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Objective: To describe the brain MRI characteristics of hereditary diffuse leukoencephalopathy with spheroids (HDLS) with known mutations in the colony-stimulating factor 1 receptor gene (CSF1R) on chromosome 5. Methods: We reviewed 20 brain MRI scans of 15 patients with autopsy- or biopsy-verified HDLS and CSF1R mutations. We assessed sagittal T1-, axial T1-, T2-, proton density-weighted and axial fluid-attenuated inversion recovery images for distribution of white matter lesions (WMLs), gray matter involvement, and atrophy. We calculated a severity score based on a point system (0-57) for each MRI scan. Results: Of the patients, 93% (14 of 15) demonstrated localized WMLs with deep and subcortical involvement, whereas one patient revealed generalized WMLs. All WMLs were bilateral but asymmetric and predominantly frontal. Fourteen patients had a rapidly progressive clinical course with an initial MRI mean total severity score of 16.7 points (range 10-33.5). Gray matter pathology and brainstem atrophy were absent, and the corticospinal tracts were involved late in the disease course. There was no enhancement, and there was minimal cerebellar pathology. Conclusion: Recognition of the typical MRI patterns of HDLS and the use of an MRI severity score might help during the diagnostic evaluation to characterize the natural history and to monitor potential future treatments. Indicators of rapid disease progression were symptomatic disease onset before 45 years, female sex, WMLs extending beyond the frontal regions, a MRI severity score greater than 15 points, and mutation type of deletion. Neurology (R) 2012;79:566-574

Purpose of review The cause of multiple sclerosis (MS) has eluded medical science for over a century. Pierre Marie speculated that MS is an infectious disease and this paradigm has had a prominent place in the discussion. A number of candidate pathogens have been proposed, but most have not survived scrutiny. In this review, we summarize the evidence that MS is caused by Epstein-Barr virus (EBV), which has been a prominent candidate for several decades. Although there is much suggestive evidence that EBV is involved in the pathogenesis of MS, the precise effect of EBV is still unclear. Recent findings EBV is more common in MS patients than in controls. A history of infectious mononucleosis, and high baseline EBV antibody titers are risk factors for MS. More controversial are findings of changes in the reactivity of the T-cell repertoire, presence of EBV antibodies in the cerebrospinal fluid, and presence of EBV in meningeal lymphoid follicles and perivenular infiltrates in the white matter. Summary The contribution of EBV to the cause of MS is not yet established, but a relationship is clearly present.

Leber hereditary optic neuropathy (LHON) is rarely associated with multiple sclerosis-like features. We present a case of a 65-year-old African American woman with LHON masquerading as neuromyelitis optica (NMO). We highlight the features of the clinical examination and MRI that were suggestive of an alternative diagnosis and review the literature regarding LHON and multiple sclerosis. The diagnosis of LHON should be considered in all cases of acute or subacute bilateral optic neuropathy, including presumed seronegative NMO.

Inflammatory-mediated demyelination of the central nervous system with well-recognized axonal injury has been described for over a hundred years. Yet, many pathologic aspects of multiple sclerosis remain poorly understood (Noseworthy et al ., 2000). Clinically, a high proportion of patients with relapsing–remitting disease advance to the secondary progressive stage of the disease (Lublin and Reingold, 1996). In contrast, ∼15% of patients never experience clinical relapses and demonstrate a steadily progressive phenotype from onset. The ability of available therapies, approved for the relapsing–remitting form of the illness, to modify the disease course in secondary or primary progressive multiple sclerosis is dismal (Compston and Coles, 2008). Paradoxically, success of the immunopathologic ‘line of thinking’ has revealed numerous deficiencies in our understanding of the neurobiology of the disease, including interdependence of the axon and oligodendrocyte (Piaton et al ., 2010). At the heart of this broadening discussion of multiple sclerosis pathology is the question of what triggers disease progression and the mechanisms that lead to increased disability. One area of research germane to this question is the expansion of focal inflammatory demyelinating lesions and the remyelinating capacity of the central nervous system in progressive phenotypes, i.e. secondary and primary progressive multiple sclerosis. Extensive cortical demyelination is a cardinal feature of progressive disease and presumably the cause of many symptoms of late-stage multiple sclerosis. Axonal injury and loss occur in association with activity of the adaptive immune response, thus leading to the question as to why this inflammation is resistant to the anti-inflammatory effects of existing therapies (Kutzelnigg et al ., 2005; Frischer et al ., 2009). The answer may partly lie in the slowly expanding demyelinating ‘front’ and the remyelinating capacity of focal lesions in the central nervous system, although much has yet to be learned about axonal–glial interactions and the state …

