Introduction on CNS injury
The CNS consists of neurons that receive, store & send information, & despite their specialized functions, there are still a growing number of injuries that affect the CNS.
The types of CNS injuries include: Acute neuronal injury (red neurons); subacute & chronic neuronal injury (degeneration); motor axons damage; neuronal inclusions; proteinopathies.
Acute neuronal injury arises from acute insults such as hypoxia, or ischemia & they result in cell death. Subacute & chronic neuronal injury is a progressive disease process that causes neuronal loss & reactive gliosis.
Motor axons damage occurs in the anterior horn of the spinal cord, with histologic changes within the cell body that cause axonal regeneration.
Neuronal inclusions result may result from aging, viral infections, & genetically-caused disorders of metabolism. There may be intracytoplasmic aggregations of lipids, carbohydrates or proteins. In viral infections there are nuclear inclusions such as Cowdry body (in herpes infections); cytoplasmic inclusions known as Negri body (in rabies); both nuclear & cytoplasmic (in CMV infections).
Proteinopathies result from mutations that lead to intracytoplasmic inclusions such as; neurofibrillary tangles (in Alzheimer disease); Lewy bodies (in Parkinson disease); neuronal vacuolization (in Creutzfeldt-Jakob disease).
Reactive changes of astrocytes & other glial cells to neuronal injuries in the CNS
Astrocytes control the flow of macromolecules between the blood, CSF & the brain in CNS. This is possible by their cytoplasmic processes wrapped around capillaries, subependymal cells, & subpial layers.
In a CNS neuronal injury of any etiology, astrocytes undergo reactive changes known as astrogliosis. The features of astrogliosis include hypertrophy, hyperplasia, & swelling (especially in acute astrocytic injuries from hypoglycemia, hypoxia etc.).
Examples of astrogliosis include: gemistocytic astrocytes; Alzheimer type II astrocytes; Rosenthal fibers; polyglucosan bodies (corpora amylacea); Lafora bodies.
Gemistocytic astrocytes have large, peripheral nuclei with prominent nucleoli, & large, brightly pinkish cytoplasm with numerous processes. Lafora bodies are cytoplasmic inclusion bodies seen in myoclonic epilepsy.
Alzheimer type II astrocytes have large central nuclei with prominent nucleolus & nuclear membrane. Found in hyperammonemia in chronic liver disease, metabolic disorders of the urea cycle, & Wilson disease.
Rosenthal fibers are thick, brightly eosinophilic cytoplasmic inclusion bodies within astrocytic processes. They are made of two heat-shock proteins (αβ-crystallin & hsp27) & ubiquitin. Seen in Alexander disease & pilocytic astrocytoma.
Polyglucosan bodies are periodic acid-Schiff (PAS)-positive cytoplasmic inclusion bodies, 5-50µm in diameter. They are made predominantly of glycosaminoglycan polymers. They increase with advancing age, & represent degenerative changes within astrocytes.
Oligodendroglial cytoplasmic processes wrap around the axons to form the myelin. Injuries and apoptosis result in demyelinating disorders & leukodystrophies. Viral nuclear inclusion bodies result in progressive multifocal leukoencephalopathy. Glial cytoplasmic inclusions made of α-synuclein are present in multiple system atrophy.
Brain edema
This is the swelling of the brain parenchyma. It may be vasogenic or cytotoxic. Vasogenic cerebral edema is the accumulation of fluid in the intercellular spaces of brain. It arises from the disruption of blood-brain barrier & increase in vascular permeability.
Cytotoxic cerebral edema is the intracellular accumulation of fluid following neuronal, glial, and endothelial cell injury. This injury may arise from hypoxia, ischemia, or metabolic damages.
Signs: In generalized edema, the gyri are wide, while the sulci are narrow.
Hydrocephalus
This is the accumulation of excessive cerebrospinal fluid (CSF) within the ventricles, which eventually raises the intracranial pressure. Normally, CSF within the subarachnoid space is drained by arachnoid granulations into dural venous sinuses.
Any impairment in flow and drainage may increase CSF volume. Another rare cause of hydrocephalus may be due to the tumor of the choroid plexus which overproduces CSF.
