Basal Cisterns Cisternogram

Figure 5. Alzheimer's disease. (A) SPECT brain perfusion in a patient presenting with dementia and moderate diffuse atrophy on CT scan. This single transaxial slice shows marked hypoperfusion bilaterally at the level of the parieto-occipital junctions (arrows). (B) 18F-FDG PET study (transaxial images) showing marked symmetrical glucose hypometabolism in the posterior parieto-temporal cortex (arrowheads). (Case provided by Dr. D. Worsely.) These scan patterns are typical of Alzheimer's disease.

Cisternogram Nuclear Medicine

Figure 6. Thrombolysis assessment. Transaxial slice from patient with acute non-hemorrhagic infarction and a limited perfusion defect (arrows). Thrombolysis with tPA should be considered within 3 hours of symptom onset when the CT scan is normal. Large or multiple lesions are probably contraindications to thrombolysis due to an unacceptably high risk of hemorrhagic transformation. (Case provided by Dr. W.D. Leslie.)

Figure 6. Thrombolysis assessment. Transaxial slice from patient with acute non-hemorrhagic infarction and a limited perfusion defect (arrows). Thrombolysis with tPA should be considered within 3 hours of symptom onset when the CT scan is normal. Large or multiple lesions are probably contraindications to thrombolysis due to an unacceptably high risk of hemorrhagic transformation. (Case provided by Dr. W.D. Leslie.)

phenomenon which is stable over such a time frame, but is obviously a drawback for activation studies where it is often difficult to perform a given task for such a long time.

Oxygen Consumption

Cerebral energy metabolism can also be assessed through measurements of molecular oxygen (O2) consumption. Oxygen (as 15O-O2) is administered by inhalation and measurement of its accumulation is used to determine the regional cerebral metabolic rate for oxygen (rCMRO2). This can aid in determining whether decreased rCBF results from a primary vascular problem (obstruction) or decreased metabolic demands (parenchymal dysfunction). By simultaneously measuring rCBF and rCMRO2 it is possible to obtain an oxygen extraction fraction (OEF). A normal OEF signals a match between needs and supply, and implies parenchymal hypoactivity; an increase indicates abnormally decreased perfusion with neural tissue attempting to extract more oxygen from a decreased supply. One day this approach may help select patients for a cerebral revascularisation procedure.

Amino Acid Metabolism

Other metabolic studies can be performed with analogues of amino acids labelled with iodine-123 (SPECT), carbon-11 (PET) and fluorine-18 (PET). Most frequently these are derivatives of tyrosine, methionine and leucine. Usually used as markers of tumoral activity, these agents can also evaluate protein and neurotransmitter synthesis.

Clinical Applications

Excellent results have been obtained in studying epilepsy and the dementias (where results are even better than with SPECT perfusion studies) with 18F-FDG PET imaging. It also can help guide biopsies, establish prognosis, evaluate recurrence of brain neoplasms, and differentiate residual masses from other conditions such as radiation necrosis (see section on Intracranial Mass Lesions). The high levels of cortical glycolysis normally observed can mask detection of low-grade brain tumors.

Studies of Neurotransmission

Nuclear medicine is still the only means for studying neurotransmission directly and non-invasively in vivo. A broad array of SPECT and PET tracers are available, including neuroreceptor ligands (generally antagonists), neurotransmitter metabolic precursors, ligands of plasma membrane and synaptic vesicle transporters, substrates of neurotransmitter catabolising enzymes and components of intracellular transduction chains (Fig. 7). PET has long dominated this landscape, but over the past ten years progress in the field of radiopharmacy has contributed many SPECT tracers.

Mathematical modeling of dynamic PET or SPECT acquisitions permits estimation of physiologically relevant parameters such as neuroreceptor densities for a large variety of chemically defined transmission systems, synthetic and catabolic enzymatic activities within those systems, numbers of neuronal terminals of a given nature, neurotransmitter concentrations in the synaptic cleft and even second messenger generation. Data acquired in these domains has revolutionised our understanding of neurologic and psychiatric diseases.

