Factor	Blastic Metastases	Paget’s Disease	Hodgkin’s Disease
Age (years)	>45	>50	20-40
Increased density	+++	+++	+++
Expansion	----	+++
Anterior Scalloping	----	----	+++
Acid phosphatase	+++	----	----
Alkaline phosphataes	++	+++	++

5. Pelvis includes protrusio acetabuli with Kohler’s teardrop and thickening of pelvic brim

6. Long bones: the tibia is the m/c lytic site

6. Complications

   1. Deformity of bone include: Shepherd’ crook deformity of the proximal femur (coxa vara), Saber shin (ant. Tibial bowing), Protrusio acetabuli.

   2. Cranial nerve neuropathies b/c foramen get smaller.

   3. Linked to increased wear and tear, early DJD

   4. Increased alkaline phospatase (up to 20x normal)

Common Causes	Uncommon Causes
Osteoblastic metastasis	Sarcoidosis
Hodgkin’s Lymphoma	Chordoma
Paget’s disease	Myeloma
Degenerative sclerosis	Osteosarcoma
Osteomyelitis (fungal or chronic)	Ewings sarcoma
Idiopathic	Osteoid osteoma
	Osteoblastoma
	Bone island

-Is a bone disease of unknown origin characterized by osteolysis followed by extensive attempts at repair.

1. Mimics: Paget’s disease mimics a Hemangioma. Hemangioma for the vertebral bodies produces a vertically striated pattern, which may closely mimic the vertical trabeculae of Paget’s disease.

2. Most likely site: Pelvis

Least likely site is the Fibula

3. List the 4 phases and describe each

   1. Stage one: Osteolytic, Destructive, or Monophasic stage- Osteoclastic over activity creates gross loss of bone density described as osteoporosis circumscripta

   2. Stage two: Combined, Mixed, or Biphasic stage – M/c encountered. Reflection of both destruction (Lytic) and production of bone (Blastic). Characterized by cortical thickening, increased radiopacity and accentuation of trabecular patterns with lucent areas mixed.

   3. Stage three: Sclerotic or Ivory Stage – Uniform thickening of trabeculae with ivory appearance

   4. Stage Four: Malignant Degeneration – Lethal stage

4. Clinical Features of Paget’s

   1. 2:1 males, m/c after 55

   2. 90% are asymptomatic. Pain, when present, is low intensity and may be associated with bowing deformities or fractures

   3. Increased hat size because enlargement of the calvaria

5. Radiological features

   1. Bone scan will be hot

   2. Skull will demonstrate in earl lesions Osteoporosis circumscripta (described in c). More advanced or combined stage demonstrates cotton wool appearance, which is fuzzy, poorly defined edges of sclerotic areas.

   3. Spine will demonstrate squared-off picture frame vertebra, which is thickened and enlarged vertebral endplates giving a squared look.

   4. Homogenous increases radiopacity of vertebral body and creates an ivory vertebra

      1. The 3 m/c causes of an ivory vertebra are: osteoblastic metastatic carcinoma, Paget’s disease, and Hodgkins lmphoma

-Can malignantly degenerate into chondrosarcoma

1. Key clinical features.

   1. m/c primary benign tumor of the hand

   2. Can be Solitary or multiple (called Ollier’s Disease)

      1. Solitary enchondroma, is a benign tumor arising in the cartilage in the metaphysis as the physis goes away.

   3. Usually a painless incidental finding

   4. Most common complication is pathological fracture

2. Key radiological features.

   1. The bone looks less dense do to cartilage tissue within the bone

   2. 40% will uptake Ca++, giving a speckled appearance- a round lesion with polka dots

3. What is Ollier’s disease? (Multiple enchondromatosis)

   1. Enchondroma’s in multiple sites

1. Shares a common presenting complaint with what process?

   1. Brodie’s Abscess

      1. The radiolucent nidus of Brodie’s is much larger (>1 or 2cm)

      2. Hole will be in the marrow

      3. The halo rim of sclerosis surrounding the nidus is much thicker and more irregular

2. Key clinical features.

   1. Pain at night relieved by aspirin

   2. A “blister” on the bone between the cortex and the periosteum. Might show up as a hole or nidus, which is lucent.

3. Key radiologic features.

   1. The nidus or hole is usually surrounded by sclerosis.

-A cortical bone tumor with a smooth contour and a continuous cortex

-Are found:

Ocuping parts of the skull that SHB spaces (sinuses)

Attached to the skull as a raised lesion

1. What syndrome includes the Osteoma as part of its classic presentation?

   1. Gardener’s Syndrome

-Hemangioma, a primary benign neoplasm, is a slowly growing lesion of bone composed of newly formed capillary, cavernous or venous vessels.

