Background

This case is important because the presentation was very unusual and initially more suggestive of other conditions. Therefore, the diagnosis was delayed despite the collaboration of an ophthalmologist, neurologist and rheumatologist. Serum ACE was misleading in this case as a positive result in conjunction with a history initially felt to be typical of sarcoidosis was non-specific.

This case shows that lymphoma should always be high on the differential diagnosis where there are unusual or confusing neurological symptoms. Although peripheral nerve syndromes are well-recognised as complications of lymphoma and other lymphoproliferative disorders, they can occur as the presenting complaint and sometimes precede the underlying diagnosis by months to years.

Case presentation

A 50-year-old engineer with a history of ulcerative colitis, autosplenectomy and thyrotoxicosis complained of flashing lights, deteriorating vision and pain on looking down affecting his left eye with occasional minor symptoms affecting the right eye. Visual acuity was 6/5 right and 6/36 on the left and an active granulomatous macular lesion was seen in the left eye with widespread chronic choroidoretinal changes. Prednisolone 60 mg daily was started with a working diagnosis of probable sarcoidosis. No evidence of systemic sarcoidosis was found and high resolution CT scan of the chest was normal. The visual symptoms improved dramatically with the prednisolone and signs of ocular inflammation largely disappeared. Five weeks later, and despite continuation of high-dose steroids, he developed a left XII nerve palsy and allodynia. A MRI scan of the brain with contrast was normal. After a further 5 weeks, the XII nerve palsy suddenly improved dramatically despite no change in treatment. Two months later he experienced diplopia on downward gaze secondary to a right IV nerve palsy in addition to numbness over the right cheek and numbness in the right ulnar nerve distribution and at the tip of the left index finger. The diplopia and numbness gradually improved. By this time it had become apparent that he was unable to reduce the dose of the steroids below 25 mg daily without recurrence of his visual symptoms so azathioprine was introduced. A repeat MRI scan of the brain with contrast was normal and nerve conduction studies showed only an attenuated right ulnar sensory potential.

The diagnosis was reviewed and vasculitis was considered as a possibility. Azathioprine was withdrawn after 8 weeks due to thrombocytopenia and was replaced by mycophenylate with an initial course of pulsed intravenous methyl prednisolone 750 mg once weekly. The patient began to experience drenching night sweats, fevers, chills and fatigue. He found the first infusion of methyl prednisolone immediately very debilitating but within an hour of the second steroid infusion he started to develop a left VII nerve palsy leading to complete paralysis of the left side of the face within the next 2 days and was re-admitted to hospital for further investigations.

General examination was normal with no lymphadenopathy or hepatomegaly. Neurological examination revealed evidence of the following cranial nerve palsies: right IV, right Vii, left VII, left XII, as well as reduced sensation in the right ulnar nerve distribution. Cerebrospinal fluid (CSF) examination and repeat MRI did not reveal any abnormalities.

Ophthalmological review at this time revealed a large amount of debris in the vitreous humor of the left eye requiring vitrectomy.

Investigations

Initial investigations when the patient first presented with the XII nerve palsy included basic biochemistry, full blood count, C reactive protein (CRP), plasma viscosity (PV), anti-nuclear antibody (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), immunoglobulins, serum electrophoresis, Venereal Disease Research Laboratory (VDRL) and Mantoux tests, all of which were normal or negative. Serum ACE was raised at 90 μ/litre.

After 10 weeks of high-dose steroid treatment, serum ACE level had returned to normal. The CRP was slight raised at 15.5 with a normal PV 1.62.

Ten months after the initial presentation flow cytometry of the vitreous humour showed lymphomatous cells. Leucocytes from the vitreous specimen were isolated by ammonium chloride lysis. In view of the small volume of sample available, a limited four-colour flow cytometry panel was used and this identified a clonal B-cell population (CD19+, sIgK+, CD5–). The diagnosis of activated B-cell type diffuse large B-cell lymphoma was confirmed on the bone marrow sample taken 7 days later using a combination of four-colour flow cytometry supplemented by immunocytochemistry on the trephine biopsy. The composite phenotype was CD5–, CD10–, BCL2+,IRF-4+, BCL-6+/–, FOX P1+,CD38+ with a cycling fraction of 70% (figure 1). A staging CT scan revealed a 16 mm superior mediastinal mass as well as widespread nodal and extra nodal disease in the abdomen.

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Figure 1

Nodule containing diffuse large B cell lymphoma in bone marrow. (i) H&E stain, (ii) showing CD20 expression.

