Routine interferon-neutralising antibody testing in patients with relapsing-remitting multiple sclerosis.

Multiple sclerosis is a leading cause of disability in young adults, with the Scottish population suffering the highest prevalence in Europe. Disease-modifying therapies, including beta-interferon (IFN-ß), are increasingly used to minimise relapse frequency in the majority of patients who present with a relapsing-remitting disease pattern. Unfortunately, neutralising antibodies (NABs) may develop against IFN-ß and are associated with reduced efficacy. These antibodies may be detected using a serum sample. Despite the importance of this problem, from both a patient's perspective and a wider community and economic standpoint, there is no universally agreed protocol for the use of NAB testing. Authorities variously suggest routine 'screening' testing or, conversely, testing only in specific situations. In Scotland, routine testing is seldom used. We report our experience of routine NAB testing in 105 patients (of whom 35 were NAB-positive) over two years in NHS Tayside and comment on its cost and implications.

Pneumoencephaly following lumbar puncture in association with an ethmoidal osteoma and porencephalic cyst.

A 50-year-old woman developed pneumoencephaly following a CSF examination for evaluation of dysequilibrium. Previous investigations had demonstrated a number of high signal T2 lesions on MRI of the brain. In addition, there was what was thought to be an asymptomatic cystic lesion in the left frontal lobe communicating with the lateral ventricle. After the lumbar puncture she developed extensive pneumoencephaly with pressure dilatation of the ventricular system. There was CSF rhinorrhoea. Further CT scans showed an osteoma in the ethmoidal air sinus with protrusion into the cystic area. This was the site of both the CSF leak and air entry. Caution must be taken when considering a CSF examination in the presence of either a presumed asymptomatic porencephalic cyst or ethmoid osteoma.

Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis.

BACKGROUND: In patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS), the extent of brain magnetic resonance imaging (MRI) lesion load influences the probability and time to development of clinically definite MS. Cerebral atrophy is recognised in established MS, but its time of onset and whether, in early disease, it is related to MRI lesion load or clinical outcome is less certain. OBJECTIVES: This study investigated ventricular enlargement over one year in CIS patients and explored its relation with lesion load and clinical outcome. METHODS: A semi-automated thresholding technique for measuring ventricular volume (MIDAS) was applied to MRI scans in a cohort of 55 patients with CIS, recruited consecutively and imaged within three months of the onset of symptoms and again after one year. RESULTS: Clinical MS had developed after one year in 16 of 40 patients with an abnormal baseline T2 scan and 2 of 15 with a normal scan. Significant ventricular enlargement was seen in 27 of 55 patients who fulfilled the new McDonald MRI criteria for MS using all available MRI at clinical follow up (median increase 0.3 cm(3), p=0.005) Significant increase in ventricular volume was also seen in the 18 of 55 patients who developed clinical MS over the follow up period (median increase 0.5 cm(3), p=0.006). There were significant but modest correlations between baseline lesion measures and subsequent ventricular enlargement. CONCLUSIONS: (1) Lesions and atrophy are both associated with early relapse leading to a diagnosis of clinical MS; (2) while lesions contribute to the development of atrophy, atrophy may also develop by other mechanisms. This suggests that MR measures have a complementary role in monitoring the course of MS, even from the earliest clinical stage.

Measurement of spinal cord area in clinically isolated syndromes suggestive of multiple sclerosis.

Atrophy of the spinal cord is known to occur in multiple sclerosis but the cause and the timing of its onset are not clear. Recent evidence suggests that atrophy may start to occur early in the disease. The aim was to determine whether atrophy of the spinal cord could be detected in vivo using MRI techniques, in patients presenting with a clinically isolated syndrome, which in many cases is the earliest clinical stage of multiple sclerosis. The cross sectional area of the spinal cord was measured in 43 patients presenting with a clinically isolated syndrome and 15 matched controls. T2 weighted imaging of the brain was also performed to determine the number and volume of high signal lesions consistent with disseminated demyelination. Both patients and controls were restudied after 1 year. The spinal cord area was significantly smaller in the 74% of patients with an abnormal brain MRI at presentation than in controls (mean areas 73.9 mm(2) and 78.1 mm(2) respectively, p=0.03). No significant difference was found in the spinal cord area between controls and patients with normal baseline brain imaging. The annual rate of change in patients did not differ significantly from controls. In conclusion, the finding of a smaller cord area in the subgroup of patients with clinically isolated syndrome with the highest risk of developing multiple sclerosis-that is, with an abnormal brain MRI, suggests that atrophy has developed in some patients with multiple sclerosis even before their first clinical symptoms. However, the lack of a detectable change in cord area over 1 year of follow up contrasts strikingly with the results of an earlier study of patients with relapsing-remitting multiple sclerosis, suggesting that the rate of atrophy increases as the disease becomes more established.

