Fetal Tissue Transplants

Fetal Tissue Transplants
By:Michelle Gomez

Words You May Need To Know
* Definitions-
+ Fetal tissue transplants
+ Parkinson’s Disease (PD)
+ Huntington’s Disease (HD)
+ Dopamine (DA)

Development of the Fetus
First Month (conception to 6 weeks)
Second Month (7-10 weeks)
Third Month (11-14 weeks)
Fourth Month (beginning of second trimester)
Fifth month (19- 22 weeks)
Seventh Month (beginning of third trimester 27-30 weeks)
Sixth Months (23-26 weeks)
Eighth month (31-34 weeks)
Ninth month (35 weeks to delivery)

History
Fun Facts
* The History of Fetal Tissue Transplants

Parkinson’s Disease
* Parkinson’s Disease
Huntington’s Disease
What does it treat?
* Parkinson’s Disease
* Huntington’s Disease
* Retina Repair
* Future:
o Epilepsy
Biological Concepts

The Process: Cell Therapy Development in PD
* Parkinson’s Disease-
o Graft Efficiency has to be increased and variability reduced
+ Patient selection
+ Graft Placement
+ Composition and Preparation of the Graft Tissue
+ Developing immunological mechanisms

2 Years After Transplantation
The Process: Cell Therapy Development in PD
Evidence and Experiments
Society for Neuroscience-
* October 24, 1999- a study was presented at the Society for Neuroscience’s annual meeting, showing that the fetal cells can produce a critical neurotransmitter, reducing patient's tremors and paralysis. (Helmuth, 886)
Retina Repair-
o The procedure that Elisabeth Bryant, from the previous slide, underwent was retinal repair. Robert Aramant at the University of Louisville in Kentucky developed the transplant technique with Magdalene Seiler. (image on next slide)

Fetal tissue inserted here
Frontier Issues
Cost and Finances
* Surgery Alone- $43,500
* Pre-Operative Costs- $4,000
* Total- Approx.- $50,000
Controversy
Pro-life vs. Fetal Tissue Transplant Supporters
Ethical Issues
* It takes six fetuses to provide enough material to treat one Parkinson’s patient.
* Who is donating?
* Cell supply is limited.
* Better areas for transplantation?
Politics
Bibliography/ References
* Barinaga, M. “Fetal neuron grafts pave the was for stem cell therapies.” Science. 5 Feb 2000 287:5457 p.1421-2. General Science Index. COSLibrary, Visalia, CA. 19 Sept 2005
* Björklund, Anders and Olle Lindvall. “Cell Therapy in Parkinson’s Disease.” NeuroRx. Oct 2004. the American Society for Experimental Therapeutics, Inc. Lund, Sweden. 13 Oct 2005. http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=534947
* Cimons, Marlene. “Bush is a threat to US stem-cell research”. Nature Medicine. 2001. COS Library, Visalia, CA. 24 Oct. 2005. http://www.nature.com/nm/journal/v7/n3/full/nm0301_263a.html
* “Dopamine.” Columbia Encyclopedia, 6th Edition. 2005. 19 Sept 2005 http://www.encyclopedia.com
* Dunnett, Stephen B. and Anne E Rosser. “Cell Therapy in HD.” NeuroRx. Oct 2004. American Society for Experimental NeuroTherapeutics, Inc. Wales, UK. 13 Oct 2005. http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=534947

Bibliography/ References
* Fackelmann, K.A. “Study sizes up fetal cells for transplant.” Science News. 7 Jan 1995. 149:1 p.6. Academic Abstracts. COS Library, Visalia, CA. 15 Sept 2005
* "Fetal Tissue Implant." Columbia Encyclopedia, 6th Edition. 2005. 19 Sept. 2005 http://www.encyclopedia.com
* Hawaleshka, Dan. “The debate over fetal tissue. (cover-story).” Maclean’s. 1996 109:4 p.48. Academic Abstracts. COS Library, Visalia, CA. 15 Sept 2005
* Helmuth, L. “Fetal cells Help Parkinson’s patients.” Science. 29 Oct 1999. 286:5441 p.886-7. General Science Index. COS Library, Visalia, CA. 19 Sept 2005
* Hopkins, John. About Huntington's Disease and Related Disorders. 2002. John Hopkins Medicine. 24 Oct 2005. http://www.hopkinsmedicine.org/bhdc/about/
* “Huntington’s Disease.” Columbia Encyclopedia, 6th Edition. 2005. 19 Sept. 2005 http://www.encyclopedia.com
* “Introduction.” Parkinson’s Disease: Hope Through Research. Sept 2003. National Institute of Neurological Disorders and Stroke. 22 Sept 2005. http://www.ninds.nih.gov/disorders/parkinsons_disease/detail_parkinsons_disease.htm
* Rae, Scott B. “The Ethics of Fetal Tissue Transplantation.” CHRISTIAN RESEARCH INSTITUTE. 2005. Talbot School of Theology. 24 Oct 2005. http://www.equip.org/free/DE192.htm

Images-
* “Development of the Fetus.” Illustration. 1998. Development of the Baby. Parents Magazine. 24 Oct 2005 http://www.csulb.edu/divisions/students2/departments/Health_Resource_Center/pregnancy.htm
* Levivier, Marc. “PET scan in patient with PD after transplantation of human fetal neurons (before and after)”. Illustration. 7 July 2003. Neural Transplants in Parkinson’s Disease: do they work?. Lancet Neurology. 6 Oct 2005 http://www.thelancet.com/journals/laneur/article/PIIS1474442203004423/fulltext.
* Rowe, Duncan. “Retina Repair.” Illustration. 31 Jan 2003. Fetal Tissue Transplants Improve Adult Sight. New Scientist Magazine. 6 Oct 2005. http://www.newscientist.com/article.ns?id=dn3319

Fetal Tissue Transplants.ppt

Read more...

Renal Failure and Dialysis in Pregnancy

Renal Failure and Dialysis in Pregnancy
By:David Shure

Differential Diagnosis
* FSGS -
Pro: HTN, non-remitting, albumin close to NL
Con: expected creatinine to be higher after several years

* Membranous Nephropathy -
Pro: wax/waning course
Con: often with lower albumin, edema

* Diabetic Nephropathy -
Pro: proteinuria, time course
Con:poor evidence for DM
4. FMD - Pro: unequal sized kidneys, young female, HTN hx, renal arteries not commented on in US

Nephrology Consult
* Is there any indication and/ or benefit to the fetus if we begin HD at this time?
* Can we preserve any residual maternal renal function?
* OB team trying to prolong in-utero growth/ length of pregnancy, not sure if pt is masking severe preeclampsia

Why did Ob Deliver the Baby?
* 7/21 pt c/o HA, and 7/23 severe RUQ tenderness and epigastric pain, decision made to deliver fetus based on:
* Severe superimposed Preeclampsia in setting of chronic HTN
* Also, mild thrombocytopenic further led to diagnosis of severe preeclampsia

Normal Physiologic Alterations of Pregnancy
Normal Renal Alterations in Pregnancy

Changes in GFR
* GFR and RBF rise markedly
* Glomerular hyperfiltration results in normal reduction in the plasma creatinine concentration to about 0.4 to 0.5 mg/dL
* Blood urea nitrogen (BUN) and uric acid levels fall for the same reason

Effects of Pregnancy on Renal Disease
* ― cases proteinuria worsen
* ž cases HTN develops
* Worsening edema if nephrotic
* 0-10% women with NL or mild reduction in GFR have permanent decline in renal function

Views on Pregnancy and Dialysis
* ‘Children of women with renal disease used to be born dangerously or not at all - not at all if their doctors had their way’, Lancet, 1975
* ‘Show me a method of birth control more effective than end stage renal disease’, Roger Rodby MD, 1991
* ‘Even if a woman on CAPD ovulates, doesn’t the egg just float away?’, Rodby, 1992

Why don’t uremic women get pregnant?
* Most beyond child bearing age
* Libido/ frequency of intercourse reduced
* Don’t ovulate
* Absence of increase in basal body temperature during the luteal phase of cycle
* Elevated circulating prolactin concentrations
* Elevated PRL impairs hypothalamic-pit function

Actually, they do get pregnant!
* 1st successful term pregnancy in 35 y/o dialysed pt in 1971, Confortini, et al.
* Yr 2000: >15,000 women of childbearing age getting dialysis
* For every person w/CKD 5, 20 have CKD 3 or 4 w/GFR <60, suggesting ~300,000 women w/CKD potentially able to bear children Course of Renal Disease in Pregnancy * Baseline azotemia = more rapid deterioration * As renal dz progresses, ability to maintain nl pregnancy deteriorates, and presence of HTN incr likelihood of renal deterioration * Renal dysfunction - greater risk for complications incl preeclapsia, premature delivery, IUGR Pregancy during dialysis: case report and management guidelines; Giatras, et al. 1998 * 32 y/o AA woman, G4, P2, A1 * FSGS and chronic interstitial nephritis * Renal/obstetric protocol implemented * Increased HD to 4 hrs/ 4 sessions/ week maintain prediaysis BUN <50 * At each HD session, blood flow gradually increased over 1st 30 minutes of HD, from 180 to 300 ml/min * Kt/V 1.02 - 1.66 Giatras Protocol * Dialysis performed in left lateral decubitus position * Est maternal dry wt incrased by 500 g every 10d * EPO administered at each HD session, to maintain HCT 32-34% * Vit D, folic acid and MVI admin * Evid of malnutrition prior to pregnancy, so 3000kcal/day diet w>100g protein/ day

Obstetric Surveillance
* From 25 wks gestation
* Serial BP
* Uterine and umbilical artery perfusion evaluation
* Cont fetal heart rate tracing before, during and after HD
* There were no signif changes in uterine or umbilical artery S/D ratios at any time of HD, and no sig alteration in maternal MAP during HD
* Pt delivered at 32 wks gestation, due to PROM

