Nuclear Medicine Resources Manual

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CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

370

It should be noted that although the haematological changes are

reversible, neurological damage may not be.

5.10.5.3. Radiopharmaceuticals

Vitamin B

(cyanocobalamin) has cobalt as a central metal atom.

Radioactive isotopes of cobalt can substitute the ‘cold’ atom, producing the

tagged form.

The following radionuclides are available:

(a) Cobalt-57: physical half-life, 270 days;

photon energy, 122 keV.

(b) Cobalt-58: physical half-life, 71 days;

photon energy, 810 keV.

5.10.5.4. Technique

The following technique is used:

(1) Ensure the patient has nothing to eat or drink after midnight.

(2) Prepare dose standards of 2 mL.

(3) Administer 18.5 kBq (0.5 mCi) of

Co labelled vitamin B

in 0.5 mg

vitamin B

orally, together with a capsule of 18.5 kBq (0.5 mCi) of

complexed with IF.

(4) Two hours later administer 1000 mg of cold vitamin B

intramuscularly or

subcutaneously. This flushing dose is administered to saturate the

transport proteins.

(5) Make two consecutive 24 hour urine collections. Cobalt-57 vitamin B

absorbed through the gastrointestinal tract will not be bound by saturated

transport proteins and will thus be excreted in urine.

(6) Measure volume of the 24 hour collection.

(7) Pipette and count 2 mL aliquots of urine and standards.

(8) Calculate percentage of administered dose excreted over each 24 hour period.

5.10.5.5. Interpretation

Normal and abnormal findings can be characterized as follows:

5.10. HAEMATOLOGY

371

(a) Normal findings:

—More than 10% of the administered dose is excreted in the urine in the

first 24 hours. Values between 6 and 10% are considered to be indeter

minate.

(b) Abnormal findings:

(i) Pernicious anaemia – less than 6% excreted (usually in the range of

1–3%).

(ii) Intestinal malabsorption – less than 6% excreted – abnormality not

corrected by IF.

(iii) Chronic vitamin B

deficiency from pernicious anaemia can

produce atrophy of the ileal mucosa. This, in turn, causes a

decreased intestinal absorption of vitamin B

(iv) False positive results may occur in patients with diminished renal

function or obstruction. In patients with extremely poor renal

function, a collection should be performed over three days.

(v) False positive results may occur if a portion of the urine volume is

lost. Maximum excretion occurs 8–12 hours after administration.

Check for loss by:

—Measuring urine specific gravity;

—Measuring creatinine – normally greater than 1 g;

—Differences in volume between the 24 and 48 hour collections.

(vi) False negative results may occur if faecal contamination of urine

occurs, invalidating the test.

Although less readily available, a whole body counter can be used for

vitamin B

absorption studies. The main advantage of this technique is that a

flushing dose of non-radioactive vitamin B

is not needed, thus leaving vitamin

determinations, the bone marrow and haematological changes unaltered.

The results are also not dependent on renal function.

5.10.6. Radiolabelled platelets

5.10.6.1. Anatomy and physiology

(a) Platelets

Platelets are formed in the bone marrow by megakaryocytes. Platelets are

small disc shaped cells and do not have a nucleus. They have the ability to

change shape on contact with foreign materials or subendothelial surfaces,

stimulating the release of substances involved in haemostasis.

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(b) Haemostasis

Haemostasis is characterized by:

—Platelet adhesion to the periphery of the wound;

—Localized vasoconstriction;

—Platelet plug formation;

—Reinforcement of plugs with fibrin;

—Removal of clots by the fibrinolytic system.

When platelets are activated, thromboxane A2 is released. This is one of

the most potent vasoconstrictors known and also promotes platelet aggre

gation. Prostacyclin, produced in the vessel wall, inhibits the effects of throm-

boxane. Aspirin and other drugs that decrease platelet aggregation do so by

inhibiting cyclo-oxygenases. This blocks the conversion of arachidonic acid to

peroxidase, reducing thromboxane A2 levels.

5.10.6.2. Technique

Two types of platelet labels are used:

(1) Cohort (pulse) labels – taken up by megakaryocytes and incorporated

into the components of forming platelets. With these labels, only freshly

released platelets of uniform age are labelled. These labels are currently

not used in clinical practice.

