difficulty with all eye movements

• Mild progressive dementia in most patients




• The onset of the disease is usually between the fifth and seventh decades, and males are affected approximately twice as frequently as are females

• The disease is often fatal within 5 to 7 years of onset


• The onset of the disease is usually between the fifth and seventh decades, and males are affected approximately twice as frequently as are females

• The disease is often fatal within 5 to 7 years of onset



• Corticobasal Degeneration (CBD)

• This is a disease of the elderly, with considerable clinical and neuropathologic heterogeneity

• The extrapyramidal signs and symptoms result in this disorder’s also being grouped with syndromes of basal ganglia dysfunction


• This is a disease of the elderly, with considerable clinical and neuropathologic heterogeneity

• The extrapyramidal signs and symptoms result in this disorder’s also being grouped with syndromes of basal ganglia dysfunction




• On macroscopic examination, there is cortical atrophy, mainly of the motor, premotor, and anterior parietal lobes

• The regions of cortex show severe loss of neurons, gliosis, and “ballooned” neurons (neuronal achromasia) that can be highlighted with immunocytochemical methods for phosphorylated neurofilaments


• On macroscopic examination, there is cortical atrophy, mainly of the motor, premotor, and anterior parietal lobes

• The regions of cortex show severe loss of neurons, gliosis, and “ballooned” neurons (neuronal achromasia) that can be highlighted with immunocytochemical methods for phosphorylated neurofilaments





• Clusters of tau-positive processes around an astrocyte (“astrocytic plaques”) and the presence of tau-positive threads in gray and white matter may be the most specific pathologic findings of CBD

• Recently proposed consensus diagnostic criteria for CBD focus on the presence of tau-positive inclusions in neurons and glia of the cortex and striatum, including astrocytic plaques, associated with neuronal loss from substantia nigra and cortex


• Clusters of tau-positive processes around an astrocyte (“astrocytic plaques”) and the presence of tau-positive threads in gray and white matter may be the most specific pathologic findings of CBD

• Recently proposed consensus diagnostic criteria for CBD focus on the presence of tau-positive inclusions in neurons and glia of the cortex and striatum, including astrocytic plaques, associated with neuronal loss from substantia nigra and cortex






• The disease is characterized by extrapyramidal rigidity, asymmetric motor disturbances (jerking movements of limbs: “alien hand”), and sensory cortical dysfunction (apraxias, disorders of language)

• Cognitive decline occurs, and may be prominent in some cases

• Although tau deposits are a hallmark of CBD, it is rare to find CBD pathology in individuals with mutations in the tau gene



• The disease is characterized by extrapyramidal rigidity, asymmetric motor disturbances (jerking movements of limbs: “alien hand”), and sensory cortical dysfunction (apraxias, disorders of language)

• Cognitive decline occurs, and may be prominent in some cases

• Although tau deposits are a hallmark of CBD, it is rare to find CBD pathology in individuals with mutations in the tau gene



• Frontotemporal Dementias Without Tau Pathology

• Some cases with clinical and pathologic findings involving these brain regions do not show evidence of tau deposition

• Some cases with this pattern are found in association with motor neuron disease -- in this setting, tau-negative, ubiquitin-positive inclusions can be found in superficial cortical layers in temporal and frontal lobe and in the dentate gyrus

• This pattern of pathology is termed motor neuron disease inclusion dementia

• It has also been described in the absence of ALS-like pathology


• Some cases with clinical and pathologic findings involving these brain regions do not show evidence of tau deposition

• Some cases with this pattern are found in association with motor neuron disease -- in this setting, tau-negative, ubiquitin-positive inclusions can be found in superficial cortical layers in temporal and frontal lobe and in the dentate gyrus

• This pattern of pathology is termed motor neuron disease inclusion dementia

• It has also been described in the absence of ALS-like pathology




• Other cases show no specific inclusions but rather have cortical atrophy and some thalamic gliosis

• This pattern of injury has been termed dementia lacking distinctive histology (DLDH)

• With time and increased biochemical and molecular investigations, these unusual entities are likely to be reclassified


• Other cases show no specific inclusions but rather have cortical atrophy and some thalamic gliosis

• This pattern of injury has been termed dementia lacking distinctive histology (DLDH)

• With time and increased biochemical and molecular investigations, these unusual entities are likely to be reclassified



• Vascular Dementia

• Some individuals with a rapidly progressive cognitive decline have vasculitis and will often show improvement with treatment

• Among the irreversible disorders, several specific entities have been identified, which can be separated in part by their clinical course (typically a stepwise progression rather than a gradual decline) and imaging features

• Various etiologies include small areas of infarction (granular atrophy from cortical microinfarcts, multiple lacunar infarcts, cortical laminar necrosis associated with reduced perfusion/oxygenation) and diffuse white matter injury (Binswanger disease, CADASIL)


• Some individuals with a rapidly progressive cognitive decline have vasculitis and will often show improvement with treatment

• Among the irreversible disorders, several specific entities have been identified, which can be separated in part by their clinical course (typically a stepwise progression rather than a gradual decline) and imaging features

• Various etiologies include small areas of infarction (granular atrophy from cortical microinfarcts, multiple lacunar infarcts, cortical laminar necrosis associated with reduced perfusion/oxygenation) and diffuse white matter injury (Binswanger disease, CADASIL)




• Additionally, dementia has been associated with so-called strategic infarcts, which are usually embolic and involve brain regions such as the hippocampus, dorsomedial thalamus, or frontal cortex including cingulate gyrus


• Additionally, dementia has been associated with so-called strategic infarcts, which are usually embolic and involve brain regions such as the hippocampus, dorsomedial thalamus, or frontal cortex including cingulate gyrus

Degenerative Diseases of

Basal Ganglia and

Brainstem

Degenerative Diseases of

Basal Ganglia and

Brainstem

Degenerative Diseases of Basal Ganglia and Brainstem

Degenerative Diseases of Basal Ganglia and Brainstem

• Diseases affecting these regions of the brain are frequently associated with movement disorders, including rigidity, abnormal posturing, and chorea

• They can manifest either a reduction of voluntary movement or an abundance of involuntary movement

• The most important disorders in this group are those associated with parkinsonism and Huntington chorea

• Diseases affecting these regions of the brain are frequently associated with movement disorders, including rigidity, abnormal posturing, and chorea

• They can manifest either a reduction of voluntary movement or an abundance of involuntary movement

• The most important disorders in this group are those associated with parkinsonism and Huntington chorea

ParkinsonismParkinsonism

ParkinsonismParkinsonism• Parkinsonism is a clinical syndrome characterized

by diminished facial expression, stooped posture, slowness of voluntary movement, festinating gait (progressively shortened, accelerated steps), rigidity, and a “pill-rolling” tremor

• This type of motor disturbance is seen in a number of conditions that have in common damage to the nigrostriatal dopaminergic system

• Parkinsonism may also be induced by drugs that affect this system, particularly dopamine antagonists and toxins

• Parkinsonism is a clinical syndrome characterized by diminished facial expression, stooped posture, slowness of voluntary movement, festinating gait (progressively shortened, accelerated steps), rigidity, and a “pill-rolling” tremor

• This type of motor disturbance is seen in a number of conditions that have in common damage to the nigrostriatal dopaminergic system

• Parkinsonism may also be induced by drugs that affect this system, particularly dopamine antagonists and toxins

ParkinsonismParkinsonism• The principal diseases that involve the nigrostriatal

system are:

• Parkinson disease (PD)

• Multiple system atrophy, a disorder that may have parkinsonism as a prominent symptom (clinical presentation as striatonigral degeneration) as well as other symptoms (cerebellar ataxia and autonomic dysfunction)

• Postencephalitic parkinsonism, which was observed in the wake of the influenza pandemic that occurred between 1914 and 1918 and is now vanishingly rare

• The principal diseases that involve the nigrostriatal system are:

• Parkinson disease (PD)

• Multiple system atrophy, a disorder that may have parkinsonism as a prominent symptom (clinical presentation as striatonigral degeneration) as well as other symptoms (cerebellar ataxia and autonomic dysfunction)

• Postencephalitic parkinsonism, which was observed in the wake of the influenza pandemic that occurred between 1914 and 1918 and is now vanishingly rare

ParkinsonismParkinsonism


• Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), which are movement disorders that may also exhibit cognitive impairment

• They share some pathologic and genetic features with each other and with other taupathies


• Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD), which are movement disorders that may also exhibit cognitive impairment

• They share some pathologic and genetic features with each other and with other taupathies

Parkinson Disease

Parkinson Disease

Parkinson DiseaseParkinson Disease• Pathogenesis and Molecular Genetics

• The dopaminergic neurons of the substantia nigra project to the striatum, and their degeneration in Parkinson disease is associated with a reduction in the striatal dopamine content

• The severity of the motor syndrome is proportional to the dopamine deficiency

• Treatment does not reverse the morphologic changes or arrest the progress of the disease, and with progression, drug therapy tends to become less effective, and symptoms become more difficult to manage


• The dopaminergic neurons of the substantia nigra project to the striatum, and their degeneration in Parkinson disease is associated with a reduction in the striatal dopamine content

• The severity of the motor syndrome is proportional to the dopamine deficiency

• Treatment does not reverse the morphologic changes or arrest the progress of the disease, and with progression, drug therapy tends to become less effective, and symptoms become more difficult to manage

Parkinson DiseaseParkinson Disease


• Studies of PD took a major step forward when the gene encoding α-synuclein, an abundant lipid-binding protein associated with synapses, was identified as the basis for an inherited autosomal-dominant for of PD, prompting the recognition that it was a major component of the Lewy body


• Studies of PD took a major step forward when the gene encoding α-synuclein, an abundant lipid-binding protein associated with synapses, was identified as the basis for an inherited autosomal-dominant for of PD, prompting the recognition that it was a major component of the Lewy body

Parkinson DiseaseParkinson Disease• Clinical Features

• About 10% to 15% of patients with PD develop dementia, with increasing incidence with advancing age

• Characteristic features of this disorder include a fluctuating course, hallucinations, and prominent frontal signs

• Symptomatic response to L-DOPA therapy is one of the features, in addition to clinical signs and symptoms, that support a diagnosis of PD


