Characteristics of Progressive Multifocal Leukoencephalopathy Associated With Sarcoidosis Without Therapeutic Immune Suppression.

Importance: Progressive multifocal leukoencephalopathy can occur in the context of systemic sarcoidosis (S-PML) in the absence of therapeutic immune suppression and can initially be mistaken for neurosarcoidosis or other complications of sarcoidosis. Earlier recognition of S-PML could lead to more effective treatment of the disease. Objective: To describe characteristics of patients with S-PML. Design, Setting, and Participants: For this case series, records from 8 academic medical centers in the United States were reviewed from 2004 to 2022. A systematic review of literature from 1955 to 2022 yielded data for additional patients. Included were patients with S-PML who were not receiving therapeutic immune suppression. The median follow-up time for patients who survived the acute range of illness was 19 months (range, 2-99). Data were analyzed in February 2023. Exposures: Sarcoidosis without active therapeutic immune suppression. Main Outcomes and Measures: Clinical, laboratory, and radiographic features of patients with S-PML. Results: Twenty-one patients with S-PML not receiving therapeutic immune suppression were included in this study, and data for 37 patients were collected from literature review. The median age of the 21 study patients was 56 years (range, 33-72), 4 patients (19%) were female, and 17 (81%) were male. The median age of the literature review patients was 49 years (range, 21-74); 12 of 34 patients (33%) with reported sex were female, and 22 (67%) were male. Nine of 21 study patients (43%) and 18 of 31 literature review patients (58%) had simultaneous presentation of systemic sarcoidosis and PML. Six of 14 study patients (43%) and 11 of 19 literature review patients (58%) had a CD4+ T-cell count greater than 200/µL. In 2 study patients, a systemic flare of sarcoidosis closely preceded S-PML development. Ten of 17 study patients (59%) and 21 of 35 literature review patients (60%) died during the acute phase of illness. No meaningful predictive differences were found between patients who survived S-PML and those who did not. Conclusions and Relevance: In this case series, patients with sarcoidosis developed PML in the absence of therapeutic immune suppression, and peripheral blood proxies of immune function were often only mildly abnormal. Systemic sarcoidosis flares may rarely herald the onset of S-PML. Clinicians should consider PML in any patient with sarcoidosis and new white matter lesions on brain magnetic resonance imaging.

Superficial siderosis associated with an iatrogenic posterior fossa dural leak identified on CT cisternography.

Superficial siderosis refers to hemosiderin deposition along the pial surface of the brain and spinal cord. It results from chronic and repetitive low-grade bleeding into the subarachnoid space. Dural tears are a common cause of superficial siderosis. Although such tears typically occur in the spine, dural tears can also occur in the posterior fossa. In many cases, posterior fossa dural tears are iatrogenic, and patients may present with neuroimaging evidence of postoperative pseudomeningoceles. We present a case of superficial siderosis caused by a persistent posterior fossa dural leak. The patient presented with superficial siderosis 30 years after a Chiari I malformation repair. A pinhole-sized dural tear was identified preoperatively using computed tomography cisternography. The dural defect was successfully repaired. An additional small tear that was not seen on imaging was also identified at surgery and successfully repaired.

Utility of MRI Enhancement Pattern in Myelopathies With Longitudinally Extensive T2 Lesions.

