Magnetic resonance imaging (MRI) has significantly contributed to our capabilities of diagnosis multiple sclerosis (MS) since it is able to detect demyelinating lesions in almost 100% of patients. However, there are modest correlations between irreversible disability and white matter lesion load, as measured by T2-weighted MRI scans, which represents the clinicoradiological paradox of MS. We report the case of a patient with MS and few neurological manifestations despite extensive T2 visible morphologic abnormalities. The use of non-conventional MRI techniques, which are more specific in the analysis of the pathological substrate of demyelinating lesions and normal appearing brain matter (both white and gray matter), might assist us to overcome this limitation of conventional MRI.
Magnetic resonance imaging (MRI) has become an essential tool in the diagnosis of multiple sclerosis (MS) since it is able to demonstrate dissemination in space (DIS) and time (DIT) of demyelinating lesions and to rule out alternative diagnosis. Our ability to make an early diagnosis of MS in patients with clinically isolated syndromes (CIS) with the support of conventional MRI techniques has been strongly demonstrated. However, its role as a prognostic marker for disability progression is less clear. This is especially applicable to the T2 lesion volume, where studies have only shown modest clinicoradiological correlations [1-5].
To illustrate the clinico-radiological dissociation of MS, we report the case of a patient of 46 years admitted to our hospital because of a progressive episode of dizziness, gait unsteadiness, and double vision. The patient had previously experienced neither fever nor signs of infection. She denied having contact with animals or having recently received vaccinations. As medical history, she had exclusively suffered an episode of left hemifacial hypoesthesia from which she recovered spontaneously two years ago. In addition, she refused toxic habits or to receive any treatment. She did not refer any other symptoms. The general examination on admission was normal. At neurological examination, left limb hyperreflexia and gait ataxia with positive Romberg sign were observed. We did not identify any nystagmus or ophthalmoparesis despite the binocular diplopia the patient mentioned. Cranial MRI was performed and showed multiple typical demyelinating lesions both in supratentorial and infratentorial regions Figures 1 and 2. These lesions tended to confluence in some localizations. The T2 lesion burden was high and lesions were extensively scattered throughout the periventricular and juxtacortical regions. The corpus callosum and posterior fossa were also affected. In isolation, few of these lesions appeared hypointense on T1-weighted images, and some showed gadolinium-enhancement
enzyme, immunological and serological examinations was normal except for an ESR value of 30 mm/h. The cerebrospinal fluid analysis was also normal, except for the detection of IgG oligoclonal bands not presented in blood, a finding that confirmed the existence of intrathecal IgG synthesis typical of MS. Brainstem relapse in the context of relapsing-remitting MS was diagnosed. The patient received high-dose steroid treatment and experienced a great improvement of her deficits, only persisting mild unsteadiness. Because of the diagnosis of relapsing-remitting MS and the large T2 lesion load, disease modifying therapy was initiated.
MRI is the most sensitive method for revealing demyelinating lesions in the central nervous system (CNS) [
value in predicting the accumulation of disability in MS [1-5]. In the case of our patient, it is remarkable the large T2 lesion load and the minimum clinical activity in terms of relapses and disability progression. Several theories have been proposed in an attempt to explain what is known as clinico-radiological paradox in MS. It is considered that this discordance between clinical and imaging measures is mainly due to the own limitations of the T2 sequence because of its lack of histopathological specificity. Thus, regardless of the stage, MS plaques appear hyperintense on this sequence. Therefore, this finding is not specific and only reflects an increase in tissue concentration of free water, not being able to discern whether the hyperintensity is secondary to oedema, inflammation, demyelination, axonal loss, remyelination and/or reactive gliosis [1-5]. These pathological substrates confer different degrees of neurological impairment, however, all T2 hyperintensities are interpreted in the same way, which explains, at least partially its poor correlation with the irreversible disability of individual patients. Still, we should consider that clinico-radiological dissociation in MS has a multifactorial origin and that this paradox can be explained by other causes such as the presence of lesions in clinically silent regions, no performance of spinal MRI in some cases, underestimation of damage to the normal appearing brain tissue (both white and gray matter) and compensation by cortical adaption [1-5]. Finally, another cause of this discordance could be the utilization of inappropriate clinical rating scales. The limitations of the Expanded Disability Status Scale (EDSS) are well known. They include incomplete coverage of CNS domains, non-linearity and observer bias [
In this context, non-conventional MRI methods such as magnetization transfer imaging (MTI), diffusion-tensor imaging (DTI) and proton MR spectroscopic imaging (H-MRSI) have demonstrated a greater specificity for the study of the heterogeneous pathological substrate of demyelinating lesions. Besides, they may reveal otherwise undetectable tissue damage in MS [11-19]. For all these reasons, their utilization would more precisely define tissue injury and dysfunction, and consequently may more closely predict clinical course and response to therapy.
MTI quantifies the interaction between MRI-visible free water protons and MRI-invisible protons associated with macromolecules (lipids and proteins), providing a measure of tissue integrity, especially myelin, in brain [
With DTI, the three-dimensional diffusion of water molecules is quantified, which in turn can be used to describe the orientation and integrity of fibers tracts, as axons [
H-MRSI reveals metabolic information in particular regions of a tissue. The most prominent peak in the spectrum from brain tissue is N-acetylaspartate (NAA), which is almost exclusively contained within neurons and their processes. Chronic demyelinating lesions are characterized by a reduced concentration of NAA, which reflects the permanent axonal loss [17,18]. In acute plaques has been also seen a decrease in the NAA peak, which may be transient or may represent an irreversible axonal injury, as well as an increase of choline and lactate concentrations associated with an increase in myelin turnover and anaerobic metabolism of inflammatory cells, respectively. In addition, in such plaques has been detected the presence of relatively high lipid peaks as a reliable indicator of active demyelination. Besides, with H-MRSI it was found that the concentration of NAA decreases in normal appearing white matter of patients with MS too [
On the other hand, focal damage in MS can lead to neural plasticity or reassignment of functions to other anatomic sites. Functional MRI (f-MRI) can be used to measure the effects of brain plasticity. F-MRI utilizes the different magnetic properties of oxygenated and deoxygenated blood to detect regions of increased or decreased cerebral blood flow. In this way, an increase in brain activity results in increased local blood flow and glucose consumption, without elevation of the tissue oxygen consumption. These changes lead to an increase in the oxyhemoglobin concentration compared with the deoxyhemoglobin concentration resulting in an increment in the signal of the activated cortical areas. In MS patients, f-MRI has revealed the existence of functional reorganization phenomena. Thus, patients with a higher degree of tissue damage but with a mild disability show extensive changes in the reassignment of functions, while this phenomenon is not so obvious when the disability is severe [20,21].
In conclusion, conventional MRI has an established role in helping to make the diagnosis of MS due to its high sensitivity in detecting demyelinating lesions in the CNS and its ability to exclude alternative pathologies. However, its limited histopathological specificity and underestimation of damage to the normal appearing brain tissue (both white and gray matter), especially of the T2-weighted scans, justify its reduced value as a prognostic marker for the development of disability. These limitations might be overcome by the introduction of nonconventional MRI techniques with more accurate measurements of disease burden, which could provide valuable insights for the monitoring and management of MS patients.