Atypical presentation of massive glioblastoma mimicking rapidly progressive dementia

INTRODUCTION

Psychiatric, cognitive, and behavioral symptoms are common in patients with brain tumors, often manifesting concurrently, making it challenging to distinguish them from a primary psychiatric illness.^[1] Symptomatology ranging from a change in personality and behavior, mood symptoms, cognitive symptoms, to hallucinations, delusions, and catatonia can be noticed in such cases. However, in rare instances, brain tumors can primarily present with these symptoms. In such uncommon cases, a delay in diagnosis can lead to worse outcomes, particularly in highly aggressive tumors like glioblastoma, where ‘time is brain’ and a prompt diagnosis is crucial. Glioblastoma and glioma are among the common primary malignant brain tumors, with an estimated incidence rate of 6/100,000.^[2] Patients with the World Health Organization (WHO) grade II low-grade glioma typically survive 5–15 years (median), whereas those with WHO grade III tumors have a median survival of 2–3 years.^[3] Patients with advanced WHO grade IV gliomas have a more severe prognosis, with median survival typically limited to 12–14 months.^[4] Survival strongly correlates with illness stage; an early diagnosis is of utmost importance in such cases. Here, we present a case where a large fronto-temporo-parietal glioblastoma primarily presented with cognitive and psychotic symptoms, leading to an initial diagnosis of dementia with behavioral and psychological symptoms of dementia (BPSD). The rationale of reporting this case is to underscore the importance of differentiating atypical behavioral, cognitive, and psychological symptoms from organic etiologies to facilitate timely referral and management.

CASE REPORT

A woman in her late 50s presented with a 5-month history of abrupt onset of fearfulness, self-muttering, and suspiciousness. She had good premorbid functioning and adjustment at the onset of her current illness. Initially, she started having suspicions that people, including her family members, were plotting against her, and she was being monitored throughout the day by closed-circuit television cameras. This was followed by difficulty in navigating the routes to her house, word-finding difficulty, disinhibition, and memory impairment over the past 2 months. Her condition deteriorated, and she developed an unsteady gait and slurred speech. This quickly progressed to immobility with the inability to speak. She also developed urinary and bowel incontinence. She had a history of diabetes mellitus but no prior psychiatric illness. There was no history of hallucinations or mood symptoms. Family history was unremarkable. Treatment history included a consultation with a psychiatrist, where she was diagnosed with rapidly progressive dementia with BPSD and started on tablet quetiapine (50 mg) at bedtime and tablet memantine/donepezil combination (10 mg/5 mg) once a day. However, her condition deteriorated over the next few weeks, and she gradually became completely mute and immobile. At this time, when she presented to the psychiatry outpatient department, a neurological examination revealed a Glasgow Coma Scale (GCS) of 10 (E3V2M5) with right-sided hemiplegia (0/5 power) with hemisensory deficits, and plantar reflex was extensor on the right side. She was immediately admitted for further investigation and management.

Routine blood investigations were within normal limits. Non-contrast computed tomography (NCCT) of the brain was conducted on an urgent basis, which showed a left-sided space-occupying lesion with a midline shift. Subsequent magnetic resonance imaging (MRI) with contrast on the same day confirmed a left fronto-temporal operculo-insular glioblastoma with mass effect leading to midline shift and uncal herniation [Figure 1]. Post-surgical histopathology and mutation analysis were performed. Tumor protein 53 and isocitrate dehydrogenase-1 mutation analysis was performed to predict prognosis and survival, molecular classification, and treatment decisions, all of which came out to be positive. Histopathological examination (HPE) revealed rounded epithelioid cells with eccentric nuclei and abundant eosinophilic cytoplasm, suggestive of epithelioid glioblastoma WHO Grade IV. Epithelioid glioblastoma is a rare and highly aggressive variant of glioblastoma and generally has a poorer prognosis compared to classical glioblastoma.

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Figure 1:

Pre-operative MRI brain: T2-weighted image showing left sided frontal and temporal and opercula-insular high-grade lesion with mass effect (red arrow) and midline shift (yellow arrow). MRI: Magnetic resonance imaging.

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Based on the neurological clinical examination and neuroimaging findings, diagnoses of glioblastoma, primary, not otherwise specified (NOS), secondary neurocognitive syndrome, and secondary psychotic syndrome, with delusions, were made according to the International Classification of Diseases, 11^th revision. The diagnosis was confirmed after HPE and genetic mutation studies.

She was immediately shifted to the neurosurgery department, where she underwent an urgent left fronto-temporo-parietal craniotomy and gross total tumor excision under general anesthesia. Post-surgery, she was kept under mechanical ventilation in the Intensive Care Unit. Post-surgical NCCT revealed post-operative edema and encephalomalacia in the left frontotemporal region with partially corrected midline [Figure 2]. After extubation, 72 h later, she was started on chest and limb physiotherapy. She was discharged on day 14 in a stable condition.

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Figure 2:

Post-operative non-contrast CT brain suggestive of postoperative edema and encephalomalacia in the left fronto-temporal region (red arrow) with partially corrected midline (yellow arrow). CT: Computed tomography.