OBJECTIVE: To determine whether MRI gadolinium enhancement patterns in myelopathies with longitudinally extensive T2 lesions can be reliably distinguished and assist in diagnosis. METHODS: We retrospectively identified 74 Mayo Clinic patients (January 1, 1996-December 31, 2019) fulfilling the following criteria: (1) clinical myelopathy; (2) MRI spine available; (3) longitudinally extensive T2 hyperintensity (≥3 vertebral segments); and (4) characteristic gadolinium enhancement pattern associated with a specific myelopathy etiology. Thirty-nine cases with alternative myelopathy etiologies, without previously described enhancement patterns, were included as controls. Two independent readers, educated on enhancement patterns, reviewed T2-weighted and postgadolinium T1-weighted images and selected the diagnosis based on this knowledge. These were compared with the true diagnoses, and agreement was measured with Kappa coefficient. RESULTS: Among all cases and controls (n = 113), there was excellent agreement for diagnosis using postgadolinium images (kappa, 0.76) but poor agreement with T2-weighted characteristics alone (kappa, 0.25). A correct diagnosis was more likely when assessing postgadolinium image characteristics than with T2-weighted images alone (rater 1: 100/113 [88%] vs 61/113 [54%] correct, p < 0.0001; rater 2: 95/113 [84%] vs 68/113 [60%] correct, p < 0.0001). Of the 74 with characteristic enhancement patterns, 55 (74%) were assigned an alternative incorrect or nonspecific diagnosis when originally evaluated in clinical practice, 12 (16%) received immunotherapy for noninflammatory myelopathies, and 2 (3%) underwent unnecessary spinal cord biopsy. CONCLUSIONS: Misdiagnosis of myelopathies is common. The gadolinium enhancement patterns characteristic of specific diagnoses can be identified with excellent agreement between raters educated on this topic. This study highlights the potential diagnostic utility of enhancement patterns in myelopathies with longitudinally extensive T2 lesions.

A multi-center case series of sarcoid optic neuropathy.

OBJECTIVE: The diagnosis of sarcoid optic neuropathy is time-sensitive, as delayed treatment risks irreversible vision loss. We sought to analyze its characteristics and outcomes. METHODS: We performed a multi-center retrospective study of sarcoid optic neuropathy among 5 USA medical centers. Inclusion criteria were: 1) clinical optic neuropathy; 2) optic nerve/sheath enhancement on neuroimaging; 3) pathological confirmation of systemic or nervous system sarcoidosis. RESULTS: Fifty-one patients were included. The median onset age of sarcoid optic neuropathy was 50 years (range, 17-70 years) and 71% were female. The median visual acuity at nadir in the most affected eye was 20/80 (range, 20/20 to no-light-perception). Thirty-four of 50 (68%) patients had radiologic evidence of other nervous system involvement and 20 (39%) patients had symptoms/signs of other cranial nerve dysfunction. Cerebrospinal fluid analysis revealed an elevated white blood cell count in 22 of 31 (71%) patients (median: 14/µL; range: 1-643/µL). Pathologic confirmation of sarcoidosis was by biopsy of systemic/pulmonary site, 34 (67%); optic nerve/sheath, 9 (18%); or other nervous system region, 8 (16%). Forty patients improved with treatment (78%), 98% receiving corticosteroids and 65% receiving steroid-sparing immunosuppressants, yet 11/46 patients (24%) had a visual acuity of 20/200 or worse at last follow-up. CONCLUSIONS: Sarcoid optic neuropathy frequently occurs with other clinical and radiologic abnormalities caused by neurosarcoidosis and diagnostic confirmation occasionally requires optic nerve/sheath biopsy. Improvement with treatment is common but most patients have some residual visual disability. Improved recognition and a more expeditious diagnosis and treatment may spare patients from permanent vision loss.

Rheumatoid Meningitis: Clinical Characteristics, Diagnostic Evaluation, and Treatment.

BACKGROUND AND PURPOSE: Due to the potential for high mortality and neurologic complications of rheumatoid meningitis (RM), awaiting biopsy confirmation may delay vital treatment intervention. Our aim was to describe the clinical presentations of RM in our population and determine whether meningeal biopsy impacted diagnosis, treatment, and outcomes. METHODS: A retrospective chart review was completed for patients at Mayo Clinic with a diagnosis of RM within the last 28 years. Those with identified alternative inflammatory, infectious, or neoplastic causes of pachymeningitis or leptomeningitis were excluded. RESULTS: Fourteen patients meeting inclusion/exclusion criteria were identified. All patients were positive for rheumatoid factor or cyclic citrullinated peptide. All patients had magnetic resonance imaging abnormalities characterized by pachymeningeal and/or leptomeningeal enhancement. Of the 10 patients who underwent biopsy, nonspecific findings were seen in 74%. All patients except one were treated with corticosteroids with subsequent symptomatic improvement. Radiographic improvement or resolution was seen in 10 (83%) of 12. Patients improved with corticosteroid treatment, including those who were diagnosed with RM on clinical basis without undergoing a biopsy as well. CONCLUSIONS: This retrospective review displays the myriad of clinical presentations of RM. It also suggests that with appropriate exclusion of infectious, neoplastic, and other autoimmune etiologies, biopsy may not be necessary to initiate treatment.

