Disease of the Peripheral and Central Nervous System PDF

Disease of the Peripheral and Central Nervous System Missing Slides: 28 (cellular path of CNS), 41 Diffuse axonal, 46 spinal cord injury, 53 vascular Malformations Beginning of class emphasized slides/Topics: GB, Trigeminal Neuralgia, Bell palsy (Know the associated nerves), Carpal tunnel/ compres...

Disease of the Peripheral and Central Nervous System Missing Slides: 28 (cellular path of CNS), 41 Diffuse axonal, 46 spinal cord injury, 53 vascular Malformations Beginning of class emphasized slides/Topics: GB, Trigeminal Neuralgia, Bell palsy (Know the associated nerves), Carpal tunnel/ compression neuropathies, MG, Different Muscular Dystrophies, Schwannomas, Neurofibromas, Neurofibromatosis type 1 and 2, Cerebral Edema and differing types!, Increased ICP, Neural tube defects and FOLATE, Assessment of brain injury Compare and contrast the following disease etiology, pathophysiology, and clinical manifestations: **KNOW THE CRANIAL NERVE IS ASSOCIATED** 1. Demyelination-definition - Axons are the primary target of the damage in this large group of peripheral neuropathies. - Damage occurs over an extended period of time. As a result, degenerating and regenerating axons coexist in a single biopsy. With time, damage tends to outpace repair, resulting in progressive loss of axons. In cases of toxic and metabolic insults, axons often degenerate in a length-dependent fashion with the longest axons being most susceptible, resulting in a "dying-back" type of pattern of progression. - The electrophysiologic **hallmark** of axonal neuropathies is a *reduction in signal amplitude owing to the dropout of axons from affected peripheral nerves*, with relative preservation of conduction velocity. - Patterns of peripheral nerve damage. (A) In normal motor units, type I and type II myofibers are arranged in a "checkerboard" distribution, and the internodes along the motor axons are uniform in thickness and length. (B) Acute axonal injury (left axon) results in degeneration of the distal axon and its associated myelin sheath, with atrophy of denervated myofibers. In contrast, **acute demyelinating disease** (right axon) produces random segmental degeneration of individual myelin internodes, while sparing the axons. (C) Regeneration of axons after injury (left axon) allows reinnervation of myofibers. The regenerated axon is myelinated by proliferating Schwann cells, but the new internodes are shorter and the myelin sheaths are thinner than the original ones. **Remission of demyelinating disease** (right axon) allows remyelination to take place, but the new internodes are shorter and have thinner myelin sheaths than flanking normal undamaged internodes. See Fig. 27.7 for comparison with reinnervation. - **Demyelinating neuropathies**- This definition is similar to that of demyelinating diseases that affect the CNS. - In these disorders, Schwann cells with their myelin sheaths are the primary targets of damage, whereas axons are relatively preserved. - Individual myelin sheaths degenerate in a seemingly random pattern, resulting in discontinuous damage of myelin segments. - In response to this damage, Schwann cells or Schwann cell precursors proliferate and initiate repair through the formation of new myelin sheaths, but these again tend to be shorter and thinner than the original ones. - The electrophysiologic hallmark is slowed nerve conduction velocity, reflective of the loss of myelin. - 2. Traumatic brain injury (slide 36) **Skull Fractures** - **Patho**: A fracture in which bone is displaced into the cranial cavity by a distance greater than the thickness of the bone is called a displaced skull fracture. - The thickness of the cranial bones varies; therefore, their resistance to fracture differs greatly. - **Symptoms:** referable to the lower cranial nerves or the cervicomedullary region and the presence of orbital or mastoid hematomas distant from the point of impact, raise the suspicion of a basal skull fracture - CSF leakage from the nose or ear and infection (meningitis) may follow. - **Risk**: Typically follows impact to the occiput or sides of the head. **Traumatic Brain Injury** - **Patho**: The physical forces associated with head injury may result in skull fractures, parenchymal injury, and vascular injury; all three can coexist. - The magnitude and distribution of a traumatic brain lesion depends on the shape of the object causing the trauma, the force of impact, and whether the head is in motion at the time of injury. A blow to the head may be penetrating or blunt; it may cause either an open or a closed injury. - For example, when an individual falls while awake (such as might occur when stepping off a ladder), the site of impact is often the occipital portion of the skull; in contrast, a fall that follows loss of consciousness (as might follow a syncopal attack) can result in either frontal or occipital impact. **A TBI diagnosis is best made at the time of injury or within the first 24 hours.** Manifestations of Brain Injury +-----------------+-----------------+-----------------+-----------------+ | LOC | Pupil Reflex | GCS | Corneal Reflex | +-----------------+-----------------+-----------------+-----------------+ | - \- Change | \- Indicates | \- Standardized | ​​- Wisp of | | in level of | the function of | tool for | cotton touches | | consciousne | the brainstem | assessing LOC | cornea of the | | ss | and cranial | in acutely | eye to elicit a | | (LOC) is | nerves (CN) II | brain-injured | blink response. | | most | and III | persons | | | sensitive | | | \- Absence of | | indicator | \- Changes in | \- Numeric | blink response: | | of altered | size, shape, | scores given to | indictor of | | brain | and reactivity | arousal-directe | severely | | function | of the pupil | d | impaired brain | | | early indicator | responses of | function | | - | of ICP and | eye opening, | | | | possible brain | verbal | | | \- State of | herniation | utterances, and | | | alertness and | | motor reactions | | | attentiveness | \- Eye | | | | to one's | movements | \- Mild (\>12), | | | | controlled by | moderate (9 to | | | environment and | CN III, IV, and | 12), to severe | | | situation | VI may be | (\ - Intracranial hematoma: localized collection of blood within the cranium - - - - - A person who suffers a blow to the head may develop a contusion at the point of contact (a coup injury) or on the brain surface diametrically opposite to it (a contrecoup injury). - Their macroscopic and microscopic appearances are indistinguishable, and the distinction between them is based on identification of the point of impact. In general, if the head is immobile at the time of trauma, only a coup injury is found.  - If the head is mobile, both coup and contrecoup lesions may be found, though the latter predominate and are thought to develop when the brain strikes the opposite inner surface of the skull after sudden deceleration. - Sudden impacts that result in violent posterior or lateral hyperextension of the neck (as occurs when a pedestrian is struck from the rear by a vehicle) may separate the pons from the medulla or the medulla from the cervical cord, causing instant death. 4. Cerebrovascular disease and stroke (ischemic and hemorrhagic and sequalae) (slide 47-49) **Cerebrovascular disease** - **Patho**: Iinjury to the brain as a consequence of altered blood flow---can be grouped into ischemic and hemorrhagic etiologies, with tissue infarction the ultimate consequence of both. "**Stroke**" is the clinical designation applied to these conditions and is defined as *neurologic signs and symptoms that can be explained by a vascular mechanism, have an acute onset, and persist beyond 24 hours.* (If symptoms disappear within 24 hours, the event is termed "*transient ischemic even*t.") - **S/S**: contralateral hemiplegia, hemisensory loss, and contralateral visual field blindness - **Clinical Manifestations**: 3rd leading cause of death and most prevalent cause of morbidity and mortality from neurologic disease. - **Dx**: CT, MRI, NIHSS - - Most common form of CVA - **Risk factors:** Results from sudden occlusion of cerebral artery secondary to thrombus formation or emboli. Thrombotic strokes associated with atherosclerosis and coagulopathies. Embolic strokes associated with cardiac dysfunction or dysrhythmias (atrial fibrillation). TIAs are important warning signs of thrombotic disease and carry a significant risk for subsequent stroke - Focal cerebral ischemia follows reduction or cessation of blood flow to a localized area of the brain due to partial or complete arterial obstruction. Occlusive vascular disease of severity sufficient to lead to cerebral infarction may be due to embolization from a distant source, in situ thrombosis, or various vasculitides - Because the brain has end-organ circulation with limited collateral supply, occlusive brain infarcts generally start as nonhemorrhagic. - **Dx**: Brain infarcts are subdivided into two broad groups based on the presence of secondary hemorrhage. Secondary hemorrhage can occur from ischemia-reperfusion injury following spontaneous or therapeutic dissolution or fragmentation of the intravascular occlusive material. Clinically, these nonhemorrhagic infarcts are called ischemic, a confusing term as every infarct, not just this type, is caused by tissue ischemia. - This process develops if the causative ischemic event lasts long enough to damage small blood vessels in the affected area; the resulting reperfusion hemorrhages are largely petechial in nature but may be multiple or even confluent. - Evidence have suggested that the mechanisms of ischemia-reperfusion injury include [oxidative stress, leukocyte infiltration, platelet adhesion and aggregation, complement activation, mitochondrial mediated mechanisms, and blood-brain-barrier (BBB) disruption], which altogether ultimately lead to edema or hemorrhagic transformation (HT) in the brain. - - **Risk factors:** Usually occurs secondary to severe, chronic hypertension. Females affected more often than males. Similar to those for other atherosclerotic vascular diseases (hypertension, DM, hyperlipidemia, smoking, advancing age, family history). - **Clinical Manifestations**: Most occur in basal ganglia or thalamus. Degree of secondary injury and associated morbidity and mortality is much higher in hemorrhagic stroke than ischemic stroke - Global cerebral hypoxia or ischemia occurs when there is a generalized reduction of cerebral perfusion (as in cardiac arrest, shock, and severe hypotension) or decreased oxygen carrying capacity of the blood (e.g., in carbon monoxide poisoning). - The clinical management of patients with nonhemorrhagic and hemorrhagic infarcts differs greatly, although the underlying causes are the same (for instance, thrombolytic therapy is contraindicated in a patient with brain hemorrhage of any etiology). - - **Patho**: Once a vessel has been torn, the extravasation of blood under arterial pressure can cause the dura to separate from the periosteum, creating a space. The expanding hematoma compresses the underlying brain. When blood accumulates slowly, patients may