Primary leptomeningeal lymphoma masquerading as infectious tubercular meningitis

Background

Primary central nervous system lymphoma (PCNSL) is a rare extra nodal non-Hodgkin’s lymphoma accounting for 3%–4% of newly diagnosed central nervous system (CNS) tumours. As the name implies, it is confined to the brain, spinal cord and eyes.1 PCNSL poses frequent diagnostic challenges due to its location, varied and non-specific clinical manifestations and lack of diagnostic tests with a high sensitivity. Clinical presentations reported in the literature include impairment of higher functions, features of raised intracranial pressure, focal neurological deficit, seizures and headache.2 Visual loss is a predominant feature in intraocular (retinal) lymphoma; however, this can also occur indirectly as a consequence of raised intracranial pressure or direct cranial nerve involvement (optic nerves) in other forms of PCNSL with meningeal infiltration.3 4 While leptomeningeal seeding of lymphoma can occur as a late manifestation of systemic lymphoma or synchronously with PCNSL, lymphoma isolated to the leptomeninges is exceedingly rare.5

We report the case of a young immunocompetent man with the diagnostic dilemma associated with a chronic meningitis presentation with prominent hypoglycorrhachia. The first diagnostic suspicion was meningeal tuberculosis (TB), considering the South Asian origin with high endemic prevalence and cerebrospinal fluid (CSF) analysis. However, further investigations disclosed a primary leptomeningeal lymphoma (PLML). Persevering with investigations when appropriate, along with early adequate CSF analysis, is pivotal in establishing timely diagnosis. This is particularly important at a time where new therapeutic regimes of highly effective chemotherapy combinations with autologous stem transplantation improve prognosis in this aggressive lymphoma subset with a potential to achieve durable remission or cure.6

Case presentation

A previously healthy 37-year-old man of South Asian origin presented with an insidious increase in fronto-occipital headaches over several weeks, which displayed high-pressure features at presentation. There was no associated fever or weight loss. He was a non-smoker and did not drink alcohol. He was born in Pakistan, lived in the UK for 17 years, and his last visit to Pakistan was 3 years ago. He had never received BCG vaccine.

An assessment by the ophthalmology emergency services confirmed the presence of papilloedema. There were no localising neurology signs. The remainder of the systemic examination and biochemistry results were normal. His visual acuity on formal ophthalmology assessment was 6/6 in both eyes. His visual fields were full bilaterally and he had no visual symptoms. A slit lamp examination did not show any evidence of anterior segment inflammation or corneal keratic precipitates. Dilated fundus examination disclosed only Frisén grade 2 papilloedema with a sphincter haemorrhage along the superior part of the disc in the right eye and Frisén grade 1 in the left (figure 1A).

Investigations

Preliminary work-up revealed a normal CT of the head and CT venogram. MRI of the head and spine with contrast failed to demonstrate any significant findings at that stage. A lumbar puncture and CSF analysis revealed raised opening pressure of 32 cmH₂O, raised CSF protein of 1.72 g/L, low glucose of 1.0 mmol/L and a white cell count of 126 cells/μL (10% polymorphs and 90% lymphocytes). CSF smears, TB PCR and cryptococcal antigen were negative (details shown in table 1). A whole body CT scan was normal. HIV, hepatitis B and C screen, and syphilis antibodies were negative. Likewise, autoimmune screen including antinuclear antibodies, extractable nuclear antigen and rheumatoid factor were within normal titres. He had normal full blood counts, ACE levels, and thyroid, liver and renal function tests. B₁₂ and folate levels were also normal, and C reactive protein was 1 mg/L.

Based on the CSF characteristics (lymphocytic pleocytosis with marked hypoglycorrhachia) and absence of other evident alternative causes, he was diagnosed with probable TB meningitis, and empirical treatment immediately started with rifampicin, isoniazid, ethambutol, pyrazinamide with pyridoxine and a tapering dose of oral dexamethasone.