Clinical Applications

While very few clinical applications are presently established for neurotransmitter studies, their potential for growth is probably the greatest in all of neuropsychiatric nuclear medicine. One suggested use is in the monitoring of therapy for psychoses. "Classical" neuroleptics, such as the phenothiazines, block the D2-subtype of the dopamine receptors. These receptors exist in high concentration in the striatum and are intimately involved in regulation of motor activity. Excessive blockade (beyond 80-85%) of striatal D2 dopamine receptors has been associated with an increased risk of developing long term side effects such as tardive dyskinesia. The level of D2 blockade can be measured with both PET and SPECT ligands, and patients found to have excessive blockade may benefit from a lower dose of medication or from an atypical neuroleptic with minimal affinity for D2 receptors.

Predicting response to dopaminergic therapy in patients with a parkinsonian syndrome might also be possible. The striatal complement of D2 dopamine receptors is normal (or even increased through receptor up-regulation) in Parkinson's disease since the lesion resides in the nigro-striatal fibres (Fig. 8). In diseases such as progressive supranuclear palsy or syndromes producing primary striatal degeneration the D2 dopamine receptor concentration is reduced. The latter are not responsive to dopaminergic therapy since the defect is on the "receiving end" of the dopaminergic transmission process. This could be quite useful since even in specialised centres Parkinson's disease and parkinsonian syndromes are confused in up to 20% of patients.

Dopamine Receptors Simplified

Figure 7. Simplified dopaminergic synapse. Dopamine (DA) is synthesized in the axon terminal, stored (via the vesicular transporter VMAT2) in secretory vesicles and released when an action potential depolarizes the terminal. Released DA diffuses toward the postsynaptic membrane where it can bind to a variety of DA receptors (5 subtypes have been cloned). DA can also bind to receptors on the presynaptic membrane (not illustrated), which modulate its synthesis and release. Some DA also diffuses out of the synapse and can act on non-synaptic DA receptors. Termination of DA action on receptors is brought about mostly by reputake into the axon terminal through the DA transporter for "repackaging" into secretory vesicles. Some DA undergoes enzymatic catabolism by MAO (intracellular) or COMT (synapse).

Figure 7. Simplified dopaminergic synapse. Dopamine (DA) is synthesized in the axon terminal, stored (via the vesicular transporter VMAT2) in secretory vesicles and released when an action potential depolarizes the terminal. Released DA diffuses toward the postsynaptic membrane where it can bind to a variety of DA receptors (5 subtypes have been cloned). DA can also bind to receptors on the presynaptic membrane (not illustrated), which modulate its synthesis and release. Some DA also diffuses out of the synapse and can act on non-synaptic DA receptors. Termination of DA action on receptors is brought about mostly by reputake into the axon terminal through the DA transporter for "repackaging" into secretory vesicles. Some DA undergoes enzymatic catabolism by MAO (intracellular) or COMT (synapse).

Cerebrospinal Fluid Assessment

Physiology

The ventriculo-subarachnoid system consists of two fluid compartments: the intracranial component occupies 140 ml (about 25 ml of which is intraventricular) and the spine is bathed with an additional 75 ml. Daily production of CSF reaches 500 ml, 90% of which is produced by the choroid plexi. The remainder comes from exudation through intraparenchymal vessels, reaching the subarachnoid space by diffusion along the spaces ofVirchow-Robbins, and from extracellular fluid reaching the ventricular system across the highly permeable ependyma. Production is largely a Parkinson's Disease

Cisternogram Nuclear Medicine

IBZM beta-CIT

B Primary Striatal Lesion

IBZM beta-CIT

Figure 8. Abnormal dopamine neurotransmission in (A) idiopathic Parkinson's disease and (B) primary striatal lesion causing parkinsonism. Note the comparative uptake of tracers that bind to the dopamine D2 receptor (123I-IBZM, left) and the dopamine transporter (123I-beta-CIT, right). Both disorders demonstrate reduced dopamine transporter function by the right basal ganglion (arrowhead). In idiopathic Parkinson's disease there is increased uptake of IBZM (arrow) due to a combination of decreased dopamine release and D2 receptor up-regulation reflecting normal neostratum with loss of dopaminergic (nigro-striatal) input. In contrast, with a primary striatal lesion there is slightly decreased IBZM uptake (arrow).