Association Between Tumor Necrosis Factor Inhibitor Exposure and Inflammatory Central Nervous System Events.

Importance: Tumor necrosis factor (TNF) inhibitors are common therapies for certain autoimmune diseases, such as rheumatoid arthritis. An association between TNF inhibitor exposure and inflammatory central nervous system (CNS) events has been postulated but is poorly understood. Objective: To evaluate whether TNF inhibitor exposure is associated with inflammatory demyelinating and nondemyelinating CNS events in patients with an indication for TNF inhibitor use and to describe the spectrum of those CNS events. Design, Setting, and Participants: A nested case-control study was conducted using the medical records of patients with autoimmune diseases treated at 3 Mayo Clinic locations (Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida) between January 1, 2003, and February 20, 2019. Patients were included if their records reported International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnostic codes for US Food and Drug Administration-approved autoimmune disease indication for TNF inhibitor use (ie, rheumatoid arthritis, ankylosing spondylitis, psoriasis and psoriatic arthritis, Crohn disease, and ulcerative colitis) and diagnostic codes for inflammatory CNS events of interest. Patients were matched 1:1 with control participants by year of birth, type of autoimmune disease, and sex. Exposures: TNF inhibitor exposure data were derived from the medical records along with type of TNF inhibitor, cumulative duration of exposure, and time of exposure. Main Outcomes and Measures: The main outcome was either inflammatory demyelinating (multiple sclerosis and other diseases such as optic neuritis) or nondemyelinating (meningitis, meningoencephalitis, encephalitis, neurosarcoidosis, and CNS vasculitis) CNS event. Association with TNF inhibitor was evaluated with conditional logistic regression and adjusted for disease duration to determine the odds ratios (ORs) and 95% CIs. Secondary analyses included stratification of outcome by inflammatory demyelinating and nondemyelinating CNS events and by autoimmune disease (rheumatoid arthritis and non-rheumatoid arthritis). Results: A total of 212 individuals were included: 106 patients with inflammatory CNS events and 106 control participants without such events. Of this total, 136 were female (64%); the median (interquartile range) age at disease onset for patients was 52 (43-62) years. Exposure to TNF inhibitors occurred in 64 patients (60%) and 42 control participants (40%) and was associated with an increased risk of any inflammatory CNS event (adjusted OR, 3.01; 95% CI, 1.55-5.82; P = .001). These results were similar when the outcome was stratified by demyelinating and nondemyelinating CNS events. Secondary analyses found the association was predominantly observed in patients with rheumatoid arthritis (adjusted OR, 4.82; 95% CI, 1.62-14.36; P = .005). Conclusions and Relevance: This study found that exposure to TNF inhibitors in patients with autoimmune diseases appeared to be associated with increased risk for inflammatory CNS events. Whether this association represents de novo or exacerbated inflammatory pathways requires further research.

End of life: Expert care and support, not physician-hastened death.

In legal physician-hastened death, a physician prescribes medication with the primary intent of causing the death of a willing terminally ill patient. This practice differs radically from palliative sedation, intended to relieve a patient's suffering rather than cause a patient's death. In this position paper, we argue that the practice of physician-hastened death is contrary to the interests of patients, their families, and the sound ethical practice of medicine. Therefore, the American Academy of Neurology should advise its members against this practice, as it had done until 2018.

Characteristics of Spontaneous Spinal Cord Infarction and Proposed Diagnostic Criteria.

