W. Oliver Tobin

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study

Objective: To characterize patients misdiagnosed with multiple sclerosis (MS). Methods: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. Results: Of 110 misdiagnosed patients, 51 (46%) were classified as “definite” and 59 (54%) “probable” misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. Conclusions: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

Identification of Stroke Mimics in the Emergency Department Setting

Background and Purpose Previous studies have shown a stroke mimic rate of 9%–31%. We aimed to establish the proportion of stroke mimics amongst suspected acute strokes, to clarify the aetiology of stroke mimic and to develop a prediction model to identify stroke mimics. Methods This was a retrospective cohort observational study. Consecutive “stroke alert” patients were identified over nine months in a primary stroke centre. 31 variables were collected. Final diagnosis was defined as “stroke” or “stroke mimic”. Multivariable regression analysis was used to define clinical predictors of stroke mimic. Results 206 patients were reviewed. 22% were classified as stroke mimics. Multivariable scoring did not help in identification of stroke mimics. 99.5% of patients had a neurological diagnosis at final diagnosis. Discussion 22% of patients with suspected acute stroke had a stroke mimic. The aetiology of stroke mimics was varied, with seizure, encephalopathy, syncope and migraine being commonest. Multivariable scoring for identification of stroke mimics is not feasible. 99.5% of patients had a neurological diagnosis. This strengthens the case for the involvement of stroke neurologists/stroke physicians in acute stroke care.

Exploring the overlap between multiple sclerosis, tumefactive demyelination and Baló’s concentric sclerosis

The availability of magnetic resonance imaging (MRI) has led to increasing recognition that multiple sclerosis (MS), tumefactive demyelination (TD) and Baló’s concentric sclerosis (BCS) share many overlapping features. Baló-like lesions, which exhibit limited features of BCS, may represent an intermediate between BCS and typical MS demyelination. Lesions labeled as tumefactive are typically larger, but otherwise have much in common with conventional MS lesions, and TD and BCS lesions can also overlap. In this article, we explore the similarities between typical MS, TD and BCS cases, and reflect on the potential insights that intermediate or overlapping phenotypes may contribute towards an understanding of MS immunopathogenesis, and question whether these atypical forms of demyelination should be classified as separate demyelinating diseases, as different lesional manifestations of demyelination of any cause or as part of a spectrum with conventional MS.

Prevalence of Myelin Oligodendrocyte Glycoprotein and Aquaporin-4–IgG in Patients in the Optic Neuritis Treatment Trial

Importance Autoantibodies to aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) are recently established biomarkers of autoimmune optic neuritis whose frequency and accompanying phenotype, especially for MOG-IgG, are still being characterized. The Optic Neuritis Treatment Trial (ONTT) was a well-known randomized clinical trial in optic neuritis; therefore, knowledge of the serostatus and accompanying phenotype of these patients would be useful to determine the frequency of these antibodies in patients presenting with typical monocular optic neuritis and their outcomes. Objectives To determine the AQP4-IgG and MOG-IgG serostatus of patients within the ONTT and describe the clinical features of seropositive patients. Design, Setting, and Participants In this follow-up study of the randomized clinical trial, ONTT, conducted between July 1, 1988, and June 30, 1991, analysis of serum for AQP4-IgG and MOG-IgG was performed from January 1 to April 30, 2017. A total of 177 patients from the ONTT with acute optic neuritis and serum available for analysis were enrolled from 13 academic referral centers. Interventions Analysis of serum for AQP4-IgG and MOG-IgG was performed at Mayo Clinic Neuroimmunology Laboratory in 2017 with a flow cytometry, live cell, AQP4- and MOG-transfected cell-based assay. Main Outcomes and Measures Aquaporin-4–IgG and MOG-IgG serostatus. Results Of the 177 patients in the study (135 women and 42 men; mean [SD] age, 32.8 [6.9] years), 3 were positive for MOG-IgG (1.7%) and none were positive for AQP4-IgG. All 3 patients positive for MOG-IgG had disc edema at presentation. Two patients later had a single episode of recurrent optic neuritis. All 3 patients had complete recovery of visual acuity, and none were corticosteroid dependent, although peripheral visual field loss persisted in 1 patient. None of the 3 patients positive for MOG-IgG had demyelinating lesions on magnetic resonance imaging scans, and none had developed multiple sclerosis at the 15-year follow-up. Conclusions and Relevance Frequency of MOG-IgG was rare in the ONTT, and AQP4-IgG was not found in patients in the ONTT. Characteristics of patients positive for MOG-IgG in the ONTT support the previously described phenotype of MOG-IgG optic neuritis. Myelin oligodendrocyte glycoprotein–related disease appears to be a different entity than multiple sclerosis. Overall, AQP4-IgG and MOG-IgG may be less common in isolated optic neuritis than previously reported.

