Grey matter lesions in MS

Although multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the white matter (WM) of the central nervous system, several pathological and magnetic resonance imaging (MRI) studies have shown that a large amount of lesions are located in the cortical and deep gray matter. The histopathological and immunological characteristics of cortical lesions differ significantly from those located in the WM, which suggests a location-dependent expression of the MS immunopathological process. More recently, the availability of not-conventional MRI sequences having higher sensitivity for the gray matter has allowed to depict in vivo a portion of such lesions. The available MRI data obtained on large cohorts of patients, having different clinical forms of the disease, indicate that cortical lesions can be detected early in the disease course, sometimes even before the appearance of WM lesions, and correlate with the severity of physical disability and cognitive impairment, and with the evolution of the disease toward the secondary progressive phase. This review provides a summary of the main histopathological and MRI findings of cortical lesions in MS and discusses their possible clinical implications.     

Imaging Surrogates of Disease Activity in Neuromyelitis Optica Allow Distinction from Multiple Sclerosis

Inflammatory demyelinating lesions of the central nervous system are a common feature of both neuromyelitis optica and multiple sclerosis. Despite this similarity, it is evident clinically that the accumulation of disability in patients with neuromyelitis optica is relapse related and that a progressive phase is very uncommon. This poses the question whether there is any pathological evidence of disease activity or neurodegeneration in neuromyelitis optica between relapses. To investigate this we conducted a longitudinal advanced MRI study of the brain and spinal cord in neuromyelitis optica patients, comparing to patients with multiple sclerosis and controls. We found both cross-sectional and longitudinal evidence of diffusely distributed neurodegenerative surrogates in the multiple sclerosis group (including thalamic atrophy, cervical cord atrophy and progressive widespread diffusion and myelin water imaging abnormalities in the normal appearing white matter) but not in those with neuromyelitis optica, where localised abnormalities in the optic radiations of those with severe visual impairment were noted. In addition, between relapses, there were no new silent brain lesions in the neuromyelitis optica group. These findings indicate that global central nervous system neurodegeneration is not a feature of neuromyelitis optica. The work also questions the theory that neurodegeneration in multiple sclerosis is a chronic sequela to prior inflammatory and demyelinating pathology, as this has not been found to be the case in neuromyelitis optica where the lesions are often more destructive.     

Characterization of tissue damage in multiple sclerosis by nuclear magnetic resonance

Nuclear magnetic resonance (NMR) imaging is an established diagnostic medium to diagnose multiple sclerosis (MS). In clinically stable MS patients, NMR detects silent disease activity, which is the reason why it is being used to monitor treatment trials, in which it serves as a secondary outcome parameter. The absence of a clear correlation with clinical disability, the so-called 'clinico-radiological' paradox, and the poor predictive value of NMR prohibit the use of NMR as a primary outcome parameter in clinical trials. This is--among others--a result of the limited histopathological specificity of conventional, or 'T2-weighted' imaging, the most commonly used NMR technique. In this paper we review additional NMR techniques with higher tissue specificity, most of which show marked heterogeneity within NMR-visible lesions, reflecting histopathological heterogeneity. Gadolinium enhancement identifies the early inflammatory phase of lesion development, with active phagocytosis by macrophages. Persistently hypointense lesions on T1-weighted images ('black holes') relate to axonal loss and matrix destruction, and show a better correlation with clinical disability. Marked prolongation of T1 relaxation time correlates with enlargement of the extracellular space, which occurs as a result of axonal loss or oedema. Axonal viability can also be measured using the concentration of N-acetyl aspartate (NAA) using NMR spectroscopy; this technique is also capable of showing lactate and mobile lipids in lesions with active macrophages. The multi-exponential behaviour of T2 relaxation time in brain white matter provides a tool to monitor the myelin water component in MS lesions (short T2 component) as well as the expansion of the extracellular space (long T2 component). Chemical exchange with macromolecules (e.g. myelin) can be measured using magnetization transfer imaging, and correlates with demyelination, axonal loss and matrix destruction. Increased water diffusion has been found in MS lesions (relating to oedema and an expanded extracellular space) and a loss of anisotropy may indicate a loss of fibre orientation (compatible with demyelination). Apart from the histopathological heterogeneity within focal MS lesions, the normal-appearing white matter shows definite abnormalities with all quantifiable NMR techniques. A decrease in the concentration of NAA, decreased magnetization transfer values and prolonged T1 relaxation time values are probably all related to microscopic abnormalities, including axonal damage. This 'invisible' lesion load may constitute a significant proportion of the total lesion load but is not visible on conventional NMR. Similarly, mechanisms for clinical recovery exist, which are not distinguished using MR imaging. Therefore, it is highly unlikely that the clinico-radiological paradox will ever be solved completely. However, NMR provides an opportunity to sequentially measure tissue changes in vivo. Using MR parameters with (presumed) histopathological specificity, the development of (irreversible) tissue damage can be monitored, which perhaps allows the identification of factors that determine lesional outcome in MS. Since the absence of severe tissue destruction is prognostically favourable, NMR monitoring of the extent to which such changes can be prevented by treatment will ultimately benefit the selection of future treatment strategies.     