Importance: Spinal cord infarction (SCI) is often disabling, and the diagnosis can be challenging without an inciting event (eg, aortic surgery). Patients with a spontaneous SCI are often misdiagnosed as having transverse myelitis. Diagnostic criteria for SCI are lacking, hindering clinical care and research. Objective: To describe the characteristics of spontaneous SCI and propose diagnostic criteria. Design, Setting, and Participants: An institution-based search tool was used to identify patients evaluated at Mayo Clinic, Rochester, Minnesota, from January 1997 to December 2017 with a spontaneous SCI. Patients provided written consent to use their records for research. Participants were 18 years and older with a diagnosis of spontaneous SCI (n = 133), and controls were selected from a database of alternative myelopathy etiologies for validation of the proposed diagnostic criteria (n = 280). Main Outcomes and Measures: A descriptive analysis of SCI was performed and used to propose diagnostic criteria, and the criteria were validated. Results: Of 133 included patients with a spontaneous SCI, the median (interquartile range) age at presentation was 60 (52-69) years, and 101 (76%) had vascular risk factors. Rapid onset of severe deficits reaching nadir within 12 hours was typical (102 [77%]); some had a stuttering decline (31 [23%]). Sensory loss occurred in 126 patients (95%), selectively affecting pain/temperature in 49 (39%). Initial magnetic resonance imaging (MRI) spine results were normal in 30 patients (24%). Characteristic MRI T2-hyperintense patterns included owl eyes (82 [65%]) and pencil-like hyperintensity (50 [40%]); gadolinium enhancement (37 of 96 [39%]) was often linear and located in the anterior gray matter. Confirmatory MRI findings included diffusion-weighted imaging/apparent diffusion coefficient restriction (19 of 29 [67%]), adjacent dissection/occlusion (16 of 82 [20%]), and vertebral body infarction (11 [9%]). Cerebrospinal fluid showed mild inflammation in 7 of 89 patients (8%). Diagnostic criteria was proposed for definite, probable, and possible SCI of periprocedural and spontaneous onset. In the validation cohort (n = 280), 9 patients (3%) met criteria for possible SCI, and none met criteria for probable SCI. Conclusions and Relevance: This large series of spontaneous SCIs provides clinical, laboratory, and MRI clues to SCI diagnosis. The diagnostic criteria proposed here will aid clinicians in making the correct diagnosis and ideally improve future care for patients with SCI. The validation of these criteria supports their utility in the evaluation of acute myelopathy.

Definition and Consensus Diagnostic Criteria for Neurosarcoidosis: From the Neurosarcoidosis Consortium Consensus Group.

Importance: The Neurosarcoidosis Consortium Consensus Group, an expert panel of physicians experienced in the management of patients with sarcoidosis and neurosarcoidosis, engaged in an iterative process to define neurosarcoidosis and develop a practical diagnostic approach to patients with suspected neurosarcoidosis. This panel aimed to develop a consensus clinical definition of neurosarcoidosis to enhance the clinical care of patients with suspected neurosarcoidosis and to encourage standardization of research initiatives that address this disease. Observations: The work of this collaboration included a review of the manifestations of neurosarcoidosis and the establishment of an approach to the diagnosis of this disorder. The proposed consensus diagnostic criteria, which reflect current knowledge, provide definitions for possible, probable, and definite central and peripheral nervous system sarcoidosis. The definitions emphasize the need to evaluate patients with findings suggestive of neurosarcoidosis for alternate causal factors, including infection and malignant neoplasm. Also emphasized is the need for biopsy, whenever feasible and advisable according to clinical context and affected anatomy, of nonneural tissue to document the presence of systemic sarcoidosis and support a diagnosis of probable neurosarcoidosis or of neural tissue to support a diagnosis of definite neurosarcoidosis. Conclusions and Relevance: Diverse disease presentations and lack of specificity of relevant diagnostic tests contribute to diagnostic uncertainty. This uncertainty is compounded by the absence of a pathognomonic histologic tissue examination. The diagnostic criteria we propose are designed to focus investigations on NS as accurately as possible, recognizing that multiple pathophysiologic pathways may lead to the clinical manifestations we currently term NS. Research recognizing the clinical heterogeneity of this diagnosis may open the door to identifying meaningful biologic factors that may ultimately contribute to better treatments.

Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis.

