Diffusion-weighted imaging characteristics of biopsy-proven demyelinating brain lesions.

OBJECTIVES: To describe lesional diffusion-weighted imaging characteristics in a cohort of patients with biopsy-proven CNS inflammatory demyelinating disease (IDD) and compare diffusion characteristics of ring-enhancing CNS IDD lesions vs abscesses and tumors. METHODS: Forty prebiopsy apparent diffusion coefficient (ADC) maps were reviewed from 30 patients with CNS IDD. Lesions were analyzed for size, T2-weighted (T2W) hypointense rim, enhancement, and ADC pattern. ADC patterns of CNS IDD ring-enhancing lesions were compared with a published cohort of 35 patients with ring-enhancing tumors and abscesses. RESULTS: IDD lesions displayed a spectrum of peripheral ADC patterns at the lesion edge: restricted diffusion (low ADC), 33%; increased diffusion (high ADC), 60%; and normal diffusion (homogeneously isointense), 7%. Of biopsied lesions, 93% enhanced (ring, 52%; heterogeneous, 34%; homogeneous, 7%). A hypointense T2W rim was observed in 53%. A ring pattern on ADC (isointense or dark) was associated with T2W hypointense rims (p = 0.02) but not with ring enhancement. On serial imaging, 4 of 7 (57%) patients demonstrated changes in ADC patterns. Peripheral restriction was more common in IDD (p = 0.006) than in tumors or abscesses, whereas central restriction was only observed in abscesses. Restricted lesions in the same stage were more common in the non-IDD cohort (42% vs 20%), with a uniform restricted pattern seen only in abscesses. CONCLUSIONS: In ring-enhancing lesions, peripheral diffusion restriction is more common in IDD than in tumors/abscesses, whereas central restriction is more common among abscesses. Rapid ADC pattern changes in IDD probably reflect dynamic lesion evolution and may distinguish IDD from tumors.

Azathioprine: tolerability, efficacy, and predictors of benefit in neuromyelitis optica.

OBJECTIVE: To evaluate the efficacy, tolerability, optimal dosing, and monitoring of azathioprine in patients with neuromyelitis optica (NMO). METHODS: This was a chart review and telephone follow-up study of 99 patients with NMO spectrum of disorders (NMOSD) treated with azathioprine (1994-2009). NMOSD were NMO (2006 diagnostic criteria) or partial NMO forms (NMO-immunoglobulin G seropositive). Wilcoxon signed rank test was used to compare pretreatment and postinitiation of azathioprine (posttreatment) annualized relapse rates (ARR), Expanded Disability Status Scale (EDSS) score, and visual acuity outcome. Linear regression was used to assess the effects of various factors on ARR change and disability. RESULTS: The median duration of NMOSD symptoms prior to initiation of azathioprine was 2 years (range 1-27); 79 patients were women. Eighty-six patients had NMO and 13 limited NMO versions, including transverse myelitis in 8 and optic neuritis in 5. Median posttreatment follow-up was 22 months. Thirty-eight patients discontinued drug (side effects, 22; no efficacy, 13; lymphoma, 3). Among 70 patients with >12 months follow-up, 48 received ≥2.0 mg/kg/day (ARR: pretreatment, 2.20; posttreatment, 0.52); 22 received <2.0 mg/kg/day (ARR: pretreatment, 2.09; posttreatment, 0.82); 52 received concomitant prednisone (ARR: pretreatment, 2.20; posttreatment, 0.89) and 18 did not (ARR: pretreatment, 1.54; posttreatment, 0.23); p < 0.0001 for each comparison. EDSS was stable or improved despite ongoing attacks in 22 patients (31%). Twenty-six patients tolerated azathioprine and were relapse-free (37%, median follow-up 24 months; range 12-151). Mean corpuscular volume increase influenced ARR change (p = 0.049). CONCLUSIONS: Azathioprine is generally effective and well-tolerated. Early initiation, adequate dosing, and hematologic parameter monitoring may optimize efficacy. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that azathioprine is effective for reducing relapse rates and improving EDSS and visual acuity scores in patients with NMO spectrum of disorders.

Tumefactive demyelination and glioblastoma: a rare collision lesion.