experience a lucid period before the onset of neurologic signs. - **S/S**: A symptomatic epidural hematoma is a neurosurgical emergency; without prompt diagnosis and drainage, fatal brain herniation may occur within a few hours. - **Risk Factors:** most notably the middle meningeal artery, is vulnerable to traumatic injury. - In adults, this most often occurs with temporal skull fractures in which the fracture crosses the course of the vessel. - In children, in whom the skull is deformable, a temporary displacement of the skull bones leading to laceration of a vessel can occur in the absence of a skull fracture. - **Clinical Manifestations:** primary injury is minor; may suffer only a brief period of disturbed consciousness followed by a period of normal cognition (lucid interval), then consciousness rapidly deteriorates - - **Patho**: Traumatic displacement of the brain can tear the veins at the point where they penetrate the dura. The extravasated blood dissects through the two layers of the dura, producing a subdural hematoma.The dura is composed of two layers---an external collagenous layer and an inner more cellular layer containing fibroblasts. Bridging veins travel from the convexities of the cerebral hemispheres through the subarachnoid space and dura to empty into the dural sinuses. The brain is suspended in CSF, but the venous sinuses are fixed relative to the dura; as a result, traumatic displacement of the brain can tear the veins at the point where they penetrate the dura. - Acute: symptoms within 24 hours of injury - Subacute: increased ICP (headache, vomiting, blurred vision) 2 to 10 days later - **Risk Factors:** In older individuals with brain atrophy, the bridging veins are stretched, hence the increasing incidence of subdural hematoma with aging. Infants are also very susceptible to subdural hematomas because their bridging veins are thin-walled. - **S/S**: Symptomatic subdural hematomas most often manifest within 48 hours of injury. They are most common over the lateral aspects of the cerebral hemispheres and are bilateral in about 10% of cases. - Neurologic signs are attributable to the pressure exerted on the adjacent brain. There may be focal signs, but often the clinical manifestations are non-localizing and include headache and confusion. Slowly progressive neurologic deterioration is typical, but acute decompensation may also occur. - The treatment of subdural hematomas is to remove the blood and associated organizing tissue. The risk of repeat bleeding is greatest in the first few months after the initial hemorrhage. - - Subarachnoid Hemorrhage and Ruptured Saccular Aneurysm - **Patho**: The most frequent cause of spontaneous subarachnoid hemorrhage is rupture of a saccular ("berry") aneurysm in a cerebral artery. Saccular aneurysm is the most common type of intracranial aneurysm; other aneurysm types include atherosclerotic (fusiform; mostly of the basilar artery), mycotic, traumatic, and dissecting. These latter three, like saccular aneurysms, are most often found in the anterior circulation, but more often cause cerebral infarction rather than subarachnoid hemorrhage. - **Risk Factors**: Cerebral aneurysms and arteriovenous malformations (AVMs) are the most common causes of subarachnoid hemorrhage. - 1/3 of cases it is associated with acute increases in intracranial pressure, such as with straining at stool or sexual orgasm. Structural abnormalities of the cerebral arteries predispose to intracerebral bleeding and hemorrhage. Hypertension, acute alcohol intoxication, and recreational drug use (especially cocaine) - Overall, aneurysms rupture at a rate of 1.3% per year, but the risk is higher for larger aneurysms; for example, aneurysms greater than 10 mm in diameter have a roughly 50% risk of bleeding per year. - **S/S:** Rupture of an aneurysm leading to subarachnoid hemorrhage is most frequent in the fifth decade and is slightly more frequent in women. - Blood under arterial pressure is forced into the subarachnoid space, and affected individuals are stricken with a sudden, excruciating headache ("the worst headache I\'ve ever had") and rapidly lose consciousness. - - In the first few days after a subarachnoid hemorrhage, regardless of the etiology, there is an increased risk of additional ischemic injury from vasospasm affecting vessels bathed in the extravasated blood. - Between 25% and 50% of patients die with the first rupture, but patients who survive often improve and recover consciousness in minutes. - - classified into 4 principal groups: arteriovenous malformations, cavernous malformations, capillary telangiectasias, and venous angiomas. Two below - Of these, the first two are the types associated with risk of hemorrhage and development of neurologic symptoms. - **[Arteriovenous malformations]** (tangled networks of wormlike vascular channels with high blood flow due to prominent, pulsatile arteriovenous shunting) may involve vessels in the subarachnoid space, the brain, or both. - Arteriovenous malformations are the most common clinically significant vascular malformation. - Large arteriovenous malformations occurring in the newborn period can lead to congestive heart failure because of shunt effects, especially if the malformation involves the vein of Galen. - **[Cavernous malformations]** consist of distended, loosely organized vascular channels arranged back-to-back with collagenized walls of variable thickness; there is usually no brain parenchyma between vessels in this type of malformation. - Cavernous malformations are unique among this group of disorders in that familial forms are relatively common. Multiplicity of lesions is a hallmark of familial cases, which are inherited as a highly penetrant autosomal dominant trait. - They occur most often in the cerebellum, pons, and subcortical regions, in decreasing order of frequency, and are "low-flow" channels that do not participate in arteriovenous shunting. - - **Risk**: Males are affected twice as frequently as females. The lesion often presents between 10 and 30 years of age as 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. - - Motor and Sensory Deficits 1. Initially motor deficits occur as flaccidity or paralysis; recovery of motor function occurs with onset of spasticity 2. Contralateral to the side of the brain where the stroke occurred 3. Active/passive range of motion exercises should be started in acute phase of recovery 4. Elevate edematous limbs, use elastic stockings, and maintain body alignment 5. Aggressive rehabilitation commonly required 6. Sensory disturbances occur in same locations as motor paralysis and may involve neglect or visual impairment 7. Loss of visual field on the paralyzed side also contributes to neglect 8. Contralateral field blindness: homonymous hemianopsia, the same side of the retina in each eye is blinded - - A broad range of neurologic syndromes may become manifest months or years after brain trauma of any cause. 1. Posttraumatic hydrocephalus is largely due to obstruction of CSF resorption from hemorrhage into the subarachnoid space. 2. Chronic traumatic encephalopathy (CTE, previously referred to as "dementia pugilistica") is a dementing illness that develops after repeated head trauma. Affected brains are atrophic, with enlarged ventricles, and show accumulation of tau-containing neurofibrillary tangles in a characteristic pattern involving gyral depths and perivascular regions in the frontal and temporal lobe cortices. 3. Other important sequelae of brain trauma include posttraumatic epilepsy, risk of infection, and psychiatric disorders. 4. These have gained increasing notice in the context of litigation involving issues of compensation for those in the civilian work force, professional athletes, and the military services. 5. Although concussion is thought of as having no structural consequences, it is clear that repeated events are antecedents to CTE; however, it remains uncertain which factors determine whether encephalopathy will ultimately develop (the number, frequency, and/or severity of individual traumatic events, or some combination of these). 5. Seizure disorder-including types of seizures (slide 70-72) **Seizure Disorder** - **Patho**: Transient neurologic event of paroxysmal abnormal or excessive cortical electrical discharges. Epilepsy or seizure disorder refers to recurrent seizures.Due to an alteration in membrane potential that makes certain neurons abnormally hyperactive and hypersensitive to changes in their environment (epileptogenic focus). Nearby and distant neurons can be recruited into the seizure - Aura/prodrome: subjective sense of an impending seizure - **Risk Factors: c**erebral injury, lesions, metabolic/nutritional disorders, idiopathic (no known cause) - May be triggered by specific stimuli such as flashing lights, fever, loud noises - **S/S:** Manifested by disturbances of skeletal motor function, sensation, autonomic visceral function, behavior, or consciousness - **Clinical Manifestations:** - **Generalized**: whole brain surface is affected during the seizure - Involvement of thalamus and RAS system results in loss of consciousness - Examples: - [Absence (petite mal):] occurs in children, staring spells that last only seconds - [Atypical absence:] myoclonic jerks, automatisms with the staring spell - [Myoclonic:] single/several jerks - [Atonic (drop attack):] fall down - [Tonic-clonic (grand mal)]: jerking of many muscles - **Status epilepticus**: continuing series of seizures without a period of recovery between episodes; can be life-threatening - [Partial seizures]: abnormal electrical activity restricted to one brain hemisphere - [Simple:] No change in level of consciousness; motor, sensory, and/or autonomic symptoms common - [Complex:] change in consciousness - Partial with secondary generalization - - The postictal state is the altered state of consciousness after an epileptic seizure. - - 6. Dementia **Alzhheimers Disease** - **Patho:** The fundamental abnormality in AD is the accumulation of two proteins **(Aβ and tau)** in specific brain regions, likely as a result of excessive production and defective removal. - The two pathologic hallmarks of AD, particularly evident in the end stages of the illness, are amyloid plaques and neurofibrillary tangles. - *Plaques are deposits of aggregated Aβ peptides in the neuropil.