OBJECTIVE: To evaluate the incidence and prevalence of autoimmune encephalitis and compare it to that of infectious encephalitis. METHODS: We performed a population-based comparative study of the incidence and prevalence of autoimmune and infectious encephalitis in Olmsted County, Minnesota. Autoimmune encephalitis diagnosis and subgroups were defined by 2016 diagnostic criteria, and infectious encephalitis diagnosis required a confirmed infectious pathogen. Age- and sex-adjusted prevalence and incidence rates were calculated. Patients with encephalitis of uncertain etiology were excluded. RESULTS: The prevalence of autoimmune encephalitis on January 1, 2014 of 13.7/100,000 was not significantly different from that of all infectious encephalitides (11.6/100,000; p = 0.63) or the viral subcategory (8.3/100,000; p = 0.17). The incidence rates (1995-2015) of autoimmune and infectious encephalitis were 0.8/100,000 and 1.0/100,000 person-years, respectively (p = 0.58). The number of relapses or recurrent hospitalizations was higher for autoimmune than infectious encephalitis (p = 0.03). The incidence of autoimmune encephalitis increased over time from 0.4/100,000 person-years (1995-2005) to 1.2/100,000 person-years (2006-2015; p = 0.02), attributable to increased detection of autoantibody-positive cases. The incidence (2.8 vs 0.7/100,000 person-years, p = 0.01) and prevalence (38.3 vs 13.7/100,000, p = 0.04) of autoimmune encephalitis was higher among African Americans than Caucasians. The prevalence of specific neural autoantibodies was as follows: myelin oligodendrocyte glycoprotein, 1.9/100,000; glutamic acid decarboxylase 65, 1.9/100,000; unclassified neural autoantibody, 1.4/100,000; leucine-rich glioma-inactivated protein 1, 0.7/100,000; collapsin response-mediator protein 5, 0.7/100,000; N-methyl-D-aspartate receptor, 0.6/100,000; antineuronal nuclear antibody type 2, 0.6/100,000; and glial fibrillary acidic protein α, 0.6/100,000. INTERPRETATION: This study shows that the prevalence and incidence of autoimmune encephalitis are comparable to infectious encephalitis, and its detection is increasing over time. Ann Neurol 2018;83:166-177.

Glial fibrillary acidic protein immunoglobulin G as biomarker of autoimmune astrocytopathy: Analysis of 102 patients.

OBJECTIVE: A novel autoimmune central nervous system (CNS) disorder with glial fibrillary acidic protein (GFAP)-IgG as biomarker was recently characterized. Here, 102 patients with GFAP-IgG positivity are described. METHODS: The 102 included patients had: (1) serum, cerebrospinal fluid (CSF), or both that yielded a characteristic astrocytic pattern of mouse tissue immunostaining; (2) confirmation of IgG reactive with specific GFAP isoforms (α, ɛ, or κ) by cell-based assays; and (3) clinical data available. Control specimens (n = 865) were evaluated by tissue (n = 542) and cell-based (n = 323) assays. RESULTS: Median symptom onset age was 44 years (range = 8-103), and 54% were women. The predominant phenotype (83 patients; 81%) was inflammation of meninges, brain, spinal cord, or all 3 (meningoencephalomyelitis). Among patients, highest specificity for those phenotypes was observed for CSF testing (94%), and highest sensitivity was for the GFAPα isoform (100%). Rare GFAP-IgG positivity was encountered in serum controls by tissue-based assay (0.5%) or cell-based assay (1.5%), and in CSF controls by cell-based assay (0.9%). Among patients, striking perivascular radial enhancement was found on brain magnetic resonance imaging in 53%. Although cases frequently mimicked vasculitis, angiography was uniformly negative, and spinal imaging frequently demonstrated longitudinally extensive myelitic lesions. Diverse neoplasms encountered were found prospectively in 22%. Ovarian teratoma was most common and was predicted best when both N-methyl-D-aspartate receptor-IgG and aquaporin-4-IgG coexisted (71%). Six patients with prolonged follow-up had brisk corticosteroid response, but required additional immunosuppression to overcome steroid dependency. INTERPRETATION: GFAPα-IgG, when detected in CSF, is highly specific for an immunotherapy-responsive autoimmune CNS disorder, sometimes with paraneoplastic cause. Ann Neurol 2017;81:298-309.

Autoimmune Glial Fibrillary Acidic Protein Astrocytopathy: A Novel Meningoencephalomyelitis.

