MC Lau, CK Chow, CK Ma

Abstract

Opsoclonus-myoclonus syndrome (OMS) is one of the differential diagnoses in acute cerebellar ataxia. This is caused by a paraneoplastic antibody, which irreversible damages the nervous system. It typically causes the triad of opsoclonus, ataxia and myoclonus. Our paper reports the case of an 8-year-old child with OMS correlated with a ganglioneuroblastoma. She presented with a subtle neurological symptom, cerebellar ataxia. Her symptoms then evolved into myoclonus and, later, urinary incontinence. She was given steroids, intravenous immunoglobulin and rituximab with clinical improvement, although there was some residual neurological deficit. This demonstrates that early recognition with aggressive treatment of OMS is necessary to prevent permanent damage to the neurological system.

Introduction

Opsoclonus-myoclonus syndrome (OMS), also known as dancing eye syndrome, is one of the differential diagnoses of acute cerebellar ataxia. OMS was first described by Dr Marcel Kinsbourne in 1962.¹ It is associated with paraneoplastic antibodies produced by neural crest tumours such as neuroblastoma and ganglioneuroblastoma. These autoantibodies target cerebellar tissue, leading to the clinical triad of opsoclonus, ataxia and myoclonus. Our case presents a paediatric OMS patient who had cerebellar ataxia. She gradually deteriorated and developed urinary incontinence and myoclonus. She was subsequently found to have a ganglioneuroblastoma. This illustrates the importance of judiciously searching for tumours, early diagnosis and treatment.

Case Presentation

An 8-year-old girl with a history of poor weight gain and speech delay and was referred to the speech therapist and the child assessment centre (CAC) at 2 years old. At that time of assessment by the CAC, she was found to be delayed by 6 to 9 months. She did make optimal progress after training in the early education and training centre (EETC). Hence, no thorough investigations were performed until the admission for cerebellar ataxia.

She presented at the age of four with unsteady gait and frequent falling. Her only symptom was vomiting, with no other prodromal symptoms such as coryzal symptoms, skin rash, fever or recent vaccination. There was no family history of neurological disease or parental consanguinity.

Physical examination did not find any dysmorphic signs. However, she was noted to have cerebellar signs, including a wide-based gait, intentional tremor, and past-pointing, but no nystagmus or opsoclonus. The sepsis screen, abdominal X-ray, computed tomography (CT) and magnetic resonance imaging (MRI) of the brain were all normal. The lumbar puncture was traumatic but showed no significant increase in white cell count. The plasma amino acid profile, copper, ceruloplasmin, urine organic acid, reducing sugar, and toxicology were all normal. The initial presumptive diagnosis was parainfectious cerebellar ataxia because of the acute presentation. Differential diagnoses such as a brain tumour, cerebellar abscess and poisoning were ruled out. Intravenous immunoglobulin (IVIG) was initially suggested but was declined by the parents.

However, her cerebellar symptoms fluctuated. The cerebellar symptoms transiently improved, but she had residual cerebellar signs. There were three episodes of repeated deterioration between the ages of five and six, all unrelated to infection, but the degrees of deterioration were similar. Her condition never returned to the baseline. At her best moments, she could walk independently for a short distance with an unsteady gait. When walking outdoors or using the stairs, she required assistance from adults. At her worst, she could not walk at all, and her intentional tremor worsened. Other aspects of development were also delayed.

Regarding her fine motor skills, she could write the alphabets and numbers. However, she could not button up her clothing. She fed herself with a spoon slowly and messily. She spoke with scanning speech in short phrases. Subsequently, she was diagnosed with limited intelligence.

At 6 years old, she evolved to have more neurological symptoms. Urge incontinence was noted despite being toilet-trained for many years. Irregular, brief myoclonus, without impairment of consciousness, was also found, lasting from a few seconds to a minute. It could occur for more than 5 times per day, in both daytime and sleep. There were no triggering factors noticed by the caregiver.

Electroencephalography (EEG) showed a normal background without epileptiform discharge. The myoclonus movements were captured but were not associated with electrographic changes. Slow saccade of her eyes and opsoclonus were noted. She also suffered from difficulty falling asleep. There was a difficulty to express her wants, resulting in frequent crying.

In view of the new symptoms, MRI brain and spine scans were performed, which found a fusiform lesion situated anterior to the left side of her L5/S1 vertebrae. The mass measured around 3.8 cm x 1.6 cm in size. It was already noticed in a CT of the abdomen and pelvis (for the workup of her frequent vomiting and abdominal pain) when she was 4 years old, and the size remained similar at the age of 6.

The radiologist initially diagnosed the mass to be a lymph node at the left iliac region just medial to the left psoas muscle and anterior to the spine at the level of bifurcation of left common iliac vessel. Dedicated interval USG did not show an increment in size. Until the dedicated MRI in 6 years old (Figure 1), it was finally determined to be a neuroma which showed contrast enhancement.

