Siddharama Pawate

Although often regarded as a protean illness with myriad clinical and imaging manifestations, neurosarcoidosis typically presents as recognizable syndromes that can be approached in a rational, systematic fashion. Understanding of neurosarcoidosis has progressed significantly in recent years, including updated diagnostic criteria and advances in treatment. The diagnosis of neurosarcoidosis is established by the clinical syndrome, imaging and histopathological findings, and exclusion of other causes. Mounting evidence supports the use of tumor necrosis factor inhibitors as an important addition to the therapeutic armamentarium, along with glucocorticoids and steroid-sparing cytotoxic immunosuppressants. In this narrative review, we summarize recent advances in the diagnosis and treatment of neurosarcoidosis.

Objective: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor–α. Methods: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes. Results: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24–71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4–8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. Conclusions: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. Classification of evidence: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.

The objective of this work is to report on a series of five patients with adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia (ALSP). ALSP is a rare adult-onset leukodystrophy, which encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmentary orthochromatic leukodystrophy. This was a retrospective chart review and literature review. Five previously healthy women presented with a rapidly progressive neurological disorder at ages 39, 37, 40, 30, and 47, respectively. All five individuals were initially diagnosed as suffering from multiple sclerosis. The clinical courses of the five patients were dominated by progressive spastic quadriparesis (patient 5, newly diagnosed, has paraparesis at this time) and dementia. Brain magnetic resonance imaging (MRI) showed diffuse cerebral atrophy, corpus callosal atrophy, and diffuse T2 hyperintensities in the subcortical and periventricular white matter with no gadolinium enhancing lesions. Three patients showed involvement of pyramidal tracts from motor cortex to the brainstem. Cerebrospinal fluid was normal in all cases. Diagnosis of ALSP was established by biopsy (two cases) and autopsy (two cases). Histopathology showed the presence of neuroaxonal spheroids in all four cases and pigmented glia in three. In the fifth case, diagnosis was established by genetic analysis alone that showed a disease-causing mutation in the colony-stimulating factor 1 receptor (CSF1R) gene. Genetic analysis was done in three patients with available DNA, and identified the disease-causing mutation in all three, including a novel mutation F828S. ALSP may be suspected in adults with rapid to subacute progression of neurological disease when (1) MRI shows corpus callosal atrophy on a background of generalized brain atrophy and diffuse white matter disease without postcontrast enhancement, (2) CSF studies are normal, and (3) studies for systemic inflammatory diseases and specific leukodystrophies are normal. Diagnosis may be made without histopathological evidence when a disease-causing mutation is demonstrated in the CSF1R gene.

To investigate differences in T2 intensity of deep gray matter (dGM) structures by magnetic resonance imaging (MRI) in multiple sclerosis (MS) patients undergoing various immunomodulatory therapies. In MS, dGM T2 hypointensities by MRI are hypothesized to represent iron deposition and are known to be associated with worse disease stage as assessed by brain atrophy, cognitive and physical disability. The relation between immunotherapies and T2 intensity, however, has been not been investigated in detail. A total of 255 MS patients were stratified into those on no treatment (NON, n= 45), and those on immunomodulatory treatments for ≥6 months (ie, interferon beta [IFNβ]n= 118, glatiramer acetate [GA]n= 41, natalizumab [NAT]n= 39, and mycophenolate mofetil [MMF]n= 12). T2 intensities of dentate nucleus (DN), substantia nigra (SN), red nucleus (RN), and globus pallidus (GP) were measured. Group differences in T2 intensities were assessed using a linear regression model with T2 intensities as outcome variable, treatment group as main independent variable, and clinical measures such as Expanded Disability Status Scale (EDSS) score, years of MS, and 25-feet walk time (T25-FW) as covariates. To compare T2 intensities before and after treatment in a subset of NAT-treated patients, we used the Wilcoxon signed-rank test. When adjusted for EDSS, duration of disease and T25-FW, across all deep nuclei, NAT-treated patients had significantly higher T2 intensities than untreated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), IFNβ-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ), and GA-treated patients (DN p= 1.65 × 10(-5) ; SN p= 2.37 × 10(-5) ; RN p= 3.90 × 10(-6) ; GP p= 1.05 × 10(-6) ). In a subset of MS patients receiving NAT, there was a significant increase in T2 intensities in all the dGM nuclei after 24 months of treatment (DN p= 0.00021; SN p= <0.0001; RN p= 0.00015; GP p= 0.00011). Our preliminary observations suggest that long-term NAT therapy in MS patients may affect T2 intensity levels of dGM brain nuclei, hence suggesting a potential effect of NAT beyond anti-inflammatory effect. Prospective studies are warranted to provide more insights into our preliminary observations.