• About 10% to 15% of patients with PD develop dementia, with increasing incidence with advancing age

• Characteristic features of this disorder include a fluctuating course, hallucinations, and prominent frontal signs

• Symptomatic response to L-DOPA therapy is one of the features, in addition to clinical signs and symptoms, that support a diagnosis of PD

Parkinson DiseaseParkinson Disease• Clinical Features

• Over time, L-DOPA becomes less able to help the patient through symptomatic relief and begins to lead to fluctuations in motor function on its own

• Alternative therapies (experimental):

• Neuronal transplantation

• Stereotactic implants of fetal mesencephalic tissue into the striatum

• Strategic placement of lesions elsewhere in the extrapyramidal system to compensate for the loss of nigrostriatal function

• Strategic placement of stimulating electrodes (deep brain stimulation) can also provide relievf of motor symptoms of PD


• Over time, L-DOPA becomes less able to help the patient through symptomatic relief and begins to lead to fluctuations in motor function on its own

• Alternative therapies (experimental):

• Neuronal transplantation

• Stereotactic implants of fetal mesencephalic tissue into the striatum

• Strategic placement of lesions elsewhere in the extrapyramidal system to compensate for the loss of nigrostriatal function

• Strategic placement of stimulating electrodes (deep brain stimulation) can also provide relievf of motor symptoms of PD

Multiple System Atrophy




• Used to describe a group of disorders characterized by the presence of glial cytoplasmic inclusions (GCIs), typically within the cytoplasm of oligodendrocytes

• The three clinicopathologic entities of striatonigral degeneration, Shy-Drager syndrome, and olivopontocerebellar atrophy were gathered into a single pathologic category

• Subsequently the identification of α-synuclein as the major component of the inclusions has resulted in this disorder being considered as a synucleinopathy

• Unlike PD, with which it shares the feature of α-synuclein-containing inclusions, no mutations in the gene for this synaptic protein have been found in cases of MSA

• Used to describe a group of disorders characterized by the presence of glial cytoplasmic inclusions (GCIs), typically within the cytoplasm of oligodendrocytes

• The three clinicopathologic entities of striatonigral degeneration, Shy-Drager syndrome, and olivopontocerebellar atrophy were gathered into a single pathologic category

• Subsequently the identification of α-synuclein as the major component of the inclusions has resulted in this disorder being considered as a synucleinopathy

• Unlike PD, with which it shares the feature of α-synuclein-containing inclusions, no mutations in the gene for this synaptic protein have been found in cases of MSA



• Macroscopic: atrophy of the cerebellum, including the cerebellar peduncles, pons (especially the basis pontis), medulla (especially the inferior olive), substantia nigra, and striatum (especially putamen)

• These regions show evidence of neuronal loss

• The shared diagnostic feature of these disorders, the cytoplasmic inclusions, have been shown to contain α-synuclein as well as ubiquitin and αβ-crystallin

• Macroscopic: atrophy of the cerebellum, including the cerebellar peduncles, pons (especially the basis pontis), medulla (especially the inferior olive), substantia nigra, and striatum (especially putamen)

• These regions show evidence of neuronal loss

• The shared diagnostic feature of these disorders, the cytoplasmic inclusions, have been shown to contain α-synuclein as well as ubiquitin and αβ-crystallin





• The two principal symptoms of MSA are parkinsonism and autonomic dysfunction, particularly orthostatic hypotension

• When these are present in relative isolation, the syndrome may be referred to as striatonigral degeneration and Shy-Drager syndrome, respectively

• Presentation as an isolated ataxic disorder with cerebellar dysfunction (olivopontocerebellar atrophy) is much rarer


• The two principal symptoms of MSA are parkinsonism and autonomic dysfunction, particularly orthostatic hypotension

• When these are present in relative isolation, the syndrome may be referred to as striatonigral degeneration and Shy-Drager syndrome, respectively

• Presentation as an isolated ataxic disorder with cerebellar dysfunction (olivopontocerebellar atrophy) is much rarer

Huntington Disease

Huntington Disease

Huntington Disease

Huntington Disease

• Huntington disease is an inherited autosomal-dominant disease characterized clinically by progressive movement disorders and dementia and histologically by degeneration of striatal neurons

• The movement disorder chorea consists of jerky, hyperkinetic, sometimes dystonic movements affecting all parts of the body

• Patients may later develop parkinsonism with bradykinesia and rigidity

• The disease is relentlessly progressive, with an average course of about 15 years to death

• Huntington disease is an inherited autosomal-dominant disease characterized clinically by progressive movement disorders and dementia and histologically by degeneration of striatal neurons

• The movement disorder chorea consists of jerky, hyperkinetic, sometimes dystonic movements affecting all parts of the body

• Patients may later develop parkinsonism with bradykinesia and rigidity

• The disease is relentlessly progressive, with an average course of about 15 years to death

Huntington Disease

Huntington Disease

• Macroscopic: the brain is small and shows striking atrophy of the caudate nucleus and, less dramatically, the putamen

• Atrophy is frequently also seen in the frontal lobe, less often in the parietal lobe, and occasionally in the entire cortex

• Microscopic: there is severe loss of striatal neurons

• The most dramatic changes are found in the caudate nucleus, especially in the tail and portions nearer the ventricle

• Macroscopic: the brain is small and shows striking atrophy of the caudate nucleus and, less dramatically, the putamen

• Atrophy is frequently also seen in the frontal lobe, less often in the parietal lobe, and occasionally in the entire cortex

• Microscopic: there is severe loss of striatal neurons

• The most dramatic changes are found in the caudate nucleus, especially in the tail and portions nearer the ventricle


Huntington disease (HD). Normal hemisphere on the left compared with the hemisphere with HD on the right showing

atrophy of the striatum and ventricular dilation.

Huntington disease (HD). Normal hemisphere on the left compared with the hemisphere with HD on the right showing

atrophy of the striatum and ventricular dilation.

Huntington Disease

Huntington Disease


• The functional significance of the loss of medium spiny striatal neurons is to dysregulate the basal ganglia circuitry that modulates motor output

• The HD gene, located on 4p16.3, encodes a predicted protein, called huntingtin

• Normal HD genes contain 6 to 35 copies of the repeat polymorphic CAG trinucleotide

• The larger the number of repeats, the earlier the onset of the disease

• Newly occurring mutations are uncommon


• The functional significance of the loss of medium spiny striatal neurons is to dysregulate the basal ganglia circuitry that modulates motor output

• The HD gene, located on 4p16.3, encodes a predicted protein, called huntingtin

• Normal HD genes contain 6 to 35 copies of the repeat polymorphic CAG trinucleotide

• The larger the number of repeats, the earlier the onset of the disease

• Newly occurring mutations are uncommon

Huntington Disease

Huntington Disease


• Motor symptoms often precede the cognitive impairment

• The movement disorder of HD is choreiform, with increased and involuntary jerky movements of all parts of the body

• Writhing movements of the extremities are typical

• Early symptoms of higher cortical dysfunction include forgetfulness and thought and affective disorders, but there is progression to a severe dementia

• HD patients have an increased risk of suicide, with intercurrent infection being the most common natural cause of death


• Motor symptoms often precede the cognitive impairment

• The movement disorder of HD is choreiform, with increased and involuntary jerky movements of all parts of the body

• Writhing movements of the extremities are typical

• Early symptoms of higher cortical dysfunction include forgetfulness and thought and affective disorders, but there is progression to a severe dementia

• HD patients have an increased risk of suicide, with intercurrent infection being the most common natural cause of death

Spinocerebellar

Degenerations

Spinocerebellar

Degenerations

Spinocerebellar DegenerationsSpinocerebellar Degenerations

• The clinical spectrum of these diseases includes cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy

• This is a clinically heterogenous group of illnesses that include several distinct diseases

• These can be distinguished on the basis of their patterns of inheritance, age at onset, and pattern of signs and symptoms

• The clinical spectrum of these diseases includes cerebellar and sensory ataxia, spasticity, and sensorimotor peripheral neuropathy

• This is a clinically heterogenous group of illnesses that include several distinct diseases

• These can be distinguished on the basis of their patterns of inheritance, age at onset, and pattern of signs and symptoms

Spinocerebellar Ataxias




• This group of genetically distinct diseases are characterized by neuronal loss from the affected areas with secondary degeneration of white matter tracts

• The clinically identified spinocerebellar ataxias can be separated on the basis of inheritance pattern into autosomal dominant and recessive types

• This group of genetically distinct diseases are characterized by neuronal loss from the affected areas with secondary degeneration of white matter tracts

• The clinically identified spinocerebellar ataxias can be separated on the basis of inheritance pattern into autosomal dominant and recessive types



• Friedreich Ataxia

• This is an autosomal-recessive progressive illness, generally beginning in the first decade of life with gait ataxia, followed by hand clumsiness and dysarthria

• Deep tendon reflexes are depressed or absent, but an extensor plantar reflex is typically present

• Joint position and vibratory sense are impaired, and there is sometimes loss of plain and temperature sensation and light touch

• Most patients develop pes cavus and kyphoscoliosis


• This is an autosomal-recessive progressive illness, generally beginning in the first decade of life with gait ataxia, followed by hand clumsiness and dysarthria

• Deep tendon reflexes are depressed or absent, but an extensor plantar reflex is typically present

• Joint position and vibratory sense are impaired, and there is sometimes loss of plain and temperature sensation and light touch

• Most patients develop pes cavus and kyphoscoliosis




• There is a high incidence of cardiac disease with arrhythmias and congestive heart failure

• Concomitant diabetes is found in about 10% of patients

• Most patients become wheel-chair bound within about 5 years of onset

• The cause of death is intercurrent pulmonary infections and cardiac disease


• There is a high incidence of cardiac disease with arrhythmias and congestive heart failure

• Concomitant diabetes is found in about 10% of patients

• Most patients become wheel-chair bound within about 5 years of onset

• The cause of death is intercurrent pulmonary infections and cardiac disease




• The gene for Friedreich ataxia has been mapped to chromosome 9q13, and in most cases, there is a GAA trinucleotide repeat expansion in the first intron of a gene encoding a protein named frataxin