OBJECTIVE: Inflammatory demyelination occasionally forms a solitary mass lesion clinically and radiographically indistinguishable from glioma, replete with enhancement and mass effect. Termed "tumefactive demyelination" it often prompts a brain biopsy. DESIGN: We undertook neuroimaging and morphologic analysis of a unifocal demyelinating lesion intimately associated with glioblastoma. MRI characteristics of the lesion were assessed as were biopsy and resection specimens by both histological and immunohistochemical methods. RESULTS: The patient, a 49-year-old woman, presented with subacute onset headaches. An MRI T1W scan revealed a hemispheric mass with centrally reduced signal and ring enhancement. T2W images showed increased central signal with a rim of reduced signal co-localized to the enhancing ring. A biopsy was initially misinterpreted as demyelination alone, given abundance of histiocytes, the presence of hypertrophic astrocytes with micronuclei ("Creutzfeldt-Peters cells"), and occasional mitoses. Upon consultative review, two histologically distinct components, one inflammatory demyelination and the other an anaplastic astrocytoma were revealed. Subsequent complete resection of the abnormality demonstrated a WHO grade IV astrocytoma (glioblastoma multiforme). CONCLUSION: Our experience underscores the importance of adequate tissue sampling during biopsy for suspected glioma, and confirms the fact that active inflammatory demyelination may coexist with a high-grade glioma. Despite detailed study, the basis for the association remains elusive.

A case of multiple sclerosis presenting with inflammatory cortical demyelination.

OBJECTIVE: To describe a patient presenting with a clinically silent, incidentally found, and pathologically confirmed active demyelinating solitary cortical lesion showing MRI gadolinium contrast enhancement, in whom biopsy was performed before the radiographic appearance of disseminated white matter lesions. METHODS: Neurologic examination, MRI, CSF and serologic analyses, and brain biopsy were performed. Sections of formalin-fixed paraffin-embedded biopsied brain tissue were stained with histologic and immunohistochemical stains. RESULTS: Biopsy revealed an inflammatory subpial lesion containing lymphocytes and myelin-laden macrophages. Recurrent relapses with dissemination of MRI-typical white matter lesions characterized the subsequent course. CONCLUSIONS: Our findings highlight that cortical demyelination occurs on a background of inflammation and suggest that the noninflammatory character of chronic cortical demyelination may relate to long intervals between lesion formation and autopsy. This case provides pathologic evidence of relapsing-remitting MS presenting with inflammatory cortical demyelination and emphasizes the importance of considering demyelinating disease in the differential diagnosis of patients presenting with a solitary cortical enhancing lesion.

Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis.

Atypical imaging features of multiple sclerosis lesions include size >2 cm, mass effect, oedema and/or ring enhancement. This constellation is often referred to as 'tumefactive multiple sclerosis'. Previous series emphasize their unifocal and clinically isolated nature, however, evolution of these lesions is not well defined. Biopsy may be required for diagnosis. We describe clinical and radiographic features in 168 patients with biopsy confirmed CNS inflammatory demyelinating disease (IDD). Lesions were analysed on pre- and post-biopsy magnetic resonance imaging (MRI) for location, size, mass effect/oedema, enhancement, multifocality and fulfilment of Barkhof criteria. Clinical data were correlated to MRI. Female to male ratio was 1.2 : 1, median age at onset, 37 years, duration between symptom onset and biopsy, 7.1 weeks and total disease duration, 3.9 years. Clinical course prior to biopsy was a first neurological event in 61%, relapsing-remitting in 29% and progressive in 4%. Presentations were typically polysymptomatic, with motor, cognitive and sensory symptoms predominating. Aphasia, agnosia, seizures and visual field defects were observed. At follow-up, 70% developed definite multiple sclerosis, and 14% had an isolated demyelinating syndrome. Median time to second attack was 4.8 years, and median EDSS at follow-up was 3.0. Multiple lesions were present in 70% on pre-biopsy MRI, and in 83% by last MRI, with Barkhof criteria fulfilled in 46% prior to biopsy and 55% by follow-up. Only 17% of cases remained unifocal. Median largest lesion size on T2-weighted images was 4 cm (range 0.5-12), with a discernible size of 2.1 cm (range 0.5-7.5). Biopsied lesions demonstrated mass effect in 45% and oedema in 77%. A strong association was found between lesion size, and presence of mass effect and/or oedema (P < 0.001). Ring enhancement was frequent. Most tumefactive features did not correlate with gender, course or diagnosis. Although lesion size >5 cm was associated with a slightly higher EDSS at last follow-up, long-term prognosis in patients with disease duration >10 years was better (EDSS 1.5) compared with a population-based multiple sclerosis cohort matched for disease duration (EDSS 3.5; P < 0.001). Given the retrospective nature of the study, the precise reason for biopsy could not always be determined. This study underscores the diagnostically challenging nature of CNS IDDs that present with atypical clinical or radiographic features. Most have multifocal disease at onset, and develop RRMS by follow-up. Although increased awareness of this broad spectrum may obviate need for biopsy in many circumstances, an important role for diagnostic brain biopsy may be required in some cases.