1. Key clinical features

   1. M/c primary benign tumor of the spine

   2. No history of going malignant

2. Key radiologic features

   1. Corduroy cloth or striated vertebra appearance which is accentuated vertical trabeculae.

   2. Barrel shaped vertebra

   3. In the skull,, it appears as one large lesion. Most occur in the frontal bone, creating a round or oval radiolucency, radiating sunburst or poked-wheel appearance

-lesion consisting of a cystic cavity filled with blood.

1. Key clinical features?

   1. 75% 5-20 yoa

   2. Previous history of trauma. 80% occur in long bone (femur, tibia and spine)

2. Key radiological features

   1. Only benign bone tumor known to cross the epiphyseal plate

   2. Cortical ballooning or Blown-out appearance

   3. Periostel buttressing at the edge of the lesion is characteristic.

-Hereditary Multiple Exostosis is an inherited autosomal dominant metaphyseal overgrowth that is characterized by multiple osteochondromas

1. Key radiological features

   1. Multiple, painless lumps and bumps around joints

   2. Bayonet deformity of the wrist

   3. Broad metaphyses

   4. Calcified cauliflower cartilaginous caps

-Not to be confused with the congenital anomaly called Suprachondylar process.

-Also known as Coat-hanger exostosis

-Is a bony exostosis projecting from the external surface of a bone; usually has a cartilaginous cap.

1. Key clinical features

   1. Occurs ~20 yoa

   2. Points away from the joint, there is no ligament

   3. Most are asymptomatic. M/c complaint is a painless mass around the joint

2. Key radiological features

   1. 2 types of Osteochondroma:

      1. Sessile: On a broad, flat base and no stalk; common in the humerus and scapula.

      2. Pedunculated: On a long stalk, with a cauliflower top. Extending away from the joint.

   2. Coat-hanger exostosis represents the pedunculated.

   3. Has a continuous cortex until you reach the tip. Then it is cartilaginous

3. Most common complication

   1. Aggressive biopsy

   2. Trauma or fractures then can become malignant.

-Is a neoplasm that originates from non-bone forming supportive connective tissue of the marrow. Contains multiple nucleated giant cells

1. Clinical Features

   1. Males:

      1. Tumor tends to be malignant

   2. Females:

      1. Tumor tends to be benign

   3. 80% are benign, 60% are lytic

2. Key Radiologic features

   1. Most lesions begin in metaphysis and extend to subarticular location.

   2. Thin, expanded cortex, which gives the Soap Bubble Pattern in 40%

   3. May have delicate periosteal reaction.

   4. M/c in distal femor and proximal tibia

3. Most worrisome complication

   1. 20% of the time could be malignant

-primary malignant bone tumor that produces varying amounts of collagen and has no tendency to form tumor bone, osteoid, or cartilage, either in its primary site or in its metastases.

1. Age group?

   1. 30-50 years of age

2. Key clinical features.

   1. 2 types of lesions meduallary and periosteal

   2. pain and swelling for long duration

   3. the metaphysis is the classic location

   4. Most occur about the knee, femur, tibia, and humerus

3. Key radiological features

   1. Highly destructive meduallary lesion, lytic and placed within long bone

   2. Produces the largest soft-tissue mass of all primary malignant tumors

-Is a primitive primary malignant tumor of bone it is composed of tumor cells derived from the connective tissue framework of bone marrow

1. How common? Age group?

   1. 7% of all primary bone tumors. 4^th m/c primary malignant bone tumor behind (multiple myeloma, osteosarcoma, and chondrosarcoma).

   2. 10-25 years of age

2. Key clinical features

   1. Mimics: Infection; systemic signs of slight fever, secondary anemia leukocytosis, and increase ESR

   2. Affects long tubular bones of the Lower extremity.

3. Key radiologic features

   1. Saucerization: Cortical saucerization is a characteristic sign. This irregular defect effaces the outside of the bone occasionally, exhibiting a marginal scalloping effect.
      