Assessing the risk of early multiple sclerosis in patients with clinically isolated syndromes: the role of a follow up MRI.

OBJECTIVES: With increasing evidence that permanent tissue damage occurs early in the course of multiple sclerosis, it is important that treatment trials include patients in the earliest stages of the disease. For many patients with multiple sclerosis the first presentation is a clinically isolated syndrome. Not all patients with a clinically isolated syndrome develop multiple sclerosis, however, and treatment of all such patients would be unwarranted. A single abnormal brain MRI identifies patients at a higher risk for the early development of multiple sclerosis, but current criteria are limited by either poor specificity (T2 lesions) or sensitivity (contrast enhancing lesions). The aim of the study was to assess the positive predictive value, sensitivity, and specificity of MRI indices for the development of multiple sclerosis after 1 year from two MRI examinations obtained 3 months apart. METHODS: MRI examinations were performed in 68 patients with a clinically isolated syndrome, with a clinical assessment after 1 year. RESULTS: Contrast enhancing lesions at both time points were the most predictive indices for developing multiple sclerosis (positive predictive value 70%) but had low sensitivity (39%). The combination of T2 lesions at baseline with new T2 lesions at follow up had the best overall positive predictive value (53%), sensitivity (83%), and specificity (76%). In patients with T2 lesions at baseline, the presence or absence of new T2 lesions at follow up significantly altered the risk of multiple sclerosis within 1 year (55% and 5% respectively, p<0.001). Multiple sclerosis also developed in 10% of patients with a normal baseline MRI. CONCLUSIONS: Serial imaging in patients with clinically isolated syndromes improved the positive predictive value, sensitivity, and specificity of MRI for the development of early multiple sclerosis and also identified patients at a lower risk of early multiple sclerosis than would have been expected from their abnormal baseline MRI. Selection of patients with clinically isolated syndromes for therapeutic intervention or clinical trials may benefit from serial MRI, to target those at greatest risk of early development of multiple sclerosis.

Detection of ventricular enlargement in patients at the earliest clinical stage of MS.

The aim of this study was to determine whether atrophy could be detected at the earliest clinical stages of MS. Patients were selected from a 1-year follow-up MRI study of clinically isolated syndromes. Nine patients who developed MS were compared with eight matched patients who had no further symptoms. Significant ventricular enlargement occurred in the group that developed MS but not in the other group. Our findings show that atrophy, albeit mild, can be detected early in the course of MS.

Multisequence MRI in clinically isolated syndromes and the early development of MS.

OBJECTIVE: To apply multisequence MRI techniques to patients with clinically isolated syndromes, to document the pattern and frequency of abnormalities at baseline and early follow-up, and to determine their predictive values for the early development of clinical MS. BACKGROUND: Disseminated lesions on T2-weighted brain MRI confer an increased risk of progression to clinically definite MS. Newer MRI techniques increase detection of lesions in both brain and spinal cord, and clarify further their pathology. The predictive value of such techniques for the development of clinical MS needs to be defined. METHODS: Brain and spinal MRI were performed on 60 patients after their first demyelinating event. A total of 50 patients were followed for 1 year, and 49 underwent repeat brain MRI 3 months after the initial scan. RESULTS: At baseline, 73% of patients had lesions on T2-weighted fast spin-echo (FSE) brain images and 42% had asymptomatic spinal cord lesions. Fast fluid-attenuated inversion-recovery brain did not improve detection of brain lesions. Repeat brain MRI demonstrated new FSE lesions in 43% of patients. After 1 year, 26% of patients developed MS. The MRI features that provided the best combination of sensitivity and specificity for the development of MS were the presence of new FSE lesions at follow-up and enhancing lesions at baseline. The frequency of developing clinical MS was higher for those with both brain and spinal cord lesions at baseline (48%) than brain lesions alone (18%). CONCLUSIONS: The combination of baseline MRI abnormalities and new lesions at follow-up, indicating dissemination in space and time, was associated with a high sensitivity and specificity for the early development of clinical MS. These data suggest a potential role for new diagnostic criteria for MS based on early MRI activity. Such criteria may be useful in selecting patients for therapeutic trials at this early clinical stage.