CNS aquaporin-4 autoimmunity in children.

BACKGROUND: In adult patients, autoantibodies targeting the water channel aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. METHODS: A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58. RESULTS: Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4-18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjögren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months). CONCLUSIONS: Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.

Sporadic adult-onset leukoencephalopathy with neuroaxonal spheroids mimicking cerebral MS.

BACKGROUND: Leukoencephalopathy with neuroaxonal spheroids is a rare cause of severe, subacute dementia that usually presents in childhood and is inherited in an autosomal dominant pattern. The authors present clinical, radiologic, and pathologic features of adult-onset, sporadic cases mimicking cerebral-type progressive MS. METHODS: Five patients referred to an MS subspecialty clinic from 1999 to 2006 suspected of having primary cerebral MS. All patients were reviewed clinically, radiologically, and pathologically at Mayo Clinic Rochester. Diagnostic brain biopsies were examined by two neuropathologists. RESULTS: All patients had severe, progressive cognitive and motor impairment, often with prominently asymmetrical features and diffuse nonenhancing subcortical white matter lesions on brain MRI. Cerebrovascular and spinal cord imaging were normal. CSF showed elevated neuron-specific enolase without elevated oligoclonal bands or IgG index. Extensive evaluations for alternative diagnoses were unrevealing. Pathologic examination confirmed leukodystrophy with neuroaxonal spheroids and pigmented glia on all patients. Therapies initiated did not alter the severe progressive disease course. CONCLUSIONS: Leukoencephalopathy with neuroaxonal spheroids occurs sporadically, in adults, and mimics cerebral-type MS or other leukodystrophies. Brain biopsy may be diagnostic in life; however, no treatment is known to be effective. Pathologic diagnosis is important to avoid potentially toxic therapies aimed at CNS inflammatory diseases such as MS.

Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders.

OBJECTIVE: To determine seroprevalence of neuromyelitis optica (NMO)-IgG in childhood CNS inflammatory demyelinating disorders. METHODS: We analyzed demographic, clinical, and radiologic data in a blinded fashion and assessed serum NMO-IgG status for 87 children: 41 with relapsing-remitting multiple sclerosis (RRMS), 17 with NMO, 13 with monophasic/recurrent optic neuritis (ON), 13 with transverse myelitis, of whom 10 were longitudinally extensive on MRI spine (LETM), and another 3 with LETM in the context of acute disseminated encephalomyelitis (ADEM). RESULTS: Ten of the 87 children (11%) were seropositive. Eight of 17 with NMO (47%) were seropositive (7 of 9 with relapsing NMO [78%], 1 of 8 with monophasic NMO [12.5%]). Two other children were seropositive: 1 of 5 with recurrent ON and one child with recurrent LETM. No seropositive case was identified among 41 with RRMS (14% of whom had LETM at some point in their clinical course), 8 with monophasic ON, 9 with monophasic LETM, or 3 with LETM in the context of ADEM. CONCLUSIONS: The similar frequency of neuromyelitis optica (NMO)-IgG in both childhood and adult cases of NMO, and its rarity in relapsing-remitting multiple sclerosis, supports the concept that these diseases have a similar pathogenesis in childhood and adulthood. It is noteworthy that none of nine children with monophasic longitudinally extensive transverse myelitis (LETM) was NMO-IgG-seropositive. Furthermore, LETM does not appear to be as predictive of an NMO spectrum disorder in children as it is in adults. Longitudinal studies of larger pediatric LETM cohorts are required to ascertain whether the absence of NMO-IgG is a negative predictor for relapse in this childhood entity.

Myelin oligodendrocyte glycoprotein antibodies in pathologically proven multiple sclerosis: frequency, stability and clinicopathologic correlations.