Common Themes in Dialysing Pregnant Patients

1. Keeping BUN < 50 2. Increasing dialysis time and frequency 3. BP control 4. Managing anemia with increasing doses of ESA 5. Fetal monitoring once viability reached BUN <50 Hypothesis? * 1963 150 women varying degrees of CKD, none on dialysis, found the single most important factor influencing fetal outcome was BUN * Fetal mortality directly proportional to BUN * Hypothesis: intensive dialysis in pregnant women w/renal dz might improve fetal outcomes Increasing frequency and time on dialysis? * May be beneficial in reducing incidence of polyhydramnios by reducing urea and water load * Less dialysis-induced hypotension * More liberal diet * American Jrnl Kid Diseases * Spurred by the report of 5 pregnancies in 5 pts on chronic HD in 2 dialysis units bet 1989-1996 * 1st national survey of its kind which revealed a total of 15 pregnancies in HD - all dialysis centers in Belgium questioned for pts bet 1975-1996 Study Population Figures Case Characteristics/ Outcomes Dialysis Dosing * 15 pregnancies went beyond 1st trimester * Frequency of HD was increased immediately or progressively to 16 to 24 hrs * No difference bet successful pregnancies and failed ones for # mths on HD prior to conception or age at conception. * For successful pregnancies + correlation bet birth wt and excess dialysis hrs delivered over entire pregnancy. Success Rate * 80% (4/5) when HD initiated after onset of pregnancy (pregnancy first) * 50% (5/10) when HD was the first event * ‘‘Pregnancy first’ cases have a significant residual renal function and even may benefit from ‘preventive dialysis’, to be taken on dialysis at a stage of renal failure that would not justify dialysis in the eyes of many were it not for the very special setting of a pregnant state’’ Obstetrical Problems * Main Problem: premature births * In this study 3 died due to severe prematurity * Polyhydramnios present in almost all cases, may be cause of preterm labor * Growth retarded babies at highest risk for intrauterine death * Maternal prognosis is good Should we Initiate Dialysis in Pts w/Low Cr Clearance? * Hou, S., Pregnancy in Women on Hemodialysis, 1994, revealed better outcomes of pregnancy in women w/ significant residual renal function or who initiate pregnancy before they need dialysis. * May reduce incidence of polyhydramnios, lower urea and lowers water load, also reducing risk of dialysis-induced hypotension Registry of Pregnancy in Dialysis Patients USRDS Frequency of Prematurity and Low Birth Rate is less in those conceived before beginning dialysis Women who Start Dialysis During Pregnancy * Likelihood of infant surviving is good * Termination of a pregnancy after renal function has begun to deteriorate rarely rescues the kidneys * NEJM, Jones and Hayslett, 1996, looked at 82 pregnancies in 67 women w/CRI, only 15% of those w/deteriorating renal function had a return of renal function to baseline in 6 mths post partum Survival Statistics Renal Failure and Dialysis in Pregnancy.ppt

Read more...

Hemolytic Disease of the Newborn

Hemolytic Disease of the Newborn, Current Methods of Diagnosis and Treatment
By:Terry Kotrla, MS, MT(ASCP)BB

Objectives
* List the classifications of Hemolytic Disease of the Newborn and the most antibody specificities involved.
* State the testing to perform on the mother to monitor the severity of HDN.
* List the laboratory tests and values which indicate that an infant is affected by HDN both in the fetus and newborn.
* State the treatment options for intrauterine treatment of HDN.
* State the treatment options for HDN in the moderately and severely affected newborn.
* State the requirements of blood to be used for transfusion of the fetus and newborn.

Cause of Hemolytic Disease
* Maternal IgG antibodies directed against an antigen of paternal origin present on the fetal red blood cells.
* IgG antibodies cross the placenta to coat fetal antigens, cause decreased red blood cell survival which can result in anemia.
* Produced in response to previous pregnancy with antigen positive fetus OR exposure to red blood cells, ie transfusion.

Three Classifications of HDN
* ABO
* “Other” – unexpected immune antibodies other than anti-D – Jk, K, Fy, S, etc.
* Rh – anti-D alone or may be accompanied by other Rh antibodies – anti-C, -c, -E or –e.

ABO Hemolytic Disease
* Mother group O, baby A or B
* Group O individuals have anti-A, -B and –A,B in their plasma, fetal RBCs attacked by 2 antibodies
* Occurs in only 3%, is severe in only 1%, and <1:1,000 require exchange transfusion. * The disease is more common and more severe in African-American infants. “Other” Hemolytic Disease * Uncommon, occurs in ~0.8% of pregnant women. * Immune alloantibodies usually due to anti-E, -c, -Kell, -Kidd or -Duffy. * Anti-K o disease ranges from mild to severe o over half of the cases are caused by multiple blood transfusions o is the second most common form of severe HDN * Anti-M very rare Rh Hemolytic Disease * Anti-D is the commonest form of severe HDN. The disease varies from mild to severe. * Anti-E is a mild disease * Anti-c can range from a mild to severe disease - is the third most common form of severe HDN * Anti-e - rare * Anti-C - rare * antibody combinations (ie anti-c and anti-E antibodies occurring together) - can be severe HDN * Maternal antibodies destroy fetal red blood cells o Results in anemia. o Anemia limits the ability of the blood to carry oxygen to the baby's organs and tissues. * Baby's responds to the hemolysis by trying to make more red blood cells very quickly in the bone marrow and the liver and spleen. o Organs enlarge - hepatosplenomegaly. o New red blood cells released prematurely from bone marrow and are unable to do the work of mature red blood cells. * As the red blood cells break down, bilirubin is formed. o Babies unable to get rid of the bilirubin. o Builds up in the blood (hyperbilirubinemia ) and other tissues and fluids of the baby's body resulting in jaundice. o The placenta helps get rid of some of the bilirubin, but not all. Complications During Pregnancy * Severe anemia with enlargement of the liver and spleen When these organs and the bone marrow cannot compensate for the fast destruction of red blood cells, severe anemia results and other organs are affected. * Hydrops Fetalis This occurs as the baby's organs are unable to handle the anemia. The heart begins to fail and large amounts of fluid build up in the baby's tissues and organs. A fetus with hydrops is at great risk of being stillborn. Hydrops Fetalis Clinical Presentation * Varies from mild jaundice and anemia to hydrops fetalis (with ascites, pleural and pericardial effusions) * Chief risk to the fetus is anemia. * Extramedullary hematopoiesis due to anemia results in hepatosplenomegaly. * Risks during labor and delivery include: o asphyxia and splenic rupture. * Postnatal problems include: o Asphyxia o Pulmonary hypertension o Pallor (due to anemia) o Edema (hydrops, due to low serum albumin) o Respiratory distress o Coagulopathies ( platelets & clotting factors) o Jaundice o Kernicterus (from hyperbilirubinemia) o Hypoglycemia (due to hyperinsulinemnia from islet cell hyperplasia) Kernicterus * Kernicterus (bilirubin encephalopathy) results from high levels of indirect bilirubin (>20 mg/dL in a term infant with HDN).
* Kernicterus occurs at lower levels of bilirubin in the presence of acidosis, hypoalbuminemia, prematurity and certain drugs (e.g., sulfonamides).
* Affected structures have a bright yellow color.
* Unbound unconjugated bilirubin crosses the blood-brain barrier and, because it is lipid soluble, it penetrates neuronal and glial membranes.
* Bilirubin is thought to be toxic to nerve cells
* The mechanism of neurotoxicity and the reason for the topography of the lesions are not known.
* Patients surviving kernicterus have severe permanent neurologic symptoms (choreoathetosis, spasticity, muscular rigidity, ataxia, deafness, mental retardation).

Laboratory Findings
* Vary with severity of HDN and include:
* Anemia
* Hyperbilirubinemia
* Reticulocytosis (6 to 40%)
* nucleated RBC count (>10/100 WBCs)
* Thrombocytopenia
* Leukopenia
* Positive Direct Antiglobulin Test
* Hypoalbuminemia
* Rh negative blood type or ABO incompatibility
* Smear: polychromasia, anisocytosis, no spherocytes

Blood Smear
* Polychromasia
* Anisocytosis
* Increase NRBCs
* no spherocytes

Blood Bank Testing
Bilirubin Nomogram
* Total Serum Bilirubin (TSB) monitored to determine risk of kernicterus.
* Measure bilirubin in cord blood and at least every 4 hours for the first 12 to 24 hours. Plot bilirubin concentrations over time.

Transcutaneous Monitoring
* Transcutaneous bilirubinometry can be adopted as the first-line screening tool for jaundice in well, full-term babies.
* This leads to about 50% decrease in blood testing.
* http://tinyurl.com/36jazx

Intrauterine Transfusion (IUT)
* Given to the fetus to prevent hydrops fetalis and fetal death.
* Can be done as early as 17 weeks, although preferable to wait until 20 weeks
* Severely affected fetus, transfusions done every 1 to 4 weeks until the fetus is mature enough to be delivered safely. Amniocentesis may be done to determine the maturity of the fetus's lungs before delivery is scheduled.
* After multiple IUTs, most of the baby’s blood will be D negative donor blood, therefore, the Direct Antiglobulin test will be negative, but the Indirect Antiglobulin Test will be positive.
* After IUTs, the cord bilirubin is not an accurate indicator of rate of hemolysis or of the likelihood of the need for post-natal exchange transfusion.

Intrauterine Transfusion
* An intrauterine fetal blood transfusion is done in the hospital. The mother may have to stay overnight after the procedure.
* The mother is sedated, and an ultrasound image is obtained to determine the position of the fetus and placenta.
* After the mother's abdomen is cleaned with an antiseptic solution, she is given a local anesthetic injection to numb the abdominal area where the transfusion needle will be inserted.
* Medication may be given to the fetus to temporarily stop fetal movement.
* Ultrasound is used to guide the needle through the mother's abdomen into the fetus's abdomen or an umbilical cord vein.
* A compatible blood type (usually type O, Rh-negative) is delivered into the fetus's abdominal cavity or into an umbilical cord blood vessel.
* The mother is usually given antibiotics to prevent infection. She may also be given tocolytic medication to prevent labor from beginning, though this is unusual.
* Increasingly common and relatively safe procedure since the development of high resolution ultrasound particularly with colour Doppler capability.
* MCA Doppler velocity as a reliable non-invasive screening tool to detect fetal anemia.
o The vessel can be easily visualized with color flow Doppler as early as 18 weeks’ gestation.
o In cases of fetal anemia, an increase in the fetal cardiac output and a decrease in blood viscosity contribute to an increased blood flow velocity
* The risk of these procedures is now largely dependent on the prior condition of the fetus and the gestational age at which transfusion is commenced.
* Titer greater than 32 for anti-D and 8 for anti-K OR four fold increase in titer indicates need for analysis of amniotic fluid.
* Amniocentesis
o Perform at 28 wks if HDN in previous child
o Perform at 22 wks if previous child severely affected
o Perform if maternal antibody increases before 34th wk.
* High values of bilirubin in amniotic fluid analyses by the Liley method or a hemoglobin concentration of cord blood below 10.0 g/mL.
* Type fetus -recent development in fetal RhD typing involves the isolation of free fetal DNA in maternal serum. In the United Kingdom, this technique has virtually replaced amniocentesis for fetal RhD determination in the case of a heterozygous paternal phenotype
* Maternal plasma exchange may be instituted if the fetus is too young for intrauterine transfusion.