Importance of the field: Multiple sclerosis (MS) is a neurologic disease that is the most common nontraumatic cause of serious disability in young adults. Areas covered in this review: We discuss the natural history of the disease, methods of measuring disease activity and burden, and cellular and molecular mechanisms of damage, in particular recent advances. These imply new therapeutic targets, which are beginning to be tested in animal models of MS as well as in patients. What the reader will gain: The reader will learn about some recent advances in understanding MS, especially the evolution from an inflammatory phase to a neurodegenerative phase, which have different therapeutic approaches. Take home message: MS has a long-term course of accumulating deficit in which neuroinflammation evolves into neurodegeneration, which require different treatment strategies – immune modulation and neuroprotection. Neuroprotective strategies are still under development.

Glatiramer acetate is an immunomodulating drug used in the treatment of multiple sclerosis. It consists of a copolymer of amino acid residues in the same stoichiometric proportions as in myelin basic protein. Its mechanism of action is not entirely known and is probably multifaceted, with deletion of some immune cell populations and stimulation of others in these patients. Some mechanisms involve neuroprotectant effects. There is ample evidence of its efficacy in relapsing-remitting disease, using both clinical and imaging measures of disease activity, and in this paper we review the clinical and basic studies of this drug. Finally we discuss how some of its neuroprotectant effects may be useful in neurodegeneration such as is seen in more advanced cases of multiple sclerosis and other diseases such as amyotrophic lateral sclerosis and Parkinson’s disease.

We examined the clinical course after switching disease-modifying therapy (DMT) in patients with relapsing-remitting multiple sclerosis (RRMS). Eighty-five consecutive RRMS patients who received weekly interferon beta-1a (IFN beta-1a) 6 MU i.m. for at least 18 months were enrolled. Baseline annualized relapse rate (ARR) for the 2 years prior to initiating therapy with IFN beta-1a was obtained from charts. All 85 patients received treatment with IFN beta-1a at 6 MU i.m. weekly for 18-24 months (mean 19.7 months). Treatment with IFN beta-1a reduced the mean ARR from 1.41 to 1.23 (P=0.005). All 85 patients were then switched to glatiramer acetate (GA) 20 mg s.c. daily and prospectively followed up for 36-42 months (mean 37.5 months). Patients were switched because of persistent clinical disease activity (n=62) or persistently unacceptable toxicity (n=23) as determined by the treating neurologist. Treatment with GA reduced the mean ARR from 1.23 to 0.53 (P=0.0001). Subgroup analysis showed that in patients who were switched because of lack of efficacy (n=62), the mean ARR was reduced from 1.32 on IFN beta-1a to 0.52 on GA (P=0.0001). In contrast, in patients who switched because of persistent toxicity (n=23), the mean ARR was reduced from 0.61 on IFN beta-1a to 0.47 on GA (P, non-significant). Our observations suggest that clinical observations such as relapse rate and tolerability may be used as criteria for switching DMT in clinical practice. More definitive consensus criteria incorporating magnetic resonance imaging and clinical observations for defining optimal response and tolerability need to be developed for the routine clinical management of RRMS patients receiving DMT.

Unilateral retrobulbar optic neuritis developed in a 43-year-old man with acquired immune deficiency syndrome (AIDS). This was secondary to varicella zoster virus (VZV) as confirmed by cerebrospinal fluid (CSF) polymerase chain reaction (PCR) detection of VZV in the cerebrospinal fluid. There was no typical cutaneous infection and no evidence of retinitis. The onset of unexplained visual loss due to optic neuritis in HIV positive individuals may be due to VZV infection. Prompt recognition, and early intervention with antiVZV therapy may preserve vision. Retrobulbar optic neuritis secondary to VZV infection should be considered in immunocompromised patients even in the absence of cutaneous or retinal lesions. Previous cases are reviewed and the varied nature of viral transport in the nervous system is noted.

