Identifying and treating patients with suboptimal responses.

Multiple sclerosis (MS) is an immune-mediated neurologic disease in which acute inflammatory events early in the disease course contribute to subsequent neurologic disability. The early relapsing inflammatory phase is followed by a progressive degenerative phase in which the frequency of acute inflammatory attacks diminishes but progressive loss of neurologic function continues. Current immune therapies are most effective in suppressing the acute inflammatory events that characterize the earlier stages of disease. Optimal suppression of these inflammatory events is likely to have the best potential for delaying or preventing loss of axons and decline in neurologic function. In view of these considerations, and because MS is a heterogeneous disease and response to disease-modifying agents (DMA) varies across individuals, it is important to identify suboptimal responders as early as possible to allow therapeutic modification while the opportunity to avert future loss of function remains. At present, no criteria for identifying suboptimal responders have been validated. In January 2004, a group of neurologists from 16 MS centers in the United States met to develop a consensus on criteria for defining suboptimal response for use in compelling clinical situations and to prompt clinical studies to validate the efficacy of these criteria. Consensus criteria included relapse rates of either 1/year or unchanged from pretreatment rates, incomplete recovery from multiple attacks, evolution of polyregional neurologic involvement, recurrent brainstem or spinal cord lesions, and cumulative loss of neurologic function sufficient to disrupt daily activities. The panel then considered the use of mitoxantrone for patients with worsening MS and a suboptimal response to DMA therapy.

Fatigue in multiple sclerosis and its relationship to depression and neurologic disability.

We studied multiple sclerosis fatigue (MSF) and its relationship to depression and disability. Seventy-one patients [50 relapsing-remitting, 21 secondary progressive] were grouped by Fatigue Severity Scale (FSS) into MS-fatigue (MSF) (FSS>/=5; n=46) or MS-nonfatigue (MSNF) (FSS

Brain MRI lesions and atrophy are related to depression in multiple sclerosis.

It is unclear whether brain MRI lesions are associated with depression in multiple sclerosis (MS). Neurological dysfunction in depressed (n= 19) and non-depressed (n = 29) MS patients was rated by expanded disability status scale (EDSS). EDSS was weakly predictive of the presence of (p = 0.03) and severity of (p = 0.01) depression. After correcting for EDSS, the presence of depression was predicted by superior frontal and superior parietal hypointense TI lesions (p<0.01); the severity of depression was predicted by superior frontal, superior parietal and temporal TI lesions, lateral and third ventricular enlargement, and frontal atrophy (p<0.01). Depression was not related to bright T2 lesions or enhancement. We conclude that atrophy and cortical-subcortical disconnection due to frontal and parietal white matter destructive lesions may contribute to depression in MS.

Fatigue in multiple sclerosis: cross-sectional correlation with brain MRI findings in 71 patients.

Fatigue is an unexplained but common and disabling symptom in MS. We assessed fatigue in 71 patients with MS and identified MS-fatigue (MSF) and MS-nonfatigue (MSNF) groups. Fatigue severity did not correlate with regional or global MRI plaque load or atrophy assessed by conventional sequences. No significant differences were noted in any MRI measures between MSF and MSNF groups. We suggest that brain MRI disease topography or severity does not explain fatigue in MS and that fatigue is likely due to mechanisms poorly characterized by conventional MRI.

MRI findings in 32 consecutive lipomas using conventional and advanced sequences.

Intracranial lipomas are histologically benign and usually incidental magnetic resonance imaging findings that must be differentiated from ominous lesions. The authors describe 32 lipomas in 30 patients using conventional spin-echo (CSE) T1-weighted images (T1WI), CSE proton density (PDWI), CSE T2-weighted images (T2WI), fast spin-echo (FSE) T2WI, and FSE fluid-attenuated inversion recovery (FLAIR). Lipomas occurred most commonly in the trigonal choroid plexus, cerebral convexity, pericallosal, and quadrigeminal cistern regions. Lipomas were hyperintense on CSE T1WI and of variable appearance on CSE PDWI and CSE T2WI. Lipomas were isointense to hyperintense on FSE T2WI and hyperintense on FLAIR. Chemical shift artifact (CSA) usually was present on either CSE PDWI or CSE T2WI but was not seen on FSE images. One patient had intracranial hypotension associated with a large convexity lipoma. The authors conclude that lipomas appear different on CSE T2WI than on FSE T2WI. CSE PDWI and CSE T2WI are complementary in detecting CSA. The lack of CSA being detected in lipomas on FSE images most likely relates to inherent bandwidth differences compared with those of CSE. The hyperintense appearance of lipomas on FSE FLAIR and FSE T2WI may be confused with subacute hematomas. The authors recommend that if CSE technique by itself is used to exclude lipomas (in centers that are not using FSE), then T1WI, PDWI, and T2WI usually are sufficient. For centers using FSE routinely, fat saturation or CSE sequences also may be needed to exclude lipomas. Finally, the authors' series suggests that intracranial lipomas may occur in lateral locations more frequently than reported previously.

