Somatostatin receptor positron emission tomography/computed tomography (PET/CT) in the evaluation of opsoclonus-myoclonus ataxia syndrome.

Opsoclonus-myoclonus ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome of childhood, associated with occult neuroblastoma in 20%-50% of all cases. OMA is the initial presentation of neuroblastoma in 1%-3% of children. Conventional radiological imaging approaches include chest radiography and abdominal computed tomography (CT). Nuclear medicine techniques, in form of (123)I/(131)I-metaiodobenzylguanidine (MIBG) scintigraphy have been incorporated in various diagnostic algorithms for evaluation of OMA. We describe use of somatostatin receptor PET/CT with (68)Gallium- DOTA-DPhe(1), Tyr(3)-octreotate (DOTATATE) in diagnosis of neuroblastoma in two cases of OMA.

INTRODUCTION

Opsoclonus-myoclonus ataxia (OMA) syndrome is the most common paraneoplastic neurological syndrome of childhood. It is an acute neurological disorder characterized by involuntary, chaotic eye movements (opsoclonus) and/or by myoclonus and ataxia of the limbs ("dancing feet"), the trunk, and the eyelids.[1] Other names of this syndrome are: Kinsbourne syndrome, dancing eyes syndrome and infantile myoclonic encephalopathy.[234] It is a rare presentation of neuroblastoma (1-3% of cases), but in as many as 50% of patients with this syndrome, neuroblastoma (NB) is the cause.[5] We describe use of somatostatin receptor PET/CT (SSR PET/CT) with 68Gallium-DOTA-DPhe1, Tyr3-octreotate (DOTATATE) in diagnosis of NB in two cases of OMA.

CASE REPORTS

Case 1

A two year old male child presented with acute onset of ataxia. His parents reported involuntary eye movements in child of two weeks duration. There was no history of fever and other systemic complaints. On clinical examination, he was found to have OMA syndrome. His previous investigation included chest X-ray, urinary vanillylmandelic acid (VMA) measurement, brain MRI and CSF examination, which did not reveal any abnormality. With suspicion of underlying neuroblastoma, SSR PET/CT with 68Gallium DOTATATE was performed. 1.5 mCi of 68Gallium-DOTATATE was injected intravenously to the patient. After 1 hr of injection, patient was scanned on dedicated 16 slice PET /CT. Whole body diagnostic CT scan was obtained as part of PET/ CT protocol on Multislice CT with 3.5 mm slice thickness.

The scan demonstrated increased tracer uptake in left paravertebral region at the level of T3-T5 vertebrae [Arrow in Figure 1a]. Maximum standardized uptake value SUVmax of the lesion was 10.1. On CT and fused PET/CT images the uptake localized to a soft tissue density lesion with specks of calcification within [Figure 1b and 1c, arrows]. Physiological tracer distribution was noted in the spleen, kidneys and urinary bladder. The paravertebral lesion was suggestive of NB. Surgical resection of lesion confirmed diagnosis of NB. Post surgery and short course of steroids, OMA resolved. At present, one year after the initial presentation; this child has no evidence of disease.

Figure 1

A 2-year-old male child underwent 68Gallium-DOTA-DPhe1, Tyr3- octreotatephoton emission tomography/computed tomography (PET/CT) for evaluation of opsoclonus-myoclonus ataxia syndrome. The scan shows increased tracer uptake in left paravertebral region at the level of T3-T5 vertebrae (black arrow in a). CT reveals a soft-tissue density lesion with specks of calcification within (b, red arrow). Fused PET/CT demonstrates increased tracer uptake in this lesion, SUVmax of uptake was 10.1 (c, white arrow). Physiological tracer distribution was noted in the spleen, liver, kidneys and urinary bladder. The paravertebral lesion was found to be neuroblastoma on surgical resection

Case 2

A two and half year old male child presented with acute onset of myoclonus, occasional opsoclonus and ataxia. Previous evaluation included a lumbar puncture and brain MRI, both failing to show an abnormality. Suspicion of paravertebral mass was raised in a recent chest X-ray. Considering the possibility of the mass being neuroblastoma, the patient was referred to the nuclear medicine department for further evaluation. We evaluated the child with SSR PET/CT using 68Gallium DOTATATE. 1.5 mCi of 68Gallium-DOTATATE was injected intravenously to the patient. After 1 hr of injection, patient was scanned on dedicated 16 slice PET /CT (GE – STE 16). Whole body diagnostic CT scan was obtained as part of PET/CT protocol on Multislice CT with 3.5 mm slice thickness.

The SSR PET/CT revealed intense tracer uptake in chest which localized to a soft tissue density mass in the paravertebral region (T1-T4 levels) with SUVmax of 21.0 [Figure 2a, long arrow]. On CT the lesion showed evidence of calcification in it [Figure 2b, arrow]. Considering patient's symptoms, these CT findings along with positivity for somatostatin receptor expression on PET, suggested diagnosis of NB. Additionally multiple areas of increased tracer uptake were noted in the bone marrow of long bones and almost entire axial skeleton with no obvious CT demonstrable abnormality [Figure 2a and 2c]. These features were indicative of widespread marrow metastases. Biopsy of the paravertebral mass confirmed the diagnosis of NB. Considering the extensive disease, the child is receiving chemotherapy for last four months. There is mild clinical improvement in the OMA.