• Friedreich ataxia shares biologic features with other spinocerebellar ataxias (anatomic distribution of pathology, trinucleotide repeat expansion) and the mitochondrial encephalopathies


• The gene for Friedreich ataxia has been mapped to chromosome 9q13, and in most cases, there is a GAA trinucleotide repeat expansion in the first intron of a gene encoding a protein named frataxin

• Friedreich ataxia shares biologic features with other spinocerebellar ataxias (anatomic distribution of pathology, trinucleotide repeat expansion) and the mitochondrial encephalopathies



• Ataxia-Telangiectasia

• Ataxia-telangiectasia is an autosomal-recessive disorder characterized by an ataxic-dyskinetic syndrome beginning in early childhood, caused by neuronal degeneration predominantly in the cerebellum, the subsequent development of telangiectasias in the conjunctiva and skin, and immunodeficiency

• The ataxia-telangiectasia locus on chromosome 11q22-23 has been identified as a large gene


• Ataxia-telangiectasia is an autosomal-recessive disorder characterized by an ataxic-dyskinetic syndrome beginning in early childhood, caused by neuronal degeneration predominantly in the cerebellum, the subsequent development of telangiectasias in the conjunctiva and skin, and immunodeficiency

• The ataxia-telangiectasia locus on chromosome 11q22-23 has been identified as a large gene





• This disease relentlessly progresses to death early in the second decade

• Patients first come to medical attention because of recurrent sinopulmonary infections and unsteadiness in walking

• Later on, speech is noted to become dysarthric, and eye movement abnormalities develop

• Many affected individuals develop lymphoid malignant disease (T-cell leukemia, T-cell lymphoma)

• Gliomas and carcinomas have been reported in some



• This disease relentlessly progresses to death early in the second decade

• Patients first come to medical attention because of recurrent sinopulmonary infections and unsteadiness in walking

• Later on, speech is noted to become dysarthric, and eye movement abnormalities develop

• Many affected individuals develop lymphoid malignant disease (T-cell leukemia, T-cell lymphoma)

• Gliomas and carcinomas have been reported in some

Degenerative Diseases Affecting

Motor Neurons

Degenerative Diseases Affecting

Motor Neurons

Degenerative Diseases Affecting Motor NeuronsDegenerative Diseases Affecting Motor Neurons

• These are a group of inherited or sporadic diseases that, in variable degrees of severity, affect:

• Lower motor neurons in the anterior horns of the spinal cord

• Lower motor neurons in certain cranial nerve motor nuclei (V, VII, IX, XII) but not those that control eye movements (III, IV, VI)

• Upper motor neurons (Betz cells) in the motor cortex

• These are a group of inherited or sporadic diseases that, in variable degrees of severity, affect:

• Lower motor neurons in the anterior horns of the spinal cord

• Lower motor neurons in certain cranial nerve motor nuclei (V, VII, IX, XII) but not those that control eye movements (III, IV, VI)

• Upper motor neurons (Betz cells) in the motor cortex

Degenerative Diseases Affecting Motor NeuronsDegenerative Diseases Affecting Motor Neurons

• The disorders occur in all age groups

• Denervation of muscles from loss of lower motor neurons and their axons results in muscular atrophy, weakness, and fasciculations

• The corresponding histologic changes in nerve and muscle will be discussed presently

• The clinical manifestations include paresis, hyperreflexia, spasticity, and extensor plantar responses (Babinski sign)

• The disorders occur in all age groups

• Denervation of muscles from loss of lower motor neurons and their axons results in muscular atrophy, weakness, and fasciculations

• The corresponding histologic changes in nerve and muscle will be discussed presently

• The clinical manifestations include paresis, hyperreflexia, spasticity, and extensor plantar responses (Babinski sign)

Amyotrophic Lateral

Sclerosis (Motor Neuron

Disease)

Amyotrophic Lateral

Sclerosis (Motor Neuron

Disease)

Amyotrophic Lateral Sclerosis (Motor Neuron

Disease)


Disease)• Amyotrophic lateral sclerosis (ALS) is

characterized by neuronal muscle atrophy (amyotrophy) and hyperreflexia due to loss of lower motor neurons in the anterior horns of the spinal cord and upper motor neurons that project in corticospinal tracts, respectively

• The disease affects men slightly more frequently than women and becomes clinically manifest in the fifth decade or later

• Five per cent to 10% of cases are familial, mostly with autosomal-dominant inheritance

• Amyotrophic lateral sclerosis (ALS) is characterized by neuronal muscle atrophy (amyotrophy) and hyperreflexia due to loss of lower motor neurons in the anterior horns of the spinal cord and upper motor neurons that project in corticospinal tracts, respectively

• The disease affects men slightly more frequently than women and becomes clinically manifest in the fifth decade or later

• Five per cent to 10% of cases are familial, mostly with autosomal-dominant inheritance


Disease)


Disease)

• Pathogenesis

• For a subset of the familial cases, the genetic locus has been mapped to the copper-zinc superoxide dismutase gene (SOD1) on chromosome 21

• Pathogenesis

• For a subset of the familial cases, the genetic locus has been mapped to the copper-zinc superoxide dismutase gene (SOD1) on chromosome 21

Amyotrophic lateral sclerosis. Spinal cord showing loss of myelinated fibers (lack of stain) in corticospinal tracts. The

anterior roots are smaller than the posterior roots.

Amyotrophic lateral sclerosis. Spinal cord showing loss of myelinated fibers (lack of stain) in corticospinal tracts. The

anterior roots are smaller than the posterior roots.


Disease)


Disease)


• Early symptoms include asymmetric weakness of the hands, manifested as dropping objects and difficulty in performing fine motor tasks, and cramping and spasticity of the arms and legs

• The term progressive muscular atrophy applies to those relatively uncommon cases in which lower motor neuron involvement predominates


• Early symptoms include asymmetric weakness of the hands, manifested as dropping objects and difficulty in performing fine motor tasks, and cramping and spasticity of the arms and legs

• The term progressive muscular atrophy applies to those relatively uncommon cases in which lower motor neuron involvement predominates


Disease)


Disease)


• In some patients, degeneration of the lower brainstem cranial motor nuclei occurs early and progresses rapidly, a pattern referred to as progressive bulbar amyotrophic lateral sclerosis

• In these individuals, abnormalities of deglutition and phonation dominate, and the clinical course is inexorable during a 1- or 2-year period


• In some patients, degeneration of the lower brainstem cranial motor nuclei occurs early and progresses rapidly, a pattern referred to as progressive bulbar amyotrophic lateral sclerosis

• In these individuals, abnormalities of deglutition and phonation dominate, and the clinical course is inexorable during a 1- or 2-year period

Bulbospinal Atrophy

(Kennedy Syndrome)

Bulbospinal Atrophy

(Kennedy Syndrome)

Bulbospinal Atrophy (Kennedy Syndrome)Bulbospinal Atrophy (Kennedy Syndrome)

• This X-linked adult-onset disease is characterized by distal limb amyotrophy and bulbar signs such as atrophy and fasciculations of the tongue and dysphagia

• Affected individuals manifest androgen insensitivity with gynecomastia, testicular atrophy, and oligospermia

• This X-linked adult-onset disease is characterized by distal limb amyotrophy and bulbar signs such as atrophy and fasciculations of the tongue and dysphagia

• Affected individuals manifest androgen insensitivity with gynecomastia, testicular atrophy, and oligospermia

Spinal Muscular Atrophy




• This group of diseases affects mainly the lower motor neurons in children

• It includes several entities with distinct clinical courses (Chapter 27)

• This group of diseases affects mainly the lower motor neurons in children

• It includes several entities with distinct clinical courses (Chapter 27)

Genetic Metabolic Diseases




• Neuronal storage diseases are mostly autosomal-recessive diseases caused by a deficiency of a specific enzyme involved in the catabolism of sphingolipids, mucopolysaccharides, or mucolipids

• They are often characterized by the accumulation of the substrate of the enzyme within the lysosomes of neurons, leading to neuronal death

• Neuronal storage diseases are mostly autosomal-recessive diseases caused by a deficiency of a specific enzyme involved in the catabolism of sphingolipids, mucopolysaccharides, or mucolipids

• They are often characterized by the accumulation of the substrate of the enzyme within the lysosomes of neurons, leading to neuronal death



• Leukodystrophies show a selective involvement of myelin (either abnormal synthesis or turnover), and generally exhibit no neuronal storage defects

• Diffuse involvement of white matter leads to deterioration in motor skills, spasticity, hypotonia, or ataxia

• Although most are autosomal-recessive disorders, adrenoleukodystrophy, an X-linked disease, is a notable exception

• Subtypes, or variants, are recognized for as many of these disorders

• Leukodystrophies show a selective involvement of myelin (either abnormal synthesis or turnover), and generally exhibit no neuronal storage defects

• Diffuse involvement of white matter leads to deterioration in motor skills, spasticity, hypotonia, or ataxia

• Although most are autosomal-recessive disorders, adrenoleukodystrophy, an X-linked disease, is a notable exception

• Subtypes, or variants, are recognized for as many of these disorders



• Mitochondrial encephalomyopathies are a group of disorders of oxidative phosphorylation, usually resulting form mutations in the mitochondrial genome

• They typically involve gray matter as well as skeletal muscle

• Mitochondrial encephalomyopathies are a group of disorders of oxidative phosphorylation, usually resulting form mutations in the mitochondrial genome

• They typically involve gray matter as well as skeletal muscle

Leukodystrophies

Leukodystrophies

Krabbe DiseaseKrabbe Disease

Krabbe DiseaseKrabbe Disease• The disease is an autosomal-recessive leukodystrophy

resulting from a deficiency of galactocerebroside β-galactosidase (galactosylceramidase), the enzyme required for the catabolism of galactocerebroside to ceramide and galactose

• The gene encoding for this enzyme, located on chromosome 14q31, presents multiple mutations

• While some accumulation of galactocerebroside may occur, this is not the direct toxic agent in this disease

• It appears that an alternative catabolic pathway removes a fatty acid from this molecule, generating galactosylsphingosine, which is a cytotoxic compound that could cause oligodendrocyte injury

