Abstract
Nasopharyngeal carcinoma can present with epistaxis, cervical lymphadenopathy, audiological symptoms secondary to eustachian tube dysfunction, pain, or neurological symptoms from tumours directly invading the skull base. It is unusual for patients to present with indirect systemic manifestations. Paraneoplastic neurological syndrome can precede clinically overt malignancy by up to 5 years; therefore, a combination of thorough clinical, laboratory and radiological investigations is required to reach a diagnosis. Intravenous immunoglobulin and steroids might improve neurological symptoms initially and prevent irreversible neuronal damage, but treatment of the underlying cancer is important for long-term resolution. Our case adds to a small but growing body of literature related to anti-Ri antibodies, opsoclonus-myoclonus syndrome presentations, and is the first reported association of this combination with nasopharyngeal carcinoma.
Keywords: Head and neck cancer, Pathology, Immunology
Background
A paraneoplastic neurological syndrome occurs when antibodies targeting a malignancy inadvertently react against the host nervous system. It can involve a single system or be multifocal.1 Several ‘classic’ paraneoplastic neurological syndromes have been described.2
Many other organ systems as well as the neurological system can be affected by paraneoplastic syndromes, including the endocrine, dermatological, rheumatological and haematological systems. Non-neurological paraneoplastic syndromes are more frequently encountered.3 Dermatomyositis is the most common paraneoplastic syndrome associated with nasopharyngeal carcinoma.
We report the rare case of a patient with nasopharyngeal carcinoma (NPC) presenting with anti-Ri antibody positive opsoclonus-myoclonus syndrome (OMS). We describe this patient’s clinical course and compare this with the literature.
Case presentation
A Caucasian man in his mid-50s presented by ambulance to the accident and emergency department with irregular breathing, extreme fatigue and abnormal eye movements. Four weeks previously he had received oral antibiotics for a lower respiratory tract infection from his general practitioner. He reported nausea and dizziness and received vestibular sedatives for presumed labyrinthitis. His mobility deteriorated, and he was spending most of his time in bed. One week previously, his general practitioner had noticed that his left eye was twitching and he complained of diplopia. There were abnormal facial movements and his speech was impaired.
Past medical history included hypertension and obesity. He was a non-smoker and consumed 12 units of alcohol a week.
On general observation he appeared flushed, shaky and had a stuttering voice. His temperature was 37.9°C, heart rate 70 bpm, blood pressure 147/68 mm Hg, respiratory rate 18/min and oxygen saturation 95% on air. He was alert and oriented and neurological examination found full power in all four limbs, but evidence of facial and limb myoclonus. Truncal ataxia was evident, and there were uncontrolled irregular eye movements in all directions of gaze (opsoclonus). He was found to be in severe type II respiratory failure, with admission blood gas results included in table 1. He required admission to the intensive care unit for intubation and ventilation.
Table 1.