Figure 2

Somatostatin receptor photon emission tomography/computed tomography (CT) of a 2½-old male child with opsoclonus-myoclonus ataxia, revealed intense tracer uptake in chest (a, long arrow), corresponding to a soft-tissue density mass with specks of calcification within, in the paravertebral region at T1-T4 levels (b, long white arrow). These findings suggested diagnosis of neuroblastoma. Multiple areas of increased tracer uptake seen in the bone marrow of long bones and axial skeleton with no CT demonstrable abnormality (short arrows in a) suggesting marrow metastases. Representative uptake in bone marrow of bilateral femora is shown(c, short white arrows)

DISCUSSION

Though encountered rarely, identification of paraneoplastic syndromes is important for accurate management of the underlying malignancies. OMA is one such syndrome. In children this syndrome is typical for neuroblastoma and was first described by Kinsbourne in 1962.[2] OMA syndrome very rarely can also develop in association with viral infections or vaccination or without any noticeable reason. In idiopathic cases it is assumed that the syndrome could have developed in the course of neuroblastoma which had undergone a complete spontaneous regression.[67] This syndrome develops very rarely in adult patients with breast cancer in association with Ri antibodies and patients with small cell lung cancer without any characteristic antibodies.[8] The pathogenesis of OMA is still unclear, although the presence of anti-neuronal antibodies against unknown membrane antigens of neuroblastoma cells and cerebellar neurons suggests that the disorder is immunologically mediated.[9] Children with OMA do not improve spontaneously and in order to improve their neurological status along with treatment of NB, therapy with steroids or immunosuppressive or cytotoxic drugs is required.[8]

In children with OMA, battery of diagnostic tests needs to be performed to diagnose occult NB. These include-chest radiography, abdominal CT, urinary VMA measurement. Nuclear medicine techniques, in form of 123I/131I- metaiodobenzylguanidine (MIBG) scintigraphy have been incorporated in various diagnostic algorithms for evaluation of OMA.[5] In most OMA cases the tumor is of a small size, without any clinical symptoms related to its primary location. Therefore at times repeated imaging examinations must be carried out.[4]

Somatostatin receptor (SSR) overexpression in NBs and many other neuroendocrine tumors (NETs) has enabled development of scintigraphy using radiolabeled somatostatin analogs. To date, 5 SSRs have been characterized, all of which are expressed in differing frequencies in NET.[10] In our patients, we used DOTATATE, an SSR-2 analog,[11] labeled with 68Gallium, a positron emitter. 68Gallium is produced from a 68Germanium — 68Gallium generator and therefore is not dependent on a cyclotron. The automated labeling of this radiopharmaceutical done according to good laboratory practice under sterile conditions in an isolator takes approximately 60 min. The yield of 68Gallium-DOTATATE is more than 98% with this method. The PET/CT is performed 45 min- 1 hour after the injection of tracer. SSR PET/CT is known to be useful tools in evaluation of NB.[1213] A study by Kroiss et al., compared 123I-MIBG with SSR PET/CT, which suggests that SSR PET/CT has equal sensitivity for NB detection on per-patient basis and higher sensitivity on a per-lesion basis.[12] Additionally SSR imaging could provide prognostic information; in fact a longer survival has been reported in patients with SS receptor-positive NB.[13]

The distinct advantages of SSR PET/CT over 123I/131I-MIBG scintigraphy are-superior resolution of PET/CT technology as compared to gamma camera imaging, comparable sensitivity with 123I MIBG, no need of special patient preparation (such as blocking the thyroid uptake with iodine administration, need to stop interfering medications), prognostic information, round the clock availability due to generator production.[1011121314] Unlike 123I/131I-MIBG, tracer administration and imaging is done on the same day and entire procedure takes only few hours. Considering all these factors SSR PET/CT appears to be an effective alternative to 123I/131I-MIBG in evaluation of patients with OMA.

Especially the availability factor is crucial in our country, where 131I-MIBG is supplied on once/twice-a-month basis and usually a long waiting list makes it difficult to accommodate all the referred patients. In fact in the described cases, non-availability of 123I/131I-MIBG, prompted us to use SSR PET/CT as the modality to evaluate patients of OMA. In consideration of cost efficiency, the value of a sensitive and specific screening modality for patients with suspected neuroblastoma is extremely important. A single screening study which is sensitive, specific and able to identify both soft tissue and osseous metastatic disease would provide more rapid diagnosis, simultaneous staging and possibly improve outcome. 131I/123I-MIBG has shown its value in this regard.[5] SSR PET/CT has potential to become another efficient nuclear medicine technique for this purpose. SSR PET/CT can bring together anatomical information of CT and functional information of PET and hence will possibly result in better characterization of disease. In the second case described above demonstrates this point. In this case, SSR PET/CT not only characterized the mass seen on CT but also diagnosed CT negative marrow metastases. With advent of peptide receptor therapy with 177Lu-DOTATATE, the SSR PETCT can also serve as selection criteria of patients for this targeted therapy.[15]

To conclude, we present valuable role played by SSR PET/CT in evaluation of children with OMA. SSR PET/CT can provide rapid diagnosis and staging in cases of OMA and hence guide optimal patient management.