Long term MRI follow-up of patients with post infectious encephalomyelitis: evidence for a monophasic disease.

Post infectious encephalomyelitis and multiple sclerosis are both inflammatory demyelinating disorders of the central nervous system. Whereas multiple sclerosis is a multi phasic disease with recurrent episodes disseminated in time and place, post infectious encephalomyelitis is usually considered to be a monophasic illness. This study used serial brain MRI to clarify whether the latter hypothesis holds for the long term. Post infectious encephalomyelitis was defined as the development of a central nervous system white matter disorder occurring in close temporal relationship with a viral, bacterial or other infection. There were eleven patients, mean age at presentation 21 years (4-48), and mean period of follow-up of 8 years (3.5-11). T2-weighted brain MRI was abnormal in all 11 cases during the acute stages of the illness. On follow-up 6 patients had made a complete clinical recovery, 4 patients had mild residual deficits and one severe neurological deficits necessitating ventilatory support. No patient experienced an exacerbation during the follow-up period. MRI revealed complete resolution of abnormalities in 3 and partial resolution in 7; new white matter lesions were seen in only one patient. This long term follow-up study suggests that there is a definable group with post infectious encephalomyelitis who exhibit a monophasic clinical and MRI pattern in the long term.

Quantitative MRI in patients with clinically isolated syndromes suggestive of demyelination.

OBJECTIVE: To assess the long-term predictive value of quantitative lesion load measurement on brain MRIs in patients after a 10-year follow-up who presented initially with a clinically isolated syndrome of the optic nerve, brainstem, or spinal cord. BACKGROUND: Quantitative MRI measurement is being used in treatment trials as a surrogate marker in MS, but there is a lack of long-term MRI follow-up data in assessing the natural course of the disease from the earliest stages. METHODS: Using a semiautomated threshold technique, the total lesion volume (TLV), the course of the disease, and disability were assessed in 58 patients at onset and after 5 and 10 years. RESULTS: The TLV at presentation correlated significantly (r = 0.81, p = 0.0001) with the TLV and also with the Expanded Disability Status Scale (EDSS) score (r = 0.45, p = 0.001) at 10-year follow-up. In contrast there was no correlation of the TLV at 5 years with subsequent change in EDSS score over the next 5 years (r = 0.18, p = 0.12). The change in TLV over the first 5 years in patients who developed clinically definite MS (CDMS) differed significantly according to the type of disease course (relapsing-remitting with disability, secondary progressive, or benign) manifesting at 10-year follow-up. CONCLUSION: Quantification of changes detected by T2-weighted brain MRI at the earliest clinical stages is strongly predictive of the subsequent development of CDMS as well as the clinical course and level of disability 10 years later.

T1 hypointense lesion load in secondary progressive multiple sclerosis: a comparison of pre versus post contrast loads and of manual versus semi automated threshold techniques for lesion segmentation.

Magnetic resonance imaging (MRI) is increasingly being used as a monitoring tool for disease activity in therapeutic trials in multiple sclerosis. There is, however, only a limited relationship between MRI findings and clinical outcome measurements. It has been suggested that hypointense lesion load on T1 weighted imaging has a better correlation with disability than the more conventional T2 hyper intense lesion load. This study was undertaken to (i) evaluate different measurement techniques used to quantify T1 hypointense lesion load, and (ii) to compare lesion load as measured using different parameters and disability. Twenty-five patients with secondary progressive multiple sclerosis, mean age of 40 years (23-57), mean EDSS 5.7 (4-7) were analysed. T2 lesion load on FSE correlated well with both the hypointense lesion load on T1 pre-gadolinium (r = 0.8, P < 0.0001) and T1 post-gadolinium (r = 0.8, P < 0.0001) but less so with the enhancing lesion load (r = 0.4, P < 0.05). There was a very strong correlation with T1 hypo-intense lesion volume pre and post gadolinium (r = 0.96, P < 0.001). However, the EDSS was not correlated with the T2 lesion load (r = -0.27, P = 0.2), T1 pre-gadolinium load (r = -0.3, P = 0.1), T1 post gadolinium load (r = -0.4, P = 0.7) and enhancing lesion load (r = -0.28, P = 0.2), or with the degree of hypointensity of T1 weighted images determined using the threshold technique. There is a strong correlation between T1 hypointense lesion volume both pre and post gadolinium and also between T1 and T2 lesion volumes.