Liley Graph
Selection of Blood
* CPD, as fresh as possible, preferably <5 days old. * A hematocrit of 80% or greater is desirable to minimize the chance of volume overload in the fetus. * The volume transfused ranges from 75-175 mL depending on the fetal size and age. * CMV negative * Hemoglobin S negative * IRRADIATED * O negative, lack all antigens to which mom has antibodies and Coomb’s compatible. Treatment of Mild HDN * Phototherapy is the treatment of choice. * Phototherapy process slowly decomposes/converts bilirubin into a nontoxic isomer, photobilirubin, which is transported in the plasma to the liver. * HDN is judged to be clinically significant (phototherapy treatment) if the peak bilirubin level reaches 12 mg/dL or more. Bilirubin Degradation by Phototherapy Phototherapy * The therapy uses a blue light (420-470 nm) that converts bilirubin so that it can be excreted in the urine and feces. * Soft eye shields are placed on the baby to protect their eyes from damage that may lead to retinopathy due to the bili lights. Phototherapy * Lightweight, fiberoptic pad delivers up to 45 microwatts of therapeutic light for the treatment of jaundice while allowing the infant to be swaddled, held and cared for by parents and hospital staff. * Compact unit is ideal for hospital and homecare. Exchange Transfusion * Full-term infants rarely require an exchange transfusion if intense phototherapy is initiated in a timely manner. * It should be considered if the total serum bilirubin level is approaching 20 mg/dL and continues to rise despite intense in-hospital phototherapy. * The procedure carries a mortality rate of approximately 1% and there may be substantial morbidity Goals of Exchange Transfusion * Remove sensitized cells. * Reduce level of maternal antibody. * Removes about 60 percent of bilirubin from the plasma, resulting in a clearance of about 30 percent to 40 percent of the total bilirubin. * Correct anemia by providing blood that will have normal survival. * Replacement with donor plasma restores albumin and any needed coagulation factors. * Rebound – usually a 2 volume exchange is needed as bilirubin in tissues will return to blood stream. Testing Baby * Antibody elution testing from cord red blood cells. * ABO/D typing o If baby received intrauterine transfusions will type as O negative o If baby’s Direct Antiglobulin Test is strongly positive due to anti-D may get FALSE NEGATIVE immediate spin reaction with reagent anti-D (blocking phenomenon), weak D (Du) test will be STRONGLY positive * Antibody screen * Coomb’s crossmatch antigen negative donor. Testing Mom * Type and screen on mom. * Identification of unexpected antibodies. * More than 40 antigens have been identified as causing HDN. * Select blood that lacks antigens to which mom has antibodies. * Perform coomb’s crossmatch with Mom and baby’s blood. Selection of Donor Blood * CPD, as fresh as possible, preferably <5 days old. * CMV negative * Hemoglobin S negative * Irradiated if possible Preparation of Donor Unit * Physician will specify a hematocrit. * Reconstitute donor unit with plasma. * Most facilities prefer to use group O red cells and AB plasma. * Reference for procedure at end of this presentation. Summary * Three types of HDN vary in severity. * Laboratory testing key to diagnosing and monitoring- great care to be taken when interpreting ABO/D typing on affected infants. * Therapy dependent on severity: phototherapy alone or with transfusion. References Hemolytic Disease of the Newborn, Current Methods of Diagnosis and Treatment.ppt

Read more...

Hemolytic Disease of the Newborn and Fetus

Hemolytic Disease of the Newborn and Fetus
By:Renee Newman Wilkins, MS, MT(ASCP), CLS(NCA)
CLS 325/435 Clinical Immunohematology
School of Health Related Professions
University of Mississippi Medical Center

What is HDN?
* Destruction of the RBCs of the fetus and newborn by antibodies produced by the mother
* Only IgG antibodies are involved because it can cross the placenta (not IgA or IgM)
Mother’s antibodies
Pathophysiology
* Although transfer of maternal antibodies is good, transfer of antibodies involved in HDN are directed against antigens on fetal RBCs inherited by the father
* Most often involves antigens of the Rh and ABO blood group system, but can result from any blood group system
* Remember: The fetus is POSITIVE for an antigen and the mother is NEGATIVE for the same antigen

Pathophysiology
* HDN develops in utero
* The mother is sensitized to the foreign antigen present on her child’s RBCs usually through some seepage of fetal RBCs (fetomaternal hemorrhage) or a previous transfusion
* HDN occurs when these antibodies cross the placenta and react with the fetal RBCs

ABO HDN
* ABO incompatibilities are the most common cause of HDN but are less severe
* Usually, the mother is type O and the child has the A or B antigen…Why?
* ABO HDN can occur during the FIRST pregnancy b/c prior sensitization is not necessary
* ABO HDN is less severe than Rh HDN because there is less RBC destruction
o Fetal RBCs are less developed at birth, so there is less destruction by maternal antibodies
Diagnosis of ABO HDN
* Infant presents with jaundice 12-48 hrs after birth
* Testing done after birth on cord blood samples:
Treatment of ABO HDN
* Only about 10% require therapy
* Phototherapy is sufficient
* Rarely is exchange transfusion needed
* Phototherapy is exposure to artificial or sunlight to reduce jaundice
* Exchange transfusion involves removing newborn’s RBCs and replacing them with normal fresh donor cells

Phototherapy
Fluorescent blue light in the 420-475 nm range
Exchange transfusion
* CMV negative
* Irradiated
* Fresh Whole Blood (to avoid Ca++)
* Maternal blood if possible
* Leukoreduced

What type of blood to give fetus:

Rh HDN
* Mother is D negative (d/d) and child is D positive (D/d)
* Most severe form of HDN
* 33% of HDN is caused by Rh incompatibility
* Sensitization usually occurs very late in pregnancy, so the first Rh-positive child is not affected
o Bleeds most often occur at delivery
o Mother is sensitized
o Subsequent offspring that are D-positive will be affected

About 1 in 10 pregnancies involve an Rh-negative mother and an Rh-positive father
FetoMaternal Hemorrhage
* Sensitization occurs as a result of seepage of fetal cells into maternal circulation as a result of a fetomaternal hemorrhage

Risk
* Rh-negative women can be exposed to Rh-Positive cells through transfusion or pregnancy
* Each individual varies in their immune response (depends on amount exposed to)
Pathogenesis
* Maternal IgG attaches to antigens on fetal cells
o Sensitized cells are removed by macrophages in spleen
o Destruction depends on antibody titer and number of antigen sites
o IgG has half-life of 25 days, so the condition can range from days to weeks
* RBC destruction and anemia cause bone marrow to release erythroblasts, hence the name “erythroblastosis fetalis”)

Increased immature RBCs
Pathogenesis
* When erythroblasts are used up in the bone marrow, erythropoiesis in the spleen and liver are increased
Bilirubin
* Hemoglobin is metabolized to bilirubin
Diagnosis & Management
* Serologic Testing (mother & newborn)
* Amniocentesis and Cordocentesis
* Intrauterine Transfusion
* Early Delivery
* Phototherapy & Newborn Transfusions

Serologic testing on mother
* ABO and Rh testing
* Antibody Screen
* Antibody ID
* Paternal phenotype
* Amniocyte testing
* Antibody titration
Marsh score
Example:
Amniocentesis & Cordocentesis
* About 18-20 weeks’ gestation
* Cordocentesis takes a sample of umbilical vessel to obtain blood sample
* Amniocentesis assesses the status of the fetus using amniotic fluid
Analysis of amniotic fluid (example)
Liley graph
What to do?
* Intrauterine transfusion is done if:
* Removes bilirubin
* Removes sensitized RBCs
* Removes antibody

Other treatments
* Early Delivery
* Phototherapy (after birth)
* Newborn transfusion

Postpartum testing
* ABO – forward only
* Rh grouping – including weak D
* DAT
* Elution
Prevention
* RhIg (RhoGAM®) is given to the mother to prevent immunization to the D antigen

Postpartum administration of RhIg
Dose
Rosette Test
* A qualitative measure of fetomaternal hemorrhage

Fetomaternal Hemorrhage:
Kleihauer-Betke acid elution
Calculating KB test
Step 1) stain and count the amount of fetal cells out of 1000 total cells counted
Step 2) calculate the amount of fetal blood in cirulation by multiplying %fetal cells by 50 mL
Step 3) divide mL of fetal blood by 30 (each vial protects against a 30 mL bleed
Step 4) Round the calculated dose up and add one more vial for safety

Considerations
* RhIg is of no benefit once a person has formed anti-D
* It is VERY important to distinguish the presence of anti-D as:
o Residual RhIg from a previous dose OR
o True immunization from exposure to D+ RBCs
* RhIg is not given to the mother if the infant is D negative (and not given to the infant)

* Make sure presence of anti-D is not due to antenatal administration of Rh immune globulin
Hemolytic Disease of the Newborn and Fetus.ppt

Read more...