Objective: To evaluate the efficacy and tolerability of lamotrigine (LTG) for the treatment of pain in HIV-associated sensory neuropathies. Methods: In a randomized, double-blind study, patients with HIV-associated distal sensory polyneuropathy (DSP) received LTG or placebo during a 7-week dose escalation phase followed by a 4-week maintenance phase. Randomization was stratified according to whether or not patients were currently using neurotoxic antiretroviral therapy (ART). Results: The number of patients randomized was 92 (62 LTG, 30 placebo) in the stratum receiving neurotoxic ART and 135 (88 LTG, 47 placebo) in the stratum not receiving neurotoxic ART. Mean change from baseline in Gracely Pain Scale score for average pain was not different between LTG and placebo at the end of the maintenance phase in either stratum, but the slope of the change in Gracely Pain Scale score for average pain reflected greater improvement with LTG than with placebo in the stratum receiving neurotoxic ART ( p = 0.004), as did the mean change from baseline scores on the Visual Analogue Scale for Pain Intensity and the McGill Pain Assessment Scale and patient and clinician ratings of global impression of change in pain ( p ≤ 0.02). The incidence of adverse events, including rash, was similar between LTG and placebo. Conclusions: Lamotrigine was well-tolerated and effective for HIV-associated neuropathic pain in patients receiving neurotoxic antiretroviral therapy. Additional research is warranted to understand the differing response among patients receiving neurotoxic antiretroviral therapy compared with those not receiving neurotoxic antiretroviral therapy.

Epstein-Barr virus (EBV) is a double-stranded DNA virus of 172 kbp. It is classified as a lymphocryptovirus in the gammaherpesvirus group. Infection with EBV is very common, usually occurring early in life, and is endemic in all human populations. There are two main types of EBV infection, lytic and latent. The infection occurs even in populations that are geographically isolated, thus indicating that EBV is a fairly ancient virus. Encephalitis is an uncommon manifestation of acute EBV infection but is well described. The diagnosis of EBV-related disease must be planned thoughtfully, choosing appropriate methods to answer well-defined questions. Primary central nervous system (CNS) lymphomas (PCNSL) is an EBV-associated opportunistic neoplasm of the brain found in patients with very advanced HIV disease, having very low CD4+ T-cell counts. This is the most common CNS manifestation of EBV infection in AIDS patients, although with the advent of highly effective combination antiretroviral therapy, the disease has become quite uncommon. Infection with EBV is common and lifelong in humans and rarely results in severe disease. Treatment of opportunistic neoplasms is difficult, and the prognosis is still not very good despite the progress that has been made in understanding these tumors. On the other hand, recent basic research has suggested a number of new approaches, and much clinical trial work remains to be done.

The 1980s brought a story in the setting of the emerging disease AIDS. Here, retinitis, gastrointestinal disease, and nervous system infection predominated. Cytomegalovirus (CMV) is an enveloped double-stranded DNA virus in the beta subgroup of the herpesvirus family. Well-documented shedding of virus in human breast milk, urine, saliva, tears, semen, and cervical secretions, some of which occurs in healthy hosts, suggests that epithelial cells may harbor latent but reactivatable virus. Autopsy studies of homosexual men with AIDS have shown that multiple strains of CMV can infect different tissues. Longitudinal serial isolates from homosexual men show that 29% have two or more strains and semen was the most common site of viral shedding (40%). The pathology of CMV radiculomyelitis usually consists of inflammation and necrosis, with typical cytomegalic inclusion cells in the lumbosacral roots. The broad spectrum of observed central nervous system (CNS) disease in AIDS is likely related to a broader range of viral load secondary to the immunodeficiency. The hematogenous-endothelial mode of entry is postulated to lead to diffuse disease. There is one report of its successful use in AIDS-associated ventriculoencephalitis with both clinical improvement and reversion of CSF to CMV negative by PCR.

A prospective, non-randomized, open-label treatment trial was performed in patients with relapsing-remitting multiple sclerosis (RRMS), with follow up for 12 months. Our primary objective was to prospectively compare the effect of IFNbeta-1a (Avonex), IFNbeta-1b (Betaseron), and glatiramer acetate (GA, Copaxone) on the relapse rate in patients with RRMS. Between August 1996 and September 1999, 156 consecutive patients with clinically definite RRMS with a Kurtzke scale (EDSS) score of 4 or less were followed for 12 months, from the time of initiating therapy or electing to remain untreated. Prior 2-year relapse history and available chart information was carefully reviewed at the time of enrolment. Thirty-three of 156 elected no treatment (mean age 32.5 years; mean EDSS 2.64) at enrolment; 40 elected IFNbeta-1a (mean age 32.4 years; mean EDSS 2.69), 41 IFNbeta-1b (mean age 32.1 years; mean EDSS 2.56), and 42 chose GA (mean age 31.5 years; mean EDSS 2.57). Annual relapse rate based upon the 2 years prior to enrolment was 1.08 in the untreated group, 1.20 in the AV group, 1.21 in the BE group, and 1.10 in the GA group. There were no statistically significant differences among the four groups at enrolment. After 12 months of treatment, patients in the untreated groups had a relapse rate of 0.97, whereas patients in the IFNbeta-1a, IFNbeta-1b, and GA groups had relapse rate of 0.85, 0.61, and 0.62, respectively. Compared to the untreated group, reduction in the relapse rate was statistically significant only in the GA (P=0.003) and IFNbeta-1b (P=0.002) groups, in contrast to the IFNbeta-1a treated patients, who did not show a significant reduction (P=0.309). Compared to the untreated patients, mean EDSS was significantly reduced only in the GA (P=0.001) and IFNbeta-1b (P=0.01), in contrast to IFNbeta-1a treated patients (P=0.51). In this prospective, controlled, open-label, non-randomized 12-month study, treatment with only GA and IFNbeta-1b significantly reduced the relapse rate compared to untreated patients, supporting early treatment in RRMS. Our results are similar to the observations made after 12 months of therapy in phase III studies of IFNbeta-1a, IFNbeta-1b, and GA. Despite some limitations of the study design, the results provide helpful clinical information regarding the relative efficacy of each therapy in mildly affected treatment-naïve RRMS patients.