• The disease is an autosomal-recessive leukodystrophy resulting from a deficiency of galactocerebroside β-galactosidase (galactosylceramidase), the enzyme required for the catabolism of galactocerebroside to ceramide and galactose

• The gene encoding for this enzyme, located on chromosome 14q31, presents multiple mutations

• While some accumulation of galactocerebroside may occur, this is not the direct toxic agent in this disease

• It appears that an alternative catabolic pathway removes a fatty acid from this molecule, generating galactosylsphingosine, which is a cytotoxic compound that could cause oligodendrocyte injury

Krabbe DiseaseKrabbe Disease• The clinical course is rapidly progressive, with onset of

symptoms often between the ages of 3 and 6 months

• Survival beyond 2 years of age is uncommon

• The clinical symptoms are dominated by motor signs, including stiffness and weakness, with gradually worsening difficulties in feeding

• The brain shows loss of myelin and oligodenrocytes in the CNS and a similar process in peripheral nerves

• A unique feature of Krabbe disease is the aggregation of macrophages filled with cerebroside, forming multinucleated cells (globoid cells), around blood vessels

• The clinical course is rapidly progressive, with onset of symptoms often between the ages of 3 and 6 months

• Survival beyond 2 years of age is uncommon

• The clinical symptoms are dominated by motor signs, including stiffness and weakness, with gradually worsening difficulties in feeding

• The brain shows loss of myelin and oligodenrocytes in the CNS and a similar process in peripheral nerves

• A unique feature of Krabbe disease is the aggregation of macrophages filled with cerebroside, forming multinucleated cells (globoid cells), around blood vessels

Metachromatic

Leukodystrophy

Metachromatic

Leukodystrophy

Metachromatic LeukodystrophyMetachromatic Leukodystrophy

• This disorder is transmitted in an autosomal-recessive pattern and results from a deficiency of the lysosomal enzyme arysulfatase A

• Enzyme deficiency leads to an accumulation of the sulfatides, especially cerebroside sulfate

• The gene for arylsulfatase A has been localized to chromosome 22q

• This disorder is transmitted in an autosomal-recessive pattern and results from a deficiency of the lysosomal enzyme arysulfatase A

• Enzyme deficiency leads to an accumulation of the sulfatides, especially cerebroside sulfate

• The gene for arylsulfatase A has been localized to chromosome 22q


• Clinical subtypes of the disorder include a late infantile form (the most common), a juvenile form, and an adult form

• The two forms with childhood onset often present with motor symptoms and progress gradually, leading to death in 5 to 10 years

• In the adult form, psychiatric or cognitive symptoms are the usual initial complaint, with motor symptoms coming later, and the disease has a slower course

• Clinical subtypes of the disorder include a late infantile form (the most common), a juvenile form, and an adult form

• The two forms with childhood onset often present with motor symptoms and progress gradually, leading to death in 5 to 10 years

• In the adult form, psychiatric or cognitive symptoms are the usual initial complaint, with motor symptoms coming later, and the disease has a slower course


• The most striking histologic finding is demyelination with resulting gliosis

• Macrophages with vacuolated cytoplasm are scattered throughout the white matter

• The membrane-bound vacuoles contain complex crystalloid structures composed of sulfatides

• When bound to certain dyes such as toludine blue, sulfatides shift the absorbance spectrum of the dye, a property called metachromasia

• The detection of metachromatic material in the urine is also a sensitive method of establishing the diagnosis

• The most striking histologic finding is demyelination with resulting gliosis

• Macrophages with vacuolated cytoplasm are scattered throughout the white matter

• The membrane-bound vacuoles contain complex crystalloid structures composed of sulfatides

• When bound to certain dyes such as toludine blue, sulfatides shift the absorbance spectrum of the dye, a property called metachromasia

• The detection of metachromatic material in the urine is also a sensitive method of establishing the diagnosis

Metachromatic leukodystrphy. Demyelination is extensive. The

subcortical fibers in the cerebral hemisphere are

spared (Luxol fast blue PAS stain for

myelin)

Metachromatic leukodystrphy. Demyelination is extensive. The

subcortical fibers in the cerebral hemisphere are

spared (Luxol fast blue PAS stain for

myelin)

Adrenoleukodystrophy




• This disorder is a progressive disease with symptoms referable to myelin loss from the CNS and peripheral nerves as well as adrenal insufficiency

• The X-linked form usually presents in the early school years with neurologic symptoms and adrenal insufficiency and is rapidly progressive and fatal

• When it develops in adults, it is usually a slowly progressive disorder with predominantly peripheral nerve involvement developing over a period of decades

• The disease is associated with mutations in the ALD gene on chromosome Xq28

• This disorder is a progressive disease with symptoms referable to myelin loss from the CNS and peripheral nerves as well as adrenal insufficiency

• The X-linked form usually presents in the early school years with neurologic symptoms and adrenal insufficiency and is rapidly progressive and fatal

• When it develops in adults, it is usually a slowly progressive disorder with predominantly peripheral nerve involvement developing over a period of decades

• The disease is associated with mutations in the ALD gene on chromosome Xq28

Pelizaeus-Merzbacher

Disease

Pelizaeus-Merzbacher

Disease

Pelizaeus-Merzbacher Disease

Pelizaeus-Merzbacher Disease

• This is an X-linked, invariably fatal, leukodystrophy beginning either in early childhood or just after birth, and characterized by slowly progressive signs and symptoms resulting from widespread white matter dysfunction

• Patients present with pendular eye movements, hypotonia, choreoathetosis, and pyramidal signs early in the disease, followed later by spasticity, dementia, and ataxia

• Although myelin is nearly completely lost in the cerebral hemispheres, patches may remain, giving a “tigroid” appearance to tissue sections stained for myelin

• This is an X-linked, invariably fatal, leukodystrophy beginning either in early childhood or just after birth, and characterized by slowly progressive signs and symptoms resulting from widespread white matter dysfunction

• Patients present with pendular eye movements, hypotonia, choreoathetosis, and pyramidal signs early in the disease, followed later by spasticity, dementia, and ataxia

• Although myelin is nearly completely lost in the cerebral hemispheres, patches may remain, giving a “tigroid” appearance to tissue sections stained for myelin

Canavan DiseaseCanavan Disease

Canavan DiseaseCanavan Disease

• The disease is characterized by megalocephaly, severe mental deficits, blindness, and signs and symptoms of white matter injury beginning in early infancy and relentlessly progressing to death by 18 months of age

• The disease is characterized by megalocephaly, severe mental deficits, blindness, and signs and symptoms of white matter injury beginning in early infancy and relentlessly progressing to death by 18 months of age

Mitochondrial Encephalomyopath

ies

Mitochondrial Encephalomyopath

ies

Mitochondrial Encephalomyopathies

Mitochondrial Encephalomyopathies

• Some of them involve the central nervous system either as a primary target or in addition to skeletal muscle

• Some of them involve the central nervous system either as a primary target or in addition to skeletal muscle

Leigh Syndrome (Subacute Necrotizing

Encephalopathy)


Encephalopathy)


Encephalopathy)


Encephalopathy)• This disease of early childhood is

characterized by lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extraocular palsies, and weakness with hypotonia

• Death usually occurs within 1 to 2 years

• There are multifocal, moderately symmetric regions of destruction of brain tissue with a spongiform appearance and proliferation of blood vessels

• This disease of early childhood is characterized by lactic acidemia, arrest of psychomotor development, feeding problems, seizures, extraocular palsies, and weakness with hypotonia

• Death usually occurs within 1 to 2 years

• There are multifocal, moderately symmetric regions of destruction of brain tissue with a spongiform appearance and proliferation of blood vessels


Encephalopathy)


Encephalopathy)

• When there is higher degree of heteroplasmy with normal mitochondria, the disease takes on a different clinical and pathologic appearance, as neuropathy, ataxia, and retinitis pigmentosa (NARP)

• When there is higher degree of heteroplasmy with normal mitochondria, the disease takes on a different clinical and pathologic appearance, as neuropathy, ataxia, and retinitis pigmentosa (NARP)

Other Mitochondrial

Encephalomyopathies

Other Mitochondrial

Encephalomyopathies

Other Mitochondrial EncephalomyopathiesOther Mitochondrial

Encephalomyopathies• Myoclonic epilepsy and ragged red fibers (MERRF)

is a maternally transmitted disease in which patients have myoclonus, a seizure disorder, and evidence of a myopathy

• Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is another syndrome caused by mitochondrial abnormalities, in which children have acute episodes of neurologic dysfunction, cognitive changes, and evidence of muscle involvement with weakness and lactic acidosis

• Pathologically, areas of infarction are observed, often with vascular proliferation and focal calcification

• Myoclonic epilepsy and ragged red fibers (MERRF) is a maternally transmitted disease in which patients have myoclonus, a seizure disorder, and evidence of a myopathy

• Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is another syndrome caused by mitochondrial abnormalities, in which children have acute episodes of neurologic dysfunction, cognitive changes, and evidence of muscle involvement with weakness and lactic acidosis

• Pathologically, areas of infarction are observed, often with vascular proliferation and focal calcification

Other Mitochondrial EncephalomyopathiesOther Mitochondrial

Encephalomyopathies

• Kearns-Sayre syndrome (KSS) (“ophthalmoplegia plus”) is a sporadic disorder

• It may present with cerebellar ataxia in addition to the progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects

• Kearns-Sayre syndrome (KSS) (“ophthalmoplegia plus”) is a sporadic disorder

• It may present with cerebellar ataxia in addition to the progressive external ophthalmoplegia, pigmentary retinopathy, and cardiac conduction defects

Toxic and Acquired Metabolic Diseases

Toxic and Acquired Metabolic Diseases

Vitamin Deficiencies

Vitamin Deficiencies

Thiamine (Vitamin B1) Deficiency




• Thiamine deficiency may lead to the development of psychotic symptoms or ophthalmoplegia that begin abruptly, a syndrome termed Wernicke encephalopathy

• The acute stages, if unrecognized and untreated, may be followed by a prolonged and largely irreversible condition, Korsakoff syndrome, characterized clinically by memory disturbances and confabulation