independent of the pressure found within the ventriculo-subarachnoid space. Normally, CSF produced by the choroid plexi flows through the ventricular system to the fourth ventricle, where it exits the intracerebral spaces through the foramina of Luschka and Magendie. From there, some CSF descends into the perispinal sub-arachnoid spaces while the remainder enters the cisternae at the base of the brain and the cerebellum. Most of the CSF flows around and between the hemispheres, converging towards the superior sagittal sinus where it re-enters the circulation through arachnoidal invaginations into the lumen of the sinus (called Paccionian granulations). A small portion of the CSF is reabsorbed across the arachnoid into blood vessels along the neuraxis. Progression of the CSF along these different paths is ensured by a pressure gradient between the production and resorption sites, vascular pulsations, and intracranial and intraspinal pressure waves of multifactorial origin.

Nuclear Cisternography

The circulation of the CSF can be studied with nuclear cisternography in which an inert radiotracer (usually 99mTc- or mIn-DTPA) is injected into the lumbar subarachnoid space. Sequential scintigrams of the spine and head are obtained for 24-72 hours. A normal study shows rapid progression of radioactivity from the injection site towards the head, with intracranial activity noted anywhere between 1 and 3 hours post-administration. Activity progressively permeates all of the intracranial subarachnoid space without significant penetration into the ventricular system (though transient but minimal ventricular penetration is not unusual). By 24 hours, most of the activity should have been transferred to the superior sagittal sinus and excreted through the kidneys with most remaining intracranial activity superior to the cerebral convexities (Fig. 9).

Clinical Applications

Hydrocephalus

Since an increase in CSF pressure does not block its formation, CSF can accumulate intracranially with symptoms that vary depending on the speed at which the build-up occurs. For instance, malformations, hemorrhages or tumors in the posterior fossa can obstruct the egress of CSF from the ventricular system, giving rise to a condition known as non-communicating hydrocephalus (i.e., no communication between the ventricular system and subarachnoid space). More commonly, scinticisternography is performed for suspicion of communicating hydrocephalus. After such events as meningitis, subarachnoid hemorrhage or intracranial surgery, the subarachnoid space may become obstructed, impeding the normal flow of CSF. This situation can give rise to normal pressure hydrocephalus (NPH). The term NPH is a misnomer: by the time the disease comes to clinical attention spinal opening pressure may be normal because compensatory mechanisms have come into play to reduce intracranial pressure. Before this stage is reached, CSF pressure is probably periodically increased, resulting in ventricular dilatation. The "classic" clinical triad of NPH is dementia, gait disturbance and incontinence. The dementia is potentially reversible, and in a small number of carefully selected individuals there is a dramatic response to CSF shunting.

The major compensatory mechanism to NPH is a marked increase in transependymal passage of CSF into brain parenchyma. This is accompanied by an inverted flow of CSF from the subarachnoid space into the ventricles. This phenomenon is well depicted by scinticisternography, where marked ventricular activity will accumulate and persist for a sustained period of time. This pattern is considered confirmatory of the clinical diagnosis of NPH. Most neurologists do not recommend performing this test on a routine basis, reserving it for atypical cases that do not manifest the "classic" clinical presentation. It has been suggested that reflux of radioactivity into the ventricles that lasts for more than 24 hours indicates

Csf Cisternography Nuclear

Figure 9. Normal radionuclide cisternography. 111In-DTPA was injected into the lumbar subarachnoid space. Note initial activity within the extracerebral subarachnoid spaces and basal cisterns (arrowheads) which progresses to the Sylvian and interhemispheric fissures by 6 hours (arrows). By 24 hours resorption is almost complete. Normally the ventricular system is not visualized.

Figure 9. Normal radionuclide cisternography. 111In-DTPA was injected into the lumbar subarachnoid space. Note initial activity within the extracerebral subarachnoid spaces and basal cisterns (arrowheads) which progresses to the Sylvian and interhemispheric fissures by 6 hours (arrows). By 24 hours resorption is almost complete. Normally the ventricular system is not visualized.

that compensatory reabsorption is not well established and that deterioration is likely (Fig. 10). This may indicate a better response to ventriculo-peritoneal shunting than when only transient reflux is observed, since the latter suggests a stabilised condition with established, nonreversible damage to the periventricular brain tissue. In fact, no test (including scinticisternography) is particularly successful at predicting the response to surgery, emphasizing the importance of recognizing the "typical" clinical presentation.