Zoonotic Helminthiasis

ZOONOTIC HELMINTHIASIS
* Helminth: parasitic worm (Greek)
o Platyhelminthes (flukes, tapeworms)
o Nematodes (roundworms)

* Pathogenic helminths are some of most common parasites
* Worlwide distribution
* Toxocariasis (visceral/ocular larval migrans)
o Toxocara canis, T. cati
* Meningoencephalitis
o Balysascaris procyonis
* Trichinosis
o Trichinella spiralis
* Taeniasis
o Taenia soleum, T. saginata
* Hydatid disease
o Echinococcus granulosus, E. multilocularis

TOXOCARIASIS
* Agent:
o Toxocara canis - roundworm of dogs and cats
o Toxocara cati - roundworm of cats (less frequently involved)
* Other names for diseae:
o visceral larval migrans (VLM)
o ocular larval migrans (OLM)

TOXOCARIASIS
Egg
Adult female - head
* Life cycle:
Epidemiology
* Reservoir:
o dogs, cats, small mammals
* Distribution:
o worldwide, most attention in US and UK
o seroprevalence: 3%; 23% in some groups
* Transmission:
o direct or indirect by ingestion of infective eggs from fecal contamination or contaminated soil
o larvae in contaminated undercooked liver from poultry, beef

Clinical features
* Incubation period:
o children - weeks to months
o OLM may be 2-4 years later
* Symptoms:
o asymptomatic to chronic, mild disease (usually)
o predominantly in young children
o increasingly recognized in adults
o symptoms related to migration of larval stage through tissues
* Symptoms:
o VLM - may persist for year or longer
+ fever
+ anorexia
+ weight loss
+ cough
+ eosinophilia
+ rash
+ hepatosplenomegaly
+ death (rarely) due to severe cardiopulmonary and neurologic manifestations
* Symptoms:
o OLM
+ misdiagnosed as retinoblastoma, leading to surgical enucleation
+ endophthalmitis at entry of larva
+ loss of vision
+ eosinophilia rare
+ visceral manifestation rare
+ occurs in children and adults
Diagnosis
* Direct (fecal) examination no use - larva does not develop into adult, no ova passed in feces
* Antibody detection confirmatory only in presence of clinical signs and history
o EIA (enzyme immunoassay)
+ larval antigen extracts from
# embryonated eggs
# cultured TES (Toxocara excretory-secretory antigens) - preferred
+ 1:32

Treatment
* Supportive treatment
* Anthelmentics - effectiveness uncertain
o DEC (diethylcarbamazine)
o Albendazole
o Mebendazole
* Corticosteroids for severe eye problems

Prevention/Control
* Education, especially pet owners
* Routine examination of pets
* Effective deworming program for puppies and kittens
* Removal of feces from environment
* Routine hygiene after handling pets, soil

TAENIASIS
* Agent:
o Tanea soleum - pork tapeworm
o T. saginata - beef tapeworm
* Other names for disease:
o taeniasis - intestinal infection of either tapeworm in animals or humans
o cystiserciasis; cysticercosis - tissue infection with T. soleum larva

Epidemiology
* Reservoir:
o humans definitive host for both T. saginata and T. soleum
* Occurrence:
o worldwide
o highest in Latin America, Africa, SE Asia, Eastern Europe
o T. soleum rare in US, Canada, UK, but increasingly recognized in immigrants

Epidemiology
* Transmission:
Clinical features
* Incubation period:
o taeniasis - eggs appear in 8-14 weeks
o cystercosis - days to years
* Symptoms:
o Taeniasis
+ mild abdominal symptoms
+ occasionally appendicitis or cholangitis from migrating proglottids
+ passage of proglottids (active or passive)
Clinical features
* Cysticercosis:
TANEIASIS
Diagnosis
* Taeniasis
* Cysticercosis
Treatment
* Taeniasis
o praziquantel
* Cystercosis
o praziquentel if active cystercosis, but only under hospitalization due to acute inflammatory reaction; steroids given to control inflammation
o surgical
+ shunt - ventriculoperitoneal shunt to drain CSF
+ cyst removal
+ endoscopic fenestration (hole in cyst wall)

Prevention/Control
* Education
* Identification and immediate treatment of infected individuals
* Freezing meat at -5ºC (23ºF) for > 4 days effectively kills cysticerci
* Irradiation

Agent
Echinococcus granulosus
E. multilocularis
E. vogeli
E. oligarthrus
Disease
Cystic hydatid disease;
unilocular echinococcosis
Alveolar hydatid disease;
multilocular echinococcosis
Polycystic alveolar disease
Rare in humans

UNILOCULAR ECHINOCOCCOSIS
Hydatid “sand”-protoscolices from fluid aspirate of hydatid cyst
Note: normally invaginated; evaginates in saline (right)

Epidemiology
* Transmission:

Clinical features
* Incubation period: months to years
* Symptoms:
o cysts grow slowly, asymptomatic until noticeable mass effect
o compatible with slow-growing tumor
o symptoms depend on location, size, and number of cysts
o anaphylactoid reaction if cyst ruptures/leaks

MULTILOCULAR ECHINOCOCCOSIS
Epidemiology
Clinical features
POLYCYSTIC ECHINOCOCCOSIS
Clinical features
Diagnosis
Serological diagnosis
Treatment
DIPHYLLOBOTHRIASIS
Epidemiology
* Occurrence:
Clinical features
Diagnosis
Treatment
Prevention and Control
ANISAKIASIS
Epidemiology
* Occurrence:
Clinical features
Diagnosis
* Direct examination:
o parasite coughed up
o Fiber optic exam
o laparotomy
* Radioallergosorbent (skin test) developed but not available commercially

Treatment
* surgical excision
Prevention and control
* Avoid ingestion of raw/undercooked fish
* Heating for 10 minutes @ 140ºF (60ºC)
* Freezing:
o “blast freezing” for 15 hours @ -31ºF (-35ºC)
o regular freezing for 7 days @ -10ºF (-23ºC)
* irradiation
* proper cleaning/evisceration as soon as caught

Zoonotic Helminthiasis.ppt

Read more...

Parasitic Pathogens Affecting the CNS

Parasitic Pathogens Affecting the CNS
By:Mark F. Wiser
Department of Tropical Medicine
School of Public Health

Protozoa Affecting the CNS
Rare cases
Free-living ameba
Rare invasion of the brain
Entamoeba histolytica
Cerebral Malaria
Plasmodium falciparum
African Sleeping Sickness
African Trypanosomes
Associated with congenital defects and AIDS
Toxoplasma gondii
Disease

Protozoan
Amebas Affecting the CNS
* Entamoeba histolytica
o normally found in large intestine
o can become invasive (primarily liver)
* Free-living Amebas

GAE; skin or lung lesions
Balamuthia mandrillaris
GAE; skin or lung lesions; amebic keratitis
Acanthamoeba species
PAM

Naegleria fowleri
Diseases
Ameba

Toxoplasma gondii
* cosmopolitan distribution
* seropositive prevalence rates vary
o generally 20-75%
* generally causes very benign disease in immunocompetent adults
o congenital transmission
o AIDS associated
* tissue cyst forming coccidia
o predator-prey life cycle
o felines are definitive host
o infects wide range of birds and mammals (intermediate hosts)

Definitive Host
* adult forms
* sexual reproduction

Intermediate Host
* immature forms
* asexual reproduction

chronic stage = bradyzoites
acute stage = tachyzoites
* ingestion of sporulated oocysts (cat feces + incubation)
* ingestion of zoites (undercooked meat)
* congenital infection (only during acute stage)
* organ transplants
o chronic infection in donor
o immunosuppression
* blood transfusions (only during acute stage)

Human Transmission
Acquired Postnatal Toxoplasmosis
* 1-2 week incubation period
* acute parasitemia persists for several weeks until development of tissue cysts
o often asymptomatic (>80%)
o a common symptom is lymphadenopathy without fever
o occasionally mononucleosis-like (fever, headache, fatigue, myalgia)
* likely persists for life of patient
* immunosuppression can lead to reactivation (eg, organ transplants)

Congenital Toxoplasmosis
* 1o infection must occur during or shortly before pregnancy
o can only occur once
o 1/3 will pass infection to fetus
* incidence ~1 per 1000 births
* severity varies with age of fetus
o move severe early in pregnancy
o more frequent later in pregnancy
* infection can result in: spontaneous abortion, still birth, premature birth, or full-term ą overt disease
* typical disease manifestations include: retinochoroiditis, psychomotor disturbances, intracerebral calcification, hydrocephaly, microcephaly

Toxoplasmic Encephalitis
* common complication associated with AIDS during the 1980's
* recrudescence of latent infection
* multifocal disease associated with immunosuppression
* lesions detectable with CT or MRI
* little spread to other organs
* symptoms include: lethargy, apathy, incoordination, dementia
* progressive disease  convulsions
* usually fatal if untreated

Diagnosis
* various serological tests
* active (acute) vs chronic infection
o compare samples at 2 week intervals
o IgM > IgG; Ab titers
* seldom by direct parasite demonstration
o biopsy
o inoculation into mice or cell culture (only acute stage)
* CT scans or MRI for toxoplasmic encephalitis

Prevention
But dog contact is highly correlated with Toxoplasma transmission.
Several studies show no correlation between cat contact and Toxoplasma.

An Enigma
Some Helminths Affecting the CNS
Taenia solium and Cysticercosis
* adult tapeworm infects GI tract of humans
* larval stages infect tissues causing cysticercosis or neurocysticercycosis
* most common parasitic disease of the CNS
* endemic throughout much of the developing world
o especially prevalent in Central and South America, Sub-Saharan Africa, Southeast Asia and Central and Eastern Europe
* prevalence of 3.6% in some regions of Mexico
* greatest cause of acquired epilepsy worldwide

Cysticercosis in the United States
* has become an important parasitic disease, particularly in California
* estimated that 1000 new cases of neurocysticercosis will be diagnosed each year
* increasing prevalence attributed to the migration of large numbers of rural immigrants from developing countries
* also improvements in neuro-imaging leading to better diagnosis

http://www.dpd.cdc.gov/dpdx/
Disease States
* Taeniasis = adult tapeworm in small intestine
o Usually asymptomatic (eggs or proglottids in feces)
o Vague abdominal symptoms occasionally report
* Cysticercosis = T. solium larvae in human tissues (eg, muscle)
o Usually asymptomatic
o Painless subcutaneous nodules in arms and chest
* Neurocysticercosis (NCC) = cysts in the central nervous system
o Most severe manifestation

Pathogenesis of Cysticerci
* larva (cysticercal cysts) survive up to 5 years
* living larva produce little inflammation
* death of larva leads to inflammation and edema resulting in symptoms
* cellular reaction eventually destroys parasite and leaves a calcified nodule

Clinical Manifestations
* presentation is varied—depends on stage, number, size and location of cysts
* seizures/convulsions most common symptoms
* blocked circulation of CSF can lead to intracranial hypertension or hydrocephalus
* occasionally large cysts can mimic tumors
* can also cause a variety of mental and motor changes

Diagnosis
* onset of epileptic seizures
* person from endemic area
* CT scans and MRI are most useful
o 1-2 cm cystic lesions
o with or without edema and inflammation
* some serological tests available
o problems with sensitivity and specificity

Treatment
* symptomatic treatment (eg, antiepileptic drugs)
o spontaneous cures noted especially in children
* praziquantel and albendazole kill the cysts faster
o limited clinical benefit
o administer with corticosteroids (anti-inflammatory)
* surgical excision of cysts was previous treatment

Prevention and Control
* Enhanced personal hygiene
* Thorough cooking/ freezing of pork to kill cysticerci
* Enhanced environmental sanitation
o proper disposal of human feces
* Agricultural inspection of pork
* Vaccination of pigs?

