Faculty Bibliography

Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare, fatal, neoplastic condition of infiltrating glial cells into the meninges without evidence of primary tumor in the brain or spinal cord parenchyma. Primary diffuse leptomeningeal gliomatosis often presents with symptoms and physical findings of chronic inflammatory meningitis and raised intracranial pressure, and lacks specific clinical, radiologic, and diagnostic criteria. We report a case of PDLG diagnosed post-mortem, highlighting the diagnostic difficulty in identifying PDLG as the cause of chronic meningitis, even when a neoplastic etiology is suspected. Because multiple cytologies and even a leptomeningeal biopsy did not reveal the diagnosis ante-mortem, we emphasize the consideration of multi-site or repeat leptomeningeal biopsy when a persistent inflammatory infiltrate is found and neurological symptoms are progressive.

BACKGROUND: Optic neuritis is often the initial presentation of multiple sclerosis (MS). As established by the Optic Neuritis Treatment Trial, an abnormal baseline brain MRI is a strong predictor of MS after isolated optic neuritis in adults. However, the rate of conversion to MS after optic neuritis in children based upon brain MRI findings is unknown. METHODS: We reviewed the medical records of children (<18 years) presenting with optic neuritis between 1993 and 2004 at the Children's Hospital of Philadelphia. Children with a history of demyelinating disease or prior optic neuritis were excluded. Symptoms, ophthalmologic findings, MRI findings, and clinical outcomes were recorded. RESULTS: We identified 29 consecutive children with idiopathic optic neuritis. Eleven patients (38%) had white matter T2/FLAIR lesions in the brain (not including the optic nerves). Eighteen patients were followed for more than 24 months, and 3 of the 18 (17%) developed MS. All 3 patients had an abnormal brain MRI scan at their initial presentation of optic neuritis. None of the patients with a normal brain MRI scan at presentation developed MS over an average follow-up of 88.5 months. Patients with one or more white matter lesions on MRI were more likely to develop MS (3/7 vs 0/11, p = 0.04, Fisher exact test). CONCLUSIONS: Children with brain MRI abnormalities at the time of the diagnosis of optic neuritis have an increased risk of multiple sclerosis. Larger collaborative studies are needed to further define the prognosis for childhood optic neuritis.

The AFFIRM and SENTINEL studies showed that natalizumab was effective both as monotherapy and in combination with interferon beta (IFNbeta)-1a in patients with relapsing multiple sclerosis (MS). Further analyses of AFFIRM and SENTINEL data were conducted to determine the efficacy of natalizumab in prespecified patient subgroups according to baseline characteristics: relapse history 1 year before randomization (1, 2, > or = 3), Expanded Disability Status Scale score (< or = 3.5, > 3.5), number of T2 lesions (< 9, > or = 9), presence of gadolinium-enhancing (Gd+) lesions (0, > or = 1), age (< 40, > or = 40) and gender (male, female). A post hoc analysis was conducted to determine the efficacy of natalizumab in patients with highly active disease (i. e., > or = 2 relapses in the year before study entry and > or = 1 Gd+ lesion at study entry). In both AFFIRM and SENTINEL studies natalizumab reduced the annualized relapse rates across all subgroups (except the small subgroups with < 9 baseline T2 lesions) over 2 years. In AFFIRM, natalizumab significantly reduced the risk of sustained disability progression in most subgroups. In SENTINEL, natalizumab significantly reduced the risk of sustained disability progression in the following subgroups: > or = 9 T2 lesions at baseline, > or = 1 Gd+ lesions at baseline, female patients and patients < 40 years of age. Natalizumab reduced the risk of disability progression by 64 % and relapse rate by 81 % in treatment- naive patients with highly active disease and by 58 % and 76 %, respectively, in patients with highly active disease despite IFNbeta-1a treatment. These results indicate that natalizumab is effective in reducing disability progression and relapses in patients with relapsing MS, particularly in patients with highly active disease.

BACKGROUND: Trigeminal neuralgia is a syndrome of paroxysmal excruciating, lancinating unilateral facial pain. REVIEW SUMMARY: There are several clinical features that are characteristic of trigeminal neuralgia, but there may be red flags that should suggest alternative diagnoses. There is convincing evidence that the idiopathic form develops from focal demyelination at the trigeminal root entry zone with subsequent ephaptic cross-talk between axons. Vascular compression of the nerve root causes this demyelination in most patients. Medical management of this condition, using anticonvulsant therapy and other agents, aims to dampen the abnormal electrical signals and to ameliorate symptoms. In refractory cases, a number of surgical interventions can be considered, the most common of which is microvascular decompression of the trigeminal nerve. Gamma knife therapy is emerging as an alternative treatment for the patient with medically refractive trigeminal neuralgia, particularly in the elderly patient with comorbid conditions. CONCLUSION: Knowledge of the proper diagnosis and management of trigeminal neuralgia is essential to the successful management of these patients.

BACKGROUND: The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. METHODS: Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. FINDINGS: 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. INTERPRETATION: Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.