Signs/symptoms: In infants, macrocephaly (before cranial suture closure); expanded ventricles without macrocephaly (after suture closure).
Brain herniation
The displacement of particular regions of the brain following an increase in brain volume and elevated intracranial pressure. They are caused by mass effects generated following generalized edema, tumors, hemorrhage & abscesses.
Types of brain herniation include: subfalcine (cingulate); transtentorial (uncinate); & tonsillar herniation.
Subfalcine herniation is the displacement of the cingulate gyrus below the falx cerebri, arising from unilateral expansion of cerebral hemisphere. This may compress branches of the anterior cerebral artery.
Transtentorial herniation is the compression of the medial region of temporal lobe against the free margin of the tentorium cerebelli. This may result in 3rd cranial nerve compression eventually leading to pupillary dilation & impairment of ocular movements on same side of lesion; compression of the contralateral side of cerebral peduncle resulting in same side hemiparesis; secondary brainstem/Duret hemorrhages in the midbrain & pons.
Tonsillar herniation is the displacement of the cerebellar tonsils through the foramen magnum. It may compress the brainstem, eventually affecting respiratory and cardiac centers in the medulla oblongata.
Neural tube defects
These are malformations affecting the CNS neural tissues, meninges, overlying bone & soft tissues. They arise from failure of the closure of the neural tube, or reopening after closure.
They include: encephalocele; spinal bifida occulta; myelomeningocele; meningocele; anencephaly.
Encephalocele is the outpouching of abnormal CNS tissue through a defect in the cranium around the occipital or posterior fossa region. Spinal bifida occulta is an asymptomatic vertebral bone defect with intact CNS tissue.
Myelomeningocele is the protrusion of an abnormal CNS tissue with meninges through a vertebral bone defect. This is common in the lumbosacral region & may cause sensory & motor function impairment, including loss of bladder & bowel control.
Meningocele is the outpouching of just the meninges through the vertebral bone defect.
Anencephaly is the absence of forebrain and cranial vault resulting from malformation of the anterior region of neural tube.
Predisposing factor: folate deficiency. Diagnosis is by antenatal screening of maternal blood samples for high α-fetoprotein & ultrasound imaging.
Lissencephaly, Polymicrogyria, Neuronal heterotopias
These are developmental abnormalities affecting especially the forebrain. Lissencephaly is a decrease or total absence in the number of gyri, resulting in a smooth-surfaced brain. Results from mutation in gene coding for microtubule-associated protein LIS-1, which complexes with dynein & affects function of centrosome in nuclear movement.
Polymicrogyria are small, abnormally numerous, irregularly formed cerebral convolutions. They may arise from localized tissue injury towards the end of neuronal migration.
The types of neuronal heterotopias are periventricular & subcortical white matter, & they consist of collections of neurons in inappropriate locations. They arise from defective migration of neurons from the periventricular region to the cerebral cortex during fetal development. This causes epilepsy.
Megalencephaly, Microencephaly
These are also congenital anomalies that affect the forebrain. Megalencephaly is an abnormally large brain resulting from an expansion of proliferating precursor neuronal cells in the developing brain. This eventually leads to overproduction of neurons.
Microencephaly is an abnormally small brain resulting from a decrease in proliferating neuronal cells in the developing brain. This then results in an overall reduction in the generation of neurons.
Holoprosencephaly
Holoprosencephaly is an embryologic malformation that leads to the fusion of the cerebral hemispheres across the midline. It may manifest together with either cyclopia (single eye) or arrhinencephaly (congenital absence of CN 1, olfactory bulb, & olfactory tract.)
This condition develops from mutation affecting the sonic hedgehog (shh) protein or it’s signaling pathway. Shh is produced by the notochord and neural plates during neural development. This condition is associated with trisomy 13.
Dandy Walker malformation, Arnold-Chiari malformation type 1 & 2
These are congenital anomalies that affect the posterior fossa of the brain. Dandy Walker malformation consists of a posterior fossa enlargement, with a midline cyst in place of an absent cerebellar vermis. This cyst represents an expanded roofless IV ventricle.