Parasitic Pathogens Affecting the CNS.ppt

Read more...

Cysticcercosis

CYSTICERCOSIS
By:Palak Parikh

EPIDEMIOLOGY
* Found in approximately 50 million people worldwide (probably an underestimate)
* Endemic in several countries in Central and South America, sub-Saharan Africa, India, and Asia
* Prevalence in this country often higher in rural areas
* 221 deaths identified in the US from 1990-2002 (62% had emigrated from Mexico)

CYSTICERCOSIS TRANSMISSION
* Caused by the larval stage of Taenia solium, the pork tapeworm
* Humans develop by ingestion of T. solium eggs; they can spread infection by:
o Egg-containing feces contaminating water supplies in endemic areas
o Contaminating food directly, as eggs are sticky and can often be found under the fingernails of tapeworm carriers.

LIFE CYCLE
* Once eggs ingested, embryos are released in the small intestine and invade the bowel wall.
* They then disseminate hematogenously to other tissues and develop into cysticerci over 3 weeks to 2 months.
* Cysticerci – liquid-filled vesicles consisting of a membranous wall and a nodule containing the invaginated scolex.
* Scolex – head armed with suckers and hooks and a rudimentary body.

PATHOGENESIS
* Cysticerci initially viable but do not cause much inflammation in surrounding tissues – asymptomatic infection
* Host develops immune tolerance to cysticerci, which remain in this stage for several years.
o Postulated mechanisms of tolerance:
+ Taenia elaborate substances that inhibit or divert complement pathways away from parasite
+ Humoral antibodies do not kill mature taenia.
+ Poorly defined factors may interfere with lymphocyte proliferation and macrophage function, inhibiting normal cellular immune defenses.
* Clinical manifestations occur when inflammatory response develops around degenerating cysticercus.

SYMPTOMATIC DISEASE
* Divided into:
o Neurocysticercosis
o Extraneural cysticercosis

NEUROCYSTICERCOSIS
* 80% of infections are asymptomatic
* Symptoms mainly due to mass effect, inflammatory response, or obstruction of foramina and ventricular system of brain.
* Most common symptoms:
o Seizures
o Focal neurological signs
o Intracranial hypertension
* Peak estimated to occur 3-5 years after infection

NEUROCYSTICERCOSIS
* Increased risk of seizures with a single calcific granuloma.
* Risk of seizures highest when lesions are degenerating and are surrounded by inflammation.
* Encephalitis and diffuse brain edema most common in children and young females.
* 1-3% of cases involve the spinal cord, with thoracic lesions the most common.

NEUROCYSTICEROSIS IN ENDEMIC COUNTRIES
* Most common cause of adult-onset seizures
* Risk of seizures in seropositive individuals 2-3 times higher than seronegative controls.
* Punctate calcifications most frequent finding on neuroimaging of brain.

EXTRANEURAL CYSTICERCOSIS
* Typically involves:
o Eyes – in 1-3% of all infections
o Muscle
o Subcutaneous tissue – nodules most common in patients from Asia and Africa than from Latin America

DIAGNOSIS
* Serologic testing
* Peripheral eosinophilia only if cyst is leaking
* CT scan or MRI
o Pathognomonic Lesion: Scolex – mural nodule within a cyst
* Brain biopsy (only in symptomatic patients with equivocal serology and radiologic tests)

SEROLOGIC TESTING
* ELISA
* Complement fixation (CF)
* Radioimmunoassay
* Enzyme linked immunoelectrotransfer blot (EITB) assay – test of choice

EITB ASSAY
* Enzyme-linked immunoelectrotransfer blot assay
* Test of choice for detecting anticysticercal antibodies
* Uses affinity-purified glycoprotein antigens
* Higher sensitivity (83-100%) and specificity (93-98%) than ELISA
* Can be performed on serum or CSF but has a higher sensitivity on serum.
* Detected 94% of pathologically confirmed NCC with 2 or more lesions compared to only 28% with a single lesion in one study.

CT VS MRI
* MRI preferred since it is more sensitive in detecting:
o small lesions
o brainstem or intraventricular lesions
o perilesional edema around calcific lesions
o scolex
o degenerative changes in the parasite
* CT scan cheaper and better at detecting:
o small areas of calcifications.
o cysticercal infestation of extraocular muscles.

* Perform CT scan first followed by MRI in patients with inconclusive findings or in those with negative CT scans where strong clinical suspicion persists.

PERUVIAN STUDY
POTENTIAL TREATMENTS
* Albendazole (15 mg/kg/day) X 15 days + corticosteroids (30-40 mg prednisolone or 12-16 mg dexamethasone daily) – per UpToDate
* Praziquantel (50 mg/kg/day) X 15 days + corticosteroids (30-40 mg prednisolone or 12-16 mg dexamethasone daily) – per UpToDate
* Corticosteroids alone
* Anticonvulsants in patients who present with seizures or are at high risk for seizures
* Surgery

ALBENDAZOLE VS PRAZIQUANTEL
* Albendazole
o Destroys 75-90% of parenchymal brain cysts
o Does not interact with anticonvulsants
o Levels not adversely affected w/ co-administration of corticosteroids
* Praziquantel
o Destroys 60-70% of cysts 3 months after administration
o Decreased efficacy compared to Albendazole
o Available for oral administration
o Does not cross the blood-brain barrier well, so CSF levels only approx 20% of plasma levels.
o Involves cytochrome P-450 hepatic metabolism, which is induced by corticosteroids, phenytoin, and phenobarbital

* No blinded randomized controlled trials comparing albendazole to praziquantel.
Because of the above, praziquantel is generally considered second-line therapy.

TREATMENT
* One randomized, double-blind, placebo-controlled trial
o 120 pts with living cysticerci in the brain and seizures treated with antiepileptic drugs
+ Randomized to either albendazole (800 mg qd) and dexamethasone (6 mg qd X 10 days) or double placebo
+ Followed for 30 months or until they were seizure-free for 6 months after tapering of antiepileptic drugs
o Results:
+ Resolution of intracranial cystic lesions more common in treatment arm
+ Number of patients experiencing generalized seizures declined in the treatment arm
+ No significant change between the two groups in patients experiencing partial seizures

NEUROCYSTICERCOSIS
* Treatment in those with:
o 5-50 cysts (both antiparasitic and steroids)
o Steroids alone in patients w/ > 50 cysts
* No Treatment in those with:
o Asymptomatic nonviable neurocysticercosis
o Calcified cysts
o Single viable cysts
o Fewer than 5 cysts

ANTICONVULSANTS
* Recommended for patients who present with seizures
* Should be stopped if patient remains seizure-free during therapy to see if the patient remains asymptomatic
* Should be reinitiated chronically if the patient has recurrent seizures
* Should be considered in patients w/ multiple cysts who have no history of seizure activity

SURGICAL INTERVENTION
* Used in some patients with intracranial hypertension
* Shunting improves hydrocephalus, although recurrent blockages of shunts common
* Surgical intervention recommended for cysts:
o Located in the 4th ventricle
o Attached to middle cerebral artery
o Compressing the optic chiasm
o Located in the spine

TREATMENT OF EXTRANEURAL CYSTICERCOSIS
* None if pt asymptomatic
* Surgical excision for intraocular disease
* Medical therapy for involvement of extraocular muscles or optic nerve.
* NSAIDs for patients w/ symptomatic subcutaneous or intramuscular lesions.
* Excision of solitary lesions if NSAIDs fail or not tolerated.

BEFORE INITIATING MEDS…
* Apply PPD.
* Consider treating with a single dose of ivermectin before beginning corticosteroids, as many patients have risk factors for strongyloidiasis.
* Consult ophthalmology to rule out ocular cysticercosis.

PATIENT MONITORING
* Intermittent surveillance w/ imaging until cyst(s) resolve(s).
o Perhaps every 3-6 months if patient improving or earlier if patient symptomatic.
* Reimaging of brain 2 months after completion of treatment
* Consider antiparasitic therapy if cysts growing off therapy

POSSIBLE PREVENTION
* Human Tapeworm Infections
o Inspection of pork for cysticerci
o Freezing or adequately cooking meat to destroy cysticerci
o Administering antiparasitic agents to pigs
* Infection in Pigs
o Confining animals and not allowing them to roam freely
o Improved sanitary conditions
* Egg Transmission to Humans
o Good personal hygiene and hand washing prior to food preparation
o Identifying human carriers of tapeworms
o Mass community programs to treat tapeworm carriers.
* Possible Vaccine – porcine vaccine currently in the works

TAKE HOME POINTS
* Cysticercosis caused by the larval stage of Taenia solium, the pork tapeworm
* Pay special attention if pt from Central and South America, sub-Saharan Africa, India, and Asia, as neurocysticercosis is the most common cause of adult-onset seizures in these endemic areas.
* Order Head CT first to diagnose neurocysticercosis; if negative and suspicion still high, order Brain MRI.
* EITB test of choice for serology.
* Place PPD before starting treatment.
* Obtain Ophthalmology consult before starting treatment.
* Albendazole and Dexamethasone comprise first-line treatment for symptomatic cysticercosis. Consider concurrent anticonvulsants if pt presents with seizures.