Asymptomatic spinal cord lesions in clinically isolated optic nerve, brain stem, and spinal cord syndromes suggestive of demyelination.

OBJECTIVES: Conventional T2 weighted MRI studies have highlighted the fact that the presence of clinically silent brain lesions increases the risk of developing clinically definite multiple sclerosis after an isolated syndrome of the optic nerve, brain stem, or spinal cord. The objectives of the present study are: (1) to show whether or not these patients also have asymptomatic abnormalities of the spinal cord, and (2) to recruit a new cohort of such patients using high resolution MRI of both brain and spinal cord. METHODS: The brain was imaged in the axial plane with 3 mm thick contiguous slices using a proton density and T2 weighted fast spin echo (FSE) sequence; a T1 weighted sequence after the injection of gadolinium-DTPA; and a fast fluid attenuated inversion recovery (fFLAIR) sequence. The spinal cord was imaged in the sagittal plane with 3 mm thick slices using a T2 weighted FSE and a T1 weighted gadolinium enhanced sequence. RESULTS: Thirty three patients, mean age 31 (16-46) were recruited. There were 14 men and 19 women. Brain MRI was abnormal in 22 (67%); no patient was seen with abnormalities on only one or other sequence. Six patients (18%) displayed one or more gadolinium enhancing lesions on brain MRI. In the spinal cord, nine (27%) patients displayed one or more clinically silent lesions on FSE. Two patients showed one and two gadolinium enhancing lesions in the spinal cord respectively. CONCLUSION: This high incidence of spinal cord lesions emphasises that asymptomatic demyelinating lesions may also involve clinically eloquent pathways. Follow up studies are required to determine their prognostic importance.

The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up.

A definitive diagnosis of multiple sclerosis cannot be made at presentation on patients with a clinically isolated syndrome of the optic nerve, spinal cord or brainstem suggestive of demyelination, as dissemination in time is not established. To determine the long-term risk of abnormalities on brain MRI for the development of multiple sclerosis and disability we performed a 10-year follow-up on 81 such patients who had T2-weighted brain MRI at presentation. Initial brain MRI was abnormal in 54 (67%). Follow up of those patients with an abnormal MRI revealed progression to clinically definite multiple sclerosis in 45 out of 54 (83%), of whom 11 (20%) had relapsing/remitting disease (EDSS > 3), 13 (24%) secondary progressive and 21 (39%) benign (relapsing/remitting with EDSS < or = 3) disease. For those with a normal MRI progression to clinically definite multiple sclerosis occurred in only three out of 27 (11%), all benign. There was a significant relationship between the number of lesions at presentation and both EDSS (r = 0.45, P < 0.001) and the type of disease at follow-up (P < 0.0001). Brain MRI at presentation with a clinically isolated syndrome is predictive of the long-term risk of subsequent development of multiple sclerosis, the type of disease and extent of disability.

MRI lesion volume measurement in multiple sclerosis and its correlation with disability: a comparison of fast fluid attenuated inversion recovery (fFLAIR) and spin echo sequences.

OBJECTIVES: To assess whether multiple sclerosis lesion volume measurements derived using the fast fluid attenuated inversion recovery (fFLAIR) sequence show better reproducibility or correlation with disability than those derived using the conventional spin echo (CSE) sequence. METHODS: Part I: twenty five patients with multiple sclerosis were scanned with CSE, fast spin echo (FSE), and fFLAIR. Lesion volume was determined twice for each sequence using a local threshold segmentation technique. Part II: fifty six patients with multiple sclerosis were scanned with CSE and fFLAIR. Total and regional brain lesion volumes were compared with the Kurtzke extended disability scale (EDSS) and functional systems scores (FSS). RESULTS: Part I: analysis times were significantly longer for CSE than for FSE or fFLAIR. There was no significant difference in the reproducibility of the three sequences. Part II: total lesion volumes were similar but posterior fossa lesion volumes were significantly greater for CSE and subcortical lesion volumes significantly greater for fFLAIR. There was a significant correlation between total volume and EDSS with both sequences (CSE r=0.49; fFLAIR r=0.44). Correlations for the two sequences showed minor differences when anatomical region and FSS were considered separately. CONCLUSIONS: CSE, FSE, and fFLAIR are equally reproducible; FSE yields lower volumes than CSE; fFLAIR gives similar volumes to CSE but underscores the posterior fossa. Overall clinical correlations are similar for CSE and fFLAIR.

