Isolated third cranial nerve palsy as the first presentation of multiple myeloma

Abstract

A 50-year-old woman presented with a right-sided isolated third cranial nerve palsy. MRI brain showed a mass lesion arising from the right clivus with extension into the cavernous sinus. Blood investigations and bone marrow biopsy were suggestive of multiple myeloma with hypercalcaemia and renal dysfunction. It was unclear at first if the intracranial lesion was due to myelomatous involvement or a separate disease entirely. The patient declined consent for a biopsy and cerebrospinal fluid analysis was inconclusive. She was treated with bortezomib based chemotherapy and the palsy resolved by day 6, which helped clinch the rare diagnosis of central nervous system (CNS) involvement by multiple myeloma. Most patients with CNS myeloma have a dismal survival of under 6 months but she is on therapy for relapse 26 months after diagnosis. While placed under the umbrella of CNS myeloma, patients with osteodural myeloma have better outcomes, perhaps due to their distinct aetiopathogenesis.

Background

Intracranial involvement is an extremely rare presentation of multiple myeloma (MM) and occurs in 1%–1.8% of all myeloma patients.^{1 2} Of those who develop intracranial involvement, 76% do so at relapse while only 24% do so at the time of diagnosis.³ We report a case of MM presenting as a stroke mimic. Our patient, who is a middle-aged woman, presented to the emergency department with an isolated third nerve palsy. While the palsy initially was thought to be due to a cerebrovascular accident or a space occupying lesion due to a solid malignancy, it was later confirmed to be secondary to intracranial involvement by MM. Central nervous system (CNS) myeloma has a dismal overall survival (OS) of 1–4 months^{3 4}; however, our patient continues to be on therapy more than 2 years after her diagnosis. The case highlights that outcomes in CNS MM are heterogeneous, given that patients with osteodural subtype, attainment of very good partial response (VGPR), absence of prior myeloma therapy and absence of poor cytogenetics are likely to perform better than others.^{5 6}

Case presentation

A 50-year-old woman presented to us with a history of diplopia lasting for a few hours following which the diplopia resolved and she developed ptosis of the right eye for the last 2 days. The patient did not report any facial deviation, facial numbness, difficulty in swallowing, weakness of limbs or swaying while walking. There was no history of headache, vomiting, trauma or fever. Personal history was negative for diabetes mellitus, hypertension or stroke.

On examination, the patient was fully conscious, cooperative and oriented. She was afebrile with a pulse rate of 76 bpm and blood pressure of 126/72 mm Hg. Pallor was present but there was no icterus, clubbing, cyanosis, lymphadenopathy or oedema. CNS examination revealed normal higher mental function, a right-sided complete ptosis with hypotropia and exotropia of the right eye. She had difficulty in adducting, elevating and depressing the right eye. The right pupil was dilated and non-reactive to light. The fundus examination revealed no abnormality. Other cranial nerves were normal. There was no sensory or motor weakness and the cerebellar examination were within normal limits. The findings were suggestive of an isolated right oculomotor palsy. The remaining systemic examination was within normal limits.

Investigations

The patient underwent an MRI brain on emergency basis. The MRI showed a mass lesion arising from the right clivus with extension into the right cavernous sinus (figure 1). A space occupying lesion due to a solid malignancy was considered, and it offered a possible explanation for the isolated right oculomotor palsy. However, the routine investigations unveiled a different picture. There was normocytic normochromic anaemia with a haemoglobin of 40 g/L. Total and differential leucocyte count and platelet count were normal and the peripheral smear revealed a background staining. There was renal dysfunction with a creatinine of 2.3 mg/dL. Corrected calcium was 15 mg/dL and albumin was 1.2 g/dL, A:G ratio was 0.1. These investigations were highly suggestive of MM. Subsequently, her bone marrow aspiration was a dry tap and bone marrow biopsy revealed a hypercellular marrow with diffuse infiltration by plasma cells which accounted for 70% of the total marrow cellularity and rest of the haematopoietic cells were markedly reduced (figure 2). Reticulin stain showed dense grade 3 fibrosis. Immunohistochemistry revealed kappa restriction. Serum protein electrophoresis and immunofixation were positive for an IgG kappa type of myeloma with an M spike of 5.88 gm/dL. The serum-free light chain ratio was 35.8, beta2 microglobulin were 13 358 ng/dL and skeletal survey was suggestive of multiple lytic lesions. Fluorescence in situ hybridisation for myeloma could not be performed due to lack of a bone marrow aspirate sample. She was diagnosed with stage III MM as per the international staging system (ISS). ISS stage 3 is suggestive of an advanced disease with a median survival of 29 months.