   2. Classic presentation is a diaphyseal permeative lesion with a delicate onion skin or peel periosteal response.

   3. The most common primary malignant bone tumor to metastasize to bone

-Is a malignant tumor of chondrogenic origin that remains essentially cartilaginous throughout its evolution.

1. How common is Chondrosarcoma? What age group?

   1. Represents the third most common primary malignant bone tumor, following multiple myeloma and osteosarcoma.

   2. Age group is 40-60 years 2:1 male predominance.

2. Key clinical features

   1. Pain usually presents late in the disease process, often after large soft tissue masses develop

   2. Severe pain follows pathologic fracture

   3. The most common sites are the pelvis, proximal femur and humerus, ribs, scapula, sternum, craniofacial bones, distal femur, and proximal tibia. The normal variance notes states that Chonndrosarcoma is the m/c primary malignant tumor of the hand.

3. Key radiological features

   1. Round or oval radiolucencies with ill-defined margins evident.

   2. Lesions re metaphseal or diaphyseal

   3. Endosteal scalloping occurs secondary to pressure erosion from the enlarging lobular mass

   4. Popcorn matrix calcification in the lesion occurs in 2/3 of cases; 1/3 are purely radiolucent

   5. Laminated or speculated periosteal response occurs

   6. Metastatic disease is usually to lung

4. Prognosis

   1. Prognosis is good, with 90% survival after early surgery

-Is a primary malignant tumor of bone; it is derived from undifferentiated connective tissue and forms neoplastic osteoid

1. How common is Osteosarcoma? Age group?

   1. It is the second most common primary malignant bone tumor, representing 20% of all primary malignant bone tumors.

   2. It is 2x more common than chondrosarcoma, 3x more frequent than Ewings sarcoma.

   3. 75% of cases occur in the 10-25 year age range, with 2:1 male predominance.

2. Key clinical features.

   1. Painful swelling of the involved limb is a common presenting symptom

   2. The metaphyses of the distal femur, proximal tibia, and proximal humerus are the most common sites.

   3. Only 3.5-7% occur in the spine

3. Key radiologic features

   1. The classic lesion presents as a permeative or ivory medullary lesion in the metaphysis of a long tubular bone with a poorly defined zone of transition.

   2. A sunburst or sunray periosteal response is characteristic

      1. Sunburst= periosteal reaction that often takes place within an extracortical, dense soft tissue mass that displays transverse spicules or radiating striations.

   3. Often, Codman’s triangle is found associated with the destructive lesions

      1. This is a reactive response to the lifting of the periosteum and is not pathognomonic for osteosarcoma b/c it may also be found in benign conditions such as traumatic periostitis, osteomyelitis, eosinophilic granuloma, and thyroid acropachy.

   4. Cortical disruption with soft tissue mass formation, often growing to large dimensions, occurs. The peripheral edge of an eccentric lobulated mass whose margins are roughened and irregular may be referred to as the cumulus cloud appearance.

4. Prognosis

   1. A 20% 5-year survival rate has been traditional; studies using intensive chemotherapy report 80% survival rate

   2. Amputation has offered the best tx when the lesion is surgically accessible.

-is a disorder of unknown cause in which skeletal aberrations constitute the cardinal feature.

1. Key clinical features.

   1. Café au Lait spots with a “coast of Maine” appearance, pigmentation changes

   2. Common in late childhood before puberty during skeletal growth

   3. Polystotic m/c for derormities

2. Key Radiological features

   1. Clear zone in the center with a “Ground Galss Appearance” – beveled / fine fuzzy opaque edges

   2. Stimulates blastic reaction of surrounding tissue = “Rind of Sclerosis”

   3. Can change the contour of bone (expansile), with widening of meduallary, endostal thinning and scalloping

   4. Sheperds crook deformity common

1. Coast of Maine Café au Lait spots is associated with Polystatic fibrous dysphasia
   

2. Coast of California Café au Lait spots are associated with Neurofibromatosis

3. Most common malignancy of bone? METS
4. Most common primary malignancy of bone? Multiple Myeloma
5. Most common benign tumor of the hand? Enchondroma
6. Most common Primary malignancy of the hand? Chondrosarcoma
7. Most common benign tumor to a growth plate? ABC (Aneurysmal Bone Cyst)
8. Most common benign tumor of the spine? Hemangioma