Diagnostic Yield and Safety of Cerebellar and Brainstem Parenchymal Biopsy

OBJECTIVE We aimed to determine the diagnostic yield and safety of posterior fossa parenchymal biopsy. METHODS One-hundred-thirty-six patients who underwent 137 posterior fossa (brainstem or cerebellar) parenchymal biopsies at Mayo Clinic (Rochester, Minnesota, USA) between 1996 and 2009 were identified by chart review. Case histories; radiologic, surgical, and pathologic reports; and safety outcomes were assessed. RESULTS Posterior fossa parenchymal biopsies were performed on 78 male and 58 female patients of median age 47 years (interquartile range 28-61). Preoperative clinical diagnosis in the majority of cases was of a malignant neoplasm. Glial neoplasm (51%) was the most common finding followed by lymphoma (7%) and neurosarcoidosis (7%). Normal tissue or nonspecific changes were observed in 28 cases (20%). Three deaths occurred: 2 at the time of biopsy (1%) and 1 due to underlying disease. All deaths occurred in patients who had a cerebellar biopsy. Transient neurologic deficits occurred in 15 patients (11%): worsening of presenting symptoms (4), cardiac arrhythmia (3), vertigo (2), diplopia (2), ataxia (3), seizure (1), decreased consciousness (1), and limb numbness (3). Sustained neurologic deficits occurred in 3 patients: fourth nerve palsy (1), hemiparesis (1), and facial numbness (1). CONCLUSIONS The diagnostic yield of posterior fossa parenchymal biopsy in Mayo Clinic patients with diverse pathologies was 80%. The complication rate was 11% with the majority being transient, but 2 deaths were attributed to biopsy. Evaluation of the diagnostic yield and complication rate at individual neurosurgical centers is needed to determine generalizability of these results.

Clinical–radiological–pathological spectrum of central nervous system–idiopathic inflammatory demyelinating disease in the elderly

Background: The spectrum of central nervous system–idiopathic inflammatory demyelinating disease (CNS-IIDD) in the elderly is uncertain. Objective: To describe the clinical, radiological, and pathological features of a cohort of 30 pathologically proven CNS-IIDD patients ⩾65 years. Methods: Elderly multiple sclerosis (MS)/clinically isolated syndrome (CIS) patients were compared to a cohort of 125 patients with pathologically proven MS/CIS and symptom onset <65 years. Results: Median age at symptom onset was 69 years (interquartile range (IQR) = 68–75). Median follow-up was 1.9 years (IQR = 1.0–5.6). Diagnoses were MS (14/30), CIS (11/30), neuromyelitis optica (NMO; 4/30), and acute disseminated encephalomyelitis (ADEM; 1/30). Disability was higher in patients with MS/CIS ⩾65 compared to patients <65 (median Expanded Disability Status Scale (EDSS) 4 (IQR = 2.5–7) vs 2.5 (IQR = 1.5–4); p = 0.002). When compared to patients <65 years, there was no difference in the lesion size, number of patients fulfilling Barkhof’s criteria, edema, or mass effect. Confluent demyelination was observed in 27 patients (MS/CIS (23/25), NMO (4)), 2 had a mixed perivenular/confluent pattern (MS (1), ADEM (1)), and 1 patient with MS had a mixed confluent/perivenular/coalescent pattern. Early active lesions were found in 19/30 patients ((MS (4), CIS (13), NMO (2); 53%). Cortical demyelination was present in 7/12 (58%) patients (MS (3), CIS(3), ADEM (1)). Conclusion: A spectrum of CNS-IIDD can develop in the elderly, with presenting symptoms similar to younger patients. Early diagnosis of CNS demyelinating disease is essential to avoid invasive and disabling procedures.

Disease-modifying therapies can be safely discontinued in an individual with stable relapsing-remitting MS – NO

As we approach the 25th anniversary of the introduction of interferon beta-1b, the first disease-modifying therapy (DMT) for multiple sclerosis (MS), consensus has emerged that MS disease-modifying treatments are safe and favorably alter not only short-term but also long-term outcomes,1–3 although not every study has reached this conclusion.4 However, no consensus has been reached as to whether or when DMTs can be safely discontinued. Given that DMT for MS accounts for ~75% of the cost of care for a patient with MS who is on a DMT, an era of rapidly rising healthcare inflation makes addressing the issue of DMT discontinuation urgent.

