Diagnosis and management of leptomeningeal disease secondary to grade IV astrocytic glioma

Background

Leptomeningeal disease (LMD) secondary to astrocytic glioma is a rare complication of an uncommon condition. LMD is most commonly secondary to melanoma, breast and lung cancers in adults and has a poor prognosis; median survival after diagnosis of LMD is 3–6 months.1 Treatment is often limited to palliative options, with the goal of preserving neurological function and prolonging survival.2 Correctly diagnosing LMD is important to allow for effective symptom control. However, symptoms and signs can be non-specific and can overlap with more common pathologies such as infective meningitis. The build-up of cerebrospinal fluid (CSF) and the increase in subarachnoid pressure can lead to irreversible visual loss and be detrimental to a patient’s quality of life. Initial blood tests, observations and CT head scan findings can be unremarkable, leading to difficulty and delay in reaching the diagnosis.

Here, we report a case of LMD secondary to grade IV astrocytic glioma presenting 1-year postresection of the primary tumour, and discuss challenges faced by clinicians at a small rural district general hospital (DGH) in diagnosing and managing this condition during the COVID-19 pandemic.

Case presentation

A man in his mid40s presented to a DGH with acute confusion, photophobia, vomiting, headaches and visual changes. The patient spoke English and Welsh fluently. One year prior, the patient was diagnosed with an isocitrate dehydrogenase mutant grade IV left temporal astrocytic glioma (figure 1) and underwent total surgical resection of the lesion at a tertiary centre, followed by radiotherapy at a different tertiary centre. The primary tumour was MGMT methylated (O⁶-methylguanine-DNA-methyltransferase gene) and deemed favourable for temozolomide chemotherapy. However, the patient chose not to undergo chemotherapy due to concerns about immunosuppression and the risk of COVID-19 associated with attending hospital for treatment. The patient experienced receptive dysphasia postoperatively.

Observations and blood tests on this admission were unremarkable. On general neurological examination, expressive dysphasia and gait ataxia were noted. Cranial nerve examination was unremarkable. Upper limb examination revealed generalised hyper-reflexia bilaterally. Lower limb examination revealed positive right sided Babinski reflex, joint proprioception abnormality of the right first interphalangeal joint and absent vibration sense of the right first interphalangeal joint (though not the metatarsophalangeal joint). There was no light touch sensory loss or muscle power loss in the upper or lower extremities.

The patient was referred to an ophthalmologist and found to have severe papilloedema with significant visual field defects. Visual acuity was 6/6–2 on the right and 6/12+2 on the left.

Investigations

Following surgical resection of the primary tumour, the patient had had several MRI head scans for disease surveillance. The MRI head scan 1 month prior to admission was stable and the radiological report indicated no interval change (figure 2). The MRI head scan on the current admission showed new abnormal leptomeningeal enhancement involving the base of the brain and brainstem (figures 3 and 4). The quick development of these changes was deemed highly suspicious of acute meningitis by the consultant radiologist.

On the initial lumbar puncture (LP), a CSF protein of 20.11 g/L (normal range: 0.15–0.45), CSF glucose 5.9 mmol/L (normal range: 2.2–3.9), CSF lactate 8.2 mmol/L (normal: <3.0) with an opening pressure of >35 cmH2O were recorded. CSF culture was negative. The cytology was limited by extensive cell degeneration, which is not uncommon in CSF preparations, and was analysed both locally and sent to a tertiary centre for a second opinion. Atypical cells with a few multinucleate forms were identified on both the Grocott methenamine silver and periodic acid-Schiff stain preparations, some with larger nuclei and significant pleomorphism. MRI spine, which was performed of the complete neuraxis to rule out further sinister pathology, did not reveal spinal metastases (figure 5A–C).3 The neuroradiology multidisciplinary team (MDT) reviewed all the prior imaging, and reported that the most recent imaging showed significantly increased T2 hyperintensities indicating more extensive caking of the posterior fossa and cerebral hemispheres when compared with previous MRI scans (figure 4).

Differential diagnosis

The initial neurological examination findings were suspicious of upper motor neuron pathology, which could not be fully explained by the existing knowledge of the patient’s condition. Following consultation with neurologists at a tertiary centre, it was deemed that the right side upgoing plantar reflex and expressive dysphasia could be explained by the surgical resection of the primary tumour. However, the other findings meant that further investigation was warranted. The new acute changes on the MRI head compared with the images 1 month prior meant that an acute meningitis secondary to infection was the working differential diagnosis. One of the most alarming CSF findings was the extremely high protein level, and therefore, a diagnosis of tuberculous meningitis had to be considered. However, considering the low prevalence of tuberculosis in the area, lack of foreign travel in the clinical history and the high glucose level on the CSF (normally low in tuberculous meningitis), this diagnosis was felt unlikely.