Investigation results
| Arterial blood gas (on 40% oxygen) | |||
| pH | 7.12 | ||
| PaCO2 | 14.99 | kPa | |
| PaO2 | 9.17 | kPa | |
| HCO3− | 23.7 | mmol/L | |
| Base excess | 1.57 | mmol/L | |
| Oxygen saturation | 90% | ||
| Haematology | |||
| White blood cells | 8.4 | x109/L | |
| Red blood cells | 5.34 | x1012/L | |
| Haemoglobin | 166 | g/L | |
| Haematocrit | 48.5 | % | |
| Platelets | 234 | x109/L | |
| Neutrophils | 5.31 | x109/L | |
| Lymphocytes | 1.87 | x109/L | |
| Monocytes | 1.03 | x109/L | High |
| Eosinophils | 1.03 | x109/L | |
| Basophils | 0.07 | x109/L | |
| Prothrombin time | 11 | s | |
| APPT | 23 | s | |
| Fibrinogen | 3.2 | g/L | |
| ESR | 5 | mm/h | |
| Biochemistry | |||
| Sodium | 139 | mmol/L | |
| Potassium | 4.7 | mmol/L | |
| Urea | 2.5 | mmol/L | |
| Creatinine | 59 | µmol/L | |
| eGFR | >60 | mL/min/1.73 m2 | |
| Bicarbonate | 34 | mmol/L | High |
| Albumin | 45 | g/L | |
| Alkaline phosphatase | 58 | U/L | |
| Alanine transaminase | 67 | U/L | High |
| Bilirubin | 13 | µmol/L | |
| Glucose | 7 | mmol/L | High |
| C-reactive protein | 1.3 | mg/L | |
| Lactate | 1.7 | mmol/L | |
| Calcium | 2.18 | mmol/L | Low |
| Corrected calcium | 2.24 | mmol/L | |
| Phosphate | 1.73 | mmol/L | High |
| Magnesium | 0.82 | mmol/L | |
| Chloride | 91 | mmol/L | Low |
| Creatine kinase | 51 | U/L | |
| Procalcitonin | 1.18 | ng/mL | High |
| TSH | 1.78 | mU/L | |
| Serum osmolality | 299 | mmol/kg | High |
| Urine osmolality | 553 | mmol/kg | |
| Urine sodium | 176 | mmol/L |
| Lumbar puncture | Result | Unit |
| CSF glucose | 5.7 | mmol/L |
| CSF protein | 510 | mg/L |
| CSF microscopy | Clear and colourless | |
| CSF white cell count | 52 Cells/µL (predominantly lymphocytes) | |
| CSF oligoclonal bands | Multiple IgG oligoclonal bands (nil in serum) | |
| CSF Gram stain | No bacteria seen | |
| CSF culture | No growth | |
| CSF viral and bacterial screen | Negative | |
| Microbiology | ||
| Aerobic peripheral blood culture | Negative | |
| Anaerobic peripheral blood culture | Negative | |
| Urine | Negative | |
| Legionella antigen | Negative | |
| MRSA swab | Negative | |
| Respiratory virus swab PCR | Negative | |
| Bacterial meningitis screen | Negative | |
| Hepatitis B virus PCR | Not detected | |
| Immunology | ||
| Borrelia burgdorferi serology (Lyme disease) | Not detected | |
| Connective tissue disorder screen | Negative | |
| C3 | Negative | |
| C4 | Negative | |
| HIV antigen/antibody | Negative | |
| Syphilis EIA screening test | Negative | |
| Anti-GMB | Negative | |
| Anti-PR3 | Negative | |
| Anti-MPO | Negative | |
| Anti-Ri antibody | Positive | |
| IgA | 7.05 | g/L |
| IgA | 2.76 | g/L |
| IgM | 0.49 | g/L |
| Hepatitis B core total antibody | Positive | |
| Hepatitis B surface antibody | 319 | mIU/mL |
| Hepatitis B surface antigen | Negative | |
| Hepatitis C antigen/antibody | Negative | |
| HEV IgM VIDAS | Negative | |
| Imaging | |
| Chest radiograph | Cardiomegaly, pulmonary venous congestion and perihilar oedema. No effusions |
| CT head | Non-contrast. No acute intracranial pathology |
| MRI head | Multiple small areas of abnormal signal in the deep white and subcortical white matter of both hemispheres. Focal abnormal signal in the brainstem. particularly the left posterior medulla, extending to the adjacent left cerebellar peduncle, but with normal enhancement. Appearance consistent with a form of encephalitis |
| CT venogram intracranial | No acute focal intracranial structural abnormality is demonstrated, no features to suggest venous sinus thrombosis |
| CT chest, abdomen and pelvis | Non-contrast. No evidence of malignancy. Bibasal lung consolidation |
| FDG PET whole body | 2 cm mass in the right nasopharynx which is metabolically active (SUV max 14.6 g/mL). Right retropharyngeal nodes which are enlarged and metabolically active (SUV max 17.4 g/mL) |
| CT neck and chest with contrast | Right-sided nasopharyngeal tumour extending into parapharyngeal space, with involved right retropharyngeal and right level II cervical lymph nodes, and further suspicious right level III and V nodes. No pulmonary metastases |
| MRI neck with contrast | Right-sided nasopharyngeal tumour with involved right retropharyngeal and right level II cervical lymph nodes, and further subcentimetre, but asymmetric, suspicious right level II, III and V nodes |
| Pathology | |
| Tissue postnasal space | Lymphoepithelial carcinoma (undifferentiated) |
| EBP (LMP-1) positive, cytokeratin AE1/3 positive, P63 positive, P40 positive |
AAPT, activated partial thromboplastin time; CSF, cerebrospinal fluid; EBV, Epstein-Barr Virus; eGFR, estimated glomerular filtration rate; EIA, enzyme immunoassay; ESR, erythrocte sedimentation rate; GMB, glomerular basement membrane; HEV, hepatitis E virus; LMP, latent memrane protein; MPO, myeloperoxidase; MRSA, methicillin-resistant Staphylococcus aureus; PaCO2, alveolar carbon dioxide tension (or pressure); PaO2, alveolar oxygen tension (or pressure); PCR, polymerase chain reaction; SUV, standardised uptake value; TSH, thyroid-stimulating hormone.