Efficacy of biological agents in the treatment of Erdheim-Chester disease

Erdheim-Chester disease (ECD) is a histiocytic neoplasm characterized by tissue infiltration of CD68CD1a histiocytes. Recently, identification of activating MAP-ERK pathway somatic mutations has led to successful treatment with BRAF and MEK inhibitors (Diamond et al, 2016a,b). However, these treatments are not yet approved by the US Food and Drug Administration, and not all ECD patients who need systemic therapy have an identifiable mutation or tissue available for genetic testing. Tissue samples of ECD have demonstrated disruption of various cytokines and chemokines (Arnaud et al, 2011). Hence, there are reports of treatment with biological agents, such as interlukin-1 (IL1) receptor antagonists (anakinra) and anti-tumour necrosis factor-alpha (TNF-a) inhibitors (infliximab, etanercept) (Henter et al, 2001; Aouba et al, 2010; Dagna et al, 2012; Killu et al, 2013; Cohen-Aubart et al, 2016; Diamond et al, 2016c). In this study, we describe a large, single-institution experience utilizing biological agents in the treatment of ECD. This study was a retrospective review of ECD patients treated with biologicals from 1 January 998, to 6 April 2016 at Mayo Clinic. In all cases, the diagnosis was made according to the established clinicopathological criteria. All records were independently reviewed by 3 investigators. As post-therapy responses were not uniformly assessed, we used clinical and radiological response criteria previously described (Goyal et al, 2017). For clinical response, the following criteria were used based on change in symptoms: complete response (CR; complete resolution), partial response (PR; partial resolution), stable disease (SD; no change for ≥3 months), and progressive disease (PD; progression or worsening). In our series, most patients did not undergo positron emission tomography– computed tomography (PET-CT). Hence, we reviewed other available imaging studies, including radiographs, magnetic resonance imaging, CT and radionuclide bone scans. For radiological response, the following categories were used based on change in radiological appearance of the proven or suspected ECD lesion(s): CR, PR, SD and PD. A total of 63 adult ECD patients were identified, with a median age of 54 years (range 34–80). Of these, 12 (19%) received treatment with a biological agent (Table I). The median age at diagnosis of this cohort was 59 5 years (range, 34–76). Most common sites of disease involvement were bone (91%), kidney/retroperitoneum (67%), and central nervous system (CNS; 42%). BRAF V600E mutation was detected in 8 of 9 patients who were tested. Overall, the 3 biological agents were used 14 times in the treatment course. The median duration of therapy was 12 months (range, 1–133). Anakinra was most commonly used (8/14). Overall clinical response rate with anakinra was 50% (1 CR, 3 PR, and 3 PD). The median duration of response was 42 5 months (range, 29–133); one patient had an ongoing response after 33 months of therapy. Radiological responses were seen in 25% of patients (2 PR, 3 SD, 2 PD, 1 unknown) (Fig 1). One of the patients had cerebellar lesions that progressed on anakinra. Treatment-related adverse effects were seen in 3/8 (38%) patients: one patient with grade 2 thrombocytopenia, and 2 others had grade 1 liver enzyme elevations. Infliximab was used in 5 patients. No clinical or radiological responses were seen with its use, although one patient noted stability of dizziness for 25 months. Infusion-related grade 3 adverse reaction was seen in 1 patient with the third dose of infliximab, and 1 patient had grade 1 liver enzyme abnormalities. Etanercept was used in 2 patients, with progressive disease in both. Both these patients had worsening bone pain after etanercept, indicating disease progression. Our series demonstrates that the IL1 inhibitor anakinra has moderate clinical efficacy in ECD patients. One of the patients showed a reduction in activity of the right atrial mass on PET-CT scan. The disease sites that demonstrated response included bone, heart and lungs. One of the patients had CNS disease that failed to respond to anakinra, the reason for which is unclear. A recent case series of 12 ECD patients treated with anakinra demonstrated a similar 50% clinical response rate (Cohen-Aubart et al, 2016). The ECD sites that responded to anakinra in this series were spine, pleura and bones. This study included 2 patients who had CNS involvement, and they failed to response to anakinra. However, both of these patients had already been exposed to interferon-a (IFN-a) prior to receiving anakinra. There was a subsequent report of 2 patients with ECD involving the CNS who were IFN-a na€ıve and responded to anakinra clinically as well as radiologically (Diamond et al, 2016c). Similarly, prior studies of anakinra have shown responses in disease sites like bones, kidney/retroperitoneum, (Aouba et al, 2010) and heart (Killu et al, 2013). In our study, the TNF-a monoclonal antibodies, infliximab and etanercept, did not result in any responses. A prior report of infliximab use showed responses in cardiac and peri-aortic disease along with improved symptoms of dyspnea. None of the patients with cardiac involvement in our series received infliximab therapy so it might be a therapeutic Correspondence

Neuromyelitis Optica and Herpes Simplex Virus 2

The clinical and radiographic spectrum of Neuromyelitis optica spectrum disorder has broadened following the description of the aquaporin-4 antibody. The initial triggering event and reason for disease quiescence between relapses is unclear. We present a case of myeloradiculitis associated with aquaporin-4 antibody and concomitant herpes simplex virus 2 infection.

Reply to: “Crowell et al. Idiopathic Central Nervous System Inflammatory Disease in the Setting of HLA-B27 Uveitis”

Sir, Dr Crowell and colleagues report a case of HLAB27-associated uveitis occurring with an enhancing brainstem lesion. A diagnosis of CLIPPERS was made following application of suggested diagnostic criteria to the case. Brain MRI demonstrated postgadolinium enhancement within the right dorsal midbrain, leptomeningeal enhancement, and T2 abnormality within the midbrain, pons, and cerebellum. The enhancement resolved following administration of prednisone. No pathological examination was possible. This case does not appear to satisfy the diagnostic criteria for probable CLIPPERS due to the following concerns: (1) absence of punctate postgadolinium enhancement; (2) the gadolinium-enhancing lesion is greater than 3 mm in diameter; and (3) the T2-signal abnormality substantially exceeds the area of post-gadolinium enhancement. For these reasons, the patient does not fulfill the diagnostic criteria for probable CLIPPERS. Please see Figure 1 for comparison of a typical CLIPPERS case compared to this case.