• The syndrome is particularly common in the setting of chronic alcoholism, but may also be encountered in patients with thiamine deficiency resulting from gastric disorders, including carcinoma, chronic gastritis, or persistent vomiting

• Thiamine deficiency may lead to the development of psychotic symptoms or ophthalmoplegia that begin abruptly, a syndrome termed Wernicke encephalopathy

• The acute stages, if unrecognized and untreated, may be followed by a prolonged and largely irreversible condition, Korsakoff syndrome, characterized clinically by memory disturbances and confabulation

• The syndrome is particularly common in the setting of chronic alcoholism, but may also be encountered in patients with thiamine deficiency resulting from gastric disorders, including carcinoma, chronic gastritis, or persistent vomiting



• Wernicke encephalopathy is characterized by foci of hemorrhage and necrosis, particularly in the mammillary bodies but also adjacent to the ventricle, especially the third and fourth ventricles

• Wernicke encephalopathy is characterized by foci of hemorrhage and necrosis, particularly in the mammillary bodies but also adjacent to the ventricle, especially the third and fourth ventricles


Vitamin B12 DeficiencyVitamin B12 Deficiency

Vitamin B12 DeficiencyVitamin B12 Deficiency

• Deficiency of vitamin B12 often causes anemia, but its most severe and potentially irreversible effects are related to nervous system lesions

• Complete paraplegia may occur, usually only later in the course of the disease

• The combined degeneration of both ascending and descending tracts of the spinal cord is characteristic of vitamin B12 deficiency and has led to the designation of the disorder as subacute combined degeneration of the spinal cord

• Deficiency of vitamin B12 often causes anemia, but its most severe and potentially irreversible effects are related to nervous system lesions

• Complete paraplegia may occur, usually only later in the course of the disease

• The combined degeneration of both ascending and descending tracts of the spinal cord is characteristic of vitamin B12 deficiency and has led to the designation of the disorder as subacute combined degeneration of the spinal cord

Neurologic Sequelae of Metabolic

Disturbances

Neurologic Sequelae of Metabolic

Disturbances

HypoglycemiaHypoglycemia

HypoglycemiaHypoglycemia• Some regions of the brain are more sensitive to

hypoglycemia than are others

• Glucose-deprivation initially leads to selective injury to large pyramidal neurons of the cerebral cortex, which, if it is severely involved, may result in pseudolaminar necrosis of the cortex, predominantly involving layers II to V

• The hippocampus is also vulnerable to glucose depletion, as it is to hypoxia, and may show a dramatic loss of pyramidal neurons in Sommer sector (area CA1 of the hippocampus)

• Some regions of the brain are more sensitive to hypoglycemia than are others

• Glucose-deprivation initially leads to selective injury to large pyramidal neurons of the cerebral cortex, which, if it is severely involved, may result in pseudolaminar necrosis of the cortex, predominantly involving layers II to V

• The hippocampus is also vulnerable to glucose depletion, as it is to hypoxia, and may show a dramatic loss of pyramidal neurons in Sommer sector (area CA1 of the hippocampus)

HypoglycemiaHypoglycemia

• Purkinje cells of the cerebellum are also vulnerable to hypoglycemia, although to a lesser extent than to hypoxia

• If the level and duration of hypoglycemia are of sufficient severity, there may be widespread injury to many areas of the brain

• Purkinje cells of the cerebellum are also vulnerable to hypoglycemia, although to a lesser extent than to hypoxia

• If the level and duration of hypoglycemia are of sufficient severity, there may be widespread injury to many areas of the brain

Hyperglycemia

Hyperglycemia

HyperglycemiaHyperglycemia

• Hyperglycemia is most commonly found in the setting of inadequately controlled diabetes mellitus and can be associated with either ketoacidosis or hyperosmolar coma

• The patient becomes dehydrated and develops confusion, stupor, and eventually coma

• The fluid depletion must be corrected gradually, otherwise severe cerebral edema may follow

• Hyperglycemia is most commonly found in the setting of inadequately controlled diabetes mellitus and can be associated with either ketoacidosis or hyperosmolar coma

• The patient becomes dehydrated and develops confusion, stupor, and eventually coma

• The fluid depletion must be corrected gradually, otherwise severe cerebral edema may follow

Hepatic Encephalopat

hy

Hepatic Encephalopat

hy

Hepatic Encephalopathy

Hepatic Encephalopathy

• The cellular response in the CNS is predominantly glial

• Alzheimer type II changes are evident in the cortex and basal ganglia and other subcortical gray matter regions

• The cellular response in the CNS is predominantly glial

• Alzheimer type II changes are evident in the cortex and basal ganglia and other subcortical gray matter regions

Toxic Disorders

Toxic Disorders

Carbon MonoxideCarbon

Monoxide

Carbon MonoxideCarbon Monoxide

• Selective injury to the neurons of layers III and V of the cerebral cortex, Sommer sector of the hippocampus, and Purkinje cells is the recognized consequence of carbon monoxide exposure

• Bilateral necrosis of the globus pallidus may also occur, and is more common in carbon monoxide-induced hypoxia than in hypoxia from other causes

• Demyelination of white matter tracts may be a later event

• Selective injury to the neurons of layers III and V of the cerebral cortex, Sommer sector of the hippocampus, and Purkinje cells is the recognized consequence of carbon monoxide exposure

• Bilateral necrosis of the globus pallidus may also occur, and is more common in carbon monoxide-induced hypoxia than in hypoxia from other causes

• Demyelination of white matter tracts may be a later event

MethanolMethanol

MethanolMethanol

• The pathologic findings of methanol toxicity are seen in the retina, where degeneration of retinal ganglion cells may cause blindness

• Selective bilateral putamenal necrosis and focal white matter necrosis also occur when the exposure is severe

• The pathologic findings of methanol toxicity are seen in the retina, where degeneration of retinal ganglion cells may cause blindness

• Selective bilateral putamenal necrosis and focal white matter necrosis also occur when the exposure is severe

EthanolEthanol

EthanolEthanol• The effects of acute ethanol intoxication are reversible, but

chronic alcohol abuse is associated with a variety of neurologic sequelae, including Wernicke-Korsakoff syndrome

• The “toxic” effects of chronic alcohol intake may be either direct effects of ethanol or secondary nutritional deficits

• Cerebellar dysfunction occurs in about 1% of chronic alcoholics, associated with a clinical syndrome of truncal ataxia, unsteady gait, and nystagmus

• The histologic changes are atrophy and loss of granule cells predominantly in the anterior vermis

• In advanced cases, there is loss of Purkinje cells and proliferation of the adjacent astrocytes (Bergmann gliosis) between the depleted granular cell layer and the molecular layer of the cerebellum

• The effects of acute ethanol intoxication are reversible, but chronic alcohol abuse is associated with a variety of neurologic sequelae, including Wernicke-Korsakoff syndrome

• The “toxic” effects of chronic alcohol intake may be either direct effects of ethanol or secondary nutritional deficits

• Cerebellar dysfunction occurs in about 1% of chronic alcoholics, associated with a clinical syndrome of truncal ataxia, unsteady gait, and nystagmus

• The histologic changes are atrophy and loss of granule cells predominantly in the anterior vermis

• In advanced cases, there is loss of Purkinje cells and proliferation of the adjacent astrocytes (Bergmann gliosis) between the depleted granular cell layer and the molecular layer of the cerebellum

Alcoholic cerebellar degeneration. The anterior portion of the vermis (upper portion of figure) is atrophic with widened

spaces between the folia.

Alcoholic cerebellar degeneration. The anterior portion of the vermis (upper portion of figure) is atrophic with widened

spaces between the folia.

RadiationRadiation

RadiationRadiation• Delayed effects of radiation include headaches,

nausea, vomiting, and papilledema that may develop months to years after irradiation

• The pathologic findings consist of large areas of coagulative necrosis with adjacent edema

• Adjacent to the area of coagulative necrosis, proteinaceous spheroids may be identified, and blood vessels exhibit thickened walls with intramural fibrin-like material

• Radiation can also induce tumors and include poorly differentiated sarcomas, gliomas, and meningiomas

• Delayed effects of radiation include headaches, nausea, vomiting, and papilledema that may develop months to years after irradiation

• The pathologic findings consist of large areas of coagulative necrosis with adjacent edema

• Adjacent to the area of coagulative necrosis, proteinaceous spheroids may be identified, and blood vessels exhibit thickened walls with intramural fibrin-like material

• Radiation can also induce tumors and include poorly differentiated sarcomas, gliomas, and meningiomas

Combined Methotrexate

and Radiation-Induced Injury

Combined Methotrexate

and Radiation-Induced Injury

Combined Methotrexate and Radiation-Induced

Injury


Injury

• Symptoms often begin with drowsiness, ataxia, and confusion, and may progress rapidly

• While some patients recover function after the initial onset of symptoms, others may become comatose

• Rarely, methotrexate neurotoxicity may be responsible for the patient’s death

• Symptoms often begin with drowsiness, ataxia, and confusion, and may progress rapidly

• While some patients recover function after the initial onset of symptoms, others may become comatose

• Rarely, methotrexate neurotoxicity may be responsible for the patient’s death


Injury


Injury

• The pathologic basis of the symptoms are focal areas of coagulative necrosis within white matter, often adjacent to the lateral ventricles but at times distributed throughout the white matter or in the brainstem

• Surrounding axons are often dilated and form axonal spheroids

• Axons and cell bodies in the vicinity of the lesions undergo dystrophic mineralization, and there is adjacent gliosis

• The pathologic basis of the symptoms are focal areas of coagulative necrosis within white matter, often adjacent to the lateral ventricles but at times distributed throughout the white matter or in the brainstem

• Surrounding axons are often dilated and form axonal spheroids

• Axons and cell bodies in the vicinity of the lesions undergo dystrophic mineralization, and there is adjacent gliosis

TumorsTumors

TumorsTumors• The annual incidence of tumors of the

CNS ranges from 10 to 17 per 100,000 persons for intracranial tumors and 1 to 2 per 100,000 persons for intraspinal tumors

