Spinal Cord Sarcoidosis Occurring at Sites of Spondylotic Stenosis, Mimicking Spondylotic Myelopathy: A Case Series and Review of the Literature.

Sarcoidosis is a multisystem granulomatous disease, with intramedullary spinal cord involvement seen in <1% of cases. This case series illustrates the clinical presentations and imaging findings of 5 patients with intramedullary spinal neurosarcoidosis occurring at sites of spondylotic spinal canal stenosis, which can be indistinguishable from spondylotic myelopathy with cord enhancement. Both entities are most common in middle-aged men and present with weeks to months of motor and sensory symptoms. On imaging, both can have focal spinal cord enhancement and longitudinally extensive signal abnormality centered at or just below the level of spinal canal stenosis. On the basis of our experience, we suggest that in patients with cord enhancement centered at or just below a site of spinal canal stenosis, consideration should be given to chest imaging and lymph node biopsy when applicable, to assess for the possibility of underlying sarcoidosis before surgical decompression.

Progressive multifocal leukoencephalopathy or immune reconstitution inflammatory syndrome after fingolimod cessation? A case report.

BACKGROUND: Fingolimod is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML); however, its discontinuation may cause severe immune reconstitution inflammatory syndrome (IRIS). As both of these conditions (especially fingolimod induced PML) are rarely described in medical case reports distinguishing between PML-IRIS and MS-IRIS may be diagnostically challenging. CASE PRESENTATION: We report a patient with severe clinical decline (Expanded Disability Status Scale (EDSS) increasing from 3.5 to 7.5) and multiple, large, contrast-enhancing lesions on brain magnetic resonance imaging (MRI) a few months after fingolimod withdrawal. The diagnostic possibilities included IRIS due to fingolimod withdrawal versus PML-IRIS. The JC virus (JCV) antibody index was positive (2.56); however, cerebrospinal fluid (CSF) JCV real-time polymerase chain reaction (JCV-PCR) was negative and brain biopsy was not performed. After a long course of aggressive treatment (several pulsed methylprednisolone infusions, plasmapheresis, intravenous dexamethasone, oral mirtazapine) the patient gradually recovered (EDSS 2.5) and MRI lesions decreased. CONCLUSIONS: This case report demonstrates the importance of monitoring patients carefully after the discontinuation of fingolimod for PML-IRIS and rebound MS with IRIS as these conditions may manifest similarly.

Dynamic expression of JC virus in urine and its relationship to serostatus.

BACKGROUND: There is limited information regarding the daily shedding of JC virus (JCV) in urine and its correlation with serum JCV antibody levels. METHODS: The dynamic expression of JCV in urine and its correlation with JCV antibody status in patients receiving disease modifying therapy for multiple sclerosis were examined in a longitudinal case-control study. JCV antibody index levels were determined using a two-step ELISA (Stratify). JCV shedding in urine samples was determined by quantitative PCR during two 30-day study periods separated by intervals of at least 6 months. RESULTS: Of 42 study subjects (57% female; ages 22-56, average age 39.6 years), 27 (64.3%) were JCV antibody positive (index >0.40) at initial urine collection. Twelve seropositive subjects (44.4%) had detectable JCV in their urine with values ranging from 290 to 5.08 × 108 copies/mL. Daily viral shedding in these patients remained fairly constant throughout the study. Urinary JCV shedding was not detected in any JCV antibody index negative or indeterminate subject. In JCV urinary shedders, the average JCV antibody index was 2.69 (range 1.67-3.57). The average anti-JCV antibody index for the remaining JCV seropositive individuals without viral urinary shedding was 1.35 (range 0.46-3.91). CONCLUSION: MS patients displayed a consistent pattern of JCV shedding over days and months in which higher levels of viruria appeared to have driven higher levels of JCV antibody index. The findings provide additional insights into the dynamic expression of JCV and host response; however, studies in larger populations and of longer duration will be needed to determine their significance to the development of progressive multifocal leukoencephalopathy (PML).

Determinants of survival in progressive multifocal leukoencephalopathy.