BACKGROUND- Nervous system manifestation of sarcoidosis (neurosarcoidosis) may occur in 5 to 10% of patients who have systemic sarcoidosis. Neurosarcoidosis may also occur in patients who have not had a previous diagnosis of sarcoidosis (primary neurosarcoidosis). We discuss the clinical presentation of primary neurosarcoidosis, treatment response, and outcome in this study. REVIEW SUMMARY- Records of 22 patients with neurosarcoidosis who were not known to have systemic sarcoidosis at the time of neurologic presentation were reviewed. The clinical presentation and diagnostic procedures that led to the diagnosis in these patients are summarized. Neurologic presentations were highly variable. Neuroimaging was abnormal in all patients when contrast was used; meningeal enhancement was the most common finding. Spinal fluid was abnormal in 95% of patients. Seventy percent of chest x-rays and 80% of chest CT scans performed at the time of presentation were abnormal. All 12 gallium scans that were performed were abnormal. Diagnosis was confirmed by biopsy of neural tissue in 36% and of non-neural tissue in 64%. Initial response to oral corticosteroids was favorable, but more than half of the patients at 1 year had deteriorated. CONCLUSIONS- The evaluation of patients with primary neurosarcoidosis can be optimized by combining clinical suspicion, based on presenting symptoms and signs, with spinal fluid and neuroimaging studies. Appropriate use of chest x-ray and CT and gallium scans frequently leads to diagnosis from lymph node or lacrimal gland biopsy. CONCLUSIONS- (THE NEUROLOGIST 6:126-133, 2000)

Objective: In a large multi-center clinical trial of combination reverse transcriptase inhibitors (RTls), we assessed the impact of antiretroviral therapy on neurological function, the relationship between neurological and systemic benefit, and the prognostic value of neurological performance in late HIV-1 infection. Design: Neurological evaluations incorporated in a randomized, multi-center trial of combination antiretroviral therapy. Setting: Forty-two AIDS Clinical Trials Group sites and seven National Hemophilia Foundation sites Patients: Adult HIV-infected patients (n = 1313) with CD4 counts < 50 × 10 6 cells/l. Interventions: Four combinations of reverse transcriptase inhibitors consisting of zidovudine (ZDV), alternating monthly with didanosine (ddl), or in combination with zalcitabine (ddC), ddl or ddl and nevirapine. Main outcome measures: Mean change from baseline of a four-item quantitative neurological performance battery score, the QNPZ-4, administered to 1031 subjects. Results: Triple therapy and ZDV/ddl combination preserved or improved neurological performance over time compared with the alternating ZDV/ddl and ZDV/ddC regimens (P < 0.001), paralleling their impact on survival in the same trial as previously reported. QNPZ-4 scores were predictive of survival (P < 0.001), after adjusting for CD4 counts and HIV-1 plasma RNA concentrations. Conclusions: Combination antiretroviral therapy can have a salutary effect on preserving or improving neurological function. Superior systemic treatments may likewise better preserve neurological function. The significant association of poor neurological performance with mortality, independent of CD4 counts and HIV-1 RNA levels indicates that neurological dysfunction is an important cause or a strong marker of poor prognosis in late HIV-1 infection. This study demonstrates the value of adjunctive neurological measures in large therapeutic trials of late HIV-1 infection.