• About half to three-quarters are primary tumors, and the rest are metastatic

• Tumors of the CNS account for 20% of all cancers of childhood

• The annual incidence of tumors of the CNS ranges from 10 to 17 per 100,000 persons for intracranial tumors and 1 to 2 per 100,000 persons for intraspinal tumors

• About half to three-quarters are primary tumors, and the rest are metastatic

• Tumors of the CNS account for 20% of all cancers of childhood

TumorsTumors

• 70% of childhood CNS tumors arise in the posterior fossa

• A comparable number of tumors in adults arise within the cerebral hemispheres above the tentorium

• 70% of childhood CNS tumors arise in the posterior fossa

• A comparable number of tumors in adults arise within the cerebral hemispheres above the tentorium

TumorsTumors• Tumors of the nervous system have unique

characteristics:

• The distinction between benign and malignant lesions is less evident in the CNS than in other organs

• The ability to surgically resect infiltrating glial neoplasms without compromising neurologic function is limited

• The anatomic site of the neoplasm can have lethal consequences irrespective of histologic classification

• The pattern of spread of primary CNS neoplasms differs from that of other tumors

• Tumors of the nervous system have unique characteristics:

• The distinction between benign and malignant lesions is less evident in the CNS than in other organs

• The ability to surgically resect infiltrating glial neoplasms without compromising neurologic function is limited

• The anatomic site of the neoplasm can have lethal consequences irrespective of histologic classification

• The pattern of spread of primary CNS neoplasms differs from that of other tumors

TumorsTumors

• The four major classes of brain tumors are:

• Gliomas

• Neuronal tumors

• Poorly differentiated neoplasms

• Meningiomas

• The four major classes of brain tumors are:

• Gliomas

• Neuronal tumors

• Poorly differentiated neoplasms

• Meningiomas

GliomasGliomas

GliomasGliomas

• Gliomas are derived from glial cells, and they include astrocytomas, oligodendrogliomas, and ependymomas

• Gliomas are derived from glial cells, and they include astrocytomas, oligodendrogliomas, and ependymomas

GliomasGliomas

• Astrocytoma

• Fibrillary (Diffuse) Astrocytomas and Glioblastomas

• These account for about 80% of adult primary brain tumors

• Usually found in the cerebral hemisphere, although they may also occur in the cerebellum, brainstem, or spinal cord, most often in the fourth through sixth decades

• Astrocytoma


• These account for about 80% of adult primary brain tumors

• Usually found in the cerebral hemisphere, although they may also occur in the cerebellum, brainstem, or spinal cord, most often in the fourth through sixth decades

GliomasGliomas

• Astrocytoma


• Range: anaplastic astrocytoma to glioblastoma

• Macroscopic appearance of diffuse fibrillary astrocytoma: poorly defined, gray, infiltrative tumor that expands and distorts the invaded brain

• Astrocytoma


• Range: anaplastic astrocytoma to glioblastoma

• Macroscopic appearance of diffuse fibrillary astrocytoma: poorly defined, gray, infiltrative tumor that expands and distorts the invaded brain


Well-differentiated astrocytoma. A, the

right frontal tumor has expanded gyri, which

led to flattening (arrows).

Well-differentiated astrocytoma. A, the

right frontal tumor has expanded gyri, which

led to flattening (arrows).

GliomasGliomas

• Astrocytoma


• 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

• Astrocytoma


• 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


B, Glioblastoma multiforme appearing

as a necrotic, hemorrhagic, infiltrating

mass.

B, Glioblastoma multiforme appearing

as a necrotic, hemorrhagic, infiltrating

mass.

GliomasGliomas

• Astrocytoma


• Radiologic studies show mass effect as well as changes in the brain adjacent to the tumor, such as edema

• Astrocytoma


• Radiologic studies show mass effect as well as changes in the brain adjacent to the tumor, such as edema


GliomasGliomas

• Astrocytoma


• Gemistocytic astrocytoma is used for tumors in which the predominant neoplastic astrocyte shows a brightly eosinophilic cell body from which emanate abundant, stout processes

• Astrocytoma


• Gemistocytic astrocytoma is used for tumors in which the predominant neoplastic astrocyte shows a brightly eosinophilic cell body from which emanate abundant, stout processes


GliomasGliomas

• Astrocytoma


• Glioblastoma (previously called glioblastoma multiforme)

• Astrocytoma


• Glioblastoma (previously called glioblastoma multiforme)


Glioblastoma. Foci of necrosis with pseudopalisading of malignant nuclei.

Also, glomeruloid body.

Glioblastoma. Foci of necrosis with pseudopalisading of malignant nuclei.

Also, glomeruloid body.

GliomasGliomas

• Astrocytoma


• Gliomatosis cerebri: multiple regions in the brain, in some cases the entire brain, are infiltrated by neoplastic astrocytes

• Astrocytoma


• Gliomatosis cerebri: multiple regions in the brain, in some cases the entire brain, are infiltrated by neoplastic astrocytes


GliomasGliomas• Astrocytoma


• Molecular Genetics

• Among the alterations that are most commonly found in the low-grade astrocytomas are inactivation of p53 and overexpression of PDGF-A and its receptor

• The transition to higher-grade astrocytoma is associated with additional disruption of tumor-suppressor genes, the RB gene, the p16/CDKNZA gene, and a putative tumor suppressor on chromosome 19q

• Astrocytoma



• Among the alterations that are most commonly found in the low-grade astrocytomas are inactivation of p53 and overexpression of PDGF-A and its receptor

• The transition to higher-grade astrocytoma is associated with additional disruption of tumor-suppressor genes, the RB gene, the p16/CDKNZA gene, and a putative tumor suppressor on chromosome 19q




• Two distinct clinical histories associated with glioblastoma:

• A short, rapidly progressive disease arising without a preexisting low-grade tumor, typically in older individuals (primary glioblastoma)

• A disease of comparable clinical course that arose in younger patients with a previously diagnosed lower-grade astrocytoma (secondary glioblastoma)

• Astrocytoma



• Two distinct clinical histories associated with glioblastoma:

• A short, rapidly progressive disease arising without a preexisting low-grade tumor, typically in older individuals (primary glioblastoma)

• A disease of comparable clinical course that arose in younger patients with a previously diagnosed lower-grade astrocytoma (secondary glioblastoma)




• The presenting symptoms of astrocytomas depend, in part, on the location of the tumor and its rate of growth

• With well-differentiated astrocytomas, the symptoms may remain static or progress only slowly over a number of years, with a mean survival of more than 5 years

• Astrocytoma



• The presenting symptoms of astrocytomas depend, in part, on the location of the tumor and its rate of growth

• With well-differentiated astrocytomas, the symptoms may remain static or progress only slowly over a number of years, with a mean survival of more than 5 years




• The prognosis for patients with glioblastoma is very poor

• With current treatment, consisting of resection when feasible together with radiotherapy and chemotherapy, the mean length of survival after diagnosis is only 8 to 10 months

• Fewer than 10% of patients are alive after 2 years

• Astrocytoma



• The prognosis for patients with glioblastoma is very poor

• With current treatment, consisting of resection when feasible together with radiotherapy and chemotherapy, the mean length of survival after diagnosis is only 8 to 10 months

• Fewer than 10% of patients are alive after 2 years

GliomasGliomas

• Astrocytoma

• Pilocytic Astrocytoma

• Occur in children and young adults and are usually located in the cerebellum but may also appear in the floor and walls of the third ventricle, the optic nerves, and occasionally the cerebral hemispheres

• These tumors grow very slowly

• Astrocytoma

• Pilocytic Astrocytoma

• Occur in children and young adults and are usually located in the cerebellum but may also appear in the floor and walls of the third ventricle, the optic nerves, and occasionally the cerebral hemispheres

• These tumors grow very slowly

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

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


• Pleomorphic Xanthoastrocytoma

• This is a tumor that occurs most often relatively superficially in the temporal lobe of children and young adults, usually with a history of seizures

• On microscopic examination, the tumor consists of neoplastic, occasionally bizarre, astrocytes, which are sometimes lipidized

• Survival rate: 80% at 5 years

• Astrocytoma

• Pleomorphic Xanthoastrocytoma

• This is a tumor that occurs most often relatively superficially in the temporal lobe of children and young adults, usually with a history of seizures

• On microscopic examination, the tumor consists of neoplastic, occasionally bizarre, astrocytes, which are sometimes lipidized

• Survival rate: 80% at 5 years


• Brainstem Glioma

• A clinical subgroup of astrocytomas, brainstem gliomas occur mostly in the first two decades of life and make up about 20% of primary brain tumors in this age group

• Among the rarer brainstem gliomas affecting adults, most are intrinsic pontine gliomas

• Astrocytoma

• Brainstem Glioma

• A clinical subgroup of astrocytomas, brainstem gliomas occur mostly in the first two decades of life and make up about 20% of primary brain tumors in this age group

• Among the rarer brainstem gliomas affecting adults, most are intrinsic pontine gliomas

GliomasGliomas• Oligodendroglioma

• These tumors constitute 5% to 15% of gliomas and are most common in the fourth and fifth decades

• Patients may have had several years of neurologic complaints, often including seizures

• The lesions are found mostly in the cerebral hemispheres, with a predilection for white matter

• Oligodendroglioma

• These tumors constitute 5% to 15% of gliomas and are most common in the fourth and fifth decades

• Patients may have had several years of neurologic complaints, often including seizures

• The lesions are found mostly in the cerebral hemispheres, with a predilection for white matter

GliomasGliomas• Oligodendroglioma


• The most common genetic alterations in oligodendrogliomas are loss of heterozygosity for chromosomes 1p and 19q

• Additional genetic alterations tend to accumulate: loss of 9p, loss of 10q, and mutation in CDKN2A

• Tumors with loss of 1p and 19q but without other alterations have a consistent and long-lasting response to therapy (chemotherapy and radiation)

• Those with additional genetic changes have a shorter-lived response, and those without loss of 1p and 19q appear to be refractory to these therapies



• The most common genetic alterations in oligodendrogliomas are loss of heterozygosity for chromosomes 1p and 19q

• Additional genetic alterations tend to accumulate: loss of 9p, loss of 10q, and mutation in CDKN2A