* - *Tangles are aggregates of the microtubule binding protein tau* which develop intracellularly and then persist extracellularly after neuronal death. - Both plaques and tangles appear to contribute to the neural dysfunction, and the interplay between the processes that lead to the accumulation of these two types of abnormal protein aggregates is a critically important aspect of AD pathogenesis that has yet to be fully unraveled. - **S/S:** As the disease progresses increasing difficulty with judgment, abstract thinking, problem solving, communication, assistance for completing activities of daily living (ADLs), difficulty with eating and swallowing, weight loss, loss of bladder and bowel control, eventual complete loss of the ability to ambulate, personality and behavior changes - **Clinical Manifestations:** As the disease progresses, deficits in memory, visuospatial orientation, judgment, personality, and language gradually emerge; over a course of 5 to 10 years, the affected individual becomes profoundly disabled, mute, and immobile. **Vascular Dementia (64-65)** Vascular dementia is a chronic condition that occurs when the brain\'s blood supply is disrupted, damaging blood vessels and preventing the brain from getting enough oxygen. [The National Institute on Aging (NIA) website provides](https://www.nia.nih.gov/health/vascular-dementia/vascular-dementia-causes-symptoms-and-treatments) information about vascular dementia, including its causes, symptoms, and treatments. It\'s the second most common type of dementia, after Alzheimer\'s disease. [The Alzheimer\'s Society website explains](https://www.alzheimers.org.uk/about-dementia/types-dementia/vascular-dementia) what vascular dementia is and lists its early symptoms. **Symptoms include:** - Difficulty with memory, thinking, and behavior - Difficulty reading and writing - Loss of interest - Personality changes - Difficulty planning, organizing, or following steps - Difficulty paying attention or concentrating - Short periods of confusion - Difficulty with calculations, making decisions, or solving problems - Visual orientation problems or hallucinations - Impaired motor skills, such as weakness or tremors  Vascular dementia can occur alone or in combination with other dementias, such as Alzheimer\'s disease. Symptoms can vary depending on the person, the cause, and the areas of the brain affected. [The Alzheimer\'s Association website discusses](https://www.alz.org/alzheimers-dementia/what-is-dementia/types-of-dementia/vascular-dementia) vascular dementia, its symptoms, and treatments, including information about sudden post-stroke changes. There\'s no cure for vascular dementia, but treatments can help slow its progression and improve symptoms. Treatments include: Lifestyle changes, Medicines to treat underlying causes, Surgery to improve blood flow to the brain, and Alzheimer\'s drugs to help control cognitive symptoms. 7\. Cerebral Edema (29) **Cerebral Edema** - **Patho**:Result of increased fluid leakage from blood vessels and injury to various cells of the CNS. There are two main pathways of edema formation in the brain. - - The paucity of lymphatics greatly impairs the resorption of excess extracellular fluid. Vasogenic edema may be either localized, e.g., adjacent to inflammation or neoplasms, or generalized, as may occur following a global ischemic injury. - - [In generalized edema,] the gyri are flattened, the intervening sulci are narrowed, and the ventricular cavities are compressed. As the brain expands, herniation may occur. 8. Hydrocephalus (30) - - - - - 4 Types: - - - - Refers to a compensatory increase in ventricular volume secondary to a loss of brain parenchyma. **[Normal Pressure Hydro]** - **Patho**: Normal pressure hydrocephalus (NPH) is an abnormal buildup of cerebrospinal fluid (CSF) in the brain\'s ventricles, or cavities. It occurs if the normal flow of CSF throughout the brain and spinal cord is blocked in some way. This causes the ventricles to enlarge, putting pressure on the brain. - **Risk factors**: Normal pressure hydrocephalus can occur in people of any age, but it is most common in the elderly. - - - **S/S**: progressive mental impairment and dementia, problems with walking, and impaired bladder control. - - - 9. Increased Intracranial Pressure (30, 33, 57) **Increased ICP** - **Patho:** Volume of cranium composed of three elements: brain tissue, cerebrospinal fluid (CSF), blood; normal ICP 0 to 15 mm Hg. Increased ICP can occur with space-occupying lesions, vasogenic or cytotoxic edema, or with obstruction or excessive production of CSF. - - **S/S**:Headache, vomiting, and altered level of consciousness (drowsiness), Blurry vision, and edema of the optic disk (papilledema) - **Clinical Manfiestation:** As ICP rises to higher levels, level of consciousness decreases, pupil responsiveness to light becomes impaired; altered respiratory patterns and unresponsive to stimulation; unable to move, verbalize, or open the eyes - *Monro-Kellie hypothesis:* compensatory responses to change in volume in any of these components - [Herniation] is the displacement of brain tissue past rigid dural folds (the falx and tentorium) or through openings in the skull because of increased intracranial pressure. Brain herniation is mostly caused by mass effects, either diffuse (generalized brain edema) or focal (tumors, abscesses, or hemorrhages). - Elevated intracranial pressure may also compress the vasculature and reduce perfusion of the brain, causing ischemic injury and further exacerbating cerebral edema. 10. Multiple Sclerosis (59-60) - **Patho**: Autoimmune demyelinating disorder characterized by distinct episodes of neurologic deficits that are separated in time and are attributable to patchy white matter lesions that are separated in space. MS is caused by an autoimmune response directed against components of the myelin sheath. - most common of the demyelinating disorders, prevalence of 1:1000 persons in the US and Europe. - **Risk Factors**: The disease may become clinically apparent at any age, although onset in childhood or after 50 years of age is relatively rare. Women are affected twice as often as are men. - Marked by exacerbations and remissions; exacerbated by heat, infection, trauma, stress - **S/S:** Vision loss, Pain, Fatigue, Impaired coordination, Muscle weakness, Numbness, prickling, or \"pins and needles\" , Thinking and memory problems, Bowel and bladder incontinence, Mood changes double/blurred vision, weakness, poor coordination, and sensory deficits - **Clinical manifestations:** clinical course takes the form of relapsing/remitting episodes of variable duration (weeks to months to years) marked by neurologic defects, followed by gradual and partial recovery of neurologic function. - The frequency of relapses tends to decrease over time, but there is a steady neurologic deterioration in most affected individuals - Unilateral visual impairment due to involvement of the optic nerve (optic neuritis) is a frequent initial manifestation of MS. However, only a minority of individuals (10% to 50%, depending on the population studied) with an episode of optic neuritis go on to develop MS (which requires multiple episodes to support the diagnosis). 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 loss of bladder control. - Notes: MS, an autoimmune demyelinating disease primarily affecting young adults, is the most common disorder of myelin. It often pursues a relapsing-remitting course, with eventual progressive accumulation of neurologic deficits that is thought to reflect secondary axon loss. - CNS demyelination caused by an autoimmune disorder. - Demyelination can occur throughout the CNS but often affects the optic and oculomotor nerves and spinal nerve tract 11. Parkinson disease (66-67)  - - Dopamine deficiency in the basal ganglia (substantia nigra) associated with motor impairment; Lewy bodies. - About 10% to 15% of individuals with PD develop dementia, particularly with advancing age. - - - **Notes:** α-synuclein--containing aggregates (Lewy bodies and Lewy neurites) are first seen in the medulla and then in contiguous areas of the brain, ascending through the brainstem and extending into limbic structures and finally the neocortex. - General lack of movement, loss of facial expression, drooling, propulsive (shuffling) gait, and absent arm swing - Treatment: no cure; restoring brain dopamine levels or activity by administration of dopamine precursors, dopamine agonists, monoamine oxidase inhibitors, and anticholinergics; antidepressant therapy may be needed - Ablative surgical procedures may be helpful for motor symptoms 12. Spina Bifida/Neural tube defects (34,35) **Spina Bifida** - **Spinal dysraphism or spina bifida** (the most common neural tube defects) may be an asymptomatic bony defect (spina bifida occulta) or a severe malformation with a flattened, disorganized segment of spinal cord, associated with an overlying meningeal outpouching. **Neural tube defects** - - **[Anencephaly]** is a malformation of the anterior end of the neural tube that leads to absence of most of the brain and calvarium. - **[Myelomeningocele]** (or meningomyelocele) refers to extension of CNS tissue through a defect in the vertebral column; the term meningocele applies when there is only a meningeal extrusion. Myelomeningoceles occur most commonly in the lumbosacral region (Fig. 28.5). - Affected individuals have motor and sensory deficits in the lower extremities as well as disturbances of bowel and bladder control. They are often complicated by superimposed infection of the cord due to defective barrier function of the thin, overlying skin. - **[Encephalocele]** refers to an extrusion of malformed brain tissue through a midline defect in the cranium. It most often occurs in the occiput, although nasofrontal variants involving the orbit, ethmoid, or cribriform plate (sometimes misleadingly referred to as a "nasal glioma") also are seen. - Two distinct pathogenic mechanisms are contributory: - \(1) [failure of neural tube closure], in which secondary mesenchymal tissue defects stem from aberrant skeletal modeling around the malformed tube (e.g., anencephaly and myelomeningocele) - \(2) [primary bony defects] that are caused by abnormal axial mesoderm development and lead to secondary CNS abnormalities (e.g., encephalocele, meningocele, and spina bifida). - **Clinical Features:** The frequency of neural tube defects varies widely among different ethnic groups, with the overall recurrence rate for a neural tube defect in subsequent pregnancies estimated at 4% to 5%. 13. ALS **Amyotrophic Lateral Sclerosis (ALS)** - **Patho**: ALS is a progressive disorder where there is loss of upper motor neurons in the cerebral cortex and lower motor neurons in the spinal cord and brainstem, often in association with toxic protein accumulation. Hereditary forms of ALS has mutations in the gene encoding **copper-zinc superoxide dismutase (SOD1) on chromosome 21** - - - - **S/S**: Early symptoms of ALS include asymmetric weakness of the hands, manifested as dropping of objects and difficulty performing fine-motor tasks, and cramping and spasticity of the arms and legs. - - FYI The term progressive muscular atrophy applies to uncommon cases in which lower motor neuron involvement predominates, while primary lateral sclerosis refers to cases with mostly upper motor neuron involvement. In some affected individuals, degeneration of the lower brainstem cranial motor nuclei occurs early and progresses rapidly, a pattern referred to as progressive bulbar palsy or bulbar ALS. In these individuals, abnormalities of swallowing and speech dominate, and the clinical course is inexorable during a 1- or 2-year period. 14. Bell's Palsy (13) **Bell's Palsy** - **Patho:** Idiopathic neuropathy of the facial nerve Nerve **VII**; paralysis of the muscles on one side of the face - **Risk Factors:** virus - **Clinical manifestations**: develop rapidly over 24 to 48 hrs, unilateral facial weakness, facial droop, diminished eye blink, Hyperacusis, decreased lacrimation. 