Non-lyme tick-borne diseases: a neurological perspective.

Tick-borne diseases are prevalent throughout the world and present a diagnostic challenge owing to their nonspecific clinical symptoms. Many tick-borne diseases involve the central and peripheral nervous systems. Early diagnosis or at least suspicion of a tick-borne cause is necessary to institute early empiric treatment. After a brief review of tick biology, we present the most common tick-borne diseases. A brief discussion of epidemiology, the transmission route, and pathogenesis is followed by a discussion of the clinical manifestations, diagnosis and treatment options when available. The review emphasizes the infectious causes with a significant neurological manifestation.

Primary intracranial plasma cell granulomas presenting as malignant neoplasms.

Plasma cell granuloma (PCG) is an uncommon non-neoplastic mass lesion of unknown etiology. It is characterized by a polyclonal proliferation of chronic inflammatory cells, mostly mature plasma and other mononuclear cells. PCGs arising in the central nervous system are particularly rare. We report two additional cases of intracranial PCG exclusively involving the brain parenchyma. A 47 year-old woman, presenting with partial motor seizures and fluent aphasia, underwent complete excision of a well-demarcated, enhancing left parietal mass. The second patient was a 56 year-old man presenting with headaches and right-sided weakness who underwent stereotactic biopsy of an ill-defined, heterogeneously enhancing lesion in the left basal ganglia. Immunohistochemical analysis of surgical specimens showed polyclonal plasma cells and mature lymphocytes but no etiological agent. A histopathologic diagnosis of intracranial PCG was made in both cases. PCG should be part of the differential diagnosis of enhancing mass lesions of the brain. The etiology and natural history of these tumor-like lesions is not fully understood. Complete surgical excision appears to be curative. Lesions where total resection is not possible may benefit from adjuvant treatment including corticosteroids and possibly radiation therapy.

Evidence for viral etiology of multiple sclerosis.

The etiology of multiple sclerosis (MS) is unknown, and several hypotheses have been advanced over the past century to explain it. Despite much effort, no single cause has been established. One of the most appealing hypotheses is that of infection due to a neurotropic infectious agent, possibly a virus. There are several lines of data to support this hypothesis. First, there are clear examples of inflammatory demyelinating disease caused directly or indirectly by viral infections in both humans and animals. Second, there is a strong environmental component to multiple sclerosis. Finally, there is aberrant immune reactivity against various viruses. Recent candidates have included measles and the related canine distemper virus, human herpesvirus 6, human endogenous retroviruses, and Epstein-Barr virus. The evidence is most extensive for the latter and will be discussed in some detail.

Intense immunosuppression in patients with rapidly worsening multiple sclerosis: treatment guidelines for the clinician.

Several lines of evidence link immunosuppression to inflammation in patients with multiple sclerosis (MS) and provide a rationale for the increasing use of immunosuppressive drugs in the treatment of MS. Treatment-refractory, clinically active MS can quickly lead to devastating and irreversible neurological disability and treating these patients can be a formidable challenge to the clinician. Patients with refractory MS have been treated with intense immunosuppression, such as cyclophosphamide or mitoxantrone, or with autologous haematopoeitic stem cell transplants. Evidence shows that intense immunosuppression might be effective in patients who are unresponsive to immunomodulating therapy, such as interferon beta and glatiramer acetate. Natalizumab, a new addition to the armamentarium for treating MS, might also have a role in the treatment of this MS phenotype. This Review describes the use of intense immunosuppressant drugs and natalizumab in patients with rapidly worsening MS and provides clinicians with guidelines for the use of these drugs in this patient group.

Acute transverse myelitis with normal brain MRI : long-term risk of MS.