Figure 1.

MRI brain shows a mass lesion arising from the right clivus with extension into the right cavernous sinus.

Figure 2.

Bone marrow biopsy shows near total replacement by plasma cells.

Differential diagnosis

At the time of presentation, the most likely causes for an isolated third nerve palsy in a middle-aged woman were either a cerebrovascular accident, or a space occupying lesion due to a solid malignancy. The MRI suggested that a space occupying lesion could have caused the third nerve palsy. The blood, biochemical investigations and bone marrow, however, were suggestive of MM. Since her sensorium was normal, metabolic encephalopathy was less likely. CNS thrombosis was still a possibility, but this was excluded by MRI findings. Since CNS involvement in MM is extremely rare, especially at initial presentation, it was unclear whether the mass arising from the clivus was perhaps a plasmacytoma or if we were dealing with two different diseases altogether. Caught between Occam’s razor and Hickam’s dictum, we wanted to exercise caution before making such a rare diagnosis and wished to obtain a biopsy from the clivus lesion. However, the patient declined consent for the biopsy. Her cerebrospinal fluid (CSF) analysis was inconclusive and did not reveal any presence of plasma cells.

Treatment

Hypercalcaemia was corrected with aggressive hydration using isotonic saline, salmon calcitonin 200 IU (international units) subcutaneous three times a day for 2 days and a single dose of injection pamidronate 90 mg administered intravenously over 4 hours. In view of renal failure, chemotherapy was initiated with bortezomib, cyclophosphamide and dexamethasone protocol. The patient showed a dramatic improvement in symptoms with resolution of the third nerve palsy by day 6 of therapy thus proving that the clivus lesion was indeed a plasmacytoma. She also received 45 gray radiation over 25 fractions to the base of skull over the next 5 weeks. MRI brain repeated after initiation of therapy and improvement in ocular symptoms revealed a significant reduction in the size of the lesion (figure 3).

Figure 3.

MRI brain performed after initiation of therapy shows a significant reduction in the size of the intracranial lesion.

Outcome and follow-up

She achieved VGPR following six cycles of bortezomib-based therapy following which she was counselled for autologous stem cell transplant but the patient was unwilling for it due to personal reasons. As the renal function had improved on therapy, she was initiated on maintenance therapy with lenalidomide. The patient developed a biochemical relapse 12 months into her maintenance and was shifted to the second line therapy, which she has continued for 7 months at last follow-up.

Discussion

MM can exhibit a myriad of neurological symptoms. Most of these symptoms occur due to spinal cord compression from pathological fractures or due to metabolic causes such as hypercalcaemia, paraproteinaemia and uraemia. Very rarely, they result from intracranial involvement by myeloma. Myeloma may infiltrate the CNS in three different patterns: osteodural, leptomeningeal or parenchymal involvement. The exact aetiopathogenesis is unknown but it is believed that osteodural involvement, as seen in our patient, occurs due to direct spread from contiguous bone lesions while leptomeningeal and parenchymal involvement are a result of haematogenous spread.⁶ Extramedullary disease in myeloma is believed to occur due to mutations in Rat Sarcoma (RAS) and TP53 genes which may allow the tumour cells to proliferate independent of the bone marrow microenvironment.^{7 8} The downregulation of CD56 (cluster of differentiation) expression, which is an adhesion molecule on myeloma cells, is known to promote extravasation of plasma cells and may play a role in extramedullary disease. While a few studies have shown increased prevalence of loss of CD56 in CNS MM, its exact role in CNS MM is unclear.⁹

In an ideal setting, the diagnosis of CNS myeloma should be made on the basis of imaging and the presence of monoclonal plasma cells in CSF.¹⁰ Histopathological analysis of the CNS lesion would also serve to confirm the diagnosis, however, it is often not feasible due to procedure related risks, financial constraints and unwillingness of the patient. Also, arranging urgent MRI, coordination with neurosurgical team and anaesthesia clearance for procedure in malignancy patient, in need for urgent therapy are common hindrances faced in real life patient management. In a study by Jurczyszyn et al, 93% of CNS MM patients who underwent MRI brain/ spine had evidence of disease on the scan whereas 81% of those who underwent CT scan brain/spine had evidence of CNS disease on imaging, thus making MRI a preferred imaging modality for diagnosis in CNS MM.⁹ CSF cytology and flowcytometry together help establish the presence of monoclonal plasma cells in the CSF. On detection of plasma cells in the CSF, establishing monoclonality is a must as polyclonal plasma cells may be present in other conditions as well.¹¹ However, the absence of plasma cells does not rule out the diagnosis of CNS MM. In the real-world scenario, performing all the investigations to establish the diagnosis may not be feasible and the diagnosis may have to be made with limited positive investigations. In our patient, consent for a histopathological assessment could not be obtained and the CSF did not reveal any plasma cells, the presence of osteodural type of pattern on MRI and the rapid improvement of symptoms on therapy helped establish the diagnosis ex juvantibus.