Interplay between susceptibility genes and environmental factors is considered important player in the genesis of multiple sclerosis (MS). Among environmental factors, a role for an infectious pathogen has long been considered central to the disease process. This opinion has support both from epidemiological data and the findings of immunological abnormalities in spinal fluid that reflect an immune response to an as yet undetermined antigen, possibly a pathogen, in the cerebrospinal fluid. Our review will outline the current understanding of the role of infection in the causation and progression of MS. We will review the data that point to an infectious cause of MS and consider the specific agents Chlamydophila (Chlamydia) pneumoniae, Human Herpes Virus 6, and Epstein-Barr Virus, that are implicated in either the development or progression of MS.

Objective: To report on the clinical presentations, laboratory abnormalities, treatment and outcomes in 54 patients with neurosarcoidosis (NS). Background: Sarcoidosis is an inflammatory granulomatous disease affecting multiple organ systems. Neurosarcoidosis (CNS involvement) is seen in approximately 25% of patients with systemic sarcoidosis, although it is subclinical in most of these cases. Because of its rarity, exposure of neurologists to the clinical spectrum of NS is limited to case reports or short case series. Patients and Methods: A database of 3900 patients treated at the Vanderbilt Multiple Sclerosis Clinic between 1995 and 2008 was searched for ‘neurosarcoidosis’, ‘neurosarcoid’, ‘sarcoidosis’ and ‘sarcoid’. Of the 162 patient records that were retrieved, 54 patients were found to meet the criteria for definite, probable or possible neurosarcoidosis and were reviewed, including their clinical presentation, Cerebrospinal fluid (CSF) findings, Magnetic resonance imaging (MRIs), biopsy results, treatment, and where available, outcomes 4 months to 20 years after onset of the presenting illness. Results: Clinical presentations and imaging findings in NS were varied. Cranial nerve abnormalities were the most common clinical presentation and involvement of the optic nerve in particular was associated with a poor prognosis for visual recovery. Isolated involvement of lower cranial nerves had a more favorable outcome. T₂ hyperintense parenchymal lesions were the most common imaging finding followed by meningeal enhancement. Long-term treatment consisted of prednisone and/or other immunomodulators (azathioprine, methotrexate or mycophenolate mofetil). Conclusions: Unlike systemic sarcoidosis, there is difficulty in making tissue diagnosis when involvement of CNS is suspected. MRI and CSF studies are sensitive in the detection of CNS inflammation but lack specificity, making the ascertainment of neurosarcoidosis a clinical challenge. In addition the low prevalence of the disease makes clinical trials difficult and therapeutic decisions are likely to be made from careful reporting from case studies.

We report a series of four patients with Susac’s syndrome, which is characterized by the triad of visual loss due to branch retinal artery occlusions, sensorineural hearing loss due to cochlear involvement, and encephalopathy due to cerebral microangiopathy. However, as we describe in this series, the clinical triad may not be apparent for years, resulting in delays in diagnosis. We also report the variable cerebrospinal fluid and brain magnetic resonance imaging findings, and treatment using a combination of steroids and intravenous immunoglobulin, followed by mycophenolate mofetil.

Retrospective chart review. To report six patients with isolated longitudinal myelitis (LM). Outpatients at Multiple Sclerosis Center/Clinic Vanderbilt University Medical Center. Patients treated for LM in whom evidence for multiple sclerosis (MS), neuromyelitis optica (NMO) and systemic inflammatory disorders such as systemic lupus erythematosus (SLE) was lacking. 2. Interventions: Clinical, laboratory and imaging data, treatment and outcomes were reviewed. 3. Main Outcome Measures: LM in the absence of optic neuritis, normal or nonspecific brain magnetic resonance imaging (MRI) findings, the absence of NMO antibody. All presented with monophasic myelitis with variable loss of motor, sensory and bowel/bladder functions. MRIs of the brain were normal (five cases), and in the sixth showed a single T2 hyperintense lesion, which was interpreted as an ischemic lesion due to small-vessel disease. MRIs of the spinal cord of all patients showed swelling and T2 hyperintense lesions with patchy contrast enhancement that extended from the cervicomedullary junction to the conus medullaris. Two of these patients received rituximab with clinical benefit. Another patient received one dose of rituximab, developed an allergic reaction, received further treatments with azathioprine and also made a good recovery. In one patient, approval for rituximab was obtained several months after the inflammation had subsided, and she has shown only a minimal improvement. The two patients who did not receive rituximab made no significant recovery from their maximal neurological deficits. Isolated LM may be a new clinical syndrome, or a variant of NMO.