CSF Leaks

The second major indication for scinticisternography is in the identification of a CSF leak. Such leaks can occur after skull fractures, destructive infections or neoplasms, surgical interventions, and radiation therapy. This can lead to repeated

Nuclear Cisternogram
Figure 10. Normal pressure hydrocephalus (NPH). Radionuclide cisternography shows early, persistent ventricular penetration with absence of progression along the convexities indicating an obstructed sub-arachnoid space. (Case provided by Dr. W.D. Leslie.)

episodes of meningitis and requires surgical closure of the defect. Scinticisternography can confirm CSF leak by finding high levels of radioactivity in fluid draining from a craniofacial orifice (rhinorrhea or otorrhea). Identifying the anatomical origin often requires multiple projections and positioning of the head to increase the flow.

Intracranial Mass Lesions

The high sensitivity and superb anatomic resolution of conventional neuroimaging (CT and especially MRI) has relegated nuclear medicine methods to a secondary role in the evaluation of intracranial masses. Nuclear medicine's contribution is in characterizing the nature of a known mass lesion, and in well-defined conditions can narrow the differential diagnosis. Numerous reports have suggested that agents such as 18F-FDG, thallium-201, 99mTc-sestamibi, 99mTc-tetrofosmin and pentavalent 99mTc-DMSA can detect primary intra-cranial tumours with sensitivities and specificities that are over 80%. Among these agents, 99mTc-labelled radiopharmaceuticals offer better spatial definition than thallium-201 and have some

Positive Cisternogram

Figure 11. Brain mass lesion with 99mTc-sestamibi uptake. This 39 year old HIV positive man was admitted to hospital with dyspnea and fever in association with Staphylococcus aureus bacteremia and then developed new-onset seizures. A CT scan (left) showed an enhancing mass lesion in the periventricular white matter of the left parietal-occipital lobe (arrow) measuring approximately 3 cm in diameter with peritumoral edema. The radiologic fetatures were most consistent with CNS lymphoma, with toxoplasmosis considered a less likely alternative. SPECT sestamibi brain scanning (right) confirmed increased uptake in the lesion (arrow) further supporting a diagnosis of lymphoma which is almost uniformly sestamibi-avid while toxoplasmosis is usually negative. (Case provided by Dr. W.D. Leslie.)

differences in their distribution (for example, 99mTc-sestamibi normally shows intense pituitary and choroid plexus uptake).

Mass Lesions in AIDS

One established indication is in the differential diagnosis of infectious and neoplastic lesions in immunosupressed subjects with AIDS. Most neoplastic lesions will take up the agents listed above (Fig. 11), while most infectious causes such as toxoplasmosis will not (Fig. 12). The CT and MRI appearance of primary CNS lymphoma and toxoplasmosis can be indistinguishable, but therapy is radically different.

Radiation Necrosis

These radiopharmaceuticals can also distinguish radiation necrosis and tumour persistence or recurrence in areas shown to be abnormal by CT or MRI. Usually radiation necrosis shows little or no tracer uptake, though rare cases have been described with elevated uptake.

Figure 12. Brain mass lesion without 99mTc-sestamibi uptake. This 28 year old man with HIV (CD4 count only 6) presented to hospital with a two week history of gradually progressive left-sided weakness (arm worse than leg) and left homonymous hemianopsia. The patient had declined anti-retroviral therapy, with the result that he had numerous infectious complications from HIV. A CT scan showed decreased attenuation in the right temporal lobe white matter without contrast enhancement, hemorrhage or significant mass effect. An MRI scan (left) showed extensive white matter changes in the right temporal lobe extendng into the right internal and external capsule, the right frontal lobe, the right midbrain and the right cerebellar peduncle. There was no evidence of gadolinium enhancement or mass effect. Differential diagnosis was felt to be most likely progressive multi-focal leukoencepholopathy or non-enhancing lymphoma. Brain SPECT (right) was performed with 99mTc-sestamibi and failed to show any uptake (arrow). This is strong evidence against CNS lymphoma which is typically strongly avid for flow tracers such as sestamibi and thallium. PML is more variable in its appearance, since it can show absent or increased uptake, but is strongly supported by the absence of uptake in this case. The patient's clinical condition deteriorated and he died with a tentative diagnosis of PML without a post-mortem examination. (Case provided by Dr. W.D. Leslie.)