15. Trigeminal neuralgia (12) (VS facial pain of Zoster) **Trigeminal Neuralgia** - **Patho:** characterized by sudden, brief, and excruciating facial pain attacks in one or more of the **V** branches, leading to a severe reduction in the quality of life of affected patients. - **S/S:** Classic trigeminal neuralgia is associated with neurovascular compression in the trigeminal root entry zone, which can lead to demyelination and a dysregulation of ***voltage-gated sodium channel expression** in the membrane*. (She emphasized this sentence) - These alterations may be responsible for pain attacks in trigeminal neuralgia patients. - **Trigeminal Neuralgia:** Compression, degeneration or inflammation of the **V** cranial nerve may result in a condition called trigeminal neuralgia or tic douloureux. This condition is characterized by recurring episodes of intense stabbing , excoriating pain radiating from the angle of the jaw along a branches of the trigeminal nerve.  - Usually involves maxillary & mandibular nerves, rarely in the ophthalmic division. - **Patho:** Neuronopathies result from destruction of neurons, leading to secondary degeneration of axonal processes. - - Because the damage is at the level of the neuronal cell body, peripheral nerve dysfunction caused by neuronopathies is equally likely to affect proximal and distal parts of the body (unlike peripheral axonopathies, which preferentially affect the distal extremities). 16. Inflammatory neuropathy **Gillian-Barre Syndrome** **"Acute Inflammatory Demylenating Polyneuropathy"** - **Patho:** Acute-onset immune-mediated demyelinating peripheral neuropathy that may lead to life-threatening respiratory paralysis. Annual incidence is 1 case per 100,000 persons. Histologic features are inflammation and demyelination of spinal nerve roots and peripheral nerves (radiculoneuropathy). - **Risk Factors**: Approximately two-thirds of cases are preceded by an acute, influenza-like illness from which the affected individual has recovered by the time the neuropathy becomes symptomatic. - Infections with Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus, and Mycoplasma pneumoniae as well as prior vaccination have significant epidemiologic associations with Guillain-Barré syndrome. - No infectious agent has been demonstrated in affected nerves, and an immunologic reaction is favored as the underlying cause. - **S/S:** characterized clinically by weakness beginning in the distal limbs that rapidly advances to affect proximal muscle function ("ascending paralysis"). - **Clinical Manifestations:** is dominated by ascending paralysis and areflexia. Deep tendon reflexes disappear early in the process. Sensory involvement, including loss of pain sensation, is often present but is usually not a prominent feature. Nerve conduction velocities are slowed because of multifocal destruction of myelin segments in many axons within a nerve. - Many patients spend weeks in the intensive care unit (ICU) before recovering normal function. - With improved supportive respiratory care, cardiovascular monitoring, and prophylaxis against deep venous thrombosis, the mortality rate has fallen. - - **Patho:** most common chronic acquired inflammatory peripheral neuropathy, characterized by s*ymmetric mixed sensorimotor polyneuropathy that persists for 2 months or more.* - often the disease evolves over years, usually with relapses and remissions. - T cells as well as antibodies are implicated in the inflammatory process. Molecules expressed at the Schwann cell--axon junction and in noncompact areas of myelin appear to be the target of the immune response. - **S/S:** symmetric, mixed sensorimotor polyneuropathy, but some patients may present with predominantly sensory or motor impairment. - **Tx:** Clinical remissions can often be achieved with intravenous immunoglobulin or immunosuppressive therapies. - The time course and the response to steroids distinguish chronic inflammatory demyelinating polyradiculoneuropathy from Guillain-Barré syndrome. 17. Infectious Neuropathies **Infectious Neuropathies** - Neuronopathies result from destruction of neurons, leading to secondary degeneration of axonal processes. - Infections like herpes zoster and toxins like platinum compounds are examples of insults that may lead to neuronopathies. - Because the damage is at the level of the neuronal cell body, peripheral nerve dysfunction caused by neuronopathies is equally likely to affect proximal and distal parts of the body (unlike peripheral axonopathies, which preferentially affect the distal extremities). **Varicella Zoster** - **Patho**: One of the most common viral infections of the peripheral nervous system. Following chickenpox, a latent infection persists within neurons of sensory ganglia. - If the virus is reactivated, sometimes many years later, it may be transported along the sensory nerves to the skin. Here it infects keratinocytes, leading to a painful, vesicular skin eruption in a distribution that follows sensory dermatomes (shingles). - Most common is the involvement of thoracic or trigeminal nerve dermatomes. - Affected ganglia show neuronal death, usually accompanied by abundant mononuclear inflammatory cell infiltrates; focal necrosis and hemorrhage may also be found. - Peripheral nerves show degeneration of the axons that belong to the dead sensory neurons. Focal destruction of the large motor neurons of the anterior horns or cranial nerve motor nuclei may be seen at the corresponding levels. - The factors underlying reactivation of the virus are not fully understood, but decreased cell-mediated immunity is suspected to play a role. In a small proportion of patients, weakness is also apparent in the same distributions. 18. Compression Neuropathies **Compression Neuropathies** - Neuropathies Caused by Physical Forces - Peripheral nerves are commonly injured by trauma or entrapment. - Compression neuropathy (entrapment neuropathy) occurs when a peripheral nerve is chronically subjected to increased pressure, often within an anatomic compartment. **Carpal Tunnel (14-15)** - **Patho**: the most common entrapment neuropathy, results from compression of the median nerve at the level of the wrist within the compartment delimited by the transverse carpal ligament. - **Risk**: Women \ men, and the problem is frequently bilateral. May be associated with many conditions including tissue edema, pregnancy, inflammatory arthritis, hypothyroidism, amyloidosis, acromegaly, diabetes mellitus, and excessive repetitive motions of the wrist. - **S/S**: Symptoms are limited to dysfunction of the median nerve and typically include numbness and paresthesia\'s of the tips of the thumb and first two digits. - **Clinical Manifestations**: Other nerves prone to compression neuropathies include the ulnar nerve at the level of the elbow, the peroneal nerve at the level of the knee, and the radial nerve in the upper arm; the latter occurs from sleeping with the arm in an awkward position ("Saturday night palsy"). - Another form of compression neuropathy is found in the foot, affecting the interdigital nerve at intermetatarsal sites. This problem, which occurs more often in women than in men, leads to foot pain (metatarsalgia) (d/t high heels) and is associated with a histologic lesion called a Morton neuroma, which is marked by perineural fibrosis. 19. Myasthenia Gravis (16-17) **Myasthenia Gravis** - **Patho**: Myasthenia gravis is an autoimmune disease associated with autoantibodies directed against ACh receptors. - **Risk Factors:** prevalence 150 to 200 per 1 million and shows a bimodal age distribution. In young adults, the female-to-male ratio is 2:1, but in older adults there is a male predominance - About 85% of patients have autoantibodies against postsynaptic ACh receptors, while most of the remaining patients have antibodies against the sarcolemmal protein muscle-specific receptor tyrosine kinase. - **S/S**: Anti--ACh receptor antibodies are thought to lead to the aggregation and degradation of the receptors, as well as to damage of the postsynaptic membrane through complement fixation. - As a result, postsynaptic membranes show alterations in morphology and are depleted of ACh receptors. This limits the ability of myofibers to respond to ACh. - There is a strong association between pathogenic anti--ACh receptor autoantibodies and thymic abnormalities. Approximately 10% of patients with myasthenia gravis have a thymoma, a tumor of thymic epithelial cells. - **Clinical Manifestations**: Patients with anti--ACh receptor antibodies typically present with fluctuating weakness that worsens with exertion and often over the course of the day. Diplopia and ptosis due to involvement of extraocular muscles are common and distinguish myasthenia gravis from myopathies, in which involvement of extraocular muscles is unusual. In some patients, symptoms are confined to ocular muscles, while others develop generalized weakness that can be so severe as to require mechanical ventilation. Cases with antibodies against muscle-specific receptor tyrosine kinase differ from typical cases by exhibiting more focal muscle involvement (neck, shoulder, facial, respiratory, and bulbar muscles). - **Diagnosis:** is based on clinical history, physical findings, identification of autoantibodies, and electrophysiologic studies. Electrophysiologic studies reveal a decrement in muscle response with repeated stimulation, a characteristic of this disorder - Autoantibodies directed against muscle-specific receptor tyrosine kinase do not fix complement. Instead, these antibodies seem to interfere with the trafficking and clustering of ACh receptor within the sarcolemmal membrane, the net effect again being decreased ACh receptor function. 20. Muscular Dystrophy (18-22) - **Patho**: Dermatomyositis is a systemic autoimmune disease that typically presents with proximal muscle weakness and skin changes. Damage to small blood vessels contributes to muscle injury. - **Risk Factors:** Dermatomyositis may occur in adults or in children. The average age of onset of juvenile dermatomyositis is 7 years, whereas adult cases tend to present from the fourth to sixth decade of life. Dermatomyositis is the most common inflammatory myopathy in children. - **S/S:** The vasculopathic changes can be seen as telangiectasias (dilated capillary loops) in the nail folds, eyelids, and gums and as dropout of capillary vessels in skeletal muscle. - **Clinical Features:** Muscle weakness is slow in onset, symmetric, and often accompanied by myalgias. typically affects the proximal muscles first. As a result, tasks such as getting up from a chair and climbing steps become increasingly difficult. - - Anti-Mi2 antibodies (directed against a helicase implicated in nucleosome remodeling) show a strong association with prominent Gottron papules and heliotrope rash (described later). - - **Patho:** Polymyositis is an adult-onset inflammatory myopathy that shares myalgia and weakness with dermatomyositis but lacks its distinctive cutaneous features and is, therefore, to some degree, a diagnosis of exclusion. The pathogenesis of polymyositis is uncertain, but it is believed to have an immunologic basis. - - **Muscular Dystrophies** - **Patho**: Muscular dystrophies, characterized by progressive muscle damage that typically comes to attention after infancy. Muscular dystrophies include many inherited disorders of skeletal muscle that have in common progressive muscle damage - Typically manifests between childhood and adulthood - Congenital muscular dystrophies, by contrast, tend to present in infancy and are often associated with developmental abnormalities of the CNS as well as progressive muscle damage. - Congenital muscular dystrophies include two important groups: - *Conditions with defects in extracellular matrix surrounding myofibers.