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Parainfectious opsoclonus-myoclonus syndrome: high dose intravenous immunoglobulins are effective
  1. K Glatz,
  2. H-M Meinck,
  3. B Wildemann
  1. Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany
  1. Correspondence to:
    Dr K Glatz;
    katharina_glatz{at}med.uni-heidelberg.de

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Opsoclonus-myoclonus syndrome (OMS) is a rare neuro-ophthalmical disorder that affects children more often than adults. Opsoclonus is characterised by involuntary, irregular, but conjugate saccadic eye movements either multidirectional or horizontal (“ocular flutter”) precipitated by change of fixation.1 Pathophysiologically, a disordered interaction of “burst” and “omnipause” cells located in the brain stem has been suggested.2 The associated myoclonus is typically exacerbated by muscle activation and predominantly involves the face, limbs, and trunk. Among various aetiologies of OMS, paraneoplastic, paraviral or idiopathic encephalitis are the most common causes and an autoimmune mediated brain stem dysfunction is the suggested underlying pathomechanism.3 Tumour related childhood OMS occurs predominantly in association with neuroblastoma and ganglionneuroblastoma. Paraneoplastic OMS in adults may evolve with lung, breast or uterus cancer, or neuroblastoma.2 Parainfectious and idiopathic forms account for about 50% of cases.1 As OMS is rare there is no standard treatment recommendation. Some cases resolve spontaneously or with symptomatic treatment including clonazepam, valproic acid, piracetam, thiamine, reserpine, chlormethiazole. ACTH seems to be the treatment of choice in children with paraneoplastic OMS whereas in adult onset OMS the role of immunotherapy is less well established.2 Here we report a patient with parainfectious OMS whose symptoms were well controlled with repeated administration of high dose intravenous immunoglobulin (Ig).

Case report

A few days after recovery from flu-like symptoms a 36 year old computer specialist experienced subacute evolution of jerking involving his arms and legs that exacerbated while moving his limbs. His gait became increasingly unsteady. He noticed visual instability and reported severe oscillopsia interfering with reading. He also felt irritable. Neurological examination, performed four weeks after the onset of symptoms showed brief and small amplitude horizontal eye oscillations, sometimes associated with jerky horizontal head movements. Vertical, but not horizontal smooth pursuit eye movements over an increasing angle progressively increased the frequency of both horizontal eye oscillations and jerky head movements. While resting or in action he showed non-rhythmic myoclonic jerks involving neck, arm, and leg muscles. There was moderate dysmetria on finger-nose testing and mild truncal ataxia. The remaining neurological and physical examinations were unremarkable. Routine laboratory testing, including full blood count, electrolytes, liver function tests was normal as were serum electrophoresis and complement studies. The cerebrospinal fluid (CSF) had 48 white cells/μl with 84% lymphocytes, 3% monocytes, and 14% plasma cells, a protein content of 63 mg/dl (normal <50 mg/dl) and intrathecal production of IgM and positive oligoclonal bands. Serum titres of antibodies against Purkinje cells (anti-Yo) and neuronal nuclear antigens (anti-Hu/Ri) as well as glutamic acid decarboxylase (anti-GAD) were negative as were antinuclear antibodies (ANA) and antibodies against cytoplasmic granulocyte antigens (ANCA). Serological tests for infectious pathogens (borrelia burgdorferi, chlamydia, HSV, VZV, EBV, HHV6, HTLV-1) were unremarkable and tumour markers (carcinoembryonic antigen, α fetoprotein, CA 19-9, neuron specific enolase and prostatic acid phosphatase) were not detectable. Serum and CSF angioconverting enzyme activities were not increased. Combined electro-oculography and electromyography showed high frequency conjugate ocular oscillations occasionally associated with myoclonic neck muscle activity (fig 1). Visual, sensory, and motor evoked potentials as well as EEG were normal. Cranial magnetic resonance imaging (MRI) was unremarkable. Radiological studies included normal chest roentgenogram as well as chest and abdominal computed tomography. Abdominal and thyroid ultrasonography were unremarkable. The patient received valproic acid 1800 mg per day and methylprednisolone 500 mg for five consecutive days, followed by oral tapering off. OMS remained unchanged for seven days. Therefore, on hospital day nine a five day course of 30 g/d intravenous Ig was started. Within two days clinical symptoms improved considerably and rapidly. At two month follow up the patient had mild residual opsoclonus and some myoclonic jerking on the left. Repeated administration of 5×30 g intravenous Ig led to a complete clinical recovery with no recurrence of OMS since then.

Figure 1

Polygraph recordings of horizontal and vertical eye movements (top two registrations in each panel, AC recording, time constant 1.6 s) from the splenius capitis muscles on the right and left (SPC r, SPC 1). Top and middle, both, the frequency of horizontal ocular oscillations and the myoclonus irradiation into the neck muscles depend on the amplitude of vertical eye movements. Bottom, with feet closed while standing (artefact in the electrooculogramm), irregular myoclonus occurred simultaneously in the right and left tibialis anterior (TA) muscles without, however, associated myoclonic eye movements (50 Hz artefact in the horizontal eye recording).

Comment

The patient reported here developed opsoclonus, myoclonus, and moderate ataxia in close temporal association with a flu-like illness. Intensive diagnostic assessment revealed no evidence of a remote neoplasm and thus, parainfectious OMS was the most probable diagnosis. As serological tests did not confirm a recent infection, classification as idiopathic OMS would also be appropriate.1 The disabling symptoms responded dramatically to treatment with high dose intravenous Ig. Resolution of opsoclonus, myoclonus, and cerebellar signs coincided closely with intravenous Ig administration suggesting that intravenous Ig and not the preceding corticosteroid pulse therapy accelerated recovery. However, corticosteroids may be beneficial in some cases and a delayed corticosteroid effect cannot be excluded in our case. Consistent with our observation, a response to intravenous Ig was previously reported in some children and adults with idiopathic or parainfectious OMS, among them some whose symptoms did not respond to corticosteroids.3,4 In a recent retrospective analysis, Bataller et al5 observed a more benign clinical evolution and a better response to immunotherapy in adults with idiopathic as compared with patients with paraneoplastic OMS. In this series 8 of 10 patients with idiopathic OMS were treated with either intravenous Ig (n=4), corticosteroids (n=2), combined intravenous Ig and corticosteroids (n=1), or azathioprine (n=1). Accelerated recovery was observed in all patients treated with intravenous Ig and in one patient after corticosteroids. In contrast, 9 of 10 patients with paraneoplastic OMS consistently improved after tumour removal whereas immunotherapy with intravenous Ig and corticosteroids alone or in combination as well as plasmapheresis had no effect. Altogether, the available evidence suggests that intravenous Ig is an effective treatment in parainfectious and idiopathic OMS and superior to corticosteroids. Intravenous Ig therefore may prove useful as first line treatment. Moreover, a favourable response to intravenous Ig or other immunotherapies may help to differentiate parainfectious or idiopathic OMS from paraneoplastic forms of the syndrome. The effectiveness of intravenous Ig as an immunomodulatory agent supports the assumption that autoimmune pathomechanisms are involved in the emergence of parainfectious and idiopathic OMS. Treatment with intravenous Ig is safe, very rarely hyperviscosity, and consecutive thromboembolic events may complicate its use.3

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