Metaiodobenzylguanidine (MIBG) scan (Figure 1) showed a subtle increase in uptake in the lesion. An anti-neuronal antibody panel found anti-Hu antibodies, while anti-Yo and anti-Ri were negative. Elevated adrenaline/creatinine (26 nmol/mmol Cr; Normal <15) and noradrenaline/creatinine ratio (159 nmol/mmol Cr; Normal <60) were detected in the urine sample. Based on the symptoms, imaging findings, and biochemical results, she was diagnosed with a neurogenic tumour leading to opsoclonus-myoclonus syndrome.

Figure 1 MRI and MIBG scan images for the patient.

Bone marrow biopsy was performed but displayed no tumour infiltrate. Even with the resection of the tumour, there would be an ongoing production of the paraneoplastic antibodies.² Before the resection, she was put on oral prednisolone (2 mg/Kg/day BD) and IVIG (monthly 1 gm/kg/dose) based on the literature suggestion.¹ Steroids could suppress B lymphocytes from producing antibodies, while IVIG helped to reduce the dose of steroids required significantly. After 2 months of treatment, she showed good neurological improvement. She spoke more fluently and could walk independently, and there were fewer myoclonic jerks while asleep, although other cerebellar signs, such as past-pointing, persisted. Tumour excision was eventually done, and the histology showed a stroma-rich, intermixed-type ganglioneuroblastoma. Given the improvement, the steroids were gradually tapered off. However, her clinical condition relapsed after stopping steroids/IVIG. Therefore, they were resumed, and rituximab and cyclophosphamide were added, aiming at steroid-sparing in the long run.

Cognitively, the patient still suffered from limited intelligence. On the re-assessment by the CAC, she was found to have a delay by 2-3 years when compared to her chronological age. Together with her other disabilities, she needed to attend Primary 4 at the special school at the age of 12 (repeated class due to her medical problems). Currently, she still had a delay for around 2-3 years according to the physiotherapists' and occupational therapists' assessments.

At present, she no longer had myoclonus or opsoclonus. There were greatly minimised cerebellar signs as well, although she could not manage some tasks that had high demand for coordination, e.g. jumping rope. She could write, walk sideway or straight but would be clumsy when walking upstair/downstair. She could manage to cope with usual tasks in daily living for herself such as bathing/hair-washing/toileting with mild assistance.

Discussion

Opsoclonus-myoclonus syndrome, as its name suggests, consists of a triad of opsoclonus, myoclonus, and ataxia. Opsoclonus means a random chaotic eye movement that is different from nystagmus. It is characterised by rapid, conjugate, non-phasic eye movement that occurs in all directions, or even diagonally. Myoclonus is a short, involuntary twitching of a muscle with no regular rhythm. It could be aggravated by action. Fine motor activities could be intervened. Truncal and appendicular ataxia is another salient feature of OMS.²

The worldwide incidence is around 1 in 1,000,000 people. It usually occurs in young children, ranging from 1 to 4 years,³ following a bell-shaped distribution with the median age of 1.5 years. Infection could be one of the triggers in older children. There is a slight female predominance. It is not an inheritable disease. But there is a higher incidence of autoimmune disorders in the family, which suggested genetic susceptibility to other autoimmune conditions.⁴

Prodromal symptoms include coryzal symptoms, vomiting, fever, etc. Like our case, significant vomiting and ataxia could be the only symptom in the early phase of the disease. These symptoms could occur acutely and get worse in days to weeks. Unlike acute cerebellar ataxia, the symptoms would relapse with minor illness or stress from time to time.¹ Another difference is the association with marked irritability, sleep disturbance, and cognitive impairment like the regression of speech (especially expressive). Some patients develop obsessive-compulsive disorder (OCD) or attention-deficit/hyperactivity disorder (ADHD).² Imaging showing neuroblastoma and the presence of anti-neuronal antibody also point towards OMS.

Neuroblastoma is a type of neural crest tumour. Other subtypes include ganglioneuroblastoma, ganglioneuroma. It is an embryonal malignancy of the sympathetic nervous system arising from neuroblasts. Around 50% of OMS patients have one of these tumours. However, only a few percent of patients with neuroblastoma develop OMS.⁴ The demographics and clinical characteristics are similar between neuroblastoma and ganglioneuroblastoma, although the aggressiveness of each tumour differs.⁵ Similar to our case, ganglioneuroblastomas are relatively benign but could lead to poor neurological outcomes, when compared to neuroblastoma.^6,7

Since some tumours are too small or minimally biologically active, they may not secrete catecholamines at a high enough rate to produce abnormal urine catecholamine levels or take up tracers for MIBG scans. Even without detectable tumours, one should have regular imaging surveillance such as 6 months. CT/MRI from neck to pelvis is more sensitive to detect these tumours.⁸

OMS-associated neuroblastomas usually have a better differentiation and lower stages than neuroblastomas without OMS. Hence patients have a better prognosis in terms of the tumour itself. The tumour causes OMS due to mimicry-driven autoimmune processes.⁴ There are similarities between antigens among different pathogens, neuroblastoma, and body tissues (Figure 2). The neuronal antigen leads to autoantibodies, mediated by Th2 cells and B cells. Transmigration of activated B- or T-cells into the CNS occurs. B cells produce autoantibodies that attack the brain tissue. Even after treatment, the autoantibodies do not decrease. Therefore, it cannot be used to predict the success of resection or response to drugs.