* - *Conditions with abnormalities in receptors for extracellular matrix.* - Historically, inherited myopathies have been subdivided into several broad categories based on inheritance pattern, anatomic pattern of muscle involvement, onset age, clinical course, and underlying pathogenesis - **Patho:** Duchenne and Becker muscular dystrophy are caused by loss-of-function mutations in the dystrophin gene on the X chromosome. Dystrophin is thought to provide mechanical stability to the myofiber and its cell membrane during muscle contraction. Defects in the complex may lead to small membrane tears that permit influx of calcium, triggering events that result in myofiber degeneration. - The most common muscular dystrophies are X-linked and stem from mutations that disrupt the function of a large structural protein called dystrophin. - **S/S:** Boys with Duchenne muscular dystrophy appear normal at birth. Very early motor milestones are met, but walking is often delayed. The first indications of muscle weakness are clumsiness and inability to keep up with peers. Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle. Enlargement of the muscles of the lower leg associated with weakness, termed pseudohypertrophy, is often present. The mean age of wheelchair dependence is around 9.5 years. - Develop joint contractures, scoliosis, worsening respiratory reserve, and sleep hypoventilation. - Dystrophin deficiency in cardiac muscle often leads to the development of cardiomyopathy and arrhythmias, particularly in older patients. - Cognitive impairment and learning disabilities, presumably due to a functional role for dystrophin in the brain, is also common and sometimes produces frank intellectual disability. - **[Duchenne muscular dystrophy]:** The most common early-onset form. It has an incidence of 1 per 3500 live male births and has a severe progressive phenotype. - **Clincal Manifestations:** Despite supportive care, the mean age of death for patients is 25 to 30 years of age, with most patients succumbing to respiratory insufficiency, pulmonary infection, or heart failure. - **[Becker muscular dystrophy]** is a second relatively common dystrophinopathy that is characterized by later disease onset and a milder phenotype. - **Clinical Manifestations:** Typically presents in later childhood, adolescence, or adult life; has slower progression; and may have a near-normal life expectancy. - **Limb-girdle muscular dystrophies:** Heterogeneous group of at least 8 autosomal dominant and 23 autosomal recessive entities. Their overall incidence is 1 in 25,000 to 50,000 individuals. As indicated by the name, all forms are characterized by muscle weakness that preferentially involves proximal muscle groups. Both age of onset and disease severity are highly variable. 21. Schwannomas (24-27) - **Patho**: The vast majority of benign and malignant neoplasms of peripheral nerve sheaths are composed of cells that show evidence of Schwann cell differentiation. There is an abrupt transition between myelination by oligodendrocytes (central myelin) and myelination by Schwann cells (peripheral myelin) that occurs as nerves extend out from the substance of the brain. Thus, peripheral nerve tumors sometimes arise within the dura as well as along the distal course of peripheral nerves. - Peripheral nerve sheath tumors have several unique features. - Firstly, their association with relatively common familial tumor syndromes, including neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis. - Secondly, MPNSTs seen in the context of NF1 are thought to arise through malignant transformation of preexisting benign plexiform neurofibromas. - These include the three common types: - Schwannoma - Neurofibroma - Malignant Peripheral Nerve Sheath Tumor (MPNST). - - Although malignant transformation of a preexisting benign lesion is a common origin for certain carcinomas (e.g., colon cancer), it is unusual in soft tissue tumors. **Schwannomas** Benign tumors that exhibit Schwann cell differentiation and often arise directly from peripheral nerves. - **Patho**: Commonly associated with inactivating mutations in the **NF2 gene on chromosome 22.**Loss of expression of the **NF2** gene product, merlin, is a consistent finding in all schwannomas. - - - **S/S:** Affected individuals often present with tinnitus and hearing loss; the tumor is commonly referred to as an acoustic neuroma---a double misnomer, since the tumor neither arises from the acoustic portion of the nerve nor is it a neuroma. - **Clinical Features**: Most schwannomas cause symptoms by local compression of the involved nerve or adjacent structures (e.g., brainstem or spinal cord). - Surgical removal is curative. 22. Neurofibromatosis Type 1 and Type 2 (26-27) **Neurofibromas** - **Patho:** Benign nerve sheath tumors that are more heterogeneous in composition than schwannomas. - The neoplastic Schwann cells are admixed with perineurial-like cells, **fibroblasts, mast cells, and CD34+** spindle cells. Different types of neurofibroma can be distinguished depending on their growth pattern. - [Superficial cutaneous neurofibromas] often present as pedunculated nodules that can be seen isolated (if sporadic) or multiple (if NF1-associated). - [Diffuse neurofibromas] often present as a large plaque-like elevation of skin and are typically **NF1-associated.** - [Plexiform neurofibromas] can be found in deep or superficial locations in association with nerve roots or large nerves and are uniformly **NF1-associated.** - Neurofibromas may be either sporadic or **NF1-associated.** **Neurofibromatosis Type 1 and Type 2** Malignant Peripheral Nerve Sheath Tumors +-----------------------+-----------------------+-----------------------+ | | Type 1 | Type 2 | +-----------------------+-----------------------+-----------------------+ | **Patho** | Common autosomal | Autosomal dominant | | | dominant disorder | disorder resulting in | | | with a frequency of 1 | a range of tumors. | | | in 3000. | | +-----------------------+-----------------------+-----------------------+ | **Risk Factors** | Autosomal Dominant. | Autosomal Dominant. | | | | | | | The disease is caused | The NF2 gene is | | | by **loss-of-function | located on chromosome | | | mutations in the NF1 | 22q12 and is also | | | gene, located at | commonly mutated in | | | 17q11.2,** which | sporadic meningiomas | | | encodes the tumor | and schwannomas. | | | suppressor | | | | neurofibromin. | | | | | | | | The neoplastic cells | | | | in NF1-related tumors | | | | lack neurofibromin | | | | due to biallelic | | | | defects in the NF1 | | | | gene. | | +-----------------------+-----------------------+-----------------------+ | **S/S:** | Systemic disease | Tumors most commonly | | | associated with | [bilateral **VIII** | | | nonneoplastic | nerve schwannomas, | | | manifestations and | multiple meningiomas, | | | with a variety of | and ependymomas of | | | tumors, including | the spinal | | | neurofibromas of all | cord.] | | | types, Malignant | | | | Peripheral Nerve | much less common than | | | Sheath Tumors | NF1, having a | | | (MPNST), gliomas of | frequency of 1 in | | | the optic nerve, | 40,000 to 50,000. | | | other glial tumors | | | | and hamartomatous | | | | lesions, and | | | | pheochromocytomas. | | +-----------------------+-----------------------+-----------------------+ | **Clinical | Other features | **Clinical | | Manifestations:** | include intellectual | Manifestations:** | | | disability or | Many individuals with | | | seizures, skeletal | NF2 also have | | | defects, pigmented | nonneoplastic | | | nodules of the iris | lesions, which | | | (Lisch nodules), and | include nodular | | | cutaneous | ingrowth of Schwann | | | hyperpigmented | cells into the spinal | | | macules (café au lait | cord (schwannosis), | | | spots). | meningioangiomatosis | | | | (a proliferation of | | | | meningeal cells and | | | | blood vessels that | | | | grows into the | | | | brain), and glial | | | | hamartia. | +-----------------------+-----------------------+-----------------------+ - **Huntington's ? Wasn\'t on here but may as well add it..** - **Patho**: An autosomal dominant disease caused by degeneration of striatal neurons and characterized by a progressive movement disorder and dementia. - **HD is a prototypic polyglutamine trinucleotide repeat expansion disease**. The gene for HD, *HTT,* located on chromosome 4p16.3, encodes a 348-kD protein known as *huntingtin.* - Normal *HTT* genes contain 6 to 35 copies of the repeat; when the number of repeats is increased beyond this level, it is associated with disease. - **S/S**: Jerky, hyperkinetic, sometimes dystonic movements involving all parts of the body (chorea) are characteristic; affected individuals may later develop bradykinesia and rigidity. - Early symptoms of higher cortical dysfunction include forgetfulness as well as cognitive and affective dysfunction, with progression to a severe dementia. - **Clinical Manifestations:** The loss of striatal neurons, which function to dampen motor activity, results in increased motor output, often manifested as choreoathetosis. - The cognitive changes associated with the disease are probably related to the neuronal loss in cerebral cortex. The age at onset is most commonly in the fourth and fifth decades and is related to the length of the CAG repeat in the HTT gene. - Motor symptoms often precede 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. - **Death Notes:** The most common immediate cause of death in HD patients is pneumonia, typically occurring at an advanced stage of the disease. Tragically, HD patients resort to suicide at a rate that is approximately twice that of the general population. Given the ability to screen for disease-causing mutations, one might assume that genetic screening of individuals at risk would be routine; however, this is a situation in which the ability to detect the likelihood of disease has surpassed any possible treatment. - The disease is relentlessly progressive and uniformly fatal, with an average course of about 15 years. **Unit 14** 1. **Rickets (\#13-Osteomalacia is on this point)** (11/14) - **The major function of vitamin D is the maintenance of adequate plasma levels of calcium and phosphorus to support metabolic functions, bone mineralization, and neuromuscular transmission.