Arnold-Chiari malformation type II consists of a small posterior fossa, with downward extension of vermis through the foramen magnum, hydrocephalus & lumbar myelomeningocele. Type 1 relates to downward extension of the cerebellar tonsils into the vertebral canal.
Syringomyelia, Syringobulbia, Hydromyelia
Syringomyelia is the formation of a fluid-filled cyst within the spinal cord. Syringobulbia is the presence of a fluid-filled cyst within the brainstem. Hydromyelia is the abnormal expansion of the CSF fluid-filled portion of the spinal cord central canal.
Predisposing factors for Syringomyelia include: Arnold-Chiari malformation type 1, traumatic injury, intraspinal tumors. Syringomyelia causes loss of pain & temperature sensation in the upper extremities, & manifests between. 20 & 30 yrs. of age.
Cerebral palsy
This is a nonprogressive neurologic motor deficit, with combinations of spasticity, dystonia, athetosis, & paresis. They arise from brain injuries sustained during prenatal & perinatal periods.
The causes include intraparenchymal hemorrhage, ischemia & infarction. The caudate, putamen, & thalamus are regions of the brains affected.
Traumatic brain injury (TBI)
This is a CNS trauma that affects the brain tissues and vessels, with or without a skull fracture. The causes include: jolting head movements; explosions; firearms; motor vehicle accidents. The degree of injury depends on the shape of injurious object, the force of impact, & moving head.
Signs of TBI include mastoid and orbital hematoma, CSF discharge from nose or ear, & traceable lower cranial nerve symptoms. These are all indicative of a basal skull fracture.
The sequelae of TBI that occur months or years after a TBI are: post-traumatic hydrocephalus; post-traumatic dementia & punch-drunk syndrome following years of repeated head trauma over a time duration; post-traumatic epilepsy; meningioma; psychiatric disorders; infectious diseases.
Types of traumatic TBIs include: concussion; contusion & laceration; diffuse axonal injury; epidural hemorrhage; subdural hemorrhage; & subarachnoid hemorrhage; & intracerebral hemorrhage.
Concussion
This is a brain injury brought about by a sudden impact of a rigid object against a moving head. Signs & symptoms include: transient loss of consciousness & reflexes; persistent amnesia of events leading to injury; & temporary respiratory arrest.
Contusion & Laceration
These are direct brain tissue lesions. Contusion is a hemorrhage & tissue injury brought about by a rapid brain tissue displacement & subsequent vascular disruption.
The mechanism involves transmission of kinetic energy to the brain from the site of direct impact (either by a blow). This may result in a coup injury (contusion at point of impact) or contrecoup injury (contusion opposite the point of impact). They are common on the frontal lobes (along orbital ridges) & temporal lobes.
Laceration is the tearing of brain tissue that arises from a penetrating object to the skull. In both lesions, hemorrhage spread across the cerebral cortex, white matter, & subarachnoid space.
Diffuse axonal injury
These are widespread, asymmetric axonal swellings that appear within an hour of injury, with focal hemorrhagic lesions. The swellings may persist for much longer & may arise during an angular accelerating motion of the head.
Signs/symptoms: coma shortly after trauma.
Affected areas include: deep white matter regions (corpus callosum, paraventricular, & hippocampal areas in the supratentorial compartment); cerebral peduncles; brachium conjunctivum; superior colliculi; & deep reticular formation in the brainstem.
Epidural hemorrhage
This is the extravasation of blood above the dura matter, resulting in the separation of the dura & inner skull surface. The middle meningeal artery of the dura matter is usually involved following a temporal bone fracture. Bleeding doesn’t cross the suture line.
Signs/symptoms: onset of neurological deficits following a lucid interval. Expanding hemorrhage has a smooth inner contour that compresses brain surface, & requires a quick neurosurgical intervention.
Subdural hemorrhage
A bleeding that occurs in the space between the internal layer of dura and outer layer of arachnoid matter. It arises from tearing of the bridging veins & dural venous sinuses when the brain is displaced in trauma. Bleeding crosses suture lines & are common over the lateral aspects of cerebral hemispheres.
Predisposing factors: older individuals with brain atrophy, infants, head trauma.