Regression and spreading of self-recognition during the development of autoimmune demyelinating disease.

The autoimmune T cell repertoire in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) is characterized by CD4(+)T cells of the Th1 phenotype that recognize peptide determinants of central nervous system (CNS) myelin proteins in an MHC class II-restricted manner. Our recent studies and those performed by others have shown that progression to chronicity in EAE and MS is accompanied by a broadening of the T cell repertoire with time. This acquired neo-autoreactivity is commonly referred to as epitope spreading and is presumably the result of endogenous priming to new self-determinants during the CNS inflammation that accompanies disease onset and relapse. In the present study we extend our earlier observations by showing that disease progression in both EAE and MS is accompanied by two concurrent events, viz. (1) the spontaneous regression of the primary established autoimmune repertoire associated with disease onset, and (2) the emergence of the epitope spreading cascade associated with disease progression. Our data show that disease initiation and disease progression in both EAE and MS are typically associated with distinctly different autoimmune T cell repertoires. Our data support the view that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an 'epitope du jour' and 'moving target' perspective.

MRI in cerebral intraventricular hemorrhage: analysis of 50 consecutive cases.

MRI of intraventricular haemorrhage (IVH) has not been studied formally. We aimed to describe the degradation rate and patterns shown on 1.5 T MRI in IVH, comparing them to other coexisting brain hemorrhage. We studied 50 consecutive cases using T1-, proton-density, and T2-weighted images. IVH was seen in two forms: layered (free-flowing in ventricles) (37 cases) and/or clotted (31). Both were best shown by proton-density image. Layered IVH was seen in the dependent portions of the lateral ventricles with fluid ("blood-CSF") levels, degrading more slowly than both clotted IVH and intraparenchymal hemorrhages (IPH) (acute blood products persisting for several more days; P < 0.05). Clotted IVH degraded at a rate comparable to IPH. IVH cleared rapidly and did not form hemosiderin. Subarachnoid hemorrhage (SAH) cleared faster and was less conspicuous than IVH. Hypertensive (22), aneurysmal (11), traumatic (2), idiopathic (9), or vascular malformation-related (6) IVH were seen. IVH coexisted with IPH (30) or SAH (12), or both (12). The high rate of layering with blood-CSF levels in IVH is most likely due to different densities of blood components and CSF and the fibrinolytic capability of the latter. Delayed degradation of layered IVH probably reflects high intraventricular oxygen and glucose content. Further study is necessary to determine if MRI characteristics of IVH are helpful in excluding other intraventricular diseases such as neoplasia and pyocephalus.

MRI findings in lumbar puncture headache syndrome: abnormal dural-meningeal and dural venous sinus enhancement.

Intracranial hypotension (IH) is a treatable cause of persistent headaches. Persistent cerebrospinal fluid (CSF) leak at a lumbar puncture (LP) site may cause IH. We present postcontrast MRI of a patient with post-lumbar-puncture headache (LPHA) showing abnormal, intense, diffuse, symmetric, contiguous dural-meningeal (pachymeningeal) enhancement of the supratentorial and infratentorial intracranial dura, including convexities, interhemispheric fissure, tentorium, and falx. MRI also showed abnormal dural venous sinus enhancement, a new finding in LPHA, suggesting compensatory venous expansion. Thus, IH and venodilatation may play a role in the development of LPHA.

Fluid-attenuated inversion-recovery MR imaging in acute and subacute cerebral intraventricular hemorrhage.