To elucidate the full extent of the disease and rule out a neoplastic cause, an MRI whole spine was requested. An urgent ophthalmology referral was made to definitively characterise the visual deficits, which identified severe papilloedema. This finding reinforced the urgency to find a diagnosis and provided a baseline from which we could monitor the patient’s intracranial pressure and consequent visual symptoms. Monitoring was conducted by the DGH, and updates were provided to the neurosurgical and neuro-oncology MDT at the tertiary centre. From CSF cytology alone, it was difficult to confidently diagnose a malignant infiltrate. When correlated with clinical and radiological features, and after discussion at the neuro-oncology MDT, a diagnosis of leptomeningeal metastatic infiltration by glioma was made.

Treatment

Treatment was initiated with high-dose intravenous dexamethasone with intravenous antibiotics for meningitis, and symptoms initially improved but intermittently recurred. After discussion with the neurosurgical team and the neuro-oncology MDT, it was felt that the focus of treatment should be palliative as no curative options were available. Of immediate concern was the threat to the patient’s vision due to the high subarachnoid pressure. It was agreed that a permanent CSF diversion with a ventriculoperitoneal (VP) shunt was the ideal way to relieve this pressure, though noting that there would be a significant risk of blockage given the elevated CSF protein levels. Daily therapeutic LPs to remove 30–50 mL of CSF were advised, with the vast majority of these being performed in a sterile operating theatre environment to reduce the risk of infection.

The patient’s symptoms initially improved and the LPs were therefore reduced to alternate days for the patient’s comfort. A temozolomide regimen with palliative intent was started on the ward at the DGH, with the aim to bring the protein level down to allow for the VP shunt to be performed and to improve prognosis.

The therapeutic LPs became increasingly ineffective and within 2 weeks, visual acuity deteriorated to 6/18 on the right and worse than 6/60 on the left. A COVID-19 outbreak on the neurosurgical ward at this time led to a detailed virtual discussion between the neurosurgeons in the tertiary centre, the local oncology team, the patient and their next of kin. The discussion pertained to the treatment options available at the time, which included: (1) a return to daily LPs until the COVID-19 outbreak on the ward had settled; (2) transfer to a tertiary centre for a lumbar or external ventricular drain to alleviate the pain of having daily LPs or (3) insertion of a VP shunt, accepting the risk of acute blockage. All involved understood that options 2 and 3 had an increased risk of COVID-19 infection with the added risk that the completed cycle of temozolomide could dampen the patient’s immunity. The patient informed us that he was not concerned about the discomfort of the LPs and decided to continue with option 1.

There continued to be a serious risk of the patient losing their vision before the CSF protein level was low enough for the VP shunt, with no guarantee that it would ever reach the required level. With the COVID-19 situation improved on the neurosurgery ward and the CSF protein levels reaching 4.01 g/L, the lowest recorded level for the patient since the LMD diagnosis, the decision was made in conjunction with the patient’s wishes to proceed with a VP shunt.

Outcome and follow-up

The patient’s postoperative recovery was uneventful. He was repatriated to his local hospital and discharged home. Due to a low platelet count, the dose for the palliative temozolomide regimen was reduced to 85% in cycle 2. The patient’s symptoms improved, and LPs were no longer required. For the next 3 months, the patient enjoyed a good quality of life without requiring any further hospital admissions. The patient continued to have a degree of expressive dysphasia but was able to maintain a conversation. He was able to mobilise safely with a stick without any balance issues and reported returning to reading as a hobby. He was able to read large letters clearly, but found smaller letters blurry. On follow-up with ophthalmology, unaided visual acuities were 6/9–1 on the right and 6/60 on the left, improving to 6/36 with pinhole view. Fundus examination showed well defined disc margins in the right eye with definite pallor but no oedema. On the left there was old swelling of the optic nerve nasally with temporal pallor. There were optic nerve changes present in both eyes secondary to hydrocephalus, but the changes were felt by the ophthalmologist to be old.

Symptoms gradually worsened 3 months post-VP shunt insertion with the patient developing increased confusion, agitation, vomiting, blurred vision and seizures. Symptom control with medications including antiepileptics was initiated. A CT head scan in the patient’s final hospital admission showed the ventricles were dilated more than previously. An MRI head scan showed that extensive leptomeningeal dural disease had developed. The patient passed away peacefully on the ward, 6 months after the VP shunt was inserted.