(2) Random labels – these label platelets of all ages.

Cr-chromate and

111

In-

oxine are examples.

(a) Collection of blood

The anticoagulant used in the blood collecting syringe is critical. ACD has

a less deleterious effect on platelet function than other anticoagulants.

(b) Centrifugation

There are two steps in the technique of centrifugation:

(1) First, centrifugation at 1750–2700g min

–1

produces platelet-rich plasma

(PRP). If too high centrifugal forces are used, too many platelets will be

5.10. HAEMATOLOGY

373

lost. Lower forces cause excessive RBC contamination. The duration of

centrifugation is also important. With increased time, younger platelets,

which are more adhesive, tend to sediment out.

(2) Second, centrifugation (at 10 000–20 000g min

–1

) of PRP forms platelet

pellets to remove plasma.

111

In-oxine

Because of its physical characteristics,

111

In is superior to

Cr as a platelet

label. Labelling in plasma, although reducing labelling efficiencies, may

improve platelet function.

(d) Other chelates

Other agents that may have less toxic effect on platelets include

Tropolone.

(e) Radiation effects

Individual platelets incubated with 37 MBq (1 mCi) of

111

In may be

exposed to radiation doses of up to 129 Gy (12 900 rad). This high value is due

to their relatively small size and long biological lifespan. Since they lack nuclei

they are highly radioresistant. Normal survival times and function have been

reported at radiation doses of 500–700 Gy.

5.10.6.3. Clinical uses

Radiolabelled platelets have various uses:

(a) One of the most common uses is measurement of platelet lifespan:

(i) Survival curves are normally linear. Disappearance of platelets from

the circulation is related to age dependent destruction by the reticu

loendothelial system (RES).

(ii) Lifespan is normally about nine days.

(iii) Platelet survival is diminished in a number of conditions and by

some surgical treatments including:

—Idiopathic thrombocytopenic purpura (IT);

—Prosthetic heart valves;

—Arterial grafts;

—Peripheral vascular disease;

—Atherosclerotic coronary heart disease;

CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

374

—Eisenmenger’s syndrome;

—Primary pulmonary hypertension;

—Diabetes mellitus;

—Hepatic cirrhosis;

—Hyperlipidaemia;

—Renal transplantation.

(b) Deep venous thrombosis:

(i) In animals, heparin prevents visualization of thrombi. In humans,

however, this effect does not appear as significant.

(ii) The degree of uptake is dependent on the age of the thrombus. Less

localization occurs in older thrombi.

(iii) Delayed imaging at 24–48 hours is often necessary, especially in

older thrombi.

(i) Heparin appears to prevent embolus visualization.

(ii) The length of time a thrombus is present in the lung is more

important for sensitivity than the age of the thrombus itself. With

time, in situ adherence of platelets to emboli diminishes.

(iii) Large emboli that completely occlude an artery may cause a false

negative study because emboli are not exposed to the labelled

platelets.

5.10.6.4. Interpretation

Labelled platelets are rarely used for the diagnosis of pulmonary

embolism because of the complexity of their preparation. Their main use is to

aid a decision on splenectomy in patients with idiopathic thrombocytopenic

purpura. High splenic uptake as determined by external counting is taken as an

indication for splenectomy.

5.10.7. Bone marrow imaging

5.10.7.1. Anatomy and physiology

The functional red marrow approximately equals the liver in total size,

with a total mass of about 1.5 kg. In adults, active marrow is found primarily in

the axial skeleton including the vertebral bodies, pelvis, sternum, scapula, skull

and in the appendicular skeleton, generally in the proximal third of the femora

and humeri. In children, the volume of active marrow depends on age, while in

newborns it extends the full length of the extremities. As the child grows, the

marrow gradually retracts until an adult pattern is reached at the age of 10.

5.10. HAEMATOLOGY

375

5.10.7.2. Radiopharmaceuticals

(a) Radioiron

Radioiron and its analogues bind to transferrin and are incorporated into

active erythroid precursors in the bone marrow. Iron-2 would be the most

physiological to use, but it requires a cyclotron for its production and has a half-

life of only eight hours; it normally requires high quality images produced with

a positron camera.