Phase-Sensitive Inversion-Recovery MRI Improves Longitudinal Cortical Lesion Detection in Progressive MS

Previous studies comparing phase sensitive inversion recovery (PSIR) to double inversion recovery (DIR) have demonstrated that use of PSIR improves cross-sectional in vivo detection of cortical lesions (CL) in multiple sclerosis. We studied the utility of PSIR in detection/characterization of accrual of CL over time in a 1-year longitudinal study in primary progressive multiple sclerosis (PPMS) compared to DIR. PSIR and DIR images were acquired with 3T magnetic resonance imaging (MRI) in 25 patients with PPMS and 19 healthy controls at baseline, and after 1 year in 20 patients with PPMS. CL were classified as intracortical, leucocortical or juxtacortical. Lesion counts and volumes were calculated for both time points from both sequences and compared. Correlations with measures of physical and cognitive disability were determined as well as new CL counts and volumes. Compared to DIR, PSIR led to detection of a higher number of CL involving a larger proportion of patients with PPMS both cross-sectionally (p = 0.006, 88%) and longitudinally (p = 0.007, 95%), and led to the reclassification of a third of CL seen on DIR at each time point. Interestingly, PSIR was more sensitive to new CL accumulation over time compared to DIR. PSIR is a promising technique to monitor cortical damage and disease progression in patients with PPMS over a short-term follow-up.     

CROP – The Clinico-Radiologico-Ophthalmological Paradox in Multiple Sclerosis: Are Patterns of Retinal and MRI Changes Heterogeneous and Thus Not Predictable?

Background

To date, no direct scientific evidence has been found linking tissue changes in multiple sclerosis (MS) patients, such as demyelination, axonal destruction or gliosis, with either steady progression and/or stepwise accumulation of focal CNS lesions. Tissue changes such as reduction of the retinal nerve fiber layer (RNFL) and the total macular volume (TMV), or brain- and spinal cord atrophy indicates an irreversible stage of tissue destruction. Whether these changes are found in all MS patients, and if there is a correlation with clinical disease state, remains controversial. The objective of our study was to determine, whether there was any correlation between the RNFL or TMV of patients with MS, and: (1) the lesion load along the visual pathways, (2) the ratios and absolute concentrations of metabolites in the normal-appearing white matter (NAWM), (3) standard brain atrophy indices, (4) disease activity or (5) disease duration.

Methods

28 MS patients (RRMS, n = 23; secondary progressive MS (SPMS), n = 5) with moderately-high disease activity or long disease course were included in the study. We utilised: (1) magnetic resonance imaging (MRI) and (2) -spectroscopy (MRS), both operating at 3 Tesla, and (3) high-resolution spectral domain-OCT with locked reference images and eye tracking mode) to undertake the study.

