Книги по МРТ КТ на английском языке / MR Imaging in White Matter Diseases of the Brain and Spinal Cord - K Sartor Massimo Filippi Nicola De Stefano Vincent Dou

Proton MR Spectroscopy in Metabolic Disorders of the Central Nervous System

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Fig. 13.4a,b. Conventional MRI of two elderly patients (over 70 year of age) with hypertension, loss of memory, previous cerebral transitory ischemic attacks (a, b) and their proton MR spectra coming from voxels localized to the deep periventricular white matter (square and circle, respectively). The volume of interest of the multi-voxel spectroscopic examination is shown in both images. In both patients, conventional MRI shows periventricular lesions suggestive of leukoaraiosis. In one patient (right), there is high resonance intensity of lactate (LA) in the proton spectrum. This patient was subsequently diagnosed as having MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes), despite a strokelike episode never being reported in the clinical history. The other patient (left) does not show changes in lactate resonance intensity and was subsequently diagnosed as having initial cerebrovascular dementia

rons and their processes in mature brains decreases in this metabolite are interpreted as an index of axonal damage (Matthews et al. 1998; Bjartmar et al. 2002). This is most likely due to a secondary axonal dysfunction and/or loss, suggestive of the relevance of neuro-axonal damage in both demyelinating and dysmyelinating disorders. Recent studies suggest that NAA may provide a surrogate measure that can be relevant to clinical disability in patients with several white matter disorders (de Stefano et al. 2000b).

13.3

Diagnostic-Specific MRS Changes in WM Disorders

As already mentioned, most of the metabolic changes detected in white matter disorders are not diseasespecific. However, in some specific circumstances, proton MRS can offer information useful for the differential diagnosis beyond what is currently available in routine clinical use or can even provide typical brain metabolic patterns characteristic of a given disorder.

As proton MRS can provide a specific and accurate interpretation of the pathological processes un-

derlying the white matter lesions, this can be used to differentiate brain lesions appearing similar on MRI. Different pathophysiology might be seen, for example, in hypoxic-ischemic white matter lesions with a complex pathogenesis existing in rare metabolic conditions such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) (Dubeau et al. 2000). Patients with MELAS can show very large increases in levels of brain parenchymal Lac in the area of the acute stroke (Fig. 13.3). Also, large increases in brain parenchymal Lac can be found in the brain tissue even in patients without history of acute ischemic attack (Fig. 13.4). Thus, proton MRS findings can allow for an accurate differentiation of this maternally inherited condition from any other acute and chronic cerebrovascular disorders.

In other very rare metabolic disorders such as ethylmalonic encephalopathy (Grosso et al. 2004) and cerebrotendinous xanthomatosis (de Stefano et al. 2001), the findings of diffuse brain mitochondrial impairment have strongly contributed to the interpretation of the complex pathogenetic mechanisms of these disorders. In the first case (Grosso et al. 2004), the diffuse MRS increase in brain Lac detected in a multi-voxel MRSI study (Fig. 13.5) was underlying a primary mitochondrial disorder, as later demonstrated by biochemical and genetic studies (Coburn

2004).In the latter condition (de Stefano et al.2001), single-voxel proton MRS data (Fig. 13.6) add to morphological and biochemical evidence of mitochondrial dysfunction (Federico et al. 1991; Dotti et al. 1995) (probably secondary to the toxic effect of high cholestanol and/or bile alcohol levels), suggesting the presence of a diffuse impairment of mitochondrial oxidative metabolism in patients with cerebrotendinous xanthomatosis.

There are also conditions in which proton MRS can provide typical brain metabolic patterns able to address the diagnosis. One example of a disease in which MRS provides a diagnostic pattern is a spongiform leukoencephalopathy known as Canavan disease. In this disorder, the deficiency of the enzyme aspartoacylase (which breaks down NAA) is responsible for abnormally high levels of NAA in the brain, which can be considered pathognomonic (Austin et al. 1991; Grodd et al. 1990). Another characteristic metabolic MRS pattern has been shown recently in other spongiform leukoencephalopathies such as megalencephalic cystic leukoencephalopathy (MCL)