** - Fat-soluble vitamin required to prevent bone diseases known as *rickets*, osteomalacia, and *hypocalcemic tetany*. - With respect to tetany, vitamin D maintains the correct concentration of ionized calcium in the extracellular fluid compartment. - When deficiency develops, the drop in ionized calcium in the extracellular fluid results in continuous excitation of muscle (tetany) - The normal reference range for circulating 25-(OH)-D is 20 to 100 ng/mL; concentrations of less than 20 ng/mL constitute vitamin D deficiency. \- Any reduction in the level of serum calcium is usually corrected by increased secretion of parathyroid hormone followed by bone resorption; hence, tetany is quite uncommon. **- The major source of vitamin D for humans is its endogenous synthesis from a precursor, 7-dehydrocholesterol, in a photochemical reaction that requires solar or artificial UV light in the range of 290 to 315 nm (UVB radiation).** This reaction results in the synthesis of *cholecalciferol,* known as *vitamin D~3~* **Characterized by** **a deficient mineralization of bone without a loss in bone matrix** **Osteomalacia**: ***Adult*** onset - Etiology: inadequate concentration of vitamin D, calcium, or phosphorus; poor vitamin D metabolism, renal disease. - Kyphosis, genu valgum (***"knock knee"***), ***skeletal pain in adults***, increased risk for fracture. Bone demineralization - ***↓ serum calcium, ↓ serum phosphate, ↑ PTH, ↑ alkaline phosphatase*** **Rickets** is characterized by developing ***bones failing to mineralize, resulting in soft, weak bones;*** Develops in ***growing children*** - Genetic causes: Vit D-dependent rickets and congenital hypophosphatemic rickets - Vit D-dependent rickets: defects in synthesis of Vit D or defects in Vit D receptor **VDR** - Occipital bones may be flattened, parietal bones buckle, craniotabes, frontal bossing or squared head appearance, deformation of chest, Lumbar lordosis, ***genu varum "bowleg"*** \- Osteomalacia describes a disorder of \"bone softening\" in adults that is usually due to prolonged deficiency of vitamin D. This results in abnormal osteoid mineralization. \- They may result from diets deficient in calcium and vitamin D, but an equally important cause of vitamin D deficiency is limited exposure to sunlight. This most often affects inhabitants of northern latitudes, but can even be a problem in tropical countries, in heavily veiled women, and in children born to mothers who have frequent pregnancies followed by lactation. In all of these situations, vitamin D deficiency can be prevented by a diet high in fish oils. Other, less common causes of rickets and osteomalacia include renal disorders causing decreased synthesis of 1,25-dihydroxyvitamin \- Active vitamin D is responsible for raising serum calcium and phosphate levels by acting on the kidney (↑ reabsorption of calcium and phosphate), intestine (↑ absorption of calcium and phosphate) and bone (↑ resorption of calcium and phosphate). Thus if vitamin D is reduced, serum calcium and phosphate will also be reduced. Parathyroid hormone (PTH) is increased to compensate for the low calcium level. Alkaline phosphatase is increased as there is osteoblast hyperactivity- osteoblasts produce osteoid but there is defective mineralization of the osteoid and the mineralization is needed to form bone, so there is an excess of osteoid. \- Rickets **- Genetic causes** of rickets may be classified broadly into two types: vitamin D-dependent rickets (calcipenic type), and congenital hypophosphatemic rickets (phosphopenic type). **Vitamin D-dependent rickets:** This group is characterized by defects in either synthesis of the active form of vitamin D (1,25-dihydroxy vitamin D), or defect in vitamin D receptor (VDR), or vitamin D-VDR interactions. 2. **Osteomyelitis (29)** - Tends to occlude local blood vessels, which causes bone necrosis and local spread of infection. Infection may expand through the bone cortex and spread under the periosteum, with the formation of subcutaneous abscesses that may drain spontaneously through the skin. - Pyogenic osteomyelitis is almost always caused by bacterial infection - ***Staphylococcus aureus*** is responsible for 80% to 90% - Organisms reach bone through the bloodstream, adjacent soft tissue, or direct introduction of organisms into bone - Adjacent soft tissue: due to burns, sinus disease, trauma, malignant tumor necrosis, periodontal infection, infected pressure ulcer - Direct infection due to open fracture, penetrating wounds, surgical contamination, or insertion of prostheses, metal plates, or screws \- Osteomyelitis frequently manifests as a primary solitary focus of the disease but can also be a complication of any systemic infection. All types of organisms, including viruses, parasites, fungi, and bacteria, can produce osteomyelitis, but certain pyogenic bacteria and mycobacteria are the most common culprits. In the United States, unusual infections in immigrants from lower income countries and opportunistic infections in immunosuppressed individuals have made the diagnosis and treatment of osteomyelitis challenging. *Pts with chronic illnesses such as autoimmune disorders or diabetes are at increased risk for opportunistic infections because of impaired wound healing*. - **Hematogenous osteomyelitis** occurs when the infectious agent is introduced by blood from infection elsewhere in the body (Most common) - Usually occurs in children \ - It begins with malaise, fatigue, and generalized musculoskeletal pain in about half of patients; joint involvement develops after weeks to months. - Generally symmetrical and affects small joints before larger ones. - Symptoms usually develop in the hands and feet, followed in decreasing frequency by the wrists, ankles, elbows, and knees. - Involved joints are swollen, warm, and painful. - Progressive joint enlargement and decreasing range of motion during a chronic waxing and waning course - Inflammation in tendons, ligaments, and occasionally adjacent skeletal muscle frequently accompanies arthritis and produces characteristic radial deviation of the wrist, ulnar deviation of the fingers, and flexion-hyperextension of the fingers (swan-neck and boutonnière deformities). - Radiographic hallmarks include joint effusions and juxta-articular osteopenia with erosions and narrowing of the joint space and loss of articular cartilage \- Inflammatory response in rheumatoid joint leads to accumulation of immune cells and infiltration of the synovium \- Granulation tissue forms over articular cartilage leading to pannus formation - pannus can erode and destroy articular cartilage, resulting in bone erosion, bone cysts, and fissures \- In the hands, the metacarpophalangeal and proximal interphalangeal joints are involved, in contrast to OA (see earlier). 5. **Osteoporosis (20-21)** - **Osteopenia** refers to decreased bone mass - **Osteoporosis** is defined as osteopenia that is severe enough to significantly increase the risk of fracture. - The clinical manifestations depend on which bones are involved. - Vertebral fractures that frequently occur in the thoracic and lumbar regions are painful, and, when multiple, can cause significant loss of height and deformities such as lumbar lordosis and kyphoscoliosis. - Fractures of the femoral neck, pelvis, or spine lead to immobilization and complications such as pulmonary embolism and pneumonia - Diagnostics: DEXA or CT scan - Diagnosis: based on gradations of bone mineral density (BMD); measure by dual energy x-ray absorptiometry (DXA) - T score [\ - **Primary gout initially presents as acute arthritis with:** - **sudden-onset, excruciating joint pain** - **localized hyperemia and warmth** - **occasionally, mild fever** - **constitutional symptoms are uncommon.** - **Most first attacks are monoarticular** - **50% occur in the first metatarsophalangeal joint of the big toe.** - **Untreated, acute gouty arthritis may last for hours to weeks** \- Only about 10% of individuals with hyperuricemia develop gout. - The distinctive patterns of gout are (1) acute arthritis, (2) chronic tophaceous arthritis, (3) accumulation of tophi in extraarticular sites, and (4) urate (gouty) nephropathy. - **Four Phases of Clinical presentation:** 1. Asymptomatic hyperuricemia - No clinical signs; however, serum urate levels are elevated; no treatment required 2. Acute gouty arthritis - Weight-bearing joints most commonly affected; ***warm, red, and tender to palpation*** - Great toe most often involved - Urate crystals present in synovial fluid 3. Intercritical gout - Intervals between acute attacks, no symptoms 4. Chronic tophaceous gout- approx 10 yrs after initial attack - Advanced deforming gout; tophi develops in tendon sheaths, bursae, synovium, ***ear cartilage***, aorta, corneas, sclerae, kidneys **- Acute arthritis** is characterized by a dense neutrophilic infiltrate that permeates the synovium and synovial fluid. Slender, needle-shaped urate crystals are arranged in small clusters in the synovium and are frequently found in the cytoplasm of neutrophils within aspirated joint fluid. The edematous and congested synovium also contains scattered lymphocytes, plasma cells, and macrophages. The acute attack remits when the episode of crystallization abates and crystals are solubilized. **- Chronic tophaceous arthritis** evolves from repetitive precipitation of urate crystals during acute attacks. Urate encrusts the articular surface and forms visible deposits in the synovium, which becomes hyperplastic, fibrotic, and thickened by inflammatory cells. The resulting pannus destroys the underlying cartilage and leads to juxta-articular bone erosions. In severe cases, fibrous or bony ankylosis ensues, resulting in loss of joint function. **- Tophi** are the pathognomonic hallmark of gout. They are formed by large aggregations of urate crystals surrounded by an intense inflammatory reaction of foreign-body giant cells. Tophi may appear in the articular cartilage, ligaments, tendons, and bursae. Less frequently they occur in soft tissues (earlobes, fingertips) or kidneys. Superficial tophi can ulcerate through the overlying skin. **- Urate nephropathy** refers to the renal complications caused by urate crystals or tophi in the renal medullary interstitium or tubules. Complications include uric acid nephrolithiasis and pyelonephritis, particularly when urinary obstruction occurs. 7. **Pseudogout - *Calcium Pyrophosphate Crystal Deposition Disease* (53)** - Usually occurs in individuals older than 50 years of age and becomes more common with increasing age - Divided into sporadic (idiopathic), hereditary, and secondary types. - An autosomal dominant variant is caused by germline gain-of-function mutations in *ANKH,* an inorganic pyrophosphate transporter, that result in crystal deposition and osteoarthritis at relatively early ages. - ***Inflammation is caused by activation of the inflammasome in macrophages*** - CPPD is frequently asymptomatic. \- However, it may produce acute, subacute, or chronic arthritis that can be confused with osteoarthritis or rheumatoid arthritis clinically. Joint involvement may last from several days to weeks and may be monoarticular or polyarticular; the knees, followed by the wrists, elbows, shoulders, and ankles, are most commonly affected. Chondrocalcinosis, radiographically evident calcification of hyaline or fibrocartilage, is often present but is not synonymous with CPPD. Ultimately, approximately 50% of affected individuals experience significant joint damage. Therapy is supportive to minimize symptoms. There is no known treatment that prevents or slows crystal formation. 