OBJECTIVE: To investigate the long-term risk of developing MS in patients presenting with acute transverse myelitis (ATM) and normal brain MRI scans at onset. METHODS: We studied 58 ATM patients with normal brain MRI at presentation for up to 5 years with serial neurologic and imaging studies. All patients underwent CSF analysis at onset which was defined positive if two or more IgG oligoclonal bands and/or elevated IgG index were present. Brain and spinal cord MRI scans were obtained every 6 months for the first 2 years, and annually thereafter unless the patient experienced a second neurologic attack different from the initial episode to confirm CDMS or there was demonstration of MRI lesions confirming dissemination in time and space to fulfill McDonald imaging criteria to diagnose MS. RESULTS: Seventeen of 58 (29%) patients developed MS of which 7 (41%) patients developed CDMS and 10 (59%) developed MS using McDonald Imaging Criteria. Mean time to CDMS by a second clinical attack was 11. 1 months compared to 19. 2 months by MRI lesions (P = 0. 03). None of the patients developed MS after 24 months of onset. All 17 patients who developed MS had positive CSF although 15 patients who had positive CSF did not develop MS during the 5 years of follow-up. CONCLUSIONS: The majority of patients with ATM and normal brain MRI do not develop MS after 5 years of follow-up confirming the relatively low risk compared to patients with abnormal brain MRI scans. CSF is helpful in distinguishing patients more likely to develop MS. Compared to clinical attacks, serial imaging may not lead to an earlier diagnosis in ATM patients with normal brain MRI.

Long-term safety of rituximab induced peripheral B-cell depletion in autoimmune neurological diseases.

BACKGROUND: B-cells play a pivotal role in several autoimmune diseases, including patients with immune-mediated neurological disorders (PIMND), such as neuromyelitis optica (NMO), multiple sclerosis (MS), and myasthenia gravis (MG). Targeting B-cells has been an effective approach in ameliorating both central and peripheral autoimmune diseases. However, there is a paucity of literature on the safety of continuous B-cell depletion over a long period of time. OBJECTIVE: The aim of this study was to examine the long-term safety, incidence of infections, and malignancies in subjects receiving continuous therapy with a B-cell depleting agent rituximab over at least 3 years or longer. METHODS: This was a retrospective study involving PIMND who received continuous cycles of rituximab infusions every 6 to 9 months for up to 7 years. The incidence of infection related adverse events (AE), serious adverse events (SAE), and malignancies were observed. RESULTS: There were a total of 32 AE and 4 SAE with rituximab treatment. The 3 SAE were noted after 9 cycles (48 months) and 1 SAE was observed after 11 cycles (60 months) of rituximab. There were no cases of Progressive multifocal leukoencephalopathy (PML) and malignancies observed throughout the treatment period. Rituximab was well tolerated without any serious infusion reactions. Also, rituximab was found to be beneficial in treating PIMND over a 7-year period. CONCLUSIONS: This study demonstrates that long-term depletion of peripheral B-cells appears safe and efficacious in treating PIMND. Longer and larger prospective studies with rituximab are needed to carefully ascertain risks associated with chronic B-cell depletion, including malignancies. Recognizing that this is a small, retrospective study, such data nonetheless complement the growing literature documenting the safety and tolerability of B-cell depleting agents in neurological diseases.

HIV-related peripheral neuropathy and glucose dysmetabolism: study of a public dataset.

AIMS AND METHODS: The authors analyzed the public dataset of Multicenter AIDS Cohort Study to examine the association of glucose dysmetabolism with HIV-related peripheral neuropathy. RESULTS: Among 5,622 participants in the data, 282 (5%) had peripheral neuropathy, of which 225 had sensory neuropathy. Of 225 participants with sensory neuropathy, 191 (84.8%) had exposure to highly active antiretroviral therapy. Of 225 with sensory neuropathy, 46 had fasting sugars measured; 26 of them (56.5%) had either impaired fasting glucose (fasting glucose >or=110 mg/dl) or diabetes (fasting glucose >or=126 mg/dl). Among 693 participants without neuropathy, who had fasting sugars measured, 441 (63.7%) had glucose dysmetabolism (p = 0.33). The mean HbA(1c) levels in participants with sensory neuropathy (5.1 +/- 1.02, n = 51) were significantly higher than in those without sensory neuropathy (4.8 +/- 0.6, n = 164, p = 0.02), though its clinical relevance is unclear. Among 739 participants who had fasting sugars measured, 63.2% had glucose dysmetabolism, showing high prevalence of glucose dysmetabolism among participants with HIV infection. CONCLUSIONS: Except for slightly higher HbA(1c) levels, there was no significant difference in prevalence of glucose dysmetabolism among participants with and without sensory neuropathy. The study brings up important aspects of using public datasets for epidemiologic studies including its limitations and a unique opportunity for pilot studies for new investigators.

