Challenge Case Report: Acute Onset of Expressive Aphasia, Visual Disturbances, and Severe Headache

Case Presentation

X-MW, age early 50 years, who was right-handed, presented to an outside (nontertiary) hospital after acute onset of expressive aphasia and the presence of bright spots in the right peripheral vision in the setting of severe headache. Speech and vision changes spontaneously improved after 30 minutes, but headache persisted. Noncontrast CT and MRI of the brain with and without contrast were obtained (Figure 1). Providers at the outside hospital suspected multiple sclerosis (MS) or another demyelinating process, and X-MW was treated with IV methylprednisolone 1000 mg for 3 days, followed by 40 mg prednisone by mouth daily for 7 days, followed by a taper of 10 mg every 7 days. Subsequent improvement was seen with all presenting symptoms.

After the steroid taper, symptoms worsened with an increase in positional headache and right-sided visual field deficits. Repeat MRI (Figure 2) was performed in consideration of an alternate diagnosis. X-MW presented for a second opinion at the authors’ institution after another episode with transient speech changes occurred.

Neurologic examination upon presentation for the second opinion revealed subtle flattening of the right nasolabial fold and slight pronation without drift of the right upper extremity along with right homonymous hemianopsia and mild optic disc edema.

MRI brain and spine scans with and without contrast were repeated. Lumbar puncture (see results detailed in the following section) and brain biopsy (Figure 3) were performed.

Diagnostic Process

The neurologic findings are suggestive of a process involving the left hemisphere. The reported episode of transient expressive aphasia is suggestive of a cortical sign involving Broca’s area in the dominant hemisphere. The mild optic disc edema is concerning for increased intracranial pressure, possibly secondary to a space-occupying lesion.

CT and MRI scans were performed with results depicted in Figures 1 and 2.

Cerebrospinal fluid (CSF) analysis revealed opening pressure of 30 cm H₂O, 20 white blood cells/µL, a protein level of 89 mg/dL, and a glucose level of 61 mg/dL. The meningitis panel had negative results. Negative CSF results included oligoclonal bands, myelin basic protein, anti–myelin oligodendrocyte glycoprotein, aquaporin 4 antibodies, cytology, flow cytometry, and angiotensin converting enzyme. Liquid biopsy of the CSF was negative for circulating tumor DNA (ctDNA).

Figure 3 shows results of histopathologic and molecular analysis.

Questions and Answers:

1. An individual undergoes resection of an expansile mass. Immunohistochemical stains are negative for IDH1 R132H mutation with additional stains consistent with astrocytoma. Pathology does not demonstrate microscopic features of necrosis or vascular proliferation. Which of the following molecular features would lead to a diagnosis of World Health Organization (WHO) grade 4 glioblastoma as per 2021 WHO Classification guidelines?

A. O6-methylguanine-DNA methyltransferase promoter unmethylated

B. Gain of chromosome 10 and loss of chromosome 7

C. TP53 gene variation

D. Ki67 score >50%

2. An individual with previously diagnosed MS presents with a T1-enhancing lesion. Which of the following MRI features could provide additional diagnostic support for a tumefactive demyelinating lesion?

A. Decreased perfusion

B. T2 fluid-attenuated inversion recovery hyperintensity (FLAIR)

C. Diffusion restriction

D. Heterogenous enhancement pattern

Acute Onset of Expressive Aphasia, Visual Disturbances, and Severe Headache

Case Resolution

X-MW was ultimately diagnosed with glioblastoma (IDH-wildtype), WHO grade 4, involving the left hemisphere and splenium with leptomeningeal dissemination.

Standard of care treatment in the upfront setting of glioblastoma consists of maximal safe resection¹ followed by concomitant temozolomide (alkylating chemotherapy) with radiation at 60 Gy in 2 Gy fractions, then 6 adjuvant cycles of temozolomide.² There is newer evidence that proton craniospinal irradiation might provide dual benefit of symptomatic relief and survival improvement in people with neoplastic leptomeningeal disease secondary to solid tumors.³

X-MW started treatment with proton craniospinal irradiation with concomitant temozolomide. Resection was not performed because of the diagnosis of leptomeningeal dissemination. A ventriculoperitoneal shunt was placed for symptomatic relief. X-MW was started on levetiracetam (Keppra; UCB, Atlanta, GA) because her recurrent stereotyped transient neurologic events most likely represent focal seizures. More than 60% of individuals with glioblastoma will develop brain tumor–related epilepsy. If an individual has a brain tumor and new onset of seizure, it is recommended to start antiseizure medication.⁴ If an individual has a brain tumor but has never had a seizure, there are no data to support starting prophylactic antiseizure medication.