BACKGROUND: We sought to characterize the role of immunologic, virologic, and radiologic determinants of survival in patients with progressive multifocal leukoencephalopathy (PML). METHODS: We recorded the clinical outcome of 60 patients with PML (73% HIV+) who were prospectively evaluated between 2000 and 2007 for the presence of JC virus (JCV)-specific CD8+ cytotoxic T-lymphocytes (CTL) in blood. RESULTS: Estimated probability of survival at 1 year was 52% for HIV+/PML and 58% for HIV- patients with PML. Patients with PML with detectable CTL within 3 months of diagnosis had a 1-year estimated survival of 73% compared to 46% for those without CTL (hazard ratio [HR] for death = 0.47, 95% confidence interval [CI] 0.13-1.75, p = 0.26). Patients with CTL response had an increased likelihood of having contrast enhancement of PML lesions and immune reconstitution inflammatory syndrome (odds ratio 3.7 and 7.8). Estimated 1-year survival was 48% in HIV+ patients with PML with CD4 count <200/microL at PML diagnosis compared to 67% in those with CD4 >200/microL (HR for death 1.41, 95% CI 0.27-7.38, p = 0.68). JCV DNA was detected in the urine of 48% and in the blood of 56% of patients with PML, but viruria and viremia were not associated with survival. CONCLUSIONS: The presence of JC virus (JCV)-specific cytotoxic T-lymphocytes (CTL) was associated with a trend toward longer survival in patients with progressive multifocal leukoencephalopathy (PML), which was more pronounced than the impact of CD4 count in HIV+ patients with PML early after diagnosis. Despite the association of contrast enhancement and immune reconstitution inflammatory syndrome with JCV-specific CTL, these cannot be considered as surrogate markers for the prognostic value of the CTL. Strategies aiming at improving the cellular immune response may improve the course of PML.

A brainstem paraneoplastic syndrome associated with prostate cancer.

BACKGROUND: Paraneoplastic syndromes are seldom observed with prostate cancer. A rare paraneoplastic brainstem syndrome associated with prostate cancer is described, and the presence of antineuronal antibodies with this syndrome is demonstrated for the first time. SETTING: Tertiary referral centre for neurological disorders. PATIENT: This 59-year-old man developed ophthalmoplegia, dysarthria, dysphagia, pruritus, ataxia, corticobulbar and corticospinal signs in association with prostate cancer. The disorder was unaffected by treatment of the underlying malignancy, but responded initially to high-dose corticosteroid administration and intravenous immunoglobulins. RESULTS: Antibody to intracellular neuronal antigens was demonstrated in both the serum and the cerebrospinal fluid. CONCLUSIONS: This unique paraneoplastic syndrome chiefly affecting the brainstem may be a diagnostic clue to the presence of unsuspected prostate adenocarcinoma. Further studies will be required to determine the precise antigenic target.

Paradoxically aggressive multiple sclerosis in the face of natalizumab therapy.

In the pivotal trials of natalizumab in the treatment of relapsing-remitting multiple sclerosis (AFFIRM and SENTINEL), a dramatic reduction in relapse rate, new or enlarging T2-hyperintense lesions, and mean number of gadolinium-enhancing lesions was observed. While both relapses and new MRI lesions were observed in these trials, there has been no comment on the presence of aggressive disease in the face of natalizumab treatment. I report a 31-year-old woman with relapsing remitting MS of 12 years duration who developed aggressive demyelinating disease four months after the initiation of natalizumab. The clinical worsening was accompanied by a significant increase in new large T2-hyperintense signal abnormalities and in both solid and C-shaped contrast-enhancing lesions. Neither the clinical severity nor the striking MRI abnormalities had been noted earlier in her disease course. Neutralizing antibodies to natalizumab were not detected. She subsequently responded to combination therapy of pulsed methylprednisolone and daily glatiramer acetate.

Reactivation of JC virus and development of PML in patients with multiple sclerosis.

The attention of researchers and clinicians specializing in both multiple sclerosis (MS) and JC virus (JCV), the etiologic agent of progressive multifocal leukoencephalopathy (PML), was rekindled by the development of PML in two patients with MS enrolled in a clinical trial of combination therapy with natalizumab (Tysabri) and interferon beta-1A (Avonex) in recent years. PML had not been previously reported with either MS or treatment with interferon beta alone. This occurrence of PML with alpha4beta1-integrin inhibition in MS raised a number of issues in terms both of the scientific understanding of these diseases and for the future of immunomodulatory treatment for MS. In this review, we examine the current status of knowledge of the virus, its molecular biology, life cycle, and pathogenetic mechanisms, and how this relates to the basic science and clinical perspectives of MS. A better understanding of the specific steps from JCV infection to the development of PML is key to this issue. Other critical issues for further investigation include the role of alpha4beta1-integrin inhibition by natalizumab in the re-expression of JCV from latent sites and in the inhibition of entry into the brain and peripheral sites.

Natalizumab and progressive multifocal leucoencephalopathy.

Current data suggest that as many as 1 in 1000 treated individuals may develop progressive multifocal leucoencephalopathy (PML) in concert with the use of natalizumab. Natalizumab was withdrawn in early 2005. The present paper provides a comprehensive description of PML and reviews the role of natalizumab in the pathogenesis of PML. It is likely that use of drugs which cause specific perturbations of the immune system will be accompanied by similar rare infections. Thus researchers should be on the alert when using such agents in clinical trials.

