Offering Sharper Tools for Neurological Disorders
While most neurological research is still in early development, SPECT and PET-based strategies already have a clinical impact for patients with Parkinson’s disease (PD) and epilepsy. Recent advancements have refined diagnosis and treatment planning to raise confidence that therapy will lead to positive outcomes.
Molecular imaging—especially PET using the radioligand fluorine-18 fluorodopa—has been crucial to understanding cerebral dopamine deficiency and movement disorders including PD and deficient cerebral dopamine production.
PET and SPECT performed with numerous dopamine-related radiopharmaceutical probes have confirmed post-mortem findings of nigrostriatal dopamine nerve terminal in not only PD but also in Parkinson plus syndromes, such as multiple system atrophy and progressive supranuclear palsy.
In January, the FDA approved the first molecular imaging agent, Iodine-123 ioflupane (DaTscan, GE Healthcare), to assist in the evaluation of adult patients with suspected Parkinsonian syndromes. The SPECT agent is approved in 34 countries outside the U.S.
DaTscan seeks to detect the presence of dopamine transporters to distinguish between patients with PD or Parkinson-plus syndromes on the basis of their decreased transporter activity from patients with essential tremor or dystonia, which are conditions associated with normal transporter functions.
Interim results of a multicenter randomized trial, presented at SNM 2011, suggest that clinicians had greater confidence in their diagnoses for the 119 patients who underwent I-123 Ioflupane studies than the 136 patients who did not receive the procedure. DaTscan had a significant effect on patient management, modifying the treatment regime for 49 percent of patients evaluated with SPECT in the three months following scanning, compared with modifications for 31 percent of the subjects who did not receive the scans.
The agent may reduce the uncertainty of diagnosis for patients with few clinical abnormalities despite evidence of decreased dopamine production in early stage PD or parkinsonism. However, the agent cannot distinguish PD from Parkinson-plus syndromes, says Nicolaas I. Bohnen, MD, PhD, an associate professor of radiology and neurology at the University of Michigan in Ann Arbor.
Without access to DaTscan, Levodopa—the primary pharmaceutical treatment for PD—played double duty to diagnostically distinguish between PD and other mimicking conditions, Bohnen says. The agent often is prescribed for patients thought to have one of the maladies. A good therapeutic response to Levodopa helps support the diagnosis of PD while a lack of response is observed among patients with essential tremor and similar conditions.
Bohnen predicts experienced diagnosticians will order DaTscan for cases that continue to be problematic after initial treatment. Primary care practitioners, who often are the first physicians to examine suspected PD cases, may now be more likely to render a preliminary diagnosis themselves with DaTscan.
Radio-labeled dopaminergic ligands for PET imaging are in the midst of human trials as part of the FDA new drug application approval process. F-18 DTBZ, an agent developed by Avid Pharmaceuticals, shows promise.
The profound and sometimes debilitating disease stems from abnormal neuronal circuitry originating at a nidus, a small area of malfunctioning tissue in the brain. Neurons around the nidus lack normal neurological pathways to brain tissue. When they fire, their electrical energy can manifest itself as a seizure, says James M. Mountz, MD, PhD, chief of nuclear medicine at the University of Pittsburgh Medical Center.
Epilepsy is commonly diagnosed, Mountz says, through a physical exam, anatomic MRI and long-scalp video EEG involving a week-long hospitalization to detect the frequency, intensity and point of origin of the seizures.
Molecular imaging is reserved for patients who have a normal MRI despite persistent epileptic episodes. It also is ordered when seizures continue despite antiepileptic medication. Under these conditions, clinical interest turns toward localizing the anatomic point of origin for the disease to surgically excise the epileptogenic tissue causing the seizures.
Fluorine-18 FDG-PET and Tc-99m-ethyl cysteinate dimer (ECD) or Tc-99m HMPAO are performed in the interictal period between seizures to lateralize and localize the focus. However, ictal studies also can be performed. Precise localization with non-invasive molecular imaging is integral to a successful temporal lobectomy, Mountz says. Some hospitals do not perform the procedures because their neurosurgeons lack confidence in PET and SPECT to provide adequate presurgical guidance.
During the interictal phase, epileptic foci exhibit relatively low FDG uptake indicative on PET of its lower glucose metabolism rate than surrounding tissue. Seizure sites are characterized by a 15 percent or greater reduction in FDG uptake than normal brain tissue, notes William H. Theodore, MD, chief of the clinical epilepsy section at the National Institutes of Health.
ECD SPECT and HMPAO SPECT both measure cerebral blood flow to map synaptic neuronal activity. The epileptogenic foci have relatively low blood flow compared with normal brain matter during the interictal phase.
