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Anti-MOG antibodies with longitudinally extensive transverse myelitis preceded by CLIPPERS
Abstract
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory brainstem syndrome of uncertain etiology, with distinct radiologic features.1 Autoimmunity has been postulated, although specific CNS antibodies have not been reported. Our patient initially presented with classical clinicoradiologic features of CLIPPERS. Five months later, she developed a longitudinally extensive spinal cord inflammatory lesion affecting mainly the conus, and had antibodies to myelin-oligodendrocyte glycoprotein (MOG). Although neuromyelitis optica spectrum disorders (NMOSD) with brainstem involvement may feature in the broad differential diagnosis of CLIPPERS, this is the first report describing an overlap with the anti-MOG phenotype of NMOSD, and highlights that CLIPPERS may not be a distinct nosologic entity.
... This proposed exogenous trigger is supported by the predominance of CD4+ T-cells on histopathology, which respond to MHC-II proteins typically carrying exogenous proteins. Recent correlation with anti-myelin-oligodendrocyte glycoprotein antibodies (MOGAb) could indicate an etiology more akin to demyelinating disease [5]. Understanding the pathophysiology of CLIPPERS syndrome in greater detail could greatly benefit the diagnostic process and guide future refinement of treatment strategies. ...
... The presence of demyelinating lesions and perivascular T-cells is an atypical finding for CLIPPERS and might suggest a possible pathophysiological connection between CLIPPERS and demyelinating diseases. This connection is further supported by a previously proposed relationship between CLIPPERS and anti-MOGAb [5]. MOGAb have received increasing attention in recent years, and although our study is limited by a lack of testing for anti-MOG, the brain biopsy result of active inflammatory demyelinating processes contributes to the idea that a pathophysiological connection between CLIPPERS and demyelinating diseases may exist and contribute to the disease pathology. ...
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently identified diagnosis that can cause a variety of severe symptoms, including ataxia, dysarthria, diplopia, paraparesis, and vertigo. These symptoms rarely present in isolation but often accompany one another in various combinations. Magnetic Resonance Imaging (MRI) of the brain is critical for making the diagnosis and typically reveals scattered enhancement within the pons and adjacent structures. The syndrome responds well to high-dose steroids, and maintenance therapy is required to prevent a recurrence. In this report, we present a case of a 62-year-old man who developed CLIPPERS syndrome. The patient presented with hemiparesis and dysarthria, which developed over four months and then acutely worsened within 24 hours. After diagnosing CLIPPERS, the patient was placed on high-dose steroids and experienced rapid clinical improvement, as well as improvement on repeat MRI. The patient's treatment was complicated by an incidental diagnosis of tuberculosis, which required simultaneous management with isoniazid.
... After steroid weaning, MOG-seropositive longitudinally extensive transverse myelitis (LETM) involving the conus appeared, but in absence of brainstem lesions. 1 A diagnosis of CLIPPERS is difficult in this clinical picture. ...
... Taieb and Labauge raised in response to our recent report. 1 Our patient presented with clinical and radiologic features consistent with CLIPPERS, even though the subsequent episode of LETM involving the conus had not been previously reported as part of this disease spectrum. While CLIPPERS can relapse, typically with recurrence of brainstem inflammatory features, this does not form key diagnostic criteria and the diagnosis could be consistent with a single episode. ...
... Core clinical manifestations above (ON, TM, ADEM, cerebral/cerebellar syndromes, CCE) were included in the proposed 2023 diagnostic criteria for MOGAD [3••], but individual cases have highlighted additional rare clinical and radiologic features. Involvement of cranial and spinal nerve roots [72,73], combined central and peripheral demyelination [74][75][76], and brainstem syndromes with an imaging appearance mimicking chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) have all been reported [77][78][79]. Tumefactive demyelinating lesions (TDLs) may also be seen, but do not appear to be associated with a poorer prognosis compared to MS and NMOSD. Lack of diffusion restriction, lack of T2 or peripheral ring enhancement, and resolution on follow-up imaging are all more common in MOGAD-TDLs than MS or NMOSD [80]. ...
Purpose of Review
Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a distinct neuroinflammatory condition characterized by attacks of optic neuritis, transverse myelitis, and other demyelinating events. Though it can mimic multiple sclerosis and neuromyelitis optica spectrum disorder, distinct clinical and radiologic features which can discriminate these conditions are now recognized. This review highlights recent advances in our understanding of clinical manifestations, diagnosis, and treatment of MOGAD.
Recent Findings
Studies have identified subtleties of common clinical attacks and identified more rare phenotypes, including cerebral cortical encephalitis, which have broadened our understanding of the clinicoradiologic spectrum of MOGAD and culminated in the recent publication of proposed diagnostic criteria with a familiar construction to those diagnosing other neuroinflammatory conditions. These criteria, in combination with advances in antibody testing, should simultaneously lead to wider recognition and reduced incidence of misdiagnosis. In addition, recent observational studies have raised new questions about when to treat MOGAD chronically, and with which agent.
Summary
MOGAD pathophysiology informs some of the relatively unique clinical and radiologic features which have come to define this condition, and similarly has implications for diagnosis and management. Further prospective studies and the first clinical trials of therapeutic options will answer several remaining questions about the peculiarities of this condition.
... [1,5,9] Brain stem lesions may be accompanied by transverse myelitis, ADEM, supratentorial brain lesions or optic neuritis [8,10]. In one patient the MRI resembled CLIPPERS (Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) at disease onset [11]. Only 60% of patients with brain stem lesions were symptomatic presenting with ataxia, diplopia, nausea, vomiting, cranial nerve palsy or vertigo [8]. ...
Background
Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a relatively new entity of demyelinating diseases, clinically presenting with optic neuritis, transverse myelitis, or encephalic symptoms. Typical radiological features include demyelinating cerebral and spinal lesions, cortical involvement, leptomeningeal enhancement, or tumefactive lesions. Here we present a rare case of a young patient with extensive brain stem lesion on the MRI while exhibiting nystagmus, singultus and somnolence.
Case presentation
A 30-year-old male patient presented initially with fever and impaired consciousness, but furthermore developed nystagmus, singultus and tetraparesis during the following week. Repeated MRI examinations revealed extensive brain stem edema with notable bilateral affection of the cerebellar peduncles and the pons. Antiviral and antibiotic treatment was changed to intravenous corticosteroids and immunoglobulins as soon as the diagnosis of MOGAD was established by testing serum and cerebrospinal fluid positive for MOG specific antibodies. MRI alterations vanished completely over time with a delayed, nearly complete clinical recovery of our patient.
Conclusion
Brain stem affection in MOGAD is rare. However, in patients presenting with an unclear brain stem encephalitis the possibility of MOGAD should be considered and tested using MOG antibodies. In case of a positive testing treatment with steroids and immunoglobulins seems recommendable.
... This phenotype is also extremely rare in MOGAD. To the best of our knowledge, MOG-IgG has been detected in only 5 patients with CLIPPERS so far (3,17,18). The lesions of these 5 patients were confined to the hindbrain. ...
Background
The clinical spectrum of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is expanding over time. However, the long-term management and prognosis of this disorder are still controversial. Therefore, this study aimed to report the clinical profiles and treatment outcomes of MOGAD in our center.
Methods
This was a single-center case-series study. Clinical and para-clinical data, along with treatment outcomes of patients with MOGAD were analyzed.
Results
A total of 27 patients were identified, of which 19 (70%) patients were women, and the median age at disease onset was 40 years (range 20–67). A total of 47 episodes were observed, with optic neuritis (53%) being the most frequent presentation and 60% of them were unilateral. Other presentations included rhombencephalitis (RE) (17%), limbic encephalitis (9%), simultaneous optic neuritis and myelitis (9%), acute disseminated encephalomyelitis (ADEM)-like presentation (6%), myelitis (4%), and ADEM (2%). One patient presenting with RE also met the diagnostic criteria of area postrema syndrome (APS). Another patient with RE presented with imaging characteristics of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS). A total of 29 lumbar punctures were recorded, among which an elevated protein level was found in 34% of the samples, pleocytosis was found in 14% of the samples, and positive intrathecal oligoclonal bands were found in 19% of the patients. One patient was found to have anti-N-methyl-D-aspartate receptor antibodies both in his serum and cerebrospinal fluid. Intravenous methylprednisolone (IVMP) was administrated for 85% of the attacks while both IVMP and intravenous immunoglobulin were for 6% of the attacks. Moreover, nine patients received maintenance therapy. Among them, six patients were treated with mycophenolate mofetil, three patients were treated with prednisone, rituximab, and teriflunomide, respectively. The median follow-up period was 20 months (range 6–127). At follow-up, twelve (44%) patients experienced a relapsing course, and the median time to the first relapse was 9.5 months (range 2–120). The median Expanded Disability Status Scale score at nadir was 3.5 (range 2–8) and was 0 (range 0–3) at the last follow-up.
Conclusion
The clinical spectrum of MOGAD is heterogenous, wherein APS and CLIPPERS-form can occur. The long-term outcome of MOGAD seems benign. Further studies are warranted to determine the risk factors of relapse and identify the optimal steroid-sparing agents.