IMPORTANCE: A novel astrocytic autoantibody has been identified as a biomarker of a relapsing autoimmune meningoencephalomyelitis that is immunotherapy responsive. Seropositivity distinguishes autoimmune glial fibrillary acidic protein (GFAP) meningoencephalomyelitis from disorders commonly considered in the differential diagnosis. OBJECTIVE: To describe a novel IgG autoantibody found in serum or cerebrospinal fluid that is specific for a cytosolic intermediate filament protein of astrocytes. DESIGN, SETTING, AND PARTICIPANTS: Retrospective review of the medical records of seropositive patients identified in the Mayo Clinic Neuroimmunology Laboratory from October 15, 1998, to April 1, 2016, in blinded comprehensive serologic evaluation for autoantibody profiles to aid the diagnosis of neurologic autoimmunity (and predict cancer likelihood). MAIN OUTCOMES AND MEASURES: Frequency and definition of novel autoantibody, the autoantigen's immunochemical identification, clinical and magnetic resonance imaging correlations of the autoantibody, and immunotherapy responsiveness. RESULTS: Of 103 patients whose medical records were available for review, the 16 initial patients identified as seropositive were the subject of this study. Median age at neurologic symptom onset was 42 years (range, 21-73 years); there was no sex predominance. The novel neural autoantibody, which we discovered to be GFAP-specific, is disease spectrum restricted but not rare (frequency equivalent to Purkinje cell antibody type 1 [anti-Yo]). Its filamentous pial, subventricular, and perivascular immunostaining pattern on mouse tissue resembles the characteristic magnetic resonance imaging findings of linear perivascular enhancement in patients. Prominent clinical manifestations are headache, subacute encephalopathy, optic papillitis, inflammatory myelitis, postural tremor, and cerebellar ataxia. Cerebrospinal fluid was inflammatory in 13 of 14 patients (93%) with data available. Neoplasia was diagnosed within 3 years of neurologic onset in 6 of 16 patients (38%): prostate and gastroesophageal adenocarcinomas, myeloma, melanoma, colonic carcinoid, parotid pleomorphic adenoma, and teratoma. Neurologic improvement followed treatment with high-dose corticosteroids, with a tendency of patients to relapse without long-term immunosuppression. CONCLUSIONS AND RELEVANCE: Glial fibrillary acidic protein-specific IgG identifies a distinctive, corticosteroid-responsive, sometimes paraneoplastic autoimmune meningoencephalomyelitis. It has a lethal canine equivalent: necrotizing meningoencephalitis. Expression of GFAP has been reported in some of the tumor types identified in paraneoplastic cases. Glial fibrillary acidic protein peptide-specific cytotoxic CD8+ T cells are implicated as effectors in a transgenic mouse model of autoimmune GFAP meningoencephalitis.

Discriminating long myelitis of neuromyelitis optica from sarcoidosis.

OBJECTIVE: To compare longitudinally extensive myelitis in neuromyelitis optica spectrum disorders (NMOSD) and spinal cord sarcoidosis (SCS). METHODS: We identified adult patients evaluated between 1996 and 2015 with SCS or NMOSD whose first myelitis episode was accompanied by a spinal cord lesion spanning ≥3 vertebral segments. All NMOSD patients were positive for aquaporin-4-immunoglobulin G, and all sarcoidosis cases were pathologically confirmed. Clinical characteristics were evaluated. Spine magnetic resonance imaging was reviewed by 2 neuroradiologists. RESULTS: We studied 71 patients (NMOSD, 37; SCS, 34). Sixteen (47%) SCS cases were initially diagnosed as NMOSD or idiopathic transverse myelitis. Median delay to diagnosis was longer for SCS than NMOSD (5 vs 1.5 months, p < 0.01). NMOSD myelitis patients were more commonly women, had concurrent or prior optic neuritis or intractable vomiting episodes more frequently, had shorter time to maximum deficit, and had systemic autoimmunity more often than SCS (p < 0.05). SCS patients had constitutional symptoms, cerebrospinal fluid (CSF) pleocytosis, and hilar adenopathy more frequently than NMOSD (p < 0.05); CSF hypoglycorrhachia (11%, p = 0.25) and elevated angiotensin-converting enzyme (18%, p = 0.30) were exclusive to SCS. Dorsal cord subpial gadolinium enhancement extending ≥2 vertebral segments and persistent enhancement >2 months favored SCS, and ringlike enhancement favored NMOSD (p < 0.05). Maximum disability was similar in both disorders. INTERPRETATION: SCS is an under-recognized cause of longitudinally extensive myelitis that commonly mimics NMOSD. We identified clinical, laboratory, systemic, and radiologic features that, taken together, help discriminate SCS from NMOSD.