Results

There was no consistency in the pattern of CNS metabolites, brain atrophy indices and the RNFL/TMV between individuals, which ranged from normal to markedly-reduced levels. Furthermore, there was no strict correlation between CNS metabolites, lesions along the visual pathways, atrophy indices, RNFL, TMV, disease duration or disability.

Conclusions

Based on the findings of this study, we recommend that the concept of ‘clinico-radiologico paradox’ in multiple sclerosis be extended to CROP–‘clinico-radiologico-ophthalmological paradox’. Furthermore, OCT data of MS patients should be interpreted with caution.     

Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody

IL-12p40 is a shared subunit of two cytokines with overlapping activities in the induction of autoreactive Th1 cells and therefore a potential target of therapy in Th1-mediated diseases. We have examined whether ongoing disease in a nonhuman primate model of multiple sclerosis (MS) can be suppressed with a new human IgG1kappa Ab against human IL-12p40. Lesions developing in the brain white matter were visualized and characterized with standard magnetic resonance imaging techniques. To reflect the treatment of MS patients, treatment with the Ab was initiated after active brain white matter lesions were detected in T2-weighted images. In placebo-treated control monkeys we observed the expected progressive increase in the total T2 lesion volume and markedly increased T2 relaxation times, a magnetic resonance imaging marker of inflammation. In contrast, in monkeys treated with anti-IL-12p40 Ab, changes in the total T2 lesion volume and T2 relaxation times were significantly suppressed. Moreover, the time interval to serious neurological deficit was delayed from 31 +/- 10 to 64 +/- 20 days (odds ratio, 0.312). These results, in a disease model with high similarity to MS, are important for ongoing and planned trials of therapies that target IL-12 and/or IL-23.     

Abnormal Control of Orbicularis Oculi Reflex Excitability in Multiple Sclerosis

Brain lesions in patients with multiple sclerosis may lead to abnormal excitability of brainstem reflex circuits because of impairment of descending control pathways. We hypothesized that such abnormality should show in the analysis of blink reflex responses in the form of asymmetries in response size. The study was done in 20 patients with relapsing-remitting multiple sclerosis and 12 matched healthy subjects. We identified first patients with latency abnormalities (AbLat). Then, we analyzed response size by calculating the R2c/R2 ratio to stimulation of either side and the mean area of the R2 responses obtained in the same side. Patients with significantly larger response size with respect to healthy subjects in at least one side were considered to have abnormal response excitability (AbEx). We also examined the blink reflex excitability recovery (BRER) and prepulse inhibition (BRIP) of either side in search for additional indices of asymmetry in response excitability. Neurophysiological data were correlated with MRI-determined brain lesion-load and volume. Eight patients were identified as AbLat (median Expanded Disability Status Scale–EDSS = 2.75) and 7 of them had ponto-medullary lesions. Nine patients were identified as AbEx (EDSS = 1.5) and only 2 of them, who also were AbLat, had ponto-medullary lesions. In AbEx patients, the abnormalities in response size were confined to one side, with a similar tendency in most variables (significantly asymmetric R1 amplitude, BRER index and BRIP percentage). AbEx patients had asymmetric distribution of hemispheral lesions, in contrast with the symmetric pattern observed in AbLat. The brainstem lesion load was significantly lower in AbEx than in AbLat patients (p = 0.04). Asymmetric abnormalities in blink reflex response excitability in patients with multiple sclerosis are associated with lesser disability and lower tissue loss than abnormalities in response latency. Testing response excitability could provide a reliable neurophysiological index of dysfunction in early stages of multiple sclerosis.     