Criteria	Benign	Primary aggressive	Secondary aggressive
Age (decades)	1-3	1-7	4-7
Size
0-6cm	+++	+	+
6+cm	+	+++	+++
Monostotic	+++	+++	++
Polystotic	+	+	+++
Cortical destruction	----	+++	+++
Periosteal reaction
Solid	+++	+	----
Laminated	++	++	----
Spiculated	----	+++	+
Codman’s	++	++	+
Destruction
Geographical	+++	+	----
Moth-eaten	----	+++	+++
Permeative	----	+++	+++
Margins
Sharp	+++	+	+
Imperceptible	----	+++	+++
Matrix	+++	++	----
Soft tissue mass	----	+++	+
Joint space	----	----	----

The text spends a lot of time going through the description of epilepsy, which is measured by the EEG for partial seizures, local seizures, grand mal seizures, petit mal seizures… these are all terms that go back to the turn of the last century when electrical recording began to be used. Epilepsy is diagnosed by electroencephalogram. The goal of therapy is to manage the pts symptoms, so that they have some quality of life. Some newer drugs only control 30-40% of pts. So the search for an ideal anti-epileptic drug continues.


There is a condition known as “status epilepticus” that is life threatening! If this occurs in your dental office, you’ll need to dust off the emergency drug kit and give i.v. Valium (diazepam), immediately. It turns out that this is an obsolete drug, because the new paradigm for treating status epilepticus involves use of a benzodiazepine, and the protocol is in the handout (not text). By the way, “obsolete” only means that there is a superior drug available, not that the older drug is illegal or contraindicated.


This describes the frequencies of types of seizures that occur. 35% of seizures are complex partial (temporal lobe), 30% are grand mal (tonic-clonic). Except for status epilepticus, seizures will be self limiting.



When you’re taking your history, be sure that you understand when the pt was first diagnosed, sometimes its very early. For example, at birth a fever is often associated with seizures, mothers are taught to put their baby into a cold bath with ice and to cool the body temp so the seizure will stop. Head trauma is another indication where there is physical damage that can lead to seizures…



So infection also can cause seizures. Then there can be idiopathic seizures, where we don’t know what’s causing it.


Local anesthetic toxicity: The toxic manifestations of all local anesthetics, as you approach the maximum recommended dose (you need to know this in mg/kg weight), you can precipitate convulsions and seizures. There is no antidote to local anesthetic-induced convulsions. You can manage the symptoms, but there is no specific antidote. This is why we need to know the number of carpules, and mg/kg, that we can use in an adult.


As far as drug therapy, the real decision of the neurologist is based on the tolerability of the drug. The efficacy is sometimes low, but the decision which drug to use is based on the side effects profile, and avoiding drug interactions.


Carbamazepine (Tegretol) is an adjunct for neuropathic pain, but was developed only for epilepsy. So if your pt is taking Tegretol you must specify why they are taking it (seizures or peripheral neuropathy). Phenytoin (Dilantin) is very old. Although both of these drugs are “obsolete” compared to the newer agents, they still have some role. The newer agents, such as Valproic acid, have tremendous risk of toxicity and significant warnings which have implications in terms of dental practice.


The action of Dilantin on the Na+ channel facilitates its results. Dilantin blocks the sodium flux by blocking the channel and so prolongs the inactive state of the sodium channel. We don’t know how the newer agents work, all we know is that they control seizures.


There’s a need to monitor blood levels when a pt is taking these drugs (carbamazepine, phenytoin, ethosucimide, valproic acid). Because there is tremendous variability in bioavailability and serum levels associated with both brand name and generic Dilantin. So there are drugs that when the physician is titrating the drugs they must monitor blood levels, obviously this adds to the cost of treating a disorder.


We see that half-lives are relatively long, over 10-15 hours sustained release allows for once a day dosing. This improves compliance.



With regards to the drugs of choice, in grand mal carbamazepine, phenytoin and valproate tend to be our first choices. You’ll notice Phenobarbital here, which was used long before the other drugs, but the side effects included drowsiness, sedation and tolerance, which decreases the effectiveness over time. For partial seizures, including secondarily generalized, we have the same choice drugs. Neurologists have many choices of drugs and where they switch from one to another depends on the response of the pt.


Regarding status epilepticus, i.v. diazepam (which has many indications: anxiety, hypnotic, and parenterally anti-seizure properties) is in our emergency dentist kits. Now, Lorazepam is preferred because it is superior in efficacy.