(Hanefeld et al. 1993; van der Knaap et al. 1995) and childhood ataxia with diffuse CNS hypomyelination (CACH, also called vanishing white matter disease) (Tedeschi et al. 1995; van der Knaap et al. 1997). In these disorders, conventional MRI findings of extensive white matter abnormalities with sparing of central brain structures are seen together with a peculiar MRS pattern. This is characterized by the almost complete disappearance of all normally detected metabolites in the white matter, presence of small increases in Lac and sparing of gray matter that is structurally and metabolically normal. In MCL, although MRS abnormalities tend to be more pronounced with increasing age, these are generally mild and the frontal white matter is significantly less involved than other white matter regions (Fig. 13.7). In patients with CACH disease, increases in glucose resonance intensities may also be present. This MRS metabolic profile is perhaps due to little brain white matter tissue left and the great increase in extracellular spaces. In both diseases, white matter increases in Lac resonance intensities are small and inconstant

suggesting that they might be due to a disturbance in Lac removal after accumulation of foamy macrophages in pathologically active areas more than to a primary impairment of the oxidative metabolism. In any case, these MRS patterns appear to be sufficiently specific to differentiate these spongiform leukoencephalopathies from other white matter disorders with similar clinical and radiological appearance.

As mentioned before, distinctive white matter changes can also be seen in a number of mitochondrial encephalopathies (Bardosi et al. 1987;

Burgeois et al. 1992; Leutner et al. 1994; Nakai et al. 1994). Significant decreases in Cho have been observed in some mitochondrial encephalopathies even in the absence of white matter abnormality on conventional MRI (Arnold and Matthews 1996; de Stefano et al. 1995c). These are likely related to be associated vacuolar myelinopathy which has been described pathologically in Kearns-Sayre syndrome and some of its variance (Matthews et al. 1993). Proton MRS studies also show decrease in NAA and increases in Lac relative resonance intensities in primitive mitochondrial encephalopathies (Matthews et al. 1993; Arnold and Matthews

1996). The latter, in particular, represents an important biochemical marker of these disorders.Lac levels are transiently increased in a number of acute pathological conditions associated with inflammatory cells

(Arnold et al. 1992; Petroff et al. 1992; Arnold and Matthews 1996), but extensive pathological increases in Lac both within and outside of MRI lesions may be indicative of widespread energy failure associated with mitochondrial dysfunction (Matthews et al. 1993; de Stefano et al. 1995c). Accordingly, classical primitive mitochondrial such as pyruvate dehydrogenase deficiency, Leigh’s and Kearns-Sayre syndromes show diffuse increases in brain parenchymal Lac (Fig. 13.8).

Other rare metabolic conditions also may provide diagnostic-specific proton MRS findings. In the phenylketonuria, patients show a specific peak due to the elevated phenylalanine and proton MRS can be used in patients with this metabolic disorder to follow the influx of phenylalanine from blood into brain tissue as well as to monitor the response of diet therapy (Kreis et al. 1995; Pietz et al. 2003). In the leukoencephalopathy associated with the disturbance of the metabolism of the polyols (van der Knaap et al. 1999), the diffuse decrease of all normally detected metabolites is associated with the increases of arabitol and sorbitol in both white and grey matter regions. In maple syrup disease, a relatively specific broad peak is detectable at 0.9 ppm.This region of the spectrum is usually attributed to lipids, but in maple syrup disease is believed to represent resonances of methyl protons from branched-chain amino-acids

and branched-chain alpha-keto acids that accumulate as a result of defective oxidative decarboxylation of leucine, isoleucine and valine (Jan et al. 2003).Also proton MRS studies on patients with Niemann-Pick type C disease have shown increased resonance intensity of the lipid region of the spectrum (Fig. 13.9), probably due, in this case, to a defective metabolism of cholesterol with ceramide accumulation (Sylvain et al. 1994; Battisti et al. 2003). In both maple syrup and Niemann-Pick type C disease, the abnormal broad peak detectable at 0.9 ppm seem to decrease with appropriate therapy (Jan et al. 2003; Sylvain et al. 1994).

Finally, specific metabolic syndromes have recently been revealed by using proton MRS. This is the case of the creatine deficiency syndromes, which include defects in the guanidinoacetate methyltransferase and in the arginine-glycine amidinotransferase (Stockler et al. 1994; Schulze 2003), and the X-linked creatine deficiency syndrome (Bizzi et al. 2002). In the first two forms of the diseases, the Cr resonance intensity is undetectable in the brain on proton MRS, but cerebral levels of Cr do increase after creatine supplementation. In the X-linked form of creatine deficiency, as the metabolic defect is due to the transport of creatine into the central nervous system, patients are unresponsive to treatment and the Cr resonance intensity levels are unchanged after creatine supplementation (Fig. 13.10). Another

condition with very specific proton MRS spectrum is the unique case of a child with minor developmental delay and absence of cerebral NAA, in whom the most prominent peak of proton MRS at 2.02 ppm was undetectable (Martin et al. 2001). Both creatine deficiency syndromes and the absence of NAA are characterized by mild or absent abnormalities on conventional MRI suggesting the unique potential of proton MRS in revealing metabolic abnormalities in MRI normal-appearing tissue.