Molecular targets of opiate drug abuse in neuroAIDS.

Opiate drug abuse, through selective actions at mu-opioid receptors (MOR), exacerbates the pathogenesis of human immunodeficiency virus-1 (HIV-1) in the CNS by disrupting glial homeostasis, increasing inflammation, and decreasing the threshold for pro-apoptotic events in neurons. Neurons are affected directly and indirectly by opiate-HIV interactions. Although most opiates drugs have some affinity for kappa (KOR) and/or delta (DOR) opioid receptors, their neurotoxic effects are largely mediated through MOR. Besides direct actions on the neurons themselves, opiates directly affect MOR-expressing astrocytes and microglia. Because of their broad-reaching actions in glia, opiate abuse causes widespread metabolic derangement, inflammation, and the disruption of neuron-glial relationships, which likely contribute to neuronal dysfunction, death, and HIV encephalitis. In addition to direct actions on neural cells, opioids modulate inflammation and disrupt normal intercellular interactions among immunocytes (macrophages and lymphocytes), which on balance further promote neuronal dysfunction and death. The neural pathways involved in opiate enhancement of HIV-induced inflammation and cell death, appear to involve MOR activation with downstream effects through PI3-kinase/Akt and/or MAPK signaling, which suggests possible targets for therapeutic intervention in neuroAIDS.

MRI findings in Susac's syndrome.

BACKGROUND: Susac syndrome (SS) is a self-limited syndrome, presumably autoimmune, consisting of a clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss. All three elements of the triad may not be present or recognized, and MR imaging is often necessary to establish the diagnosis. OBJECTIVE: To determine the spectrum of abnormalities on MRI in SS. METHODS: The authors reviewed the MR images of 27 previously unreported patients with the clinical SS triad, and 51 patients from published articles in which the MR images were depicted or reported. RESULTS: All 27 patients had multifocal supratentorial white matter lesions including the corpus callosum. The deep gray nuclei (basal ganglia and thalamus) were involved in 19 (70%). Nineteen (70%) also had parenchymal enhancement and 9 (33%) had leptomeningeal enhancement. Of the 51 cases from the literature, at least 32 had callosal lesions. The authors could not determine the presence of callosal lesions in 18 of these patients, and only one was reported to have a normal MRI at the onset of encephalopathy. CONCLUSIONS: The MR scans in SS show a rather distinctive pattern of supratentorial white matter lesions that always involve the corpus callosum. There is often deep gray matter, posterior fossa involvement, and frequent parenchymal with occasional leptomeningeal enhancement. The central callosal lesions differ from those in demyelinating disease, and should support the diagnosis of SS in patients with at least two of the three features of the clinical triad.

Oxidative stress in HIV demented patients and protection ex vivo with novel antioxidants.

OBJECTIVE: To determine the role of oxidative stress in mediating HIV dementia and to identify novel therapeutic compounds that may block this oxidative stress. METHODS: Brain tissue from patients with HIV encephalitis and macaques with simian immune deficiency virus encephalitis was immunostained for lipid peroxidation. Oxidized proteins in CSF of patients with various stages of HIV dementia were quantitated and we determined whether CSF from these patients could alter mitochondrial function. Several novel compounds with antioxidant effects were screened to determine their relative efficacy in protecting against CSF-induced neurotoxicity. RESULTS: Evidence for oxidative stress was present both in brain and in CSF. The presence of oxidized proteins in the CSF and CSF-induced progressive decrease in mitochondrial activity correlated with the severity of cognitive impairment, but only the group of patients with moderate to severe dementia reached statistical significance. L-deprenyl, didox, imidate, diosgenin, and ebselen blocked the CSF-induced toxicity. No effect of trimidox, ruthenium red, or Quercetin was seen. CONCLUSIONS: Increased oxidative stress is present in brain and CSF of HIV-infected patients. There is also an accumulation of toxic substances in the CSF that are capable of inducing oxidative stress. The authors have identified several novel compounds that are capable of blocking the CSF-induced toxicity, the therapeutic potential of which is worthy of further exploration.

CNS angiitis in graft vs host disease.

Graft-vs-host disease (GVHD) is a potentially treatable cause of progressive neurologic decline after bone marrow transplantation (BMT). The authors present histologic confirmation of CNS granulomatous angiitis in a child with chronic GVHD after BMT. Since cranial MRI showed only nonspecific findings, CNS vasculitis associated with GVHD after BMT may be underdiagnosed.

