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February 2025 CASE CHALLENGE: ACUTE ONSET OF EXPRESSIVE APHASIA, VISUAL DISTURBANCES AND SEVERE HEADACHEBy: Ditte Primdahl, MD; Pouya Jamshidi, MD; Jared T. Ahrendsen, MD, PhD; Shawn Kothari, MD; and Daniel Destiche, MD, of Northwestern Medicine Neurology
Case Presentation
A right-handed patient in their early 50s presented to an outside (nontertiary) hospital with acute onset of expressive aphasia and bright spots in the right peripheral vision, accompanied by a severe headache. Speech and vision changes spontaneously improved after 30 minutes, but the headache persisted. Non-contrast CT and MRI of the brain, with and without contrast, were performed (Figure 1). The initial differential diagnosis included multiple sclerosis (MS) or another demyelinating process. The patient was treated with intravenous methylprednisolone 1,000 milligrams (mg) for three days, followed by oral prednisone 40 mg daily for seven days, with a subsequent taper of 10 mg every seven days. The patient showed improvement in all presenting symptoms. 
Figure 1. Nonspecific brain imaging abnormalities of the posterior left cerebral hemisphere and cervical spinal cord. Axial non-contrast CT of the brain demonstrates ill-defined hyperdensity within the posterior left temporoparietal periventricular/subcortical white matter with associated confluent posterior left cerebral hemisphere white matter hypodensity (A). Contrast-enhanced MRI of the brain demonstrates subtle intrinsic T1 hyperintensity corresponding to hyperdensity on CT (B), subtle corresponding enhancement (C), and associated confluent fluid-attenuated inversion recovery hyperintensity of the posterior left cerebral hemisphere white matter extending across the splenium of the corpus callosum with questionable expansile left parietal cortical fluid-attenuated inversion recovery hyperintensity (D through F). Contrast-enhanced MRI of the cervical spine demonstrates diffuse nodular and thick confluent leptomeningeal enhancement on sagittal (G) and axial (I) sequences at the C3–C4 level, with some areas of associated cord T2 hyperintensity (sagittal [H] and axial [J] at the C3–C4 level).
Following the steroid taper, the patient experienced a worsening of symptoms, including increased positional headaches and right-sided visual field deficits. A repeat MRI (Figure 2) was conducted to explore alternative diagnoses. The patient sought a second opinion at Northwestern Medicine after experiencing another episode of transient speech changes.
Figure 2. Progression of nonspecific brain parenchymal signal abnormalities two months after initial MRI. Diffusion-weighted imaging trace (A) and apparent diffusion coefficient (B) in contrast-enhanced MRI of the brain demonstrate subtle heterogenous diffusion restriction and T2 shine-through of the left temporoparietal periventricular/subcortical white matter and splenium of the corpus callosum. Interval worsening of associated confluent fluid-attenuated inversion recovery hyperintensity of the posterior left cerebral hemisphere extends across the splenium of the corpus callosum with likely expansile left parietal cortical fluid-attenuated inversion recovery hyperintensity (C through E). Interval worsening of internal ill-defined enhancement in a perivascular distribution (F and G) and nodular leptomeningeal enhancement involving the right dorsal pons, quadrigeminal plate and cervicomedullary junction (not shown) are seen, which was not well-appreciated on previous examination (H). Concurrent contrast-enhanced whole spine MRI demonstrated grossly unchanged signal abnormality of the cervical cord with similar findings throughout the thoracolumbar spine (not shown).
Upon presentation for a second opinion, the neurologic examination revealed subtle flattening of the right nasolabial fold, slight pronation without drift of the right upper extremity, right homonymous hemianopsia and mild optic disc edema.
Repeat MRI scans of the brain and spine, both with and without contrast, were performed. Additionally, a lumbar puncture (results detailed in the following section) and a brain biopsy (Figure 3) were conducted. 
Figure 3. Histopathology and molecular findings. Histologic appearance (hematoxylin and eosin–stained section) of high-grade glioma notable for densely cellular and infiltrative malignant glial cells (A). The background is notable for pseudopalisading necrosis and microvascular proliferation. Copy number variation plot (derived from DNA methylation data) shows characteristic changes in glioblastoma, including gain of chromosome 7, loss of chromosome 10 and amplification of CDK4 and MDM2 genes (B). Low (C) and high (D) magnification views of the t-distributed stochastic neighbor embedding plot show the case of glioblastoma to cluster within the RTK I subgroup of IDH-wildtype glioblastoma.
Diagnostic Process
The neurologic findings suggest involvement of the left hemisphere. The episode of transient expressive aphasia indicates a cortical sign affecting Broca’s area in the dominant hemisphere. Mild optic disc edema raises concerns about increased intracranial pressure, potentially due to a space-occupying lesion. CT and MRI scans were performed, with results shown in Figures 1 and 2. Cerebrospinal fluid (CSF) analysis revealed:
The meningitis panel had negative results. Negative CSF results included:
Liquid biopsy of the CSF was negative for circulating tumor DNA (ctDNA). Figure 3 presents the results of histopathologic and molecular analysis. Questions
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 WHO grade 4 glioblastoma, per 2021 WHO Classification guidelines?
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?
Reproduced with permission from Primdahl D, Jamshidi P, Ahrendsen JT, Kothari S, Destiche D. Acute onset of expressive aphasia, visual disturbances, and severe headache. Practical Neurology (US). 2025;24(1):42-44,46-47.
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