Clinical Problems

Tegretol (Carbamazepine) can result in agranulocytosis and aplastic anemia.

Dilantin (Phenytoin) can result in gingival hyperplasia, among other things such as Hirsutism (excessive hair growth), ataxia and nystagmus (rapid movement of the eyes), plus some CNS effects which clearly limits the use of this drug.

Valproic Acid can result in liver problems.

Phenobarbital results in drowsiness, sedation, cognitive impairment, and because the liver p450 system is actually stimulated other drugs are metabolized faster.


Trade Names

A pharmacist was sued when he substituted a generic version of Dilantin when the MD ordered “do not substitute.” The pt was killed. So there’s a new law: when a generic drug is introduced, the drug company must prove efficacy.

-the incidence of cleft palate with mothers taking Dilantin: 2-5%

-the incidence of cleft palate in normal pregnancy (no drugs): 0.5%

-Lidocaine + epi pregnancy category: B

-Dilantin pregnancy category: D

Pregnancy categories range from A (being absolutely safe, there are no drugs that are absolutely safe for pregnant women to take) to B (practically no risk) to C to D to X (being absolutely contraindicated for pregnant women because of proven harmful effects to the baby). When you see a drug that is a “D” that means that there’s lots of evidence, in humans that the drug should be avoided. So clearly, the court found that the cleft palate was not from using lidocaine judiciously, but from use of Dilantin.



Epilepsy is the third most common neurologic disorder. Epilepsy is diagnosed as a discreet clinical event, accompanied by an abnormal electrical discharge in the brain. Not all seizures indicate epilepsy; if you O.D. your pt with lidocaine you can induce seizures. Provoked seizures are less predictive than epilepsy. As soon as you see any excitation, be aware that you can quickly provoke a seizure disorder.



If you had to get a med consult, it would only be to determine whether or not the pt is controlled. The neurologist would probably say they have some generalized seizures, either myoclonic, tonic-clonic, tonic, clonic, atonic, or absence. Absense refers to a peculiar seizure in which a pt just stares blankly into space, not thrashing around, but it is a seizure and is diagnosed by that behavior and an EEG. Partial seizures are less likely to be encountered because they’re minor.


Goals of therapy for epileptics include: eliminating seizures or reducing seizure frequency as much as possible, avoiding acute and chronic side effects of therapy (almost impossible to do, ie. Dilantin pts may show some or all side effects associated with use), maintaining or restoring normal psychosocial/vocational adjustment (basically ensuring quality of life as much as possible).




If we understood the etiology of disease better, we could treat epileptics better. All drugs that we’re discussing today are CNS depressants and decrease neuronal firing. Two neurotransmitters prevalent in human brains, Glutamate and Aspartate, clinically cause excitation, so these are nice targets for drugs. However, maybe pts have seizures because they lack inhibitory neurotransmitters, such as GABA. This theory was used in developing Neurontin (gabapentin) as a drug. But alas, gabapentin doesn’t work that way… its anti-epileptic properties have nothing to do with GABA receptors. So although it’s a good rational, it just didn’t pan out the way they planned.



Keppra is a newer agent, not discussed in the book. It is an anti-epileptic drug for the treatment of seizures in adults. The exact anti-epileptic effect is unknown. Protection against secondarily generalized activity from focal seizures induced by two chemoconvulsants that induce seizures (ie. lidocaine overdose) was observed. Keppra is rapidly and almost completely absorbed, and is not affected by food; good bioavailability, low protein binding. The drug is metabolized by the cytochrome system p450 enzymes. Metabolites are inactive. Clinical trials say that you control between 20-40% of pts. This is the newest and preferred agent of neurologists now, probably because of lack of interactions with other drugs.



Gabapentin is an amino acid, an analog of GABA that is effective against partial seizures. Originally planned as a spasmolytic (smooth muscle relaxing agent), it was found to be more effective as an anti-epileptic drug… it was a serendipitous discovery.



Gabapentin is unbound in plasma proteins. NSAIDS have a very high affinity for serum albumin, any drug bound to these proteins will have a drug interaction. Gabapentin’s mechanism of anti manic properties is not known. It is used as adjunctive therapy in the treatment of partial seizures; not monotherapy.


Adverse effects of Gabapentin include fatique, somnolence, dizziness, ataxia and nystagmus. From these effects we can see that this is a CNS depressant.