Controversy exists regarding the pathogenic or predictive role of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with multiple sclerosis (MS). Four immunopathological patterns (IP) have been recognized in early active MS lesions, suggesting heterogeneous pathogenic mechanisms. Whether MOG antibodies contribute to this pathological heterogeneity and potentially serve as biomarkers to identify specific pathological patterns is unknown. Here we report the frequencies of antibodies to human recombinant MOG (identified by Western blot and enzyme-linked immunoabsorbent assay (ELISA)) in patients with pathologically proven demyelinating disease, and investigate whether antibody status is associated with clinical course, HLA-DR2-genotype, IP or treatment response to plasmapheresis. The biopsy cohort consisted of 72 patients: 12 pattern I, 43 pattern II and 17 pattern III. No association was found between MOG antibody status and conversion to clinically definite MS, DR-2 status, IP or response to plasmapheresis. There was poor agreement between Western blot and ELISA (kappa = 0.07 for MOG IgM). Fluctuations in antibody seropositivity were seen for 3/4 patients tested serially by Western blot. This study does not support a pathologic pattern-specific role for MOG-antibodies. Variable MOG-antibody status on serial measurements, coupled with the lack of Western blot and ELISA correlations, raises concern regarding the use of MOG-antibody as an MS biomarker and underscores the need for methodological consensus.

Clinical course, pathological correlations, and outcome of biopsy proved inflammatory demyelinating disease.

BACKGROUND: A pathological classification has been developed of early active multiple sclerosis (MS) lesions that reveals four patterns of tissue injury: I-T cell/macrophage associated; II-antibody/complement associated; III-distal oligodendrogliopathy, and IV-oligodendrocyte degeneration in the periplaque white matter. Mechanisms of demyelination in early MS may differ among the subgroups. Previous studies on biopsied MS have lacked clinicopathological correlation and follow up. Critics argue that observations are not generalisable to prototypic MS. OBJECTIVE: To describe the clinicopathological characteristics of the MS Lesion Project biopsy cohort. METHODS: Clinical characteristics and disability of patients with pathologically confirmed inflammatory demyelinating disease (excluding ADEM) classified immunopathologically (n = 91) and patients from the Olmsted County MS prevalence cohort (n = 218) were determined. RESULTS: Most patients who underwent biopsy and had pathologically proved demyelinating disease ultimately developed definite (n = 70) or probable (n = 12) MS (median follow up 4.4 years). Most had a relapsing remitting course and 73% were ambulatory (EDSS < or =4) at last follow up. Nine patients remained classified as having an isolated demyelinating syndrome at last follow up. Patients with different immunopathological patterns had similar clinical characteristics. Although presenting symptoms and sex ratios differed, the clinical course in biopsy patients was similar to the prevalence cohort. Median EDSS was <4.0 in both cohorts when matched for disease duration, sex, and age. CONCLUSIONS: Most patients undergoing biopsy, who had pathologically confirmed demyelinating disease, were likely to develop MS and remain ambulatory after a median disease duration of 4.4 years. The immunopathological patterns lacked specific clinical correlations and were not related to the timing of the biopsy. These data suggest that pathogenic implications derived largely from MS biopsy studies may be extrapolated to the general MS population.

Role of the blink reflex in the evaluation of sensory neuronopathy.

Because of an incidental observation that the blink reflex was normal in paraneoplastic sensory neuronopathy (SN) and frequently abnormal in nonparaneoplastic SN, the authors reviewed the electromyographic records of patients with SN in whom blink reflex studies were performed. The blink reflex was normal in all 17 patients with paraneoplastic SN and abnormal in 20 of 43 patients with nonparaneoplastic SN. Although it does not exclude paraneoplastic SN, an abnormal blink reflex favors a nonparaneoplastic etiology.

Paraneoplastic and oncologic profiles of patients seropositive for type 1 antineuronal nuclear autoantibodies.

Type 1 antineuronal nuclear autoantibody (ANNA-1, also known as "anti-Hu") is a marker of neurologic autoimmunity that is highly associated with small-cell lung carcinoma (SCLC). To determine the spectrum of symptoms and signs as well as the frequency of cancer in adult patients who are seropositive for ANNA-1, we reviewed 162 sequential patients (67% female) identified as ANNA-1-positive in a comprehensive immunofluorescence screening test. In 21% of these patients, the antibody test requested by the physician was not ANNA-1. By the end of the follow-up period, cancer had been found in 142 patients (88%). Ten of these lacked evidence of SCLC (4 had prostate carcinoma, 3 breast carcinoma, 1 both prostate carcinoma and melanoma, 1 lymphoma, and 1 squamous-cell lung carcinoma). Of the 132 patients (81%) with proven SCLC, 17 had one or more coexisting malignant neoplasms (6 had renal carcinoma, 4 another lung primary carcinoma, 3 prostate carcinoma, 3 breast carcinoma, and 4 assorted neoplasms). The diagnosis of SCLC in 128 patients (97%) followed the onset of paraneoplastic symptoms. SCLC was identified in 10 patients by chest MRI after an equivocal chest radiograph or CT; in 28 by bronchoscopy, mediastinoscopy, or thoracotomy; and in 7 at autopsy. Neurologic signs in decreasing frequency were neuropathy (sensory > mixed somatic > autonomic > cranial [especially cranial nerve VIII] > motor), cerebellar ataxia, limbic encephalitis, polyradiculopathy, associated Lambert-Eaton myasthenic syndrome, myopathy, myelopathy, opsoclonus/myoclonus, motor neuronopathy, brachial plexopathy, and aphasia. Nineteen patients had a solely gastrointestinal initial presentation, including gastroparesis, pseudo-obstruction, esophageal achalasia, or other dysmotility. We conclude that seropositivity for ANNA-1 can expedite the diagnosis and treatment of otherwise occult cancer in patients, especially tobacco abusers, with varied neurologic and gastroenterologic presentations. The search for SCLC should not end on discovering a different neoplasm.

