Dh Miller

Diffusion tensor imaging of lesions and normal-appearing white matter in multiple sclerosis

Objective: To determine whether diffusion tensor imaging (DTI) can detect structural changes in normal-appearing white matter, and to distinguish between plaques of different pathologic severity, in patients with MS. Background: Conventional MRI detects lesions sensitively in MS but has limited pathologic specificity. The diffusion of water molecules in brain tissue, most fully expressed mathematically by a tensor quantity, reflects its intrinsic microstructure. It is now possible to estimate the diffusion tensor noninvasively in the human brain using MR DTI. This method is unique in providing precise and rotationally invariant measurements of the amount and directional bias (anisotropy) of diffusion in white matter tracts relating to tissue integrity and orientation. Methods: DTI was performed in six patients with MS and in six age-matched control subjects. Diffusion was characterized in normal-appearing white matter in both groups, and in lesions of different pathologic subtypes (inflammatory, noninflammatory, T1 hypointense, and T1 isointense). Results: DTI identified significantly altered water diffusion properties in the normal-appearing white matter of patients compared with control subjects (p < 0.001), and distinguished between lesion types. The highest diffusion was seen in destructive (T1 hypointense) lesions, whereas the greatest change in anisotropy was found in inflammatory (gadolinium-enhancing) lesions. Conclusions: DTI detects diffuse abnormalities in the normal-appearing white matter of MS patients, and the findings in lesions appear to relate to pathologic severity. Its use in serial studies and in larger clinical cohorts may increase our understanding of pathogenetic mechanisms of reversible and persistent disability.

Differential diagnosis of suspected multiple sclerosis: a consensus approach

Background and objectives Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. Methods Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. Results We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of “clinically isolated syndromes” (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. Conclusions Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

Therapeutic effect of mitoxantrone combined with methylprednisolone in multiple sclerosis: a randomised multicentre study of active disease using MRI and clinical criteria.

OBJECTIVE: To evaluate the efficiency of mitoxantrone in multiple sclerosis. METHODS: Forty two patients with confirmed multiple sclerosis, selected as having a very active disease on clinical and MRI criteria were randomised to receive either mitoxantrone (20 mg intravenously (IV) monthly) and methylprednisolone (1 g iv monthly) or methylprednisolone alone over six months. In the steroid alone group five patients dropped out due to severe exacerbation. RESULTS: Blinded analysis of MRI data showed significantly more patients with no new enhancing lesions in the mitoxantrone group compared with the steroid alone group, (90% v 31%, P < 0.001). In the mitoxantrone group there was a month by month decrease almost to zero in the number of new enhancing lesions, and in the total number of enhancing lesions, whereas both remained high in the steroid alone group. The differences were significant for both indices at all months from 1-6. Unblinded clinical assessments showed a significant improvement in change in EDSS at months 2-6 in the mitoxantrone group, with a final mean improvement of more than one point (-1.1 v + 0.3; P < 0.001). There was a significant reduction in the number of relapses (7 v 31; P < 0.01), and an increase in the number of patients free of exacerbation (14 v 7; P < 0.05). CONCLUSION: In this selected group of patients with multiple sclerosis with very active disease, mitoxantrone combined with methylprednisolone was effective in improving both clinical and MRI indices of disease activity over a period of six months whereas methylprednisolone alone was not. Further double blinded long term studies are needed to properly evaluate the effect of mitoxantrone on progression in disability.

Diagnostic criteria for primary progressive multiple sclerosis: a position paper.

The unique clinical characteristics of primary progressive multiple sclerosis (PPMS) pose particular diagnostic difficulties, both in excluding other causes of progressive syndromes and in confirming the diagnosis of MS, which is not adequately addressed by current diagnostic criteria. This article presents new diagnostic criteria developed by a group of investigators on the basis of a review of their considerable experience with PPMS. (We conclude that at least 1 year of clinical progression must be documented before a diagnosis of PPMS is made.) Three levels of diagnostic certainty have been defined—definite, probable, and possible—based on clinical findings, abnormal cerebrospinal fluid, abnormalities on magnetic resonance imaging (MRI) of the brain and spinal cord, and evoked potentials. In definite PPMS, evidence of intrathecal synthesis of immunoglobulin G together with one of the following three MRI criteria is required: (1) nine brain lesions, (2) two spinal cord lesions, or (3) four to eight brain lesions and one spinal cord lesion. Preliminary testing of these criteria was carried out on a cohort of 156 patients participating in a European natural history study of PPMS: 64% fulfilled the criteria for definite PPMS, 35% for probable PPMS, and only 1% for possible PPMS. These criteria now require prospective validation in a cohort of newly diagnosed patients and by postmortem examination. Ann Neurol 2000;47:831–835

Clinical, CSF, and MRI findings in Devic's neuromyelitis optica.