Felbamate (Felbatol) was popular a few years ago, but with chronic use was found to cause aplastic anemia (bone marrow suppression) and severe hepatitis at unexpectedly high rates, and so has been relegated to a third-line drug for refractory cases. Despite the seriousness of the adverse effects, approximately 10,000-15,000 pts in the USA remain on the med. So neurologists must weigh the risks involved, this drug is expensive because of the blood monitoring that must be involved.



According to published and unpublished reports, Valproic Acid (Depakene) may produce teratogenic effects in the offspting of human females receiving the drug during pregnancy. The dilemma is this: the mother must be controlled because if she gets seizures during pregnancy there is an even greater risk for the child than the teratogenic possibilities from taking the drugs to control her.

Tegretol (carbamazepine): xerostomia, oral ulcers, glossitis

Dilantin (phenytoin): gingival hyperplasia; blood dyscrasias (rare)

Depakene (Valproic Acid): increased bleeding tendency, anti-platelet effect; blood dyscrasias (rare)

Luminal (Phenobarbital): CNS depressant; liver enzyme inducer, hypoventilation; apnea

Klonopin (clonazepam): xerostomia; CNS depressant

Zarontin (ethosuximide): gingival bleeding; gingival hyperplasia, swollen tongue (megaglossia, rare); blood dyscrasias

Mysoline (primidone): CNS depressant; barbiturate derivative

Keppra (Levetiracetam): asthenia, somnolence, incoordination

Neurontin (gabapentin): somnolence, ataxia, vertigo, gingivitis, hypertension

Felbatol (felbamate): Warnings- aplastic anemia, hepatic failure! Moniter blood and liver values and functions!

Must maintain airway and vital signs, then determine what must be done for therapy. Many people wonder why Valium isn’t the preferred agent anymore…



It turns out that i.v. lorazepam is generally enough to control the seizure, but if it continues you must proceed to i.v. Fosphenytoin (a dilantin derivative), then i.v. Phenobarbital, then admit to the ICU and start Midazolam anesthesis or Propofol.



You must distinguish status epilepticus from a grand or petit mal seizure. The primary way to do this is to see if the seizure subsides after about a minute. If it does stop, the pt may be depressed and or embarrassed about his or her condition. If it doesn’t stop, begin treatment for status epilepticus.

Desmopressin:

1. increases factor X
2. increases factor V
3. causes sustained severe hypertension
4. can be used to improve haemostasis in haemophilia
5. increases factor VIII activity

Click Here For Answer & Discussion

1. Kills AIDS patient quickly (months)

2. 500X’s higher incidence, fatal in 80%

3. more likely to develop extrapulmonary disease-lymph nodes, GU, or CNS. Multiple organ systems

4. military TB

5. low CD4+ -no macrophages activated

6. can respond to med if done in time

7. MAI infx- more drug resistant

8. Tx- new mactolides, rifabutin, ethambutol, clofazimine, or fluoroquinolones

1. General

   1. Slim, rod shaped

   2. Acid fast- affects permeability

   3. Resists drying, chemicals, and germicides.

   4. Strictly aerobic

   5. .2-.4 X 10 m

   6. non-motile

   7. non-spore forming

   8. cell wall of N-glycolymuranic acid with a high % of mycoic acid on peptide and polysaccharides

   9. 10% CO₂, pH of 6.5-6.8, Lowenstein-Jensen (60% hom egg) with malachite to inhibit other bacteria

   10. Semisythetic Middlebrook 7H-11

   11. slow growth, mean generation time of 12-24 hrs

2. Virulenc factors

   1. Grow inside macrophages and monocytes

   2. Probably prevent phagosome-lysosome fusion or escapes the phagosome- MHC I associated cytotoxic T cell response

   3. LLO homologue (hemolysin)- escape from phagosome

   4. produces NH₄ to counteract acid in phagosome

   5. mycolic acids are toxic- immune response

   6. TNF -a causes lung damage

3. Epidemiology

   1. Inhalation of droplet nuclei, sometimes infx trough GI or skin. 1 cough has 3000 droplet nuclei, <10>

   2. Decline of mortality. 1985 steady decline stopped, and mortality increase 20% from economic conditions, IV drug use, and AIDS