Tumor Grading

PET and SPECT imaging with 18F-FDG, thallium-201, 99mTc-sestamibi or 99mTc-tetrofosmin also seem to offer prognostic information on the behaviour of brain tumours Those with the highest uptake tend to have a higher grade and more aggressive behavior. Early imaging after the initiation of therapy has been reported to be a good predictor of the final therapeutic response, and PET/SPECT is superior to CT or MRI for this purpose.

Somatostatin Receptors

Finally, 111In- or 99mTc-pentetreotide, somatostatin analogues used essentially for the diagnosis of neuroendocrine tumours, can be taken up by the somatostatin receptors found on the cells of gliomas, glioblastomas, meningiomas and possibly schwannomas. These agent cannot cross the intact BBB and will not detect lesions

What Shuntogram

Figure 13. Ventriculo-peritoneal shuntogram. 99mTc-MAA was injected into the subcutaneous reservoir. Immeditae passage into the intracanial tube is observed with reflux of activity into the ventricles after pumping of the reservoir. No activity is seen in the efferent limb immediately inferior to the reservoir indicating distal obstruction at the level of the reservoir valve.

Figure 13. Ventriculo-peritoneal shuntogram. 99mTc-MAA was injected into the subcutaneous reservoir. Immeditae passage into the intracanial tube is observed with reflux of activity into the ventricles after pumping of the reservoir. No activity is seen in the efferent limb immediately inferior to the reservoir indicating distal obstruction at the level of the reservoir valve.

with somatostatin receptors that do not disturb the BBB, such as low-grade gliomas. Tumours which are outside of the BBB, such as meningiomas, consistently concentrate the tracer.

Conclusions

The full scope of nuclear medicine's role in the clinical evaluation of brain disorders is still evolving. Some applications have emerged as clearly useful, but others must be used in a prudent manner until there is additional documentation of their efficacy. Research in psychiatry, neurology and nuclear imaging should help us to characterise diseases affecting the human brain at their most fundamental, molecular level. Nuclear medicine imaging techniques are uniquely suited to the in vivo, non invasive measurement of such parameters. Neuropsychiatric nuclear medicine is probably at the threshold of an explosion in its clinical use.

Frequently Asked Questions (FAQs)

What is a "shuntogram"?

A "shuntogram" is a nuclear medicine procedure used in patients who have previously had a ventriculo-peritoneal or venticulo-atrial shunt inserted. The tubing may become obstructed at different levels (intracranial segment, extracranial subcutaneous tubing, reservoir, reservoir exit valve, or subcutaneous tubing to the peritoneal cavity or left atrium). It is simple to inject radioactive tracer directly into the reservoir and then follow its migration. Depending upon shunt design, the reservoir may optionally be "pumped" to facilitate CSF movement. The pattern of CSF flow can be used to deduce the site of obstruction, if any (Fig. 13).

How is a "brain death" study done and what is its accuracy?

The development and evolution of the concept of brain death has been necessary due to our technologic advances in medical care and organ transplantation. The

Brain Death Scan Vasc Flow Study

Figure 14. Brain death. This young woman sustained anoxic brain injury while recovering from emeregency surgical replacement of a mitral valve prosthesis infected with Staphylococcus aureus. Cardiorespiratory arrest led to 18 minutes of anoxia before circulation could be restored and she remained in a comatose state. Neurological assessment of brain stem function strongly suggested brain death, but a confirmatory test was requested before discontinuation of support. The patient was injected with 99mTc-ECD in the intensive care unit and scanned in Nuclear Medicine shortly thereafter. The scan demonstrates only scalp and facial flow with an "empty skull". There is absent perfusion of the cerebral cortex and brain stem. (Case provided by Dr. W.D. Leslie.)