REFERENCES
* aapredbook.aappublications.org
* UpToDate.
* www.dpd.cdc.gov
* www.e-radiology.net
* www.parasite-diagnosis.ch
* www.stanford.edu/class/cysticercosis/symptoms

CYSTICERCOSIS.ppt

Read more...

The Basal Ganglia

The Basal Ganglia

Outline
* Components of the basal ganglia
* Arrangement of basal ganglia components in the brain
* Architecture: cytology & neurochemistry
* Pathways & circuitry
* Function(s) of the basal ganglia
* Dysfunction and pathology
* Differences between human and rodent basal ganglia?

What are the Basal Ganglia?
The basal ganglia include…
* Neostriatum
o Caudate nucleus
o Putamen
o Nucleus Accumbens
* Globus Pallidus
o Internal segment
o External segment
o Ventral pallidum
* Subthalamic nucleus
* Substantia nigra
o Pars compacta
o Pars reticulata
* Pedunculopontine nucleus**
Subgroups of the basal ganglia
* Striatum
o Caudate nucleus
o Putamen
* Lenticular nuclei
o Globus pallidus
o Putamen
* Corpus striatum
o Caudate
o Lenticular nuclei

How are the basal ganglia arranged in the brain?
Caudate Nucleus
o C shaped structure
o Lateral wall of lateral ventricle
o Head, body and tail of caudate

Putamen and Globus Pallidus
* Putamen + Globus Pallidus = lentiform or lenticular nuclei
* Fills in space between the inferior horn and the anterior horn and body of the lateral ventricle.
* Gap between the lentiform nuclei and the lateral ventricle filled by the caudate nucleus.
* The posterior limb of the internal capsule separates the lentiform nuclei from the thalamus.

* Claustrum
* Septum pellucidum
* Insular cortex
* Corpus callosum
* Caudate nucleus
* Putamen
* Nucleus accumbens
* Internal capsule
* External capsule
* Extreme capsule
* Caudate nucleus
* Putamen
* Globus pallidus external (GPe)
* Globus pallidus internal (GPi)
* Ventral pallidum
* Anterior commissure
* Substantia innominata
* Internal capsule
* Lentiform nucleus**
* Caudate (Head, body, tail)
* Putamen
* GPe & GPi
* Lateral ventricle, anterior and temporal horn
* Internal capsule, anterior and posterior horn
* Caudate nucleus (body and tail)
* Putamen
* Globus pallidus
* Subthalamic nucleus
* Substantia nigra

- Pars compacta
- Pars reticulata
* Subthalamic nucleus
* Substantia nigra
* Globus pallidus external
* Subthalamic nucleus
* Substantia nigra
* Ventral tegmental area

Functions of the Basal Ganglia
* Extrapyramidal motor system
* Motor planning, sequencing and learning
* Striatal neuronal activity is not sufficiently explained by the stimuli presented or the movements performed
* Dependent on certain behavioral situations, certain conditions or particularly types of trials
+ -sensory stimuli but only when they elicit movements
+ -instruction cues (go-no go)
+ -memory related cues
+ -reward (especially ventral striatum)
+ -self-initiated moves
* Basal ganglia distinguished from cerebellum by connections with limbic system

Architecture of the basal ganglia: cellular and neurochemistry

Cytoarchitecture
* Main neurotransmitter in basal ganglia is GABA
* 95% of neurons in neostriatum are medium spiny neurons
o Contain GABA
o Principal neurons: project to globus pallidus and SNpr
o Subpopulations are distinguished by peptides, neurotransmitter receptors and connections
o Receive bulk of afferent input
* Several populations of interneurons
o aspiny
o ACh, somatostatin, GABA/parvalbumin
Neuronal circuitry of the basal ganglia
The Neostriatal Mosaic
* Neostriatum divided into two compartments:
patch (striosome) & matrix
* First described by Ann Graybiel in 1978 using AChE stain
* Not visible in Nissl stains (“hidden chemoarchitecture”)
* Define input/output architecture of neostriatum

Neostriatal Mosaic and Input/Output Organization
* Most inputs to the neostriatum terminate in a patchy fashion (“matrisomes”)
* Input from a given cortical region terminates over an extended anterior-posterior extent
* Functionally related cortical areas project to the same patches
* Output neurons to a given efferent subregion are also arranged in patches
* Neurons in patches project to both GPi/SNpr and GPe

Functional subdivisions
* Sensorimotor
o Putamen + globus pallidus/SNpr
o SNpc
* Association
o Caudate nucleus + globus pallidus/SNpr
o SNpc
* Limbic
o Nucleus accumbens + ventral pallidum
o VTA

Basal ganglia connections and pathways
Connections
* Afferents/inputs (neostriatum):
o Cerebral cortex (entire cortex)
o Thalamus (intralaminar and midline nuclei)
o Amygdala (basolateral nucleus)
o Raphe, substantia nigra pars compacta, VTA
* Efferents/output (GPi, VP, SNpr)
o Ventral tier nuclei of thalamus
o Subthalamic nucleus
o Superior colliculus
Organization of inputs to basal ganglia
Organization of basal ganglia outputs

All regions of cerebral cortex project to the basal ganglia, but output of basal ganglia is directed towards the frontal lobe, particularly pre-motor and supplementary motor cortex
Basic Circuit of Basal Ganglia

Neostriatum
GPi/SNpr
Cerebral Cortex
VA/VL thalamus
Direct vs. indirect pathways
* Different populations of spiny neurons
* Neuromodulators/co-transmitters
* Striosomes vs. matrix
* Dopamine receptor subtypes
Both

Recurrent loops
* Motor loop
o sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA ->SMA
* Ocularmotor loop
o prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC
* Cognitive loop
o prefrontal cortical areas 9,12 -> caudate -> GP -> VA -> prefrontal cortex
* Limbic loop
o cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate.
Topography is maintained within each loop!

Motor loop
Somatotopic subdivisions of the input remain segregated throughout the circuit.
Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990
Processing in the basal ganglia
Huntington’s and Parkinson’s diseases
* Neurodegenerative diseases
* Motor dysfunction
* Brainwide pathology with focus on basal ganglia elements
* Genetic and/or environmental causes
Huntington’s Disease
Clinical symptoms
* Hyperkinetic & hemiballistic movements

Pathology hallmarks
* Striopallidal degeneration
* Decreased striatal volume
* Decrease in 5-HT1B receptors in ventral pallidum
Hyperkinetic hypothesis
* Reduced Glu (+) from STN to GPi, due either to STN lesions or reduced striatopallidal inhibitory influences along the in direct pathway lead to reduced inhibitory outflow from GPi/SNr and excessive disinhibition of the thalamus.
* Increased Glu (+) to cortical areas engaged by the motor circuit (SMA, PMC, MC) results in hyperkinetic movements.
Parkinson’s Disease
Clinical symptoms
* Hypokinetic movement
* Cogwheel rigidity

Pathology hallmarks
* Nigostriatal degeneration
* DA neuronal degeneration in SN
Hypokinetic hypothesis
* Inhibition of GPe within the indirect pathway leads to disinhibition of the STN
* Increased STN to the basal ganglia output nuclei (Gpi/SNr), leads to excessive thalamic inhibition.
* This is reinforced by reduced inhibitory input to Gpi/SNr through the direct pathway.
* Overall result is a reduction in reinforcing influence of the motor circuit upon cortically initiated movements.

PD Therapeutics: The approaches
* Pharmacology
o DA, mGluR, MAO(B) inhibitors, antioxidants, iron chelators
* Surgical
o Pallidal ablation
o DBS of globus pallidus or STN
* Transplantation
o Fibroblast cells
o Stem cells
* Vaccines
* RNA interference (RNAI)-based treatments

DBS: Deep Brain Stimulation of STN
Common themes in neurodegeneration
* Neurotoxicity
* Inflammation (glia)
* Apoptosis
* Abnormal protein aggregation
Thank you!
Notable differences between basal ganglia of human and rodents …..
There are differences in:
* Divisions & nomenclature
* Proportions
* Topography of afferent and efferent projections
Globus pallidus and entopeduncular nucleus (rodent)
vs.
Globus pallidus (external) and Globus pallidus (internal) (primate)
Regional proportion by volume
(% of total volume)
Spinal Cord

Major projection differences

* Neurons projecting to the motor and associative striatum
o Rats: reside in distinct regions
o Primates: arranged in interdigitating clusters.
* Terminal fields of projections arising from the motor and associative striatum
o rats: largely segregated
o Primates: not segregated
* Organization of patch- and matrix-projecting dopamine cells
o Rats: organized in spatially, morphologically, and histochemically distinct ventral and dorsal tiers,
o Primates: no (bi)division of the dopaminergic system that results in two areas which have all the characteristics of the two tiers in rats.

The Basal Ganglia.ppt
http://login.ncmir.ucsd.edThe Basal Ganglia

Outline
* Components of the basal ganglia
* Arrangement of basal ganglia components in the brain
* Architecture: cytology & neurochemistry
* Pathways & circuitry
* Function(s) of the basal ganglia
* Dysfunction and pathology
* Differences between human and rodent basal ganglia?

What are the Basal Ganglia?
The basal ganglia include…
* Neostriatum
o Caudate nucleus
o Putamen
o Nucleus Accumbens
* Globus Pallidus
o Internal segment
o External segment
o Ventral pallidum
* Subthalamic nucleus
* Substantia nigra
o Pars compacta
o Pars reticulata
* Pedunculopontine nucleus**
Subgroups of the basal ganglia
* Striatum
o Caudate nucleus
o Putamen
* Lenticular nuclei
o Globus pallidus
o Putamen
* Corpus striatum
o Caudate
o Lenticular nuclei

How are the basal ganglia arranged in the brain?
Caudate Nucleus
o C shaped structure
o Lateral wall of lateral ventricle
o Head, body and tail of caudate

Putamen and Globus Pallidus
* Putamen + Globus Pallidus = lentiform or lenticular nuclei
* Fills in space between the inferior horn and the anterior horn and body of the lateral ventricle.
* Gap between the lentiform nuclei and the lateral ventricle filled by the caudate nucleus.
* The posterior limb of the internal capsule separates the lentiform nuclei from the thalamus.

