Rhombencephalomyelitis due to possible paraneoplastic syndrome associated with Hodgkin’s lymphoma

Abstract

We report a unique case of rhombencephalomyelitis with unclear aetiology, diagnosed with Hodgkin’s lymphoma (HL) on follow-up.

A woman in her 50s was presented with gait difficulty, dysarthria, left Horner’s syndrome and left trigeminal sensory loss. MRI of the brain revealed an enhanced T2 and fluid attenuated inversion recovery hyperintense lesion at the cervico-medullary junction, suggesting rhombencephalomyelitis. The initial differential diagnosis included demyelination, other inflammatory conditions like sarcoidosis, Behcet’s disease and paraneoplastic syndrome. Cerebrospinal fluid analysis, serum myelin oligodendrocyte glycoprotein, neuromyelitis optica antibodies, vasculitis work-up, onconeural antibody panel and whole-body fluorodeoxyglucose-positron emission tomography scan were all unrevealing, and she was kept under close follow-up. After 18 months, she developed a prolonged fever and was diagnosed with HL. Rhombencephalomyelitis as a HL-associated paraneoplastic syndrome has not been reported in the literature. This case report highlights the importance of serial screening for occult malignancy in patients with suspected paraneoplastic syndrome.

Background

Rhombencephalitis is an inflammation of the brainstem and cerebellum (hindbrain) and has a variety of potential aetiologies like infections, demyelinating and inflammatory disorders, and paraneoplastic syndrome.¹ In some situations, inflammation can extend to the upper cervical spinal cord, causing rhombencephalomyelitis. Paraneoplastic rhombencephalitis is rare and is considered a non-classical paraneoplastic neurological syndrome. Most of the reported paraneoplastic brainstem encephalitis was associated with anti-Hu antibody-positive small cell lung carcinoma.² We report the case of a patient with possible paraneoplastic rhombencephalomyelitis associated with HL.

Case presentation

A woman in her 50s was presented with 1 week history of unsteady gait, left facial numbness, slurred speech and right lower limb numbness. Her medical history was unremarkable, except for recently diagnosed mild diabetes. On examination, she had dysarthria, left Horner’s syndrome, left trigeminal sensory loss, gait ataxia and bilateral extensor plantar reflex.

She underwent MRI of the brain which revealed a cervico-medullary lesion, hyperintense on T2 and fluid attenuated inversion recovery sequence extending from the lower medulla to the lower part of the C2 segment of the spinal cord. Lesions showed patchy nodular enhancement (figure 1). Diagnostic possibilities considered were demyelinating disorder, other inflammatory conditions like Behcet’s disease, Sjogren’s syndrome, sarcoidosis and paraneoplastic syndrome. Routine blood investigations showed haemoglobin 140.1 g/L (120–150), white blood cell count 10 340 cell/mm³, erythrocyte sedimentation rate 33 mm/hour, creatinine 0.7 mg/dL (0.5–1.1) and liver function test was normal. Serum angiotensin-converting enzyme level, rheumatoid factor, antinuclear antibody, neuromyelitis optica antibody and myelin oligodendrocyte glycoprotein antibody were all negative. Cerebrospinal fluid analysis was normal. Chest radiograph and thorax CT scan were unremarkable. A whole-body fluorodeoxyglucose (FDG)-positron emission tomography (PET) scan to look for any evidence of systemic malignancy was also normal. Considering the possibility of demyelination—seronegative neuromyelitis optica spectrum disorder, she was treated with parenteral methylprednisolone 1 g/day for 5 days. She reported partial improvement. MRI of the brain was repeated after 2 months which revealed almost the same findings. At 12 months follow-up, MRI of the brain revealed few new lesions involving the pons, but the extent of contrast enhancement decreased (figure 2A–D).

Figure 1.

Top panel —MRI T2 sequence of brainstem and cervical spinal cord. (A) Sagittal section showing hyperintense lesion involving medulla. (B) Axial section at medulla level shows hyperintense lesion involving both sides of medulla. (C) Sagittal section showing hyperintense lesion extending up to lower part of C2 segment of spinal cord. (D) Axial section at C2 level of spinal cord showing hyperintensity involving mainly left side. Bottom panel—MRI T1 postgadolinium contrast sequences showing patchy enhancement of medullary and cervical cord lesions. (E) Sagittal section, (F) Axial section at medullary level, (G) Coronal section and (H) Axial section at C2 spinal cord level.

Figure 2.

Follow-up MR images (A–E) and histopathology of lymph node biopsy. (A) T2 coronal section and (B) T2 sagittal section showing extension of hyperintensity up to lower cervical spinal cord (thick arrow) and pons (thin arrow). (C) T2 fluid attenuated inversion recovery axial image at pons level showing ventral midline hyperintensity at upper pons. (D) T1 postgadolinium contrast showing good resolution of enhancement of brainstem and cervical cord lesions compared with initial MRI. (E) Histopathology picture of lymph node showing binucleated atypical cells (reed Sternberg cells) suggestive of Hodgkin’s lymphoma.

Outcome and follow-up

After 18 months of follow-up, she developed a prolonged low-grade fever, night sweats and anaemia. Her inflammatory markers were elevated. So, a whole-body FDG-PET CT scan was repeated, which showed a large lymph node in the right iliac fossa. She underwent laparoscopic excision biopsy of the lymph node, and histopathology revealed HL (figure 2F). She was started on chemotherapy with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD regimen). Ten days after the first course of chemotherapy, she had a massive myocardial infarction and died at another centre.