Cerebrospinal fluid humoral immunity in the differential diagnosis of multiple sclerosis.

BACKGROUND: The diagnostic accuracy of cerebrospinal fluid oligoclonal bands (CSF-OCB) detected by isoelectric focusing (IEF) in patients with multiple sclerosis (MS) was evaluated in our study. METHODS: Three hundred and twenty-one patients with MS and other central nervous system (CNS) immune mediated disorders were assessed (CIMD). Cerebrospinal fluid and matched serum samples were examined for the presence of OCB by IEF-IB (isoelectric focusing with immunoblotting). RESULTS: Isolated oligoclonal bands (ISO-OCB) were the only predictor of MS diagnosis independent of age, gender and CSF-OCB. ISO-OCB ≥ 3.5 detected by IEF yielded a sensitivity of 98% and specificity of 87% in distinguishing MS from MS mimickers. CONCLUSIONS: For the neurologist, a score of ≥ 4 ISO-OCB supports the diagnosis of MS. On the other hand, ISO-OCB ≤3 favors CIMD. Further studies with larger population samples are warranted to confirm these findings.

Cerebral Gray Matter Atrophy Is Associated with the CSF IgG index in African American with Multiple Sclerosis.

BACKGROUND AND PURPOSE: African American (AA) patients with multiple sclerosis (MS) have been reported to have a more aggressive disease course compared to their white counterparts. We explored the relation of gray matter (GM) volume, a marker of tissue injury, and cerebrospinal fluid (CSF) IgG index in both AA and white MS patients. METHODS: This was a cross-sectional study of 150 self-identified AA and 150 white patients with MS who underwent magnetic resonance imaging scan of brain and CSF sampling. Intrathecal IgG synthesis was quantified as IgG index. The Spearman test was used for univariate correlation analysis, followed by generalized linear model (GLM) to assess the effect of race on the correlation between IgG index and GM volume. RESULTS: The GM volume was inversely related to the IgG index for the entire group (rho = -.57, P < .0004). The AA group showed a stronger correlation (rho = -.893, P < .00004), as compared to whites (rho = -.019, P = .85), between GM and IgG index. Furthermore, GLM analysis showed a significant effect of race on the relation between IgG index and GM volume (P < .0005). CONCLUSIONS: AA patients with MS have lower GM volume and a stronger inverse correlation between GM volume and CSF IgG index, compared to the whites. These findings suggest a potentially prominent role of humoral immunity in mediating tissue injury in AA patients with MS.

Glatiramer acetate therapy for multiple sclerosis: a review.

The past decade has witnessed a revolution in the treatment of multiple sclerosis (MS), the most common demyelinating disorder of the human CNS. After being considered as an untreatable disease for more than a century, six disease-modifying treatments have been approved between 1993 and 2006. Glatiramer acetate (GA) is a worldwide drug approved for the treatment of relapsing-remitting MS in 1996. The drug is a synthetic copolymer of four amino acids based on the composition of myelin basic protein, one of several putative autoantigens implicated in the pathogenesis of MS. Three separate double-blind, placebo-controlled trials have established its efficacy in relapsing-remitting MS. Observations from an ongoing study, the longest prospective study in MS therapeutics so far, suggest that the effect of GA in reducing the relapse rate and neurological disability is maintained over a 10-year period. Independent investigators have identified several putative immunological mechanisms of action of GA, with the unique observation of the generation of GA-reactive T-helper 2 (anti-inflammatory) polarised lymphocytes within days to weeks of initiating therapy and sustaining an anti-inflammatory milieu for years in the peripheral immune system and, presumably, in the CNS. Emerging data from immunological and imaging studies quantifying axonal injury in the brain point towards neuroprotective abilities of GA. Combined with its remarkable safety and tolerability, long-term efficacy and neuroprotective effect, GA presents it self as a first-line choice in relapsing-remitting MS, and holds immense promise in developing its potential as a combination therapy in MS, as well as extending its indications to other neurodegenerative diseases.

Characterizing retinal structure injury in African-Americans with multiple sclerosis.