* Claustrum
* Septum pellucidum
* Insular cortex
* Corpus callosum
* Caudate nucleus
* Putamen
* Nucleus accumbens
* Internal capsule
* External capsule
* Extreme capsule
* Caudate nucleus
* Putamen
* Globus pallidus external (GPe)
* Globus pallidus internal (GPi)
* Ventral pallidum
* Anterior commissure
* Substantia innominata
* Internal capsule
* Lentiform nucleus**
* Caudate (Head, body, tail)
* Putamen
* GPe & GPi
* Lateral ventricle, anterior and temporal horn
* Internal capsule, anterior and posterior horn
* Caudate nucleus (body and tail)
* Putamen
* Globus pallidus
* Subthalamic nucleus
* Substantia nigra

- Pars compacta
- Pars reticulata
* Subthalamic nucleus
* Substantia nigra
* Globus pallidus external
* Subthalamic nucleus
* Substantia nigra
* Ventral tegmental area

Functions of the Basal Ganglia
* Extrapyramidal motor system
* Motor planning, sequencing and learning
* Striatal neuronal activity is not sufficiently explained by the stimuli presented or the movements performed
* Dependent on certain behavioral situations, certain conditions or particularly types of trials
+ -sensory stimuli but only when they elicit movements
+ -instruction cues (go-no go)
+ -memory related cues
+ -reward (especially ventral striatum)
+ -self-initiated moves
* Basal ganglia distinguished from cerebellum by connections with limbic system

Architecture of the basal ganglia: cellular and neurochemistry

Cytoarchitecture
* Main neurotransmitter in basal ganglia is GABA
* 95% of neurons in neostriatum are medium spiny neurons
o Contain GABA
o Principal neurons: project to globus pallidus and SNpr
o Subpopulations are distinguished by peptides, neurotransmitter receptors and connections
o Receive bulk of afferent input
* Several populations of interneurons
o aspiny
o ACh, somatostatin, GABA/parvalbumin
Neuronal circuitry of the basal ganglia
The Neostriatal Mosaic
* Neostriatum divided into two compartments:
patch (striosome) & matrix
* First described by Ann Graybiel in 1978 using AChE stain
* Not visible in Nissl stains (“hidden chemoarchitecture”)
* Define input/output architecture of neostriatum

Neostriatal Mosaic and Input/Output Organization
* Most inputs to the neostriatum terminate in a patchy fashion (“matrisomes”)
* Input from a given cortical region terminates over an extended anterior-posterior extent
* Functionally related cortical areas project to the same patches
* Output neurons to a given efferent subregion are also arranged in patches
* Neurons in patches project to both GPi/SNpr and GPe

Functional subdivisions
* Sensorimotor
o Putamen + globus pallidus/SNpr
o SNpc
* Association
o Caudate nucleus + globus pallidus/SNpr
o SNpc
* Limbic
o Nucleus accumbens + ventral pallidum
o VTA

Basal ganglia connections and pathways
Connections
* Afferents/inputs (neostriatum):
o Cerebral cortex (entire cortex)
o Thalamus (intralaminar and midline nuclei)
o Amygdala (basolateral nucleus)
o Raphe, substantia nigra pars compacta, VTA
* Efferents/output (GPi, VP, SNpr)
o Ventral tier nuclei of thalamus
o Subthalamic nucleus
o Superior colliculus
Organization of inputs to basal ganglia
Organization of basal ganglia outputs

All regions of cerebral cortex project to the basal ganglia, but output of basal ganglia is directed towards the frontal lobe, particularly pre-motor and supplementary motor cortex
Basic Circuit of Basal Ganglia

Neostriatum
GPi/SNpr
Cerebral Cortex
VA/VL thalamus
Direct vs. indirect pathways
* Different populations of spiny neurons
* Neuromodulators/co-transmitters
* Striosomes vs. matrix
* Dopamine receptor subtypes
Both

Recurrent loops
* Motor loop
o sensorimotor areas 1,2,3,4,5,6 -> putamen -> GP -> VA ->SMA
* Ocularmotor loop
o prefrontal cortex & ppc 9,12, 7 -> caudate -> GP -> VA -> frontal eye fields & SC
* Cognitive loop
o prefrontal cortical areas 9,12 -> caudate -> GP -> VA -> prefrontal cortex
* Limbic loop
o cingulate -> caudate (striosomes)-> GP -> MD -> ant. cingulate.
Topography is maintained within each loop!

Motor loop
Somatotopic subdivisions of the input remain segregated throughout the circuit.
Adapted from Rothwell, 1994; from Alexander and Crutcher, 1990
Processing in the basal ganglia
Huntington’s and Parkinson’s diseases
* Neurodegenerative diseases
* Motor dysfunction
* Brainwide pathology with focus on basal ganglia elements
* Genetic and/or environmental causes
Huntington’s Disease
Clinical symptoms
* Hyperkinetic & hemiballistic movements

Pathology hallmarks
* Striopallidal degeneration
* Decreased striatal volume
* Decrease in 5-HT1B receptors in ventral pallidum
Hyperkinetic hypothesis
* Reduced Glu (+) from STN to GPi, due either to STN lesions or reduced striatopallidal inhibitory influences along the in direct pathway lead to reduced inhibitory outflow from GPi/SNr and excessive disinhibition of the thalamus.
* Increased Glu (+) to cortical areas engaged by the motor circuit (SMA, PMC, MC) results in hyperkinetic movements.
Parkinson’s Disease
Clinical symptoms
* Hypokinetic movement
* Cogwheel rigidity

Pathology hallmarks
* Nigostriatal degeneration
* DA neuronal degeneration in SN
Hypokinetic hypothesis
* Inhibition of GPe within the indirect pathway leads to disinhibition of the STN
* Increased STN to the basal ganglia output nuclei (Gpi/SNr), leads to excessive thalamic inhibition.
* This is reinforced by reduced inhibitory input to Gpi/SNr through the direct pathway.
* Overall result is a reduction in reinforcing influence of the motor circuit upon cortically initiated movements.

PD Therapeutics: The approaches
* Pharmacology
o DA, mGluR, MAO(B) inhibitors, antioxidants, iron chelators
* Surgical
o Pallidal ablation
o DBS of globus pallidus or STN
* Transplantation
o Fibroblast cells
o Stem cells
* Vaccines
* RNA interference (RNAI)-based treatments

DBS: Deep Brain Stimulation of STN
Common themes in neurodegeneration
* Neurotoxicity
* Inflammation (glia)
* Apoptosis
* Abnormal protein aggregation
Thank you!
Notable differences between basal ganglia of human and rodents …..
There are differences in:
* Divisions & nomenclature
* Proportions
* Topography of afferent and efferent projections
Globus pallidus and entopeduncular nucleus (rodent)
vs.
Globus pallidus (external) and Globus pallidus (internal) (primate)
Regional proportion by volume
(% of total volume)
Spinal Cord

Major projection differences

* Neurons projecting to the motor and associative striatum
o Rats: reside in distinct regions
o Primates: arranged in interdigitating clusters.
* Terminal fields of projections arising from the motor and associative striatum
o rats: largely segregated
o Primates: not segregated
* Organization of patch- and matrix-projecting dopamine cells
o Rats: organized in spatially, morphologically, and histochemically distinct ventral and dorsal tiers,
o Primates: no (bi)division of the dopaminergic system that results in two areas which have all the characteristics of the two tiers in rats.

The Basal Ganglia.ppt

Read more...

Anxiety Disorders

Anxiety Disorders

* Panic disorder
o Can be induced by lactate or CO2 in PD sufferers (only occasionally in normal people)
o Increased activity in parahippocampal gyrus,
o Decreased activity in anterior temporal cortex & amygdala (seems odd!)
o May have 3, rather than 2, repeats of a section on chromosome 15
+ Also have joint laxity (bend too far)

* Treatments for panic disorder
o Benzodiazepines (e.g., Valium)
+ Increase frequency of Cl- channel openings in response to GABA
+ Have little or no effect alone: safer than barbiturates
+ Allopregnanolone = endogenous agonist at benzodiazepine binding site.
o Buspirone (Buspar): 5-HT1a agonist (GI/O)
o SSRIs: fluoxetine (Prozac), paroxetine (Paxil)

Benzodiazepine receptors in brain
PTSD
* Monozygotic > dizogotic concordance
o Genetics 1/3 of variance
* NMDA mechanisms in amygdala
o May mediate both the conditioning and the extinction
+ NMDA antagonists in amygdala prevent extinction
+ Hippocampus and PFC also lose effectiveness in extinction
* Not due to high levels of glucocorticoids:
o Usually PTSD sufferers have LOWER than normal cortisol levels, despite high CRH
+ Maybe it’s the high CRH that  symptoms
+ Or maybe it’s increased responsiveness to CRH or cortisol
* Individual differences in responsiveness to trauma
* Sometimes treated with β NE antagonists (propranolol) or protein synthesis inhibitors soon after the trauma or during recall of the trauma
OCD
* Increased metabolism in orbitofrontal cortex, cingulate, and caudate nuclei.
* Decreased REM latency (~ to depression)
* At least 2 gene polymorphisms:
o For BDNF, 5-HT2A receptor
* Treatment: SSRIs
Cingulotomy to treat OCD
Tourette’s Syndrome
* In many ways opposite Parkinson’s disease
* Treated with dopamine antagonists
* Monozygotic concordance: 53-77%; dizygotic concordance: 8-23%
* Witty Ticcy Ray (by Oliver Sacks): “We Touretters…are forced into levity by our Tourette’s and forced into gravity when we take Haldol….You have a natural balance: we must make the best of an artificial balance.”