He re-presented with worsening headache 6 weeks after initiation of anti-tubercular treatment (ATT) and steroids and was assessed in a specialist neuro-ophthalmology clinic. An increase in the papilloedema by one grade was identified during this presentation with ongoing headaches (figure 1B). His visual acuity was still normal in keeping with mild to moderate papilloedema with no relative afferent pupillary defect (RAPD), full colour vision and normal intraocular pressure. A QuantiFERON TB assay had returned negative, and there were no other manifestations of pulmonary or milliary TB. Another lumbar puncture was instigated to include cytology and flow cytometry. CSF analysis (details shown in table 1) showed a similar biochemical profile with raised protein of 2.94 g/L, very low glucose of 1 mmol/L, white cell count of 190 cells/μL and red cell count of 386 cells/μL (0% polymorphs and 100% lymphocytes). Both cytology and cytospin were requested but not adequately processed due to a laboratory sampling error, with inconclusive results in the analysed lymphocytes. Beta-glucan and histoplasma antibodies were negative in CSF with no antibodies in serum against dimorphic fungi or histoplasma. Cultures for mycobacteria and fungi did not grow any organisms.

Differential diagnosis

Profound hypoglychorrachia is often considered synonymous with the presence of glucophagic micro-organisms7; however, other conditions can also cause this type of CSF. Infectious meningitis from mycobacteria or fungi followed by a haematological malignancy or neurosarcoidosis8 was the differential diagnosis when considering the insidious presentation with raised intracranial pressure, lymphocytic pleocytosis and high protein. CSF pleocytosis with low glucose may also harbour other different carcinomatous meningitis and infections (parasitic, viral and atypical bacteria and spirochetes).9

Eight weeks after first presentation, the patient reattended emergency services with visual drop in the right eye and a worsening of his headache as steroid was being tapered. Neuro-ophthalmology examination found a new retrobulbar right optic neuropathy with an evident afferent pupillary defect. A reduction of the nerve fibre layer in this eye in the following days from ensuing atrophy was seen, while there was persistent swelling in the fellow eye (figure 1C). Automated perimetry (Humphrey 24/2 visual fields) of both eyes showed a right dense central scotoma with marked reduction of sensitivity to light stimulus. The left visual field is normal (figure 2). Other cranial nerves remained intact. This was thought to represent a likely direct retrobulbar optic nerve infiltration from progressive meningeal disease. Ethambutol toxicity is a differential for visual loss in this context; however, this is typically bilateral and not compatible with a purely unilateral dense optic neuropathy.10 Another MRI of the brain with contrast showed mild cavernous sinus and subtle trigeminal nerve enhancement of the right side (figure 3A,B) with no significant hydrocephalus. A repeat MRI spine with contrast found subtle leptomeningeal enhancement and thickened cauda equina nerve roots (figure 4).

A third lumbar puncture with CSF analysis (details shown in table 1) showed an increase in the lymphocytosis to 275 cells/μL with a further drop in glucose to 0.3 mmol/L and very high protein of 8.27 g/L. Cytology found highly suspicious malignant cells, and CSF flow cytometry confirmed a diffuse large B-cell lymphoma (table 2). Bone marrow biopsy did not show any peripheral involvement, and staging with CT of the thorax, abdomen and pelvis was negative.

A positron emission tomography (PET) scan confirmed that the lymphoma was confined to the meninges, showing multiple deposits within the spinal canal, intervertebral foramina and nerve roots (figure 5A,B).

Treatment

The patient has had high-dose chemotherapy designed to penetrate the blood–brain barrier with a MATRix regimen and has received an autologous peripheral blood stem cell transplant.

Outcome and follow-up

To date, the patient had received a full course of MATRix chemotherapy with prophylactic antimicrobials and granulocyte colony-stimulating factor. He was admitted with sepsis and thrombocytopenia following the fourth cycle, which responded to treatment. MRI of the brain and spine has shown full remission, and treatment has progressed towards an autologous peripheral blood stem cell graft. The vision in the right eye remained, counting fingers with an established optic atrophy, while normal vision in the left eye was maintained throughout with a complete remission of the papilloedema.