Conventional MR imaging is, at present, the most important paraclinical modality for assessing the risk of MS in patients with acute demyelinating ON and for monitoring the progression of disease. However, there are limitations of conventional MR in imaging the optic nerve. Newer strategies, MT MR imaging, DT MR imaging, and OCT, show significant promise. Future investigations, including the use of nonconventional MR imaging techniques coupled with OCT and functional measures of anterior visual pathway function, will further assist in the early detection of clinical impairment. Serial analysis will allow for monitoring of disease progression, predict accumulation of disability, and ascertain the effects of candidate neuroprotective therapies.

BACKGROUND AND OBJECTIVES: Diagnosis of multiple sclerosis (MS) requires exclusion of diseases that could better explain the clinical and paraclinical findings. A systematic process for exclusion of alternative diagnoses has not been defined. An International Panel of MS experts developed consensus perspectives on MS differential diagnosis. METHODS: Using available literature and consensus, we developed guidelines for MS differential diagnosis, focusing on exclusion of potential MS mimics, diagnosis of common initial isolated clinical syndromes, and differentiating between MS and non-MS idiopathic inflammatory demyelinating diseases. RESULTS: We present recommendations for 1) clinical and paraclinical red flags suggesting alternative diagnoses to MS; 2) more precise definition of "clinically isolated syndromes" (CIS), often the first presentations of MS or its alternatives; 3) algorithms for diagnosis of three common CISs related to MS in the optic nerves, brainstem, and spinal cord; and 4) a classification scheme and diagnosis criteria for idiopathic inflammatory demyelinating disorders of the central nervous system. CONCLUSIONS: Differential diagnosis leading to MS or alternatives is complex and a strong evidence base is lacking. Consensus-determined guidelines provide a practical path for diagnosis and will be useful for the non-MS specialist neurologist. Recommendations are made for future research to validate and support these guidelines. Guidance on the differential diagnosis process when MS is under consideration will enhance diagnostic accuracy and precision.

Mitoxantrone, the first immunosuppressant to receive FDA approval for treatment of worsening relapsing-remitting, secondary progressive, and progressive-relapsing multiple sclerosis (MS) is a DNA topoisomerase II inhibitor that has been associated with the development of acute promyelocytic myelogenous leukemia (APML). Central nervous system APML is a rare site of extramedullary involvement following mitoxantrone therapy. We report a patient with history of multiple sclerosis who developed bilateral optic nerve involvement as the primary manifestation of APML relapse following mitoxantrone treatment.

BACKGROUND: Optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx) are similar yet provide information on different aspects of retinal nerve fiber layer (RNFL) structure (thickness values similar to histology for OCT vs birefringence of microtubules for GDx). OBJECTIVES: To compare the ability of OCT and GDx to distinguish eyes of patients with multiple sclerosis (MS) from eyes of disease-free controls and thus identify RNFL abnormalities. We also sought to examine the capacity of these techniques to distinguish MS eyes from those without a history of optic neuritis and to correlate with visual function. DESIGN: Cross-sectional study. SETTING: Academic tertiary care MS center. PARTICIPANTS: Eighty patients with MS (155 eyes) and 43 disease-free controls (85 eyes) underwent both OCT and GDx imaging using protocols that measure RNFL thickness. MAIN OUTCOME MEASURES: Areas under the curve (AUC), adjusted for within-patient, intereye correlations, were used to compare the abilities of OCT and GDx temporal-superior-nasal-inferior-temporal average RNFL thicknesses to discriminate between MS and control eyes and to distinguish MS eyes with a history of optic neuritis. Visual function was evaluated using low-contrast letter acuity and high-contrast visual acuity. RESULTS: Average peripapillary RNFL thickness (360 degrees around the optic disc) was reduced in patients with MS compared with controls for both methods. Age-adjusted AUC did not differ between OCT (0.80; 95% confidence interval [CI], 0.72-0.88) and GDx (0.78; 95% CI, 0.68-0.86; P = .38). Optical coherence tomography-measured RNFL thickness was somewhat better at distinguishing MS eyes with a history of optic neuritis from those without (OCT: AUC, 0.73; 95% CI, 0.64-0.82; GDx: AUC, 0.66; 95% CI, 0.57-0.66; P = .17). Linear correlations of RNFL thickness for OCT vs GDx were significant yet moderate (r = 0.67, P < .001); RNFL thickness measures correlated moderately and significantly with low-contrast acuity (OCT: r = 0.54, P < .001; GDx: r = 0.55, P < .001) and correlated less with high-contrast visual acuity (OCT: r = 0.44, P < .001; GDx: r = 0.32, P < .001). CONCLUSIONS: Scanning laser polarimetry with variable corneal compensation measurements of RNFL thickness corroborates OCT evidence of visual pathway axonal loss in MS and provides new insight into structural aspects of axonal loss that relate to RNFL birefringence (microtubule integrity). These results support validity for RNFL thickness as a marker for axonal degeneration and support use of these techniques in clinical trials that examine neuroprotective and other disease-modifying therapies.