THE NIGROSTRIATAL AND MESOLIMBIC DOPAMINE SYSTEMS
* Nigrostriatal and mesolimbic tracts are parallel.
o Begin in midbrain (substantia nigra & ventral tegmental area, VTA)
o End in dorsal (caudate & putamen) and ventral (N. accumbens) striatum
o Cortico-striato-pallido-thalamic-cortical loops

Nigrostriatal system
* Plans and triggers self-initiated movements
* Adjusts posture
* Degeneration  Parkinson’s disease
o Tremor at rest
o Difficulty initiating movements

Mesolimbic system
* Increases responsiveness to external and internal stimuli
* Motivation
* Motor activity
* Reward
* Drug addiction
* Schizophrenia
Nigrostriatal dopamine tract
Mesolimbic dopamine tract

Direct pathway
* Positive feedback loop
* Cortical areas that initiated the activity are further excited.
* 2 consecutive inhibitory influences
* Then an excitatory influence
* Stimulating the first inhibitory path inhibits the second inhibitory path: disinhibits the excitatory path.

Sensorimotor Cortex
Striatum
Direct pathway
* Stimulate putamen
* Inhibits GPi/SNr
via D1 receptors
Sensorimotor Cortex
Striatum
Direct Pathway
When putamen inhibits
GPi/SNr, VL/VA
is disinhibited.
Thus, VL/VA excites
sensory motor cortex.
Indirect Pathway
Negative feedback
Begins with 2
inhibitory paths:
1. Putamen to GPe
2. GPe to STN
Sensorimotor Cortex
Indirect Pathway
Those inhibitory paths disinhibit an excitatory path.
But that exc. path ends on another inhibitory path!
Function
* Direct path excites cortex; indirect path inhibits it: opposing functions.
* May “sharpen” influence on behavior
o (similar to “sharpening” receptive fields).
* May provide greater control over movement
o (similar to having both EPSPs and IPSPs on same neuron).

Effects of Dopamine
* D1 receptors excite the Direct Pathway
o (i.e., increase excitation of the cortex).
* D2 receptors inhibit the Indirect Pathway
o (i.e., decrease the inhibition of thalamus and therefore increase excitation of cortex).
* Therefore, both effects increase excitation of cortex
o (i.e., increase either movement or motivation).

The Mesolimbic System
* Circuit is parallel to nigrostriatal system:
o Direct and indirect pathways
o Prefrontal cortex vs. sensory motor
o N. accumbens (ventral striatum), vs. caudate & putamen (dorsal striatum)
o Ventral pallidum vs. GPi and GPe
o Mediodorsal thalamus vs. VL/VA
Prefrontal Cortex
VP normally inhibits

Effects of Dopamine
* D1 receptors excite the Direct Pathway
o (i.e., increase excitation of the cortex).
* D2 receptors inhibit the Indirect Pathway
o (i.e., decrease the inhibition of thalamus and therefore increase excitation of cortex).
* Therefore, both effects increase excitation of cortex
o (i.e., increase either movement or motivation).

Glutamate/DA balance in schizophrenia
* Cortical or hippocampal hypofunction may  decrease glutamate in NAcc and striatum
* decrease tonic DA release
* increase DA receptor sensitivity
* hyperresponsive to phasic input

Anxiety Disorders.ppt

Read more...

Movement Disorders

Movement Disorders

* Background
o AKA Extrapyramidal Disorders
o These disorders impair the regulation of voluntary motor activity w/o affecting the strength, sensation, or cerebellar fcn.
o Result from dysfunction of the basal ganglia
+ Caudate
+ Putamen
+ Globus Pallidus
+ Subthalamic Nucleus
+ Substantia Nigra
+ Lentiform Nucleus
# Putamen & Globus Pallidus
+ Corpus Striatum
# Lentiform Nucleus + Caudate Nucleus
* Basal Ganglia Circuitry (Fig 7-1)
o Corticocortical Loop:
Cerebral Cortex
Caudate & Putamen
Internal Segment
Globus Pallidus
Thalamus
* Basal Ganglia Circuitry (Fig 7-1)
o Nigrostriatal Loop:
Substantia Nigra
Caudate & Putamen
* Basal Ganglia Circuitry (Fig 7-1)
o Striatalpallidal Loop:
Caudate & Putamen
External Segment
Globus Pallidus
Subthalamic Nuclei
Internal Segment
Globus Pallidus
* Types of Abnormal Movements
o Tremor: rhythmic movement characterized by when it occurs
+ Postural Tremor
# During sustained posture
+ Intention Tremor
# During movement; absent at rest
+ Resting Tremor
# At rest
o Chorea: irregular muscle jerks
+ Florid Cases
# Fully developed
# Forceful movements of limbs, head, facial grimacing, & tongue movements
+ Mild Cases
# Characterized by:
* Clumsiness
* Milkmaid grasp
* Absent in sleep
o Hemiballismus
+ Unilateral Chorea
+ Involves the proximal muscles
+ Vascular disease of contralateral subthalamic nucleus
o Athetosis
+ Continued slow, sinuous, & writhing movements
o Dystonia: sustained athetotic movements
+ Segmental Dystonia
# Affects one or more limbs
+ Focal Dystonia
# Affects localized muscle groups
+ Palliative/Provocative
+ Causes
o Myoclonus
+ Definition
+ Classification
+ Generalized: widespread
# Physiological
# Essential
# Epileptic
# Symptomatic
+ Segmental: more localized
o Tics
+ Definition
+ Palliative/Provocative
+ Types
# Transient Simple: common in children, resolve w/I 1 yr
# Chronic: any age, no tx
# Persistent Simple or Multiple: onset before 15 yoa, resolve in adults
# Chronic Multiple: Tourette’s Sydrome
* Hypokinetic Movement Disorders
o Parkinson’s Disease
* Hyperkinetic Movement Disorders
o Huntington’s Disease
o Wilson’s Disease
o Tourette’s Syndrome
o Restless Leg Syndrome
* Parkinson’s Disease - Hypokinetic
o Defined as a syndrome consisting of variable combination of tremor, rigidity, bradykinesia, and characteristic disturbance of gait and posture
o Onset: mid-late life; mean age is 57 yrs
o Epidemiology:
+ Affects all ethnicities
+ has equal M/F distribution
+ occurs 1-2 per 1,000 people in general population
+ occurs 1 per 100 people that are over 65 yrs
+ 4th most common disease in the elderly
* Parkinson’s Disease - Hypokinetic
o Cause: unknown
o Pathophysiology:
+ Loss of dopaminergic cells in the substantia nigra
# Dopamine’s normal function
+ Over excitation of the caudate & putamen
+ Over excitation of the corticospinal tracts
+ Oscilation of feedback
+ Decrease in thalamic excitation of the motor cortex
o Four Hallmark Signs
+ Resting Tremor (Pill-Rolling)
+ Rigidity (Lead-Pipe or Cogwheel)
+ Bradykinesia
+ Flexed Posture with shuffling gait (Festinating)
o Examination:
+ History
+ Phsyical Findings:
# Passive movement
# Muscle Strength
# Sensory
# Deep Tendon Reflexes
# Autonomic
# Myerson’s Sign
# Pull Test
o Diagnosis:
+ Four Hallmark signs
+ Tremor is absent in 30% of patients
o Differential Diagnosis
+ Involuntary tremor vs. Intentional tremor
+ Depression
+ Wilson’s Disease
+ Huntington’s Disease
o A neurodegenerative disorder which predominately has behavioral, cognitive, or signs
o Onset: Usually begins during adult life
o Epidemiology:
+ 5-10 per 100,000 in the US
+ 50% chance to pass on the disorder
+ Anticipation
+ Paternal Descent
* Huntington’s Disease – Hyperkinetic
o Cause: Autosomal Dominant Disorder
o Pathophysiology:
+ Mutation on chromosome 4: CAG repeats
+ CAG Normal Function: codes for glutamine
+ Over-expression of the gene: i.e. excess glutamine
+ Uncertainty?
* Huntington’s Disease – Hyperkinetic
o Cause: Autosomal Dominant Disorder
o Pathophysiology:
+ Pathological Changes
# Atrophy & neuronal degeneration of cortex
# Hallmark: caudate atrophy
+ Projected Conclusion?
# Over activity
# Under activity
o Examination:
+ Physical Findings
# Initial Findings
* Gradual onset
* Slowed saccadic movements 1st sign
* In 85% chorea is predominate movement disorder
# Juvenile Form
* AKA The Westphal Variant
* Rigidity & bradykinesia
* Tremors, Dystonic postures, & Ataxia
* Mental retardation, Seizures, & myoclonus
o Examination:
+ Physical Findings
# Adult Onset
* Prominent chorea
* Bradykinesia
* Postural reflex compromise
# Terminal Phase
* Dysarthria, dysphagia, & respiratory difficulties
# General
* Cognitive impairment
* Depression
* Psychiatric disorders
* Wilson’s Disease – Hyperkinetic
o Onset
+ Hepatic Dysfunction – 11 yoa
+ Neurological Dysfunction – 19 yoa
o Epidemiology
+ Rare
+ 1 in 40,000 people
o Cause: Autosomal Recessive Disorder
o Pathophysiology
+ Abnormal copper metabolism
+ Deposition of copper in tissues
o Examination
+ Physical Findings
# Children: hepatic dysfunction predominates
* Sardonic Smile
* Behavioral problems
# Adults: neurological dysfunction predominates
* Parkinsonian features
# General
* Hallmark: Kayser-Fleischer Rings
* 1/3 experience psychiatric symptoms
* Other ocular abnormalities
* Gilles de la Tourette Syndrome – Hyperkinetic
o Diagnosed when childhood onset tics are multifocal, motor or vocal, lasting longer than 1 yr and naturally wax and wane
o Cause: unknown
o Onset: 2-21 yoa
o Male predilection
* Gilles de la Tourette Syndrome – Hyperkinetic
o Examination
+ Physical Findings
# Simple Tics
* Motor: blinking, facial grimacing, shoulder shrugging
* Vocal: throat clearing, grunting, snorting, barking
# Complex Tics
* Motor: hopping, skipping, Echopraxia
* Vocal: Coprolalia, Echolalia, Palilalia
* Restless Legs Syndrome – Hyperkinetic
o Common movement disorder
o Diagnostic Criteria
# Desire to move limbs which is associated with unpleasant sensations
# Restlessness
# Worsening of symptoms @ rest w/ temporary relief w/ movement
# Worsening of symptoms @ night
* Restless Legs Syndrome – Hyperkinetic
o Common Descriptions
+ Always unpleasant, but not necessarily painful
+ Need to move
+ Crawling
+ Tingling
+ Itching
+ Restless

Movement Disorders.ppt

Read more...