Signs/symptoms: often presents 48 hrs. following trauma; headache; confusion; mass effects; neurologic deficits.
Intracerebral hemorrhage (IH)
This is the bleeding that occurs within the brain parenchyma. It is a ganglionic hemorrhage when bleeding occurs within the basal ganglia and thalamus. When bleeding occurs within the lobes of cerebral hemispheres, it is a lobar hemorrhage.
Intracerebral hemorrhage may arise in the setting of head injuries that lead to contusion or laceration. However, two major causes of intracerebral hemorrhages are hypertension (most common cause) and cerebral amyloid angiopathy (CAA).
Persistent hypertension causes hyaline arteriolosclerosis that weakens arteriolar wall, eventually vulnerable to rupture. Chronic hypertension also causes minute aneurysm (Charcot-Bouchard microaneurysm) in small arteries <300µm, within basal ganglia.
Intraparenchymal hemorrhage most often occur in the putamen, but may occur in other brain regions including cerebellar hemispheres, pons etc. Peak incident age at diagnosis is about age 60 yrs.
In CAA, there is deposition of amyloidogenic peptides (Aβ40) in leptomeningeal and cerebral cortical arterioles and capillaries. This deposition weakens vessel wall, with a risk of vascular hemorrhage.
Other causes of non-traumatic IH include: vasculitis; tumors; vascular malformations; aneurysms; systemic coagulation disorders.
Subarachnoid hemorrhage (SH)
This is the extravasation of blood into the subarachnoid space. While it may arise in the setting of head injuries that lead to contusion or laceration, the major underlying cause is rupture of a saccular (berry) aneurysm.
Majority of saccular aneurysms are found near major arterial bifurcation points in the anterior cerebral circulation.
Predisposing factors of saccular aneurysm: Ehlers-Danlos syndrome type IV; autosomal dominant polycystic kidney disease; Marfan syndrome; neurofibromatosis type 1; coarctation of the aorta; hypertension; cigarette smoking.
Aneurysmal rupture is common at age 50 yrs. & in women. There is a 50% risk of rupture per year for aneurysms >1cm in diameter. Unruptured saccular aneurysms range from a few millimeters to 3cm, & have a bright red shiny surface with thin translucent wall.
Rupture may be aggravated by straining at defecation, sexual orgasm.
Signs/Symptoms: sudden excruciating headache; rapid loss of consciousness; ischemic injury from vasospasm affecting vessels bathed in extravasated blood, in a few days following subarachnoid hemorrhage; meningeal fibrosis & scarring leading to CSF obstruction in the healing phase.
Other causes of non-traumatic SH include: rupture of a hypertensive intracerebral hemorrhage into the ventricular system; tumors; hematologic disturbances; & vascular malformations.
Global cerebral ischemia (diffuse hypoxic/ischemic encephalopathy
This is a diffuse brain tissue injury, especially neurons, brought about by a generalized reduction in cerebral blood flow. The causes include cardiac arrest, shock, severe hypotension.
Mild conditions which are reversible produce clinical outcomes such as confusion. Severe conditions produce irreversible neuronal damage with clinical outcomes such as: persistent vegetative state (for survivors) or brain death.
Clinical criteria for diagnosis of brain death (irreversible widespread cortical injury) include: flat encephalogram; absent reflexes & respiratory drive, absent cerebral perfusion (signs of brain stem damage).
Focal cerebral ischemia
A localized brain tissue injury brought about by an arterial vessel obstruction corresponding to a particular region of brain supplied. The extent & severity of tissue damage depend on the adequacy of collateral flow. The causes include:
- Thrombosis from atherosclerotic lesions in carotid artery (at site of bifurcation); middle cerebral artery; basilar artery
- Embolism from cardiac mural thrombi in conditions such as: myocardial infarction; atrial fibrillation; valvular diseases)
- arteriolosclerotic lesions in hypertension and diabetes
- Paradoxical emboli in children with cardiac anomalies
- Fat embolism after bone fracture, which shows widespread hemorrhagic infarcts involving the white matter.