Outcome and follow-up

Following six cycles of CHOP-R (cyclophosphamide, doxorubicin, vincristine, prednisolone and rituximab) there was good, but short lived, remission of lymphoma affecting nodes and bone marrow and the IV nerve palsy largely resolved with significant improvement in the V and VII nerves and the hypersensitivity. The patient failed to respond to a second course of chemotherapy and died 6 months after diagnosis and 18 months after the onset of the first symptoms.

Discussion

Non-Hodgkin’s lymphoma is a malignant proliferation of T or B cell type and primary intraocular lymphoma, usually diffuse large B cell lymphoma, is well-recognised although extremely rare, frequently mimicking much commoner conditions and making diagnosis difficult.1 Diagnosis relies on demonstration of malignant cells in the ocular specimens in cases, such as this, where the CSF was initially normal and, therefore, is not undertaken without significant clinical suspicion. In this case the diagnosis was made by immunophenotypic analysis of the vitreous specimen using flow cytometry, which is widely used in the diagnosis and classification of intraocular lymphoma.2

Peripheral nerve syndromes, including sensory, motor or sensorimotor peripheral neuropathy, mononeuritis, mononeuritis multiplex, plexopathies and radiculopathies, are unusual complications of lymphoma and other lymphoproliferative disorders where, in a small proportion of both B, and less often, T cell lymphomas, they can occur as the presenting complaint, sometimes preceding the underlying diagnosis by several years.3 Several different mechanisms leading to peripheral nerve syndromes have been demonstrated, the commonest being meningoradiculopathy (including cranial nerves) where abnormalities in either CSF or MRI are found in over 90%. Neurolymphomatosis is the commonest mechanism of purely peripheral nerve involvement where malignant cells propagate into the peripheral nervous system in a patchy fashion; this is easily missed on biopsy unless as long a segment as possible is taken from an involved sensory nerve, rather than a standard sural nerve biopsy with many cases proven only at autopsy. The predilection for certain parts of the peripheral nervous system in individual patients is not understood but it has been shown that some patients with T cell lymphoma produce particular adhesion cells that help tumour cells cross the blood–nerve barrier. Peripheral nerve damage can also result from dysimmune inflammation and haematogenous metastatic vascular occlusion as well as a result of anti-nerve monoclonal antibodies.4 Less commonly, vasculitis or cryoglobulinaemia can cause mononeuropathy or asymmetric neuropathy.4 There remains a small group of patients in whom the link between the peripheral neuropathy and the non-Hodgkin lymphoma remains unexplained, possibly secondary to an as yet unknown paraneoplastic mechanism.

In some patients, the peripheral nerve syndromes improve or disappear with treatment of the underlying cancer and may recur with relapse of the lymphoma. In one case of haematological remission, and in the absence of evidence of systemic or central nervous system lymphoma, neurological symptoms developed that were found, at autopsy, to be secondary to infiltration by tumour of the femoral nerves.3 The interesting point about the case we present is that the individual nerve palsies developed and subsequently improved while the patients’ treatment with high-dose oral steroids was unchanged. For example, the XII nerve palsy appeared after 5 weeks of high-dose oral steroids only to improve significantly overnight a few weeks later without any alteration in treatment. The IV nerve palsy then developed while on the high-dose steroids about the time azathioprine was introduced and improved without any changes in treatment. Although lymphoma is, to a degree, steroid responsive, the facial weakness developed immediately following the second pulse of high-dose intravenous methyl prednisolone.

There was no paraprotein in this case and, due to the particular nerves involved, no biopsy has been possible but the likely mechanism for nerve damage in this patient was vasculitis or vascular occlusion, but it is difficult to hypothesis as to why such lesions that have developed on steroids might improve again without increased immunosuppression or chemotherapy. The patient did not experience any intercurrent infections or other physiological stresses coincident with the fluctuation of the symptoms. The allodynia remains unexplained, but a small fibre neuropathy could explain the pain syndrome in the context of the normal nerve conduction studies, although the nerve conduction studies were done quite early in presentation and were not repeated.

Finally, the pathway to the final diagnosis also deserves some discussion. Initially, sarcoidosis was thought to be the most likely unifying diagnosis as it is the commonest cause of uveitis and is well-known to cause cranial nerve palsies, more often via granulomatous infiltration of the meninges than associated with vasculitic mononeuritis multiplex. In this case, no hard evidence for systemic sarcoidosis was found and the serum ACE that was initially raised turned out to be non-specific and misleading. Diagnosis of primary intraocular lymphoma is challenging but it is important to recognise it as early as possible. The difficulty lies in its rarity and that it presents similarly to several much commoner diseases that are not always easy to firmly diagnose in their own right as with sarcoidosis.1 Therefore, it is important to keep lymphoma in mind when treating for a more likely alternative and to review the diagnosis early if the disease behaves atypically, as in this case, where the neurological symptoms in particular progressed in spite of treatment.