... Thus, the presumed diagnosis of CLIPPERS at the first attack was not appropriate. Despite the similar clinical and imaging features of MOG-IgG-related brainstem encephalitis and CLIPPERS (24)(25)(26), the diagnostic criteria of CLIPPERS encouraged careful consideration of other possible explanations (23). ...
Aim
Despite a significant improvement in the number of studies on myelin oligodendrocyte glycoprotein (MOG)-immunoglobulin G (IgG)-associated disorder (MOGAD) over the past few years, MOG-IgG-associated cortical/brainstem encephalitis remains a relatively uncommon and less-reported presentation among the MOGAD spectrum. This study aimed to report the clinical course, imaging features, and therapeutic response of MOG-IgG-associated cortical/brainstem encephalitis.
Methods
Data of four patients who suffered from cortical encephalitis with epileptic seizures and/or brainstem encephalitis during the course of the disease were retrospectively collected and analyzed.
Results
In this study, three male patients and one female patient, with a median age of onset of 21 years (ranging 20–51 years) were enrolled. An epileptic seizure was the main symptom of cortical encephalitis in these patients, while the manifestations of brainstem encephalitis were diverse. Cranial MRI demonstrated abnormal signals in unilateral or bilateral cortical or brainstem. Cerebrospinal fluid studies showed normal or mildly elevated leukocyte counts and protein levels, and a cell-based assay detected positive MOG-IgG in the serum of all patients. Two patients were misdiagnosed at the first attack, and both experienced a relapse. All of them accepted the first-line immunotherapy after a confirmed diagnosis and had a good outcome.
Conclusion
Early suspicion of MOG-IgG-associated encephalitis is necessary for any patient with sudden onset of seizures or symptoms of brainstem damage, especially with lesions on unilateral/bilateral cortical or brainstem on brain MRI.
... CLIPPERS associated with MOG Ab are diagnosed increasingly. 8,9 Clinically, they present with subacute onset brain stem dysfunction. Imaging revealed T2 hyperintense lesions with ill-defined margins in posterior fossa predominantly involving pons and measuring more than 2 cm. ...
... Nodular enhancement (5/6) and asymmetric involvement of the pons (4/6) were frequently seen as well. Demyelination work-up, including myelin oligodendrocyte glycoprotein antibody-associated disease, 25 returned negative results, and poor-to-partial responsiveness was noted in those who received steroids. While all cases in literature had CNS-restricted HLH (Table 3), in most (4/6) of our patients, systemic HLH signs were present. ...
Background and purpose:
Neuroimaging has an important role in detecting CNS involvement in children with systemic or CNS isolated hemophagocytic lymphohistiocytosis. We characterized a cohort of pediatric patients with CNS hemophagocytic lymphohistiocytosis focusing on neuroradiologic features and assessed whether distinct MR imaging patterns and genotype correlations can be recognized.
Materials and methods:
We retrospectively enrolled consecutive pediatric patients diagnosed with hemophagocytic lymphohistiocytosis with CNS involvement treated at 2 pediatric neurology centers between 2010 and 2018. Clinical and MR imaging data were analyzed.
Results:
Fifty-seven children (40 primary, 70%) with a median age of 36 months (interquartile range, 5.5-80.8 months) were included. One hundred twenty-three MR imaging studies were assessed, and 2 broad imaging patterns were identified. Pattern 1 (significant parenchymal disease, 32/57, 56%) was seen in older children (P = .004) with worse clinical profiles. It had 3 onset subpatterns: multifocal white matter lesions (21/32, 66%), brainstem predominant disease (5, 15%), and cerebellitis (6, 19%). All patients with the brainstem pattern failed to meet the radiologic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids. An attenuated imaging phenotype (pattern 2) was seen in 25 patients (44%, 30 studies) and was associated with younger age.
Conclusions:
Distinct MR imaging patterns correlating with clinical phenotypes and possible genetic underpinnings were recognized in this cohort of pediatric CNS hemophagocytic lymphohistiocytosis. Disruptive mutations and missense mutations with absent protein expression correlate with a younger onset age. Children with brainstem and cerebellitis patterns and a negative etiologic work-up require directed assessment for CNS hemophagocytic lymphohistiocytosis.
... However, brain lesions are found in 45% of initial cerebral MRI scans in adult MOGAD patients, mainly in combination with optico-spinal lesions (6). One patient presented with an initial MRI pattern typical of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and then subsequently developed LETM leading to a diagnosis of MOGAD (82). ...
Myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin‐4 autoantibody associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord, optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and neuroimaging characteristics of paediatric and adult MOGAD. We describe how these imaging techniques may be used to study this group of disorders and discuss how image analysis methods have led to recent insights for consideration in future studies.
... In the original description, MOG antibodies were not detected in the sera of the eight patients with CLIPPERS, nor they were detected in the subsequent 23 patients described by the same group (Pittock et al., 2010;Tobin et al., 2017). However, one group reported on a case of MOG associated transverse myelitis that followed CLIPPERS diagnosis and another group reported on a case of relapsing brainstem encephalitis in the setting of MOG seropositivity mimicking CLIPPERS ( Symmonds et al., 2015;Berzero et al., 2018). Our clinical observation may suggest several possibilities. ...
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a distinct pathologic entity of unknown etiology. Here, we describe the clinical and radiologic presentation of myelin oligodendrocyte glycoprotein associated disease (MOG-AD) with features mimicking CLIPPERS. Three patients met the 2017 CLIPPERS diagnostic criteria, while one patient had a single lesion in the pons that mimicked CLIPPERS lesions. All had an excellent response to steroids, but the three who met the CLIPPERS criteria had a relapsing course. When CLIPPERS is observed, it is crucial to test for mimickers. The ever-expanding spectrum of MOG-AD calls for further research into the immunopathogenesis of its several phenotypes.
... Whether CLIPPERS is an inflammatory disease or an overlapping syndrome with other diseases remains unknown. With an increasing number of cases reported in recent years, it is conceivable that CLIPPERS might be a pre-stage or unique presentation of other welldetermined diseases, such as lymphoma [10,15], hemophagocytic syndrome [11], neuromyelitis optica spectrum disorders or other diseases [16]. Noteworthily, in the cases aforementioned, the diagnosis of CLIPPERS took a long duration (several months to 10 years), therein, diagnosis of CLIPPERS needs a long period of observation and monitoring. ...
Background
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder with unclear causes. Paraneoplastic etiology may be a cause. We report a case of CLIPPERS with parotid carcinoma.
Case presentation
A 54-year-old man with a history of lymphoma was hospitalized with a pontocerebellar syndrome. Brain MRI revealed that the pons and cerebellum were “peppered” with punctate and curvilinear enhancement lesions that supported the diagnosis of CLIPPERS. The relapse of lymphoma was excluded by a further cerebellum biopsy revealing predominantly CD3+ T cells in white matter. The patient was relieved after pulse therapy with intravenous methylprednisolone and a large dose of corticosteroids, but he complained of a worsening gait problem when corticosteroids were tapered to a lower dose. Although the clinical symptoms gradually improved again by increasing the dosage of corticosteroids with Azathioprine, the patient still had a slight unsteady gait during follow-up. At the 7-month follow-up, a parotid mass was detected by MRI and was verified as carcinoma by biopsy. After resection of parotid carcinoma, the residual symptoms and previous MRI lesions disappeared, and no relapse occurred.
Conclusions
CLIPPERS may not be a distinct nosologic entity but an overlapping diagnosis with other diseases. Some cases of CLIPPERS might be a subtype of paraneoplastic neurological syndromes (PNS) due to the similar mechanism of antibody-mediated encephalitis. Tumor screening and serum paraneoplastic autoantibody tests are recommended for patients with CLIPPERS, especially for those who relapse when corticosteroids treatment is stopped or tapered.
... Importantly, isolated brain or brainstem lesions are rare in adults and more often occur in combination with optico-spinal lesions (6). One patient presented with an initial MRI pattern typical of chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and then subsequently developed LETM leading to a diagnosis of MOGAD (78). ...
Myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are rare in both children and adults, and have been recently suggested to be an autoimmune neuroinflammatory group of disorders that are different from aquaporin-4 autoantibody associated neuromyelitis optica spectrum disorder and from classic multiple sclerosis. In vivo imaging of the MOGAD patient central nervous system has shown some distinguishing features when evaluating magnetic resonance imaging of the brain, spinal cord, optic nerves, as well as retinal imaging using optical coherence tomography. In this review, we discuss key clinical and imaging characteristics of paediatric and adult MOGAD. We describe how these imaging techniques may be used to study this group of disorders and discuss how these imaging methods have led to recent insights for consideration in future studies.
... 19,25,29 Recently, some studies have presented that TM may merely occur due to the presence of anti-MOG without meeting NMO-SD criteria, but all are limited to case reports. [30][31][32] In the current study for the first time worldwide, there are plenty of MOG-AD cases not meeting NMO-SD criteria. Therefore, further studies regarding a new diagnosis or making new criteria as a differentiated diagnosis for the incidence of TM are strongly recommended. ...
Background: The aim of this study was to evaluate the status of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with transverse myelitis (TM) and compare the clinical and imaging characteristics of MOG immunoglobulin G (IgG)-positive with negative cases.