Arylsulfatase a gene polymorphisms in relapsing remitting multiple sclerosis: genotype-phenotype correlation and estimation of disease progression

Arylsulfatase A (ASA) is a lysosomal enzyme involved in catabolism of cerebroside-sulfate, major lipid constituent of oligodendrocyte membranes. Various polymorphisms in ASA gene have been described, leading to different levels of enzyme deficiency. Progressive demyelination occurs in metachromatic leukodystrophy (MLD), while the condition of ASA-pseudodeficiency (ASA-PD) is suggested to contribute to complex pathogenesis of multiple sclerosis (MS). This work presents usefulness of genotype-phenotype correlation in estimation of disease severity and progression. The presence of two most common mutations associated with ASA-PD was analyzed in 56 patients with diagnosis of relapsing-remitting multiple sclerosis, by polymerase chain reaction restriction fragment length polymorphism method. In MS patients confirmed as ASA-PD mutations carriers, arylsulfatase activity was determined in leukocyte homogenates by spectrophotometry. To determine whether there is a difference between disability level and/or disease progression in patients with or without mutations we have estimated disability level using Expanded disability status scale (EDSS) and disease progression using Multiple sclerosis severity score (MSSS). Correlation of genotypes and disease progression was statistically analyzed by Kruskal-Wallis test. Patients showing higher MSSS score and found to be carriers of both analyzed ASA-PD mutations were additionally examined using conventional magnetic resonance (MR) techniques. The presence of either one or both mutations was determined in 13 patients. Lower ASA activities were observed in all MS patients carrying the mutations. Nine of the mutations carriers had mild disability (EDSS=0-4.0), 1 had moderate disability (EDSS=4.5-5.5), and 3 had severe disability (EDSS > or = 6.0). On the other hand, only 3 MS patients who were mutation carriers showed MSSS values lower than 5.000 while in other MS patients-mutation carriers the MSSS values ranged from 5.267 to 9.453. Comparison of MR findings between MS patients, mutations carrier vs. non-carrier, matched for sex, age and disease duration, showed that the total number of lesions and the number of hypointense lesions on T1-weighted images was greater in MS patient carrying the ASA-PD mutations. Our results on genotype-phenotype correlation analysis indicate a possible contribution of detected arylsulfatase A gene polymorphisms to the clinical severity of multiple sclerosis, estimated by EDSS, MSSS and MR findings. The MSSS proved to be more appropriate indicator of disease progression and should be more frequently used in clinical practice especially for comparison of disease progression in different groups of patients and identification of factors that may influence disease progression such as the presence of gene polymorphisms.     

Tumefactive multiple sclerosis requiring emergent biopsy and histological investigation to confirm the diagnosis: a case report

Introduction

Tumefactive multiple sclerosis is a demyelinating disease that demonstrates tumor-like features on magnetic resonance imaging. Although diagnostic challenges without biopsy have been tried by employing radiological studies and cerebrospinal fluid examinations, histological investigation is still necessary for certain diagnosis in some complicated cases.

Case presentation

A 37-year-old Asian man complaining of mild left leg motor weakness visited our clinic. Magnetic resonance imaging demonstrated high-signal lesions in bilateral occipital forceps majors, the left caudate head, and the left semicentral ovale on fluid-attenuated inversion recovery and T2-weighted imaging, and these lesions were enhanced by gadolinium-dimeglumin. Tumefactive multiple sclerosis was suspected because the enhancement indistinctly extended along the corpus callosum on magnetic resonance imaging and scintigraphy showed a low malignancy of the lesions. But oligoclonal bands were not detected in cerebrospinal fluid. In a few days, his symptoms fulminantly deteriorated with mental confusion and left hemiparesis, and steroid pulse therapy was performed. In spite of the treatment, follow-up magnetic resonance imaging showed enlargement of the lesions. Therefore, emergent biopsy was performed and finally led to the diagnosis of demyelinating disease. The enhanced lesion on magnetic resonance imaging disappeared after one month of prednisolone treatment, but mild disorientation and left hemiparesis remained as sequelae.

Conclusions

Fulminant aggravation of the disease can cause irreversible neurological deficits. Thus, an early decision to perform a biopsy is necessary for exact diagnosis and appropriate treatment if radiological studies and cerebrospinal fluid examinations cannot rule out the possibility of brain tumors.     