(b) Colloid imaging

Colloids are removed from the blood by the phagocytic cells of RES that

line bone marrow sinusoids. Normally, the erythroid and RES distributions are

parallel; thus RES scintigraphy shows an identical marrow distribution to that

with radioiron. About 92% of an injectable dose of

99m

Tc-SC is removed by

phagocytes in the liver and spleen; only the remaining 8% localizes in bone

marrow. With the usual dose of SC used for liver-spleen imaging and the

relatively short imaging times, activity in the bone marrow is not normally seen.

Higher doses and enhanced display techniques such as thresholding and

masking allow the bone marrow to be visualized.

5.10.7.3. Technique

The following technique is used:

(a) Inject the patient with 12–15 mCi of

99m

Tc-SC (intravenously).

(b) Image with a large FOV camera using a low energy, all purpose (LEAP)

collimator.

(d) Obtain 50 000–200 000 counts per image.

(e) Image the entire body, both anteriorly and posteriorly.

5.10.7.4. Interpretation

Normal and abnormal characterizations are as follows:

(a) Normal findings

(i) Technetium-99m SC:

—The majority of the uptake is in the axial skeleton.

CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

376

—The activity in the appendicular skeleton should not extend

beyond the proximal one third.

—The skull has a variable degree of uptake.

—The sternum and ribs are often difficult to visualize although they

contain active marrow.

—The lower thoracic and upper lumbar regions of the spine are not

well seen because of intense uptake in the liver and spleen.

(ii) Radioiron:

—Activity is confined primarily to the axial skeleton.

—Not normally accumulated in the spleen.

(b) Abnormal findings:

(i) Decreased central marrow.

(ii) Peripheral extension.

(iii) Focal defects.

(iv) Increased liver and spleen size.

(v) Increased uptake outside normal regions of the extramedullary

haematopoiesis.

5.10.7.5. Clinical applications

There are clinical applications of bone marrow imaging in the following

areas:

(a) Avascular necrosis, especially of the femoral head;

(b) Extramedullary haematopoiesis;

patients being considered for splenectomy in myeloproliferative

disorders such as myeloid metaplasia;

(d) Evaluation of any disparity between the patient’s marrow histology and

peripheral blood smear;

(e) Diagnosis of bone marrow infarcts and haemolytic anaemias;

(f) Detection of metastases.

BIBLIOGRAPHY TO SECTION 5.10

DATZ, F.L., TAYLOR, A., The clinical use of radionuclide bone marrow imaging,

Semin. Nucl. Med. 25 (1985) 239–259.

5.11. INFLAMMATION AND INFECTION

377

INTERNATIONAL COMMITTEE FOR STANDARDIZATION IN HEMATOLOGY

Recommended method for radioisotope red cell survival studies, Blood 38 (1971) 378–

386.

Recommended methods for radioisotopic erythrocyte survival studies, Am. J. Clin.

Pathol. 58 (1972) 71–80.

Standard techniques for the measurement of red cell and plasma volume, Br. J.

Haematol. 25 (1973) 801–814.

Recommended methods for surface counting to determine site of red cell destruction,

Br. J. Haematol. 30 (1975) 249–264.

Recommended methods for radioisotope platelet survival study, Blood 50 (1977) 1137–

1144.

Recommended method for radioisotope red-cell survival studies, Br. J. Haematol. 45

(1980a) 659–666.

Recommended method for measurement of red-cell and plasma volume, J. Nucl. Med.

21 (1980b) 793–800.

5.11. INFLAMMATION AND INFECTION

5.11.1. Introduction

The choice of imaging agents depends on the biological processes of

inflammation, whether it is acute or chronic, and the cause and site as well as

the clinical problem to be addressed. The nuclear medicine imaging of inflam

matory processes and infection is a form of tissue characterization which has

moved from the generally sensitive, but non-specific or context specific, agents,

to more disease specific agents.

5.11.2. Inflammation

Acute inflammation is typically initiated by trauma, burns or infective

agents resulting in tissue injury and tissue necrosis. These factors initiate

defence mechanisms, such as the release of cytokines, complements and

antibodies, which are associated with vasodilation and increased capillary

permeability resulting in extravasation of proteins and cells to the affected

area. Leucocytes are recruited by adhesion molecules on the endothelium

which are activated and bind to white cells such as E-selectin, ICAM-1 and

CHAPTER 5. GUIDELINES FOR GENERAL IMAGING

378

V-CAM, so that cells roll and adhere to the endothelium and diapedesis. They

migrate down the chemoattractant gradient and lead to the classical

combination of swelling, redness, pain and protective loss of function. Labelled

leucocytes are appropriate for imaging of acute inflammation.

