Clinical Neurology and Neurosurgery 149 (2016) 11–14
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Case Report
Paraneoplastic opsoclonus associated with squamous cell carcinoma of the tongue DonRaphael Wynn (MD) a,1 , Joseph Merriman (MD) b,1 , Ami B. Patel (MD) c , Ying J. Hitchcock (MD) d , Ignacio Garrido-Laguna (MD) c , David Renner (MD) a , Stacey L. Clardy (PhD) a,∗ a
University of Utah, Department of Neurology, Salt Lake City, UT, United States University of Utah, Department of Internal Medicine, Salt Lake City, UT, United States c University of Utah, Division of Oncology, Huntsman Cancer Institute, Salt Lake City, UT, United States d University of Utah, Department of Radiation Oncology, Huntsman Cancer Institute, Salt Lake City, UT, United States b
a r t i c l e
i n f o
Article history: Received 5 September 2015 Received in revised form 14 May 2016 Accepted 22 May 2016 Available online 14 July 2016 Keywords: GAD65 antibodies Opsoclonus Paraneoplastic syndrome Squamous cell carcinoma
1. Introduction Opsoclonus is a pathological eye movement phenomenon in which the eyes experience involuntary, arrhythmic, rapid, multidirectional, conjugate movements. It occurs in all eye positions and during smooth pursuit, and can also persist during sleep. It is differentiated from nystagmus in that there is no slow eye movement phase, and it differs from ocular flutter because the eye movement is multidirectional and not confined to the horizontal. Opsoclonus can be accompanied by tremors, cerebellar ataxia, myoclonic jerks, or encephalopathy. In addition to paraneoplastic etiologies, it is sometimes autoimmune, but frequently without an identifiable antibody [1].
∗ Corresponding author at: 729 Arapeen Drive, Salt Lake City, UT, United States. E-mail addresses:
[email protected] (D. Wynn),
[email protected] (J. Merriman),
[email protected] (A.B. Patel),
[email protected] (Y.J. Hitchcock),
[email protected] (I. Garrido-Laguna),
[email protected] (D. Renner),
[email protected] (S.L. Clardy). 1 These authors contributed equally to the manuscript. http://dx.doi.org/10.1016/j.clineuro.2016.05.023 0303-8467/Published by Elsevier B.V.
Opsoclonus is often associated with paraneoplastic or parainfectious processes but has also been reported in the settings of hydrocephalus, multiple sclerosis, thalamic hemorrhage, and as a side effect of medications [2]. In a series reviewing 55 adult cases of opsoclonus (with and without myoclonus), 11 of the patients (20%) were found to have an underlying malignancy [2]. The most commonly implicated cancers include breast and small cell lung cancer, and less commonly melanoma, esophageal and ovarian cancer [2–5]. Opsoclonus in the setting of a squamous cell carcinoma is less common, but has been reported; specifically, one case described opsoclonus and cerebellar ataxia in the setting of a squamous cell carcinoma of the thymus [6], another case described encephalopathy, ataxia and opsoclonus-myoclonus with a subsequent diagnosis of esophageal squamous cell carcinoma [3], and finally there is one report of a nasopharyngeal carcinoma that presented with opsoclonus-myoclonus [7]. Herein we report a case of opsoclonus with ataxia and tremor, with no appreciable myoclonus, in association with a squamous cell carcinoma of the base of the tongue. To our knowledge, this is the first case of a patient with a base of the tongue squamous cell carcinoma presenting with opsoclonus and tremor without myoclonus. We also review the pathophysiology of opsoclonus.