- Infectious vasculitis (CMV encephalitis, syphilis, tuberculosis, aspergillosis)
- Polyarteritis nodosa; primary angiitis of CNS (granulomatous angiitis)
- Hypercoagulable states, heroin, cocaine, amphetamines
Cerebral infarcts arising from ischemia may be red (hemorrhagic) or white. Embolism is the cause of red infarct, while thrombosis causes white infarcts. In white infarcts, thrombolytics may be given, however in red infarcts they are contra-indicated.
Lacunar infarcts
These are lake-like spaces of single small or multiple, cavitary lesions <1.5cm in diameter. It arises from chronic hypertension affecting deep penetrating cerebral arteries and arterioles, leading to arteriolar sclerosis, & eventual occlusion.
Regions of CNS affected are: lenticular nucleus, thalamus, internal capsule, deep white matter, caudate nucleus & pons.
Acute hypertensive encephalopathy, Vascular dementia, & Biswanger disease
Acute hypertensive encephalopathy arises from malignant hypertension which leads diffuse cerebral dysfunction, & possibly coma. Signs of diffuse cerebral dysfunction include headaches, confusion, vomiting, & convulsion which are related to high intracranial pressure.
Vascular dementia is a chronic condition which over time causes multiple, bilateral, gray & white matter infarcts. Clinical manifestations are dementia, gait abnormalities, pseudobulbar signs, neurologic deficits. It arises from cerebral atherosclerosis, thrombosis & embolization, cerebral arteriolar sclerosis from chronic hypertension.
Biswanger disease is a chronic condition that causes large areas of white matter infarcts. Its clinical manifestations are same as in vascular dementia.
Vascular malformations (VMs)
The types of VMs include: arteriovenous malformations (AVMs); cavernous malformations (CMs); capillary telangiectasias; venous angiomas. AVMs & CMs have a high risk of rupture & bleeding, with neurological symptoms.
Arteriovenous malformations are tangled network of wormlike vascular channels, with pulsatile high blood flow. They affect vessels in subarachnoid space extending into the brain or within the brain. They arise from areas of past hemorrhages, & are separated by gliotic tissues. Males are affected more than females, & are seen between ages of 10 & 30 yrs.
Cavernous malformations are greatly distended, loosely organized vascular channels with thin walls & low flow, without a surrounding nervous tissue. Instead, there are foci of old hemorrhages, infarcts, & calcifications surrounding them. They occur in cerebellum, pons, & subcortical areas. Existing autosomal dominant forms express multiple lesions.
Capillary telangiectasias are tiny areas of dilated thin-walled vessels, with intervening fairly normal nervous tissue. They usually occur in the pons. Venous angiomas are collections of dilated veins.
Clinical manifestations: seizure disorder; intracerebral hemorrhage; subarachnoid hemorrhage; congestive heart failure in newborns (due to large AVMs) especially in the vein of Galen.
Acute pyogenic meningitis, Waterhouse-Friderichsen syndrome
Acute pyogenic meningitis is the inflammation of the leptomeninges & CSF caused by pyogenic bacteria.
Causes: grp. B streptococci & E. coli (in neonates); S. pneumoniae & H. influenzae (in infants); S. pneumoniae & meningococcus (in adolescents & young adults); Klebsiella or anaerobic organisms (in immunosuppressed persons).
Signs/symptoms: fever; headache; irritability; photophobia; confusion; neck rigidity. Diagnosis requires spinal tab & bacterial culture.
Spinal tap laboratory findings: purulent CSF; neutrophilia (about 90000/mm3); high protein concentration; low glucose content.
Waterhouse- Friderichsen syndrome results from meningitis-associated septicemia, hemorrhagic infarction of adrenal glands; & cutaneous petechiae. The frequent causes are meningococcus, & pneumococcus.
Acute viral aseptic meningitis
This is a leptomeningeal inflammation without a recognizable microbe, in patients with meningeal irritation, fever, & confusion. They are usually caused by viruses.
Spinal tap laboratory findings: lymphocytosis; normal glucose content; moderately high protein levels.
Chronic tuberculous meningoencephalitis
This is the inflammation of the leptomeninges & brain tissues arising from an infection by Mycobacterium tuberculosis. This infection produces a fibrinous exudate.