Iron Is a Sensitive Biomarker for Inflammation in Multiple Sclerosis Lesions

MRI phase imaging in multiple sclerosis (MS) patients and in autopsy tissue have demonstrated the presence of iron depositions in white matter lesions.The accumulation of iron in some but not all lesions suggests a specific, potentially disease-relevant process, however; its pathophysiological significance remains unknown.Here, we explore the role of lesional iron in multiple sclerosis using multiple approaches: immunohistochemical examination of autoptic MS tissue, an in vitro model of iron-uptake in human cultured macrophages and ultra-highfield phase imaging of highly active and of secondary progressive MS patients.Using Perls'' stain and immunohistochemistry, iron was detected in MS tissue sections predominantly in non-phagocytosing macrophages/microglia at the edge of established, demyelinated lesions. Moreover, iron-containing macrophages but not myelin-laden macrophages expressed markers of proinflammatory (M1) polarization.Similarly, in human macrophage cultures, iron was preferentially taken up by non-phagocytosing, M1-polarized macrophages and induced M1 (super) polarization. Iron uptake was minimal in myelin-laden macrophages and active myelin phagocytosis led to depletion of intracellular iron.Finally, we demonstrated in MS patients using GRE phase imaging with ultra-highfield MRI that phase hypointense lesions were significantly more prevalent in patients with active relapsing than with secondary progressive MS.Taken together, our data provide a basis to interpret iron-sensitive GRE phase imaging in MS patients: iron is present in non-phagocytosing, M1-polarized microglia/macrophages at the rim of chronic active white matter demyelinating lesions. Phase imaging may therefore visualize specific, chronic proinflammatory activity in established MS lesions and thus provide important clinical information on disease status and treatment efficacy in MS patients.     

Evidence against the Involvement of Chronic Cerebrospinal Venous Abnormalities in Multiple Sclerosis. A Case-Control Study

Objective

Multiple sclerosis (MS) is a chronic neurodegenerative disease of the CNS. Recently a controversial vascular hypothesis for MS, termed chronic cerebrospinal venous insufficiency (CCSVI), has been advanced. The objective of this study was to evaluate the relative prevalence of the venous abnormalities that define CCSVI.

Methods

A case-control study was conducted in which 100 MS patients aged between 18–65 y meeting the revised McDonald criteria were randomly selected and stratified into one of four MS subtypes: relapsing/remitting, secondary progressive, primary progressive and benign. Control subjects (16–70 y) with no known history of MS or other neurological condition were matched with the MS cases. All cases and controls underwent ultrasound imaging of the veins of the neck plus the deep cerebral veins, and magnetic resonance imaging of the neck veins and brain. These procedures were performed on each participant on the same day.

Results

On ultrasound we found no evidence of reflux, stenosis or blockage in the internal jugular veins (IJV) or vertebral veins (VV) in any study participant. Similarly, there was no evidence of either reflux or cessation of flow in the deep cerebral veins in any subject. Flow was detected in the IJV and VV in all study participants. Amongst 199 participants there was one MS subject who fulfilled the minimum two ultrasound criteria for CCSVI. Using MRI we found no significant differences in either the intra- or extra-cranial venous flow velocity or venous architecture between cases and controls.

Conclusion

This case-control study provides compelling evidence against the involvement of CCSVI in multiple sclerosis.     