To examine retinal structure injury in African-Americans (AA) with Multiple Sclerosis (MS) compared to Caucasians (CA) with MS, we used spectral domain optical-coherence tomography (OCT) in this cross sectional study. The peripapillary retinal nerve fiber layer (pRNFL) and macular volume of 234 MS patients (149 CA; 85 AA) and 74 healthy controls (60 CA; 17 AA) were measured. Intra-retinal segmentation was performed to obtain retinal nerve fiber (RNFL), ganglion cell (GCL), inner plexiform (IPL), inner nuclear (INL), outer plexiform (OPL), outer nuclear (ONL), retinal pigment epithelium (RPE), and photoreceptor (PR) layer volumes. Study was approved by IRB, and informed consent obtained from all participants. We found that pRNFL was thicker in AA v. CA healthy controls (100.9 vs 97.00µm, p=0.004). Compared to HC, MS patients demonstrated thinner pRNFL (p<0.0001), and lower TMV (p<0.001), macular RNFL (p<0.0001), GCL (p<0.0001), and IPL (p<0.0001). AAMS patients had thinner pRNFL (87.2 vs 90.0µm, and lower TMV (8.2 vs 8.4mm(3), p=0.0001), RNFL (0.73 vs 0.79mm(3), p=0.0001), and GCL (0.94 vs 0.98mm(3), p=0.007) than CAMS patients. Sub-analysis of patients without history of AON showed thinner pRNFL (88.9 vs 93.1µm) and TMV (8.2 vs. 8.5mm(3), p<0.0001) in AAMS compared to CAMS patients. In conclusion, this cross-sectional study provides evidence supporting greater retinal structure injury in AAMS compared to CAMS patients, irrespective of history of AON. Our findings are consistent with other studies demonstrating a more severe CNS tissue injury in AAMS patients.

A case of Hashimoto's encephalopathy: association with sensory ganglionopathy.

We report a case of Hashimoto's encephalopathy with prominent unsteadiness of gait. Nerve conduction studies and electromyographic findings were consistent with a sensory ganglionopathy. Symptoms and clinical findings resolved with high-dose corticosteroid therapy and paralleled the levels of anti-microsomal antibodies. Sensory ganglionopathy seems to be another aspect of the broad clinical syndrome labeled Hashimoto's encephalopathy.

Spinal cord atrophy in multiple sclerosis and relationship with disability across clinical phenotypes.

BACKGROUND: Several studies have shown a relationship between spinal cord atrophy and clinical disability in patients with multiple sclerosis (MS). OBJECTIVES: We examined the correlation between cervical cord cross-sectional area at the C2 vertebral level (CSA-C2) and the expanded disability status scale (EDSS) in patients with relapsing-remitting and progressive forms of MS. The latter included both secondary and primary progressive MS patients. METHODS: A total of 150 patients with MS were recruited from the Wayne State University MS clinic. Ninety-three had relapsing-remitting MS and 57 patients had progressive MS. MRI scan of the cervical cord was obtained for each patient. Correlation studies and multivariate regression analysis was performed, blinded to clinical status. RESULTS: The mean age was 41.3 year old, 64.6% were women, mean disease duration was 11.2 years, CSA-C2 was 80.2mm(2) and mean EDSS was 3.8. There was significant correlation between CSA-C2 and EDSS (r -0.75, p<0.0001). Sub-group analysis showed CSA-C2 was 68.6mm(2) and 87.3mm(2) in the progressive and relapsing-remitting groups, respectively (p<0.0001). Multivariable regression showed that CSA-C2 was a significant predictor of disability independent of disease duration, and phenotype. CONCLUSIONS: Our study demonstrates that CSA-C2 has a strong correlation with clinical disability in both RRMS and progressive MS. Greater spinal cord atrophy was seen in patients with progressive than relapsing-remitting MS. CSA-C2, disease duration, and phenotype are independent predictors of disability.

Comparative assessment of immunomodulating therapies for relapsing-remitting multiple sclerosis.