Cytomegalovirus (CMV) is a member of the Herpesvirus family which is ubiquitous, and usually causes a primary infection which is asymptomatic or very mild, but occasionally severe disease, with neurologic involvement, results. Reactivation of the virus is often asymptomatic but can have catastrophic consequences in certain populations, especially those with immunodeficiency. We begin with a discussion of the general properties of the virus, its structure and lifecycle, followed by the clinical aspects of acute infection. The pathogenesis of CMV disease mostly is due to direct cytolysis, but the nature of the infection depends on the host's immune background. The effects of CMV infection on the nervous system are listed and cataloged as CMV encephalitis, myelitis, and myeloradiculitis in normal and immunosuppressed hosts. The natural history of CMV disease of the nervous system is not known, since our knowledge is based on case series and case reports. Diagnosis is made by the clinical history and laboratory findings, as well as appropriate detection of virus. Antiviral therapy is problematic in that its benefits are limited, especially in the immunosuppressed, and the medications are toxic.

For millennia, infectious diseases were viewed as the result of malignant supernatural forces or punishments by angry gods for human transgressions. In the 19th century several advances occurred. Medicine became based on clinical observations; Rudolph Virchow laid the foundation of cellular pathology; Louis Pasteur dismantled the notion of spontaneous generation, and Robert Koch established the fundamental techniques of bacteriology, together creating the revolutionary paradigm shift of germ theory. Virology was born in the last decade of the 19th century in the study of tobacco mosaic virus; the crucial characteristics were the capacity to pass through a bacteria-retaining filter and the need for living cells in which to replicate. In 1901 yellow fever was shown to be the first human disease to be caused by a “filterable virus.” In 1903 rabies would be the first disease of the nervous system to be determined to be viral in nature, and polio followed soon thereafter. Paradoxically, because no agent has yet been shown to be the cause, the modern study of epidemic encephalitis began with encephalitis lethargica in 1917. However, the flood gates of viral isolations opened in the 1930s for the arboviral encephalitides, using experimental primates and mice, starting with St. Louis encephalitis and Japanese encephalitis. Within a decade, the viral nature of aseptic meningitis and herpes simplex sporadic encephalitis was demonstrated. From the 1950s through the 1970s great interest in “slow viral diseases” arose as potential models for chronic diseases of the nervous system. The era of modern neurovirology has been characterized by two principal features. The first is the remarkable advances in technology – witness the use of polymerase chain reaction (PCR) for identifying infectious agents, magnetic resonance imaging (MRI) to image the nervous system, and the advance in therapeutics based on molecular medicine. The second has been the impact of emerging and re-emerging diseases – witness the human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic, Nipah encephalitis, and the appearance of West Nile encephalitis in the western hemisphere.

Epstein–Barr virus (EBV) is a human herpesvirus that is highly prevalent in all human populations studied. The initial infection is either asymptomatic or a self-limited febrile illness, but occasionally may be more severe and cause neurologic and systemic disease. After resolution of the initial illness, the virus persists in a “latent” asymptomatic form, kept in check by the immune system. In the modern era of immune modulation and suppression (cancer chemotherapy, transplants, monoclonal antibody therapy, acquired immunodeficiency syndrome (AIDS)), EBV can become “reactivated,” and result in a number of illnesses, some affecting the nervous system. The systemic and neurologic effects of EBV can be difficult to diagnose and manage. In part, this is due to the unusual mix of pathogenetic mechanisms of EBV, which infects and immortalizes B lymphocytes. Immune insufficiency can unleash a lymphoproliferative state. Treatment of EBV disease may require consideration of a neoplastic treatment paradigm, in addition to regular antiviral medications.

A case of encephalomyelitis with polymerase chain reaction detection of Epstein-Barr virus (EBV) in the CSF, and concurrent serologic changes consistent with acute systemic EBV infection is presented and discussed. We document involvement of the brain, spinal cord, and nerve roots, summarize some unusual imaging findings, and note the evolution of CSF oligoclonal bands.

Objectives To evaluate the efficacy, safety, and tolerability of repeated NGX-4010 treatments in the open-label extension phase of a 52-week study in patients with neuropathic pain due to HIV-associated distal sensory polyneuropathy (HIV-DSP). Methods Patients completing the 12-week, randomized, double-blind phase of the study could enter a 40-week, open-label phase, and receive up to 3, 60-minute NGX-4010 treatments. Patients recorded their "average pain for the past 24 hours" daily using the Numeric Pain Rating Scale (NPRS). Efficacy assessment included the percentage NPRS score reduction from baseline to weeks 2 to 12 after the final treatment, and Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) questionnaires at study termination. Results Of 307 patients randomized, 272 entered the open-label phase; 81, 90, 55, and 46 received 0, 1, 2, and 3 retreatments, respectively. The mean percentage decrease in NPRS score from baseline to weeks 2 to 12 after the final treatment was similar in patients receiving single or multiple NGX-4010 treatments (-25.8%, -27.1%, -24.6%, and -22.7% for 1, 2, 3, and 4 NGX-4010 treatments, respectively). PGIC and CGIC results demonstrated a benefit of NGX-4010 treatment through to the end of the study regardless of the number of treatments received. Transient local application site reactions were the most frequently reported adverse events, and were mainly mild to moderate, nonserious, and did not increase with repeated treatment. Discussion Repeated NGX-4010 treatments were generally well tolerated and resulted in consistent reductions in HIV-DSP-associated pain and improvement in patient-reported outcomes.