Chronic inflammation is characterized by a reduction in vasodilation and

capillary permeability, a reduction in leucocyte activity, and an increase in

monocytes and macrophages with lymphocytic infiltration. It is perpetuated by

continuing necrosis, followed by activation of dendritic cells and appearance of

antigen presenting cells, with possible formation of autoimmune disease

granuloma. Clearly, radiolabelled white cells and agents that depend on

vascular permeability will be less effective in this situation.

5.11.2.1. Clinical indications

Clinical problems may range from fever of unknown origin (FUO) to

localization of the site of inflammation, as in Crohn’s disease, to localization of

the site of infection when a blood culture for bacteria is positive.

An FUO requires a catch-all approach since there may be non-infective

causes of fever, including cancer, granuloma and vasculitis, making a sensitive,

non-specific agent such as

Ga-citrate,

99m

Tc labelled MDP used in bone scans

or even

FDG appropriate.

In determining the site of an inflammation, a more specific agent is

preferred such as

111

In,

99m

Tc labelled white cells or human immunoglobulin

(HIG), commonly referred to as IgG, or additionally

99m

Tc small molecular

weight dextran.

In the case of infection, a yet more specific agent is preferable, such as

one binding only to bacteria, for example

99m

Tc-ciprofloxacin (Infecton).

5.11.2.2. Inflammation and infection imaging agents and their indications

(a) Imaging inflammation

The choice of imaging agent depends on the biological processes, as

outlined above. Advantage can be taken of increased vascular permeability by

using

Ga citrate transferrin complex; polyclonal human immunoglobulin;

liposomes (100 mm), particularly if pegylated; nanocolloids; and dextrans. A

second approach is through direct targeting of inflammation by radiolabelled

leucocytes, either labelled ex vivo using

99m

Tc-HMPAO or

111

In-oxine, or

labelled in vivo using monoclonal antibody fragments with

99m

Tc. More

recently, similarly labelled peptides have come into use.

5.11. INFLAMMATION AND INFECTION

379

For chronic inflammation, direct targeting of lymphocytes using

99m

Interleukin 2 will demonstrate activated T cells in, for example, autoimmune

diseases. Macrophages and monocytes have been imaged using

99m

Tc-J001X.

The endothelium in vasculitis may be shown with E-selectin antibodies and

Amyloid by using

123

I serum amyloid protein or

99m

Tc-aprotonin.

(b) Imaging infection

The key questions to be asked are:

—Is there infection or not?

—If so, where is it?

—What is the cause?

—Has it responded to therapy?

The physical approach is to use ultrasound, local X rays, CT or MRI;

however, all these depend on the infection becoming loculated, as for example

in an abscess in the liver, which is easily demonstrable by ultrasound. Prior to

abscess formation it is difficult for radiology to demonstrate soft tissue

infection.

Nuclear medicine techniques depend on radiolabelling elements of the

inflammatory process or bacteria directly. The US Center for Disease Control

(CDC) has defined virtually all bacterial infections, with the exception of

tuberculosis, which has been defined by the WHO, and endocarditis, which has

been defined by Duke’s criteria. Evaluation as to whether a patient has an

infection or not should be made against these established systematized criteria.

They include clinical evidence and laboratory results that are not confined to

microbiology, diagnostic tests incorporating radiology and nuclear medicine,

and further supporting evidence such as response to antibiotics.

It can be seen that the imaging of inflammatory processes and infection is

a form of tissue characterization by nuclear medicine. This has moved away

from the use of more non-specific techniques that react with inflammation,

infection, granuloma and tumours, such as the conventional three phase bone

scan, with

Ga-citrate and

F-deoxyglucose, towards agents specific to inflam-

mation such as radiolabelled white cells or human immune globulin, and to

agents specific to a particular disease (Table 5.20).

The three phase bone scan (as described in Section 5.7) is still the basis

for the diagnosis of osteomyelitis, but is relatively unreliable in cases of

fracture, joint prosthesis, recent surgery and in newborns. For

Ga imaging of

infection, see Section 5.8.1.