Figure 14. Brain death. This young woman sustained anoxic brain injury while recovering from emeregency surgical replacement of a mitral valve prosthesis infected with Staphylococcus aureus. Cardiorespiratory arrest led to 18 minutes of anoxia before circulation could be restored and she remained in a comatose state. Neurological assessment of brain stem function strongly suggested brain death, but a confirmatory test was requested before discontinuation of support. The patient was injected with 99mTc-ECD in the intensive care unit and scanned in Nuclear Medicine shortly thereafter. The scan demonstrates only scalp and facial flow with an "empty skull". There is absent perfusion of the cerebral cortex and brain stem. (Case provided by Dr. W.D. Leslie.)

current definition of brain death describes the clinical state of totally absent central nervous system function in a hemodynamically stable, normothermic, nonintoxicated patient, which is followed inevitably by cardiovascular collapse. Diagnosis is based on coma, absent brain stem reflexes, and apnea (despite a documented pCO2 of > 60 mm Hg), with selective use of confirmatory testing. Under normal conditions, the presence of an electrocerebrally inactive EEG is a valid indicator of brain death. However, in some situations (such as in the presence of high doses of sedative/hypnotic medications), the EEG can be unreliable. Complete cessation of cerebral perfusion as demonstrated by brain scintigraphy, transcranial Doppler sonography, or cerebral panangiography is also evidence of brain death. Contrast angiography is least desirable since it is invasive and the contrast exposure can threaten subsequent organ harvesting. Numerous studies confirm the reliability of brain scintigraphy in the diagnosis of brain death. The great majority of patients (98.5% in one large series) judged to be brain dead by other criteria show absent brain blood flow ("empty skull") on "conventional" radionuclide angiography or rCBF imaging (Fig. 14). Even if an initial examination shows some preserved blood flow, a repeat study 72 hours later is usually diagnostic. There are no reported cases of neurological recovery following a definite scintigraphic diagnosis of brain death.

Can rCBF studies be used in brain activation studies?

Activation studies involve having the patient use the function being studied while changes in rCBF are measured as a marker of the structures being activated or inhibited. The design of such protocols is a highly specialised field calling for close collaboration between imaging specialists, statisticians, and clinical scientists from

Nuc Med Cisternogram

Figure 15. Activation study. Baseline 99mTc-ECD SPECT scans were obtained at rest with eyes closed. The patient was then exposed to bright, colored, rapidly moving geometric shapes for 10 seconds prior to and for 3 minutes after a second injection of 99mTc-ECD. Statistical maps were obtained after spatially coregistering the studies, subtracting the baseline from the activation study and superimposing activated voxels (subtraction value more than 2 SD over the mean) on an MRI atlas. Note intense activation of calcarine visual cortex regions.

Figure 15. Activation study. Baseline 99mTc-ECD SPECT scans were obtained at rest with eyes closed. The patient was then exposed to bright, colored, rapidly moving geometric shapes for 10 seconds prior to and for 3 minutes after a second injection of 99mTc-ECD. Statistical maps were obtained after spatially coregistering the studies, subtracting the baseline from the activation study and superimposing activated voxels (subtraction value more than 2 SD over the mean) on an MRI atlas. Note intense activation of calcarine visual cortex regions.

neurology, psychiatry and psychology. Presently, fMRI, by virtue of its high temporal and spatial resolutions, is considered by many to be the tool of choice for such studies, and in large measure has displaced PET for this purpose. However, SPECT with either 99mTc-HMPAO or 99mTc-ECD, has an advantage over both of these methods: as these radiopharmaceuticals "capture" the distribution of cerebral blood flow at the time of injection and allow for delayed imaging, the patient can undergo complex activation protocols using instrumentation that either cannot be brought close to the powerful magnetic field of a fMRI scanner or that cannot be physically accommodated by PET or fMRI systems. In SPECT, the subject can be prepared with a simple intravenous line and then submitted to the activation protocols during which she/he is injected with the radiopharmaceutical at the moment of maximal stimulation of the structures involved in the task (Fig. 15). Later, after completion of other measurements, the patient can be brought to the imaging laboratory for the acquisition phase of the study. SPECT rCBF is the only non-invasive approach capable of this type of intervention.

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  • ilmari
    Is cistern an amino acid?
    2 years ago

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