Atypical Parkinsonism associated with white matter pathology has been described in cerebrovascular diseases, mitochondrial cytopathies, osmotic demyelinating disorders, leukoencephalopathies leukodystrophies, and others. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal dominant disorder with symptomatic onset in midlife and death within a few years after symptom onset. Neuroimaging reveals cerebral white matter lesions that are pathologically characterized by noninflammatory myelin loss, reactive astrocytosis, and axonal spheroids. Most cases are caused by mutations in the colony-stimulating factor 1 receptor (CSF1R) gene. We studied neuropathologically verified HDLS patients with CSF1R mutations to assess parkinsonian features. Ten families were evaluated with 16 affected individuals. During the course of the illness, all patients had at least some degree of bradykinesia. Fifteen patients had postural instability, and seven had rigidity. Two patients initially presented with parkinsonian gait and asymmetrical bradykinesia. These two patients and two others exhibited bradykinesia, rigidity, postural instability, and tremor (two with resting) early in the course of the illness. Levodopa/carbidopa therapy in these four patients provided no benefit, and the remaining 12 patients were not treated. The mean age of onset for all patients was about 45 years (range, 18-71) and the mean disease duration was approximately six years (range, 3-11). We also reviewed HDLS patients published prior to the CSF1R discovery for the presence of parkinsonian features. Out of 50 patients, 37 had gait impairments, 8 rigidity, 7 bradykinesia, and 5 resting tremor. Our report emphasizes the presence of atypical Parkinsonism in HDLS due to CSF1R mutations. (c) 2013 Elsevier Ltd. All rights reserved.

The clinical and pathological characteristics of acute disseminated encephalomyelitis are briefly outlined. The possible relation between acute disseminated encephalomyelitis and other isolated monophasic inflammatory demyelinating episodes in the central nervous system, such as acute optic neuritis, transverse myelitis or brainstem lesions, is noted and the risk of progression to multiple sclerosis is examined. The surprising results of a clinical trial of corticosteroids in optic neuritis are of particular interest in this regard, and we speculate on an explanation in terms of a spread of antimyelin T cell receptor gene usage over time. Finally, the risk factors for the progression of demyelinating ther than optic neuritis to multiple sclerosis are explored. Further work to elucidate better the relationships between these pathological entities is suggested.

Intercaudate nucleus ratio (ICR) is a linear measure of brain atrophy that does not require software application and is independent of image acquisition techniques. The authors examined the relationship between ICR and disability in 190 patients with MS. The results show that ICR correlates with Expanded Disability Status Scale score (r = 0.67; p = 0.0001) and disease duration (r = 0.32; p < 0.01). Intercaudate ratio appears to be a reliable and reproducible linear measure of brain atrophy and correlates with disability and disease duration in MS.

Epstein–Barr virus and cytomegalovirus are members of the human herpesviruses that have an extremely high seroprevalence in all populations studied. The initial infection is usually asymptomatic, or causes a febrile illness, but can rarely manifest itself neurologically. These viruses are increasingly important in the modern era of immunosuppression, whether due to AIDS or in the transplant or cancer chemotherapy population, and their reactivation gives rise to a wide spectrum of neurological diseases. The pathogenesis of these infections is not completely understood, but certainly multifaceted. In CMV lytic infection damages systemic tissues directly, whereas EBV involves an activated and distorted immune system. These diseases are treatable, but need to be recognized early in their course so that antiviral intervention can be effected promptly. The choice of therapeutic strategy can be counterintuitive: while CMV infections are conventionally managed with antiviral medications, EBV infections may demand a neoplastic treatment paradigm as an addition to (or alternative to) antiviral treatment.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was originally described in a large Swedish pedigree. Since then, 22 reports describing a total of 13 kindreds and 11 sporadic cases have been published. Inheritance is autosomal dominant, albeit the gene is unknown. Here we report on the clinical findings, genealogical data, brain MRI data, and autopsy/biopsy findings of four probands from three independently ascertained novel families from Norway, Germany and US. We identified a 39-year-old female and her twin sister, a 52-year-old male and a 47-year-old male with progressive neurological illness characterized by personality changes, cognitive decline and motor impairments, such as gait problems, bradykinesia, tremor and rigidity. Brain MRI showed white matter abnormalities with frontal prominence. Brain biopsy/autopsies were consistent with HDLS. HDIS is an under-recognized disease and in reporting these cases, we aim to increase the awareness of the disorder. Due to varied and wide phenotypic presentations, which may imitate several neurodegenerative diseases, HDLS can be difficult to diagnose. Definitive diagnosis can be established only by direct brain tissue examination. Familiarity with the clinical presentation and typical neuroimaging findings may be helpful in narrowing the diagnosis. (C) 2011 Elsevier B.V. All rights reserved.