BACKGROUND AND PURPOSE: Fluid-attenuated inversion-recovery (FLAIR) MR imaging may show subarachnoid hemorrhage (SAH) with high sensitivity. We hypothesized that the FLAIR technique is effective and reliable in the diagnosis of cerebral intraventricular hemorrhage (IVH). METHODS: Two observers evaluated the 1.5-T MR fast spin-echo FLAIR images, T1- and T2-weighted MR images, and CT scans of 13 patients with IVH and the FLAIR images of 40 control subjects. RESULTS: IVH appeared bright on the FLAIR images obtained during the first 48 hours and was of variable appearance at later stages. FLAIR MR imaging detected 12 of 13 cases of IVH; no control subjects were falsely thought to have IVH (92% sensitivity, 100% specificity). However, IVH could not be fully excluded in the third ventricle (20%, n = 8) or in the fourth ventricle (28%, n = 11) on some control images because of CSF pulsation artifacts. Two cases had CT-negative IVH seen on FLAIR images. One case had FLAIR-negative IVH seen by CT. Although the sensitivities of conventional MR imaging (92%) and CT (85%) were also high, FLAIR imaging showed IVH more conspicuously than did standard MR imaging and CT in 62% of the cases (n = 8). FLAIR was as good as or better than CT in showing IVH in 10 cases (77%). FLAIR images showed all coexisting SAH. CONCLUSION: FLAIR MR imaging identifies acute and subacute IVH in the lateral ventricles with high sensitivity and specificity. In cases of subacute IVH, conventional MR imaging complements FLAIR in detecting IVH. The usefulness of the FLAIR technique for detecting third and fourth ventricular IVH may be compromised by artifacts. Blood hemoglobin degradation most likely causes the variable FLAIR appearance of IVH after the first 48 hours.

Thrombotic thrombocytopenic purpura: brain CT and MRI findings in 12 patients.

Clinical-neuroimaging analysis of 12 thrombotic thrombocytopenic purpura (TTP) patients revealed a variety of brain lesions. These included reversible cerebral edema lesions with MRI features of reversible posterior leukoencephalopathy syndrome (RPLS). Most of the RPLS patients had hypertension and renal dysfunction, suggesting RPLS due to hypertensive encephalopathy. Prompt treatment usually led to neurologic recovery and disappearance of edematous lesions. Those with infarcts or hematomas had a poorer outcome. TTP should be added to the expanding spectrum of RPLS and hypertensive encephalopathy.

Cranial magnetic resonance imaging findings in bacterial endocarditis: the neuroimaging spectrum of septic brain embolization demonstrated in twelve patients.

Infective endocarditis (IE) is an elusive systemic disorder that is often associated with neurologic complications. The contribution of brain magnetic resonance imaging (MRI) to the diagnosis of IE and the spectrum of such findings has been only sparsely described previously. The authors report cranial MRI findings in 12 patients with IE. Each of the patients had MRI evidence of cerebral embolization, with multiple brain lesions noted in most patients (n = 10). Cortical branch infarction was the most common lesion (n = 8), which usually involved the distal middle cerebral artery tree. The next most common finding (n = 7) was numerous small embolic lesions which typically lodged in the supratentorial gray-white junction, some of which were clinically silent and many of which enhanced (probable microabscesses). Brain hemorrhages were noted in four patients, most commonly subarachnoid hemorrhage (n = 3). Two patients developed multiple frank parenchymal macroabscesses/cerebritis lesions. A previously unreported finding in septic embolization, a stroke that became infected with abscess formation ("septic infarction"), was noted in two patients. MRI showed orbital cellulitis in two patients. Most patients studied with gadolinium showed enhancement of lesions (n = 5/8). The authors conclude that cranial MRI may be a valuable tool in the evaluation of patients with IE. The presence of characteristic cranial MRI lesions, especially of multiple types, may prompt early diagnosis and treatment.

The cerebral intravascular enhancement sign is not specific: a contrast-enhanced MRI study.

