MRSI allows for evaluation of heterogeneous lesions with areas of proliferating tumor and necrosis, cysts, hemorrhage or edema, and adjacent normal-appearing brain tissue (9). Proton MRS cannot supplant biopsy but may be of help in guiding brain biopsy (27,32).
Previous studies utilizing MRSI have suggested that it is possible to separate infiltrative tumors from circumscribed lesions such as metastases. Infiltrative processes such as high grade astrocytomas demonstrate abnormal NAA/Cho ratios not only in the contrast-enhancing portions of the tumor, but also in the surrounding brain tissue, perhaps a sign of tumor infiltration (9) (Fig. 4). In contrast, metastases and other circumscribed lesions such as abscesses (33) or meningiomas (34) do not show severely abnormal NAA/Cho ratios outside the lesion (Fig. 5). The area of vasogenic edema surrounding focal lesions may yield a decrease in NAA/Cho ratio but without a significant increase in Cho/Cr. The area adjacent to an encapsulated abscess may show increased lactate and decreased NAA.
Extra-axial tumors, such as meningiomas and metastases, usually displace neuronal tissue and hence show very low levels or absence of NAA (2,6,9,30). Some NAA may be seen on the spectra due to inclusion of adjacent normal brain tissue in the volume of interest being sampled, a partial volume effect. This phenomenon is common when using SVS in small lesions or near the margins of a lesion in MRSI. Like other tumors, meningiomas and metastases show increased Cho levels (30). Meningiomas may show the presence of alanine (35-37). A reported case (38) has shown an elevated resonance at 2.05 ppm of an unidentified compound, which is not NAA, in a cystic metastasis from mucinous adenocarcinoma (Fig. 5).
New contrast-enhancing lesions that appear at the site of a previously identified and treated primary intracranial neoplasm present a significant diagnostic dilemma. MRS may be useful in the differentiation of tumor recurrence from radiation necrosis (31,39). Radiation changes include decreased NAA, Cho, and Cr resonances compared with normal brain tissue. Radiation necrosis may also show a broad resonance between 0 to 2 ppm, reflecting cellular debris containing lipids, lactate, and amino acids (6). However, coexistent viable tumor and radiation necrosis may be difficult to differentiate. 2D-CSI spectroscopy has been shown to be able to differentiate recurrent tumor from radiation injury, demonstrating significantly higher Cho/NAA and Cho/Cr ratios in recurrent tumor compared with radiation injury and normal-appearing white matter (39). A recent study utilizing MRS in posterior fossa tumors demonstrated significantly elevated Cho/Cr and Cho/NAA ratios in recurrent tumors following chemotherapy or radiation (15).
In a study evaluating patients with lung cancer who had received whole brain radiation therapy, MRS detected a decline in the whole brain NAA even when MMSE scores were unchanged, suggesting that MRS may be a more sensitive measure of radiation injury (40).
Acute multiple sclerosis (MS) lesions show an initial reduction in NAA which has been shown to recover partly over time. Contrast-enhancing lesions also are likely to show increased Cho and lipids, which are myelin breakdown products (2,41). Chronic MS lesions show reduced NAA, particularly in T1 hypointense lesions (42), which may also show increased myo-inositol, possibly indicating gliosis (41).
MRS studies have revealed spectral changes in gray matter, even though cortical lesions are seldom observed on MRI (41). More significantly, recent MRS studies indicate that normal-appearing white matter on MRI may display regional increases in choline and lipids (41,43). Reduction in NAA in the normal-appearing white matter may provide a better correlation with functional impairment than the number of T2 hyperintense lesions (44). Thus, MRS may be used for detection of axonal damage and demyelination in MS, and together with MRI and diffusion tensor imaging (DTI) (45), may provide a powerful measure to monitor MS evolution (46).
Neuropsychiatric systemic lupus erythematosus (NP-SLE) occurs in 25-70% of patients with lupus and is associated with increased morbidity and mortality (47). The clinical manifestations of NP-SLE include psychosis, stroke, and epilepsy, in addition to more subtle symptoms such as headache and neurocognitive dysfunction (48). NP-SLE may present with seizures, movement disorders, altered consciousness, stroke, and coma (49). Some previous studies, mainly using single-voxel spectroscopy (SVS), have demonstrated a decrease in NAA/Cr and an increase in Cho/Cr in the white matter and basal ganglia of NP-SLE patients as compared with those of normal healthy volunteers (50-53).
In a case report, increased lactate was detected in lesions of acute disseminated encephalomyelitis (ADEM) (55). Low levels of NAA on initial MRS were reported in a case of ADEM with multiple transient brain lesions on MRI (56). At final follow-up, neurologic examination and brain MRI findings and NAA levels had all recovered to normal. In contrast to other demyelinating diseases such as MS or leukodystrophy, choline levels were normal.