Laquinimod, a second-generation quinoline-3-carboxamide, is being developed by Active Biotech AB and Teva Pharmaceutical Industries Ltd for the treatment for relapsing-remitting multiple sclerosis (RRMS). Laquinimod has demonstrated significant activity in suppressing experimental autoimmune encephalomyelitis, an animal model of RRMS. In phase I and II clinical trials, the drug was well tolerated, with some hints of efficacy in small numbers of patients with RRMS. While the mechanism of action of the drug is unknown, it likely involves Th1 to Th2/Th3 immune deviation, promotion of the synthesis and release of neurotrophic factors, and other possible neuroprotective effects. Two phase III clinical trials are ongoing and, if successful, will lead to the approval of the first oral immunomodulatory drug for suppressing multiple sclerosis disease activity.

Infections of the central nervous system can damage the brain and cause abnormal behavior. In this article, the authors examine how behavior is affected by damage to different parts of the brain. They then focus on damage caused by specific infections of the brain and how these can result in abnormal behavior with legal consequences. Examples of such infections include neurosyphilis, encephalitis lethargica, herpes simplex encephalitis, and various other viral encephalitides, both acute and chronic. The AIDS dementia complex, which results from HIV infection of the brain, causes behavioral abnormalities in addition to motor and cognitive impairments. In some cases of violence and other criminal behavior, this can be a consequence of central nervous system infection, and the authors suggest that criminal sanctions in such events are inappropriate in the absence of volitional criminal intent.

The neuromuscular aspects of West Nile virus (WNV) infection have not been characterized in detail. We have studied a group of six patients with proven WNV infection. All cases presented with acute, severe, asymmetric, or monolimb weakness, with minimal or no sensory disturbance after a mild flu-like prodrome. Four cases also had facial weakness. Three of our cases had no encephalitic signs or symptoms despite cerebrospinal fluid pleocytosis. Electrophysiological studies showed severe denervation in paralyzed limb muscles, suggesting either motor neuron or multiple ventral nerve root damage. This localization is supported further by the finding of abnormal signal intensity confined to the anterior horns on a lumbar spine magnetic resonance imaging. Muscle biopsies from three patients showed scattered necrotic fibers, implicating mild direct or indirect muscle damage from the WNV infection. In summary, we describe a group of patients with acute segmental flaccid paralysis with minimal or no encephalitic or sensory signs. We have localized the abnormality to either the spinal motor neurons or their ventral nerve roots. It will be important for physicians to consider WNV infection in patients with acute asymmetric paralysis with or without encephalitic symptoms.

In this article the authors review the important viral infections affecting humans, and how they are prevented by vaccines and controlled by antiviral drugs. The different types of drugs and vaccines are listed and their mechanisms of action are discussed. For drugs, these include toxicity and viral resistance, whereas for vaccines, these include generation of autoimmune reactions, contamination by other previously unknown pathogens, reversion of an attenuated to virulent strain, and reactogenicity. The authors discuss how these were understood and the preventative methods instituted to prevent them.

We describe a patient who became cushingoid as a result of receiving steroid therapy for thrombocytopenia purpura and who then developed spinal epidural lipomatosis 4 months after he started receiving ritonavir as part of his therapy for human immunodeficiency virus infection. We believe that ritonavir may have contributed to the development of epidural lipomatosis and that clinicians should be aware of this possible association.

Introduction of highly active antiretroviral therapy (HAART) has been associated with many changes in the complications of human immunodeficiency virus (HIV) infection. A cohort of 25 HIV patients with progressive multifocal leukoencephalopathy (PML) treated with HAART experienced a median survival of >46 weeks. This is an improvement in prognosis compared with recent historic experience and correlated with HIV RNA viral load reductions. We conclude that current HIV therapy is important in improving the outlook of PML in the setting of HIV.

