ABSTRACT
The importance of ovarian teratoma as a cause of opsoclonus myoclonus ataxia syndrome (OMAS) and other paraneoplastic syndromes continues to be underestimated. A strong suspicion and appropriate diagnosis remain keys to successful outcome of paraneoplastic OMAS with ovarian teratoma. We report a 14-year-old girl with paraneoplastic OMAS in association with an ovarian teratoma who improved completely following resection of tumour as well as immunotherapy and review the literature briefly.
KEYWORDS: Opsoclonus, myoclonus, ataxia, teratoma
Introduction
No symptom complex other than ‘opsoclonus myoclonus ataxia syndrome (OMAS)’ attracts more attention of a neurologist due primarily to its dramatic clinical presentation. Still, diagnosis of OMAS is often delayed in clinical practice due to lack of awareness of this distinct entity. Furthermore, mysteries continue to shroud its aetiology, pathogenesis and management. We report a case of OMAS developing in a young girl in association with an ovarian teratoma which resolved following resection of tumour and appropriate immunotherapy and briefly review the literature.
Case report
This 14-year-old girl was apparently normal till 15 days before presenting to our centre when she complained a stretching (pulling) sensation in her neck. Within next two days, her parents noticed her to be fearful and having jerky movements of her body on hearing sounds such as a doorbell ringing. She was noticed to be less coherent and inattentive. There was no history of irritability or alteration of sleep wake cycle. There was no history of memory loss or any other cognitive dysfunction. She was evaluated at another centre for the above complaints and was prescribed clonazepam 0.25 mg twice daily. Over next few days, she developed difficulty in walking along with dropping of objects from her hands. Her parents also noticed her to have involuntary jerky movements of her eyes while reading (video 1). There was no history of any fever, sore throat, diarrhoea or any other illness in the recent past. Personal and family histories were non-contributory. She had not received any vaccination in the recent past. Examination revealed rapid conjugate jerky involuntary eye movements suggestive of opsoclonus. She had prominent startle myoclonus (video 1) along with action myoclonus and gait ataxia. A detailed neurological examination including higher mental functions, systemic and general physical examination was normal. Based on the clinical picture, a diagnosis of OMAS was made and she was evaluated. Routine haematological and biochemical investigations, serum alpha-feto protein (AFP) and human chorionic gonadotropin (HCG) levels, magnetic resonance imaging (MRI) of her brain, cerebrospinal fluid (CSF) and autoimmune antibody profile examination were normal (Table 1). Electroencephalogram revealed diffuse slowing (theta) of background activity without any spikes or sharp waves. Ultrasonography of her abdomen revealed a right ovarian mass with both solid and cystic components suggestive of an ovarian teratoma. Based on the clinical and investigation results, a final diagnosis of ovarian teratoma with paraneoplastic OMAS was made. She underwent right-sided salpingo-oophorectomy with excision of the ovarian mass under general anaesthesia. Histology revealed an immature teratoma grade 2. Post-operatively, she was administered intravenous immunoglobulin (IVIG) 2 g/Kg body weight along with intravenous methyl prednisolone 1 g daily for 5 days, following which she started improving. Due to the immature teratoma, she also received six cycles of chemotherapy (bleomycin, etoposide and cisplatin) at intervals of 21 days. She subsequently received IVIG at a dose of 0.8 g/Kg at six weekly intervals for another three pulses. She recovered completely and has been under observation since then. She is undergoing AFP and beta HCG levels every six months which are normal (AFP: 1.6 ng/ml; HCG: 0.6 mIU/ml). Currently at two years follow up, she is asymptomatic (video 2) and pursuing her studies.
Table 1.
Investigational profile of patient.
| Investigation | Result |
|---|---|
| Haemoglobin | 11.4 g/dl |
| Total leucocyte count | 7700/cu mm |
| Platelet count | 187,000/cu mm |
| Erythrocyte sedimentation rate | 22 mm/1st hour |
| C reactive protein | 3 mg/L |
| Random blood sugar | 87 mg/dl |
| Blood urea | 22 mg/dl |
| Serum creatinine | 0.6 mg/dl |
| Serum bilirubin | 0.5 mg/dl |
| SGOT/SGPT | 24/27 IU/ml |
| Alkaline phosphate | 139 IU/ml |
| Serum albumin | 4.5 g/dl |
| Serum gamma globulin | 2.7 g/dl |
| Serum calcium/phosphorus | 9.3/2.7 mg/dl |
| Serum Alpha-feto protein | 2.6 ng/ml |
| Serum human chorionic gonadotropin | 0.8 mIU/ml |
| Gadolinium enhanced magnetic resonance imaging of brain | Normal |
| Electroencephalogram | Diffuse theta slowing |
| Cerebrospinal fluid (CSF) examination Cells Glucose Protein NMDA antibodies |
Nil 63 mg/dl 36 mg/dl Not detected |
| Autoantibody profile (anti Hu, anti-Ri, Anti Yo, Anti CV-2, Anti Ma1 and Ma2; antibodies against glutamate NMDA receptor, Glutamate AMPA1 and AMP2 receptors, contactin-associated protein 2 (CASPER2) and LGI- 1 (leucine-rich glioma inactivated protein 1) | Negative |
Discussion
OMAS is characterized by (a) opsoclonus (conjugate, chaotic, rapid, jerky, involuntary eye movements), (b) myoclonus (sudden jerky movements of limbs and axial musculature) and (c) ataxia in varying combinations and severity.1–3 Though opsoclonus was initially thought to reflect damage to omnipause cells situated in nucleus raphe interpositus in the pons, this nucleus is normal in autopsy studies.4 More recently, functional MRI studies have shown increased activity in the fastigial nuclei of the cerebellum, and disinhibition of these nuclei is believed to be responsible for opsoclonus.5