The intravascular enhancement (IVE) sign, also known as the "arterial enhancement sign", is an abnormal finding in the brain on contrast-enhanced MRI studies. IVE has been described in arterial cerebrovascular disorders, most commonly in acute or subacute arterial ischemic infarcts. However, the specificity of this sign has not been established. We describe four patients with disorders other than arterial strokes in whom gadolinium-enhanced high-field (1.5 T) MRI suggested IVE. The conditions were herpes simplex viral encephalitis, idiopathic cerebellitis, pneumococcal meningitis, and superior sagittal sinus thrombosis with venous infarction. IVE in these cases may be due to multiple factors, including arterial, venous, perivascular, and leptomeningeal or sulcal contrast medium accumulation. Our observations suggest that arterial ischemia, previously described as the cardinal cause of IVE, probably does not explain all instances, and urge caution in interpreting this sign as a specific MRI manifestation of acute arterial infarction or ischemia.

Cerebral venous infarctions presenting as enhancing space-occupying lesions: MRI findings.

Cerebral venous thrombosis is an unusual form of cerebrovascular disease that may cause cerebral venous infarction (CVI). Magnetic resonance imaging (MRI) of the brain may improve the often elusive diagnosis of CVI. However, the sensitivity, specificity, and full spectrum of such MRI findings are poorly understood. The authors present the cases of three patients with CVI whose MRI scans showed abnormally enhancing tumor-like brain lesions. Two of the CVIs were hemorrhagic and exerted mass effect. One patient showed increasingly nodular and heterogeneous ring-like enhancement progressing from the single-dose to the triple-dose gadolinium contrast images. The CVI of a second patient also showed ring-like enhancement. Biopsy was performed on one of these patients and was strongly considered for the other two patients to exclude neoplastic disease. Careful examination of the MRI appearance of venous structures and the use of specialized MRI techniques improved the recognition of CVI for two patients and prevented biopsy. This represents the first description of abnormal triple-dose MRI contrast enhancement in CVI. Consideration of CVI in the care of patients with enhancing tumor-like masses may lead to earlier diagnosis and treatment, preventing unnecessary invasive diagnostic procedures. CVI should be added to the differential diagnosis of supratentorial ring-enhancing masses.

High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis.

The authors study brain regional glucose metabolism prospectively in multiple sclerosis (MS) using high-resolution 2-[18-F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in 25 MS patients of the Dent Neurologic Institute compared with 6 healthy subjects. Glucose metabolism is measured in 20 regions of interest using a line-profile technique. Compared with control subjects, a 9% reduction in total brain glucose metabolism is noted in MS patients (p < 0.05). Hypometabolism is widespread, including the cerebral cortex, subcortical nuclei, supratentorial white matter, and infratentorial structures. This reduction represents absolute regional decreases ranging from 3% to 18%. The most dramatic absolute reductions occur in the superior mesial frontal cortex, superior dorsolateral frontal cortex, mesial occipital cortex, lateral occipital cortex, deep inferior parietal white matter, and pons. The regional hypometabolism in the superior mesial frontal cortex and superior dorsolateral frontal cortex is statistically significant (p < 0.05), whereas the changes in the mesial occipital cortex (p = 0.07) and the lateral occipital cortex (p = 0.09) approach significance. The authors' findings suggest that widespread cerebral dysfunction occurs in MS, and that diaschisis or neuronal system disconnection resulting from white matter disease plays a major role. Cortical gray matter hypometabolism may also reflect direct MS involvement. The quantitative cerebral abnormalities detected by FDG PET may serve as a marker of disease activity in understanding the pathophysiological expression and therapeutic response of MS.

Occipital lobe seizures as the major clinical manifestation of reversible posterior leukoencephalopathy syndrome: magnetic resonance imaging findings.

PURPOSE: Reversible posterior leukoencephalopathy syndrome (RPLS) is an increasingly recognized brain disorder most commonly associated with malignant hypertension, toxemia of pregnancy, or the use of immunosuppressive agents. When associated with acute hypertension, RPLS typically occurs concurrently with the fulminant clinical syndrome of hypertensive encephalopathy. We describe occipital lobe seizures, in the setting of only moderate elevations of blood pressure, as the major clinical manifestation of RPLS. METHODS: Two patients from the Dent Neurologic Institute are presented with clinical and magnetic resonance imaging (MRI) correlation. RESULTS: New onset secondarily generalized occipital seizures were noted, with MRI findings consistent with RPLS. Both of the patients had chronic renal failure and a moderate acute exacerbation of chronic hypertension. Other features of hypertensive encephalopathy were lacking, such as headache, nausea, papilledema, and an altered sensorium. Magnetic resonance imaging (MRI) showed edematous lesions primarily involving the posterior supratentorial white matter and corticomedullary junction, consistent with RPLS. With lowered blood pressure, the MRI lesions resolved and the patients became seizure-free without requiring chronic anticonvulsant therapy. CONCLUSIONS: Occipital seizures may represent the only major neurologic manifestation of RPLS due to acute hypertension, especially in patients with renal failure. Other evidence of hypertensive encephalopathy, such as cerebral signs and symptoms, need not be present. Blood pressure elevations may be only moderate. Early recognition of this readily treatable cause of occipital seizures may obviate the need for extensive, invasive investigations. Despite the impressive lesions on MRI, prompt treatment of this disorder carries a favorable prognosis.