Signs/symptoms: headache; malaise; mental confusion; vomiting, tuberculoma (granulomatous brain lesion); radiculoneuritis from affected spinal cord subarachnoid space.
Complications include hydrocephalus from arachnoid fibrosis; arterial occlusion & brain infarction from arterial endarteritis.
Spinal tap laboratory findings: moderate lymphocytosis or neutrophilia or both; high protein concentration; slightly low to normal glucose content.
Herpes encephalitis
This is a necrotizing & hemorrhagic inflammation of the brain tissues, caused by herpes simplex virus-1. HSV-1 begin by infecting inferomedial region of temporal lobe, & orbital gyri of frontal lobe. Disease is common among children and young adults.
Signs/symptoms: alterations in memories, mood, & behavior; overtime, weakness, lethargy, ataxia, & seizure ensue. PCR test of CSF samples is required for diagnosis. Viruses form Cowdry type A intranuclear viral inclusion bodies in neurons & glia cells.
Cytomegalovirus subacute encephalitis
This is the inflammation of brain tissues by CMV in immunosuppressed patients, especially one’s with AIDs. CMV infects cells producing CMV intranuclear & intracytoplasmic inclusion bodies, identified & confirmed by light microscope & immunohistochemistry respectively.
CMV infection of fetus causes periventricular necrosis, brain tissue damage, microcephaly, & periventricular calcification.
Poliomyelitis
This is the inflammation of anterior horn of spinal cord by poliovirus, resulting in neuron loss & gliosis. In non-immunized individuals, infection begins as gastroenteritis, & then secondarily infects the nervous system
Signs/symptoms: meningeal irritation with CSF picture of aseptic meningitis; flaccid paralysis, muscle wasting & hyporeflexia in the corresponding body region; respiratory muscle paralysis with long-term morbidly or death.
Rabies encephalitis
This is a widespread neuronal inflammation & degeneration caused by rabies virus, with incubation period between 1 & 3 month. It occurs through bite of a rabid animal (e.g. dog) or exposure to some bat species, & severely affects the brainstem.
Other affected neuronal regions also include the basal ganglia, spinal cord, & dorsal root ganglia. Presence of intracytoplasmic Negri bodies (round-oval eosinophilic inclusions) confirm diagnosis.
Signs/symptoms: fever, malaise, & headache. Overtime, CNS excitability with pain on slightest touch; convulsions; contracture of pharyngeal musculature on swallowing produces foaming at the mouth; hydrophobia meningismus; flaccid paralysis; alternating periods of mania & stupor; coma; respiratory center failure & death.
Creutz-Feldt Jakob Disease
A transmissible, spongiform neurodegenerative disease that arises from an aggregation of abnormal prion protein (PrPsc) in cytoplasmic vacuoles of neurons. PrPsc is resistant to digestion by proteinase K, hence why its accumulation causes neuronal cell death. The sporadic type is most common.
In the sporadic type, normal α-helix containing isoform (PrPc) spontaneously undergoes a structural change to a β-pleated sheet isoform (PrPsc). In the familial type, there is a mutation of PRNP gene that encodes for prion protein (PrP).
Clinical manifestations: memory & behavioral changes; rapidly progressive dementia; startle myoclonus; ataxia. Average age of diagnosis is 70 yrs, with a 7–month average life expectancy from symptom onset.
Predisposing factors: iatrogenic transmissions via corneal transplantation, deep implantation electrodes, & contaminated preparations of human growth hormone.
Multiple sclerosis (MS)
This is an autoimmune demyelinating white matter disorder, with relapsing & remitting episodes of variable duration. Initiation of immune reaction is by CD4 + THI & TH17 T cells that react against self-myelin antigens, & secrete cytokines. It is the most common demyelinating disorder & affects more women than in men.
Clinical manifestations: unilateral visual impairment from optic neuritis & retrobulbar neuritis; ataxia, nystagmus, & internuclear ophthalmoplegia from interruption of fibers of the medial longitudinal fasciculus. Spinal cord lesions resulting in spasticity, motor & sensory impairment of trunk & limbs, & difficulties with voluntary control of bladder function.
Spinal tab laboratory findings: moderately high protein levels; & moderate pleocytosis.