Figure 2 Mechanism for autoimmunity.

There was mixed evidence on the presentation and outcome between infection induced OMS and tumour induced OMS. According to the Hammer et al,⁹ tumour-induced OMS could lead to poorer outcome when compared to the infection-induced OMS.

In the infection-induced OMS,¹⁰ the aetiology could be due to direct invasion by the pathogen or autoimmune damage to the cerebellum or pontine tegmentum or both. Sometimes, it might be difficult to differentiate between these 2 mechanisms. A variety of infections have been reported in association with OMS,¹¹ including Mycoplasma, Streptococcus, Epstein-Barr virus, adenovirus, HIV, and dengue virus, among others, suggesting that no single aetiologic infectious agent exists. Infection screening should cover PCR and/or serology for herpes viruses (CMV, EBV, VZV, HHV-6), West Nile virus, adenovirus, enterovirus and influenza in blood, CSF, stool and nasopharyngeal aspirate as indicated by clinical circumstances. It is thought to have a better outcome and require a relatively brief immunosuppression and symptomatic treatment.¹⁰

However, in Krug et al,¹² the authors could not identify such a difference. In a cohort of 365 patients by Pranzatelli et al,¹³ the authors found out that OMS patients with or without neuroblastoma, were not distinguishable by prodromal symptoms, OMS onset age, gender, race/ethnicity, OMS severity, or rank order of neurological sign appearance.

Currently, there are front-loaded and escalation approaches. The front-loaded approach means having aggressive treatment initially. The escalation approach is the use of steroid and IVIG as first lines of treatment, reserving rituximab or cyclophosphamide for the latter stage. The choice of aggressiveness of treatment is based on the disease activity, which can be reflected by the cerebrospinal fluid (CSF) oligoclonal band and raised B-cell percentage in the CSF lymphocyte subset.¹⁴ Although the escalation approach can prevent the early use of agents with more adverse effects, the front-loaded approach is preferred because delayed treatment leads to irreversible neural damage. The pathological B-cell-related chain of CNS events occurs early in OMS.² Steroid/IVIG alone cannot stop these events. Early anti-B cell therapy may prevent B cells from differentiating into long-lasting plasma B cells which produce antibodies at a faster rate. It can also prevent the formation of ectopic lymphoid follicles in the brain. Hence, apart from steroids and IVIG, it is recommended to use rituximab or cyclophosphamide early. High dose pulse dexamethasone is preferred over other steroids because of its potent anti-inflammatory effects and shorter course of therapy with a longer duration of action.¹⁵ The addition of IVIG on a monthly schedule helps to significantly reduce the dose of steroids required.¹ It suppresses provocative dendritic immune cells. Rituximab is an anti-B cell monoclonal antibody acting against the B-cell specific antigen, CD20. It can improve outcomes and create sustained remissions, which allows for weaning off from corticosteroids completely. Cyclophosphamide is usually a salvage therapy in OMS, as it has many adverse effects, e.g. haemorrhagic cystitis and infertility. Other immunosuppressants such as 6-mercaptopurine, azathioprine, mycophenolate, cyclosporine and methotrexate are not effective.² Resection of the tumour itself does not cure the disease. According to the literature, some authors¹¹ proposed to try plasma exchange or even autologous bone marrow transplantation in order to clear the autoantibodies. A larger clinical study might be necessary to ascertain their efficacy.

This case could serve as an important illustration that the awareness of OMS is essential. Paediatricians or even neuro-ophalmologists might miss the subtle features of opsoclonus if they did not have this speculation in mind. In this child, there was a 2-year gap from the finding of ataxia and the abdominal 'lymph node' to the final diagnosis of OMS. Earlier detection and excision of ganglioneuroblastoma with a front-loaded approach of aggressive immunosuppressants (i.e. rituximab) might alter the clinical course and outcome in her case. With the delay in the treatment, she needed to receive a stronger combination of multiple immunosuppressants to achieve clinical remission.

Conclusion

OMS is one of the easily missed diseases. Similar to our case, patients can present with non-specific symptoms such as vomiting and ataxia, mimicking parainfectious cerebellar ataxia. If symptoms persist or deteriorate a paraneoplastic antibody panel and imaging tests should be done in order to locate an OMS-associated neuroma. According to the Quack et al,¹⁶ nearly 30% of children in the study had a range of antibodies detected, suggesting that autoantibody testing in serum and CSF should be included in the work-up of a child with suspected acute cerebellitis.

An early use of antibody test, which was a simple blood test, might help to identify OMS patients that could be a game changer if appropriate treatments could be given in a timely manner. Regular imaging surveillance is recommended even if the first scan is negative, as some tumours are too small, or minimally biologically active, to be detected initially. Hence, catecholamine urine testing and MIBG scans could have false-negative results. CT and MRI from the neck to the thorax are more sensitive tests for detecting tumours. A combination of steroid, IVIG and rituximab is the preferred choice of treatment.

Conflict of Interest

None

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