13.4

Metabolic Changes Beyond MRI Lesions

As extensively reported in patients with multiple sclerosis (Fu et al. 1998), also in patients with both hereditary and acquired white matter disorders the detection of brain metabolic changes is not restricted to lesions (de Stefano et al. 2000b). Metabolic changes in normal-appearing white matter are usually less severe than those found inside the lesions and mostly consist in decreases in NAA and increases in Lac and Cho.

Because axons project through lesion volumes,any axonal dysfunction or loss should extend well beyond the borders of a lesion and into normal-appearing white matter, as an expression of anterograde and

retrograde axonal degeneration. Thus, it should not be surprising that decreases in NAA can be observed beyond the borders of MS lesions as defined by T2- weighted MRI. The analysis of serial multi-voxel proton MRSI studies from patients who present with large,solitary demyelinating lesions offers special opportunities in this respect. These studies showed that decreases in NAA can be seen well outside the demyelinating lesion (de Stefano et al. 1995a) and can be transiently evident even in homologous voxels of the hemisphere contralateral to the lesion (de Stefano et al. 1999).

Increases in Lac resonance intensities in the nor- mal-appearing brain tissue represent a biochemical characteristic of mitochondrial encephalopathies. As mentioned before, Lac levels are transiently increased in a number of acute pathological conditions associated with inflammation (Arnold et al. 1992; Petroff et al. 1992), but pathological increases in Lac outside of MRI lesions may be indicative of widespread mitochondrial impairment (Matthews et al. 1993; de Stefano et al. 1995c).

Increases in Cho also could be detected in the nor- mal-appearing WM in several WM conditions. This is the case, for example, in patients with rare, inherited diseases such as adrenoleukodystrophy (Kruse et al. 1994) and adult-onset Krabbe disease (de Stefano et al. 2000a) (Fig. 13.11). In all of these cases, the detec-

a

b

c

Fig. 13.10a–c. Proton brain MR spectra of a patient with X- linked creatine deficiency. The spectra show decreases in creatine resonance intensity (a), which remains unchanged after 3 months of oral creatine monohydrate supplementation at 400 mg/kg/day (b) and after 8 months of supplementation at 800 mg/kg/day (c). (Courtesy of Alberto Bizzi)

tion of metabolic changes in tissue appearing normal on MRI should be interpreted as the first sign of white matter pathology, not yet detectable by conventional MRI.

On the other hand, brain metabolic changes sometimes can be independent of the degree of abnormalities seen on conventional MRI. This can be found, for example, in CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients with mild and severe neurological impairment who can show similar white matter abnormalities on conventional MRI and, respectively, mild and severe brain metabolic abnormalities on multi-voxel proton MRSI (Fig. 13.12). Similarly, a single voxel study showed that this is also valid in other diseases such as in congenital muscular dystrophy where, in a patient

with no central nervous system impairment, the MRS metabolic pattern was normal despite the diffuse white matter abnormalities on conventional MRI (Fig. 13.13). This confirms once again the lack of pathological specificity of the white matter lesions detected on conventional MRI and supports the hypothesis that brain lesions appearing similar on MRI may have a different pathophysiology and, as a consequence, different clinical relevance. In contrast, in both CADASIL and congenital muscular dystrophy as well as in other metabolic disorders cerebral levels of NAA correlated closely to patients’ clinical status (de Stefano et al. 2000b) suggesting that the widespread cerebral neuro-axonal dysfunction and/or loss represents the most relevant mechanism of functional impairment in several metabolic disorders affecting the cerebral white matter.

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13.5 Conclusions

Brain MRS provides chemical-pathological information that has the potential to improve both diagnostic classification and management of patients with metabolic disorders affecting the brain white matter. Metabolic indices provided by proton MRS and MRSI could be sensitive indicators of early neurological involvement, relevant to patients’ clinical status. A more extensive use of a combination of MR modalities including volumetric MRI, MRS and other nonconventional MR techniques might yield a more complete description of the dynamics responsible for pathological changes in this heterogeneous group of disorders and allow a more accurate evaluation of disease progression and response to therapy. A wider use of proton MRS techniques should be encouraged in clinical studies of patients with metabolic disorders.

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