Roughly 20 percent of FDG-PET exams are positive for patients with negative MRI or negative SPECT exams. Interical FDG-PET can detect foci as small as 4 cm2, compared with 8 cm2 for the best resolution possible from SPECT with either of the two probes, Theodore says. But PET is impractical for ictal imaging when the amount of blood flowing around the focus rises rapidly during seizures to increase its conspicuity on SPECT.
Timing is everything when attempting to capture such data. Mountz made Tc-99m ECD his department’s preferred choice for SPECT because it stays lipophilic for hours in an automatic injector at the catheterized patient’s bedside, while the staff awaits the appropriate moment for administration. The probe is trapped in the cerebral region of interest, giving the clinician several hours to perform the scan.
Mountz utilizes the SISCOM protocol, initially developed by Neurologist Elson So, MD, et al at Mayo Clinic in Rochester, Minn., which features interictal-to-ictal SPECT image subtraction and fusion with anatomic MRI. The combination improved on the side-by-side visual comparison of interictal and ictal scans for localizing temporal lobe foci before lobectomy.
The Mayo researchers introduced STATISCOM, the successor to SISCOM several years later. In addition to subtraction, STATISCOM performs a pixel-to-pixel analysis comparing the patient’s imaging data with a digital library of SPECT temporal lobe studies performed on normal volunteers. The new method eliminates the effects of technical, patient positioning and biological variations.
In a 2010 blinded comparison of the two protocols, STATISCOM led to more consistent interpretations than SISCOM from clinician-to-clinician and scan-to-scan in their evaluation of studies from 87 consecutive patients who had ictal SPECT studies and subsequent temporal lobectomy and 11 healthy volunteers (Neurology 2010;4(1):70-76). A hyperperfused focus was detected for 84 percent of the patients on the basis of their STATISCOM studies compared with 66 percent for SISCOM.
More importantly, STATISCOM correctly identified whether the temporal lobe seizure focus was located in the mesial or misocortical tissue for temporal lobe seizure onset for 68 percent of patients with STATISCAN compared with 24 percent with SISCOM.
“In other words, STATISCOM can better detect the location of the detonator of seizures of the temporal lobe,” So says.
The ability to establish this distinction had a significant effect on the surgical success rate, he notes. The study found 80 percent of the patients were seizure-free after surgery when the focal detonator was identified from the subtraction SPECT images. Only 53 percent of the patients were seizure-free when the detonator was not identified.
“The more confidence we have with presurgical planning; the more patients go ahead with surgery and get cured,” says Mountz.
Molecular imaging—especially PET using the radioligand fluorine-18 fluorodopa—has been crucial to understanding cerebral dopamine deficiency and movement disorders including PD and deficient cerebral dopamine production.
PET and SPECT performed with numerous dopamine-related radiopharmaceutical probes have confirmed post-mortem findings of nigrostriatal dopamine nerve terminal in not only PD but also in Parkinson plus syndromes, such as multiple system atrophy and progressive supranuclear palsy.
In January, the FDA approved the first molecular imaging agent, Iodine-123 ioflupane (DaTscan, GE Healthcare), to assist in the evaluation of adult patients with suspected Parkinsonian syndromes. The SPECT agent is approved in 34 countries outside the U.S.
DaTscan seeks to detect the presence of dopamine transporters to distinguish between patients with PD or Parkinson-plus syndromes on the basis of their decreased transporter activity from patients with essential tremor or dystonia, which are conditions associated with normal transporter functions.
 | |
| A normal DaTscan (left), suggesting essential tremor, shows characteristic “mirrored comma” appearance of tracer distribution in the striata. Dopaminergic neurons are intact or not affected. Abnormal DaTsan (right) indicates possible Parkinsonian syndrome from circular “period” or oval appearance of the striata with reduced image intensity in one or both hemispheres. Image source: GE Healthcare |
The agent may reduce the uncertainty of diagnosis for patients with few clinical abnormalities despite evidence of decreased dopamine production in early stage PD or parkinsonism. However, the agent cannot distinguish PD from Parkinson-plus syndromes, says Nicolaas I. Bohnen, MD, PhD, an associate professor of radiology and neurology at the University of Michigan in Ann Arbor.
Without access to DaTscan, Levodopa—the primary pharmaceutical treatment for PD—played double duty to diagnostically distinguish between PD and other mimicking conditions, Bohnen says. The agent often is prescribed for patients thought to have one of the maladies. A good therapeutic response to Levodopa helps support the diagnosis of PD while a lack of response is observed among patients with essential tremor and similar conditions.
Bohnen predicts experienced diagnosticians will order DaTscan for cases that continue to be problematic after initial treatment. Primary care practitioners, who often are the first physicians to examine suspected PD cases, may now be more likely to render a preliminary diagnosis themselves with DaTscan.