OBJECTIVES: Since Devics original description of neuromyelitis optica in 1894 there has been much debate regarding its aetiology. A specific cause has been identified in a minority of cases but in most the question has arisen whether or not Devics neuromyelitis optica is a variant of multiple sclerosis. This study was undertaken to help clarify this issue. METHODS: Neuromyelitis optica was defined as (1) a severe transverse myelitis; (2) an acute unilateral or bilateral optic neuropathy; (3) no clinical involvement beyond the spinal cord or optic nerves, and (4) a monophasic or multiphasic illness. The clinical and autoantibody status was documented. Patients underwent CSF examination and MRI of brain and spinal cord. RESULTS: Twelve patients, with a mean age of presentation of 35.1 years, were seen. Eleven were women; vision was reduced to counting fingers or worse in 10 patients and seven became confined to a wheelchair. Examination of CSF showed local synthesis of oligoclonal bands in only two patients and a neutrophil pleocytosis in two. A possible aetiology was identified in five: a specific connective tissue disorder (two), pulmonary tuberculosis (one), and possible acute disseminated encephalomyelitis (two). Six had non-specific increases in various autoantibodies. Eleven patients underwent MRI of the brain and spinal cord. In 10 there were diffuse abnormalities involving cervical and thoracic cords with extensive swelling in the acute phase. Brain MRI was normal in five; in five there were multiple deep white matter lesions, and one patient had minor age related changes. CONCLUSION: It is proposed that Devics neuromyelitis optica is a distinctive disorder with some clinical, CSF, and MRI features different from those found in classic multiple sclerosis. In most cases a specific aetiology is not identified, but an immunological mechanism of tissue damage seems likely.

Investigation of MS normal-appearing brain using diffusion tensor MRI with clinical correlations

Objective: To quantitatively investigate water diffusion changes in normal-appearing white matter (NAWM) and gray matter in patients with MS, and to evaluate whether these changes are correlated with clinical disability and disease duration. Background: Diffusion tensor imaging provides quantitative information about the magnitude and directionality (anisotropy) of water diffusion in vivo and detects pathologic changes in MS brain tissue. Methods: Diffusion tensor imaging was performed in 39 patients with MS and in 21 age-matched control subjects. Quantitative indices, including fractional anisotropy, volume ratio, and mean diffusivity, were obtained in 30 regions of interest located in normal-appearing basal ganglia, cerebellar gray matter, and supratentorial and infratentorial NAWM. Results: Patients with MS showed significantly reduced anisotropy and a trend toward increased diffusivity in the infratentorial and supratentorial NAWM, and significantly increased anisotropy in the basal ganglia. In all patients with MS, both fractional anisotropy and mean diffusivity in the cerebral peduncles were inversely correlated with the Expanded Disability Status Scale and pyramidal functional scores. In patients with relapsing-remitting MS, there was a strong correlation between Expanded Disability Status Scale score and fractional anisotropy in both supratentorial and infratentorial NAWM. In primary and secondary progressive MS, disease duration correlated strongly with mean diffusivity in infratentorial NAWM and fractional anisotropy in the cerebral peduncles, respectively. Conclusion: The most striking finding of decreased fractional anisotropy in supratentorial and infratentorial NAWM and increased fractional anisotropy in basal ganglia may result from axonal degeneration due to fiber transection in remote focal lesions. Diffusion tensor imaging indices, in particular fractional anisotropy, appear sensitive to structural damage in NAWM that is associated with disability and progression in MS.

Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis

We performed semiautomated quantitative measurement of brain magnetic resonance imaging (MRI) abnormalities seen at presentation and at 5-year follow-up in 84 patients presenting with an acute clinically isolated syndrome of the optic nerves, brainstem, or spinal cord suggestive of multiple sclerosis (MS). At follow-up, 34 (40%) had developed clinically definite and four (5%) clinically probable MS. Patients who developed MS during follow-up had a higher lesion load at presentation than those who did not. There was a strong correlation of the MRI lesion load at presentation with both the increase in lesion load over the next 5 years and disability at follow-up. Increasing initial lesion load correlated with a decreasing time to development of MS clinically (r = −0.328, p <0.05). At follow-up, disability and brain lesion load were strongly correlated in patients who had developed MS. These results establish that MRI at presentation with clinically isolated syndromes suggestive of MS is useful in predicting the subsequent clinical course and the development of new MRI lesions. This suggests that quantitative brain MRI will be helpful in selecting patients with early clinical MS for treatment trials and for subsequent monitoring of their response to treatment.