Discussion

This case highlights an unusual clinical presentation with an atypical evolution and peculiar neuroimaging. Rhombencephalomyelitis developed acutely and partially responded to steroids. Though the patient had a long lesion extending from the medulla to the upper cervical cord in the MRI, she had only minimal deficits. Common differential diagnoses of isolated cervico-medullary intra-axial lesions include neoplasms, atypical demyelination, inflammatory lesions like Bechet’s disease, Sjogren’s syndrome, sarcoidosis, paraneoplastic syndrome and infections like Listeria monocytogenes.¹ All these conditions were ruled out by appropriate investigations. Whole-body FDG-PET in search of evidence of a systemic malignancy was also normal.

This patient had a cervico-medullary lesion of unknown aetiology, which responded partially to immunosuppressants, and HL was diagnosed after 18 months. The presence of a neurological syndrome of unclear aetiology at the time of diagnosis of a tumour does not necessarily mean that the syndrome is paraneoplastic, as this could represent the coincidental occurrences of two unrelated events. In 2004, two levels of diagnostic certainty were proposed for the paraneoplastic neurological syndrome (PNS): definite and possible. After excluding other possible causes of the neurological syndrome, a definite diagnosis of PNS is made if the following criteria are satisfied. (1) A classic syndrome (ie, one of the syndrome frequently associated with cancer; table 1) and (2) cancer diagnosed within 5 years of a neurological syndrome. A non-classical PNS such as rhombencephalitis would qualify as definite PNS only if the patient has a well characterised onconeural antibody or the syndrome improves after a successful treatment of the underlying tumour.³ Our patient did not have an onconeural antibody, and we could not demonstrate a clinical improvement with the treatment of lymphoma, as the patient died immediately after the first course of chemotherapy. So rhombencephalomyelitis in this patient will qualify as a possible paraneoplastic syndrome of HL. The updated diagnostic criteria for PNS were published in 2021, which classified PNS into high-risk phenotypes and intermediate-risk phenotypes.⁴ The term onconeural antibody was replaced by high-risk, intermediate-risk and low-risk antibodies. The panel classified three levels of evidence for PNS: definite, probable and possible based on clinical phenotypes, antibody type, the presence or absence of cancer and follow-up time. According to this updated criterion for PNS, the diagnosis of definite PNS requires the presence of high-risk or intermediate-risk onconeural antibodies, and our patient will qualify for probable PNS. A significant time interval may be present between the first presentation of PNS and detection of the underlying tumour, even after extensive investigations as in our patient.⁵ It is generally recommended to use full-body PET as the investigation of choice in such situations. Where PET is negative, serial PET screening every 6 months up to 4 years is recommended.^{4 6} The clinical syndrome of brainstem encephalitis was well recognised in the initial descriptions of paraneoplastic encephalomyelitis (PEM) and was a predominant syndrome in 11% of patients with anti-Hu associated PEM.² It can also be seen with anti-Ma antibody-positive testicular germ cell tumours. MRI findings vary depending on the phase of illness. In the acute phase, T2 hyperintensity or enhancement of the cerebellum, cerebellar peduncle and brainstem are seen.⁷ PNS is rarely associated with HL. The most common HL-associated PNSs are paraneoplastic cerebellar degeneration (PCD) and limbic encephalitis. Other rare PNSs reported in HL include myelopathy, sensory neuronopathy, Stiff person syndrome, dermatomyositis/polymyositis.⁸ Onconeural antibodies are absent in most HL-associated PNSs and are the limitation of many PNSs to define as definite HL-associated PNS. Only Trotter (Tr) and metabotropic glutamate receptor type 5(mGluR5) are considered good markers for HL.⁹ PCD is the most common PNS associated with HL. PCD antedates the diagnosis of HL in 80% of patients. Tr antibody is the most common antibody in HL-associated PCD. The target antigen for this antibody is the delta and notch-like epidermal growth factor-related receptor (DNER), a transmembrane protein expressed in Purkinje cells. Unlike other PNS antigens, DNER has not been identified in tissue samples of HL, suggesting that the immune response is not triggered by ectopic tumour expression of antigens.⁹ Rhombencephalomyelitis has never been reported as a paraneoplastic syndrome associated with HL.

Table 1.

Paraneoplastic neurological syndromes

Classical syndromes	Non-classical syndromes
Encephalomyelitis	Brainstem encephalitis
Limbic encephalitis	Optic neuritis
Subacute cerebellar degeneration	Retinopathy
Opsoclonus myoclonus	Stiff person syndrome
Subacute sensory neuropathy	Necrotising myelopathy
Lambert-Eaton myasthenic syndrome	Inflammatory myopathy
	Sensori-motor neuropathy
	Motor neuron disease
	Brachial neuritis

Learning points.

• Paraneoplastic neurological syndromes often antedate the diagnosis of cancer offering an opportunity for detecting cancer at an earlier stage.

• Serial screening for occult malignancy is important in patients with suspected paraneoplastic syndrome.

• Tests for paraneoplastic antibodies are often negative and do not rule out the diagnosis of paraneoplastic neurological syndrome.

Ethics statements

Patient consent for publication

Consent obtained from next of kin.