Investigations
Lumbar puncture found white cell count 52 cells/µL (0–5 cells/µL) predominantly lymphocytes, protein 510 mg/L (<450 mg/L), normal glucose and unmatched oligoclonal bands. An MRI brain scan showed abnormal signals involving the brainstem, with particular involvement of the left posterior medulla and extension into the adjacent left cerebellar peduncle with no enhancement. Intravenous meropenem 2 g, clarithromycin 500 mg, and aciclovir 800 mg were initiated to treat possible infective meningoencephalitis. Other differential diagnoses included autoimmune encephalitis, Bickerstaff encephalitis, paraneoplastic syndrome and multiple sclerosis.
One day after admission he was started on a 5-day course of 500 mg IV methylprednisolone once daily, followed by immunoglobulin 0.4 g/kg per day for 5 days (adjusted for body weight) for treatment of OMS; a good response was achieved.
An onconeural antibody screen identified positive anti-Ri antibody (anti-neuronal nuclear antibody 2). Peripheral blood cultures, urine culture, bacterial meningitis screen, and respiratory virus tests were negative. Investigation results are summarised in table 1. He was ambulant and independent with activities of daily living and was discharged from hospital. He returned to driving 2 weeks later.
Outpatient Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) imaging found a 2 cm metabolically active mass in the right nasopharynx and activity in a right retropharyngeal node (figure 1). Flexible nasoendoscopy by the otolaryngologists found an irregularity in the right nasopharynx. General anaesthetic incisional biopsy was arranged, and pathology confirmed a lymphoepithelial carcinoma, which was Epstein–Barr virus latent membrane protein-1 positive. Staging CT and MRI imaging demonstrated a T2 N1 M0 NPC.
Figure 1.
Fluorodeoxyglucose positron emission tomography/computed tomography axial head image showing a 2 cm metabolically active area in the right nasopharynx.
Differential diagnosis
Initial antibiotic and antiviral treatment was started to manage possible infective meningoencephalitis. Other differential diagnoses included autoimmune encephalitis, Bickerstaff encephalitis, paraneoplastic syndrome and multiple sclerosis.
Treatment
One month after discharge from hospital, he reported a 2-week mobility deterioration and upper limb myoclonus. Methylprednisolone 500 mg daily orally for 5 days and IVIg 100 g daily for 2 days produced a clear improvement in his mobility. The head and neck cancer multidisciplinary team discussion recommended induction chemotherapy followed by combined chemoradiotherapy treatment with curative intent. He received cisplatin 100 mg/m2 and 5-fluorouracil 1000 mg/m2. A lower limb deep vein thrombosis was diagnosed and managed. 5-Fluorouracil and cisplatin were given again 1 month after the first chemotherapy treatment. Due to a further 7-day episode of myoclonus, opsoclonus and vertigo, oral methylprednisolone (100 mg daily for 3 days) was required again 2 weeks later. Symptom improvement lasted only for 3 days, so further methylprednisolone 500 mg daily for 3 days was given. He had planned pretreatment gastrostomy tube insertion. Concurrent chemoradiotherapy with 3-weekly cisplatin 100 mg/m2 combined with radiotherapy 70 Gy in 33 fractions over 6.5 weeks was then started. Neurological symptoms improved within 1 week of starting radiotherapy. Four months later he had returned to driving, was walking unaided and had no vertigo or oscillopsia.