Retinocochleocerebral vasculopathy.

We report 10 patients with retinocochleocerebral vasculopathy and review the clinical and diagnostic considerations in previously reported patients with this uncommonly recognized disease. The clinical manifestations include acute and subacute multifocal and diffuse encephalopathic symptoms, hearing loss, and visual loss attributable to microangiopathy affecting the arterioles of the brain, retina, and cochlea. Diagnosis is facilitated by demonstration of retinal arteriolar occlusions without uveitis or keratoconjunctivitis, mid- to low-frequency unilateral or bilateral sensorineural hearing loss, and numerous small foci of increased signal in the white and gray matter on T2 weighted brain magnetic resonance imaging. Because many conditions may produce any combination of strokelike cerebral symptoms, encephalopathy, hearing loss, and visual loss, the differential diagnosis for retinocochleocerebral vasculopathy includes connective tissue disease, demyelinating disease, procoagulant state, infection, neoplasm, and more routine mechanisms of cerebral and retinal ischemia. Brain biopsy specimens demonstrate only minimal nonspecific periarteriolar chronic inflammatory cell infiltration with or without microinfarcts. The demonstration of subclinical arteriolar microangiopathy in muscle biopsy specimens, documented in 3 of our patients may assist in making the diagnosis. The clinical course appears to be monophasic. In addition to corticosteroids, treatment options include immunosuppressant agents (cyclophosphamide or azathioprine) aspirin, calcium channel blockers (nimodipine), intravenous immunoglobulin, and plasmapheresis. The etiology of the disease is unknown, but histopathologic and laboratory evidence suggests that an immune-mediated mechanism may be involved.

5-Fluorouracil and levamisole exacerbate demyelination in susceptible mice infected with Theiler's virus.

A multifocal inflammatory leukoencephalopathy is associated with the administration of 5-fluorouracil (5-FU), a pyrimidine analogue, and levamisole (LE), an immunomodulator, in patients receiving adjuvant therapy for colon cancer. Cerebral biopsy demonstrated features indistinguishable from multiple sclerosis. We tested whether administration of these agents directly resulted in inflammatory demyelination in mice or whether they exacerbated demyelination in a host predisposed to myelin injury. We used mice intracerebrally infected with Theiler's murine encephalomyelitis virus (TMEV) which serves as an excellent model for multiple sclerosis. Varying dosages of 5-FU (240 micrograms-2.4 mg) and LE (40 micrograms-1 mg) were administered alone or in combination on a fixed schedule to 52 normal SJL mice and 61 Theiler's virus-infected mice (51 SJL/J mice susceptible to demyelination; 10 C57BL10 mice resistant to demyelination). Controls included 6 noninfected SJL and 26 infected mice (16 susceptible; 10 resistant) treated with phosphate-buffered saline (PBS). Inflammation or demyelination was not detected in brains or spinal cords of noninfected SJL mice treated with 5-FU and/or LE. TMEV-susceptible SJL mice treated with LE alone or in combination with 5-FU demonstrated more extensive inflammation and demyelination at Day 45 than mice treated with PBS. Demyelination was accelerated in infected animals treated with these agents at 45 days but at 70 days a significant difference in extent of demyelination was no longer appreciated between treatment and control groups. Treatment with 5-FU and LE did not convert normally resistant TMEV-infected C57BL/10 mice to demyelination. These experiments support the hypothesis that 5-FU and LE may exacerbate inflammatory demyelination in a susceptible host.