Triggering of MS could be due to viral infections (e.g. EBV). MS lesions are multiple, gray tan & irregularly shaped sclerotic plaques around white matter.
Alzheimer disease
The basis for histologic diagnosis is the presence of neuritic plaques & neurofibrillary tangles. Neuritic plaques are collections of dilated neuritic processes surrounding a central amyloid core. These amyloid core inclusion bodies are made of amyloidogenic beta peptides (Aβ40, Aβ42).
Neurofibrillary tangles are bundles of cytoplasmic filaments in the neurons that displace or surround nucleus. These protein aggregates are resistant to degradation through the ubiquitin-proteasome system.
Clinical manifestations: Progressive cognitive decline, with forgetfulness, memory disturbances, changes in mood and behaviors; language deficits; loss of mathematical skills & learned motor skills; incontinence; mute; unable to walk; intercurrent pneumonia.
Predisposing factors include age, and down syndrome. In diagnosis, PET scan with Pittsburgh compound B (a radioactive) can be used to visualize amyloid plaques.
Progressive supranuclear palsy
A neurodegenerative disease with widespread neuronal loss arising from aggregates of 4R tau proteins in neurons & glial cells. It affects regions including: globus pallidus, subthalamic nucleus, substantia nigra, colliculi, periaqueductal grey matter, dentate nucleus of cerebellum.
Clinical manifestations: mild progressive dementia; truncal rigidity with disequilibrium; nuchal dystonia; pseudobulbar palsy & abnormal speech; ocular disturbances; vertical gaze palsy with ophthalmoplegia.
Onset of disease begins btw. 50 & 70 yrs. of age, with fatality 5 to 7 years of onset.
Parkinson disease
This is a neurodegenerative disease of the brainstem and basal ganglia, that damages the nigrostriatal dopaminergic system.
Pathologic findings include pallor of the substantia nigra (SN). Microscopically, there is loss of pigmented catecholaminergic neurons in the SN, with gliosis. Remnant neurons contain Lewi bodies. Lewi bodies are single/multiple, cytoplasmic eosinophilic, round inclusions, with a dense core surrounded by pale halo. They are made of fine filaments of α-synuclein.
Predisposing factors: misfolded protein/stress response triggered by α-synuclein aggregation; defective proteasomal function due to loss of parkin (E3 ubiquitin ligase); pesticide exposure.
Clinical manifestations: tremor at rest; rigidity; bradykinesia; & dementia.
Huntington disease
It is is a progressive autosomal dominant neurodegenerative disease that involves damages to the striatal neurons. Age of onset is between 30 & 50 years.
Cause: Huntington gene (HD) mutation on chromosome 4 encodes a mutant protein (huntingtin), composed of a polyglutamine trinucleotide repeat expansion CAG. mutant proteins form intranuclear inclusions, that make the neurons vulnerable to oxidative injury.
Macroscopically, there is atrophy of caudate nucleus, putamen, & globus pallidus; frontal lobe atrophy; severe loss of striatal neurons.
Clinical manifestations: involuntary jerky movement of all body parts; writhing movements of the extremities; dementia; increased risk of suicide; intercurrent infection.
Amyotrophic Lateral Sclerosis (motor neuron disease)
This disease causes loss of motor neurons in the spinal cord & brainstem, & upper motor neurons in the corticospinal tracts. It affects more men than women, and usually manifest at age >40 yrs.
Cause(s): mutation of SOD1 gene, which encodes a mutant copper-zinc superoxide dismutase protein. The mutant protein eventually triggers an injurious unfolded protein response.
Macroscopically, anterior roots of spinal cord are thin, with a possible atrophy of the primary cortex (precentral gyrus).
Microscopically, there is a reduction in the number of anterior horn neurons throughout the spinal cord, with reactive gliosis. There is also loss of anterior root myelinated fibers.
Clinical manifestations: weakness of the hands (easily dropping objects); difficulty performing fine motor tasks; cramping & spasticity of arms & legs; pulmonary infections; progressive muscular atrophy (muscle weakness, muscle atrophy, fasciculations); progressive bulbar palsy/ bulbar ALS (abnormalities of phonation & deglutition).
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