Outcome and follow-up
CT imaging 3 months following treatment illustrated a good primary site response with no evidence of residual or recurrent primary site tumour. However, unfortunately multiple pulmonary metastases were identified. Second-line treatment with intravenous nivolumab 480 mg 4 weekly was then started. The risk of encephalitis was explained given the presentation with paraneoplastic neurological syndrome. He tolerated nivolumab well and received 10 cycles over 10 months.
He was admitted to hospital with respiratory distress, type II respiratory failure and reduced level of consciousness 10 days following intravenous nivolumab. Treatment for pneumonitis was started with non-invasive ventilation (bilevel positive airway pressure) and 1 mg/kg methylprednisolone and he responded well initially. There had been progressive lower limb weakness over the preceding 4 weeks. Full neurological examination found him to be oriented in time and space with fluent speech and normal cranial nerve examination. There was no opsoclonus or myoclonus. Upper limb examination was normal. Lower limb examination found normal tone, but reduced power, worse proximally, flexor plantar responses but reduced tendon reflexes. Non-radicular paraesthesia in the lower limbs was reported. There was no back pain or dysmetria and no pyramidal signs. The underlying cause of the axonal neuropathy required further investigation to ascertain if this was related to nivolumab treatment, or Guillain-Barré syndrome, or chronic inflammatory axonal polyneuropathy. An urgent CT head scan, nerve conduction studies and an MRI scan of the brain and spinal cord were requested. Lumbar puncture was not performed. Chest radiograph found prominent lung metastases. Despite the initial response to treatment, he subsequently deteriorated and active treatment was withdrawn prior to further neurological investigation. He died on day 4 of his admission.
Discussion
Presenting symptoms of NPC can include epistaxis, cervical lymphadenopathy, audiological symptoms secondary to eustachian tube dysfunction pain, or neurological symptoms from tumours directly invading the skull base. It is unusual for patients to present with indirect systemic manifestations. Paraneoplastic neurological syndrome is rare and more frequently associated with small-cell lung carcinoma (SCLC). Treatment includes management of the underlying neoplasm, immunotherapy and supportive therapy.
A literature review of paraneoplastic neurological syndrome in NPC found one other case describing neurological symptoms preceding NPC diagnosis. A middle-aged man presented with progressive lower limb weakness, weight loss and gaze-evoked nystagmus with saccades.4 Serum anti-Yo antibodies were positive and MRI imaging of the brain found leptomeningeal enhancement around the cerebellum and oculomotor nerves. A fullness in the left fossa of Rosenmuller was biopsied, confirming NPC. This patient had positive anti-Yo antibodies, not anti-Ri as in our case, and his neurological symptoms failed to improve with treatment. His cancer was last reported to be in remission following chemoradiotherapy.
There are two other case reports5 6 detailing patients who developed paraneoplastic neurological syndrome following a diagnosis of NPC. A comparison of their clinical presentation and management is summarised in table 2. Neither had onconeural antibodies identified.
Table 2.