Magnetic resonance imaging findings in acute cerebellitis.

Cerebellitis, also known as acute cerebellar ataxia, is an inflammatory syndrome of cerebellar dysfunction that may reflect an infectious, post-infectious, or post-vaccination disorder. We present serial magnetic resonance imaging (MRI) findings in a partially reversible, idiopathic cerebellitis. Bilateral cerebellar parenchymal abnormalities were noted, including hyperintensities on T2-weighted images and cerebellar swelling. After contrast administration, the cerebellum showed abnormal bilateral enhancement. The authors state this represents the first report of abnormal contrast enhancement in this condition. The MRI lesions most likely reflect the reversible, inflammatory nature of the syndrome.

Cerebral ventricular empyema associated with severe adult pyogenic meningitis: computed tomography findings.

Cerebral ventricular empyema (CVE), also known as pyocephalus, is a rare form of pyogenic ventriculitis. We present cranial computed tomography (CT) in an adult who developed a bilateral CVE associated with acute pyogenic meningitis. CT showed an obstructive ventriculomegaly and fluid-fluid levels layering in the lateral ventricles and the third ventricle. Frank neutrophilic pus was taken from the subarachnoid space. After antibiotic treatment, the pyocephalus resolved. CVE may be visualized on CT with pus layering in the ventricular CSF, creating a fluid level of intermediate hypodensity.

Effects of treatment with lovastatin and pravastatin on daytime cognitive performance.

The HMG-CoA reductase inhibitors lovastatin and pravastatin have both proven to be effective and well tolerated in the treatment of hypercholesterolemia. To evaluate whether lovastatin or pravastatin might affect daytime cognitive function, a double-blind, placebo-controlled, two-period, incomplete block, crossover study was performed in 36 patients (24 per treatment) with primary hypercholesterolemia. Patients received placebo, lovastatin (40 mg), or pravastatin (40 mg) for 4 weeks. Following a 1-week washout period, patients were crossed over to either lovastatin, pravastatin, or placebo for an additional 4 weeks. Mental performance tests (digit symbol substitution, choice reaction time, auditory vigilance, selective reminding word recall, finger tapping), visual analogue rating scales, and the Profile of Mood States were administered before test drug administration and after 2 and 4 weeks of each treatment. After 4 weeks, no statistically significant differences between treatments in changes from baseline were observed on any parameter with the exception of digit symbol substitution, for which lovastatin and pravastatin were both significantly better than placebo but did not differ from each other. Low-density lipoprotein cholesterol was reduced 38% by lovastatin and 30% by pravastatin. In summary, neither of these chemically distinct HMG-CoA reductase inhibitors impaired daytime cognitive performance after 4 weeks of treatment in patients with primary hypercholesterolemia.

Multiple giant intracranial aneurysms associated with lymphomatoid granulomatosis. A magnetic resonance imaging and angiographic study.

Lymphomatoid granulomatosis is an uncommon lymphoproliferative disorder that frequently has central nervous system manifestations. Lymphomatoid granulomatosis has clinical features similar to both vasculitis and lymphoma. The pathological hallmarks of this disease include necrotic angiocentric and angiodestructive infiltrations of premalignant or malignant lymphoid cells. There are, to the authors' knowledge, only a few magnetic resonance imaging reports and no magnetic resonance angiographic reports of this disorder. Presented here is a case of lymphomatoid granulomatosis producing multiple giant fusiform and saccular aneurysms throughout the major intracerebral arteries, along with patterns of vascular beading typically seen with vasculitis demonstrated by magnetic resonance angiography.