Radio-labeled dopaminergic ligands for PET imaging are in the midst of human trials as part of the FDA new drug application approval process. F-18 DTBZ, an agent developed by Avid Pharmaceuticals, shows promise.
MI and epilepsy treatment planning
Likewise, molecular imaging plays an important role in planning surgical remedies, especially for patients with intractable epilepsy that does not respond to antiepileptic drug treatment.The profound and sometimes debilitating disease stems from abnormal neuronal circuitry originating at a nidus, a small area of malfunctioning tissue in the brain. Neurons around the nidus lack normal neurological pathways to brain tissue. When they fire, their electrical energy can manifest itself as a seizure, says James M. Mountz, MD, PhD, chief of nuclear medicine at the University of Pittsburgh Medical Center.
Epilepsy is commonly diagnosed, Mountz says, through a physical exam, anatomic MRI and long-scalp video EEG involving a week-long hospitalization to detect the frequency, intensity and point of origin of the seizures.
Molecular imaging is reserved for patients who have a normal MRI despite persistent epileptic episodes. It also is ordered when seizures continue despite antiepileptic medication. Under these conditions, clinical interest turns toward localizing the anatomic point of origin for the disease to surgically excise the epileptogenic tissue causing the seizures.
Fluorine-18 FDG-PET and Tc-99m-ethyl cysteinate dimer (ECD) or Tc-99m HMPAO are performed in the interictal period between seizures to lateralize and localize the focus. However, ictal studies also can be performed. Precise localization with non-invasive molecular imaging is integral to a successful temporal lobectomy, Mountz says. Some hospitals do not perform the procedures because their neurosurgeons lack confidence in PET and SPECT to provide adequate presurgical guidance.
During the interictal phase, epileptic foci exhibit relatively low FDG uptake indicative on PET of its lower glucose metabolism rate than surrounding tissue. Seizure sites are characterized by a 15 percent or greater reduction in FDG uptake than normal brain tissue, notes William H. Theodore, MD, chief of the clinical epilepsy section at the National Institutes of Health.
ECD SPECT and HMPAO SPECT both measure cerebral blood flow to map synaptic neuronal activity. The epileptogenic foci have relatively low blood flow compared with normal brain matter during the interictal phase.
Roughly 20 percent of FDG-PET exams are positive for patients with negative MRI or negative SPECT exams. Interical FDG-PET can detect foci as small as 4 cm2, compared with 8 cm2 for the best resolution possible from SPECT with either of the two probes, Theodore says. But PET is impractical for ictal imaging when the amount of blood flowing around the focus rises rapidly during seizures to increase its conspicuity on SPECT.
Timing is everything when attempting to capture such data. Mountz made Tc-99m ECD his department’s preferred choice for SPECT because it stays lipophilic for hours in an automatic injector at the catheterized patient’s bedside, while the staff awaits the appropriate moment for administration. The probe is trapped in the cerebral region of interest, giving the clinician several hours to perform the scan.
Mountz utilizes the SISCOM protocol, initially developed by Neurologist Elson So, MD, et al at Mayo Clinic in Rochester, Minn., which features interictal-to-ictal SPECT image subtraction and fusion with anatomic MRI. The combination improved on the side-by-side visual comparison of interictal and ictal scans for localizing temporal lobe foci before lobectomy.
The Mayo researchers introduced STATISCOM, the successor to SISCOM several years later. In addition to subtraction, STATISCOM performs a pixel-to-pixel analysis comparing the patient’s imaging data with a digital library of SPECT temporal lobe studies performed on normal volunteers. The new method eliminates the effects of technical, patient positioning and biological variations.
In a 2010 blinded comparison of the two protocols, STATISCOM led to more consistent interpretations than SISCOM from clinician-to-clinician and scan-to-scan in their evaluation of studies from 87 consecutive patients who had ictal SPECT studies and subsequent temporal lobectomy and 11 healthy volunteers (Neurology 2010;4(1):70-76). A hyperperfused focus was detected for 84 percent of the patients on the basis of their STATISCOM studies compared with 66 percent for SISCOM.
More importantly, STATISCOM correctly identified whether the temporal lobe seizure focus was located in the mesial or misocortical tissue for temporal lobe seizure onset for 68 percent of patients with STATISCAN compared with 24 percent with SISCOM.
“In other words, STATISCOM can better detect the location of the detonator of seizures of the temporal lobe,” So says.
The ability to establish this distinction had a significant effect on the surgical success rate, he notes. The study found 80 percent of the patients were seizure-free after surgery when the focal detonator was identified from the subtraction SPECT images. Only 53 percent of the patients were seizure-free when the detonator was not identified.
“The more confidence we have with presurgical planning; the more patients go ahead with surgery and get cured,” says Mountz.