8. **Paget's disease (Osteitis Defromans) (23-24)** - Etiology unknown; possible genetic and environmental contributions - Possible mutation of SQSTM1 gene - RANK mutations - It develops in three sequential phases: 1. An initial osteolytic stage 2. A mixed osteoclastic-osteoblastic stage 3. A burned-out quiescent osteosclerotic stage in which osteoblast activity predominates \- Paget disease often presents in late adulthood and becomes progressively more common with increasing age. An intriguing aspect is the striking geographic variation in its prevalence. It is relatively common in Caucasians in England, France, Austria, regions of Germany, Australia, New Zealand, and the United States, and is rare in native populations of Scandinavia, China, Japan, and Africa. Its exact incidence is difficult to determine because many affected individuals are asymptomatic Clinical Features: - **Bone matrices are thicker but disorganized and softer.** - **Slowly progressive** - Initial phase of excessive bone resorption by osteoclasts, followed by excessive bone formation - Pain localized to the affected bone may be present due to microfractures or bone overgrowth that compresses spinal and cranial nerve roots. - Leontiasis ossea (lion face) - Weight bearing causes anterior bowing of the femurs and tibiae and distorts the femoral heads, resulting in the development of severe secondary osteoarthritis. - - **The most dreaded complication of Paget disease is sarcoma** - **The diagnosis of Paget disease can be made radiographically. Pagetic bone is typically enlarged with *thick,* coarsened cortices and medulla** - **Many affected individuals have elevated serum alkaline phosphatase levels, but serum calcium and phosphate levels are normal.** \- Enlargement of the craniofacial skeleton may produce leontiasis ossea (lion face) and a cranium so heavy that it is difficult for the person to hold the head erect. \- The sarcomas, usually osteosarcoma or fibrosarcoma, arise in Paget lesions in the long bones, pelvis, skull, and spine. \- In the absence of malignant transformation, Paget disease is usually not serious or life-threatening. Most affected individuals have mild symptoms that are readily suppressed by treatment with calcitonin and bisphosphonates. 9. **Ankylosing Spondylitis (48)** - **Destruction of articular cartilage and bony ankyloses, especially of the sacroiliac and vertebral apophyseal joints between tuberosities and processes.** - Usually in the 20's-30's - Manifestations: low back pain that improves with exercise, but is not relieved by rest and severe morning stiffness for more than 3 months, back pain at night common, limited range of motion, loss of lumbar lordosis, asymmetric peripheral arthritis, dactylitis or "sausage toes" - Lower back pain and spinal immobility - Peripheral joints, such as the hips, knees, and shoulders, are involved in at least one-third of cases. - Approximately 90% of patients are **[HLA-B27 positive]**. \- The role of HLA-B27 is unknown; it is presumably related to the ability of this MHC variant to present one or more antigens that somehow trigger the disease, but neither the antigen nor the pathogenic immune cell is known 10. **Ehlers-Danlos Syndromes (EDSs) (15-16)** - Comprises a clinically and genetically heterogeneous group of disorders that result from mutations in genes that encode collagen, enzymes that modify collagen, and less commonly other proteins present in the extracellular matrix. - Tissues rich in collagen, such as skin, ligaments, and joints, are frequently involved in most variants of EDS - Abnormal collagen fibers lack adequate tensile strength - **S*kin is hyperextensible*** - ***Joints are hypermobile*** - These features permit grotesque contortions, such as bending the thumb back to touch the forearm and bending the knee forward to create almost a right angle. \- There are several variants of EDS, all characterized by defects in collagen synthesis or assembly. Each of the variants is caused by a distinct mutation involving one of several collagen genes or genes that encode other ECM proteins like tenascin-X. - **Classic** - **Kyphoscoliosis** - **Arthrochalasia**  **THIS IS FROM THE PHOTO FROM THE SLIDE - REFORMATTED TO CONCISE SPACE.. LOL** +-----------------------------------------------------------------------+ | Individuals with EDS have a defect in their connective tissue, the | | tissue that provides support to many body parts such as the skin, | | muscles, and ligaments. The fragile skin and unstable joints found in | | EDS are the result of fatty collagen. Collagen is a protein, which | | cts as a "glue" in the body, adding strength and elasticity to | | connective tissue. | +-----------------------------------------------------------------------+ | **SIGNS & SYMPTOMS** - Symptoms vary widely based on which type of | | EDS the patient has. In each case, however, the symptoms are | | ultimately due to faulty or reduces amounts of collagen EDS typically | | affects the joints, skin, and blood vessels. | +-----------------------------------------------------------------------+ 11. **Ewing sarcoma (34-35)** M**alignant bone tumor characterized by [primitive round cells without obvious differentiation]** - Approximately 80% of patients are younger than 20 years of age. - Boys are affected slightly more often than girls, more predominant in Caucasians; African or Asian descent are rarely afflicted. - Usually arises in the diaphysis of long tubular bones, especially the femur and the flat bones of the pelvis and presents as a painful, enlarging mass. - The affected site is frequently tender, warm, and swollen - May present with pain, fever, weight loss, leukocytosis and increased erythrocyte sedimentation rate mimicking osteomyelitis and anemia \- Radiographs show a destructive lytic tumor with permeative, or moth-eaten, margins that extend into surrounding soft tissues. The characteristic periosteal reaction produces layers of reactive bone deposited in an onion-skin fashion. - Translocation involving the ***EWSR1 gene on chromosome 22***; occurs in a large majority of tumors - This gene encodes a chimeric EWS/FLI1 protein that binds to chromatin and dysregulates transcription, leading to uncontrolled growth and abnormal differentiation through uncertain mechanisms. **- Epidemiology** - Typically found in patients 5 - 25 years of age - Second most common malignant bone tumor in children **- Sites** - Particularly common locations include the paraspinal tissues, pelvis, chest wall and extremities - Most common bone locations are pelvis, distal femur, proximal tibia, femoral diaphysis and proximal humerus - \~50% are found in the diaphysis of long bones 12. **Vitamin D metabolism and deficiency (11-13)** - **The major function of vitamin D is the maintenance of adequate plasma levels of calcium and phosphorus to support metabolic functions, bone mineralization, and neuromuscular transmission.** - Fat-soluble vitamin required to prevent bone diseases known as *rickets*, osteomalacia, and *hypocalcemic tetany*. - With respect to tetany, vitamin D maintains the correct concentration of ionized calcium in the extracellular fluid compartment. - When deficiency develops, the drop in ionized calcium in the extracellular fluid results in continuous excitation of muscle (tetany) - *The normal reference range for circulating 25-(OH)-D is 20 to 100 ng/mL; concentrations of less than 20 ng/mL constitute vitamin D deficiency.* \- Any reduction in the level of serum calcium is usually corrected by increased secretion of parathyroid hormone followed by bone resorption; hence, tetany is quite uncommon. **- The major source of vitamin D for humans is its endogenous synthesis from a precursor, 7-dehydrocholesterol, in a photochemical reaction that requires solar or artificial UV light in the range of 290 to 315 nm (UVB radiation).** This reaction results in the synthesis of *cholecalciferol,* known as *vitamin D~3~* VITAMIN D SYNTHESIS 1. Photochemical synthesis of vitamin D from 7-dehydrocholesterol in the skin and absorption of vitamin D from foods and supplements in the gut 2. Binding of vitamin D from both sources to plasma α~1~-globulin (D-binding protein \[DBP\]) and transport into the liver 3. Conversion of vitamin D into 25-hydroxycholecalciferol (25-OH-D) in the liver, through the action of 25-hydroxylases, including CYP27A1 and other CYPs 4. Conversion of 25-OH-D into 1,25-dihydroxyvitamin D, the most active form of vitamin D, by the enzyme 1α-hydroxylase in the kidney - ***Hypocalcemia stimulates secretion of parathyroid hormone** (PTH),* which in turn augments the conversion of 25-OH-D into 1,25-dihydroxyvitamin D by upregulating the expression of 1α-hydroxylase. \*\*\*said in class too \*\*\* - ***Hypophosphatemia also upregulates 1α-hydroxylase expression,*** increasing the production of 1,25-dihydroxyvitamin D. - *Through a feedback mechanism,* increased levels of 1,25-dihydroxyvitamin D downregulate its own synthesis through inhibition of 1α-hydroxylase activity. EFFECTS OF VITAMIN D ON CALCIUM AND PHOSPHORUS HOMEOSTASIS - Stimulation of ***[intestinal]*** calcium absorption - Stimulation of calcium reabsorption in the kidney - Interaction with ***[PTH]*** in the regulation of blood calcium - Mineralization of bone *Stimulation of intestinal calcium absorption.* 1,25-Dihydroxyvitamin D stimulates intestinal absorption of calcium in the duodenum through the interaction of 1,25-dihydroxyvitamin D with nuclear vitamin D receptor and the formation of a complex with RXR. The complex binds to vitamin D response elements and activates the transcription of TRPV6, which encodes a critical calcium transport channel. *Stimulation of calcium reabsorption in the kidney.* 1,25-Dihydroxyvitamin D increases calcium influx in distal tubules of the kidney through the increased expression of TRPV5, another member of the transient receptor potential vanilloid family. **TRPV5 expression is also regulated by PTH in response to hypocalcemia.** *Interaction with PTH in the regulation of blood calcium.* Vitamin D maintains calcium and phosphorus at supersaturated levels in the plasma. The parathyroid glands have a key role in the regulation of extracellular calcium concentrations. These glands have a calcium receptor that senses even small changes in blood calcium concentrations. Through the secretion of hydrochloric acid and activation of proteases such as cathepsin K, osteoclasts dissolve bone and release calcium and phosphorus into the circulation. *Mineralization of bone.* Vitamin D contributes to the mineralization of osteoid matrix and epiphyseal cartilage in both flat and long bones. It stimulates osteoblasts to synthesize the calcium-binding protein osteocalcin, which is involved in the deposition of calcium during bone development 13. **Osteomalacia (14)/ Cellular terms added here!