Methods: This cohort study enrolled 71 patients diagnosed with new-onset of TM who were being followed at a referral university clinic in Isfahan, Iran, from November 2016 to January 2019. Magnetic resonance imaging (MRI) images and blood samples for anti-MOG, anti-aquaporin 4 (anti-AQP4) (using the cell-based technique), and vasculitis-related antibodies were collected from patients. Outcomes were assessed by the evolution of the Expanded Disability Status Scale (EDSS) score and brain and spinal cord imaging findings within three months. All patients underwent imaging and clinical assessment during a mean period of one year as a follow-up. We compared the characteristics of clinical and radiological outcomes in MOG-IgG-positive and negative cases.
Results: Of the total population studied, there were 26.8% men and 73.2% women, with a mean age of 33 ± 10 years. 12 (16.9%) patients were seropositive for MOG antibody and 17 (89.5%) were positive for anti-AQP4 antibodies. There was no significant association between anti-MOG antibody seropositivity and age, gender distribution, the presence of other autoimmune diseases, and number and interval of relapses. However, the involvement site of the spine at first imaging was significantly different between seronegative and seropositive patients.
Conclusion: In patients with MOG antibody disease (MOG-AD) TM, the MRI findings suggest a preferential involvement of the cervical-thoracic section in seropositive cases which may help differentiate from non-MOG demyelination TM.
... Vascular involvement has also been suggested in other forms of anti-MOG antibody-associated encephalitis. For example, in anti-MOG-associated leukoencephalopathy and brainstem encephalitis, punctate and curvilinear gadolinium enhancement (PCGE) has been reported (28)(29)(30). Cerebral PCGE with hyperintensities on T2WI and FLAIR in the corresponding areas is an MRI finding that may be seen when the bloodbrain barrier (BBB) of the small vessels is disrupted by a direct injury of the endothelial cells or by an angiocentric cellular infiltrate (31). However, since there have been other reports describing cortical lesions other than those observed in UCCE or BFCCE with anti-MOG antibodies (17), our hypothesis cannot be applied to all cases of anti-MOG antibody-associated cerebral cortical encephalitis. ...
Objective: To clarify the clinical and radiological features of adult onset anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated bilateral medial frontal cerebral cortical encephalitis (BFCCE).
Methods: We systematically reviewed the literature for patients with anti-MOG antibody-associated BFCCE. Patients who were also positive for other encephalitis-related autoantibodies were excluded from the study. The frequency of several characteristic neurological symptoms and lesion distributions were analyzed.
Results: We identified six patients with anti-MOG antibody-associated BFCCE. Among them, 6/6 had headache, 4/6 had fever, 3/6 had seizure, 2/6 had paraparesis, 2/6 had lethargy, and 2/6 had memory disturbance. CSF pleocytosis was observed in 5/6 patients, while CSF myelin basic protein was not elevated in any of the six patients. On brain MRI, 6/6 had bilateral medial frontal cortical lesions, 3/6 had corpus callosum lesions, and 3/6 had leptomeningeal enhancements. Most of the lesions were distributed in the territory of the anterior cerebral artery (ACA).
Conclusion: Our results indicate that anti-MOG antibody-associated BFCCE presents with characteristic clinical symptoms and MRI findings, which might reflect lesion formation in the ACA territory.
... Neither do children who present with isolated seizures during the first episode of MOGAD with no or only subtle MRI changes [13,34]. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) with detection of MOG-abs later in the course has so far only been described in one adult patient [35]. ...
Imaging plays a crucial role in differentiating the spectrum of paediatric acquired demyelinating syndromes (ADS), which apart from myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) includes paediatric multiple sclerosis (MS), aquaporin-4 antibody neuromyelitis optica spectrum disorders (NMOSD) and unclassified patients with both monophasic and relapsing ADS. In contrast to the imaging characteristics of children with MS, children with MOGAD present with diverse imaging patterns which correlate with the main demyelinating phenotypes as well as age at presentation. In this review we describe the common neuroradiological features of children with MOGAD such as acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, AQP4 negative NMOSD. In addition, we report newly recognized presentations also associated with MOG-ab such as the ‘leukodystophy-like’ phenotype and autoimmune encephalitis with predominant involvement of cortical and deep grey matter structures. We further delineate the features, which may help to distinguish MOGAD from other ADS and discuss the future role of MR-imaging in regards to treatment decisions and prognosis in children with MOGAD. Finally, we propose an MRI protocol for routine examination and discuss new imaging techniques, which may help to better understand the neurobiology of MOGAD.
... MOGAD can mimic infective rhomboencephalitis when a patient presents with fever, CSF leukocytosis, brainstem enhancing lesions and leptomeningeal enhancement (44,68), or Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS), when MRI shows punctate, curvilinear enhancement in the pons (71)(72)(73). ...
... Analysis of cerebrospinal fluid can be unremarkable or reveal mildly elevated protein, pleocytosis, or oligoclonal bands [63]. Like NMOSD, a CLIPPERS presentation can be associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) [66,67] although most cases are seronegative [63]. Rapid clinical and radiological improvement is seen after initiation of either intravenous or oral steroids. ...
Purpose of Review
Pediatric central nervous system demyelinating diseases include multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and acute disseminated encephalomyelitis (ADEM). As diagnostic criteria become more inclusive, the risk of misdiagnosis of atypical demyelinating diseases of rheumatologic, infectious, and autoimmune etiology increases.
Recent Findings
We review mimics of multiple sclerosis, neuromyelitis optica spectrum disorder, and acute disseminated encephalomyelitis, including rheumatologic diseases: systemic lupus erythematosus and neuro-Behçet disease; infectious diseases: human immunodeficiency virus, progressive multifocal leukoencephalopathy, and subacute sclerosis panencephalitis; and autoimmune diseases including X-linked Charcot-Marie-Tooth disease, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and autoimmune glial fibrillary acidic protein (GFAP) encephalopathy.
Summary
Atypical demyelinating disease may mimic classic neuroinflammatory diseases of the central nervous system. Imaging may meet criteria for a diagnosis of multiple sclerosis, or patients may present with optic neuritis and transverse myelitis consistent with neuromyelitis optica spectrum or myelin oligodendrocyte glycoprotein (MOG) antibody disorders. Through careful history-taking and review of atypical MRI findings, we may avoid misdiagnosis and mistreatment.
... 5 Two previous case reports have reported positive MOG antibodies at the time of relapse in patients previously thought to have CLIPPERS. 6,7 Although the pathologic role of MOG antibodies produced by B cells requires further study, the underlying biology of relapses may be different in MOG-Ab-associated demyelination than in CLIPPERS, which is characterized by a predominantly T-cell infiltrate. These differences may have implications for the safety, use, and duration of long-term steroidsparing therapies. ...
... Whether CLIPPERS is an unique entity or an unique expression of several autoimmune disorders or CNS lymphoma is not clear, despite that a recent neuropathologic study did not find an association with either. 101 Because MS-like lesions may be seen along with the typical lesions of CLIPPERS and an overlap with the anti-myelin oligodendrocyte glycoprotein (MOG) phenotype of NMOSD in a patient and similar imaging findings in another patient with a definite diagnosis of relapsing-remitting MS have been described, this relatively newly defined disorder needs to be included in the differential diagnosis of MS. 102,103 Single Lesions Suggestive of Demyelinating-Inflammatory Disease When a patient presents with a self-limited CNS neurologic episode or a progressive neurologic disease and turns out to have a nontumefactive solitary CNS lesion, the differential diagnosis may not be so easy. Depending on the clinical symptomatology and the site and type of the lesion in patients presenting with self-limited neurologic episodes, in most the clinical diagnosis will be "CIS" and its differential workup will suffice. ...
Multiple Sclerosis is increasing, so is the number of misdiagnosed cases as MS. One major source of misdiagnosis is misinterpretation of nonspecific clinical and imaging findings and misapplication of MS diagnostic criteria resulting in an overdiagnosis of MS! Since nonspecific white matter abnormalities on brain MRI and other imaging findings that may mimic MS, as well as MS-nonspecific lesions that are seen in people with MS, neurologists should be aware of all possibilities and should be able to interpret the clinical and MRI findings well and by their selves! The differential diagnosis of MS includes MS variants and inflammatory astrocytopathies and other atypical inflammatory-demyelinating syndromes, as well as a number of systemic diseases with CNS involvement. A detailed history, a through neurological examination and cerebrospinal fluid study are essential for MS diagnosis and MRI is one other tool that is most often confirmatory, but may cause confusion at times too.
... Alternative diagnoses, such as primary CNS malignancy, found in patients initially suspected to have CLIPPERS (Jones et al., 2011;Limousin et al., 2012;De Graaff et al., 2013;Lin et al., 2014;Taieb et al., 2014) led some authors to advocate for neuropathological evaluation in all suspected cases (Limousin et al., 2012). The occurrence of suspected CLIPPERS associated with systemic T cell lymphoma (Nakamura et al., 2016), Hodgkin's lymphoma (Mashima et al., 2015), chronic hepatitis B infection (Weng et al., 2015), myelin oligodendrocyte glycoprotein (MOG) antibodies (Symmonds et al., 2015), CNS lymphomatoid granulomatosis (Wang et al., 2017), primary cerebral angiitis (Buttmann et al., 2013) and multiple sclerosis (Ortega et al., 2012;Ferreira et al., 2013), further demonstrates the need for diagnostic clarity. We performed a comprehensive clinical, radiological and pathological evaluation of 35 patients reviewed at Mayo Clinic with a suspected diagnosis of CLIPPERS and propose diagnostic criteria for CLIPPERS. ...
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory syndrome predominantly affecting the brainstem, cerebellum, and spinal cord. Following its initial description, the salient features of CLIPPERS have been confirmed and expanded upon, but the lack of formalized diagnostic criteria has led to reports of patients with dissimilar features purported to have CLIPPERS. We evaluated clinical, radiological and pathological features of patients referred for suspected CLIPPERS and propose diagnostic criteria to discriminate CLIPPERS from non-CLIPPERS aetiologies. Thirty-five patients were evaluated for suspected CLIPPERS. Clinical and neuroimaging data were reviewed by three neurologists to confirm CLIPPERS by consensus agreement. Neuroimaging and neuropathology were reviewed by experienced neuroradiologists and neuropathologists, respectively, both of whom were blinded to the clinical data. CLIPPERS was diagnosed in 23 patients (18 male and five female) and 12 patients had a non-CLIPPERS diagnosis. CLIPPERS patients' median age of onset was 58 years (interquartile range, 24-72) and were followed a median of 44 months (interquartile range 38-63). Non-CLIPPERS patients' median age of onset was 52 years (interquartile range, 39-59) and were followed a median of 27 months (interquartile range, 14-47). Clinical symptoms of gait ataxia, diplopia, cognitive impairment, and facial paraesthesia did not discriminate CLIPPERS from non-CLIPPERS. Marked clinical and radiological corticosteroid responsiveness was observed in CLIPPERS (23/23), and clinical worsening occurred in all 12 CLIPPERS cases when corticosteroids were discontinued. Corticosteroid responsiveness was common but not universal in non-CLIPPERS [clinical improvement (8/12); radiological improvement (2/12); clinical worsening on discontinuation (3/8)]. CLIPPERS patients had brainstem predominant perivascular gadolinium enhancing lesions on magnetic resonance imaging that were discriminated from non-CLIPPERS by: homogenous gadolinium enhancing nodules <3 mm in diameter without ring-enhancement or mass effect, and homogenous T2 signal abnormality not significantly exceeding the T1 enhancement. Brain neuropathology on 14 CLIPPERS cases demonstrated marked CD3-positive T-lymphocyte, mild B-lymphocyte and moderate macrophage infiltrates, with perivascular predominance as well as diffuse parenchymal infiltration (14/14), present in meninges, white and grey matter, associated with variable tissue destruction, astrogliosis and secondary myelin loss. Clinical, radiological and pathological feature define CLIPPERS syndrome and are differentiated from non-CLIPPERS aetiologies by neuroradiological and neuropathological findings.
... OCB is often observed in CLIPPERS (1). Although the patient was not examined for antibodies to myelinoligodendrocyte glycoprotein (MOG), a CLIPPERS patient with longitudinally extensive transverse myelitis was reported to have antibodies to MOG, suggesting that CLIP-PERS is a syndrome rather than a distinct disease (6). The clinical symptoms and multiple enhanced lesions observed on MRI in the present case improved after methylprednisolone pulse therapy, which was compatible with a diagnosis of CLIPPERS (1,4). ...
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory central nervous system disorder that mainly involves in the brainstem, basal ganglia and cerebellum. We herein report the case of a patient with CLIPPERS, which was diagnosed based on the clinical and radiological features. After initially responded to steroid treatment, the patient developed limbic encephalitis. The patient presented with memory disturbance, a delirious state and emotional incontinence. A cerebrospinal fluid study revealed interleukin-6 elevation and enhanced bilateral hippocampal lesions were observed on MRI. The patient was successfully treated with methylprednisolone pulse therapy. This is the first case of CLIPPERS with limbic encephalitis involving the bilateral hippocampus.
... Since the original description of the syndrome, several other groups have reported similar cases [2,3], supporting the existence of the syndrome. The absence of a definitive diagnostic biomarker has led to some confusion in the field, with primary central nervous system (CNS) malignancy [4, 5•, 6-8], systemic T cell lymphoma [9], Hodgkin's lymphoma [10], chronic hepatitis B infection [11], myelin oligodendrocyte glycoprotein (MOG) antibodies [12], CNS lymphomatoid granulomatosis [13], and multiple sclerosis (MS) [14,15] all being described in association with neuroimaging features similar to CLIPPERS. The purpose of this review is to summarize the clinical, radiological, and pathological features of CLIPPERS and to describe a suggested evaluation and treatment plan when faced with a patient with suspected CLIPPERS. ...
Purpose of review:
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described treatable, inflammatory, brainstem predominant encephalomyelitis. The diagnosis of CLIPPERS is challenging without a specific biomarker, and thus it is important to consider if both the clinical and radiographic features are consistent with the diagnosis, or rather a disease mimicker.
Recent findings:
Many patients with CLIPPERS-like lesions have been described in the literature with follow-up revealing a range of alternative diagnoses, such as malignancies, vasculitis, and other specific inflammatory diseases. As a result, some have proposed that CLIPPERS might represent a pre-malignancy state or simply an initial clinical syndrome of a variety of possible etiologies. We describe the typical clinical, radiographic, and pathological features of CLIPPERS and emphasize consideration for alternative diagnoses when findings are not classic. A recommended diagnostic evaluation and initial treatment plan is provided.
... Before treating attack related to CLIPPERS, alternative diagnosis, also called CLIPPERS mimics, should be excluded. The second criterion of CLIPPERS, defined by brainstem punctate and curvilinear enhancements, may conceal several diseases such as sentinel lesions of primary central nervous system lymphoma, initial stage of lymphomatoid granulomatosis (grade I), primary angiitis of the central nervous system, multiple sclerosis, myelin oligodendrocyte glycoprotein antibody-associated diseases and low-grade glioma [17][18][19][20][21][22][23][24][25][26]. Except for low-grade glioma, all of these diseases could respond to high doses of steroids. ...
CLIPPERS for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, is a steroid-sensitive and steroid-dependent brainstem inflammatory disease of unknown origin. Since its first description in 2010, about 60 cases have been reported throughout the world. The mean age at onset is 50 years and men seem to be more frequently affected. In patients without chronic corticosteroid therapy or immunosuppressive agents, the disease had a relapsing remitting course, and the mean annualized relapse rate was 0.5. During attacks, although clinical and radiological improvement after high doses of corticosteroids was systematically observed, patients could display subsequent disability and hindbrain atrophy. Since no progressive course was observed, clinical and radiological sequelae were correlated with previous severe attacks. Therefore, maintaining the disease in remission may prevent the accumulation of disability. In the literature, no relapse occurred when chronic corticosteroid therapy was maintained above 20 mg per day. However, steroids side effects led to propose corticosteroid-sparing therapies. Unfortunately, no controlled therapy studies for CLIPPERS have been performed yet, and no therapeutic recommendations exist. Using the PubMed database, all articles having the following keywords “chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids” and “CLIPPERS” have been analysed. Considering that the mean annual relapse rate was 0.5, and that no relapse occurred when corticosteroid therapy was maintained above 20 mg per day, the therapeutic efficiency of corticosteroid-sparing agents was considered as “probable” when patients had a relapse-free period ≥24 months, in the absence of concomitant corticosteroid therapy. Corticosteroid-sparing agents whose efficiency is “probable” are methotrexate in two cases, cyclophosphamide in one case and hydroxychloroquine in one case. Considering the risk benefit ratio of corticosteroid-sparing agents, methotrexate seems to be the most suitable. Nevertheless, randomized controlled trials testing the different corticosteroid-sparing agents in CLIPPERS are necessary.
... Our patient also had anti MAG positive antibodies. Anti-MOG antibodies are also described in some cases of CLIPPERS [4]. We cannot exclude the possibility that our patient developed antibodies subsequent to his initial pontine inflammation, as anti-MAG antibodies were not checked at original presentation. ...
... Whether CLIPPERS is an unique entity or an unique expression of several autoimmune disorders or CNS lymphoma is not clear, despite that a recent neuropathologic study did not find an association with either. 101 Because MS-like lesions may be seen along with the typical lesions of CLIPPERS and an overlap with the anti-myelin oligodendrocyte glycoprotein (MOG) phenotype of NMOSD in a patient and similar imaging findings in another patient with a definite diagnosis of relapsing-remitting MS have been described, this relatively newly defined disorder needs to be included in the differential diagnosis of MS. 102,103 Single Lesions Suggestive of Demyelinating-Inflammatory Disease When a patient presents with a self-limited CNS neurologic episode or a progressive neurologic disease and turns out to have a nontumefactive solitary CNS lesion, the differential diagnosis may not be so easy. Depending on the clinical symptomatology and the site and type of the lesion in patients presenting with self-limited neurologic episodes, in most the clinical diagnosis will be "CIS" and its differential workup will suffice. ...
An increasing number of patients referred for neuroimaging studies unrelated to multiple sclerosis (MS) are found to have incidental lesions suggestive of MS in their nervous systems but many such patients do not develop clinical symptoms and signs and remain as "subclinical MS" (SCMS). MRI and cerebrospinal fluid (CSF) studies in monozygotic twins and siblings of MS patients, as well as necropsy studies in asymptomatic persons also reveal findings consistent with SCMS. Clinically isolated syndromes (CIS), acute disseminated encephalomyelitis (ADEM), benign MS, relapsing-remitting MS, primary and secondary progressive MS, optico-spinal MS, Balo's and Marburg's diseases, are considered different forms of MS by many because of their heterogeneous clinical, imaging and pathological features. Studies of disease susceptibility, type, course and severity have given different results in different populations, consistent with "genetic heterogeneity". The various forms of the disease may change from one to another, and their clinical and imaging features became similar after a number of years. The current data support the concept that MS, whether it is a single disease or a group of disorders, is an immune-mediated disease of the CNS, with both inflammatory and degenerative features with available therapies being only partially and temporarily effective for the inflammatory phase of the disease. Making the diagnosis of MS may not be an absolute indication for early treatment with disease modifying agents. The use of new technology such as microarray and other techniques in diagnosing and understanding the MS spectrum may make it possible to recognize the different molecular subtypes of these diseases and develop better therapies.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory syndrome with characteristic clinical, radiological, and pathological features, and can be effectively treated with corticosteroid-based immunotherapies. The exact pathogenesis of CLIPPERS remains unclear, and specific diagnostic biomarkers are not available. According to the 2017 diagnostic criteria, probable CLIPPERS should be considered in middle-aged patients with subacute onset of pontocerebellar symptoms and typical punctuate and curvilinear gadolinium enhancement lesions (“salt-and-pepper” appearance) located in the hindbrain (especially pons) on magnetic resonance imaging. In addition, CLIPPERS-mimics, such as central nervous system (CNS) lymphoma, and several antibody-associated autoimmune CNS diseases (e.g., myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune glial fibrillary acidic protein astrocytopathy, and anti-N-methyl-d-aspartate receptor encephalitis), should be extensively excluded. The prerequisite for definite CLIPPERS is the perivascular T-cell-predominant inflammatory infiltration observed on pathological analysis. A biopsy is strongly suggested when clinical/radiological red flags are present. Most patients with CLIPPERS respond well to corticosteroids and have a good prognosis. Long-term low-dose corticosteroid maintenance therapy or corticosteroids coupled with immunosuppressants are recommended to prevent the recurrence of the syndrome. The potential progression of CLIPPERS to lymphoma has been suggested in some cases; therefore, at least 2-year clinical and radiological follow-up is essential. Here, we critically review the recent developments and provided an update on the clinical characteristics, diagnostic criteria, differential diagnoses, and therapeutic management of CLIPPERS. We also discuss the current controversies in this context that can be resolved in future research studies.
Background: MOG antibody disease presents along a spectrum that includes acute disseminated encephalomyelitis, transverse myelitis, and optic neuritis. CLIPPERS is a rare condition that may complicate an accurate MOGAD diagnosis. This is in part due to overlapping clinical and imaging features with MOGAD.
Case report: Here we report a case of a 63-year-old woman with relapsing optic neuritis due to MOGAD that was initially concerning for CLIPPERS. The patient was seropositive for MOG-ab and responded well to high dose corticosteroid therapy which was tapered over 9-months.
Conclusion: This case underscores the importance of recognizing the overlap in clinical presentation that may occur between MOGAD and CLIPPERS despite both conditions having distinct biological origins. CLIPPERS criteria and the exclusion of alternative causes can help distinguish between the two. A MOG-ab titer should be used to screen MOGAD as a CLIPPERS mimicker. Antibody testing, clinical imaging, steroid responsiveness, history of present illness, and the extent of existing disability may provide a complete diagnostic picture.
Purpose of review:
Anti-myelin oligodendrocyte glycoprotein (MOG) autoantibodies have become a recognized cause of a pathophysiologically distinct group of central nervous system (CNS) autoimmune diseases. MOG-associated disorders can easily be confused with other CNS diseases such as multiple sclerosis or neuromyelitis optica, but they have a distinct clinical phenotype and prognosis.
Recent findings:
Most patients with MOG-associated disorders exhibit optic neuritis, myelitis, or acute disseminated encephalomyelitis (ADEM) alone, sequentially, or in combination; the disease may be either monophasic or relapsing. Recent case reports have continued to expand the clinical spectrum of disease, and increasingly larger cohort studies have helped clarify its pathophysiology and natural history.
Summary:
Anti-MOG-associated disorders comprise a substantial subset of patients previously thought to have other seronegative CNS diseases. Accurate diagnosis is important because the relapse patterns and prognosis for MOG-associated disorders are unique. Immunotherapy appears to successfully mitigate the disease, although not all agents are equally effective. The emerging large-scale data describing the clinical spectrum and natural history of MOG-associated disorders will be foundational for future therapeutic trials.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory syndrome characterized by the predominant involvement of the pons, the cerebellum and the spinal cord with a distinct corticosteroid responsiveness. To date, several cases of neurological disorders with a CLIPPERS-like phenotype have been described, including patients with Immunoglobulin G (IgG) antibodies binding to myelin oligodendrocyte glycoprotein (MOG). We herein report the case of a man with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) fulfilling the diagnostic criteria for probable CLIPPERS and a literature review of CLIPPERS-mimicking patients with MOG-IgG.
CLIPPERS (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) is an inflammatory disorder of the central nervous system (CNS), predominantly involving the brainstem with a characteristic magnetic resonance imaging (MRI) appearance and clinical and radiological responsiveness to glucocorticosteroids. Yet diagnostic biomarkers are missing and other immune-mediated, (para-) infectious and malignant causes mimic CLIPPERS-like MRI presentations. We report the case of a 51-year-old male patient with CLIPPERS who repeatedly responded well to high-dose corticosteroids. After 7 months, however, treatment failed, and he had a biopsy-confirmed diagnosis of a CNS B-cell lymphoma. Clinical and MRI signs of CLIPPERS include a wide spectrum of differential diagnoses which often arise only later during the course of disease. Similar to the case presented here, delayed diagnosis and specific therapy may contribute to an unfavorable outcome. Hence, we propose that in the absence of other diagnostic markers, brain biopsy should be performed as early as possible in CLIPPERS patients.
Background/aims:
Optic neuritis (ON) is the primary ophthalmic manifestation of myelin oligodendrocyte glycoprotein-IgG-associated disorder (MOGAD), but numerous reports have expanded the visual manifestations of this condition. The goal of this study was to synthesise the extensive literature on this topic to help ophthalmologists understand when testing for MOG-IgG should be considered.
Method:
A systematic review of the English-language literature was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and searches were conducted using Ovid MEDLINE (from January 1, 1948 to April 1, 2020) and Ovid EMBASE (from January 1, 1947 to April 1, 2020). Inclusion criteria included studies describing non-isolated ON ophthalmic manifestations where cell-based assays were used for the detection of MOG antibodies.
Results:
Fifty-one articles representing 62 patients with a median age of 32.0 (range 2-65), female gender (51%) and follow-up of 20.0 months (range: 1-240) were included. Twenty-nine patients had non-isolated ON afferent visual manifestations: uveitis, peripheral ulcerative keratitis, acute macular neuroretinopathy, neuroretinitis, venous stasis retinopathy, large preretinal macular haemorrhage, orbital inflammatory syndrome, orbital apex syndrome, optic perineuritis, papilloedema and homonymous visual field defects. Incomplete recovery of ON was associated with a case of Leber's hereditary optic neuropathy. Efferent ophthalmic manifestations included cranial neuropathies, internuclear ophthalmoplegia, central nystagmus, saccadic intrusions and ocular flutter. Cranial nerve involvement was secondary to enhancement of the cisternal portion or brainstem involvement. All included cases were treated with corticosteroids with 31% of cases requiring additional immunosuppressive therapy.
Conclusions:
MOGAD has been associated with various afferent and efferent ophthalmic manifestations apart from isolated ON. Awareness of these findings may result in earlier diagnosis and treatment.
CLIPPER is a chronic inflammatory disorder in the CNS, which is characterized by MRI appearance of punctate and curvilinear gadolinium enhancement that involve the pons and the cerebellum and exquisite response to steroid. We report a patient presented with clinical and radiological features suggestive of CLIPPERS. However, despite the initial response to steroid, there were dramatic changes in the course of his disease that were conducive to considering another diagnosis. We searched PubMed using word (CLIPPERS) till December 2018. The pathogenesis, clinical manifestations, imaging features, treatment and prognosis of this disorder are summarized. A review of the literature for cases of CLIPPERS demonstrated a subset of patients who later discovered to have an alternative pathology. Indeed, clinicians should be scrupulous to diagnose this disease based solely on the clinical and radiological findings and they should have a lower threshold of having a brain biopsy.
Background:
We studied patients with chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) associated with or without lymphoma and measured risk factors suggestive of an underlying lymphoma and follow-up outcomes.
Methods:
CLIPPERS patients associated with or without lymphoma were included into this study. Clinical presentations were documented, risk factors suggestive of an underlying lymphoma were tested, and prognostic differences in terms of death were compared.
Results:
Ten patients had a diagnosis of CLIPPERS associated with lymphoma, with 6 B-cell non-Hodgkin lymphoma, 2 T-cell non-Hodgkin lymphoma and 2 Hodgkin lymphoma. Using multivariate logistic analysis, the following 3 independent risk factors were found to be related to a final diagnosis of lymphoma: hyperreflexia (HR 16.56; 95% CI 1.03-265.29; p = 0.032), elevated protein in CSF (HR 11.59; 95% CI 1.24-108.39; p = 0.047), and recurrences between 2 months and 1 year after treatment (HR 29.27; 95% CI 2.09-409.58; p = 0.012). The model calibration was satisfactory (p = 0.392 with the Hosmer-Lemeshow test), and the discrimination power was good (area under the receiver operating characteristic curve 0.921; p < 0.001, 95% CI 0.826-1.000). Patients with CLIPPERS associated with lymphoma had higher mortality rate and lymphoma was a significant predictor of total mortality (HR 0.040; 95% CI 0.006-0.262; p = 0.001).
Conclusions:
Hyperreflexia, elevated protein in CSF and recurrences between 2 months and 1 year after treatment are risk factors suggesting an underlying lymphoma. Relapses during high-dose steroids maintenance therapy can be indicative of lymphoma, too. Patients having CLIPPERS associated with lymphoma have a worse prognosis than those without lymphoma.
Objective
To evaluate the accuracy of the recently proposed diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS).
Methods
We enrolled 42 patients with hindbrain punctate and/or linear enhancements (<3 mm in diameter) and tested the CLIPPERS criteria.
Results
After a median follow-up of 50 months (IQR 25–82), 13 out of 42 patients were CLIPPERS-mimics: systemic and central nervous system lymphomas (n=7), primary central nervous system angiitis (n=4) and autoimmune gliopathies (n=2). The sensitivity and specificity of the CLIPPERS criteria were 93% and 69%, respectively. Nodular enhancement (≥3 mm in diameter), considered as a red flag in CLIPPERS criteria, was present in 4 out of 13 CLIPPERS-mimics but also in 2 out of 29 patients with CLIPPERS, explaining the lack of sensitivity. Four out of 13 CLIPPERS-mimics who initially met the CLIPPERS criteria displayed red flags at the second attack with a median time of 5.5 months (min 3, max 18), explaining the lack of specificity. One of these four patients had antimyelin oligodendrocyte glycoprotein antibodies, and the three remaining patients relapsed despite a daily dose of prednisone/prednisolone ≥30 mg and a biopsy targeting atypical enhancing lesions revealed a lymphoma.
Conclusions
Our study highlights that (1) nodular enhancement should be considered more as an unusual finding than a red flag excluding the diagnosis of CLIPPERS; (2) red flags may occur up to 18 months after disease onset; (3) as opposed to CLIPPERS-mimics, no relapse occurs when the daily dose of prednisone/prednisolone is ≥30 mg; and (4) brain biopsy should target an atypical enhancing lesion when non-invasive investigations remain inconclusive.
Purpose of review:
The clinical interest for auto-antibodies against myelin oligodendrocyte glycoprotein (MOG) has recently reemerged, with the use of more specific detection methods. Large national cohorts have allowed characterizing a more precise clinical spectrum delineated by the presence of human MOG-antibodies.
Recent findings:
In adults with MOG-antibodies, optic neuritis is the most frequent clinical presentation, with features different from multiple sclerosis (MS), including bilateral involvement and predilection for the anterior part of the optic nerve. Myelitis and brainstem syndrome are also frequent, and may clinically mimic neuromyelitis optica spectrum disorders (NMOSD). Despite the frequently severe clinical presentation, most of patients recover quickly after steroids initiation. Other less typical presentations include encephalitis with seizures, cranial nerve involvement, and chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids-like. Although the majority of adult patients follow a relapsing course, long-term prognosis differs from aquaporin-4-antibodies NMOSD, with only a small proportion of patients with a poor outcome.
Summary:
MOG-antibodies-associated disease is a new entity in the spectrum of inflammatory demyelinating diseases, distinct from both MS and NMOSD. There is a crucial need to identify factors associated to the risk of relapse or poor outcome, to seek patient subgroups in which immunoactive treatments could be beneficial.
A 69-year-old man was admitted to our hospital because of disturbed consciousness and gait disturbance. He had herpes zoster (HZ) in his left thigh 10 days before admission, and motor paresis of four extremities developed. A dark red rash was observed in his left buttock and thigh (L2–3 region), which was also scattered in the right lower leg, chest wall, and both upper extremities. Brain MRI showed no lesions of demyelinating plaques. Spine MRI showed no abnormal signals in the lumbar region; however, high signals in the spinal cord from the bottom of the medulla oblongata to the upper (Th 2) thoracic region were observed. High signals were observed mainly in the central white matter. These lesions might correspond to longitudinally extensive transverse myelitis (LETM). Cerebrospinal fluid (CSF) showed increased protein and cell counts of lymphocytes and was positive for varicella-zoster virus (VZV)-DNA. His serum sample tested negative for anti-aquaporin (AQP)4 antibody but positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibody (cell-based assay). Disseminated HZ was suspected on the basis of the widely scattered rash, and damage to the both lungs and liver. This is the first report of HZ-associated LETM with a high titer anti-MOG antibodies. Our case showed that HZ may trigger anti-MOG-IgG positive myelitis.
Myelin oligodendrocyte glycoprotein (MOG), a member of the immunoglobulin (Ig) superfamily, is a myelin protein solely expressed at the outermost surface of myelin sheaths and oligodendrocyte membranes. This makes MOG a potential target of cellular and humoral immune responses in inflammatory demyelinating diseases. Due to its late postnatal developmental expression, MOG is an important marker for oligodendrocyte maturation. Discovered about 30 years ago, it is one of the best-studied autoantigens for experimental autoimmune models for multiple sclerosis (MS). Human studies, however, have yielded controversial results on the role of MOG, especially MOG antibodies (Abs), as a biomarker in MS. But with improved detection methods using different expression systems to detect Abs in patients’ samples, this is meanwhile no longer the case. Using cell-based assays with recombinant full-length, conformationally intact MOG, several recent studies have revealed that MOG Abs can be found in a subset of predominantly pediatric patients with acute disseminated encephalomyelitis (ADEM), aquaporin-4 (AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD), monophasic or recurrent isolated optic neuritis (ON), or transverse myelitis, in atypical MS and in N-methyl-d-aspartate receptor-encephalitis with overlapping demyelinating syndromes. Whereas MOG Abs are only transiently observed in monophasic diseases such as ADEM and their decline is associated with a favorable outcome, they are persistent in multiphasic ADEM, NMOSD, recurrent ON, or myelitis. Due to distinct clinical features within these diseases it is controversially disputed to classify MOG Ab-positive cases as a new disease entity. Neuropathologically, the presence of MOG Abs is characterized by MS-typical demyelination and oligodendrocyte pathology associated with Abs and complement. However, it remains unclear whether MOG Abs are a mere inflammatory bystander effect or truly pathogenetic. This article provides deeper insight into recent developments, the clinical relevance of MOG Abs and their role in the immunpathogenesis of inflammatory demyelinating disorders.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disorder of the CNS with distinct clinical and radiologic features.(1) In this study, we report an atypical case of CLIPPERS presenting with prominent spinal symptoms and diffuse white matter involvement. Our patient exhibited a good response to steroid therapy and recovered fully, suggesting there are variations in the clinical and radiologic presentations of CLIPPERS, and highlighting the importance of recognizing this rare syndrome as a potentially treatable disorder.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a rare central nervous system (CNS) disorder with distinct radiological features. However, CLIPEERS may mimic CNS lymphoma, and several cases in which CLIPPERS occurred premonitory to CNS lymphoma have been reported. We report a 31-year-old man presenting with progressive gait ataxia and the characteristic MRI features of CLIPPERS. He was diagnosed with stage II Hodgkin's lymphoma at the age of 15, and we considered the possibility of newly emerged CNS lymphoma occurring in the immunosuppressive condition after the treatment of Hodgkin's lymphoma. Histological findings showed no evidence of CNS lymphoma and the neurological symptoms were resolved by steroids. Although CLIPPERS developed in the reverse order in this case, CLIPPERS should be considered in different diagnosis for CNS lymphoma.
A 21-year-old woman presented with headaches and left eye visual loss. Examination revealed acuity 20/20 OD and finger counting OS, a left afferent pupillary defect, papilledema OD, and optic atrophy OS. Left atrophy was unexplained until orbital MRI revealed left nerve compression by the gyrus rectus (figure, A), displaced by an intraventricular central neurocytoma (figure, B). Foster-Kennedy syndrome is characterized by optic atrophy on one side due to direct optic nerve mass lesion compression with contralateral papilledema. This case is termed pseudo-Foster-Kennedy with indirect compressive optic neuropathy due to brain displacement from a tumor distant from the optic nerve.
Importance
Most patients with neuromyelitis optica (NMO) and many with NMO spectrum disorder have autoantibodies against aquaporin-4 (AQP4-Abs), but recently, myelin-oligodendrocyte glycoprotein antibodies (MOG-Abs) have been found in some patients. Here, we showed that patients with NMO/NMOSD with MOG-Abs demonstrate differences when compared with patients with AQP4-Abs.Objective
To characterize the features of patients with NMO/NMOSD with MOG-Abs and compare them with patients with AQP4-Ab–positive NMO/NMOSD.Design, Setting, and Participants
This observational study was conducted at a single UK specialist center for NMO. Patients with a first demyelinating event between January 1, 2010, and April 1, 2013, seen within the Oxford NMO service and who tested positive for MOG-Abs or AQP4-Abs were included in the study.Exposure
Cell-based assays using C-terminal–truncated human MOG and full-length M23-AQP4 were used to test patient serum samples for AQP4-Abs and MOG-Abs.Main Outcomes and Measures
Demographic, clinical, and disability data, and magnetic resonance imaging findings.Results
Twenty AQP4-Ab–positive patients and 9 MOG-Ab–positive patients were identified. Most patients in both groups were white. Ninety percent of AQP4-Ab–positive patients but only 44% MOG-Ab–positive patients were females (P = .02) with a trend toward older age at disease onset in AQP4-Ab–positive patients (44.9 vs 32.3 years; P = .05). MOG-Ab–positive patients more frequently presented with simultaneous/sequential optic neuritis and myelitis (44% vs 0%; P = .005). Onset episode severity did not differ between the 2 groups, but patients with MOG-Abs had better outcomes from the onset episode, with better recovery Expanded Disability Status Scale scores and a lower risk for visual and motor disability. Myelin-oligodendrocyte glycoprotein antibody–positive patients were more likely to have conus involvement on spinal magnetic resonance imaging (75% vs 17%; P = .02) and involvement of deep gray nuclei on brain magnetic resonance imaging (P = .03). Cerebrospinal fluid characteristics were similar in the 2 groups. A higher proportion of AQP4-Ab–positive patients relapsed (40% vs 0%; P = .03) despite similar follow-up durations.Conclusions and Relevance
Despite the fact that patients with MOG-Abs can fulfill the diagnostic criteria for NMO, there are differences when compared with those with AQP4-Abs. These include a higher proportion of males, younger age, and greater likelihood of involvement of the conus and deep gray matter structures on imaging. Additionally, patients with MOG-Abs had more favorable outcomes. Patients with AQP4-Ab–negative NMO/NMOSD should be tested for MOG-Abs.
To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin-4 (AQP4) antibodies, or seronegativity for both antibodies.
Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells.
Among the 215 patients with NMOSD, 7.4% (16/215) were positive for MOG antibodies and 64.7% (139/215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG antibodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demonstrated better functional recovery after an attack.
Patients with NMOSD with MOG antibodies have distinct clinical features, fewer attacks, and better recovery than patients with AQP4 antibodies or patients seronegative for both antibodies.
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently defined inflammatory central nervous system (CNS) disorder, prominently involving the brainstem and in particular the pons. The condition features a combination of clinical symptoms essentially referable to brainstem pathology and a characteristic MRI appearance with punctate and curvilinear gadolinium enhancement "peppering" the pons. The radiological distribution is focused in the pons and adjacent rhombencephalic structures such as the cerebellar peduncles, cerebellum, medulla, and the midbrain. While the lesion burden with a perivascular pattern is typically most dense in these pontine and peripontine regions, enhancing lesions may additionally extend into the spinal cord and supratentorial structures such as the thalamus, basal ganglia, capsula interna, corpus callosum, and the cerebral white matter. Another core feature is clinical and radiological responsiveness to glucocorticosteroid (GCS) based immunosuppression. As withdrawal of GCS treatment results commonly into disease exacerbation, a long-term immunosuppressive therapy appears to be mandatory for sustained improvement. Diagnosis of CLIPPERS is challenging and requires careful exclusion of alternative diagnoses. A specific serum or CSF biomarker for the disorder is currently not known. Pathogenesis of CLIPPERS remains poorly understood and the nosological position of CLIPPERS has still to be established. Whether CLIPPERS represents an independent, actual new disorder or a syndrome that includes etiologically heterogeneous diseases and/or their prestages, remains a debated and not finally clarified issue. Clinicians and radiologists should be aware of this condition and its differential diagnoses, given that CLIPPERS constitutes a treatable condition and that patients may benefit from an early introduction of GCS ensued by a long-term immunosuppression. Based on previous reports in literature - currently encompassing more than 50 reported cases of CLIPPERS - this review addresses clinical features, diagnostic criterias, differential diagnoses and therapeutic management of this peculiar disorder.
Myelin oligodendrocyte glycoprotein (MOG) has been identified as a target of demyelinating autoantibodies in animal models of inflammatory demyelinating diseases of the CNS, such as multiple sclerosis (MS). Numerous studies have aimed to establish a role for MOG antibodies in patients with MS, although the results have been controversial. Cell-based immunoassays using MOG expressed in mammalian cells have demonstrated the presence of high-titre MOG antibodies in paediatric patients with acute disseminated encephalomyelitis, MS, aquaporin-4-seronegative neuromyelitis optica, or isolated optic neuritis or transverse myelitis, but only rarely in adults with these disorders. These studies indicate that MOG antibodies could be associated with a broad spectrum of acquired human CNS demyelinating diseases. This Review article discusses the current literature on MOG antibodies, their potential clinical relevance, and their role in the pathogenesis of MOG antibody-associated demyelinating disorders.
Background:
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease.
Objective:
To describe the disease course of CLIPPERS.
Design:
A nationwide study was implemented to collect clinical, magnetic resonance imaging, cerebrospinal fluid, and brain biopsy specimen characteristics of patients with CLIPPERS.
Setting:
Academic research.
Patients:
Twelve patients with CLIPPERS.
Main outcome measures:
The therapeutic management of CLIPPERS was evaluated.
Results:
Among 12 patients, 42 relapses were analyzed. Relapses lasted a mean duration of 2.5 months, manifested frequent cerebellar ataxia and diplopia, and were associated with a mean Expanded Disability Status Scale (EDSS) score of 4. Besides typical findings of CLIPPERS, magnetic resonance imaging showed brainstem mass effect in 5 patients, extensive myelitis in 3 patients, and closed ring enhancement in 1 patient. Inconstant oligoclonal bands were found on cerebrospinal fluid investigation in 4 patients, with an increased T-cell ratio of CD4 to CD8. Among 7 available brain biopsy specimens, staining was positive for perivascular CD4 T lymphocytes in 5 samples. Thirty-eight of 42 relapses were treated with pulse corticosteroid therapy, which led to improvement, with a mean residual EDSS score of 1.9 (range, 0-7). In 1 patient with untreated relapses, scores on the EDSS progressively increased to a score of 10 at death. Among 5 patients without long-term corticosteroid therapy, the mean annualized relapse rate was 0.5 (range, 0.25-2.8). Among 7 patients taking oral corticosteroids, no relapses occurred in those whose daily dose was 20 mg or higher. No progressive course of CLIPPERS was observed. Four patients with a final EDSS score of 4 or higher had experienced previous severe relapses (EDSS score, ≥5) and brainstem and spinal cord atrophy.
Conclusions:
CLIPPERS is a relapsing-remitting disorder without progressive forms. Long-term disability is correlated with the severity of previous relapses. Further studies are needed to confirm that prolonged corticosteroid therapy prevents further relapses.
Sir, Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a newly defined clinical and radiological inflammatory entity prominently involving the pons. Patients with this condition present with an evolving brainstem syndrome and have characteristic punctate and curvilinear gadolinium enhancing lesions ‘peppering the pons’, extending variably into adjacent CNS structures. This condition is said to be responsive to corticosteroids, with patients requiring prolonged steroid or immunosuppressive therapy (Pittock et al. , 2010). Here, we report two patients with brainstem syndromes and MRI scans compatible with CLIPPERS. One had a steroid-dependent syndrome, as described by Pittock et al. (2010). However, another—with a typical presentation and MRI scan—had biopsy findings favouring a low-grade glioma and failed to respond to dexamethasone and radiotherapy. This raises the possibility that ‘radiologically compatible CLIPPERS’ may conceal a number of pathologies.
A 70-year-old female presented in September 2010 with 1 month history of intermittent rotational vertigo and nausea, fluctuating diplopia and mild gait ataxia. She had a past history of a superficial melanoma excised from her nose in 2006 but was otherwise fit and well. MRI at presentation showed multiple curvilinear enhancing lesions within the pons, with a small number of lesions scattered throughout both cerebellar hemispheres (Fig. 1A). None of …
The classification and pathological mechanisms of many central nervous system inflammatory diseases remain uncertain. In this article we report eight patients with a clinically and radiologically distinct pontine-predominant encephalomyelitis we have named 'chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids' (CLIPPERS). The patients were assessed clinically, radiologically and pathologically at Mayo Clinic, USA and Ghent University Hospital, Belgium from 1999 to 2009. Median follow-up duration from clinical onset was 22 months (range 7-144 months). Patients underwent extensive laboratory (serum and cerebrospinal fluid), radiological and pathological testing (conjunctival, transbronchial and brain biopsies) to search for causes of an inflammatory central nervous system disorder. All eight patients (five female, three male) presented with episodic diplopia or facial paresthesias with subsequent brainstem and occasionally myelopathic symptoms and had a favourable initial response to high dose glucocorticosteroids. All patients had symmetric curvilinear gadolinium enhancement peppering the pons and extending variably into the medulla, brachium pontis, cerebellum, midbrain and occasionally spinal cord. Radiological improvement accompanied clinical response to glucocorticosteroids. Patients routinely worsened following glucocorticosteroid taper and required chronic glucocorticosteroid or other immunosuppressive therapy. Neuropathology of biopsy material from four patients demonstrated white matter perivascular, predominantly T lymphocytic, infiltrate without granulomas, infection, lymphoma or vasculitis. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids is a definable, chronic inflammatory central nervous system disorder amenable to immunosuppressive treatment. The T cell predominant inflammatory pathology in affected central nervous system lesions and the clinical and radiological response to immunosuppressive therapies is consistent with an immune-mediated process.
The m-AAA (ATPases Associated with a variety of cellular Activities) is an evolutionary conserved metalloprotease complex located in the internal mitochondrial membrane. In the mouse, it is a hetero-oligomer variably formed by the Spg7, Afg3l1, and Afg3l2 encoded proteins, or a homo-oligomer formed by either Afg3l1 or Afg3l2. In humans, AFG3L2 and SPG7 genes are conserved, whereas AFG3L1 became a pseudogene. Both AFG3L2 and SPG7 are involved in a neurodegenerative disease, namely the autosomal dominant spinocerebellar ataxia SCA28 and a recessive form of spastic paraplegia, respectively.
Using quantitative RT-PCR, we measured the expression levels of Spg7, Afg3l1, and Afg3l2 in the mouse brain. In all regions Afg3l2 is the most abundant transcript, followed by Spg7, and Afg3l1, with a ratio of approximately 5:3:1 in whole-brain mRNA. Using in-situ hybridization, we showed that Spg7, Afg3l1 and Afg3l2 have a similar cellular pattern of expression, with high levels in mitral cells, Purkinje cells, deep cerebellar nuclei cells, neocortical and hippocampal pyramidal neurons, and brainstem motor neurons. However, in some neuronal types, differences in the level of expression of these genes were present, suggesting distinct degrees of contribution of their proteins.
Neurons involved in SCA28 and hereditary spastic paraplegia display high levels of expression, but similar or even higher expression is also present in other types of neurons, not involved in these diseases, suggesting that the selective cell sensitivity should be attributed to other, still unknown, mechanisms.
Autosomal dominant spinocerebellar ataxias (SCAs) are genetically heterogeneous neurological disorders characterized by cerebellar dysfunction mostly due to Purkinje cell degeneration. Here we show that AFG3L2 mutations cause SCA type 28. Along with paraplegin, which causes recessive spastic paraplegia, AFG3L2 is a component of the conserved m-AAA metalloprotease complex involved in the maintenance of the mitochondrial proteome. We identified heterozygous missense mutations in five unrelated SCA families and found that AFG3L2 is highly and selectively expressed in human cerebellar Purkinje cells. m-AAA-deficient yeast cells expressing human mutated AFG3L2 homocomplex show respiratory deficiency, proteolytic impairment and deficiency of respiratory chain complex IV. Structure homology modeling indicates that the mutations may affect AFG3L2 substrate handling. This work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration.
The m-AAA protease, an ATP-dependent proteolytic complex in the mitochondrial inner membrane, controls protein quality and regulates
ribosome assembly, thus exerting essential housekeeping functions within mitochondria. Mutations in the m-AAA protease subunit paraplegin cause axonal degeneration in hereditary spastic paraplegia (HSP), but the basis for the unexpected
tissue specificity is not understood. Paraplegin assembles with homologous Afg3l2 subunits into hetero-oligomeric complexes
which can substitute for yeast m-AAA proteases, demonstrating functional conservation. The function of a third paralogue, Afg3l1 expressed in mouse, is unknown.
Here, we analyze the assembly of paraplegin into m-AAA complexes and monitor consequences of paraplegin deficiency in HSP fibroblasts and in a mouse model for HSP. Our findings
reveal variability in the assembly of m-AAA proteases in mitochondria in different tissues. Homo-oligomeric Afg3l1 and Afg3l2 complexes and hetero-oligomeric assemblies
of both proteins with paraplegin can be formed. Yeast complementation studies demonstrate the proteolytic activity of these
assemblies. Paraplegin deficiency in HSP does not result in the loss of m-AAA protease activity in brain mitochondria. Rather, homo-oligomeric Afg3l2 complexes accumulate, and these complexes can
substitute for housekeeping functions of paraplegin-containing m-AAA complexes. We therefore propose that the formation of m-AAA proteases with altered substrate specificities leads to axonal degeneration in HSP.
To the Editor:
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory disease of the CNS first described by Pittock et al in 2010 (1). Patients usually present with subacute ataxia, diplopia, and a range of other clinical features related to brainstem involvement. Brain magnetic resonance imaging (MRI) shows “punctate” and/or “curvilinear” gadolinium enhancement peppering the pons and extending variably into the brachium pontis, cerebellum, and adjacent CNS structures. An extensive laboratory, radiologic, and pathologic analysis is essential to exclude other diseases (2). Patients have favorable clinical and radiologic response to steroids requiring chronic immunosuppression (2); otherwise, without a specific treatment, progression seems to be relapsing-remitting (3). Lesion biopsies have revealed perivascular CD4-dominated T-cell or lymphohistiocytic infiltrates and activated microglia, involving predominantly the white matter (2). The pathogenesis and pathophysiology of CLIPPERS are unknown. Herein, we present the first case of CLIPPERS with detailed brain autopsy, expanding the knowledge of its pathologic features.
A 76-year-old woman with a medical history of vascular risk factors (type 2 diabetes, hypertension, dyslipidemia) and no relevant family history developed headache, dizziness, and imbalance, becoming bedridden because of gait instability. This was followed by nausea, vomiting, and finally dysarthria and diplopia for 3 weeks. When first seen, she was alert, with preserved cortical neurologic functions; she had right abducens and left facial nerve pareses and a bilateral static and kinetic cerebellar syndrome, more prominent on the left side. Magnetic resonance imaging of the brain showed T2 hyperintense patchy lesions in the brainstem, more pronounced on the left side, mainly affecting the pons, but also extending to the midbrain (cerebral peduncles, right red nucleus, and superior cerebellar peduncle decussation), medulla oblongata tegmentum, middle and inferior cerebellar peduncles, and cerebellum subcortical white xmatter (Fig. 1A–C). Postcontrast T1-weighted images showed multiple foci …
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) has been described as a clinically and radiologically distinct pontine-predominant encephalomyelitis with a favorable response to high dose corticosteroids and usually requiring chronic immunosuppresive therapy. Brain magnetic resonance imaging (MRI) reveals a characteristic pattern of punctate and curvilinear enhancement lesions in the pons extending variably to surrounding areas. We herein describe such imaging findings in a patient with a definite diagnosis of relapsing-remitting multiple sclerosis (MS).
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disease of the CNS with a predilection for the hindbrain and responsive to immunotherapy. Five further cases are described with detailed pathology and long term evaluation. CLIPPERS does not represent a benign condition, and without chronic immunosuppression the disease may relapse. The radiological distribution is focused not only in the pons but also in the brachium ponti and cerebellum. Pontocerebellar atrophy occurred early, even in cases treated promptly. Significant cognitive impairment was seen in some cases and was associated with additional cerebral atrophy. The pathology included distinctive histiocytic as well as lymphocytic components and evidence of neuro-axonal injury. Additional subclinical systemic findings on investigation were identified. Relapse was associated with withdrawal of corticosteroids, and disability was least marked in cases where both the presentation and relapses were treated promptly. We propose that the title of the syndrome be amended to chronic lymphocytic inflammation with pontocerebellar perivascular enhancement responsive to steroids to more accurately reflect the distribution of the radiological findings.
Friedreich ataxia is the most frequent hereditary ataxia, with an estimated prevalence of 3-4 cases per 100,000 individuals. This autosomal-recessive neurodegenerative disease is characterized by progressive gait and limb ataxia, dysarthria, lower-limb areflexia, decreased vibration sense, muscular weakness in the legs, and a positive extensor plantar response. Non-neurological signs include hypertrophic cardiomyopathy and diabetes mellitus. Symptom onset typically occurs around puberty, and life expectancy is 40-50 years. Friedreich ataxia is usually caused by a large GAA-triplet-repeat expansion within the first intron of the frataxin (FXN) gene. FXN mutations cause deficiencies of the iron-sulfur cluster-containing subunits of the mitochondrial electron transport complexes I, II, and III, and of the iron-sulfur protein aconitase. Mitochondrial dysfunction has been addressed in several open-label, non-placebo-controlled trials, which indicated that treatment with idebenone might ameliorate hypertrophic cardiomyopathy; a well-designed phase II trial suggested concentration-dependent functional improvements in non-wheelchair-bound children and adolescents. Other current experimental approaches address iron-mediated toxicity, or aim to increase FXN expression through the use of erythropoietin and histone deacetylase inhibitors. This Review provides guidelines, from a European perspective, for the diagnosis of Friedreich ataxia, differential diagnosis of ataxias and genetic counseling, and treatment of neurological and non-neurological symptoms.