Since CNS MM is rare and there is limited information available on treatment outcomes, there are no guidelines available for the management of CNS MM. The options include systemic chemotherapy, radiation and intrathecal therapy (IT) chemotherapy, used alone or in combination. With the availability of newer agents, systemic chemotherapy forms the backbone of treatment. However, its optimisation in CNS MM is ridden with challenges. The drugs must cross the blood–brain barrier (BBB) and the possibility of drug resistant myeloma must be considered in previously treated myeloma patients. Bortezomib does not cross the BBB but has activity against CNS MM perhaps due to disruption of BBB by inflammatory changes and increased vascular permeability of the tumour.⁶ Thalidomide and lenalidomide have limited CSF penetrance and whether optimal drug levels are achieved is uncertain.¹² Pomalidomide crosses the BBB and has shown sustained responses in anecdotal cases.¹³ Dexamethasone is known to have CNS penetration but is ineffective alone. Myeloma is exquisitely sensitive to radiotherapy (RT), and in one review, cranial irradiation was associated with a statistically significant benefit in improving survival (median 3 vs 0.81 months) compared with those who did not receive RT.¹⁴ However, in a study by Gonzetti et al, RT significantly improved the outcome only when associated with new agents.⁶ The role of IT in myeloma is uncertain as it has not proven effective in monotherapy or in combination with RT in the absence of systemic chemotherapy.⁹ Plasma cells are not considered particularly sensitive to cytarabine or methotrexate used in IT. Our patient had an excellent response to systemic chemotherapy and also received RT later on. Since osteodural lesions are expected to draw their blood supply from the bone, systemic chemotherapy would play a crucial role in such patients.

The median OS of CNS MM is under 6 months.⁴ Our patient is on therapy for over 26 months; a better understanding of the prognostic factors revealed that despite having CNS MM, our patient had several of the prognostic factors associated with relatively better outcomes. In a retrospective study of 172 CNS MM patients by Jurczysyzn et al, history of therapy for myeloma and having more than one adverse risk cytogenetics were risk factors for poor OS. OS for patients who had none, one or both these risk factors was 25 months, 5.5 months and 2 months, respectively.⁹ In another study, multivariant analysis revealed that patients with beta 2 microglobulin >5 mmol/L had a poor OS and progression-free survival (PFS) (HR 3.27; 95% CI) whereas patient who achieved complete remission+VGPR had an improved OS and PFS (HR 0.39; 95% CI).⁶ Patients receiving a combination of systemic chemotherapy, RT and IT appear to do better than those who do not receive systemic chemotherapy, although prospective randomised control trials are lacking.⁹ Another subgroup of CNS MM that has relatively better outcomes is the osteodural type. For patients with osteodural involvement, the median OS ranges from 1 year to 25 months as compared with the median OS of 6 months for leptomeningeal or parenchymal type.⁶ This is possibly due to its distinctive aetiopathogenesis allowing systemic chemotherapy to have better penetrance and in turn improving response to therapy. However, this would need to be substantiated with further evidence.

Patient’s perspective.

I had been to a couple of hospitals before coming here but none of them could establish my diagnosis conclusively which was very worrying. The doctors here told me that I had multiple myeloma which is a type of cancer of blood cells. While the thought of having cancer was frightening at first, the rapid improvement in my eye symptoms was very reassuring and made me feel that the treatment was working well.

Other than the occasional pain in my bones, I have been feeling well for the last 2 years.

Learning points.

• Intracranial involvement by multiple myeloma (MM) is rare, occurring in about 1% of myeloma patients. 76% of these present at relapse while 24% present at initial diagnosis.

• Metabolic derangements such as hypercalcaemia, uraaemia, paraproteinaemia and pathological spinal fractures may act as confounding factors thus making the diagnosis of central nervous system, MM challenging.

• Ideally, the diagnosis is made on the basis of imaging and the presence of plasma cells in cerebrospinal fluid or on the basis of histopathology although it may not always be feasible.

• There is no consensus on therapy but patients who receive a combination of systemic chemotherapy with newer agents and radiotherapy with or without intrathecal therapy do better.

• The median overall survival (OS) is dismal at 1–4 months, however, the osteodural subtype has a better OS of 1 year possibly due to its distinct aetiopathogenesis.