• Tumors with loss of 1p and 19q but without other alterations have a consistent and long-lasting response to therapy (chemotherapy and radiation)

• Those with additional genetic changes have a shorter-lived response, and those without loss of 1p and 19q appear to be refractory to these therapies

GliomasGliomas



• Oligodendrogliomas have a better prognosis than do patients with astrocytomas

• Current treatment with surgery, chemotherapy, and radiotherapy has yielded an average survival of 5 to 10 years



• Oligodendrogliomas have a better prognosis than do patients with astrocytomas

• Current treatment with surgery, chemotherapy, and radiotherapy has yielded an average survival of 5 to 10 years

GliomasGliomas• Ependymoma and Related Paraventricular

Mass Lesions

• In the first two decades of life, ependymomas typically occur near the fourth ventricle and constitute 5% to 10% of the primary brain tumors in this age group

• In adults, the spinal cord is their most common location

• Tumors in this site are particularly frequent in the setting of neurofibromatosis type 2

• Ependymoma and Related Paraventricular Mass Lesions

• In the first two decades of life, ependymomas typically occur near the fourth ventricle and constitute 5% to 10% of the primary brain tumors in this age group

• In adults, the spinal cord is their most common location

• Tumors in this site are particularly frequent in the setting of neurofibromatosis type 2

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

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

GliomasGliomas


• Tumor cells may form gland-like round or elongated structures (rosettes, canals) that resemble the embryologic ependymal canal, with long, delicate processes extending into the lumen

• More frequently present are perivascular pseudorosettes, in which tumors are arranged around vessels with an intervening zone consisting of thin ependymal processes directed toward the wall of the vessel


• Tumor cells may form gland-like round or elongated structures (rosettes, canals) that resemble the embryologic ependymal canal, with long, delicate processes extending into the lumen

• More frequently present are perivascular pseudorosettes, in which tumors are arranged around vessels with an intervening zone consisting of thin ependymal processes directed toward the wall of the vessel


Ependymoma. B, Microscopic apearance

of ependymoma.

Ependymoma. B, Microscopic apearance

of ependymoma.


Mass Lesions


• Because of the association of spinal ependymomas with neurofibromatosis type 2, the NF2 gene on chromosome 22 has been examined as a candidate locus for alterations in ependymomas

• It appears that alterations at this site may be involved in the pathogenesis of ependymomas in the spinal cord but not at other sites



• Because of the association of spinal ependymomas with neurofibromatosis type 2, the NF2 gene on chromosome 22 has been examined as a candidate locus for alterations in ependymomas

• It appears that alterations at this site may be involved in the pathogenesis of ependymomas in the spinal cord but not at other sites


Mass Lesions


• Posterior fossa ependymomas often manifest with hydrocephalus secondary to progressive obstruction of the fourth ventricle rather than invasion of the pons or medulla

• Prognosis is poor

• CSF dissemination is a common occurrence

• An average survival of about 4 years after surgery and radiotherapy has been reported



• Posterior fossa ependymomas often manifest with hydrocephalus secondary to progressive obstruction of the fourth ventricle rather than invasion of the pons or medulla

• Prognosis is poor

• CSF dissemination is a common occurrence

• An average survival of about 4 years after surgery and radiotherapy has been reported

GliomasGliomas• Ependymoma and Related Paraventricular Mass Lesions

• Several other tumors occur either immediately below the ependymal lining of the ventricle or in association with the other cell type that forms the walls of the ventricular system: choroid plexus

• Subependymomas are solid, sometimes calcified, slow-growing nodules attached to the ventricular lining and protruding into the ventricle

• They are usually asymptomatic; if they are sufficiently large or strategically located, they may cause hydrocephalus

• They are most often found in the lateral and fourth ventricles


• Several other tumors occur either immediately below the ependymal lining of the ventricle or in association with the other cell type that forms the walls of the ventricular system: choroid plexus

• Subependymomas are solid, sometimes calcified, slow-growing nodules attached to the ventricular lining and protruding into the ventricle

• They are usually asymptomatic; if they are sufficiently large or strategically located, they may cause hydrocephalus

• They are most often found in the lateral and fourth ventricles

GliomasGliomas• Ependymoma and Related Paraventricular Mass Lesions

• Several other tumors occur either immediately below the ependymal lining of the ventricle or in association with the other cell type that forms the walls of the ventricular system: choiroid plexus

• Choroid plexus papillomas can occur anywhere along the choroid plexus and are most common in children in whom they are most often found in the lateral ventricles

• In adults, they are more often found in the fourth ventricle

• There are rare cases of choroid plexus carcinoma

• These are usually found in children and may be associated with Li-Fraumeni syndrome



• Choroid plexus papillomas can occur anywhere along the choroid plexus and are most common in children in whom they are most often found in the lateral ventricles

• In adults, they are more often found in the fourth ventricle

• There are rare cases of choroid plexus carcinoma

• These are usually found in children and may be associated with Li-Fraumeni syndrome

GliomasGliomas• Ependymoma and Related Paraventricular Mass

Lesions


• Colloid cyst of the third ventricle is a non-neoplastic lesion that most often occurs in young adults

• Headache, sometimes positional, is an important clinical symptom



• Colloid cyst of the third ventricle is a non-neoplastic lesion that most often occurs in young adults

• Headache, sometimes positional, is an important clinical symptom

Neuronal Tumors

Neuronal Tumors

Neuronal TumorsNeuronal Tumors

• Ganglion Cell Tumors

• Several types of CNS tumors contain mature-appearing neurons (ganglion cells), these may constitute the entire population of the lesion (gangliocytomas)

• More commonly, there is an admixture with a glial neoplasm, and the lesion is termed ganglioglioma

• Ganglion Cell Tumors

• Several types of CNS tumors contain mature-appearing neurons (ganglion cells), these may constitute the entire population of the lesion (gangliocytomas)

• More commonly, there is an admixture with a glial neoplasm, and the lesion is termed ganglioglioma

Neuronal TumorsNeuronal Tumors

• Other Tumors with Glial and Neuronal Components

• Dysembryoplastic neuroepithelial tumor (DNT) is a distinctive, low-grade tumor of childhood that often presents as a seizure disorder, showing slow growth and a relatively good prognosis after surgical extirpation

• Other Tumors with Glial and Neuronal Components

• Dysembryoplastic neuroepithelial tumor (DNT) is a distinctive, low-grade tumor of childhood that often presents as a seizure disorder, showing slow growth and a relatively good prognosis after surgical extirpation

Neuronal TumorsNeuronal Tumors• Tumors with Only Neuronal Elements

• Cerebral neuroblastomas are rare neoplasms that occur in the hemispheres of children and show highly aggressive clinical behavior

• Central neurocytoma typically is a low-grade neuronal neoplasm found within and adjacent to the ventricular system (most commonly the lateral or third ventricles)

• Tumors with Only Neuronal Elements

• Cerebral neuroblastomas are rare neoplasms that occur in the hemispheres of children and show highly aggressive clinical behavior

• Central neurocytoma typically is a low-grade neuronal neoplasm found within and adjacent to the ventricular system (most commonly the lateral or third ventricles)

Poorly Differentiated

Neoplasms

Poorly Differentiated

Neoplasms

Poorly Differentiated Neoplasms


• Medulloblastoma

• This tumor occurs predominantly in children and exclusively in the cerebellum

• Medulloblastoma

• This tumor occurs predominantly in children and exclusively in the cerebellum



• Medulloblastoma

• In children, medulloblastomas are located in the midline of the cerebellum, but lateral locations are more often found in adults

• Rapid growth may occlude the flow of CSF, leading to hydrocephalus

• The tumor is often well circumscribed, gray, and friable and may be seen extending to the surface of the cerebellar folia and involving the leptomeninges

• Medulloblastoma

• In children, medulloblastomas are located in the midline of the cerebellum, but lateral locations are more often found in adults

• Rapid growth may occlude the flow of CSF, leading to hydrocephalus

• The tumor is often well circumscribed, gray, and friable and may be seen extending to the surface of the cerebellar folia and involving the leptomeninges


Medulloblastoma. B, Sagittal section of brain showing medulloblastoma destroying the superior

midline cerebellum.

Medulloblastoma. B, Sagittal section of brain showing medulloblastoma destroying the superior

midline cerebellum.

Medulloblastoma. C, Microscopic appearance of medulloblastoma.

Medulloblastoma. C, Microscopic appearance of medulloblastoma.



• Medulloblastoma

• The desmoplastic variant is characterized by areas of stromal response with collagen and reticulin deposition and nodules of cells forming “pale islands” that have more neuropil and lack the reticulin deposition

• Medulloblastoma

• The desmoplastic variant is characterized by areas of stromal response with collagen and reticulin deposition and nodules of cells forming “pale islands” that have more neuropil and lack the reticulin deposition




• Medulloblastoma


• The most common genetic alteration is loss of material from the short arm of chromosome 17

• Medulloblastoma


• The most common genetic alteration is loss of material from the short arm of chromosome 17



• Medulloblastoma


• The tumor is highly malignant, and the prognosis of untreated patients is dismal

• However, it is an exquisitely radiosensitive tumor

• Prognosis is also related to the amount of tumor resected, with better survival rates following complete resection

• In addition, radiation of the brain and spinal cord decreases the likelihood of recurrence

• With total excision and radiation, the 5-year survival rate may be as high as 75%

• Medulloblastoma


• The tumor is highly malignant, and the prognosis of untreated patients is dismal

• However, it is an exquisitely radiosensitive tumor

• Prognosis is also related to the amount of tumor resected, with better survival rates following complete resection

• In addition, radiation of the brain and spinal cord decreases the likelihood of recurrence

• With total excision and radiation, the 5-year survival rate may be as high as 75%



• Atypical Teratoid/Rhabdoid Tumor (AT/RT)

• This is a highly malignant tumor of young children

• The lesions are found in the posterior fossa and supratentorial compartments in nearly equal proportion


• This is a highly malignant tumor of young children

• The lesions are found in the posterior fossa and supratentorial compartments in nearly equal proportion





• One of the distinguishing features that allowed this lesion to be recognized as a separate entity was the frequent (>90%) evidence of loss of genetic material from chromosome 22