Acceleration of HIV dementia with methamphetamine and cocaine.

We report a patient with rapidly accelerating HIV dementia accompanied by seizures and an unusual movement disorder despite highly potent antiretroviral therapy. This clinical constellation was associated with the non-parenteral use of methamphetamine and cocaine. Fractional enhancement time on post contrast magnetic resonance imaging studies revealed a progressive breakdown of the blood brain barrier particularly in the basal ganglia. The movement disorder but not the dementia responded to a combination of dopamine replacement and anticholinergic therapy. While the movement disorder may have been unmasked by concomitant anticonvulsant therapy, we suggest in this instance, that prior drug abuse synergized with HIV to cause a domino effect on cerebral function. Careful attention and analysis to histories of remote non-injecting drug abuse may help substantiate our hypothesis.

Cerebrospinal fluid 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in HIV-1 infection.

Reduced level of serotonin (5-hydroxytryptamine, 5-HT) in humans has been associated with a number of mental health and behavioral problems including depression, aggression, violence, sexual dysfunctions, sleep and eating disorders. Even though among HIV-1-infected individuals, prevalence of mental health and behavioral problems are common, their relationship with central nervous system serotonin functions is not clearly understood. This investigation was carried out to study the status of CSF 5-HT in HIV-1+ subjects (n = 21), in the early stage of infection, and HIV-1- control subjects (n = 24). Samples of CSF were obtained by lumbar puncture and were analyzed for 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA), using high-performance liquid chromatography equipped with electrochemical detector. Levels of CSF 5-HT were significantly lower in the HIV-1+ group compared to the HIV-1- group. There was no significant difference in the CSF 5-HIAA levels between the two groups. In both groups, however, there was a significant correlation between CSF 5-HT and 5-HIAA. In the HIV-1 + group, although CSF 5-HT level was significantly negatively correlated with serostatus, there was no correlation between either CSF 5-HT or 5-HIAA levels and CD4 cell number or any behavioral measures evaluated in this study, including Beck's Depression Inventory and state/trait anxiety scores. These data suggest that HIV-1 infection affects the CNS 5-HT status with no significant association with measures of depression and anxiety, at least in the early stage of infection.

Acute multifocal placoid pigment epitheliopathy and central nervous system involvement: nine new cases and a review of the literature.

OBJECTIVE: The authors describe nine new cases of acute multifocal placoid pigment epitheliopathy (AMPPE) with associated central nervous system (CNS) involvement and permanent visual sequelae. The study includes a review of the literature and discussion of evaluation, management, and treatment options. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS: Nine patients were identified with AMPPE and CNS involvement in addition to 22 patients reviewed in the literature. MAIN OUTCOME MEASURES: A review of nine patients with AMPPE and CNS involvement was performed. Charts were reviewed for age, gender, preceding viral prodromes, visual acuity, ophthalmologic examination findings, CNS findings, and treatment. RESULTS: Thirty-one patients (nine new patients) were diagnosed with AMPPE and various degrees of CNS involvement. Ages ranged from 8 to 54 years, with an average of 27 years. Twenty-one males (68%) and 10 females (32%) were identified. Eleven patients (35%) had antecedent viral illnesses. Visual acuity was variable and ranged from 20/20 to count fingers. The spectrum of CNS findings ranged from headaches to sagittal sinus thrombosis. CONCLUSIONS: Acute multifocal placoid pigment epitheliopathy can be associated with CNS abnormalities and permanent visual deficits. Neuroimaging, lumbar puncture, and cerebral angiography analysis provide useful diagnostic tools when CNS involvement is suspected. Intravenous corticosteroids and collaboration with neurovascular colleagues should be considered in these situations. In cases complicated by CNS arteritis, immunosuppressive agents can be a beneficial adjunct to corticosteroids.

HIV dementia: the role of the basal ganglia and dopaminergic systems.

The clinical features of human immunodeficiency virus (HIV) dementia exhibit the hallmarks of a subcortical dementia. These features include psychomotor slowing, apathy, bradykinesia and altered posture and gait similar to those observed in advanced Parkinson's disease. The dementia has the hallmarks attributed to subcortical dementia. The exquisite sensitivity of many of these patients to dopamine receptor blockade suggested a profound and, perhaps, selective abnormality of striatal dopaminergic systems. Additional investigations, electrophysiological, pathological, virological, metabolic and radiological studies, indicate that the basal ganglia are a major target of HIV infection. In this review, we describe the evidence for involvement of basal ganglia and, in particular, the dopaminergic systems, in HIV dementia. We also suggest novel therapeutic strategies that may be beneficial in the treatment of this disorder.