Objective: To describe the MRI characteristics of HDLS patients with a known gene mutation on chromosome 5. Background Adult-onset leukoencephalopathies are a heterogeneous group of rare disorders, with natural histories ranging from being asymptomatic to inexorably progressive and fatal. Hereditary diffuse leukoencephalopathy with spheroids (HDLS) was first described in 1984, and is an autosomal dominant disorder. Currently, 23 HDLS reports have been published. The pathological hallmark of HDLS is cerebral white matter lesions (WML) with axonal spheroids.Recently, a chromosome 5 mutation, CSF1R , was identified. Design/Methods: Twenty brain MRIs of 15 patients with autopsy/biopsy verified HDLS and chromosome 5 mutations were reviewed. Sagittal T1-, axial T1-, T2- weighted, and FLAIR images were assessed for distribution of WML, grey matter involvement, and atrophy. Results: In this study, the mean age of onset was 44 years (range, 19-71); mean disease duration was 5 years (range, 3-11); and the mean age at death was 50 years (30-75). 80 % (12/15) demonstrated focal WML, whereas in two the lesions were patchy. One patient had generalized WMLs. All patients had bilateral, though slightly asymmetric lesions. WMLs with frontal predominance, involving deep and subcortical regions, were found in all cases. 93 % (14/15) had periventricular involvement, while 73% (11/15) had involvement of the corpus callosum. Of the latter, seven had more than one callosal segment affected and five had involvement of the entire corpus callosum. Typically, brain atrophy was present in the same region as the WMLs; however, in three cases isolated atrophy of the parietal, occipital and temporal cortices were found, respectively. Central atrophy was invariably present. Corticospinal tract involvement occurred late in the disease course. The grey matter, brain stem and cerebellum were spared, and enhancement was absent. Conclusions: MRI is valuable in helping to define the natural history of HDLS and will be useful in assessing future treatment responses. The MRI patterns of HDLS are sufficiently typical to aid in diagnosis. Supported by: ZKW is partially supported by the NIH/NINDS 1RC2NS070276, NS057567, P50NS072187, Mayo Clinic Florida (MCF) Research Committee CR program (MCF #90052030), Dystonia Medical Research Foundation, and a gift from Carl Edward Bolch, Jr., and Susan Bass Bolch (MCF #90052031/PAU #90052). SF is partially supported by MCF Research Committee CR program ( MCF #90052030). CS was partially supported by Anna-Lisa och Bror Bjornssons-, Sven and Dagmar Salens-, Signe och Olof Wallenius- and Gamla Tjanarinnor Foundations, Sweden. The Swedish Society of Medicine Gothenburg (GLS), Sweden, The Swedish Society of Medicine Sweden, The Swedish and Gothenburg Societies for the Neurologically Disabled and The Gothenburg Foundation for Neurological Research. Disclosure: Dr. Sundal has nothing to disclose. Dr. Fujioka has nothing to disclose. Dr. Van Gerpen has nothing to disclose. Dr. Wider has nothing to disclose. Dr. Aasly has nothing to disclose. Dr. Shuster has nothing to disclose. Dr. Ghetti has received personal compensation for activities with Bayer Pharmaceuticals Corporation. Dr. Ghetti has received research support from the National Institute of Health. Dr. Garbern has received personal compensation for activities with Genzyme Corporation, Lundbeck Research USA, Inc., StemCells, Inc, and Serono, Inc. as a consultant and/or speaker. Dr. Garbern has received personal compensation in an editorial capacity for Medlink Neurology. Dr. Garbern has received research support from Genzyme Corporation. Dr. Tselis has received research support from Teva Neuroscience and Biogen Idec. Dr. Swerdlow has received personal compensation for activities with Eisai, Inc. as a consultant. Dr. Miller has nothing to disclose. Dr. Rademakers has nothing to disclose. Dr. Dickson has nothing to disclose. Dr. Broderick has nothing to disclose. Dr. Wszolek has received personal compensation in an editorial capacity for Parkinsonism and Realted Disorders and European Journal of Neurology. Dr. Roeber has nothing to disclose.

Intravenous Immunoglobulins in Clinical Practice edited by Martin L. Lee and Vibeke Strand, 536 pp., ill., New York, Marcel Dekker, 1997, $150.00 Unlike other recent treatises on specialized topics, this book is quite comprehensive. There are five parts. In the first overview part, there are chapters on the preparation of intravenous immunoglobulin (IVIG), its pharmacokinetics, its …