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At a 2-month follow-up, her GCS has now improved to 14 (E4V2M5), with persistent right-sided weakness and speech impairment. She is maintaining well on levetiracetam (1000 mg), alongside oral hypoglycemic agents. At present, the suspiciousness, self-muttering behavior, and memory complaints have also improved. She has now been planned for radiation therapy under the radiation oncology department.

DISCUSSION

In general, space-occupying lesions in the brain present with neurological signs depending on the site of the tumor and due to mass effect.^[5] Although uncommon, brain tumors may initially manifest solely with psychiatric symptoms. According to Keschner et al., approximately 78% of brain tumor patients exhibited psychiatric symptoms, with 18% presenting exclusively with psychiatric symptoms as their first clinical sign.^[1] Madhusoodanan et al. found that while mood disturbances were most frequent (36% of cases), psychotic symptoms occurred in 22% of patients.^[6] In these cases of psychotic symptoms, the tumors were found more commonly in the cerebral cortical, pituitary, pineal, and posterior locations. Among these, the pituitary gland was the most common location for psychotic symptoms. However, in another study, temporal lobe tumors were closely related to psychotic manifestations.^[7] Depression was the most commonly seen psychiatric manifestation in both frontal and temporal lobe tumors. Malignant brain tumors have a higher association with psychiatric disorders compared to benign brain tumors. Rapidly growing tumors tend to trigger psychiatric disorders early in their development, whereas slowly growing tumors (like meningiomas) may allow the brain to adapt gradually, resulting in psychiatric symptoms appearing without accompanying neurological signs. In these cases, if neuroimaging is not performed early, accurate diagnosis may be delayed.^[8]

It has been hypothesized that glioblastoma and Alzheimer’s dementia (AD) may share a common cause by a peripheral tissue pathway defect that can promote the progression of both diseases.^[9] Biopsy-proven AD and cerebral amyloid angiopathy have been reported to co-exist with glioblastoma.^[10] Alongside, the peak incidence of dementia has been found to be around age 65–95 years, while glioblastoma usually appears around age 65– 85 years.^[11] All these observations have led to the inference that neurodegenerative dementia and glioblastoma might have a direct association.

Several factors have been proposed to explain this association, such as inflammation, neurodegeneration-associated protein deposits, and alterations in the intestinal microbiome.^[10] However, evidence is conflicting regarding whether all patients recently diagnosed with dementia should undergo mandatory neuroimaging. Most research suggests that structural neuroimaging provides minimal additional clinical information beyond what’s already suspected from patient history and physical examination that would meaningfully impact treatment decisions.^[12,13] Routine neuroimaging is thus not recommended. However, any suspicion in clinical history and neurological examination demands urgent neuroimaging to rule out a treatable brain space-occupying lesion.^[13] The National Institute for Health and Care Excellence (NICE) guidelines on dementia suggest “offer structural imaging to rule out reversible causes of cognitive decline and to assist with subtype diagnosis, unless dementia is well established and the subtype is clear.” However, NICE also suggests that any patient with seizures, signs and symptoms of raised intracranial pressure, acute or rapid onset of symptoms, any focal neurological symptoms or signs not explained by past medical history (e.g. limb weakness and ataxia), and a non-amnestic pattern of cognitive deficits (e.g. dysphasia, behavioral presentations, prominent visuospatial, or praxis deficits) should undergo neuroimaging. In addition, NICE also suggests that while a computed tomography scan is a more suitable option for most older patients, MRI should be considered in suspected cases of vascular origin.^[14]

The initial presentation of late-onset acute psychosis, especially those with an abrupt onset, significant neurological signs, and absence of a personal or family history of psychiatric illness, should raise suspicion about an organic etiology. In addition, atypical presentations of such cognitive and psychiatric symptoms may also suggest the presence of brain tumors. A detailed medical history and physical examination must be done before confidently making a diagnosis of neurodegenerative dementia in such cases that primarily present with cognitive symptoms.^[6] Several of these red flag signs were initially missed in this case, leading to a delay and management.

Brain imaging is the primary diagnostic method used to rule out the presence of brain tumors. Surgical tumor resection or decreasing the size of the tumor by irradiation or chemotherapy may completely resolve the psychiatric, cognitive, or behavioral symptoms. In addition, treating the acute mass effects, such as increased intracranial pressure or hydrocephalus, may improve cognitive functioning and decrease behavioral symptoms.^[15] Correct and timely diagnosis is of utmost importance for these patients. Delayed diagnosis often renders surgical and radiotherapeutic options unviable. This case aims to emphasize once more the well-established importance of maintaining a high level of clinical vigilance in atypical presentations, where early diagnosis is critically essential.

CONCLUSION

Behavioral, cognitive, and psychiatric symptoms may be the only presenting feature of brain tumors. Thorough history and medical examination with a high index of suspicion are important for early diagnosis. Neuroimaging should be considered in patients with new-onset behavioral or cognitive symptoms and atypical features or neurological examination findings.