The past decade has seen unprecedented advances in the development of disease-modifying therapies for relapsing-remitting multiple sclerosis (RRMS), a disease that has a worldwide prevalence of two million patients. Four agents with the ability to modulate the immune system are now being widely used for RRMS. Of these, three are forms of interferon (IFN)-beta [IFNbeta-1b and two preparations of IFNbeta-1a (Avonex and Rebif], and one is a polypeptide of four amino acids (glatiramer acetate) with a unique mechanism of action. The administration regimens for the IFNbeta-1a products differ, with Avonex being given as 30 microg intramuscularly once a week and Rebif being given as 22 or 44 microg subcutaneously three times a week. It appears safe to predict that both forms of IFNbeta and glatiramer acetate will remain standard treatments for MS for years to come. However, with four therapeutic options available for RRMS, selecting a single therapy is often difficult and necessitates comparisons of the agents, which can be contentious. All four agents have shown superiority over placebo in pivotal phase III trials. Three recent prospective comparative studies have indicated that IFNbeta-1b, Rebif and glatiramer acetate may be more optimal choices than Avonex for patients with RRMS. In a pharmaceutical environment with an estimated worldwide market of $US2.5 billion annually for RRMS, comparative studies are understandably provocative, but at the same time provide meaningful information to clinicians and patients.

Paraneoplastic neuromyelitis optica spectrum disorder associated with metastatic carcinoid expressing aquaporin-4.

IMPORTANCE: Reports of neuromyelitis optica spectrum disorder (NMOSD) occurring in the setting of neoplasia suggest that aquaporin-4 autoimmunity may in some cases have a paraneoplastic basis. OBSERVATIONS: In this case report, we describe a patient with NMOSD whose test results were seropositive for aquaporin-4 IgG and who had a hepatic metastasis from a small-bowel neuroendocrine tumor. The tumor cells expressed aquaporin-4 immunoreactivity. She presented to the Neurology Department at Wayne State University with bilateral leg weakness, ascending paresthesias, and decreased sensation. CONCLUSIONS AND RELEVANCE: This case extends the context of NMOSD as a paraneoplastic disorder.

Effect of disease-modifying therapies on brain volume in relapsing-remitting multiple sclerosis: results of a five-year brain MRI study.

OBJECTIVE: To compare the long-term effect of disease-modifying therapies (DMT) on brain volume loss in relapsing-remitting MS (RRMS) patients. METHODS: We conducted a study to examine the effect of daily glatiramer acetate (GA), weekly low dose interferon beta (LD-IFNB), and high-dose high-frequency interferon beta disease (HD-IFNB) on brain volume loss over 5 years in RRMS patients. All patients were previously treatment naïve, had disease duration ≤5 years at the time of initiating DMT, and subsequently received the same DMT for 5 years continuously. The percentage change in brain volume (PCBV) was measured using fully automated software. MRI analysis was performed blinded to treatment allocation. RESULTS: The adjusted PCBV from baseline to year 5 was -2.27% in GA, -2.62% in LD-IFNB, and -3.21% in the HD-IFNB groups (-2.27 vs -2.62, p=0.0036; -2.27 vs -3.21, p<0.0001; -2.62 vs -3.21, p<0.0001). These data remained unchanged from year 1 to year 5, after adjusting for pseudoatrophy in the first year. A group of RRMS patients that remained untreated for a period ranging from 8 to 24 months, served as controls. All treatment groups were significantly better than the rate of projected brain volume loss in the untreated group over 5 years (p<0.0001). CONCLUSIONS: Global brain volume loss is a dynamic process even in relatively early RRMS patients that occurs despite intervention with therapy. However, all DMT significantly reduced the loss of brain volume compared to no treatment. The GA-treated group experienced the least reduction in brain volume over 5 years, compared to the LD-IFNB and HD-IFNB treated groups. These differences could be partly related to the immunologic consequences of GA therapy in RRMS.

Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids.

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an autosomal-dominant central nervous system white-matter disease with variable clinical presentations, including personality and behavioral changes, dementia, depression, parkinsonism, seizures and other phenotypes. We combined genome-wide linkage analysis with exome sequencing and identified 14 different mutations affecting the tyrosine kinase domain of the colony stimulating factor 1 receptor (encoded by CSF1R) in 14 families with HDLS. In one kindred, we confirmed the de novo occurrence of the mutation. Follow-up sequencing identified an additional CSF1R mutation in an individual diagnosed with corticobasal syndrome. In vitro, CSF-1 stimulation resulted in rapid autophosphorylation of selected tyrosine residues in the kinase domain of wild-type but not mutant CSF1R, suggesting that HDLS may result from partial loss of CSF1R function. As CSF1R is a crucial mediator of microglial proliferation and differentiation in the brain, our findings suggest an important role for microglial dysfunction in HDLS pathogenesis.