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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

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 …

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.

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.

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.

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.

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.