** REFER TO RICKETS - \#1 - **Cellular terms to know** - **Osteoblasts** - **Osteocytes** - **Osteoclasts.** - **Osteocytes** are interconnected by an intricate network of dendritic cytoplasmic processes through tunnels (canaliculi) within the matrix. - Osteocytes help control calcium and phosphate levels in the microenvironment, detect mechanical forces, and translate those forces into biologic activity. - **Osteoclasts** are specialized multinucleated macrophages that are derived from circulating monocytes and resorb bone. - Surface integrin proteins allow osteoclasts to attach to the matrix and create a sealed extracellular trench (resorption pit). - Secretion of acid and neutral proteases, predominantly matrix metalloproteases (MMPs), into the pit results in the dissolution of inorganic and organic bone components - **Osteoblasts** on the surface of the osteoid matrix synthesize, transport, and assemble matrix and regulate mineralization. - Osteoblast activity is tightly regulated by hormonal and local mediators. **Joint Terms to know** - **Synovial joints:** have a joint space that allows for a wide range of motion. - Situated between the ends of bones formed via endochondral ossification, they are strengthened by a dense fibrous capsule reinforced by ligaments and muscles - Synovial membranes are lined by two types of cells arranged in one to four cell deep layers. - Type A synoviocytes are specialized macrophages with phagocytic activity. - Type B synoviocytes are similar to fibroblasts and synthesize hyaluronic acid and various proteins. - - **Hyaline Cartilage** - Composed of water (70%), type II collagen (10%), proteoglycans (8%), and chondrocytes. - The collagen fibers enable resistance to tensile stresses and transmit vertical loads; water and proteoglycans limit compression and friction. - Chondrocytes synthesize and enzymatically digest matrix; secrete degradative enzymes in inactive forms and enrich the matrix with enzyme inhibitors. - Diseases that destroy articular cartilage do so by activating the degradative enzymes and decreasing the production of their inhibitors, leading to matrix breakdown. Cytokines such as **IL-1 and TNF** are released by chondrocytes, synoviocytes, fibroblasts, and inflammatory cells and trigger degradative processes. Articular cartilage destruction by indigenous cells contributes to pathogenesis of many joint diseases. - ***Hyaline articular cartilage is the most important structure of a synovial joint.*** Its main function is to protect the articular surface of bones from abrasion and to provide a smooth lubricated surface for joint movement distributing load evenly. It can withstand an astonishing amount of repetitive physical stress. 14. **Osteopetrosis (19) -** Comprises a group of rare genetic diseases characterized by reduced bone resorption due to deficient osteoclast development or function, which leads to diffuse, symmetric skeletal sclerosis. - ***Bones are brittle and fracture easily.*** - Osteopetrosis is classified into variants based on both the mode of inheritance and the severity of clinical findings. - An autosomal recessive disorder - ***Due to a carbonic anhydrase II mutation*** - Severe infantile osteopetrosis usually becomes evident in utero or soon after birth. - Fracture, anemia, and hydrocephaly are often seen, resulting in postpartum mortality. - Affected individuals who survive into their infancy have cranial nerve defects (optic atrophy, deafness, and facial paralysis) \- An acidic environment is needed for osteoclasts to remove calcium from bone. A defect in maintaining this acidic environment, leads to poor bone resorption by osteoclasts resulting in overgrowth and sclerosis of cortical bone. This abnormally thick bone fractures easily. \- Clinical features include bone fractures, anaemia, thrombocytopenia (due to bony replacement of marrow) and visual/ hearing loss due to cranial nerve compression. The patient can also develop renal tubular acidosis (defect in carbonic anhydrase leads to decreased reabsorption of bicarbonate) and hydrocephalus (narrowing of foramen magnum). 15. **Osteogenesis Imperfecta -Type 1 Collagen Diseases (18)** - ***Brittle bone disease, the most common inherited disorder of connective tissue is a phenotypically heterogeneous disorder caused by deficiencies in type I collagen synthesis.*** - OI principally affects bone but also impacts other tissues rich in type I collagen (joints, ***eyes***, ears, skin, and teeth). - Caused by mutations in genes encoding the α1 and α2 chains of type I collagen. - **The fundamental abnormality in OI is too little bone, resulting in extreme skeletal fragility.** - **Other findings include:** - Blue sclerae caused by decreased collagen content, making the sclera translucent and allowing partial visualization of the underlying choroid - Hearing loss related to both a sensorineural deficit and impeded conduction due to abnormalities in the bones of the middle and inner ear - Dental imperfections (small, misshapen, and blue-yellow teeth) secondary to dentin deficiency. \- 4 different categories ranging from compatible with life to perinatal lethal. \- Clinical findings include multiple pathologic fractures (often child abuse suspected), blue sclera due to thin scleral collagen revealing the underlying choroidal veins and deafness due to fracture of bones in the middle ear. 16. **Achondroplasia (17)** - **Most common skeletal dysplasia and a major cause of dwarfism.** - It is an *autosomal dominant disorder caused by gain-of-function mutations* in the ***FGF receptor 3 (FGFR3) gene**,* \~90% of which stem from new mutations in the paternal allele. - Retarded cartilage growth results in shortened proximal extremities, an enlarged head with bulging forehead, and depression of the root of the nose despite a *trunk of relatively **normal length*****.** - Intramembranous bone formation (flat bones) vs endochondral bone formation (long bones) - *\*\*"flat bones are not affected"*\* \- These mutations cause decreased endochondral ossification, decreased cellular hypertrophy, decreased cartilage matrix production, and inhibited proliferation of chondrocytes in growth plate cartilage. 17. **Reactive Arthritis (49)** - Defined by the triad of arthritis, nongonococcal urethritis or cervicitis, and conjunctivitis following an infection. - Has been broadened to include mono- or oligoarticular arthritis that occurs days to weeks after ***genitourinary (Chlamydia) or gastrointestinal (Shigella, Salmonella, Yersinia, Campylobacter, and Clostrdioides difficile) infections.*** - HLA-B27 is common in patients with reactive arthritis. The disease most often presents in young adults - Arthritic episodes usually wax and wane for about 6 months, but nearly 50% of patients have recurrent arthritis, tendonitis, and lumbosacral pain. \- When active disease persists for more than 6 months, the term chronic reactive arthritis is used. Spondyloarthritis can occur in these patients, and spine involvement can be indistinguishable from ankylosing spondylitis. \- Patients initially experience an acute-onset asymmetric oligoarthritis, often affecting the lower extremities, especially the knee. Inflammatory low back pain is a common accompanying symptom but is rarely the only symptom. Enthesitis occurs frequently and often involves the insertions of the Achilles tendon and plantar fascia on the calcaneus, resulting in swelling of the heel. *Dactylitis,* or inflammation of the digits, is present in a minority of patients and typically presents as sausage-like digits, joint stiffness, and low back pain. Synovitis of a digital tendon sheath produces "sausage" finger or toe. This may progress to ossification at tendoligamentous insertion sites and development of calcaneal spurs and bony outgrowths in those with chronic reactive arthritis. Extraarticular involvement includes conjunctivitis and uveitis; dysuria, pelvic pain, urethritis, balanitis, cervicitis, mucosal ulcers, skin rashes, and other cutaneous manifestations (e.g., psoriasis-like nail changes); and cardiac valvular disease (e.g., aortic insufficiency). 18. **Juvenile RA (46)** - ***Heterogeneous group of disorders of unknown cause that present with arthritis before 16 years of age and persist for at least 6 weeks.*** - More commonly associated with oligoarthritis, systemic disease, and involvement of large joints. - Antinuclear antibody (ANA) seropositivity is typical, but rheumatoid nodules are usually absent. - Shares features with adult RA, including certain HLA and PTPN22 gene variants and pathogenesis involves Th1 and Th17 cells and inflammatory mediators such as IL-1, IL-17, TNF, and IFN-γ - Long-term JIA prognosis is variable; many patients have chronic disease, but only about 10% develop serious functional disability. \- Pain, redness, swelling, warmth, and limited range of motion 19. **Fractures: The stages of healing, what each stage is and how long each stage may take. (25-26)**  -------------- --------------------------------------------------------------------------------------------------------------------------------------- *Simple* The overlying skin is intact *Compound* The bone communicates with the skin surface. *Comminuted* The bone is fragmented. *Displaced* The ends of the bone at the fracture site are not aligned. *Stress* A slowly developing fracture that follows a period of increased physical activity in which the bone is subjected to repetitive loads. *Greenstick* Extending only partially through the bone, common in infants when bones are soft. *Pathologic* Involving bone weakened by an underlying disease process, such as a tumor. -------------- --------------------------------------------------------------------------------------------------------------------------------------- FRACTURE HEALING - Occurs by periosteal or external callus formation in fractures managed by closed methods - Five stages of bone healing: 1. Hematoma formation (1 to 3 days) 2. Fibrocartilage formation (3 days to 2 weeks) 3. Callus formation (2 to 6 weeks) 4. Ossification (3 weeks to 6 months) 5. Consolidation/remodeling (6 weeks to 1 year) \- Immediately after fracture, rupture of blood vessels results in a hematoma that fills and surrounds the area of injury. The clot provides a fibrin mesh that seals the fracture site and provides a framework for the inflammatory cell influx, fibroblast ingrowth, and capillary proliferation that characterize granulation tissue. Release of PDGF, TGF-β, FGF, and other growth factors by degranulated platelets and inflammatory cells activates osteoprogenitor cells in the periosteum, medullary cavity, and surrounding soft tissues to stimulate osteoclastic and osteoblastic activity. Uncalcified tissue known as *soft tissue callus* or *procallus* forms, providing some anchorage but not structural rigidity for weight bearing. \- Within 2 weeks of injury, the activated osteoprogenitor cells deposit subperiosteal trabeculae of woven bone oriented perpendicular to the cortical axis and within the medullary cavity. These processes transform the procallus into *bony callus,* which reaches maximal girth at the end of the second