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D. Wynn et al. / Clinical Neurology and Neurosurgery 149 (2016) 11–14
Fig. 1. (A) MRI of cervical spine revealing enlarged lymph nodes along the right cervical chain with a necrotic center (arrow) (B) PET scan of the whole body with a region of hypermetabolic activity in the right cervical chain region (arrow). (C) Hematoxylin and eosin (H&E) stain of lymph node revealing epithelioid cells with a high nuclear to cytoplasmic ratio, some apoptotic bodies (thin arrow), and scattered mitoses (thick arrow) concerning for an actively proliferating tumor. Overall cell architecture is indistinct so further specialized staining was required. (D) Squamous origin of cells confirmed via P63 nuclear and cytoplasmic stain. P63 is involved in the regulation and growth of keratinocytes. (E) In-situ hybridization staining is positive for human papilloma virus (HPV).
2. Case report A 57-year-old non-smoking male with a past medical history significant for diabetes mellitus, hypertension and coronary artery disease presented with a three month history of weight loss, blurred vision, fatigue, gait instability, nausea, and vomiting. Two months
prior to presentation the patient began to experience a fine tremor, located mainly in the head but intermittently extending to all 4 extremities. He denied any viral prodrome. He had no significant family history of malignancy, and denied any history of alcohol, tobacco, or substance abuse. MRI of the brain performed at initial presentation was unremarkable. Electronystagmography (ENG)
D. Wynn et al. / Clinical Neurology and Neurosurgery 149 (2016) 11–14
revealed 40% reduction in the vestibular ocular system (VOS) in the left ear. During the course of the evaluation, he had symptomatic improvement of nausea and vomiting with ondansetron treatment. Neurological examination (Video) three months after symptom onset was remarkable for tremulous and hypophonic speech. Opsoclonus was observed in all gaze positions, including neutral. The opsoclonus was primarily horizontal, with vertical and circular components. He exhibited moderate head titubation with some intention tremor on finger-nose-finger testing. His gait was widebased and he was incapable of performing tandem walking without assistance. Routine serologic testing was unremarkable. Cerebrospinal fluid testing was significant for a mildly elevated white count of 9 K/mcL (normal 0–5 K/mcL), elevated protein of 174 mg/dL (normal 14–45 mg/dL), absence of malignant cells via flow cytometry, and one oligoclonal band exclusive to the CSF. Paraneoplastic CSF evaluation (Mayo Medical Laboratories) was negative for ANNA-1,2, and -3; PCA-1,-2, and -Trotter; Amphiphysin, CRMP-5, Striational muscle, N-and P/Q-type calcium channel, and voltage gated potassium channel complex antibodies. Paraneoplastic serum evaluation (Mayo Medical Laboratories) revealed a low positive, likely not significant, result for the neuronal acetylcholine receptor ganglionic alpha-3 antibody at 0.04 nmol/L (normal <0.02 nmol/L). Specific serum testing for GAD-65 antibody (ARUP Laboratory) was positive at 83.4 IU/mL (normal 0–5 IU/mL). MRI of the cervical spine revealed enlarged right-side cervical lymph nodes, with one node showing evidence of a necrotic center concerning for a metastatic malignancy (Fig. 1A). PET/CT revealed two right cervical enlarged and hypermetabolic lymph nodes but no other evidence of malignancy (Fig. 1B). Fine needle aspiration of the lymph nodes and subsequent core biopsy revealed a poorly differentiated, stage IVA, T1N2b, human papilloma virus (HPV) 16-positive squamous cell carcinoma of the base of the tongue (Fig. 1C–E). For treatment of the paraneoplastic syndrome, he was initially treated with methylprednisolone at a dose of 1 gm daily for three days with minimal improvement, followed by a course of intravenous immunoglobulin (IVIG) 0.4 mg/kg/day over 5 days for a total dose of two grams, with noticeable improvement in his symptoms, including the ability to ambulate without assistance. He was treated with definitive chemoradiation with simultaneous in-field boost IMRT technique and completed 6 cycles of weekly cisplatin. Three months post-treatment PET/CT showed no evidence of any residual disease. He has had no further immunotherapy, and he has been able to return to his normal functioning, including riding his motorbike. One year from diagnosis he complained only of occasional vertigo when turning in bed.