4. Pathogenesis

   1. Usually pulmonary at the periphery of the midzone of the lung. Those that reach the small bronchi or alveoli are engulfed by macrophages. Some survive and multiply in the macrophages and are carried to the hilar lymph nodes. Inflammatory- minor and non-specific. Bacilli may be deposited in the liver, spleen, kidney, bone, brain, meninges and apices, and other parts of the lung. Flu-like symptoms and large lymph nodes at primary site, seen with x-ray

   2. Cell-mediated immunity to Mtb and hypersensitivity to tuberculoprotein develop in 2-6 weeks with formation of histologic tubercles at bacillary multiplication. T-cells recognize Ia antigen on infected macrophages

   3. Macrophages secrete Il-1 activating IFNand TNF activate local macrophages and recruit monocytes. NO mediate destruction of mycobacteria. Other cytokines stimulate accumulation of fibroblasts and deposition of collagen to wall off the bacteria. This leads to a tubercle- caseous granuloma.

   4. Primary infx handled well by host. M. tb multiplication ceases. Organisms die and lesions fibrose and calcify to produce Ghon complex seen on x-ray. Sometimes, bacilli remain alive and may a potential source of reactivation. In about 5% of patients, the infx is not contained and disseminates to many organs to produce military tuberculosis. This may happen when a necrotic tubercle erodes into a blood vessel.

   5. About 10% recovering from a Primary infx develop a disease later. Associated in older men, malnutrition, alcholism, diabetes, old age, or ’s lifestyle. Reactivation occurs in area of high oxygenation and low lymphatic drainage such as the apices. Small blood vessels may be involved in destruction of tissue, so patients cough up bloody sputum- highly infectious.

   6. Innate immunity is high. Races with a history f urbanization and exposure in 18^th and 19^th centuries have greater resistance. Native Americans and Eskimos low tolerance.

   7. Acquired immunity is cell-mediated, but incomplete.

5. Diagnosis

   1. Careful Hx

   2. Chest x-ray

   3. Tuberculin test- delayed-type hypersensitivity. Purified protein derivative (PPD) Intradermal injection of .1 ml of PPD of 5 TU. Read 48-72 hrs later. Induration, hardness, or 10 mm or more with erythema- positive reaction. Positive reaction- infx at some time or strong x-reactivitity mycobacterium species. No implication of activity

   4. Lab Dx-

      1. acid-fast visualized by Ziehl-Neelson on sputum samples. Not specific for M. tuberculosis. Sputum collected in a container not subject to contamination. Inevitably contaminated with normal flora. Carbolfuchasin->rinse-> alcohol-> methylene blue-> red cells on blue background.

      2. Cultures on solid media take up to 3 weeks or longer. Radioactive ¹⁴C- labeled palmitic acid. ¹⁴CO₂ liberated monitors growth.

   5. Cultivation in 3-8 weeks for PCR

6. Treatment and prevention

   1. Isoniazid and rifampin for extracellular and intracellular organisms

   2. Streptomycin for foe extracellular

   3. Ethambutol

   4. Two or three drug course for 6-9 months. One drug-relapse from resistant strain

   5. 10^-7 – 10^-10 mutation rate

   6. Prophylactic chemotherapy- isoniazid

      1. Radiologic evidence primary complex

      2. PPD + close contact with infx

      3. Child with close contact

      4. Known PPD converter

      5. Immunosuppressed

   7. Immunoprophylaxis- BCG (Bacillus Calmette and Guerin) vaccine

      1. Attenuated M. bovis strain. Not used in US since PPD test is diagnositic here

1. Mycobacterium kansaii

   1. Photochromogenic-dark color producer, yellow-pigemneted, colonies after 2 weeks in light

   2. Prevalent since M. tb has declined. IL, OK, and TX urban areas 3% mycobacterial ifx in ES

   3. Cavitary pulmonary disease, cervical lymphadenitis, and skin infections. Causes disease in HIV patient and CD4+ Tcell counts lower than 200.

   4. PPD +

   5. Prolonged chemotherapy with isoniazid, rifampin, and ethambutanol

2. M. avium-intracellalare (MAI)

   1. Slightly faster faster than M. tb. Acid-fast. Found in macrophages

   2. world-wide in soil and water. US- SE, Pacific coast, and north –central regions.