Multiple sclerosis: the disease and its manifestations

Multiple sclerosis is an immune-mediated inflammatory demyelinating disease of the central nervous system clinically characterized by relapses and remissions of neurological disturbance. A typical relapse, exemplified by optic neuritis, increases in severity over a week or two and after approximately one month begins to remit. Resolution takes place over the course of two to three months. In the early stages, clinical recovery is virtually complete, though persistent abnormalities of conduction can usually be detected by evoked potential techniques and persistent structural abnormalities can be detected by magnetic resonance imaging (MRI). These techniques, together with cerebrospinal fluid examination for oligoclonal IgG, provide supporting evidence for the diagnosis which, in the absence of a specific test, nevertheless remains primarily clinical. The course of the disease is very variable, but after a number of years neurological deficit begins to accumulate after each relapse. In most patients, the relapsing and remitting phase of the disease is followed by a phase of continuous progression of disability. Cognitive disturbances can be detected in many patients even quite early in the course of the illness. Deficits in attention, memory and executive skills may be prominent and tend to become increasingly prominent as neurological deficit increases, although this is not always the case. There is some correlation between the extent of MRI abnormalities in the cerebral white matter and the severity of cognitive deficit. Depression and anxiety are commonly experienced but are poorly correlated to the lesion load seen on MRI. In contrast, the much rarer psychotic symptoms, euphoria and emotional lability are closely linked to the severity of white matter disease.     

Magnetic resonance imaging of the brain in multiple sclerosis

The paper deals with the diagnosis of demyelinating diseases of the central nervous system, including multiple sclerosis, by means of magnetic resonance imaging (MRI). The low-magnetic induction tomographs "Obraz" ("Image") and "Ellips" ("Ellipse") made in Russia were used to perform MRI of the brain in 255 patients diagnosed as having multiple sclerosis. Whether low-magnetic induction MRI can detectfocal changes in the brain in the presence of multiple sclerosis was assessed; the tomographic signs of the disease were clarified and classified. There was a relationship between the detection of focal changes in the brain and the duration of the disease. Particular emphasis is laid on the cases of various abnormalities at MRI, which clinically mask multiple sclerosis. The cases are summarized and a list of conditions to be particularly emphasized while making a differential diagnosis is drawn up.     

The correlation of changes of the optic nerve diameter in the acute retrobulbar neuritis with the brain changes in multiple sclerosis

The aim of this paper is to compare diameter of healthy and affected optic nerve determined by ultrasound with brain lesions in acute retrobulbar neuritis in patients with multiple sclerosis. In this prospective study 20 patients with multiple sclerosis and acute retrobulbar neuritis were examined. Optic nerve diameter was measured by ultrasound. Brain lesions were detected by magnetic resonance. Correlation between demyelinating lesions of the brain in multiple sclerosis and optic nerve diameter was tested by Kruskal-Wallis test. Significant difference in diameter between healthy and affected optic nerve in acute retrobulbar neuritis was found. Demyelinating brain changes examined by magnetic resonance revealed periventricular lesions, subcortical lesions and lesions in corpus callosum. There is statistically significant correlation between optic nerve diameter and number of brain lesions in multiple sclerosis, p < 0.05. Diameter of optic nerve in retrobulbar neuritis measured by ultrasound correlates with brain lesions detected by magnetic resonance in multiple sclerosis.     

Eight-Year Follow-Up of Neuropsychiatric Symptoms and Brain Structural Changes in Fabry Disease

Brain structural alterations and neuropsychiatric symptoms have been described repeatedly in Fabry disease, yet cognitive deficits have been shown to be only mild. Here, we aimed to investigate neuropsychiatric symptoms and brain structure longitudinally. We expected no clinically relevant increase of neuropsychiatric symptoms in parallel to increased brain structural alterations. We assessed 14 Fabry patients (46.1 ± 10.8 years) who had participated in our investigation eight years ago. Patients engaged in neuropsychiatric testing, as well as structural magnetic resonance imaging and angiography to determine white matter lesions, hippocampal volume, and the diameter of the larger intracranial arteries. While Fabry patients did not differ on cognitive performance, they showed progressive and significant hippocampal volume loss over the 8-year observation period. White matter lesions were associated with older age and higher white matter lesion load at baseline, but did not reach statistical significance when comparing baseline to follow-up. Likewise, intracranial artery diameters did not increase significantly. None of the imaging parameters were associated with the neuropsychiatric parameters. Depression frequency reduced from 50% at baseline to 21% at follow-up, but it did not reach significance. This investigation demonstrates clinical stability in cognitive function, while pronounced hippocampal atrophy is apparent throughout the 8 years. Our middle-aged Fabry patients appeared to compensate successfully for progressive hippocampal volume loss. The hippocampal volume decline indicates brain regional neuronal involvement in Fabry disease.     