Spectroscopic abnormalities have been observed in neurologically normal HIV patients or those with normal MRI results (57-59). Increases in choline and myo-inositol are seen in virtually all cases of HIV infection (59,60), even in the early asymptomatic cases (61). Neurologically asymptomatic HIV patients have minimal or no change in NAA or NAA/Cr (58,61), but HIV dementia is associated with a decrease of NAA and NAA/Cr, especially in those with severe dementia (61). NAA can be used as a non-invasive measure of neuronal loss in patients with HIV disease (62).
Increased Cho/Cr and mI/Cr, and reduced NAA/Cr can be seen in progressive multi-focal leukoencephalopathy (PML) (1). This, however, is a non-specific finding as such a pattern of abnormal metabolic ratios may be seen in other diseases.
A lipid/lactate resonance and absence of other metabolites is seen in toxoplasmosis. A similar increase in lipid and lactate to that seen in toxoplasmosis may also be seen in necrotic portions of lymphoma and other tumors, but solid tumor in lymphoma shows increased Cho levels (1,60,63). However, there is an overlap between the spectral patterns of toxoplasmosis and primary CNS lymphoma (60,64).
Another use of proton MRS is in the non-invasive differentiation of brain abscess from other cystic lesions such as necrotic tumors. MRS may show an absence of normal metabolites in the central cystic portion of a medically untreated abscess, with resonances corresponding to acetate (1.9 ppm), lactate (1.3 ppm), pyruvate, and succinate (2.4 ppm) (end products of microbial metabolism), amino acids such as valine, leucine, and isoleucine (0.9 ppm) (end products of the action of proteolytic enzymes), alanine (1.5 ppm), and lipids (0.9-1.3 ppm) (8,33) (Fig. 6).
The use of proton MRS in the evaluation of metabolic disease in children is widely documented (11,12,65-78). Although 2D CSI can be used in many disease conditions, traditionally SVS has been the more commonly used technique in the evaluation of metabolic disorders. A full description of all entities is beyond the scope of this review and only the more common diseases are discussed here.
MRI with diffusion weighting is the technique of choice in the evaluation of acute ischemic stroke (7). MRS changes include a decrease in NAA that occurs over several days after the stroke. NAA may pseudonormalize several weeks after the event due to brain atrophy. Lactate rises early after the insult in the acute phase (<24 hours) and may remain high over a long period into the chronic phase (>7 days) (2,6,8).
In cases of global hypoxic-ischemic insults, NAA and lactate levels in gray matter may have prognostic significance (8). In two studies (79,80), high lactate and lipids and low NAA were found in newborns with the worst outcome.
Temporal lobe epilepsy (TLE) is typically evaluated with high resolution MRI studies, which often show hippocampal or mesial temporal sclerosis. In many cases, however, MRI findings may be subtle or inconclusive (6,7). TLE can also be studied by MRS (3,81,82), which has shown reduced NAA representing neuronal loss or dysfunction (2). Lactate may increase in a seizure focus, persist for several hours, and be used as a marker for seizure activity (2,7,11). In the post-ictal period, the presence of lactate is helpful in lateralizing seizure activity (83).
Neurodegenerative disorders are a diverse set of conditions with varied etiologies. Patients with Alzheimer disease show reduced levels of NAA along with a significant increase in myo-inositol (2,4,6,7). Similar changes may be seen in frontotemporal dementia but in a different distribution (4,7). Findings in multi-infarct dementia are non-specific with low levels of NAA; in severe cases, lactate may be present, or myo-inositol may be increased indicating gliosis (4).
MRS has demonstrated a reduction in NAA, a reflection of diffuse axonal injury or metabolic depression. Concentrations of NAA predict cognitive outcome (84). An initial fall and subsequent recovery of NAA in white matter has been noted, suggesting a reversible metabolic derangement. In contrast, NAA concentration in gray matter was found to fall continuously after trauma (85). Elevation of Cho is also noted early after the injury, suggesting an inflammatory response. The elevation in Cho in the gray matter was seen to persist, possibly reflecting ongoing inflammation (85).
In adults, MRS studies have demonstrated metabolic changes in normal-appearing white matter and a correlation between NAA/Cr ratio and severity of head injury (86,87). Similar findings have been seen in neonates and children with significantly lower NAA/Cr ratios in those with poor outcome (88). NAA concentrations can evidently predict long-term neurologic outcome (88). However, a recent case report found an almost complete recovery in NAA in a patient with diffuse axonal injury (89).
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