Multiple sclerosis lesion detection in the brain: a comparison of fast fluid-attenuated inversion recovery and conventional T2-weighted dual spin echo.

We performed fast fluid-attenuated inversion recovery (fFLAIR) and conventional spin echo (CSE) brain MRI in 32 multiple sclerosis (MS) patients (eight each benign, relapsing-remitting, primary progressive, and secondary progressive). We compared number and site of lesions detected on each sequence. With initial separate assessment, we identified a total of 3,668 lesions-2,892 by CSE and 2,943 by fFLAIR. Following simultaneous review of the sequences, we identified an additional 217 lesions on fFLAIR and 229 on CSE. fFLAIR detected fewer lesions in the posterior fossa (66 versus 138, p = 0.001), fewer small (< 5 mm) discrete cerebral white matter lesions (671 versus 829, p = 0.0002), more subcortical lesions (542 versus 306, p < 0.0001), and more large discrete lesions (419 versus 385, p = 0.0006). Its relatively poor detection of posterior fossa lesions makes it premature for fFLAIR to replace CSE as the primary sequence for detecting MS lesions in clinical trials.

Central nervous system white matter diseases other than multiple sclerosis.

The essential difference between classical multiple sclerosis and both Devic's neuromyelitis optica and acute disseminated encephalomyelitis are outlined. Advances in identifying the multiple gene mutations responsible for adrenoleukodystrophy and possible mechanisms for the genotypic/phenotypic variability are reviewed.

Offspring recurrence rates and clinical characteristics of conjugal multiple sclerosis.

BACKGROUND: There has been no previous systematic study of conjugal multiple sclerosis. This study of conjugal pairs with complex traits investigated disease transmissibility and the genetic contribution to frequency and clinical course. METHODS: We studied 45 conjugal pairs concordant for multiple sclerosis from 58 pairs recorded in a national register of familial disease, 86 offspring of the 45 pairs were individually assessed for clinical evidence of neurological disease; those over age 16 underwent cranial magnetic resonance imaging. Clinical features were compared in 33 pairs in whom neither member had symptoms before they met. FINDINGS: Of the 86 offspring, five (6%) had clinically definite multiple sclerosis. A further five children had either characteristic imaging abnormalities or clinical symptoms consistent with demyelination, but did not meet the criteria for clinically definite disease. There was no evidence of clinical concordance, clustering at year of onset, or distortion of the expected pattern of age of onset in the second affected spouse from 33 pairs. The crude recurrence in children of conjugal pairs (1 in 17) is significantly higher than previously reported population-based risk for offspring of single affected parents (1 in 200). INTERPRETATION: Taken with the low prevalence of multiple sclerosis in the spouses of affected individuals, and the lack of concordance for age at onset in these families, the disparity in crude recurrence between children of conjugal pairs and those of single affected parents shows that the recurrence risk in children is determined by genetic factors inherited from both parents.

Superficial siderosis of the central nervous system.

Two patients with superficial siderosis of the central nervous system are reported. Both developed progressive deafness over many years; one with associated anosmia and partial seizures; the other with progressive ataxia and diplopia. The cerebrospinal fluid was xanthochromic in one and the protein was raised in both. Magnetic resonance imaging revealed a hypodense rim around the eighth cranial nerve, cerebellum, brain stem and spinal cord. Despite extensive investigations the cause of the superficial siderosis in both patients remains undetermined.

Spinal cord atrophy and disability in multiple sclerosis. A new reproducible and sensitive MRI method with potential to monitor disease progression.

Recent MRI studies in multiple sclerosis have highlighted the potential importance of spinal cord atrophy (implicating axonal loss) in the development of disability. However, the techniques applied in these initial studies have poor reproducibility which limits their application in the serial monitoring of patients. The aim of this study was to develop a highly reproducible and accurate method for the quantification of atrophy. The technique we describe demonstrates an intra-observer coefficient of variation (scan-rescan) of only 0.8%. When applied to 60 patients with clinically definite multiple sclerosis there was a strong correlation between spinal cord area and disability measured by Kurtzke's Expanded Disability Status Scale (EDSS) (r = -0.7, P < 0.001). The correlation was graded providing evidence for a causal connection. At levels 3 and 8 of the EDSS we observed a reduction in average cord area of 12 and 35%, respectively. Given its reproducibility, the magnitude of the change detected and the strong correlation with disability, this new technique should prove to be a sensitive measure of progressive neurological deterioration and could be readily incorporated into imaging protocols aimed at monitoring therapy.