Parkinsonian features in hereditary diffuse leukoencephalopathy with spheroids (HDLS) and CSF1R mutations.

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 non-inflammatory 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.

MRI characteristics and scoring in HDLS due to CSF1R gene mutations.

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.

Epstein-Barr virus cause of multiple sclerosis.

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.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS): a misdiagnosed disease entity.

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. HDLS 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.

Leber hereditary optic neuropathy mimicking neuromyelitis optica.

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.

Approaches to neuroprotective strategies in multiple sclerosis.

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.

Laquinimod, a new oral autoimmune modulator for the treatment of relapsing-remitting multiple sclerosis.

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.

Glatiramer acetate in the treatment of multiple sclerosis.

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.

Unilateral retrobulbar optic neuritis due to varicella zoster virus in a patient with AIDS: a case report and review of the literature.

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.

Behavioral consequences of infections of the central nervous system: with emphasis on viral infections.

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.

Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection.

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.