X-MW has passed away.

Discussion

Glioblastoma is the most common and most aggressive primary malignant brain tumor in adults.⁵ The incidence of leptomeningeal spread (LMS) at the time of diagnosis has been found to be ~.5% in people with glioma and ~4% at any time during the disease,⁶ reaching 25% on postmortem neuropathologic studies. It is thought that glioblastoma cells migrate from the parenchyma along brain vessels to the subpial, subarachnoid, and subependymal spaces. People with LMS can present with cranial nerve palsies (often irreversible), meningismus, hydrocephalus, increased intracranial pressure, or focal neurologic deficits. Rarer presentations that have been reported include intractable vomiting, aseptic fever, central neurogenic hyperventilation, sphincter incontinence, spinal ataxia, and radicular pain.⁷

Leptomeningeal enhancement is a nonspecific imaging finding with a broad differential, including neoplastic (primary and secondary), vascular, traumatic, inflammatory, autoimmune, toxic, and infectious etiologies.

Due to the leptomeningeal enhancement seen on imaging in this case, the concern for neurosarcoidosis or other inflammatory or infectious etiologies was raised. Leptomeningeal involvement is often seen in neurosarcoidosis in which parenchymal and spinal cord lesions can also be seen. The latter can manifest as the trident sign on imaging of the spinal cord, but a trident-like sign can also be seen in the setting of malignancy.^8,9

The imaging findings also raised concern for a demyelinating process. Tumefactive demyelinating lesions can mimic neoplasm on imaging, but in contrast to high-grade gliomas often have relatively little surrounding T2/fluid-attenuated inversion recovery changes and minimal mass effect; the enhancement tends to demonstrate an open-ring appearance (the incomplete portion facing the gray matter) and to have high apparent diffusion coefficient values and low cerebral perfusion.^10,11 Magnetic resonance spectroscopy has also been found to be useful, as elevation of the glutamate/glutamine peaks has been seen in demyelinating lesions and not seen in neoplastic processes.¹²

LMS in glioblastoma is a serious complication associated with poor prognosis. It can be a diagnostic challenge as cytology is positive in only 25% to 45% of cases on the first CSF evaluation.^6,7 Liquid CSF biopsies (to seek, for example, circulating tumor cells, cell‐free tumor DNA, microRNA, and exosomes) to make the diagnosis are being investigated and appear to have higher sensitivity than traditional cytology.¹³ However, detection of ctDNA does not necessarily indicate LMS but could possibly be seen secondary to shedding from parenchymal tumor.¹⁴ Advantages to ctDNA include the ability to quantify disease burden vs binary result (as in cytology) as well as to perform DNA sequencing. The latter is important clinically as differences in genetic alterations have been observed when comparing original brain tissue with ctDNA when the interval between collections increased.¹⁴ The validity and clinical utility of ctDNA are still under investigation and have thus far not been validated.

Conclusion

The differential diagnosis in the setting of leptomeningeal enhancement is broad, but when seen in the setting of an expansile intraparenchymal mass, there should be high suspicion for a neoplastic process. The yield of CSF is often low given the low sensitivity of cytology; in addition, the potential findings (eg, pleocytosis, elevated protein, hypoglycorrhachia) are nonspecific. There should therefore be a low threshold for expedited biopsy to establish diagnosis. The clinical utility of liquid biopsies from CSF is being investigated.

A multimodality treatment approach is needed, and standard of care includes surgery (ie, maximal safe resection if there is parenchymal disease in the noneloquent area), radiotherapy, and systemic chemotherapy. Genetic tumor profiling helps further classify the tumor and can aid in treatment planning. There may be an indication for immunotherapy, molecularly targeted therapies, or intrathecal chemotherapy. Molecularly targeted therapies in cases of actionable targets should be considered, especially in the setting of leptomeningeal disease.^7,15