   3. 2^nd to tb in significance and frequency

   4. M. avium- birds, M. intracellulare- systemic HIV infx

   5. Blood culture

3. M. scrofulaceum

   1. Acid-fast, scotochromagen, makes yeloow colonies in light or dark after 2 weeks

   2. Granulomatous cerivical lymphadenitis, scrofula, in children

   3. Manifests as an enlargement of one or more lymph nodes. Little or no pain. PPD-

   4. Surgical removal

4. M. fortuitum complex

   1. free-living, rapidly growing, acid-fast bacterium which produce colonies in 3 days

   2. Human infx rare

   3. Abscess @ injection sites of IV drug abusers are the most common lesions. Secondary pulmonary infx

5. M. marinu-

   1. grows @ 30C not @37C, photochromagen- color producer

   2. water and fish natural sources, slime on sides of swimming pools- skin superficial granulomatous lesion that ulcerates

   3. heals spontaneously in a few weeks, tetracycline and other tb drugs

6. M. ulcerans-

   1. grows @ 30C not @37C

   2. most cases in tropics: Africa, New Guinea, and N. Australia. Children mostly infected.

   3. Severe ulceration on skin and subcu tissue

   4. Surgical excision and grafting. Drugs not successful.

1. Acid-fast, cannot be grown on artificial medium

2. Infectivity low, chronic granulomatous disease of peripheral nerves and nasal mucosa

   1. Tuberculoid

      1. Large, flattened plaques on face, trunk, and limbs with raised erythematous edges.

      2. Dry, scaly, hairless centers.

      3. Peripheral nerves invaded- local noncontiguous anesthesia.

      4. Cell-mediated immunity works

      5. Delayed hypersensitivity to lepromin, tuberculin analog from leprous tissue

   2. lepromatous

      1. multibacillary

      2. cell-mediated immunity is deficient, T2 response

      3. no rxn to lepromin

      4. growth unimpeded. dense infiltration, may reach blood

      5. extensive, symmetric, depiliated, and diffuse

      6. analogous to military TB

3. Ziehl-Neelson stain the scrapings of tissue. Tuberculoid- clinically dx and histologic full-thickness biopsies

4. Sulfones block para-aminobenzoic acid metabolism, with 0rifampin and clofazimine (to prevent resistant mutants) for 6 months- controls or cures tuberculosis leprosy. Tx continued for 2 years

1. General

   1. Weakly gram+

   2. Partially acid fast

   3. Soil bacteria

   4. Strict aerobic bacilli

   5. Non-motile

   6. Non-spore forming- from branched hyphae in tissue culture

   7. Catalase +

   8. Carbs used oxidatively

   9. Non-selective media with 5-10% CO2, slow growth

   10. Sputum, infected tissues, or abscesses may have filament that are seen by acid-fast stain

2. Pathogenesis

   1. Inhalation-> colonization of oropharynx-> aspiration of oral secretions into lower airways

   2. Trauma subcutaneously. Injection can lead to abscess and necrosis

3. Clinical syndromes

   1. Most common cause of acute or chronic suppurative infections

   2. Bronchopulmonary Infections

      1. Cough, dyspnea, and fever

      2. Cavitation and spread to plura

      3. Dissemination to CNS (brain abscess) or skin

   3. Cutaneous infections

      1. Primary infections: cellulitis, pustules, Pyoderma, abscesses, mycetomas- painless, chronic infx

         1. Localized subcu swelling, suppuration, many sinus tracts open to skin

         2. Infect connective tissue, muscle, and bone

      2. Secondary spread

   4. Lymphocutaneous

      1. Regional lymph nodes

      2. Cutaneous involvement along lymphatics

   5. Ocular infections

      1. Opportunistic

      2. Unclean contact lenses or ophthalmologic manipulation

4. Epidemiology

   1. Exogenous infection- inhalation, trauma, or opportunistic

   2. Immunocompromised- higher risk

      1. Chronic pulmonary disease- bronchitis, emphysema, bronchiectasis, alveolar proteinosis

      2. Skin wounds

      3. T-cell deficiencies or immunosuppressive therapy.

   3. Ubiquitous- everywhere

5. Treatment

   1. Long term- sulfonamide with surgery

   2. Proper wound care

6. Clinically Relevant Species

   1. N. asterides-

      1. 90% Norcardia infections, world-wide

      2. Bronchopulmonary disease

      3. 1/3 involve CNS

   2. N. brasiliensis (mycetomas) N. otitidiscaviarum

      1. Primary Cutaneous infection

   3. N. farcinica