Conjunctival biopsy to diagnose neurosarcoidosis in patients with inflammatory nervous system disease of unknown etiology.

Neurosarcoidosis mimics many neurologic diseases and poses a major diagnostic challenge. Blind conjunctival biopsy is often used to help diagnose neurosarcoidosis when biopsy of affected nervous system tissue is not feasible. While this test is relatively inexpensive and well-tolerated, the diagnostic yield in patients with inflammatory nervous system disease of unknown etiology remained uncertain. We evaluated 440 patients who underwent conjunctival biopsy due to concern for neurosarcoidosis. Only a small minority of patients (3%) had positive conjunctival biopsies consistent with sarcoidosis, and some patients (1%) with positive biopsies were found to have a cause for their neurologic disease other than neurosarcoidosis. Many patients (14%) had negative conjunctival biopsies but were later confirmed to have neurosarcoidosis after additional evaluations. This study demonstrates that conjunctival biopsy has a low diagnostic yield for neurosarcoidosis in patients with inflammatory nervous system disease and suggests that alternative diagnostic means should be pursued.

Cranial base manifestations of neurosarcoidosis: a review of 305 patients.

OBJECTIVE: Neurosarcoidosis is a rare granulomatous disease that can result in cranial neuropathy, chronic meningitis, and intracranial granuloma formation. Meningeal involvement may cause focal nodular enhancement that can simulate common cranial base tumors. The objective of the current study is to further define the clinical features of neurosarcoidosis in a large cohort of patients, focusing on characteristics relevant to the skull base surgeon. STUDY DESIGN: Retrospective series. SETTING: Two tertiary academic referral centers. PATIENTS: Consecutive patients diagnosed with neurosarcoidosis. INTERVENTION(S): Review of clinical presentation, physical examination, radiologic findings, biopsy results, and laboratory testing. MAIN OUTCOME MEASURES: Prevalence and distribution of cranial neuropathy, radiologic features of meningeal enhancement, and patterns of simulated tumors. RESULTS: A total of 305 patients met study criteria. The mean age at diagnosis was 47 years and 53% were female. The optic nerve was the most commonly involved cranial nerve, followed by the trigeminal and the facial nerve. Meningeal enhancement was present in 67% of cases with 17% demonstrating focal or multicentric nodular enhancement simulating tumor. The most common locations of inflammatory tumor development included the cavernous sinus, petrous temporal bone, and sphenoid wing; six patients had bilateral internal auditory canal lesions, several mimicking neurofibromatosis type II. CONCLUSION: Establishing the diagnosis of neurosarcoidosis remains challenging. Meningeal involvement and cranial neuropathy often mimic other more common conditions. Careful review of patient history and clinical imaging can reveal important clues toward the diagnosis of neurosarcoidosis. The clinician must maintain a high index of suspicion in patients with atypical presentation to avoid misdiagnosis and facilitate early medical treatment.

DPPX potassium channel antibody: frequency, clinical accompaniments, and outcomes in 20 patients.