OMAS is currently thought to be an autoimmunedisease based on (a) the presence of autoantibodies (anti-Hu, anti-Ri, anti-Yo, anti Ma1, anti-Ta, anti CRMP-5) directed against neuronal surface antigens in serum and CSF of patients with OMAS, (b) an association with other autoimmune disorders and (c) a good response to immunotherapies including IVIG, steroids and other forms of immunosuppressive treatment. Recently, a role for cell-mediated immunity has also been suggested based on (a) the presence of increased percentage of CD19 B cells and decreased percentage of CD4 T cells in CSF of children with OMAS as well as (b) a good clinical response to rituximab, a monoclonal antibody directed against CD-20.6
Aetiologically, OMAS can be divided into two broad groups: nonparaneoplastic and paraneoplastic. The nonparaneoplastic causes include toxic (e.g. drugs such as lithium), metabolic and para- or postinfectious causes. In a large series of adult patients with OMAS (n = 114)3, 39% (n = 45) of all patients had paraneoplastic OMAS. The commonest neoplasm was lung cancer (n = 19), followed by breast cancer (n = 10), ovarian teratoma (n = 8), stomach cancer (n = 1), testicular seminoma (n = 1), thymoma (n = 1), renal cancer (n = 1) and oropharyngeal cancer (n = 1). The commonest autoantibodies known to be associated with cancer include anti-Ri, anti Ma2 and anti CRMP5. Other autoantibodies detected in OMAS include antibodies against gylcine receptors, NMDA receptors, GABA2 receptors and DPPX. Based on their observations, they suggested that ovarian teratoma is the most common cause of paraneoplastic OMAS below the age of 40 years and that periodic or aggressive testing for occult malignancy (other than teratoma) may be unnecessary in this subgroup of patients.3 For patients older than 40 years, a thorough and repeated screening should be done for lung, breast and ovarian tumours. The detailed evaluation of patients with suspected OMAS which is done in our institute is given in Table 2.
Table 2.
Work up for suspected paraneoplastic syndromes including opsoclonus myoclonus syndrome in our institute.
| 1. Complete Haematology: Haemoglobin, total and differential leucocyte counts, platelet counts, erythrocyte sedimentation rate, C reactive protein |
| 2. Complete Biochemistry: Renal, liver and thyroid function tests; serum calcium and phosphorus, serum sodium and potassium |
| 3. Antinuclear antibodies, anti-neutrophilic cytoplasmic antibodies (c and p ANCA), anti Ro and La antibodies, anti-double stranded antibodies and Smith antigen. |
| 4. Serum angiotensin converting enzyme levels |
| 5. Whole body fluoro deoxyglucose positron emission tomography (FDG-PET) scan |
| 6. Cerebrospinal fluid examination including cell count, biochemistry and cytospin for malignant cells, etc. |
| 7. Magnetic resonance imaging of brain with gadolinium |
| 8. Electroencephalogram |
| 9. Evoked potentials (whenever required) |
| 10. Serum and CSF autoantibody profile (Anti Hu, Anti Ri, Anti Yo, Anti CV-2, Anti Ma2 and Ma1, PCA-2, Anti-Tr, Anti NMDA receptor antibody, Antibodies against glutamate receptor AMPA1 and AMPA2; Antibodies against voltage gated potassium channels) |
Immature ovarian teratomas constitute approximately 20% of all germ cell tumours with neuroepithelial elements being the most easily recognizable component. Common paraneoplastic syndromes associated with ovarian teratomas include limbic encephalitis, tenosynovitis, arthritis, OMAS and haemolytic anaemia.7–11 The management of immature teratomas includes complete tumoural resection followed by chemotherapy with bleomycin, etoposide and cisplatin every 3 weeks for 3–4 cycles.7 Serum AFP and β-HCG can be used to monitor the recurrence along with abdominal imaging.7 Our patient received the above-mentioned treatment and does not have any evidence of recurrence or residual disease at two year follow-up.
Management of paraneoplastic OMAS includes immunosuppression. The various options include plasma exchange, IVIG, rituximab, steroids and alternate immunosuppressant agents. The choice degree and duration of immunosuppressive regimen is dictated by severity of illness, affordability of the patient and whether the tumour can be treated or not. For patients who are able to bear the cost of treatment, standard treatment followed in our institute for OMAS (where tumour can be successfully removed) includes pulse IVIG 2 g/Kg initial dose followed by 0.8 g/kg pulses at 6–12 weekly intervals depending upon the clinical status of the patient. We continue pulses of IVIG until the patient recovers completely. For more seriously ill patients, we use rituximab in standard doses (500 mg IV weekly doses for 4 weeks). In this patient, we used IVIG pulses for 3 months with good response. The duration of treatment is longer in paraneoplastic OMAS patients when the underlying tumour cannot be completely resected or when the tumour cannot be detected.3,6,8
To conclude, ovarian teratoma constitutes an important cause of paraneoplastic OMAS. Early diagnosis followed by treatment of the tumour and immunotherapy form the cornerstone of proper management and good outcome in these patients.
Funding Statement
We did not receive any funding for the study.
Declaration of interest statement
The authors declare they do not have any conflicts of interest.
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