Neuropathological abnormalities of the corpus callosum in schizophrenia: a diffusion tensor imaging study

OBJECTIVES Diffusion tensor imaging (DTI), a technique capable of examining water diffusion in different tissues and the organisation of white matter tracts, was used to investigate the neuropathology of the corpus callosum in vivo in patients with schizophrenia. METHODS Diffusion tensor imaging was performed in 20 schizophrenic patients and 25 healthy controls. Two complementary measures, mean diffusivity and fractional anisotropy, which are considered to be sensitive indices of axonal integrity, were obtained from regions of interest in the genu (anterior) and splenium (posterior) of the corpus callosum. RESULTS Mean diffusivity was significantly increased and fractional anisotropy significantly reduced in the splenium but not the genu of the corpus callosum in the schizophrenic group compared with controls. There were no significant sex differences in the DTI measures for either the schizophrenic or control group. Clinical variables such as age, duration of illness, dose of antipsychotic medication, and schizophrenic symptoms did not predict the DTI changes in the schizophrenic patients. CONCLUSIONS The presence of DTI changes in the splenium but not the genu of the corpus callosum suggests that there may be a focal disruption of commisural connectivity in schizophrenia. However, these findings do not exclude the possibility of abnormalities in other areas of the corpus callosum or other regions of white matter and further research using different methods of analysis may enable us to clarify this. Diffusion tensor imaging is a valuable tool in investigating the structure of white matter in schizophrenia.

Disease activity return during natalizumab treatment interruption in patients with multiple sclerosis

Background: Due to a heightened risk of progressive multifocal leukoencephalopathy (PML) with increased natalizumab exposure, some physicians interrupt treatment of patients with multiple sclerosis (MS) despite a lack of data regarding the safety of treatment interruption, the rate and severity of MS disease activity return after treatment interruption, or alternative treatment strategies. Objectives: To determine the effects of natalizumab treatment interruption on clinical and MRI measures of disease activity in relapsing patients with MS. Methods: Clinical relapses and gadolinium-enhanced (Gd+) lesions were analyzed over an 8-month period in patients from the AFFIRM, SENTINEL, and GLANCE studies of natalizumab, and their respective safety extension studies, following the voluntary suspension of natalizumab dosing that occurred in February 2005. Results: Relapses were analyzed in 1,866 patients, and Gd+ lesions were analyzed in 341 patients. Annualized relapse rates and Gd+ lesions both increased shortly after natalizumab interruption and peaked between 4 and 7 months. A consistent return of disease activity was observed regardless of overall natalizumab exposure, whether or not patients received alternative MS therapies, and in patients with highly active MS disease. A rebound of relapse or Gd+ lesion activity, beyond placebo-treated levels from the clinical studies, was not observed in any of the analyses conducted. Conclusions: Following interruption of natalizumab treatment, MS disease activity returned in a pattern that was consistent with known pharmacokinetic and pharmacodynamic properties of natalizumab, and did not show evidence of rebound.

The incidence and significance of anti-natalizumab antibodies : Results from AFFIRM and SENTINEL

Objective: To determine the incidence and clinical effects of antibodies that develop during treatment with natalizumab. Methods: In two randomized, double-blind, placebo-controlled studies (natalizumab safety and efficacy in relapsing remitting multiple sclerosis [MS, AFFIRM] and safety and efficacy of natalizumab in combination with interferon β-1a [INFβ1a] in patients with relapsing remitting MS [SENTINEL]) of patients with relapsing multiple sclerosis, blood samples were obtained at baseline and every 12 weeks to determine the presence of antibodies against natalizumab. Antibodies to natalizumab were measured using an ELISA. Patients were categorized as “transiently positive” if they had detectable antibodies (≥0.5 μg/mL) at a single time point or “persistently positive” if they had antibodies at two or more time points ≥6 weeks apart. Results: In the AFFIRM study, antibodies were detected in 57 of 625 (9%) of natalizumab-treated patients: Twenty (3%) were transiently positive and 37 (6%) were persistently positive. Persistently positive patients showed a loss of clinical efficacy as measured by disability progression (p ≤ 0.05), relapse rate (p = 0.009), and MRI (p ≤ 0.05) compared with antibody-negative patients. In transiently positive patients, full efficacy was achieved after approximately 6 months of treatment, the time when patients were becoming antibody negative. The incidence of infusion-related adverse events was significantly higher in persistently positive patients. Results of SENTINEL were similar to AFFIRM, except with regard to sustained disability progression; differences between persistently positive and antibody-negative patients were not statistically significant. Conclusions: The incidence of persistent antibody positivity associated with natalizumab is 6%. Reduced clinical efficacy is apparent in persistently positive patients. Patients with a suboptimal clinical response or persistent infusion-related adverse events should be considered for antibody testing. GLOSSARY: BLQ = below the limit of quantification; EDSS = Expanded Disability Status Scale; Gd+ = gadolinium enhancing; IFNβ1a = interferon β-1a; MS = multiple sclerosis; MSFC = multiple sclerosis functional composite; OD = optical density.