Comparison of magnetic resonance imaging and computed tomography in suspected lesions in the posterior cranial fossa.

OBJECTIVE--To compare computed tomography and magnetic resonance imaging in investigating patients suspected of having a lesion in the posterior cranial fossa. DESIGN--Randomised allocation of newly referred patients to undergo either computed tomography or magnetic resonance imaging; the alternative investigation was performed subsequently only in response to a request from the referring doctor. SETTING--A regional neuroscience centre serving 2.7 million. PATIENTS--1020 Patients recruited between April 1986 and December 1987, all suspected by neurologists, neurosurgeons, or other specialists of having a lesion in the posterior fossa and referred for neuroradiology. The groups allocated to undergo computed tomography or magnetic resonance imaging were well matched in distributions of age, sex, specialty of referring doctor, investigation as an inpatient or an outpatient, suspected site of lesion, and presumed disease process; the referring doctor''s confidence in the initial clinical diagnosis was also similar. INTERVENTIONS--After the patients had been imaged by either computed tomography or magnetic resonance (using a resistive magnet of 0.15 T) doctors were given the radiologist''s report and a form asking if they considered that imaging with the alternative technique was necessary and, if so, why; it also asked for their current diagnoses and their confidence in them. MAIN OUTCOME MEASURES--Number of requests for the alternative method of investigation. Assessment of characteristics of patients for whom further imaging was requested and lesions that were suspected initially and how the results of the second imaging affected clinicians'' and radiologists'' opinions. RESULTS--Ninety three of the 501 patients who initially underwent computed tomography were referred subsequently for magnetic resonance imaging whereas only 28 of the 493 patients who initially underwent magnetic resonance imaging were referred subsequently for computed tomography. Over the study the number of patients referred for magnetic resonance imaging after computed tomography increased but requests for computed tomography after magnetic resonance imaging decreased. The reason that clinicians gave most commonly for requesting further imaging by magnetic resonance was that the results of the initial computed tomography failed to exclude their suspected diagnosis (64 patients). This was less common in patients investigated initially by magnetic resonance imaging (eight patients). Management of 28 patients (6%) imaged initially with computed tomography and 12 patients (2%) imaged initially with magnetic resonance was changed on the basis of the results of the alternative imaging. CONCLUSIONS--Magnetic resonance imaging provided doctors with the information required to manage patients suspected of having a lesion in the posterior fossa more commonly than computed tomography, but computed tomography alone was satisfactory in 80% of cases...     

Fabry Disease – Underestimated in the Differential Diagnosis of Multiple Sclerosis?

Objective

Fabry disease is a rare X-linked inherited lysosomal storage disorder affecting multiple organ systems. It includes central nervous system involvement via micro- and macroangiopathic cerebral changes. Due to its clinical symptoms and frequent MRI lesions, Fabry disease is commonly misdiagnosed as multiple sclerosis. We present an overview of cases from Fabry centres in Germany initially misdiagnosed with multiple sclerosis and report the clinical, MR-tomographical, and laboratory findings.

Methods

Eleven Fabry patients (one male, ten females) initially diagnosed with multiple sclerosis were identified from 187 patient records (5.9%) and analyzed for presenting symptoms, results of the initial diagnostic workup, and the clinical course of the disease.

Results

Four patients were identified as having a “possible” history of MS, and 7 patients as “definite” cases of multiple sclerosis (revised McDonald criteria). On average, Fabry disease was diagnosed 8.2 years (±9.8 years) after the MS diagnosis, and 12.8 years after onset of first symptoms (±10.3 years). All patients revealed white matter lesions on MRI. The lesion pattern and results of cerebrospinal fluid examination were inconsistent and non-specific. White matter lesion volumes ranged from 8.9 mL to 34.8 mL (mean 17.8 mL±11.4 mL). There was no association between extra-neurological manifestations or enzyme activity and lesion load.