Nasopharyngeal carcinoma and paraneoplastic neurological syndrome: summary of cases
| Authors | Presentation | Symptoms | Tumour type | Tumour stage | Antibodies | Syndrome | Tumour treatment | Neurological treatment | Outcome |
| Our case | Before cancer diagnosis | Vertigo, nausea, dyspnoea, opsoclonus, myoclonus, abnormal facial movements | Nasopharyngeal carcinoma | T2 N1 M0 (TNM-8) | Anti-Ri | Opsoclonus-myoclonus, brainstem encephalitis | Induction chemotherapy, and combined chemoradiotherapy | IVIg, steroids | Good neurological response to IVIg and steroids. Developed pulmonary metastases |
| Bhardwaj S, et al4 | Before cancer diagnosis | Lower extremity weakness | Nasopharyngeal carcinoma | Not reported | Anti-Yo | Cerebellar degeneration | Chemoradiotherapy | IVIg, steroids | Poor neurological response to IVIg. Cancer in remission |
| Ng SY et al5 | After cancer diagnosis | Progressive bilateral lower limb weakness and numbness, urinary and bowel incontinence | Nasopharyngeal carcinoma undifferentiated | T1 N2 M0 | None tested | Mixed sensory and motor neuropathy | Initially refused radical radiotherapy, then had palliative radiotherapy | None | Partial early improvement in neurological function. Then lost to follow-up |
| Chan KH et al6 | After cancer diagnosis | Subacute generalised weakness, dysphagia, dyspnoea | Nasopharyngeal carcinoma | Not reported | Anti-Hu negative, no others tested | Inflammatory myelopathy, predominantly motor polyneuropathy/polyradiculopathy | Radical radiotherapy, chemotherapy, palliative radiotherapy to cervical metastases | IVIg, steroids | Partial neurological response to IVIg. Died from metastatic NPC |
NPC, nasopharyngeal carcinoma.
Paraneoplastic neurological syndrome is immune system activated, with damage occurring to neural tissues by immune-mediated inflammation. Onconeural proteins are co-expressed by the tumour. Well-characterised onconeural antibodies have been described, including anti-Hu, -Yo, -Ma2, -CRMP-5, -amphiphysin, -Ri. Anti-Yo antibodies are associated with paraneoplastic cerebellar degeneration and gynaecological malignancy.7 Anti-Hu antibodies are most commonly associated with SCLC.8 Anti-Ri antibodies are associated with brainstem encephalitis, cerebellar syndrome, OMS and myelopathy.9 Anti-Ri antibodies have been most frequently linked to SCLC and gynaecologic malignancy.10
Opsoclonus-myoclonus syndrome is characterised by rapid, chaotic, but conjugate, eye movements and generalised jerks, predominantly involving proximal muscles. Axial and abdominal muscles can be affected. It has been described in young children with neuroblastoma and reported in adults with SCLC or breast cancer. Anti-Ri antibodies are associated with this syndrome.11 Aetiology includes malignancy, parainfectious, idiopathic and toxic/metabolic causes. A 2012 Mayo clinic review of adult patients with OMS found 116 reported cases, of which 55 had a cancer detected; most commonly SCLC. A paraneoplastic antibody was identified along with a corresponding cancer in 21 patients, with anti-Ri the most common in 14 cases. A review of outcomes found that 73% of patients had complete remission or residual mild symptoms. In total, 28 patients died (24%), with 10 of these attributed to cancer.12
Paraneoplastic neurological syndrome can precede clinically overt malignancy by up to 5 years; therefore, a combination of thorough clinical, laboratory and radiological investigations isrequired to reach a diagnosis. IVIg and steroids may improve neurological symptoms initially and prevent irreversible neuronal damage, but treatment of the underlying cancer is important for long-term resolution. This case adds to a small but growing body of literature related to anti-Ri antibodies, OMS presentations, and to our knowledge, is the first reported association of this combination with NPC.
Learning points.
Nasopharyngeal carcinoma can present with paraneoplastic neurological syndrome.
Paraneoplastic neurological syndromes are uncommon but can indicate clinically covert malignancy, and thorough clinical, laboratory and radiological investigations of these syndromes is required.
A multidisciplinary approach is required and should include neurology and oncology.
Footnotes
Contributors: KES, MZ, DS and JCLY all made substantial contributions to conception and design, acquisition of data and analysis and interpretation of data. KES drafted the article and revised it critically for important intellectual content. MZ, DS, JCLY and KES all gave final approval of the version to be published. KES, MZ, DS and JCLY all 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.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.
Ethics statements
Patient consent for publication
Consent obtained from next of kin.
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