3. Discussion Regarding the anatomic pathophysiology of opsoclonus, there is no proven anatomic pathway, but several theories. Saccades are generated by burst neurons in the brainstem − specifically the paramedian pontine reticular formation or PPRF and the rostral interstitial nucleus of Cajal or riMLF − which are regulated by omnipause neurons in the midline pons. Damage to these omnipause neurons could result in disinhibition of the burst neurons resulting in constant, unwanted saccades. Experimental studies involving lesions of the omnipause cells in primates, however, have shown slowing of saccades, not opsoclonus [8]. Another theory describes opsoclonus as a result of disinhibition of the fastigial nucleus. The fastigial nucleus is involved in saccadic eye movement, and receives inhibitory input from Purkinje cells in the dorsal vermis of the cerebellum. This theory is supported by a case of opsoclonus in which damage to the inhibitory output to the fastigial nucleus was demonstrated via histopathology [9]. Additionally, functional magnetic
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resonance imaging (fMRI) studies on two patients with opsoclonus showed increased activation of the fastigial nucleus bilaterally [10]. These structures – the Purkinje cells of the dorsal vermis and their connection to the fastigial nuclei – are another possible lesion site in opsoclonus. GAD65 has previously been described in a paraneoplastic context in numerous individual case reports, but the largest series included 15 patients [11]. In this series of patients, 8 of the 15 patients had a classic paraneoplastic syndrome of the following phenotypes: 5 limbic encephalitis, 1 paraneoplastic encephalomyelitis, 1 paraneoplastic cerebellar degeneration, and 1 opsoclonus-myoclonus syndrome. In comparison to 106 nonparaneoplastic cases, those with malignancy were older, more frequently male, and more often had coexisting neuronal cellsurface antibodies. The most common tumors were lung and thymic neoplasms. In other individual case reports, stiff-person syndrome was described more frequently. 4. Conclusion The patient presented with paraneoplastic opsoclonus in the setting of a poorly differentiated squamous cell carcinoma of the base of the tongue. This case expands the spectrum of malignancies associated with paraneoplastic opsoclonus. Chemotherapy and radiation with accompanying immunosuppression resulted in significant improvement of symptoms. In the setting of opsoclonus, as in all paraneoplastic syndromes with or without identification of neuronal antibodies, it is essential to diligently screen for and treat an underlying malignancy. Author contribution All authors made substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work; and were involved in drafting the work or revising it critically for important intellectual content; and give final approval of the version to be published; and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This manuscript has not been previously published or submitted to any other journal. The authors take full responsibility for the data, the analyses and interpretation, and the conduct of the research. The corresponding author has full access to all of the data. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.clineuro.2016.05. 023. References [1] J.C. Jen, I. Lopez, R.W. Baloh, Opsoclonus: clinical and immunological features, J. Neurol. Sci. 320 (2012) 61–65. [2] K.B. Digre, Opsoclonus in adults: report of three cases and review of the literature, Arch. Neurol. 43 (1986) 1165–1175. [3] A.M. Rossor, F. Perry, A. Botha, F. Norwood, Opsoclonus myoclonus syndrome due to squamous cell carcinoma of the oesophagus, BMJ Case Rep. (March) (2014). [4] M.W. Ko, J. Dalmau, S.L. Galetta, Neuro-ophthalmologic manifestations of paraneoplastic syndromes, J. Neuroophthalmol. 28 (2008) 58–68. [5] J. Baets, P. Pals, B. Bergmans, et al., Opsoclonus-myoclonus syndrome: a clinicopathological confrontation, Acta Neurol. Belg. 106 (2006) 142–146. [6] Y. Yamaguchi, M. Wada, H. Tanji, et al., Marked improvement in opsoclonus and cerebellar ataxia after the surgical removal of a squamous cell carcinoma of the thymus: a case report, J. Neurol. Sci. 325 (2013) 156–159. [7] B.G. Taib, A.J. Kinshuck, P. Milburn-McNulty, L. Fratalia, L. Forsyth, D. Husband, T.M. Jones, A. Jacob, Opsoclonus-myoclonus syndrome associated
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