Conclusion

There are several anamnestic and clinical hints indicating when Fabry disease should be considered a relevant differential diagnosis of multiple sclerosis, e.g. female patients with asymmetric, confluent white matter lesions on MRI, normal spinal MR imaging, ectatic vertebrobasilar arteries, proteinuria, or lack of intrathecally derived immunoglobulin synthesis.     

Measles IgG antibody index correlates with T2 lesion load on MRI in patients with early multiple sclerosis

Background

B cells and humoral immune responses play an important role in the pathogenesis and diagnosis of multiple sclerosis (MS). A characteristic finding in patients with MS is a polyspecific intrathecal B cell response against neurotropic viruses, specifically against measles virus, rubella virus, and varicella zoster virus, also known as an MRZ reaction (MRZR). Here, we correlated from the routine clinical diagnostics individual IgG antibody indices (AIs) of MRZR with magnetic resonance imaging (MRI) findings in patients with first MS diagnosis.

Methods/Results

MRZR was determined in 68 patients with a clinically isolated syndrome (CIS) or early relapsing-remitting MS (RRMS). Absolute AI values for measles virus, rubella virus, and varicella zoster virus were correlated with T2 lesion load and gadolinium enhancing lesions on cerebral MRI (cMRI) and cMRI combined with spinal MRI (sMRI). Measles virus AI correlated significantly with T2 lesion load on cMRI (p = 0.0312, Mann-Whitney U test) and the sum of lesions on cMRI and sMRI (p = 0.0413). Varicella zoster virus AI also showed a correlation with T2 lesion load on cMRI but did not reach statistical significance (p = 0.2893).

Conclusion

The results confirm MRZR as part of the polyspecific immune reaction in MS with possible prognostic impact on MRI and clinical parameters.Furthermore, the data indicate that intrathecal measles virus IgG production correlates with disease activity on cMRI and sMRI in patients with early MS.     

Comparison of clinical characteristics between neuromyelitis optica spectrum disorders with and without spinal cord atrophy

Background

Spinal cord lesions is one of the predominant characteristics in patients with neuromyelitis optica spectrum disorders (NMOSD). Interestingly, mounting evidence indicates that spinal cord atrophy (SCA) is one of common clinical features in multiple sclerosis (MS) patients, and correlates closely with the neurological disability. However, Clinical studies related to the SCA aspects of NMOSD are still scarce.

Methods

We retrospectively analyzed 185 patients with NMOSD, including 23 patients with SCA and 162 patients without SCA. Data were collected regarding clinical characteristics, laboratory tests, and magnetic resonance imaging findings.

Results

12.4% of patients had SCA in NMOSD. Patients with SCA had a longer disease duration and higher EDSS at clinical onset and last visit. More importantly, SCA patients were more prone to reach disability milestones (EDSS?≥?6.0). Bowel or bladder dysfunction, movement disorders, and sensory disturbances symptoms were more common in patients with SCA. ESR and CRP were significantly higher in patients with SCA than those without SCA. Patients with SCA were more frequently complicated with cervical cord lesions. However, the ARR, progression index, seropositive rate of NMO-IgG and OCB were similar in the two groups. Futhermore, LETM did not differ significantly between patients with SCA and without SCA in NMOSD patients.

Conclusions

Patients with SCA might have longer disease duration, more severe clinical disability, and more frequently complicated with cervical spinal cord lesions. SCA might be predictive of the more severe neurologic dysfunction and worse prognosis in NMOSD. Inflammation contributes to the development of SCA in NMOSD.

     

Prevalence of grey matter pathology in early multiple sclerosis assessed by magnetization transfer ratio imaging

The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject''s GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability.