Patient 20 at initial presentation (Colorado Neurological Institute Movement Disorders Center) and after treatment with immunotherapy (6 weeks of immunotherapy with intravenous immunoglobulin and corticosteroids combined).
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Klaas JP, Ahlskog JE, Pittock SJ, et al. Adult-Onset Opsoclonus-Myoclonus Syndrome. Arch Neurol. 2012;69(12):1598–1607. doi:10.1001/archneurol.2012.1173
Author Affiliations: Departments of Neurology (Drs Klaas, Ahlskog, Pittock, Matsumoto, Aksamit, Bartleson, McEvoy, and McKeon) and Laboratory Medicine and Pathology (Drs Pittock and McKeon), Mayo Clinic College of Medicine, Rochester, Minnesota; and Colorado Neurological Institute Movement Disorders Center, Englewood (Dr Kumar).
Background Little is known about adult-onset opsoclonus-myoclonus syndrome (OMS) outside of individual case reports.
Objective To describe adult-onset OMS.
Design Review of medical records (January 1, 1990, through December 31, 2011), prospective telephone surveillance, and literature review (January 1, 1967, through December 31, 2011).
Setting Department of Neurology, Mayo Clinic, Rochester, Minnesota.
Patients Twenty-one Mayo Clinic patients and 116 previously reported patients with adult-onset OMS.
Main Outcome Measures Clinical course and longitudinal outcomes.
Results The median age at onset of the 21 OMS patients at the Mayo Clinic was 47 years (range, 27-78 years); 11 were women. Symptoms reported at the first visit included dizziness, 14 patients; balance difficulties, 14; nausea and/or vomiting, 10; vision abnormalities, 6; tremor/tremulousness, 4; and altered speech, 2. Myoclonus distribution was extremities, 15 patients; craniocervical, 8; and trunk, 4. Cancer was detected in 3 patients (breast adenocarcinoma, 2; and small cell lung carcinoma, 1); a parainfectious cause was assumed in the remainder of the patients. Follow-up of 1 month or more was available for 19 patients (median, 43 months; range, 1-187 months). Treatment (median, 6 weeks) consisted of immunotherapy and symptomatic therapy in 16 patients, immunotherapy alone for 2, and clonazepam alone for 1. Of these 19 patients, OMS remitted in 13 and improved in 3; 3 patients died (neurologic decline, 1; cancer, 1; and myocardial infarction, 1). The cause of death was of paraneoplastic origin in 60 of 116 literature review patients, with the most common carcinomas being lung (33 patients) and breast (7); the most common antibody was antineuronal nuclear antibody type 2 (anti-Ri, 15). Other causes were idiopathic in origin, 38 patients; parainfectious, 15 (human immunodeficiency virus, 7); toxic/metabolic, 2; and other autoimmune, 1. Both patients with N -methyl-D-aspartate receptor antibody had encephalopathy. Improvements were attributed to immunotherapy alone in 22 of 28 treated patients.
Conclusions Adult-onset OMS is rare. Paraneoplastic and parainfectious causes (particularly human immunodeficiency virus) should be considered. Complete remission achieved with immunotherapy is the most common outcome.
Opsoclonus-myoclonus syndrome (OMS) is well described in children (also known as Kinsbourne syndrome1), usually occurring as a paraneoplastic neurologic accompaniment of neuroblastoma1,2 with long-term neurologic, behavioral, and developmental sequelae.3,4 The OMS literature on adults is largely confined to cases and small case series. Most clinicians know that a paraneoplastic cause should be considered (eg, antineuronal nuclear antibody type 2 [ANNA-2; anti-Ri] and accompanying breast adenocarcinoma or small cell carcinoma are well known5,6). However, there are few collated data to inform physicians about which common and uncommon causes should be considered, the clinical course, and outcomes from treatment.7 We describe OMS in adults consecutively evaluated at Mayo Clinic, Rochester, Minnesota, during a 21-year period and prospectively evaluated for longitudinal outcomes. We also evaluated the 40-year cumulative literature on adult-onset OMS.
We conducted a medical record review, follow-up telephone interview, and serologic evaluation of patients with adult-onset OMS (age at onset, ≥18 years and initial examination findings predominated by opsoclonus and myoclonus) seen at the Mayo Clinic, Rochester, from 1990 to 2011. The study was approved by the Mayo Clinic Institutional Review Board (10-007942).
The Mayo Clinic medical records linkage system was retrospectively queried using the terms opsoclonus and Kinsbourne syndrome to identify adult patients who received a diagnosis of OMS at the Mayo Clinic between 1990 and 2011.
Medical records for 91 patients were reviewed by 2 of the authors (J.P.K. and A.M.). We included patients with simultaneous onset of opsoclonus and myoclonus at or after age 18 years, with OMS being the predominant clinical presentation. Seventy patients were excluded: 37 pediatric patients with symptoms persisting into adulthood, 23 patients determined to have final neurologic diagnoses other than OMS, 3 patients with only opsoclonus identified on examination, 2 patients with only myoclonus identified on examination, 4 patients for whom not enough data were available, and 1 patient with opsoclonus and myoclonus observed as part of a more widespread encephalitic disorder. The latter patient's case has been published8 and is included in the current literature review.
In addition to documenting clinical information from the medical records, we attempted to contact all 21 included patients by telephone for additional longitudinal information regarding the clinical course of the disease. For patients who had died, additional information regarding the cause of death was obtained by review of the death certificate, when available.
For each patient, a serum sample was evaluated, as previously described, by (1) standardized immunofluorescence criteria for IgG neural autoantibodies (ANNA-1 [also known as anti-Hu], -2, -3; amphiphysin antibody, Purkinje cell cytoplasmic antibody [PCA] type 1 [also known as anti-Yo], -2, and Tr antibodies; collapsin-response mediator-protein [CRMP] 5 IgG, antiglial/neuronal nuclear antibody [AGNA-1], N -methyl-D-aspartate [NMDA] receptor antibody, γ-aminobutyric acid B [GABA-B] receptor antibody, and α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate [AMPA] receptor antibody); (2) by radioimmunoprecipitation assays for antibodies targeting neuronal voltage-gated cation channels (neuronal voltage-gated potassium channel [VGKC] complex, calcium channels [P/Q-type and N-type], muscle [α1] and neuronal [α3] ganglionic nicotinic acetylcholine receptors) and glutamic acid decarboxylase 65-isoform (GAD65); (3) by human embryonic kidney transfected cell-binding assays for antibodies targeting NMDA, AMPA, and GABA-B receptors and VGKC complex proteins (disintegrin and metalloproteinase 22 [ADAM22] and a soluble binding partner of ADAM22, leucine-rich, glioma-inactivated 1 [LGI1] protein) (Euroimmun); and (4) by recombinant Western blot analysis for CRMP-5-IgG.9-16
We searched PubMed using the terms opsoclonus and myoclonus to identify case reports and case series reporting on patients aged 18 years or older with OMS or who had opsoclonus and myoclonus as part of a more widespread disorder. We included all English-language publications identified between 1967 and 2011 with complete descriptions of individual patients.
We identified 21 Mayo Clinic patients (11 women and 10 men) with adult-onset OMS who met the inclusion criteria. Median follow-up was 43 months (range, 1-187 months). The median age at symptom onset was 47 years (range, 27-78 years).
A flulike prodrome before neurologic symptom onset was reported by 6 patients. The initial neurologic symptoms included dizziness, 14 patients (67%); balance difficulties (caused by myoclonus), 14 (67%); nausea and/or vomiting, 10 (48%); vision abnormalities (caused by opsoclonus), 6 (28%); tremor/tremulousness, 4 (19%); and altered speech (caused by myoclonus), 2 (10%). Symptoms progressed rapidly, and most patients were seen by a neurologist within a median of 4 weeks after symptom onset. Levels of mobility at nadir for 18 patients were wheelchair or 2-person assistance needed to mobilize, 10 patients; gait unsteadiness but able to walk independently, 6; and cane required to walk independently, 2. Other symptoms that developed included weight loss (>4.5 kg), 10 patients; mood changes, 9 (depression, 5; irritability/emotional lability, 4); dysphagia, 3 (resulting from myoclonus or nausea/vomiting); fatigue/sleep disturbance, 3; headache, 1; and falls, 1.
All 21 patients were examined by a Mayo Clinic staff neurologist. Myoclonus (sudden, brief, shock-like, involuntary movements) was identified on clinical examination in all 21 patients (Table 1). Opsoclonus, being the ocular manifestation of myoclonus, was present in all patients. The myoclonus was typically posture- or movement-induced (action myoclonus), including 3 patients with lower extremity myoclonus that was present or worse on standing, which caused unsteadiness, tremulousness, and falls. Anatomic distribution of myoclonus on examination was extremities, 15 patients (upper and lower, 13; upper only, 1; and lower only, 1); craniocervical, 8 (hyperkinetic dysarthria, 5; and head, 3); and trunk, 4. Additional neurologic findings were reported in 3 patients as brisk, deep tendon reflexes.
Findings from magnetic resonance imaging, performed in 20 patients, were unremarkable in all but 1 patient with small-cell lung carcinoma who had metastatic lesions in both cerebellar hemispheres and in the right caudate nucleus (patient 7). Cerebrospinal fluid (CSF) analysis was available for 18 patients (86%) (Table 1) and revealed elevated protein (>45 mg/dL) in 11 patients (median, 64 mg/dL; range, 47-137 mg/dL), elevated white blood cell count (>5/μL) in 9 patients (median, 20/μL; range, 8-94/μL; all lymphocyte predominant), elevated IgG index (>0.85) in 4 patients (median, 1.14; range, 0.88-1.64), and CSF-exclusive oligoclonal bands (>3) in 5 patients (median, 5; range, 4-8).
Results of paraneoplastic antibody evaluations in serum (all patients) and CSF (12 patients) were negative. Evidence for a parainfectious source was sought in all but 3 patients (2 had a paraneoplastic cause established early in the workup). Infections for which testing was performed in 18 patients (serum, 13; CSF, 13) included Epstein-Barr virus, 13 patients; cytomegalovirus, 11; rickettsial infection, 8; mycoplasma, 5, Whipple disease, 4; herpes simplex virus, 4; varicella zoster virus, 4; and human immunodeficiency virus (HIV), 3. All results were negative. All 21 patients underwent evaluations for occult cancer, and carcinoma was documented in 3 (breast adenocarcinoma, 2; and small cell lung carcinoma, 1) (Table 1). Of the 3 patients with carcinoma, patients 7 and 10 had cancer discovered after onset of OMS and patient 2 had breast cancer diagnosis and treatment 4 years before the onset of OMS; oncologic evaluations undertaken at the time of the development of OMS did not reveal cancer recurrence, and patient 2 had remained cancer free for 9 years at the final follow-up.
Although outcomes were clearly documented, the benefits of individual treatments were usually difficult to assess because a combination of therapies was used simultaneously in all but 3 patients. Those 3 patients (2, 4, and 10) who received monotherapy (immunotherapy, 2 patients; and clonazepam, 1) improved. Final outcomes were remission, 13 patients; improvement, 3; and death, 3 (caused by neurologic decline, 1; cancer, 1; and myocardial infarction, 1). Patient 10 was symptomatic for 32 weeks before treatment and improved but required a walker to ambulate and had residual dysarthria.
We identified 116 patients reported in 66 publications5-8,17-78 (Table 3). The median age at symptom onset was 50 years (range, 19-80 years); 70 patients (60%) were women.
Opsoclonus-myoclonus syndrome was present in isolation in 83 patients and accompanied another neurologic or neuropsychiatric disorder in 33 patients. Coexisting disorders were mild behavioral, cognitive, and/or mood changes, 18 patients; encephalopathy, 9; cranial nerve palsies, 4; Lambert-Eaton myasthenic syndrome and ataxia, 1; and seizure disorder, 1. The 2 patients with NMDA receptor antibody had initial symptoms of prominent behavioral and/or mood change followed by encephalopathy, with opsoclonus and myoclonus additionally observed. The causes reported were paraneoplastic, 60 patients (breast and lung cancers were the most common; ANNA-2 was the most common paraneoplastic antibody detected); none identified, 38 (occurred during pregnancy in 2 women); proven parainfectious, 15 (including 7 with HIV infection); other autoimmune, 1 (GAD65 antibody seropositive); hyperosmolar nonketotic diabetic coma, 1; and cocaine ingestion, 1.
Outcome information was available for 115 patients (Table 3). For 41 patients, reported outcomes for a single treatment type (immunotherapy, oncologic therapy, symptomatic therapy, or other therapy) could be interpreted. Improvements were attributed to immunotherapy alone in 22 of 28 patients treated; median duration of treatment was 6 weeks (range, 1-112 weeks). These treatments were corticosteroids, 8 patients; IVIG, 6; corticosteroids and IVIG, 4; corticosteroids and plasmapheresis, 1; and other combinations, 3. Improvements were attributed to oncologic therapy in all 10 treated patients (≥1 of surgery, chemotherapy, and radiotherapy); symptomatic therapy in 8 of 9 patients treated (benzodiazepines alone, 7; benzodiazepines with valproic acid, 1); ceftriaxone sodium, 2 (both patients had neuroborreliosis and improved); combination antiretroviral therapy (neurologic symptoms in 1 HIV-positive patient resolved); and insulin, 1 (resolved on treatment of diabetic coma). Fifty-three other patients received combinations of 1 or more of the treatment types listed. Of the 21 remaining patients who received no treatment, 18 were reported to have spontaneous remission (15 patients) or improvement (3).
This study represents a large single-institution case series of consecutively evaluated patients with adult-onset OMS. We observed that many patients had an idiopathic (presumed parainfectious) disorder of short duration, with full recovery after 4 to 6 weeks of treatment, usually immunotherapy and clonazepam combined. Nonetheless, in the Mayo Clinic patients, cancer was an important cause (14%), and a few patients also had a relapsing course or a poor outcome. Findings from CSF analysis helped to confirm an autoimmune cause, but neural autoantibodies (including paraneoplastic antibodies) were not detected in any of our patients despite comprehensive serologic evaluations. Paraneoplastic autoantibody detection was similarly uncommon (2 of 24 patients with opsoclonus or OMS) in a multi-institutional Spanish study.7 Our interpretation of individual treatments (immunotherapeutic vs symptomatic) was limited because most patients received both immunologic and symptomatic therapies simultaneously. We expanded on our data with a systematic review of the literature. Several patients reported in the literature7 had mild coexisting neurologic or neuropsychiatric symptoms, but outright encephalopathy was uncommon except in paraneoplastic cases. It was informative that both patients with NMDA receptor antibodies had coexisting neuropsychiatric symptoms followed by encephalopathy.8,71
Among both the Mayo Clinic patients and those reported in the literature, lung and breast carcinomas were the most common cancers identified, and ANNA-2 was the most commonly reported paraneoplastic antibody.5-7,36,40,45,48,50,61,62 The diversity of reported paraneoplastic autoantibodies, including those with specificity for other neuronal nuclear antigens,7,35 neuronal calcium channels,69,77 and NMDA receptors,8,71 serves to emphasize the importance of comprehensive paraneoplastic serologic evaluations (rather than syndrome-specific physician-selected antibody testing) in these patients. Rarer oncologic associations that merit exclusion include melanoma41,53,55 and neoplasms of the gynecologic,34,37,40,42,55,70 urologic,6,43 hematologic,51 and gastrointestinal systems.7
Comparison of paraneoplastic and idiopathic cases was not possible within our own cohort given the low number of patients with cancer. Bataller et al7 reported that older age, higher frequency of encephalopathy, and a more severe clinical course are more common among paraneoplastic cases. Patients from our cohort were similar in age and sex profile as well as clinical presentation to patients reported in the literature. In contrast, the proportion of patients in the collated literature with an established cause (62%) was much higher than in our series. Since individual reported cases usually have rare or unique characteristics prompting description, this higher proportion of paraneoplastic cases in the literature compared with our clinical practice may represent a reporting bias. Other myoclonic presentations that ought to be recognized as possibly paraneoplastic include opsoclonus only,30 progressive encephalomyelitis with rigidity and myoclonus,79 and isolated generalized small-amplitude limb and axial myoclonus.80 This latter group has myoclonus but no opsoclonus as an additional diagnostic clue; these patients report only tremulousness and therefore may receive a misdiagnosis of tremor, and frequently have a paraneoplastic disorder.
Most patients in our cohort with an idiopathic diagnosis were assumed to have a parainfectious autoimmune cause of OMS, based on the self-limited symptoms, CSF findings, absence of cancer or paraneoplastic antibody, and response to immunotherapy; none had a specific cause identified. The findings from the literature review reinforce the importance of thorough evaluations for a parainfectious cause, including HIV.65,66,74 Opsoclonus-myoclonus syndrome may develop during the HIV seroconversion illness66,74 or during immune reconstitution after initiation of antiretroviral therapy.74 The cause of OMS in HIV is probably autoimmune, since autoimmunity is common in HIV-positive patients, and OMS is also responsive to corticosteroid therapy in this context.65 For other infectious causes, successful treatments have included corticosteroids and/or IVIG alone combined with antimicrobial therapy, when appropriate.30,44,52,56,58,68,78 Other infectious causes reported in patients with opsoclonus but without myoclonus include psittacosis, salmonella, St Louis encephalitis, and Rickettsia conorii.30
Rare nonparaneoplastic, nonparainfectious autoimmune cases have been reported, including a patient with GAD65 antibody.59 Another unusual reported entity is OMS developing during pregnancy, which is assumed (like chorea gravidarum81,82) to have an autoimmune cause and is similarly responsive to immunotherapy.49
Most Mayo Clinic patients were very responsive to treatment. Almost all patients received short-term immunotherapy in combination with symptomatic therapy and did not experience relapse on discontinuing therapy. Few required further immunotherapy for longer periods to maintain remission. The literature review clarified the benefits of immunotherapy; we were able to determine that 79% of patients who received only immunotherapies achieved remission or improvement regardless of the cause of OMS. Cancer was identified in some of these patients, and cancer-specific treatments (surgery, chemotherapy, and radiation) were effective either alone or in combination with other therapies.6,7,31,32,37,42,48,50,75,77 The benefits of chemotherapy probably stem from the elimination of cancer but also the immunosuppressant effects of those drugs. Although the prognosis with OMS is worse among paraneoplastic cases than among idiopathic cases,7 long-term survival is possible for some patients.63
It was somewhat informative to find that spontaneous remissions may occur; however, because the consequences of OMS may be profound, we do not advocate a wait-and-see approach. A practical treatment guide based on our experience and that of others could include an initial short course of either intravenous methylprednisolone acetate or IVIG, administered daily for 3 to 5 days, followed by weekly treatments for 6 weeks. Combination immunotherapy and plasma exchange could be reserved for patients whose condition is refractory to IVIG or corticosteroid monotherapy. Patients could be observed for signs of relapse once therapy is completed, before considering further treatment. The rare patient requiring longer treatment may benefit from a corticosteroid/IVIG-sparing immunosuppressant, such as mycophenolate mofetil or azathioprine. As illustrated by patient 10 (diagnosis and treatment after 32 weeks of symptoms and only partial recovery) and by the pediatric literature,83,84 early initiation of immunotherapy appears to be important to ensure an optimal neurologic outcome.
Symptomatic therapy was almost universally used among the Mayo Clinic cohort, usually as an adjunct to immunotherapy, but may be effective as monotherapy in mild cases of OMS.33,39,65,66,74 Effective reported therapies include benzodiazepines,54 gabapentin,42,85 valproic acid25,30,33,43,46,53,59,70 and levetiracetam.70,80
Correspondence: Andrew McKeon, MD, Department of Laboratory Medicine and Pathology, Hilton 3-78, Mayo Clinic, 200 First St SW, Rochester, MN 55906 (email@example.com).
Accepted for Publication: April 4, 2012.
Published Online: September 17, 2012. doi:10.1001/archneurol.2012.1173
Author Contributions:Study concept and design: Klaas and McKeon. Acquisition of data: Klaas, Matsumoto, Aksamit, Kumar, McEvoy, and McKeon. Analysis and interpretation of data: Klaas, Ahlskog, Pittock, Aksamit, Bartleson, and McKeon. Drafting of the manuscript: Klaas and McKeon. Critical revision of the manuscript for important intellectual content: Klaas, Ahlskog, Pittock, Matsumoto, Aksamit, Bartleson, Kumar, and McEvoy. Administrative, technical, and material support: Bartleson and Kumar. Study supervision: Aksamit and McKeon.
Conflict of Interest Disclosures: None reported.