• One of the distinguishing features that allowed this lesion to be recognized as a separate entity was the frequent (>90%) evidence of loss of genetic material from chromosome 22





• These are highly aggressive tumors of the very young, nearly all tumors occurring before the age of 5 and most patients living less than a year after diagnosis



• These are highly aggressive tumors of the very young, nearly all tumors occurring before the age of 5 and most patients living less than a year after diagnosis

Other Parenchymal

Tumors

Other Parenchymal

Tumors

Other Parenchymal Tumors


• Germ Cell Tumors

• Primary brain germ cell tumors occur along the midline, most commonly in the pineal and the suprasellar regions

• They account for 0.2% to 1% of brain tumors in people of European descent but up to 10% in Japanese people

• They are a tumor of the young, with 90% occurring during the first two decades


• Primary brain germ cell tumors occur along the midline, most commonly in the pineal and the suprasellar regions

• They account for 0.2% to 1% of brain tumors in people of European descent but up to 10% in Japanese people

• They are a tumor of the young, with 90% occurring during the first two decades




• Germ cell tumors, particularly teratomas, are among the more common tumors that present as congenital tumor

• Germ cell tumors in the pineal region show a strong male predominance

• The tumor frequently extends into the CSF, and it can disseminate widely along the surface of the brain and within the ventricular system, complicating therapy


• Germ cell tumors, particularly teratomas, are among the more common tumors that present as congenital tumor

• Germ cell tumors in the pineal region show a strong male predominance

• The tumor frequently extends into the CSF, and it can disseminate widely along the surface of the brain and within the ventricular system, complicating therapy



• Pineal Parenchymal Tumors

• These lesions arise from the specialized cells of the pineal gland (pineocytes)

• The tumors range in histologic appearance from well-differentiated lesions (pineocytomas) with areas of neuropil-tumor cells with small, round nuclei and no evidence of mitoses or necrosis-to high-grade tumors (pineoblastomas) of densely packed small cells with necrosis and frequent mitotic figures


• These lesions arise from the specialized cells of the pineal gland (pineocytes)

• The tumors range in histologic appearance from well-differentiated lesions (pineocytomas) with areas of neuropil-tumor cells with small, round nuclei and no evidence of mitoses or necrosis-to high-grade tumors (pineoblastomas) of densely packed small cells with necrosis and frequent mitotic figures




• The highly aggressive pineoblastoma commonly spreads throughout the CSF space, is more commonly found in children, and may occur in patients with bilateral retinoblastoma, associated with mutations in RB

• Gliomas are also found in the pineal region


• The highly aggressive pineoblastoma commonly spreads throughout the CSF space, is more commonly found in children, and may occur in patients with bilateral retinoblastoma, associated with mutations in RB

• Gliomas are also found in the pineal region

MeningiomasMeningiomas


• Meningiomas are predominantly benign tumors of adults, usually attached to the dura, that arise from the meningothelial cell of the arachnoid

• Meningiomas are predominantly benign tumors of adults, usually attached to the dura, that arise from the meningothelial cell of the arachnoid

A, parasagittal multilobular meningioma

attached to the dura with

compression of underlying brain.

B, Meningioma with a whorled pattern of cell growth and

psammoma bodies.

A, parasagittal multilobular meningioma

attached to the dura with

compression of underlying brain.

B, Meningioma with a whorled pattern of cell growth and

psammoma bodies.

MeningiomasMeningiomas• Atypical meningiomas are lesions with

a higher rate of recurrence and more aggressive local growth thta may require therapy in addition to surgery

• Anaplastic (malignant) meningioma is a highly aggressive tumor that has the overall appearance of high-grade sarcoma, although there is usually some histologic evidence that indicates a meningothelial cell origin

• Atypical meningiomas are lesions with a higher rate of recurrence and more aggressive local growth thta may require therapy in addition to surgery

• Anaplastic (malignant) meningioma is a highly aggressive tumor that has the overall appearance of high-grade sarcoma, although there is usually some histologic evidence that indicates a meningothelial cell origin


• Most meningiomas are easily separable from the brain even if they displace it; some tumors infiltrate the brain

• Meningiomas are commonly immunoreactive for epithelial membrane antigen

• Keratin is restricted to lesions with the secretory pattern, and these tumors are also positive for carcinoembryonic antigen

• Most meningiomas are easily separable from the brain even if they displace it; some tumors infiltrate the brain

• Meningiomas are commonly immunoreactive for epithelial membrane antigen

• Keratin is restricted to lesions with the secretory pattern, and these tumors are also positive for carcinoembryonic antigen



• The most common cytogenetic abnormality is loss of chromosome 22, especially the long arm (22q)


• The most common cytogenetic abnormality is loss of chromosome 22, especially the long arm (22q)



• Meningiomas are usually slow-growing lesions that present either with vague nonlocalizing symptoms or with focal findings referable to compression of underlying brain

• They are uncommon in children and show a moderate (3:2) female predominance


• Meningiomas are usually slow-growing lesions that present either with vague nonlocalizing symptoms or with focal findings referable to compression of underlying brain

• They are uncommon in children and show a moderate (3:2) female predominance

Metastatic Tumors

Metastatic Tumors

Metastatic TumorsMetastatic Tumors

• Metastatic lesions, mostly carcinomas, account for approximately a quarter of half of intracranial tumors in hospital patients

• The five most common primary sites are lung, breast, skin (melanoma), kidney, and gastrointestinal tract, accounting for about 80% of all metastases

• Metastatic lesions, mostly carcinomas, account for approximately a quarter of half of intracranial tumors in hospital patients

• The five most common primary sites are lung, breast, skin (melanoma), kidney, and gastrointestinal tract, accounting for about 80% of all metastases

Paraneoplastic SyndromesParaneoplastic Syndromes

Paraneoplastic Syndromes


• 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

• The most common tumor causing paraneoplastic syndromes is small cell carcinoma of the lung

• 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

• The most common tumor causing paraneoplastic syndromes is small cell carcinoma of the lung



• Paraneoplstic cerebellar degeneration, in which typical morphologic findings include destruction of Purkinje cells, gliosis, and mild inflammatory infiltrate

• Limbic encephalitis is characterized by subacute dementia

• Subacute sensory neuropathy may be found in association with limbic encephalitis or in isolation

• Eye movement disorders -- in children, this is most commonly associated with neuroblastoma and is found along with myoclonus

• Paraneoplstic cerebellar degeneration, in which typical morphologic findings include destruction of Purkinje cells, gliosis, and mild inflammatory infiltrate

• Limbic encephalitis is characterized by subacute dementia

• Subacute sensory neuropathy may be found in association with limbic encephalitis or in isolation

• Eye movement disorders -- in children, this is most commonly associated with neuroblastoma and is found along with myoclonus

Peripheral Nerve Sheath

Tumors

Peripheral Nerve Sheath

Tumors

Peripheral Nerve Sheath Tumors


• These tumors arise from cells of the peripheral nerve, including Schwann cells, perineurial cells, and fibroblasts

• These tumors arise from cells of the peripheral nerve, including Schwann cells, perineurial cells, and fibroblasts



• Schwannoma

• These benign tumors arise from the neural crest-derived Schwann cell and are associated with neurofibromatosis type 2

• Schwannoma

• These benign tumors arise from the neural crest-derived Schwann cell and are associated with neurofibromatosis type 2



• Schwannoma


• Within the cranial vault, the most common location of schwannomas is in the cerebellopontine angle, where they are attached to the vestibular branch of the eighth nerve

• Patients often present with tinnitus and hearing loss

• Schwannoma


• Within the cranial vault, the most common location of schwannomas is in the cerebellopontine angle, where they are attached to the vestibular branch of the eighth nerve

• Patients often present with tinnitus and hearing loss

Schwannoma. A, Bilateral eighth nerve schwannomas.

Schwannoma. A, Bilateral eighth nerve schwannomas.

Schwannoma. B, Tumor showing cellular areas, including Verocay bodies (far right), as well as looser, myxoid regions.Schwannoma. B, Tumor showing cellular areas, including

Verocay bodies (far right), as well as looser, myxoid regions.



• Neurofibroma

• The most common form occurs in the skin (cutaneous neurofibroma) or in peripheral nerve (solitary neurofibroma)

• The skin lesions are evident as nodules, sometimes with overlying hyperpigmentation; they may grow to be large and become pedunculated

• Neurofibroma

• The most common form occurs in the skin (cutaneous neurofibroma) or in peripheral nerve (solitary neurofibroma)

• The skin lesions are evident as nodules, sometimes with overlying hyperpigmentation; they may grow to be large and become pedunculated



• Neurofibroma

• The second type is the plexiform neurofibroma

• A major concern in the care of these patients is the difficulty in surgical removal of these plexiform tumors when they involve major nerve trunks, since they have a significant potential for malignant transformation

• Neurofibroma

• The second type is the plexiform neurofibroma

• A major concern in the care of these patients is the difficulty in surgical removal of these plexiform tumors when they involve major nerve trunks, since they have a significant potential for malignant transformation



• Malignant Peripheral Nerve Sheath Tumor (MPNST, Malignant Schwannoma)

• MPNSTs are highly malignant sarcomas that are locally invasive, frequently leading to multiple recurrences and eventual metastatic spread

• They arise de novo or from transformation of plexiform neurofibroma and therefore are strongly associated with neurofibromatosis type 1

• These tumors may also follow radiation therapy

• Malignant Peripheral Nerve Sheath Tumor (MPNST, Malignant Schwannoma)

• MPNSTs are highly malignant sarcomas that are locally invasive, frequently leading to multiple recurrences and eventual metastatic spread

• They arise de novo or from transformation of plexiform neurofibroma and therefore are strongly associated with neurofibromatosis type 1

• These tumors may also follow radiation therapy

Credits

Books:PBD, 7th Ed.

Photos:PBD Interactive Case Study CompanionElsevier

Internet:

http://www.med.uottawa.ca/patho/neuro/introneuropathology.htm

http://www.radnet.ucla.edu/sections/DINR/Part%2013/Part13A2.htm







Documents

The central nervous system ii