OBJECTIVE: To describe the detection frequency and clinical associations of immunoglobulin G (IgG) targeting dipeptidyl-peptidase-like protein-6 (DPPX), a regulatory subunit of neuronal Kv4.2 potassium channels. METHODS: Specimens from 20 patients evaluated on a service basis by tissue-based immunofluorescence yielded a synaptic immunostaining pattern consistent with DPPX-IgG (serum, 20; CSF, all 7 available). Transfected HEK293 cell-based assay confirmed DPPX specificity in all specimens. Sixty-nine patients with stiff-person syndrome and related disorders were also evaluated by DPPX-IgG cell-based assay. RESULTS: Of 20 seropositive patients, 12 were men; median symptom onset age was 53 years (range, 13-75). Symptom onset was insidious in 15 and subacute in 5. Twelve patients reported prodromal weight loss. Neurologic disorders were multifocal. All had one or more brain or brainstem manifestations: amnesia (16), delirium (8), psychosis (4), depression (4), seizures (2), and brainstem disorders (15; eye movement disturbances [8], ataxia [7], dysphagia [6], dysarthria [4], respiratory failure [3]). Nine patients reported sleep disturbance. Manifestations of central hyperexcitability included myoclonus (8), exaggerated startle (6), diffuse rigidity (6), and hyperreflexia (6). Dysautonomia involved the gastrointestinal tract (9; diarrhea [6], gastroparesis, and constipation [3]), bladder (7), cardiac conduction system (3), and thermoregulation (1). Two patients had B-cell neoplasms: gastrointestinal lymphoma (1), and chronic lymphocytic leukemia (1). Substantial neurologic improvements followed immunotherapy in 7 of 11 patients with available treatment data. DPPX-IgG was not detected in any of the stiff-person syndrome patients. CONCLUSIONS: DPPX-IgG is a biomarker for an immunotherapy-responsive multifocal neurologic disorder of the central and autonomic nervous systems.

Progressive multifocal leukoencephalopathy: a rare infectious complication following allogeneic hematopoietic cell transplantation (HCT).

Progressive multifocal leukoencephalopathy (PML), a demyelinating disorder caused by brain infection with JC virus, is a neurological complication of immunocompromised states and immunosuppressive therapies. While most commonly seen in the HIV/AIDS population, patients with hematologic malignancies are also at risk following treatment protocols including monoclonal antibodies such as rituximab and after hematopoietic stem cell transplantation. Here, we present the case of PML following allogeneic HCT that highlights potential diagnostic difficulties. We also review the literature regarding PML following HCT and described therapies employed to attempt to treat this disorder.

Diffuse anaplastic leptomeningeal oligodendrogliomatosis mimicking neurosarcoidosis.

Diffuse leptomeningeal oligodendrogliomatosis is a rare, frequently fatal CNS malignancy that most often affects children.1 Although potentially treatable with chemotherapy and radiation, the radiologic findings are nonspecific and pathologic confirmation of the diagnosis is difficult. We describe an adult patient whose initial presentation mimicked neurosarcoidosis. Despite extensive imaging abnormalities, 3 biopsies were required before the diagnosis of diffuse leptomeningeal oligodendrogliomatosis was confirmed.

The alien limb phenomenon.

Alien limb phenomenon refers to involuntary motor activity of a limb in conjunction with the feeling of estrangement from that limb. Alien limb serves as a diagnostic feature of corticobasal syndrome. Our objective was to determine the differential diagnoses of alien limb and to determine the features in a large group of patients with the alien limb with different underlying etiologies. We searched the Mayo Clinic Medical Records Linkage system to identify patients with the diagnosis of alien limb seen between January 1, 1996, and July 11, 2011. One hundred and fifty patients with alien limb were identified. Twenty-two were followed in the Alzheimer's Disease Research Center. Etiologies of alien limb included corticobasal syndrome (n = 108), stroke (n = 14), Creutzfeldt Jakob disease (n = 9), hereditary diffuse leukoencephalopathy with spheroids (n = 5), tumor (n = 4), progressive multifocal leukoencephalopathy(n = 2), demyelinating disease (n = 2), progressive dementia not otherwise specified (n = 2), posterior reversible encephalopathy syndrome (n = 1), corpus callosotomy (n = 1), intracerebral hemorrhage (n = 1) and thalamic dementia (n = 1). Ten of 14 cerebrovascular cases were right hemisphere in origin. All cases involved the parietal lobe. Of the 44 patients with corticobasal syndrome from the Alzheimer's Disease Research Center cohort, 22 had alien limb, and 73 % had the alien limb affecting the left extremities. Left sided corticobasal syndrome was significantly associated with the presence of alien limb (p = 0.004). These findings support the notion that the alien limb phenomenon is partially related to damage underlying the parietal cortex, especially right parietal, disconnecting it from other cortical areas.